Drug Labelling

  • 0 ::
      • Package_label_principal_display_panel ::
          • 0 : package label
        • Active_ingredient ::
            • 0 : glycerin
          • Warnings ::
              • 0 : ・Stop using the product when you have skin problems or the product disagrees with your skin ・Stop using the product immediately and consult a dermatologist if you have redness, swelling, itching or irritation on the skin while or after using the product. ・If the product gets into the eyes, don't rub but rinse with water. ・Don't place the product in any place where it will be subjected to extremely high or low temperatures or direct sunlight.
            • Inactive_ingredient ::
                • 0 : water, ethanol, sodium citrate, aminolevulinic acid hcl
              • Effective_time : 20141208
                • Openfda ::
                    • Manufacturer_name ::
                        • 0 : General Bio Co., Ltd.
                      • Unii ::
                          • 0 : PDC6A3C0OX
                        • Product_type ::
                            • 0 : HUMAN OTC DRUG
                          • Spl_set_id ::
                              • 0 : c5fe26fe-2a2d-4b8a-b7aa-d279c56ce5fa
                            • Route ::
                                • 0 : TOPICAL
                              • Generic_name ::
                                  • 0 : GLYCERIN
                                • Brand_name ::
                                    • 0 : P9 PHOTO CLEANSER
                                  • Pharm_class_cs ::
                                      • 0 : Glycerol [Chemical/Ingredient]
                                        • 1 : Allergens [Chemical/Ingredient]
                                      • Pharm_class_pe ::
                                          • 0 : Cell-mediated Immunity [PE]
                                            • 1 : Increased IgG Production [PE]
                                              • 2 : Increased Histamine Release [PE]
                                            • Product_ndc ::
                                                • 0 : 69422-4001
                                              • Pharm_class_epc ::
                                                  • 0 : Non-Standardized Chemical Allergen [EPC]
                                                • Substance_name ::
                                                    • 0 : GLYCERIN
                                                  • Spl_id ::
                                                      • 0 : f610c1d9-3e70-47cb-93f5-fd3b40b62246
                                                    • Application_number ::
                                                        • 0 : part347
                                                      • Is_original_packager ::
                                                          • 0 : 1
                                                        • Nui ::
                                                            • 0 : N0000185001
                                                              • 1 : N0000175629
                                                                • 2 : N0000171131
                                                                  • 3 : N0000185370
                                                                    • 4 : N0000006566
                                                                      • 5 : N0000184306
                                                                    • Package_ndc ::
                                                                        • 0 : 69422-4001-1
                                                                  • Keep_out_of_reach_of_children ::
                                                                      • 0 : keep out of reach of the children
                                                                    • Spl_product_data_elements ::
                                                                        • 0 : P9 PHOTO CLEANSER GLYCERIN GLYCERIN GLYCERIN WATER SODIUM CITRATE AMINOLEVULINIC ACID HYDROCHLORIDE
                                                                      • Set_id : c5fe26fe-2a2d-4b8a-b7aa-d279c56ce5fa
                                                                        • Dosage_and_administration ::
                                                                            • 0 : for external use only
                                                                          • Version : 1
                                                                            • Purpose ::
                                                                                • 0 : skin protectant
                                                                              • Id : f610c1d9-3e70-47cb-93f5-fd3b40b62246
                                                                                • Indications_and_usage ::
                                                                                    • 0 : apply proper amount to the skin and massage and wash away with warm water

Drug Labelling

  • 1 ::
      • Package_label_principal_display_panel ::
          • 0 : PACKAGE LABEL Label Image for 53808-1006 0.125mg Label Image for 0.125mg
        • Openfda ::
            • Manufacturer_name ::
                • 0 : State of Florida DOH Central Pharmacy
              • Unii ::
                  • 0 : 73K4184T59
                • Product_type ::
                    • 0 : HUMAN PRESCRIPTION DRUG
                  • Rxcui ::
                      • 0 : 197604
                    • Spl_set_id ::
                        • 0 : b69e2d2b-725c-4f2c-912d-d068da5c0f31
                      • Route ::
                          • 0 : ORAL
                        • Generic_name ::
                            • 0 : DIGOXIN
                          • Brand_name ::
                              • 0 : DIGOXIN
                            • Pharm_class_cs ::
                                • 0 : Cardiac Glycosides [Chemical/Ingredient]
                              • Product_ndc ::
                                  • 0 : 53808-1006
                                • Original_packager_product_ndc ::
                                    • 0 : 49884-514
                                  • Substance_name ::
                                      • 0 : DIGOXIN
                                    • Spl_id ::
                                        • 0 : fa8c4fad-1802-44b5-9edc-4f45659dee69
                                      • Application_number ::
                                          • 0 : NDA020405
                                        • Nui ::
                                            • 0 : N0000175568
                                              • 1 : N0000008157
                                            • Pharm_class_epc ::
                                                • 0 : Cardiac Glycoside [EPC]
                                              • Package_ndc ::
                                                  • 0 : 53808-1006-1
                                            • Carcinogenesis_and_mutagenesis_and_impairment_of_fertility ::
                                                • 0 : 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Digoxin showed no genotoxic potential in in vitro studies (Ames test and mouse lymphoma). No data are available on the carcinogenic potential of digoxin, nor have studies been conducted to assess its potential to affect fertility.
                                              • Pregnancy ::
                                                  • 0 : 8.1 Pregnancy
                                                • Pharmacokinetics ::
                                                    • 0 : 12.3 Pharmacokinetics Note: The following data are from studies performed in adults, unless otherwise stated. Absorption: Following oral administration, peak serum concentrations of digoxin occur at 1 to 3 hours. Absorption of digoxin from DIGOXIN Tablets has been demonstrated to be 60-80% complete compared to an identical intravenous dose of digoxin (absolute bioavailability). When DIGOXIN Tablets are taken after meals, the rate of absorption is slowed, but the total amount of digoxin absorbed is usually unchanged. When taken with meals high in bran fiber, however, the amount absorbed from an oral dose may be reduced. Comparisons of the systemic availability and equivalent doses for oral preparations of DIGOXIN are shown in Dosage and Administration (2.6). Digoxin is a substrate for P-glycoprotein. As an efflux protein on the apical membrane of enterocytes, P-glycoprotein may limit the absorption of digoxin. In some patients, orally administered digoxin is converted to inactive reduction products (e.g., dihydrodigoxin) by colonic bacteria in the gut. Data suggest that 1 in 10 patients treated with digoxin tablets, colonic bacteria will degrade 40% or more of the ingested dose. As a result, certain antibiotics may increase the absorption of digoxin in such patients. Although inactivation of these bacteria by antibiotics is rapid, the serum digoxin concentration will rise at a rate consistent with the elimination half-life of digoxin. Serum digoxin concentration relates to the extent of bacterial inactivation, and may be as much as doubled in some cases [see Drug Interactions (7.2)]. Patients with malabsorption syndromes (e.g., short bowel syndrome, celiac sprue, jejunoileal bypass) may have a reduced ability to absorb orally administered digoxin. Distribution: Following drug administration, a 6-8 hour tissue distribution phase is observed. This is followed by a much more gradual decline in the serum concentration of the drug, which is dependent on the elimination of digoxin from the body. The peak height and slope of the early portion (absorption/distribution phases) of the serum concentration-time curve are dependent upon the route of administration and the absorption characteristics of the formulation. Clinical evidence indicates that the early high serum concentrations do not reflect the concentration of digoxin at its site of action, but that with chronic use, the steady-state post-distribution serum concentrations are in equilibrium with tissue concentrations and correlate with pharmacologic effects. In individual patients, these post-distribution serum concentrations may be useful in evaluating therapeutic and toxic effects [see Dosage and Administration (2.1)]. Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution (approximately 475-500 L). Digoxin crosses both the blood-brain barrier and the placenta. At delivery, the serum digoxin concentration in the newborn is similar to the serum concentration in the mother. Approximately 25% of digoxin in the plasma is bound to protein. Serum digoxin concentrations are not significantly altered by large changes in fat tissue weight, so that its distribution space correlates best with lean (i.e., ideal) body weight, not total body weight. Metabolism: Only a small percentage (13%) of a dose of digoxin is metabolized in healthy volunteers. The urinary metabolites, which include dihydrodigoxin, digoxigenin bisdigitoxoside, and their glucuronide and sulfate conjugates, are polar in nature and are postulated to be formed via hydrolysis, oxidation, and conjugation. The metabolism of digoxin is not dependent upon the cytochrome P-450 system, and digoxin is not known to induce or inhibit the cytochrome P-450 system. Excretion: Elimination of digoxin follows first-order kinetics (that is, the quantity of digoxin eliminated at any time is proportional to the total body content). Following intravenous administration to healthy volunteers, 50-70% of a digoxin dose is excreted unchanged in the urine. Renal excretion of digoxin is proportional to creatinine clearance and is largely independent of urine flow. In healthy volunteers with normal renal function, digoxin has a half-life of 1.5-2 days. The half-life in anuric patients is prolonged to 3.5-5 days. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to extravascular tissues. Special Populations: Geriatrics: Because of age-related declines in renal function, elderly patients would be expected to eliminate digoxin more slowly than younger subjects. Elderly patients may also exhibit a lower volume of distribution of digoxin due to age-related loss of lean muscle mass. Thus, the dosage of digoxin should be carefully selected and monitored in elderly patients [see Use in Specific Populations (8.5)]. Gender: In a study of 184 patients, the clearance of digoxin was 12% lower in female than in male patients. This difference is not likely to be clinically important. Hepatic Impairment: Because only a small percentage (approximately 13%) of a dose of digoxin undergoes metabolism, hepatic impairment would not be expected to significantly alter the pharmacokinetics of digoxin. In a small study, plasma digoxin concentration profiles in patients with acute hepatitis generally fell within the range of profiles in a group of healthy subjects. No dosage adjustments are recommended for patients with hepatic impairment; however, serum digoxin concentrations should be used as appropriate to help guide dosing in these patients. Renal Impairment: Since the clearance of digoxin correlates with creatinine clearance, patients with renal impairment generally demonstrate prolonged digoxin elimination half-lives and greater exposures to digoxin. Therefore, titrate carefully in these patients based on clinical response, and based on monitoring of serum digoxin concentrations, as appropriate. Race: The impact of race differences on digoxin pharmacokinetics have not been formally studied. Because digoxin is primarily eliminated as unchanged drug via the kidney and because there are no important differences in creatinine clearance among races, pharmacokinetic differences due to race are not expected. Drug-drug Interactions Based on literature reports no significant changes in digoxin exposure were reported when digoxin was co-administered with the following drugs: alfuzosin, aliskiren, amlodipine, aprepitant, argatroban, aspirin, atorvastatin, benazepril, bisoprolol, black cohosh, bosentan, candesartan, citalopram, clopidogrel, colesevelam, dipyridamole, disopyramide, donepezil, doxazosin, dutasteride, echinacea, enalapril, eprosartan, ertapenem, escitalopram, esmolol, ezetimibe, famciclovir, felodipine, finasteride, flecainide, fluvastatin, fondaparinux, galantamine, gemifloxacin, grapefruit juice, irbesartan, isradipine, ketorlac, levetiracetam, levofloxacin, lisinopril, losartan, lovastatin, meloxicam, mexilitine, midazolam, milk thistle, moexipril, montelukast, moxifloxacin, mycophenolate, nateglinide, nesiritide, nicardipine, nisoldipine, olmesartan, orlistat, pantoprazole, paroxetine, perindopril, pioglitazone, pravastatin, prazosin, procainamide, quinapril, raloxifene, ramipril, repaglinide, rivastigmine, rofecoxib, ropinirole, rosiglitazone, rosuvastatin, sertraline, sevelamer, simvastatin, sirolimus, solifenacin, tamsulosin, tegaserod, terbinafine, tiagabine, ticlopidine, tigecycline, topiramate, torsemide, tramadol, trandolapril, triamterene, trospium, trovafloxacin, valacyclovir, valsartan, varenicline, voriconazole, zaleplon, zolpidem
                                                  • Drug_interactions ::
                                                      • 0 : 7 DRUG INTERACTIONS Digoxin has a narrow therapeutic index, increased monitoring of serum digoxin concentrations and for potential signs and symptoms of clinical toxicity is necessary when initiating, adjusting, or discontinuing drugs that may interact with digoxin. Prescribers should consult the prescribing information of any drug which is co-prescribed with digoxin for potential drug interaction information. •PGP Inducers/Inhibitors: Drugs that induce or inhibit PGP have the potential to alter digoxin pharmacokinetics. (7.1) •Many drug interactions. The potential for drug-drug interactions must be considered prior to and during drug therapy. See full prescribing information. (7.3, 12.3) 7.1 P-Glycoprotein (PGP) Inducers/Inhibitors Digoxin is a substrate of P-glycoprotein. Drugs that induce or inhibit P-glycoprotein in intestine or kidney have the potential to alter digoxin pharmacokinetics. 7.2 Pharmacokinetic Drug Interactions NA – Not available/reported Digoxin concentrations increased greater than 50% Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring. Captopril 58% 39% Clarithromycin NA 70% Dronedarone NA 150% Gentamicin 129-212% NA Erythromycin 100% NA Itraconazole 80% NA Nitrendipine 57% 15% Propafenone NA 60-270% Quinidine 100% NA Ranolazine 50% NA Ritonavir NA 86% Tetracycline 100% NA Verapamil 50-75% NA Digoxin concentrations increased less than 50% Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring. Carvedilol 16% 14% Diltiazem 20% NA Indomethacin 40% NA Nefazodone 27% 15% Nifedipine 45% NA Propantheline 24% 24% Quinine NA 33% Saquinavir 27% 49% Spironolactone 25% NA Telmisartan 20-49% NA Tolvaptan 30% NA Trimethoprim 22-28% NA Digoxin concentrations increased, but magnitude is unclear Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, rabeprazole, Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary. Digoxin concentrations decreased Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary. No significant Digoxin exposure changes Please refer to section 12 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure. No additional actions are required. 7.3 Potentially Significant Pharmacodynamic Drug Interactions Because of considerable variability of pharmacodynamic interactions, the dosage of digoxin should be individualized when patients receive these medications concurrently. Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin. Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin. Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin. Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium. Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin. Sympathomimetics Epinephrine Norepinephrine Dopamine Can increase the risk of cardiac arrhythmias Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin. Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients. Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block. 7.4 Drug/Laboratory Test Interactions Endogenous substances of unknown composition (digoxin-like immunoreactive substances, [DLIS]) can interfere with standard radioimmunoassays for digoxin. The interference most often causes results to be falsely positive or falsely elevated, but sometimes it causes results to be falsely reduced. Some assays are more subject to these failings than others. Several LC/MS/MS methods are available that may provide less susceptibility to DLIS interference. DLIS are present in up to half of all neonates and in varying percentages of pregnant women, patients with hypertrophic cardiomyopathy, patients with renal or hepatic dysfunction, and other patients who are volume-expanded for any reason. The measured levels of DLIS (as digoxin equivalents) are usually low (0.2-0.4 ng/mL), but sometimes they reach levels that would be considered therapeutic or even toxic. In some assays, spironolactone, canrenone, and potassium canrenoate may be falsely detected as digoxin, at levels up to 0.5 ng/mL. Some traditional Chinese and Ayurvedic medicine substances like Chan Su, Siberian Ginseng, Asian Ginseng, Ashwagandha or Dashen, can cause similar interference. Spironolactone and DLIS are much more extensively protein-bound than digoxin. As a result, assays of free digoxin levels in protein-free ultrafiltrate (which tend to be about 25% less than total levels, consistent with the usual extent of protein binding) are less affected by spironolactone or DLIS. It should be noted that ultrafiltration does not solve all interference problems with alternative medicines. The use of an LC/MS/MS method may be the better option according to the good results it provides, especially in terms of specificity and limit of quantization.
                                                    • Id : fa8c4fad-1802-44b5-9edc-4f45659dee69
                                                      • Indications_and_usage ::
                                                          • 0 : DIGOXIN is a cardiac glycoside indicated for: •Treatment of mild to moderate heart failure in adults. (1.1) •Increasing myocardial contractility in pediatric patients with heart failure. (1.2) •Control of resting ventricular rate in patients with chronic atrial fibrillation in adults. (1.3) 1.1 Heart Failure in Adults DIGOXIN is indicated for the treatment of mild to moderate heart failure in adults. DIGOXIN increases left ventricular ejection fraction and improves heart failure symptoms as evidenced by improved exercise capacity and decreased heart failure-related hospitalizations and emergency care, while having no effect on mortality. Where possible, DIGOXIN should be used in combination with a diuretic and an angiotensin-converting enzyme (ACE) inhibitor. 1.2 Heart Failure in Pediatric Patients Digoxin increases myocardial contractility in pediatric patients with heart failure. 1.3 Atrial Fibrillation in Adults DIGOXIN is indicated for the control of ventricular response rate in adult patients with chronic atrial fibrillation.
                                                        • Description ::
                                                            • 0 : 11 DESCRIPTION DIGOXIN (digoxin) is one of the cardiac (or digitalis) glycosides, a closely related group of drugs having in common specific effects on the myocardium. These drugs are found in a number of plants. Digoxin is extracted from the leaves of Digitalis lanata. The term “digitalis” is used to designate the whole group of glycosides. The glycosides are composed of 2 portions: a sugar and a cardenolide (hence “glycosides”). Digoxin is described chemically as (3β,5β,12β)-3-[(O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-O-2,6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-2,6-dideoxy-β-D-ribo-hexopyranosyl)oxy]-12,14-dihydroxy-card-20(22)-enolide. Its molecular formula is C41H64O14, its molecular weight is 780.95, and its structural formula is: Digoxin exists as odorless white crystals that melt with decomposition above 230°C. The drug is practically insoluble in water and in ether; slightly soluble in diluted (50%) alcohol and in chloroform; and freely soluble in pyridine. DIGOXIN is supplied as 125 mcg (scored) and 250 mcg (scored) tablets for oral administration. Each tablet contains the labeled amount of digoxin USP and the following inactive ingredients: corn and potato starches, lactose and magnesium stearate. The 125 mcg tablets contain D&C Yellow No. 10 and FD&C Yellow No. 6. Structural Formula
                                                          • Spl_unclassified_section ::
                                                              • 0 : LANOXIN is a registered trademark of GlaxoSmithKline Distributed By Par Pharmaceutical Companies, Inc. Spring Valley, NY 10977 Manufactured by DSM Pharmaceuticals, Inc. Greenville, NC 27834 This Product was Repackaged By: State of Florida DOH Central Pharmacy 104-2 Hamilton Park Drive Tallahassee, FL 32304 USA
                                                            • Labor_and_delivery ::
                                                                • 0 : 8.2 Labor and Delivery There are not enough data from clinical trials to determine the safety and efficacy of digoxin during labor and delivery.
                                                              • How_supplied_table ::
                                                                  • 0 :
NDC Strength Quantity/Form Color Source Prod. Code
53808-1006-1 0.125 MG 30 Tablets in a Blister Pack YELLOW 49884-514
  • Pharmacodynamics_table ::
      • 0 :
        Table 7. Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of DIGOXIN
        a Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes. b Depending upon rate of infusion.
        Product Time to Onset of Effecta Time to Peak Effecta
        DIGOXIN Tablets 0.5-2 hours 2-6 hours
        DIGOXIN Injection/IV 5-30 minutesb 1-4 hours
    • Contraindications ::
        • 0 : 4 CONTRAINDICATIONS DIGOXIN is contraindicated in patients with: •Ventricular fibrillation [see Warnings and Precautions (5.1)] •Known hypersensitivity to digoxin (reactions seen include unexplained rash, swelling of the mouth, lips or throat or a difficulty in breathing). A hypersensitivity reaction to other digitalis preparations usually constitutes a contraindication to digoxin. •Ventricular fibrillation. (4) •Known hypersensitivity to digoxin or other forms of digitalis. (4)
      • Version : 1
        • Adverse_reactions ::
            • 0 : 6 ADVERSE REACTIONS The following adverse reactions are included in more detail in the Warnings and Precautions section of the label: •Cardiac arrhythmias [see Warnings and Precautions (5.1, 5.2)] •Digoxin Toxicity [see Warnings and Precautions (5.3)] The overall incidence of adverse reactions with digoxin has been reported as 5-20%, with 15-20% of adverse events considered serious. Cardiac toxicity accounts for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse events. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact PAR Pharmaceutical, Inc at 1-800-828-9393 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. In general, the adverse reactions of DIGOXIN are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect. Hence, adverse reactions are less common when DIGOXIN is used within the recommended dose range, is maintained within the therapeutic serum concentration range, and when there is careful attention to concurrent medications and conditions. In the DIG trial (a trial investigating the effect of digoxin on mortality and morbidity in patients with heart failure), the incidence of hospitalization for suspected digoxin toxicity was 2% in patients taking DIGOXIN compared to 0.9% in patients taking placebo [see Clinical Studies (14.1)]. The overall incidence of adverse reactions with digoxin has been reported as 5-20%, with 15-20% of adverse events considered serious. Cardiac toxicity accounts for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse events. Gastrointestinal: In addition to nausea and vomiting, the use of digoxin has been associated with abdominal pain, intestinal ischemia, and hemorrhagic necrosis of the intestines. CNS: Digoxin can cause headache, weakness, dizziness, apathy, confusion, and mental disturbances (such as anxiety, depression, delirium, and hallucination). Other: Gynecomastia has been occasionally observed following the prolonged use of digoxin. Thrombocytopenia and maculopapular rash and other skin reactions have been rarely observed.
          • Information_for_patients ::
              • 0 : 17 PATIENT COUNSELING INFORMATION •Advise patients that digoxin is a cardiac glycoside used to treat heart failure and heart arrhythmias. •Instruct patients to take this medication as directed by their physician. •Advise patients that many drugs can interact with DIGOXIN. Instruct patients to inform their doctor and pharmacist if they are taking any over the counter medications, including herbal medication, or are started on a new prescription. •Advise patient that blood tests will be necessary to ensure that their DIGOXIN dose is appropriate for them. •Advise patients to contact their doctor or a health care professional if they experience nausea, vomiting, persistent diarrhea, confusion, weakness, or visual disturbances (including blurred vision, green-yellow color disturbances, halo effect) as these could be signs that the dose of DIGOXIN may be too high. •Advise parents or caregivers that the symptoms of having too high DIGOXIN doses may be difficult to recognize in infants and pediatric patients. Symptoms such as weight loss, failure to thrive in infants, abdominal pain, and behavioral disturbances may be indications of digoxin toxicity. •Suggest to the patient to monitor and record their heart rate and blood pressure daily. •Instruct women of childbearing potential who become or are planning to become pregnant to consult a physician prior to initiation or continuing therapy with DIGOXIN.
            • Dosage_forms_and_strengths ::
                • 0 : 3 DOSAGE FORMS AND STRENGTHS Scored Tablets: 125 mcg are yellow, round, scored tablets with “Y3B” imprinted on one side.. Scored Tablets: 250 mcg are white, round, scored tablets with “X3A” imprinted on one side. Scored Tablets: 62.5 and 187.5 mcg. Scored Tablets 125 and 250 mcg (3)
              • Drug_interactions_table ::
                  • 0 :
                    NA – Not available/reported
                    Digoxin concentrations increased greater than 50%
                    Digoxin Serum Concentration Increase Digoxin AUC Increase Recommendations
                    Amiodarone 70% NA Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.
                    Captopril 58% 39%
                    Clarithromycin NA 70%
                    Dronedarone NA 150%
                    Gentamicin 129-212% NA
                    Erythromycin 100% NA
                    Itraconazole 80% NA
                    Nitrendipine 57% 15%
                    Propafenone NA 60-270%
                    Quinidine 100% NA
                    Ranolazine 50% NA
                    Ritonavir NA 86%
                    Tetracycline 100% NA
                    Verapamil 50-75% NA
                    Digoxin concentrations increased less than 50%
                    Atorvastatin 22% 15% Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.
                    Carvedilol 16% 14%
                    Diltiazem 20% NA
                    Indomethacin 40% NA
                    Nefazodone 27% 15%
                    Nifedipine 45% NA
                    Propantheline 24% 24%
                    Quinine NA 33%
                    Saquinavir 27% 49%
                    Spironolactone 25% NA
                    Telmisartan 20-49% NA
                    Tolvaptan 30% NA
                    Trimethoprim 22-28% NA
                    Digoxin concentrations increased, but magnitude is unclear
                    Alprazolam, azithromycin, cyclosporine, diclofenac, diphenoxylate, epoprostenol, esomeprazole, ibuprofen, ketoconazole, lansoprazole, metformin, omeprazole, rabeprazole, Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.
                    Digoxin concentrations decreased
                    Acarbose, activated charcoal, albuterol, antacids, certain cancer chemotherapy or radiation therapy, cholestyramine, colestipol, extenatide, kaolin-pectin, meals high in bran, metoclopramide, miglitol, neomycin, penicillamine, phenytoin, rifampin, St. John’s Wort, sucralfate, sulfasalazine Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.
                    No significant Digoxin exposure changes
                    Please refer to section 12 for a complete list of drugs which were studied but reported no significant changes on digoxin exposure. No additional actions are required.
                    • 1 :
                      Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
                      Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
                      Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
                      Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
                      Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
                      Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
                      Sympathomimetics Epinephrine Norepinephrine Dopamine Can increase the risk of cardiac arrhythmias
                      Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
                      Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
                      Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
                  • Pediatric_use ::
                      • 0 : 8.4 Pediatric Use The safety and effectiveness of DIGOXIN in the control of ventricular rate in children with atrial fibrillation have not been established. The safety and effectiveness of DIGOXIN in the treatment of heart failure in children have not been established in adequate and well-controlled studies. However, in published literature of children with heart failure of various etiologies (e.g., ventricular septal defects, anthracycline toxicity, patent ductus arteriosus), treatment with digoxin has been associated with improvements in hemodynamic parameters and in clinical signs and symptoms. Newborn infants display considerable variability in their tolerance to digoxin. Premature and immature infants are particularly sensitive to the effects of digoxin, and the dosage of the drug must not only be reduced but must be individualized according to their degree of maturity.
                    • Dosage_and_administration ::
                        • 0 : DIGOXIN dose is based on patient-specific factors (age, lean body weight, renal function, etc.). See full prescribing information. Monitor for toxicity and therapeutic effect. (2) 2.1 Important Dosing and Administration Information In selecting a DIGOXIN dosing regimen, it is important to consider factors that affect digoxin blood levels (e.g., body weight, age, renal function, concomitant drugs) since toxic levels of digoxin are only slightly higher than therapeutic levels. Dosing can be either initiated with a loading dose followed by maintenance dosing if rapid titration is desired or initiated with maintenance dosing without a loading dose. Consider interruption or reduction in DIGOXIN digoxin dose prior to electrical cardioversion [see Warnings and Precautions (5.4)]. Use digoxin solution to obtain the appropriate dose in infants, young pediatric patients, or patients with very low body weight. 2.2 Loading Dosing Regimen in Adults and Pediatric Patients For adults and pediatric patients if a loading dosage is to be given, administer half the total loading dose initially, then ¼ the loading dose every 6-8 hours twice, with careful assessment of clinical response and toxicity before each dose. The recommended loading dose is displayed in Table 1. Table 1. Recommended DIGOXIN Oral Loading Dose mcg = microgram Age Total Oral Loading Dose (mcg/kg) Administer half the total loading dose initially, then ¼ the loading dose every 6 to 8 hours twice 5 to 10 years 20-45 Adults and pediatric patients over 10 years 10-15 2.3 Maintenance Dosing in Adults and Pediatric Patients Over 10 Years Old The maintenance dose is based on lean body weight, renal function, age, and concomitant products [see Clinical Pharmacology (12.3)]. The recommended starting maintenance dose in adults and pediatric patients over 10 years old with normal renal function is given in Table 2. Doses may be increased every 2 weeks according to clinical response, serum drug levels, and toxicity. Table 2. Recommended Starting DIGOXIN Maintenance Dosage in Adults and Pediatric Patients Over 10 Years Old mcg = microgram Age Total Oral Maintenance Dose, mcg/kg/day (given once daily) Adults and pediatric patients over 10 years 3.4-5.1 Table 3 provides the recommended (once daily) maintenance dose for adults and pediatric patients over 10 years old (to be given once daily) according to lean body weight and renal function. The doses are based on studies in adult patients with heart failure. Alternatively, the maintenance dose may be estimated by the following formula (peak body stores lost each day through elimination): Total Maintenance Dose = Loading Dose (i.e., Peak Body Stores) x % Daily Loss/100 (% Daily Loss = 14 + Creatinine clearance/5) Reduce the dose of DIGOXIN in patients whose lean weight is an abnormally small fraction of their total body mass because of obesity or edema. Table 3. Recommended Maintenance Dose (in micrograms given once daily) of DIGOXIN in Pediatric Patients Over 10 Years Old and Adults by Lean Body Weight and by Renal Functiona a Doses are rounded to the nearest dose possible using whole DIGOXIN tablets. Recommended doses approximately 30 percent lower than the calculated dose are designated with an *. Monitor digoxin levels in patients receiving these initial doses and increase dose if needed. b For adults, creatinine clearance was corrected to 70-kg body weight or 1.73 m2 body surface area. If only serum creatinine concentrations (Scr) are available, a corrected Ccr may be estimated in men as (140 – Age)/Scr. For women, this result should be multiplied by 0.85. For pediatric patients, the modified Schwartz equation may be used. The formula is based on height in cm and Scr in mg/dL where k is a constant. Ccr is corrected to 1.73 m2 body surface area. During the first year of life, the value of k is 0.33 for pre-term babies and 0.45 for term infants. The k is 0.55 for pediatric patients and adolescent girls and 0.7 for adolescent boys. GFR (mL/min/1.73 m2) = (k x Height)/Scr c If no loading dose administered. d The doses listed assume average body composition. Corrected Creatinine Clearanceb Lean Body Weightd Number of Days Before Steady State Achievedc kg 40 50 60 70 80 90 100 10 mL/min 62.5* 125 125 187.5 187.5 187.5 250 19 20 mL/min 125 125 125 187.5 187.5 250 250 16 30 mL/min 125 125 187.5 187.5 250 250 312.5 14 40 mL/min 125 187.5 187.5 250 250 312.5 312.5 13 50 mL/min 125 187.5 187.5 250 250 312.5 312.5 12 60 mL/min 125 187.5 250 250 312.5 312.5 375 11 70 mL/min 187.5 187.5 250 250 312.5 375 375 10 80 mL/min 187.5 187.5 250 312.5 312.5 375 437.5 9 90 mL/min 187.5 250 250 312.5 375 437.5 437.5 8 100 mL/min 187.5 250 312.5 312.5 375 437.5 500 7 2.4 Maintenance Dosing in Pediatric Patients Less Than 10 Years Old The starting maintenance dose for heart failure in pediatric patients less than 10 years old is based on lean body weight, renal function, age, and concomitant products [see Clinical Pharmacology (12.3)]. The recommended starting maintenance dose for pediatric patients between 5 years and 10 years old is given in Table 4. These recommendations assume the presence of normal renal function. Table 4. Recommended Starting DIGOXIN Oral Maintenance Dosage in Pediatric Patients between 5 and 10 Years Old Age Oral Maintenance Dose, mcg/kg/dose 5 years to 10 years 3.2-6.4 Twice daily Table 5 provides average daily maintenance dose requirements for pediatric patients between 5 and 10 years old (to be given twice daily) with heart failure based on age, lean body weight, and renal function. Table 5. Recommended Maintenance Dose (in micrograms given TWICE daily) of DIGOXIN in Pediatric Patients between 5 and 10 Years of Agea Based upon Lean Body Weight and Renal Functiona,b a Recommended are doses to be given twice daily. b The doses are rounded to the nearest dose possible using whole DIGOXIN tablets. Recommended doses approximately 30 percent lower than the calculated dose are designated with an *. Monitor digoxin levels in patients receiving these initial doses and increase dose if needed. c The modified Schwartz equation may be used to estimate creatinine clearance. See footnote b under Table 3. d If no loading dose administered. Corrected Creatinine Clearancec Lean Body Weight Number of Days Before Steady State Achievedd kg 20 30 40 50 60 10 mL/min - 62.5 62.5* 125 125 19 20 mL/min 62.5 62.5 125 125 125 16 30 mL/min 62.5 62.5* 125 125 187.5 14 40 mL/min 62.5 62.5* 125 187.5 187.5 13 50 mL/min 62.5 125 125 187.5 187.5 12 60 mL/min 62.5 125 125 187.5 250 11 70 mL/min 62.5 125 187.5 187.5 250 10 80 mL/min 62.5* 125 187.5 187.5 250 9 90 mL/min 62.5* 125 187.5 250 250 8 100 mL/min 62.5* 125 187.5 250 312.5 7 2.5 Monitoring to Assess Safety, Efficacy, and Therapeutic Blood Levels Monitor for signs and symptoms of digoxin toxicity and clinical response. Adjust dose based on toxicity, efficacy, and blood levels. Serum digoxin levels less than 0.5 ng/mL have been associated with diminished efficacy, while levels above 2 ng/mL have been associated with increased toxicity without increased benefit. Interpret the serum digoxin concentration in the overall clinical context, and do not use an isolated measurement of serum digoxin concentration as the basis for increasing or decreasing the DIGOXIN dose. Serum digoxin concentrations may be falsely elevated by endogenous digoxin-like substances [see Drug Interactions (7.4)]. If the assay is sensitive to these substances, consider obtaining a baseline digoxin level before starting DIGOXIN and correct post-treatment values by the reported baseline level. Obtain serum digoxin concentrations just before the next scheduled DIGOXIN dose or at least 6 hours after the last dose. The digoxin concentration is likely to be 10-25% lower when sampled right before the next dose (24 hours after dosing) compared to sampling 8 hours after dosing (using once-daily dosing). However, there will be only minor differences in digoxin concentrations using twice daily dosing whether sampling is done at 8 or 12 hours after a dose. 2.6 Switching from Intravenous Digoxin to Oral Digoxin When switching from intravenous to oral digoxin formulations, make allowances for differences in bioavailability when calculating maintenance dosages (see Table 6). Table 6. Comparison of the Systemic Availability and Equivalent Doses of Oral and Intravenous DIGOXIN Absolute Bioavailability Equivalent Doses (mcg) DIGOXIN Tablets 60-80% 62.5 125 250 500 DIGOXIN Intravenous Injection 100% 50 100 200 400
                      • Clinical_pharmacology_table ::
                          • 0 :
                            Table 7. Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of DIGOXIN
                            a Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes. b Depending upon rate of infusion.
                            Product Time to Onset of Effecta Time to Peak Effecta
                            DIGOXIN Tablets 0.5-2 hours 2-6 hours
                            DIGOXIN Injection/IV 5-30 minutesb 1-4 hours
                        • Effective_time : 20150103
                          • Mechanism_of_action ::
                              • 0 : 12.1 Mechanism of Action All of digoxin’s actions are mediated through its effects on Na-K ATPase. This enzyme, the “sodium pump,” is responsible for maintaining the intracellular milieu throughout the body by moving sodium ions out of and potassium ions into cells. By inhibiting Na-K ATPase, digoxin •causes increased availability of intracellular calcium in the myocardium and conduction system, with consequent increased inotropy, increased automaticity, and reduced conduction velocity •indirectly causes parasympathetic stimulation of the autonomic nervous system, with consequent effects on the sino-atrial (SA) and atrioventricular (AV) nodes •reduces catecholamine reuptake at nerve terminals, rendering blood vessels more sensitive to endogenous or exogenous catecholamines •increases baroreceptor sensitization, with consequent increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increment in mean arterial pressure •increases (at higher concentrations) sympathetic outflow from the central nervous system (CNS) to both cardiac and peripheral sympathetic nerves •allows (at higher concentrations) progressive efflux of intracellular potassium, with consequent increase in serum potassium levels. The cardiologic consequences of these direct and indirect effects are an increase in the force and velocity of myocardial systolic contraction (positive inotropic action), a slowing of the heart rate (negative chronotropic effect), decreased conduction velocity through the AV node, and a decrease in the degree of activation of the sympathetic nervous system and renin-angiotensin system (neurohormonal deactivating effect).
                            • Geriatric_use ::
                                • 0 : 8.5 Geriatric Use The majority of clinical experience gained with digoxin has been in the elderly population. This experience has not identified differences in response or adverse effects between the elderly and younger patients. However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, which should be based on renal function, and it may be useful to monitor renal function [see Dosage and Administration (2.1)].
                              • Clinical_pharmacology ::
                                  • 0 : 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action All of digoxin’s actions are mediated through its effects on Na-K ATPase. This enzyme, the “sodium pump,” is responsible for maintaining the intracellular milieu throughout the body by moving sodium ions out of and potassium ions into cells. By inhibiting Na-K ATPase, digoxin •causes increased availability of intracellular calcium in the myocardium and conduction system, with consequent increased inotropy, increased automaticity, and reduced conduction velocity •indirectly causes parasympathetic stimulation of the autonomic nervous system, with consequent effects on the sino-atrial (SA) and atrioventricular (AV) nodes •reduces catecholamine reuptake at nerve terminals, rendering blood vessels more sensitive to endogenous or exogenous catecholamines •increases baroreceptor sensitization, with consequent increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increment in mean arterial pressure •increases (at higher concentrations) sympathetic outflow from the central nervous system (CNS) to both cardiac and peripheral sympathetic nerves •allows (at higher concentrations) progressive efflux of intracellular potassium, with consequent increase in serum potassium levels. The cardiologic consequences of these direct and indirect effects are an increase in the force and velocity of myocardial systolic contraction (positive inotropic action), a slowing of the heart rate (negative chronotropic effect), decreased conduction velocity through the AV node, and a decrease in the degree of activation of the sympathetic nervous system and renin-angiotensin system (neurohormonal deactivating effect). 12.2 Pharmacodynamics The times to onset of pharmacologic effect and to peak effect of preparations of DIGOXIN are shown in Table 7. Table 7. Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of DIGOXIN a Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes. b Depending upon rate of infusion. Product Time to Onset of Effecta Time to Peak Effecta DIGOXIN Tablets 0.5-2 hours 2-6 hours DIGOXIN Injection/IV 5-30 minutesb 1-4 hours Hemodynamic Effects: Short- and long-term therapy with the drug increases cardiac output and lowers pulmonary artery pressure, pulmonary capillary wedge pressure, and systemic vascular resistance in patients with heart failure. These hemodynamic effects are accompanied by an increase in the left ventricular ejection fraction and a decrease in end-systolic and end-diastolic dimensions. ECG Changes: The use of therapeutic doses of DIGOXIN may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram. DIGOXIN may produce false positive ST-T changes on the electrocardiogram during exercise testing. These electrophysiologic effects are not indicative of toxicity. DIGOXIN does not significantly reduce heart rate during exercise. 12.3 Pharmacokinetics Note: The following data are from studies performed in adults, unless otherwise stated. Absorption: Following oral administration, peak serum concentrations of digoxin occur at 1 to 3 hours. Absorption of digoxin from DIGOXIN Tablets has been demonstrated to be 60-80% complete compared to an identical intravenous dose of digoxin (absolute bioavailability). When DIGOXIN Tablets are taken after meals, the rate of absorption is slowed, but the total amount of digoxin absorbed is usually unchanged. When taken with meals high in bran fiber, however, the amount absorbed from an oral dose may be reduced. Comparisons of the systemic availability and equivalent doses for oral preparations of DIGOXIN are shown in Dosage and Administration (2.6). Digoxin is a substrate for P-glycoprotein. As an efflux protein on the apical membrane of enterocytes, P-glycoprotein may limit the absorption of digoxin. In some patients, orally administered digoxin is converted to inactive reduction products (e.g., dihydrodigoxin) by colonic bacteria in the gut. Data suggest that 1 in 10 patients treated with digoxin tablets, colonic bacteria will degrade 40% or more of the ingested dose. As a result, certain antibiotics may increase the absorption of digoxin in such patients. Although inactivation of these bacteria by antibiotics is rapid, the serum digoxin concentration will rise at a rate consistent with the elimination half-life of digoxin. Serum digoxin concentration relates to the extent of bacterial inactivation, and may be as much as doubled in some cases [see Drug Interactions (7.2)]. Patients with malabsorption syndromes (e.g., short bowel syndrome, celiac sprue, jejunoileal bypass) may have a reduced ability to absorb orally administered digoxin. Distribution: Following drug administration, a 6-8 hour tissue distribution phase is observed. This is followed by a much more gradual decline in the serum concentration of the drug, which is dependent on the elimination of digoxin from the body. The peak height and slope of the early portion (absorption/distribution phases) of the serum concentration-time curve are dependent upon the route of administration and the absorption characteristics of the formulation. Clinical evidence indicates that the early high serum concentrations do not reflect the concentration of digoxin at its site of action, but that with chronic use, the steady-state post-distribution serum concentrations are in equilibrium with tissue concentrations and correlate with pharmacologic effects. In individual patients, these post-distribution serum concentrations may be useful in evaluating therapeutic and toxic effects [see Dosage and Administration (2.1)]. Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution (approximately 475-500 L). Digoxin crosses both the blood-brain barrier and the placenta. At delivery, the serum digoxin concentration in the newborn is similar to the serum concentration in the mother. Approximately 25% of digoxin in the plasma is bound to protein. Serum digoxin concentrations are not significantly altered by large changes in fat tissue weight, so that its distribution space correlates best with lean (i.e., ideal) body weight, not total body weight. Metabolism: Only a small percentage (13%) of a dose of digoxin is metabolized in healthy volunteers. The urinary metabolites, which include dihydrodigoxin, digoxigenin bisdigitoxoside, and their glucuronide and sulfate conjugates, are polar in nature and are postulated to be formed via hydrolysis, oxidation, and conjugation. The metabolism of digoxin is not dependent upon the cytochrome P-450 system, and digoxin is not known to induce or inhibit the cytochrome P-450 system. Excretion: Elimination of digoxin follows first-order kinetics (that is, the quantity of digoxin eliminated at any time is proportional to the total body content). Following intravenous administration to healthy volunteers, 50-70% of a digoxin dose is excreted unchanged in the urine. Renal excretion of digoxin is proportional to creatinine clearance and is largely independent of urine flow. In healthy volunteers with normal renal function, digoxin has a half-life of 1.5-2 days. The half-life in anuric patients is prolonged to 3.5-5 days. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to extravascular tissues. Special Populations: Geriatrics: Because of age-related declines in renal function, elderly patients would be expected to eliminate digoxin more slowly than younger subjects. Elderly patients may also exhibit a lower volume of distribution of digoxin due to age-related loss of lean muscle mass. Thus, the dosage of digoxin should be carefully selected and monitored in elderly patients [see Use in Specific Populations (8.5)]. Gender: In a study of 184 patients, the clearance of digoxin was 12% lower in female than in male patients. This difference is not likely to be clinically important. Hepatic Impairment: Because only a small percentage (approximately 13%) of a dose of digoxin undergoes metabolism, hepatic impairment would not be expected to significantly alter the pharmacokinetics of digoxin. In a small study, plasma digoxin concentration profiles in patients with acute hepatitis generally fell within the range of profiles in a group of healthy subjects. No dosage adjustments are recommended for patients with hepatic impairment; however, serum digoxin concentrations should be used as appropriate to help guide dosing in these patients. Renal Impairment: Since the clearance of digoxin correlates with creatinine clearance, patients with renal impairment generally demonstrate prolonged digoxin elimination half-lives and greater exposures to digoxin. Therefore, titrate carefully in these patients based on clinical response, and based on monitoring of serum digoxin concentrations, as appropriate. Race: The impact of race differences on digoxin pharmacokinetics have not been formally studied. Because digoxin is primarily eliminated as unchanged drug via the kidney and because there are no important differences in creatinine clearance among races, pharmacokinetic differences due to race are not expected. Drug-drug Interactions Based on literature reports no significant changes in digoxin exposure were reported when digoxin was co-administered with the following drugs: alfuzosin, aliskiren, amlodipine, aprepitant, argatroban, aspirin, atorvastatin, benazepril, bisoprolol, black cohosh, bosentan, candesartan, citalopram, clopidogrel, colesevelam, dipyridamole, disopyramide, donepezil, doxazosin, dutasteride, echinacea, enalapril, eprosartan, ertapenem, escitalopram, esmolol, ezetimibe, famciclovir, felodipine, finasteride, flecainide, fluvastatin, fondaparinux, galantamine, gemifloxacin, grapefruit juice, irbesartan, isradipine, ketorlac, levetiracetam, levofloxacin, lisinopril, losartan, lovastatin, meloxicam, mexilitine, midazolam, milk thistle, moexipril, montelukast, moxifloxacin, mycophenolate, nateglinide, nesiritide, nicardipine, nisoldipine, olmesartan, orlistat, pantoprazole, paroxetine, perindopril, pioglitazone, pravastatin, prazosin, procainamide, quinapril, raloxifene, ramipril, repaglinide, rivastigmine, rofecoxib, ropinirole, rosiglitazone, rosuvastatin, sertraline, sevelamer, simvastatin, sirolimus, solifenacin, tamsulosin, tegaserod, terbinafine, tiagabine, ticlopidine, tigecycline, topiramate, torsemide, tramadol, trandolapril, triamterene, trospium, trovafloxacin, valacyclovir, valsartan, varenicline, voriconazole, zaleplon, zolpidem
                                • Clinical_studies ::
                                    • 0 : 14 CLINICAL STUDIES 14.1 Chronic Heart Failure Two 12-week, double-blind, placebo-controlled studies enrolled 178 (RADIANCE trial) and 88 (PROVED trial) adult patients with NYHA Class II or III heart failure previously treated with oral digoxin, a diuretic, and an ACE inhibitor (RADIANCE only) and randomized them to placebo or treatment with DIGOXIN Tablets. Both trials demonstrated better preservation of exercise capacity in patients randomized to DIGOXIN. Continued treatment with DIGOXIN reduced the risk of developing worsening heart failure, as evidenced by heart failure-related hospitalizations and emergency care and the need for concomitant heart failure therapy. DIG Trial of DIGOXIN in Patients with Heart Failure The Digitalis Investigation Group (DIG) main trial was a 37-week, multicenter, randomized, double-blind mortality study comparing digoxin to placebo in 6800 adult patients with heart failure and left ventricular ejection fraction less than or equal to 0.45. At randomization, 67% were NYHA class I or II, 71% had heart failure of ischemic etiology, 44% had been receiving digoxin, and most were receiving a concomitant ACE inhibitor (94%) and diuretics (82%). As in the smaller trials described above, patients who had been receiving open-label digoxin were withdrawn from this treatment before randomization. Randomization to digoxin was again associated with a significant reduction in the incidence of hospitalization, whether scored as number of hospitalizations for heart failure (relative risk 75%), risk of having at least one such hospitalization during the trial (RR 72%), or number of hospitalizations for any cause (RR 94%). On the other hand, randomization to digoxin had no apparent effect on mortality (RR 99%, with confidence limits of 91-107%). 14.2 Chronic Atrial Fibrillation Digoxin has also been studied as a means of controlling the ventricular response to chronic atrial fibrillation in adults. Digoxin reduced the resting heart rate, but not the heart rate during exercise. In 3 different randomized, double-blind trials that included a total of 315 adult patients, digoxin was compared to placebo for the conversion of recent-onset atrial fibrillation to sinus rhythm. Conversion was equally likely, and equally rapid, in the digoxin and placebo groups. In a randomized 120-patient trial comparing digoxin, sotalol, and amiodarone, patients randomized to digoxin had the lowest incidence of conversion to sinus rhythm, and the least satisfactory rate control when conversion did not occur. In at least one study, digoxin was studied as a means of delaying reversion to atrial fibrillation in adult patients with frequent recurrence of this arrhythmia. This was a randomized, double-blind, 43-patient crossover study. Digoxin increased the mean time between symptomatic recurrent episodes by 54%, but had no effect on the frequency of fibrillatory episodes seen during continuous electrocardiographic monitoring.
                                  • Use_in_specific_populations ::
                                      • 0 : •Pregnant patients: It is unknown whether use during pregnancy can cause fetal harm. (8.1) •Pediatric patients: Newborn infants display variability in tolerance to DIGOXIN. (8.4) •Geriatric patients: Consider renal function in dosage selection, and carefully monitor for side effects. (8.5) •Renal impairment: DIGOXIN is excreted by the kidneys. Consider renal function during dosage selection. (8.6) 8.1 Pregnancy Pregnancy Category C. DIGOXIN should be given to a pregnant woman only if clearly needed. It is also not known whether digoxin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Animal reproduction studies have not been conducted with digoxin. 8.2 Labor and Delivery There are not enough data from clinical trials to determine the safety and efficacy of digoxin during labor and delivery. 8.3 Nursing Mothers Studies have shown that digoxin distributes into breast milk, and that the milk-to-serum concentration ratio is approximately 0.6-0.9. However, the estimated exposure of a nursing infant to digoxin via breastfeeding is far below the usual infant maintenance dose. Therefore, this amount should have no pharmacologic effect upon the infant. 8.4 Pediatric Use The safety and effectiveness of DIGOXIN in the control of ventricular rate in children with atrial fibrillation have not been established. The safety and effectiveness of DIGOXIN in the treatment of heart failure in children have not been established in adequate and well-controlled studies. However, in published literature of children with heart failure of various etiologies (e.g., ventricular septal defects, anthracycline toxicity, patent ductus arteriosus), treatment with digoxin has been associated with improvements in hemodynamic parameters and in clinical signs and symptoms. Newborn infants display considerable variability in their tolerance to digoxin. Premature and immature infants are particularly sensitive to the effects of digoxin, and the dosage of the drug must not only be reduced but must be individualized according to their degree of maturity. 8.5 Geriatric Use The majority of clinical experience gained with digoxin has been in the elderly population. This experience has not identified differences in response or adverse effects between the elderly and younger patients. However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, which should be based on renal function, and it may be useful to monitor renal function [see Dosage and Administration (2.1)]. 8.6 Renal Impairment The clearance of digoxin can be primarily correlated with the renal function as indicated by creatinine clearance. Tables 3 and 5 provide the usual daily maintenance dose requirements for digoxin based on creatinine clearance [see Dosage and Administration (2.3)]. Digoxin is primarily excreted by the kidneys; therefore, patients with impaired renal function require smaller than usual maintenance doses of digoxin [see Dosage and Administration (2.3)]. Because of the prolonged elimination half-life, a longer period of time is required to achieve an initial or new steady-state serum concentration in patients with renal impairment than in patients with normal renal function. If appropriate care is not taken to reduce the dose of digoxin, such patients are at high risk for toxicity, and toxic effects will last longer in such patients than in patients with normal renal function. 8.7 Hepatic Impairment Plasma digoxin concentrations in patients with acute hepatitis generally fall within the range of profiles in a group of healthy subjects. 8.8 Malabsorption The absorption of digoxin is reduced in some malabsorption conditions such as chronic diarrhea.
                                    • Nonclinical_toxicology ::
                                        • 0 : 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Digoxin showed no genotoxic potential in in vitro studies (Ames test and mouse lymphoma). No data are available on the carcinogenic potential of digoxin, nor have studies been conducted to assess its potential to affect fertility.
                                      • Spl_product_data_elements ::
                                          • 0 : DIGOXIN DIGOXIN DIGOXIN DIGOXIN STARCH, POTATO STARCH, CORN LACTOSE MONOHYDRATE MAGNESIUM STEARATE D&C YELLOW NO. 10 FD&C YELLOW NO. 6 LANOXIN;Y3B
                                        • Overdosage ::
                                            • 0 : 10 OVERDOSAGE 10.1 Signs and Symptoms in Adults and Children The signs and symptoms of toxicity are generally similar to those described in the Adverse Reactions (6.1) but may be more frequent and can be more severe. Signs and symptoms of digoxin toxicity become more frequent with levels above 2 ng/mL. However, in deciding whether a patient’s symptoms are due to digoxin, the clinical state together with serum electrolyte levels and thyroid function are important factors [see Dosage and Administration (2)]. Adults: The most common signs and symptoms of digoxin toxicity are nausea, vomiting, anorexia, and fatigue that occur in 30-70% of patients who are overdosed. Extremely high serum concentrations produce hyperkalemia especially in patients with impaired renal function. Almost every type of cardiac arrhythmia has been associated with digoxin overdose and multiple rhythm disturbances in the same patient are common. Peak cardiac effects occur 3-6 hours following ingestion and may persist for 24 hours or longer. Arrhythmias that are considered more characteristic of digoxin toxicity are new-onset Mobitz type 1 A-V block, accelerated junctional rhythms, non-paroxysmal atrial tachycardia with A-V block, and bi-directional ventricular tachycardia. Cardiac arrest from asystole or ventricular fibrillation is usually fatal. Digoxin toxicity is related to serum concentration. As digoxin serum levels increase above 1.2 ng/mL, there is a potential for increase in adverse reactions. Furthermore, lower potassium levels increases the risk for adverse reactions. In adults with heart disease, clinical observations suggest that an overdose of digoxin of 10-15 mg results in death of half of patients. A dose above 25 mg ingested by an adult without heart disease appeared to be uniformly fatal if no Digoxin Immune Fab (DIGIBIND®, DIGIFAB®) was administered. Among the extra-cardiac manifestations, gastrointestinal symptoms (e.g., nausea, vomiting, anorexia) are very common (up to 80% incidence) and precede cardiac manifestations in approximately half of the patients in most literature reports. Neurologic manifestations (e.g., dizziness, various CNS disturbances), fatigue, and malaise are very common. Visual manifestations may also occur with aberration in color vision (predominance of yellow green) the most frequent. Neurological and visual symptoms may persist after other signs of toxicity have resolved. In chronic toxicity, non-specific extra-cardiac symptoms, such as malaise and weakness, may predominate. Children: In pediatric patients, signs and symptoms of toxicity can occur during or shortly after the dose of digoxin. Frequent non-cardiac effects are similar to those observed in adults although nausea and vomiting are not seen frequently in infants and small pediatric patients. Other reported manifestations of overdose are weight loss in older age groups, failure to thrive in infants, abdominal pain caused by mesenteric artery ischemia, drowsiness, and behavioral disturbances including psychotic episodes. Arrhythmias and combinations of arrhythmias that occur in adult patients can also occur in pediatric patients although sinus tachycardia, supraventricular tachycardia, and rapid atrial fibrillation are seen less frequently in pediatric patients. Pediatric patients are more likely to develop A-V conduction disturbances, or sinus bradycardia. Any arrhythmia in a child treated with digoxin should be considered related to digoxin until otherwise ruled out. In pediatric patients aged 1-3 years without heart disease, clinical observations suggest that an overdose of digoxin of 6-10 mg would result in death of half of the patients. In the same population, a dose above 10 mg resulted in death if no Digoxin Immune Fab were administered. 10.2 Treatment Chronic Overdose If there is suspicion of toxicity, discontinue DIGOXIN and place the patient on a cardiac monitor. Correct factors such as electrolyte abnormalities, thyroid dysfunction, and concomitant medications [see Dosage and Administration (2.5)]. Correct hypokalemia by administering potassium so that serum potassium is maintained between 4.0 and 5.5 mmol/L. Potassium is usually administered orally, but when correction of the arrhythmia is urgent and serum potassium concentration is low, potassium may be administered by the intravenous route. Monitor electrocardiogram for any evidence of potassium toxicity (e.g., peaking of T waves) and to observe the effect on the arrhythmia. Avoid potassium salts in patients with bradycardia or heart block. Symptomatic arrhythmias may be treated with Digoxin Immune Fab. Acute Overdose Patients who have intentionally or accidently ingested massive doses of digoxin should receive activated charcoal orally or by nasogastric tube regardless of the time since ingestion since digoxin recirculates to the intestine by enterohepatic circulation. In addition to cardiac monitoring, temporarily discontinue DIGOXIN until the adverse reaction resolves. Correct factors that may be contributing to the adverse reactions [see Warnings and Precautions (5)]. In particular, correct hypokalemia and hypomagnesemia. Digoxin is not effectively removed from the body by dialysis because of its large extravascular volume of distribution. Life threatening arrhythmias (ventricular tachycardia, ventricular fibrillation, high degree A-V block, bradyarrhythma, sinus arrest) or hyperkalemia requires administration of Digoxin Immune Fab. Digoxin Immune Fab has been shown to be 80-90% effective in reversing signs and symptoms of digoxin toxicity. Bradycardia and heart block caused by digoxin are parasympathetically mediated and respond to atropine. A temporary cardiac pacemaker may also be used. Ventricular arrhythmias may respond to lidocaine or phenytoin. When a large amount of digoxin has been ingested, especially in patients with impaired renal function, hyperkalemia may be present due to release of potassium from skeletal muscle. In this case, treatment with Digoxin Immune Fab is indicated; an initial treatment with glucose and insulin may be needed if the hyperkalemia is life-threatening. Once the adverse reaction has resolved, therapy with DIGOXIN may be reinstituted following a careful reassessment of dose.
                                          • Pharmacodynamics ::
                                              • 0 : 12.2 Pharmacodynamics The times to onset of pharmacologic effect and to peak effect of preparations of DIGOXIN are shown in Table 7. Table 7. Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of DIGOXIN a Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes. b Depending upon rate of infusion. Product Time to Onset of Effecta Time to Peak Effecta DIGOXIN Tablets 0.5-2 hours 2-6 hours DIGOXIN Injection/IV 5-30 minutesb 1-4 hours Hemodynamic Effects: Short- and long-term therapy with the drug increases cardiac output and lowers pulmonary artery pressure, pulmonary capillary wedge pressure, and systemic vascular resistance in patients with heart failure. These hemodynamic effects are accompanied by an increase in the left ventricular ejection fraction and a decrease in end-systolic and end-diastolic dimensions. ECG Changes: The use of therapeutic doses of DIGOXIN may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram. DIGOXIN may produce false positive ST-T changes on the electrocardiogram during exercise testing. These electrophysiologic effects are not indicative of toxicity. DIGOXIN does not significantly reduce heart rate during exercise.
                                            • Warnings_and_cautions ::
                                                • 0 : •Risk of rapid ventricular response leading to ventricular fibrillation in patients with AV accessory pathway. (5.1) •Risk of advanced or complete heart block in patients with sinus node disease and AV block. (5.2) •Digoxin toxicity: Indicated by nausea, vomiting, visual disturbances, and cardiac arrhythmias. Advanced age, low body weight, impaired renal function and electrolyte abnormalities predispose to toxicity. (5.3) •Risk of ventricular arrhythmias during electrical cardioversion. (5.4) •Not recommended in patients with acute myocardial infarction. (5.5) •Avoid DIGOXIN in patients with myocarditis. (5.6) 5.1 Ventricular Fibrillation in Patients With Accessory AV Pathway (Wolff-Parkinson-White Syndrome) Patients with Wolff-Parkinson-White syndrome who develop atrial fibrillation are at high risk of ventricular fibrillation. Treatment of these patients with digoxin leads to greater slowing of conduction in the atrioventricular node than in accessory pathways, and the risks of rapid ventricular response leading to ventricular fibrillation are thereby increased. 5.2 Sinus Bradycardia and Sino-atrial Block DIGOXIN may cause severe sinus bradycardia or sinoatrial block particularly in patients with pre-existing sinus node disease and may cause advanced or complete heart block in patients with pre-existing incomplete AV block. Consider insertion of a pacemaker before treatment with digoxin. 5.3 Digoxin Toxicity Signs and symptoms of digoxin toxicity include anorexia, nausea, vomiting, visual changes and cardiac arrhythmias [first-degree, second-degree (Wenckebach), or third-degree heart block (including asystole); atrial tachycardia with block; AV dissociation; accelerated junctional (nodal) rhythm; unifocal or multiform ventricular premature contractions (especially bigeminy or trigeminy); ventricular tachycardia; and ventricular fibrillation]. Toxicity is usually associated with digoxin levels greater than 2 ng/ml although symptoms may also occur at lower levels. Low body weight, advanced age or impaired renal function, hypokalemia, hypercalcemia, or hypomagnesemia may predispose to digoxin toxicity. Obtain serum digoxin levels in patients with signs or symptoms of digoxin therapy and interrupt or adjust dose if necessary [see Adverse Reactions (6) and Overdosage (10)]. Assess serum electrolytes and renal function periodically. The earliest and most frequent manifestation of digoxin toxicity in infants and children is the appearance of cardiac arrhythmias, including sinus bradycardia. In children, the use of digoxin may produce any arrhythmia. The most common are conduction disturbances or supraventricular tachyarrhythmias, such as atrial tachycardia (with or without block) and junctional (nodal) tachycardia. Ventricular arrhythmias are less common. Sinus bradycardia may be a sign of impending digoxin intoxication, especially in infants, even in the absence of first-degree heart block. Any arrhythmias or alteration in cardiac conduction that develops in a child taking digoxin should initially be assumed to be a consequence of digoxin intoxication. Given that adult patients with heart failure have some symptoms in common with digoxin toxicity, it may be difficult to distinguish digoxin toxicity from heart failure. Misidentification of their etiology might lead the clinician to continue or increase DIGOXIN dosing, when dosing should actually be suspended. When the etiology of these signs and symptoms is not clear, measure serum digoxin levels. 5.4 Risk of Ventricular Arrhythmias During Electrical Cardioversion It may be desirable to reduce the dose of or discontinue DIGOXIN for 1 to 2 days prior to electrical cardioversion of atrial fibrillation to avoid the induction of ventricular arrhythmias, but physicians must consider the consequences of increasing the ventricular response if digoxin is decreased or withdrawn. If digitalis toxicity is suspected, elective cardioversion should be delayed. If it is not prudent to delay cardioversion, the lowest possible energy level should be selected to avoid provoking ventricular arrhythmias. 5.5 Risk of Ischemia in Patients With Acute Myocardial Infarction DIGOXIN is not recommended in patients with acute myocardial infarction because digoxin may increase myocardial oxygen demand and lead to ischemia. 5.6 Vasoconstriction In Patients With Myocarditis DIGOXIN can precipitate vasoconstriction and may promote production of pro-inflammatory cytokines; therefore, avoid use in patients with myocarditis. 5.7 Decreased Cardiac Output in Patients With Preserved Left Ventricular Systolic Function Patients with heart failure associated with preserved left ventricular ejection fraction may experience decreased cardiac output with use of DIGOXIN. Such disorders include restrictive cardiomyopathy, constrictive pericarditis, amyloid heart disease, and acute cor pulmonale. Patients with idiopathic hypertrophic subaortic stenosis may have worsening of the outflow obstruction due to the inotropic effects of digoxin. Patients with amyloid heart disease may be more susceptible to digoxin toxicity at therapeutic levels because of an increased binding of digoxin to extracellular amyloid fibrils. DIGOXIN should generally be avoided in these patients, although it has been used for ventricular rate control in the subgroup of patients with atrial fibrillation. 5.8 Reduced Efficacy In Patients With Hypocalcemia Hypocalcemia can nullify the effects of digoxin in humans; thus, digoxin may be ineffective until serum calcium is restored to normal. These interactions are related to the fact that digoxin affects contractility and excitability of the heart in a manner similar to that of calcium. 5.9 Altered Response in Thyroid Disorders and Hypermetabolic States Hypothyroidism may reduce the requirements for digoxin. Heart failure and/or atrial arrhythmias resulting from hypermetabolic or hyperdynamic states (e.g., hyperthyroidism, hypoxia, or arteriovenous shunt) are best treated by addressing the underlying condition. Atrial arrhythmias associated with hypermetabolic states are particularly resistant to digoxin treatment. Patients with beri beri heart disease may fail to respond adequately to digoxin if the underlying thiamine deficiency is not treated concomitantly.
                                              • Dosage_and_administration_table ::
                                                  • 0 :
                                                    Table 1. Recommended DIGOXIN Oral Loading Dose
                                                    mcg = microgram
                                                    Age Total Oral Loading Dose (mcg/kg) Administer half the total loading dose initially, then ¼ the loading dose every 6 to 8 hours twice
                                                    5 to 10 years 20-45
                                                    Adults and pediatric patients over 10 years 10-15
                                                    • 1 :
                                                      Table 2. Recommended Starting DIGOXIN Maintenance Dosage in Adults and Pediatric Patients Over 10 Years Old
                                                      mcg = microgram
                                                      Age Total Oral Maintenance Dose, mcg/kg/day (given once daily)
                                                      Adults and pediatric patients over 10 years 3.4-5.1
                                                      • 2 : 10 mL/min62.5*125125187.5187.5187.52501920 mL/min125125125187.5187.52502501630 mL/min125125187.5187.5250250312.51440 mL/min125187.5187.5250250312.5312.51350 mL/min125187.5187.5250250312.5312.51260 mL/min125187.5250250312.5312.53751170 mL/min187.5187.5250250312.53753751080 mL/min187.5187.5250312.5312.5375437.5990 mL/min187.5250250312.5375437.5437.58100 mL/min187.5250312.5312.5375437.55007
                                                        Table 3. Recommended Maintenance Dose (in micrograms given once daily) of DIGOXIN in Pediatric Patients Over 10 Years Old and Adults by Lean Body Weight and by Renal Functiona
                                                        a Doses are rounded to the nearest dose possible using whole DIGOXIN tablets. Recommended doses approximately 30 percent lower than the calculated dose are designated with an *. Monitor digoxin levels in patients receiving these initial doses and increase dose if needed. b For adults, creatinine clearance was corrected to 70-kg body weight or 1.73 m2 body surface area. If only serum creatinine concentrations (Scr) are available, a corrected Ccr may be estimated in men as (140 – Age)/Scr. For women, this result should be multiplied by 0.85. For pediatric patients, the modified Schwartz equation may be used. The formula is based on height in cm and Scr in mg/dL where k is a constant. Ccr is corrected to 1.73 m2 body surface area. During the first year of life, the value of k is 0.33 for pre-term babies and 0.45 for term infants. The k is 0.55 for pediatric patients and adolescent girls and 0.7 for adolescent boys. GFR (mL/min/1.73 m2) = (k x Height)/Scr c If no loading dose administered. d The doses listed assume average body composition.
                                                        Corrected Creatinine Clearanceb Lean Body Weightd Number of Days Before Steady State Achievedc
                                                        kg 40 50 60 70 80 90 100
                                                        • 3 :
                                                          Table 4. Recommended Starting DIGOXIN Oral Maintenance Dosage in Pediatric Patients between 5 and 10 Years Old
                                                          Age Oral Maintenance Dose, mcg/kg/dose
                                                          5 years to 10 years 3.2-6.4 Twice daily
                                                          • 4 : 10 mL/min-62.562.5*1251251920 mL/min62.562.51251251251630 mL/min62.562.5*125125187.51440 mL/min62.562.5*125187.5187.51350 mL/min62.5125125187.5187.51260 mL/min62.5125125187.52501170 mL/min62.5125187.5187.52501080 mL/min62.5*125187.5187.5250990 mL/min62.5*125187.52502508100 mL/min62.5*125187.5250312.57
                                                            Table 5. Recommended Maintenance Dose (in micrograms given TWICE daily) of DIGOXIN in Pediatric Patients between 5 and 10 Years of Agea Based upon Lean Body Weight and Renal Functiona,b
                                                            a Recommended are doses to be given twice daily. b The doses are rounded to the nearest dose possible using whole DIGOXIN tablets. Recommended doses approximately 30 percent lower than the calculated dose are designated with an *. Monitor digoxin levels in patients receiving these initial doses and increase dose if needed. c The modified Schwartz equation may be used to estimate creatinine clearance. See footnote b under Table 3. d If no loading dose administered.
                                                            Corrected Creatinine Clearancec Lean Body Weight Number of Days Before Steady State Achievedd
                                                            kg 20 30 40 50 60
                                                            • 5 :
                                                              Table 6. Comparison of the Systemic Availability and Equivalent Doses of Oral and Intravenous DIGOXIN
                                                              Absolute Bioavailability Equivalent Doses (mcg)
                                                              DIGOXIN Tablets 60-80% 62.5 125 250 500
                                                              DIGOXIN Intravenous Injection 100% 50 100 200 400
                                                          • How_supplied ::
                                                              • 0 : 16 HOW SUPPLIED/STORAGE AND HANDLING DIGOXIN Tablets have “LANOXIN” on one side. They are supplied by State of Florida DOH Central Pharmacy as follows: NDC Strength Quantity/Form Color Source Prod. Code 53808-1006-1 0.125 MG 30 Tablets in a Blister Pack YELLOW 49884-514 Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) in a dry place and protect from light. Keep out of reach of children.
                                                            • Nursing_mothers ::
                                                                • 0 : 8.3 Nursing Mothers Studies have shown that digoxin distributes into breast milk, and that the milk-to-serum concentration ratio is approximately 0.6-0.9. However, the estimated exposure of a nursing infant to digoxin via breastfeeding is far below the usual infant maintenance dose. Therefore, this amount should have no pharmacologic effect upon the infant.
                                                              • Set_id : b69e2d2b-725c-4f2c-912d-d068da5c0f31

Drug Labelling

  • 2 ::
      • Package_label_principal_display_panel ::
          • 0 : Omeprazole Delayed-Release Capsules, USP 20 mg - Carton Label label image
        • Openfda ::
            • Manufacturer_name ::
                • 0 : Midwest Drug Distribution, Inc.
              • Unii ::
                  • 0 : KG60484QX9
                • Product_type ::
                    • 0 : HUMAN PRESCRIPTION DRUG
                  • Rxcui ::
                      • 0 : 198051
                    • Spl_set_id ::
                        • 0 : ed5e0d81-0c1a-4548-bde3-03fff123f12e
                      • Route ::
                          • 0 : ORAL
                        • Generic_name ::
                            • 0 : OMEPRAZOLE
                          • Brand_name ::
                              • 0 : Omeprazole
                            • Product_ndc ::
                                • 0 : 69181-158
                              • Original_packager_product_ndc ::
                                  • 0 : 55111-158
                                • Substance_name ::
                                    • 0 : OMEPRAZOLE
                                  • Spl_id ::
                                      • 0 : 005dd5ee-80ee-4e89-9c63-96e8d57b503a
                                    • Pharm_class_moa ::
                                        • 0 : Proton Pump Inhibitors [MoA]
                                          • 1 : Cytochrome P450 2C19 Inhibitors [MoA]
                                        • Application_number ::
                                            • 0 : ANDA075576
                                          • Nui ::
                                              • 0 : N0000175525
                                                • 1 : N0000182140
                                                  • 2 : N0000000147
                                                • Pharm_class_epc ::
                                                    • 0 : Proton Pump Inhibitor [EPC]
                                                  • Package_ndc ::
                                                      • 0 : 69181-158-14
                                                • Carcinogenesis_and_mutagenesis_and_impairment_of_fertility ::
                                                    • 0 : 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44 and 140.8 mg/kg/day (about 0.4 to 34 times a human dose of 40 mg/day, as expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 3.4 times a human dose of 40 mg/day, based on body surface area) for one year, and then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of one year (94% treated vs 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for two years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a small number of males that received omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.1 to 3.9 times the human dose of 40 mg/day, based on a body surface area basis). No astrocytomas were observed in female rats in this study. In a 2-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in males or females at the high dose of 140.8 mg/kg/day (about 34 times the human dose of 40 mg/day on a body surface area basis). A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive. Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames test, an in vitro mouse lymphoma cell forward mutation assay, and an in vivo rat liver DNA damage assay. Omeprazole at oral doses up to 138 mg/kg/day in rats (about 34 times an oral human dose of 40 mg on a body surface area basis) was found to have no effect on fertility and reproductive performance. In 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals [See Warnings and Precautions (5) ] Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2-receptor antagonists.
                                                  • References ::
                                                      • 0 : 15 REFERENCES 1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically—Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol, 20, No. 2, NCCLS, Wayne, PA, January 2000.
                                                    • Pregnancy ::
                                                        • 0 : 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies with omeprazole in pregnant women. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use. Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole magnesium in rats and rabbits with doses about 68 times and 42 times, respectively, an oral human dose of 40 mg (based on a body surface area basis for a 60 kg person). However, changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40 mg (see Animal Data). Because of the observed effect at high doses of esomeprazole magnesium on developing bone in rat studies, omeprazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Human Data Four published epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H2-receptor antagonists or other controls. A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995-99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population. A population-based retrospective cohort study covering all live births in Denmark from 1996-2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837,317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester. A retrospective cohort study reported on 689 pregnant women exposed to either H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H2-blocker, or were unexposed was 3.6%, 5.5% and 4.1% respectively. A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures). The reported rates of major congenital malformations was 4% for the omeprazole group, 2% for controls exposed to non-teratogens, and 2.8% in disease-paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia. Animal Data Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis) produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138 mg/kg/day (about 3.4 to 34 times an oral human doses of 40 mg on a body surface area basis). Reproduction studies have been performed with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole magnesium. A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate postweaning timeframe were evident at doses equal to or greater than 69 mg /kg/day (about 17 times an oral human dose of 40 mg on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about 3.4 times an oral human dose of 40 mg on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). Effects onmaternal bone were observed in pregnant and lactating rats in the pre- and postnatal toxicity study when esomeprazole magnesiumwas administered at oral doses of 14 to 280 mg /kg/day (about 3.4 to 68 times an oral human dose of 40 mg on a body surface area basis). When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). A pre- and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above.
                                                      • Pharmacokinetics ::
                                                          • 0 : 12.3 Pharmacokinetics Absorption Omeprazole delayed-release capsules contain an enteric-coated granule formulation of omeprazole (because omeprazole is acid-labile), so that absorption of omeprazole begins only after the granules leave the stomach. Absorption is rapid, with peak plasma levels of omeprazole occurring within 0.5 to 3.5 hours. Peak plasma concentrations of omeprazole and AUC are approximately proportional to doses up to 40 mg, but because of a saturable first-pass effect, a greater than linear response in peak plasma concentration and AUC occurs with doses greater than 40 mg. Absolute bioavailability (compared with intravenous administration) is about 30 to 40% at doses of 20 to 40 mg, due in large part to presystemic metabolism. In healthy subjects the plasma half-life is 0.5 to 1 hour, and the total body clearance is 500 to 600 mL/min. The bioavailability of omeprazole increases slightly upon repeated administration of omeprazole delayed-release capsules. Omeprazole delayed-release capsule 40 mg was bioequivalent when administered with and without applesauce. However, Omeprazole delayed-release capsule 20 mg was not bioequivalent when administered with and without applesauce. When administered with applesauce, a mean 25% reduction in Cmax was observed without a significant change in AUC for Omeprazole delayed-release capsule 20 mg. The clinical relevance of this finding is unknown. Distribution Protein binding is approximately 95%. Metabolism Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system. Excretion Following single dose oral administration of a buffered solution of omeprazole, little if any unchanged drug was excreted in urine. The majority of the dose (about 77%) was eliminated in urine as at least six metabolites. Two were identified as hydroxyomeprazole and the corresponding carboxylic acid. The remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the metabolites of omeprazole. Three metabolites have been identified in plasma — the sulfide and sulfone derivatives of omeprazole, and hydroxyomeprazole. These metabolites have very little or no antisecretory activity. Combination Therapy with Antimicrobials Omeprazole 40 mg daily was given in combination with clarithromycin 500 mg every 8 hours to healthy adult male subjects. The steady state plasma concentrations of omeprazole were increased (Cmax, AUC0-24, and T1/2 increases of 30%, 89% and 34% respectively) by the concomitant administration of clarithromycin. The observed increases in omeprazole plasma concentration were associated with the following pharmacological effects. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when co-administered with clarithromycin. The plasma levels of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant administration of omeprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered with omeprazole than when clarithromycin was administered alone. Similar results were seen for 14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole. Table 2 Clarithromycin Tissue Concentrations 2 hours after Dose1 Tissue Clarithromycin Clarithromycin + Omeprazole Antrum 10.48 ± 2.01 (n = 5) 19.96 ± 4.71 (n=5) Fundus 20.81 ± 7.64 (n = 5) 24.25 ± 6.37 (n= 5) Mucus 4.15 ± 7.74 (n = 4) 39.29 ± 32.79 (n=4) 1mean ± SD (mcg/g) Concomitant Use with Clopidogrel In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Results from another crossover study in healthy subjects showed a similar pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole 80 mg daily when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 41% to 46% over this time period. In another study, 72 healthy subjects were given the same doses of clopidogrel and 80 mg omeprazole but the drugs were administered 12 hours apart; the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction. Concomitant Use with Mycophenolate Mofetil Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the Cmax and 23% reduction in the AUC of MPA. Special Populations Geriatric Population The elimination rate of omeprazole was somewhat decreased in the elderly, and bioavailability was increased. Omeprazole was 76% bioavailable when a single 40 mg oral dose of omeprazole (buffered solution) was administered to healthy elderly volunteers, versus 58% in young volunteers given the same dose. Nearly 70% of the dose was recovered in urine as metabolites of omeprazole and no unchanged drug was detected. The plasma clearance of omeprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers. Pediatric Use The pharmacokinetics of omeprazole have been investigated in pediatric patients 2 to 16 years of age: Table 3 Pharmacokinetic Parameters of Omeprazole Following Single and Repeated Oral Administration in Pediatric Populations Compared with Adults Single or Repeated Oral Dosing /Parameter Children† ≤ 20 kg 2 to 5 years Children†> 20 kg 6 to 16 years Adults‡(mean 76 kg) 23 to 29 years(n=12) 10 mg 20 mg Single Dosing Cmax* (ng/mL) 288 (n=10) 495 (n=49) 668 AUC* (ng h/mL) 511 (n=7) 1140 (n=32) 1220 Repeated Dosing Cmax* (ng/mL) 539 (n=4) 851 (n=32) 1458 AUC * (ng h/mL) 1179 (n=2) 2276 (n=23) 3352 Note: * = plasma concentration adjusted to an oral dose of 1 mg/kg. † Data from single and repeated dose studies ‡ Data from a single and repeated dose study Doses of 10, 20 and 40 mg omeprazole as enteric-coated granules Following comparable mg/kg doses of omeprazole, younger children (2 to 5 years of age) have lower AUCs than children 6 to16 years of age or adults; AUCs of the latter two groups did not differ. [See Dosage and Administration (2) ] Hepatic Impairment In patients with chronic hepatic disease, the bioavailability increased to approximately 100% compared with an I.V. dose, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly 3 hours compared with the half-life in normals of 0.5 to 1 hour. Plasma clearance averaged 70 mL/min, compared with a value of 500 to 600 mL/min in normal subjects. Dose reduction, particularly where maintenance of healing of erosive esophagitis is indicated, for the hepatically impaired should be considered. Renal Impairment In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and 62 mL/min/1.73 m2, the disposition of omeprazole was very similar to that in healthy volunteers, although there was a slight increase in bioavailability. Because urinary excretion is a primary route of excretion of omeprazole metabolites, their elimination slowed in proportion to the decreased creatinine clearance. No dose reduction is necessary in patients with renal impairment. Asian Population In pharmacokinetic studies of single 20 mg omeprazole doses, an increase in AUC of approximately four-fold was noted in Asian subjects compared with Caucasians. Dose reduction, particularly where maintenance of healing of erosive esophagitis is indicated, for Asian subjects should be considered.
                                                        • Drug_interactions ::
                                                            • 0 : 7 DRUG INTERACTIONS Atazanavir and nelfinavir: omeprazole reduces plasma levels of atazanavir and nelfinavir. Concomitant use is not recommended (7.1) Saquinavir: omeprazole increases plasma levels of saquinavir. Monitor for toxicity and consider dose reduction of saquinavir (7.1) May interfere with drugs for which gastric pH affects bioavailability (e.g., ketoconazole, iron salts, erlotinib, ampicillin esters, digoxin and mycophenolate mofetil). Patients treated with omeprazole and digoxin may need to be monitored for increases in digoxin toxicity. (7.2) Clopidogrel: omeprazole decreases exposure to the active metabolite of clopidogrel. (7.3, 12.3) Clopidogrel: Omeprazole decreases exposure to the active metabolite of clopidogrel. (7.3, 12.3) Cilostazol: omeprazole increases systemic exposure of cilostazol and one of its active metabolites. Consider dose reduction of cilostazol.(7.3 ) Drugs metabolized by cytochrome P450 (e.g., diazepam, warfarin, phenytoin, cyclosporine, disulfiram, benzodiazepines): omeprazole can prolong their elimination. Monitor and determine need for dose adjustments (7.3) Patients treated with proton pump inhibitors and warfarin may need to be monitored for increases in INR and prothrombin time (7.3) Combined inhibitor of CYP2C19 and 3A4 (e.g. voriconazole) may raise omeprazole levels (7.3) Tacrolimus: omeprazole may increase serum levels of tacrolimus (7.4) Methotrexate: Omeprazole may increase serum levels of methotrexate ( 7.7 ) 7.1 Interference with Antiretroviral Therapy Concomitant use of atazanavir and nelfinavir with proton pump inhibitors is not recommended. Co-administration of atazanavir with proton pump inhibitors is expected to substantially decrease atazanavir plasma concentrations and may result in a loss of therapeutic effect and the development of drug resistance. Co-administration of saquinavir with proton pump inhibitors is expected to increase saquinavir concentrations, which may increase toxicity and require dose reduction. Omeprazole has been reported to interact with some antiretroviral drugs. The clinical importance and the mechanisms behind these interactions are not always known. Increased gastric pH during omeprazole treatment may change the absorption of the antiretroviral drug. Other possible interaction mechanisms are via CYP 2C19. Reduced concentrations of atazanavir and nelfinavir For some antiretroviral drugs, such as atazanavir and nelfinavir, decreased serum levels have been reported when given together with omeprazole. Following multiple doses of nelfinavir (1250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, Cmax by 37% and 89% and Cmin by 39% and 75% respectively for nelfinavir and M8. Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hr before atazanavir), AUC was decreased by 94%, Cmax by 96%, and Cmin by 95%. Concomitant administration with omeprazole and drugs such as atazanavir and nelfinavir is therefore not recommended. Increased concentrations of saquinavir For other antiretroviral drugs, such as saquinavir, elevated serum levels have been reported, with an increase in AUC by 82%, in Cmax by 75%, and in Cmin by 106%, following multiple dosing of saquinavir/ritonavir (1000/100 mg) twice daily for 15 days with omeprazole 40 mg daily co-administered days 11 to 15. Therefore, clinical and laboratory monitoring for saquinavir toxicity is recommended during concurrent use with omeprazole. Dose reduction of saquinavir should be considered from the safety perspective for individual patients. There are also some antiretroviral drugs of which unchanged serum levels have been reported when given with omeprazole. 7.2 Drugs for which Gastric pH can affect Bioavailability Due to its effects on gastric acid secretion, omeprazole can reduce the absorption of drugs where gastric pH is an important determinant of theirbioavailability. Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) can decrease, while the absorption of drugs such as digoxin can increase during treatment with omeprazole. Concomitant treatment with omeprazole (20 mg daily) and digoxin in healthy subjects increased the bioavailability of digoxin by 10% (30% in two subjects). Co-administration of digoxin with omeprazole is expected to increase the systemic exposure of digoxin. Therefore, patients may need to be monitored when digoxin is taken concomitantly with omeprazole. Co-administration of omeprazole in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH. The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving omeprazole and MMF. Use omeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. 7.3 Effects on Hepatic Metabolism/Cytochrome P-450 Pathways Omeprazole can prolong the elimination of diazepam, warfarin and phenytoin, drugs that are metabolized by oxidation in the liver. There have been reports of increased INR and prothrombin time in patients receiving proton pump inhibitors, including omeprazole, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin may need to be monitored for increases in INR and prothrombin time. Although in normal subjects no interaction with theophylline or propranolol was found, there have been clinical reports of interaction with other drugs metabolized via the cytochrome P450 system (e.g., cyclosporine, disulfiram, benzodiazepines). Patients should be monitored to determine if it is necessary to adjust the dosage of these drugs when taken concomitantly with omeprazole. Concomitant administration of omeprazole and voriconazole (a combined inhibitor of CYP2C19 and CYP3A4) resulted in more than doubling of the omeprazole exposure. Dose adjustment of omeprazole is not normally required. However, in patients with Zollinger-Ellison syndrome, who may require higher doses up to 240 mg/day, dose adjustment may be considered. When voriconazole (400 mg Q12h x 1 day, then 200 mg x 6 days) was given with omeprazole (40 mg once daily x 7 days) to healthy subjects, it significantly increased the steady-state Cmax and AUC0-24 of omeprazole, an average of 2 times (90% CI: 1.8, 2.6) and 4 times (90% CI: 3.3, 4.4) respectively as compared to when omeprazole was given without voriconazole. Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in crossover study, increased Cmax and AUC of cilostazol by 18% and 26% respectively. Cmax and AUC of one of its active metabolites, 3,4-dihydro-cilostazol, which has 4 to 7 times the activity of cilostazol, were increased by 29% and 69% respectively. Co-administration of cilostazol with omeprazole is expected to increase concentrations of cilostazol and its above mentioned active metabolite. Therefore a dose reduction of cilostazol from 100 mg twice daily to 50 mg twice daily should be considered. Drugs known to induce CYP2C19 or CYP3A4 (such as rifampin) may lead to decreased omeprazole serum levels. In a cross-over study in 12 healthy male subjects, St John’s wort (300 mg three times daily for 14 days), an inducer of CYP3A4, decreased the systemic exposure of omeprazole in CYP2C19 poor metabolisers (Cmax and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolisers (Cmax and AUC decreased by 49.6% and 43.9%, respectively). Avoid concomitant use of St. John’s Wort or rifampin with omeprazole. Clopidogrel Omeprazole is an inhibitor of CYP2C19 enzyme. Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant administration of omeprazole with clopidogrel. When using omeprazole, consider use of alternative anti-platelet therapy [see Pharmacokinetics (12.3 )]. There are no adequate combination studies of a lower dose of omeprazole or a higher dose of clopidogrel in comparison with the approved dose of clopidogrel. 7.4 Tacrolimus Concomitant administration of omeprazole and tacrolimus may increase the serum levels of tacrolimus. 7.5 Interactions with Investigations of Neuroendocrine Tumors Drug-induced decrease in gastric acidity results in enterochromaffin-like cell hyperplasia and increased Chromogranin A levels which may interfere with investigations for neuroendocrine tumors. [see Warnings and Precautions (5.10) and Clinical Pharmacology (12) ]. 7.6 Combination Therapy with Clarithromycin Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions [see Warnings and Precautions in prescribing information for clarithromycin]. Because of these drug interactions, clarithromycin is contraindicated for co-administration with certain drugs [see Contraindications in prescribing information for clarithromycin]. 7.7 Methotrexate Case reports, published population pharmacokinetic studies, and retrospective analyses suggest that concomitant administration of PPIs and methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate. However, no formal drug interaction studies of methotrexate with PPIs have been conducted [see Warnings and Precautions (5.11) ].
                                                          • Id : 005dd5ee-80ee-4e89-9c63-96e8d57b503a
                                                            • Indications_and_usage ::
                                                                • 0 : 1 INDICATIONS AND USAGE Omeprazole is a proton pump inhibitor indicated for: Treatment in adults of duodenal ulcer (1.1) and gastric ulcer (1.2) Treatment in adults and children of gastroesophageal reflux disease (GERD) (1.3) and maintenance of healing of erosive esophagitis (1.4) The safety and effectiveness of omeprazole in pediatric patients < 1 year of age have not been established. (8.4) 1.1 Duodenal Ulcer (adults) Omeprazole delayed-release capsules are indicated for short-term treatment of active duodenal ulcer in adults. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy. Omeprazole delayed-release capsules, in combination with clarithromycin and amoxicillin, are indicated for treatment of patients with H. pylori infection and duodenal ulcer disease (active or up to 1-year history) to eradicate H. pylori in adults. Omeprazole delayed-release capsules, in combination with clarithromycin are indicated for treatment of patients with H. pylori infection and duodenal ulcer disease to eradicate H. pylori in adults. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [see Clinical Studies (14.1) and Dosage and Administration (2 ) ]. Among patients who fail therapy, Omeprazole delayed-release capsules with clarithromycin are more likely to be associated with the development of clarithromycin resistance as compared with triple therapy. In patients who fail therapy, susceptibility testing should be done. If resistance to clarithromycin is demonstrated or susceptibility testing is not possible, alternative antimicrobial therapy should be instituted. [See Microbiology section (12.4)], and the clarithromycin package insert, Microbiology section.) 1.2 Gastric Ulcer (adults) Omeprazole delayed-release capsules are indicated for short-term treatment (4 to 8 weeks) of active benign gastric ulcer in adults for upto 4 weeks. [See Clinical Studies (14.2) ] 1.3 Treatment of Gastroesophageal Reflux Disease (GERD) (adults and pediatric patients) Symptomatic GERD Omeprazole delayed-release capsules are indicated for the treatment of heartburn and other symptoms associated with GERD in pediatric patients and adults. Erosive Esophagitis Omeprazole delayed-release capsules are indicated for the short-term treatment (4 to 8 weeks) of erosive esophagitis that has been diagnosed by endoscopy in pediatric patients and adults. [See Clinical Studies (14.4) ] The efficacy of omeprazole delayed-release capsules used for longer than 8 weeks in these patients has not been established. If a patient does not respond to 8 weeks of treatment, an additional 4 weeks of treatment may be given. If there is recurrence of erosive esophagitis or GERD symptoms (e.g., heartburn), additional 4 to 8 week courses of omeprazole may be considered. 1.4 Maintenance of Healing of Erosive Esophagitis (adults and pediatric patients) Omeprazole delayed-release capsules are indicated to maintain healing of erosive esophagitis in pediatric patients and adults. Controlled studies do not extend beyond 12 months. [See Clinical Studies (14.4) ] 1.5 Pathological Hypersecretory Conditions (adults) Omeprazole delayed-release capsules are indicated for the long-term treatment of pathological hypersecretory conditions (e.g., Zollinger-Ellison syndrome, multiple endocrine adenomas and systemic mastocytosis) in adults.
                                                              • Pharmacokinetics_table ::
                                                                  • 0 :
Tissue Clarithromycin Clarithromycin + Omeprazole
Antrum 10.48 ± 2.01 (n = 5) 19.96 ± 4.71 (n=5)
Fundus 20.81 ± 7.64 (n = 5) 24.25 ± 6.37 (n= 5)
Mucus 4.15 ± 7.74 (n = 4) 39.29 ± 32.79 (n=4)
  • 1 :
    Single or Repeated Oral Dosing /Parameter Children† ≤ 20 kg 2 to 5 years Children†> 20 kg 6 to 16 years Adults‡(mean 76 kg) 23 to 29 years(n=12)
    10 mg 20 mg
    Single Dosing
    Cmax* (ng/mL) 288 (n=10) 495 (n=49) 668
    AUC* (ng h/mL) 511 (n=7) 1140 (n=32) 1220
    Repeated Dosing
    Cmax* (ng/mL) 539 (n=4) 851 (n=32) 1458
    AUC * (ng h/mL) 1179 (n=2) 2276 (n=23) 3352
  • Pharmacodynamics_table ::
      • 0 :
        Omeprazole 20 mg Omeprazole 40 mg
        Parameter Max Min Max Min
        % Decrease in Basal Acid Output 78* 58 to 80 94* 80 to 93
        % Decrease in Peak Acid Output 79* 50 to 59 88* 62 to 68
        % Decrease in 24–hr Intragastric Acidity 80 to 97 92 to 94
    • Contraindications ::
        • 0 : 4 CONTRAINDICATIONS Omeprazole delayed-release capsules are contraindicated in patients with known hypersensitivity to substituted benzimidazoles or to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute interstitial nephritis, and urticaria [see Adverse Reactions (6) ]. For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with omeprazole, refer to the CONTRAINDICATIONS section of their package inserts. Known hypersensitivity to any component of the formulation or substituted benzimidazoles (angioedema and anaphylaxis have occurred) (4)
      • Version : 1
        • Spl_medguide ::
            • 0 : MEDICATION GUIDE OMEPRAZOLE DELAYED-RELEASE CAPSULES, USP Read this Medication Guide before you start taking omeprazole delayed-release capsules and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. What is the most important information I should know about omeprazole delayed-release capsules? Omeprazole delayed-release capsules may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your doctor. Omeprazole delayed-release capsules can cause serious side effects, including: Diarrhea. Omeprazole delayed-release capsules may increase your risk of getting severe diarrhea. This diarrhea may be caused by an infection (Clostridium difficile) in your intestines. Call your doctor right away if you have watery stool, stomach pain, and fever that does not go away. Bone fractures. People who take multiple daily doses of proton pump inhibitor medicines for a long period of time (a year or longer) may have an increased risk of fractures of the hip, wrist, or spine. You should take omeprazole delayed-release capsules exactly as prescribed, at the lowest dose possible for your treatment and for the shortest time needed. Talk to your doctor about your risk of bone fracture if you take omeprazole delayed-release capsules. Omeprazole delayed-release capsules can have other serious side effects. See “What are the possible side effects of omeprazole delayed-release capsules?” What is omeprazole delayed-release capsule? Omeprazole delayed-release capsule is a prescription medicine called a proton pump inhibitor (PPI). Omeprazole delayed-release capsules reduces the amount of acid in your stomach. Omeprazole delayed-release capsules are used in adults: for up to 8 weeks for the healing of duodenal ulcers. The duodenal area is the area where food passes when it leaves the stomach. with certain antibiotics to treat an infection caused by bacteria called H. pylori. Sometimes H. pylori bacteria can cause duodenal ulcers. The infection needs to be treated to prevent the ulcers from coming back. for up to 8 weeks for healing stomach ulcers for up to 4 weeks to treat heartburn and other symptoms that happen with gastroesophageal reflux disease (GERD). GERD happens when acid in your stomach backs up into the tube (esophagus) that connects your mouth to your stomach. This may cause a burning feeling in your chest or throat, sour taste, or burping. for up to 8 weeks to heal acid-related damage to the lining of the esophagus (called erosive esophagitis or EE). If needed, your doctor may decide to prescribe another 4 weeks of omeprazole delayed-release capsules. to maintain healing of the esophagus. It is not known if omeprazole delayed-release capsules are safe and effective when used for longer than 12 months (1 year) for this purpose. for the long-term treatment of conditions where your stomach makes too much acid. This includes a rare condition called Zollinger-Ellison Syndrome. For children 2 to 16 years of age, omeprazole delayed-release capsules are used: for up to 4 weeks to treat heartburn and other symptoms that happen with gastroesophageal reflux disease (GERD). for up to 8 weeks to heal acid-related damage to the lining of the esophagus (called erosive esophagitis or EE) to maintain healing of the esophagus. It is not known if omeprazole delayed-release capsules are safe and effective when used longer than 12 months (1 year) for this purpose. It is not known if omeprazole delayed-release capsules are safe and effective for the treatment of gastroesophageal reflux disease (GERD) in children under 1 year of age. Who should not take omeprazole delayed-release capsules? Do not take omeprazole delayed-release capsules if you: are allergic to omeprazole or any of the ingredients in omeprazole delayed-release capsules. See the end of this Medication Guide for a complete list of ingredients in omeprazole delayed-release capsules. are allergic to any other Proton Pump Inhibitor (PPI) medicine. What should I tell my doctor before taking omeprazole delayed-release capsules? Before you take omeprazole delayed-release capsules, tell your doctor if you: have been told that you have low magnesium levels in your blood have liver problems have any other medical conditions are pregnant or plan to become pregnant. It is not known if omeprazole delayed-release capsules will harm your unborn baby. are breastfeeding or plan to breastfeed. Omeprazole delayed-release capsules can pass into your breast milk and may harm your baby. You and your doctor should decide if you will take omeprazole delayed-release capsules or breastfeed. You should not do both. Talk to your doctor about the best way to feed your baby if you breastfeed. Tell your doctor about all of the medicines you take including prescription and non-prescription drugs, anticancer drugs, vitamins and herbal supplements. Omeprazole delayed-release capsules may affect how other medicines work, and other medicines may affect how omeprazole delayed-release capsules works. Especially tell your doctor if you take: atazanavir (Reyataz) nelfinavir (Viracept) saquinavir (Fortovase) cilostazol (Pletal) ketoconazole (Nizoral) voriconazole (Vfend) an antibiotic that contains ampicillin, amoxicillin or clarithromycin products that contain iron warfarin (Coumadin, Jantoven) digoxin (Lanoxin) tacrolimus (Prograf) diazepam (Valium) phenytoin (Dilantin) disulfiram (Antabuse) clopidogrel (Plavix) St. John’s Wort (Hypericum perforatum) rifampin (Rimactane, Rifater, Rifamate), erlotinib (Tarceva) methotrexate mycophenolate mofetil (Cellcept) Ask your doctor or pharmacist for a list of these medicines if you are not sure. Know the medicines that you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine. How should I take omeprazole delayed-release capsules? Take omeprazole delayed-release capsules exactly as prescribed by your doctor. Do not change your dose or stop omeprazole delayed-release capsules without talking to your doctor. Take omeprazole delayed-release capsules at least 1 hour before a meal. Swallow omeprazole delayed-release capsules whole. Do not chew or crush omeprazole delayed-release capsules. If you have trouble swallowing omeprazole delayed-release capsules, you may take as follows: Place 1 tablespoon of applesauce into a clean bowl. Carefully open the capsule and empty the contents (pellets) onto the applesauce. Mix the pellets with the applesauce. Swallow the applesauce and pellet mixture right away with a glass of cool water. Do not chew or crush the pellets. Do not store the applesauce and pellet mixture for later use. If you forget to take a dose of omeprazole delayed-release capsules, take it as soon as you remember. If it is almost time for your next dose, do not take the missed dose. Take the next dose on time. Do not take a double dose to make up for a missed dose. If you take too much omeprazole delayed-release capsules, tell your doctor right away. What are the possible side effects of omeprazole delayed-release capsules? Omeprazole delayed-release capsules can cause serious side effects, including: See “What is the most important information I should know about omeprazole delayed-release capsules?” Chronic (lasting a long time) inflammation of the stomach lining (Atrophic Gastritis). Using omeprazole delayed-release capsules for a long period of time may increase the risk of inflammation to your stomach lining. You may or may not have symptoms. Tell your doctor if you have stomach pain, nausea, vomiting, or weight loss. Vitamin B-12 deficiency. Omeprazole delayed-release capsules reduces the amount of acid in your stomach. Stomach acid is needed to absorb vitamin B-12 properly. Talk with your doctor about the possibility of vitamin B-12 deficiency if you have been on omeprazole delayed-release capsules for a long time (more than 3 years). Low magnesium levels in your body. This problem can be serious. Low magnesium can happen in some people who take a proton pump inhibitor medicine for at least 3 months. If low magnesium levels happen, it is usually after a year of treatment. You may or may not have symptoms of low magnesium. Tell your doctor right away if you develop any of these symptoms: seizures dizziness abnormal or fast heart beat jitteriness jerking movements or shaking (tremors) muscle weakness spasms of the hands and feet cramps or muscle aches spasm of the voice box Your doctor may check the level of magnesium in your body before you start taking omeprazole delayed-release capsules or during treatment if you will be taking omeprazole delayed-release capsules for a long period of time. The most common side effects with omeprazole delayed-release capsules in adults and children include: headache stomach pain nausea diarrhea vomiting gas In addition to the side effects listed above, the most common side effects in children 2 to 16 years of age include: respiratory system events fever Other side effects: Serious allergic reactions. Tell your doctor if you get any of the following symptoms with omeprazole delayed-release capsules: rash face swelling throat tightness difficulty breathing Your doctor may stop omeprazole delayed-release capsules if these symptoms happen. Tell your doctor if you have any side effect that bothers you or that do not go away. These are not all the possible side effects with omeprazole delayed-release capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store omeprazole delayed-release capsules? Store omeprazole delayed-release capsules at room temperature between 20° to 25°C (68° to 77°F). Keep the container of omeprazole delayed-release capsules closed tightly. Keep the container of omeprazole delayed-release capsules dry and away from light. Keep omeprazole delayed-release capsules and all medicines out of the reach of children. General information about omeprazole delayed-release capsules Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use omeprazole delayed-release capsules for a condition for which it was not prescribed. Do not give omeprazole delayed-release capsules to other people, even if they have the same symptoms you have. It may harm them. This Medication Guide summarizes the most important information about omeprazole delayed-release capsules. For more information, ask your doctor. You can ask your doctor or pharmacist for information that is written for healthcare professionals. For more information, call 1-888-375-3784. What are the ingredients in omeprazole delayed-release capsules? Active ingredient in omeprazole delayed-release capsules delayed-release capsules: omeprazole Inactive ingredients in omeprazole delayed-release capsules: Crospovidone, hypromellose, magnesium stearate, mannitol, meglumine, methacrylic acid copolymer, poloxamer, povidone and triethyl citrate. The capsule shells contains: D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40,FD&C Yellow No. 6, yellow iron oxide, gelatin, silicon dioxide, sodium lauryl sulphate and titanium dioxide. Imprinting ink contains: D&C Yellow No. 10 aluminum lake, FD&C Blue No. 1 aluminum lake, FD&C Blue No. 2 aluminum lake, FD&C Red No. 40 aluminum lake, n-butyl alcohol, pharmaceutical glaze, propylene glycol, SDA-3A alcohol and synthetic black iron oxide. To reorder additional Medication Guides, contact Dr. Reddy’s Customer Service at 1-866-733-3952. Rx Only Manufactured by: Dr. Reddy’s Laboratories Limited Bachupally – 500 090 INDIA Revised: 0215
          • Pediatric_use ::
              • 0 : 8.4 Pediatric Use Use of omeprazole in pediatric and adolescent patients 2 to 16 years of age for the treatment of GERD and maintenance of healing of erosive esophagitis is supported by a) extrapolation of results from adequate and well-controlled studies that supported the approval of omeprazole for adults, and b) safety and pharmacokinetic studies performed in pediatric and adolescent patients. [See Clinical Pharmacology, Pharmacokinetics, Pediatric for pharmacokinetic information (12.3) and Dosage and Administration (2) . Adverse Reactions (6.1) and Clinical Studies (14.6) ]. The safety and effectiveness of omeprazole for the treatment of GERD in patients < 1 year of age have not been established. The safety and effectiveness of omeprazole for other pediatric uses have not been established. Juvenile Animal Data In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 34 to 57 times a daily human dose of 40 mg based on body surface area. Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight and femur length, and decreases in overall growth [see Nonclinical Toxicology ( 13.2 )].
            • Information_for_patients ::
                • 0 : 17 PATIENT COUNSELING INFORMATION See FDA-Approved Medication Guide Omeprazole delayed-release capsules should be taken before eating. Patients should be informed that the omeprazole delayed-release capsules should be swallowed whole. For patients who have difficulty swallowing capsules, the contents of an omeprazole delayed-release capsule can be added to applesauce. One tablespoon of applesauce should be added to an empty bowl and the capsule should be opened. All of the pellets inside the capsule should be carefully emptied on the applesauce. The pellets should be mixed with the applesauce and then swallowed immediately with a glass of cool water to ensure complete swallowing of the pellets. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. The pellets should not be chewed or crushed. The pellets/applesauce mixture should not be stored for future use. Advise patients to immediately report and seek care for diarrhea that does not improve. This may be a sign of Clostridium difficile associated diarrhea [see Warnings and Precautions (5.5) ]. Advise patients to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures, and tetany as these may be signs of hypomagnesemia [see W arnings and Precautions (5.8) ]
              • Dosage_forms_and_strengths ::
                  • 0 : 3 DOSAGE FORMS AND STRENGTHS Omeprazole delayed-release capsules, USP 10 mg are off-white to pale yellow, elliptical to spherical pellets filled in size ‘3’ hard gelatin capsules with opaque lavender coloured cap and opaque yellow coloured body, imprinted on cap ‘OMEPRAZOLE’ 10 mg and on body ‘R157’ with black ink. Omeprazole delayed-release capsules, USP 20 mg are off-white to pale yellow, elliptical to spherical pellets filled in size ‘2’ hard gelatin capsules with opaque lavender coloured cap and opaque iron grey coloured body, imprinted on cap ‘OMEPRAZOLE’ 20 mg and on body ‘R158’ with black ink. Omeprazole delayed-release capsules, USP 40 mg are off-white to pale yellow, elliptical to spherical pellets filled in size ‘Oel’ hard gelatin capsules with opaque yellow coloured cap and opaque lavender coloured body, imprinted on cap ‘OMEPRAZOLE’ 40 mg and on body ‘R159’ with black ink. Omeprazole delayed-release capsules, 10 mg, 20 mg and 40 mg (3)
                • Clinical_studies_table ::
                    • 0 :
                      Omeprazole 20 mg a.m. Placebo a.m.
                      (n=99) (n=48)
                      Week 2 *41 13
                      Week 4 *75 27
                      • 1 :
                        Omeprazole Ranitidine
                        20 mg a.m. 150 mg twice daily
                        (n = 145) (n = 148)
                        Week 2 42 34
                        Week 4 *82 63
                        • 2 :
                          Omeprazole Ranitidine
                          20 mg (n=34) 40 mg (n=36) 150 mg twice daily (n=35)
                          Week 2 *83 *83 53
                          Week 4 *97 *100 82
                          Week 8 100 100 94
                          • 3 :
                            Omeprazole +clarithromycin+amoxicillin Clarithromycin +amoxicillin
                            Per-Protocol Intent-to-Treat Per-Protocol Intent-to-Treat
                            Study 1 *77 [64, 86] *69 [57, 79] 43 [31, 56] 37 [27, 48]
                            (n = 64) (n = 80) (n = 67) (n = 84)
                            Study 2 *78 [67, 88] *73 [61, 82] 41 [29, 54] 36 [26, 47]
                            (n = 65) (n = 77) (n = 68) (n = 83)
                            Study 3 *90 [80, 96] *83 [74, 91] 33 [24, 44] 32 [23, 42]
                            (n = 69) (n = 84) (n = 93) (n = 99)
                            • 4 :
                              Omeprazole+Clarithromycin Omeprazole Clarithromycin
                              U.S. Studies
                              Study 4 74 [60, 85] †‡ 0 [0, 7] 31 [18, 47]
                              (n = 53) (n=54) (n = 42)
                              Study 5 64 [51, 76] †‡ 0 [0, 6] 39 [24, 55]
                              (n = 61) (n = 59) (n = 44)
                              Non U.S. Studies
                              Study 6 83 [71, 92] 1 [0, 7] N/A
                              (n = 60) (n = 74)
                              Study 7 74 [64, 83] 1 [0,6] N/A
                              • 5 :
                                H. pylori eradicated# H. pylori not eradicated#
                                U.S. Studies
                                6 months post-treatment
                                Study 4 *35 60
                                (n = 49) (n = 88)
                                Study 5 *8 60
                                (n = 53) (n = 106)
                                Non U.S. Studies
                                6 months post-treatment
                                Study 6 *5 46
                                (n=43) (n=78)
                                Study 7 *6 43
                                (n=53) (n=107)
                                12 months post-treatment
                                Study 6 *5 68
                                (n=39) (n=71)
                                • 6 :
                                  Treatment of Gastric Ulcer
                                  % of Patients Healed
                                  (All Patients Treated)
                                  Omeprazole Omeprazole
                                  20 mg once daily 40 mg once daily Placebo
                                  (n=202) (n=214) (n=104)
                                  Week 4 47.5 ** 55.6 ** 30.8
                                  Week 8 74.8 ** 82.7 **,+ 48.1
                                  • 7 :
                                    Treatment of Gastric Ulcer
                                    % of Patients Healed
                                    (All Patients Treated)
                                    Omeprazole Omeprazole Ranitidine
                                    20 mg once daily 40 mg once daily 150 twice daily
                                    (n=200) (n=187) (n=199)
                                    Week 4 63.5 78.1**,++ 56.3
                                    Week 8 81.5 91.4 **,++ 78.4
                                    • 8 :
                                      % Successful Symptomatic Outcomea
                                      Omeprazole Omeprazole Placebo
                                      20 mg a.m. 10 mg a.m. a.m.
                                      All patients 46*,† 31† 13
                                      (n=205) (n=199) (n=105)
                                      Patients with confirmed GERD 56*,† 36† 14
                                      (n=115) (n=109) (n=59)
                                      • 9 :
                                        Week 20 mg Omeprazole 40 mg Omeprazole Placebo
                                        (n=83) (n=87) (n=43)
                                        4 39** 45** 7
                                        8 74** 75** 14
                                        • 10 :
                                          Life Table Analysis
                                          Omeprazole Omeprazole
                                          20 mg once daily 20 mg 3 days per week Placebo
                                          (n=138) (n = 137) (n = 131)
                                          Percent in endoscopic remission at 6 months *70 34 11
                                          • 11 :
                                            Life Table Analysis
                                            Omeprazole Omeprazole Ranitidine
                                            20 mg once daily 10 mg once daily 150 mg twice daily
                                            (n=131) (n = 133) (n = 128)
                                            Percent in endoscopic remission at 12 months *77 ‡58 46
                                        • Recent_major_changes ::
                                            • 0 : Warnings and Precautions, Interactions with Diagnostic Investigations for Neuroendocrine Tumors (5.10) 03/2014 Indications and Usage, Treatment of Gastroesophageal Reflux Disease (GERD) (adults and pediatric patients) (1.3) 12/2014 Dosage and Administration, Maintenance of Healing of Erosive Esophagitis (2.5) 12/2014 Warnings and Precautions, Acute Interstitial Nephritis (5.3) 12/2014 Warnings and Precautions, Cyanocobalamin (vitamin B-12) Deficiency (5.4) 12/2014
                                          • Description ::
                                              • 0 : 11 DESCRIPTION The active ingredient in omeprazole delayed-release capsules is a substituted benzimidazole, 5-methoxy-2-[[(4-methoxy-3, 5-dimethyl-2-pyridinyl) methyl] sulfinyl]-1H-benzimidazole, a compound that inhibits gastric acid secretion. Its empirical formula is C17H19N3O3S, with a molecular weight of 345.42. The structural formula is: Omeprazole is a white to off-white powder. Melts between 150°C and 160°C with decomposition. It is soluble in dichloromethane, sparingly soluble in methanol and in alcohol. Omeprazole delayed-release capsules meets USP Drug release test 2. Omeprazole is supplied as delayed-release capsules for oral administration. Each delayed-release capsule contains either 10 mg, 20 mg or 40 mg of omeprazole in the form of enteric-coated granules with the following inactive ingredients: crospovidone, hypromellose, magnesium stearate, mannitol, meglumine, methacrylic acid copolymer, poloxamer, povidone and triethyl citrate. The capsule shells contains: D&C Red No. 28, FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No. 6, yellow iron oxide, gelatin, silicon dioxide, sodium lauryl sulphate and titanium dioxide. Imprinting ink contains: D&C Yellow No. 10 aluminum lake, FD&C Blue No. 1 aluminum lake, FD&C Blue No. 2 aluminum lake, FD&C Red No. 40 aluminum lake, n-butyl alcohol, pharmaceutical glaze, propylene glycol, SDA-3A alcohol and synthetic black iron oxide.
                                            • Dosage_and_administration ::
                                                • 0 : 2 DOSAGE AND ADMINISTRATION Omeprazole delayed-release capsules should be taken before eating. In the clinical trials, antacids were used concomitantly with omeprazole. Patients should be informed that the omeprazole delayed-release capsule should be swallowed whole. For patients unable to swallow an intact capsule, alternative administration options are available [See Dosage and Administration (2.8) ]. Indication Omeprazole Dose Frequency Treatment of Active Duodenal Ulcer (2.1) 20 mg Once daily for 4 weeks. Some patients may require an additional 4 weeks H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (2.2) Triple Therapy: Omeprazole 20 mg Each drug twice daily for 10 days Amoxicillin 1000 mg Clarithromycin 500 mg Dual Therapy: Omeprazole 40 mg Once daily for 14 days Clarithromycin 500 mg Three times daily for 14 days Gastric Ulcer (2.3) 40 mg Once daily for 4 to 8 weeks GERD (2.4) 20 mg Once daily for 4 to 8 weeks Maintenance of Healing of Erosive Esophagitis (2.5) 20 mg Once daily Pathological Hypersecretory Conditions (2.6) 60 mg (varies with individual patient) Once daily Pediatric Patients (2 to 16 years of age) (2.7) Weight Dose GERD 10 < 20 kg 10 mg Once daily And Maintenance of ≥ 20 kg 20 mg Healing of Erosive Esophagitis 2.1 Short-Term Treatment of Active Duodenal Ulcer The recommended adult oral dose of omeprazole delayed-release capsules is 20 mg once daily. Most patients heal within four weeks. Some patients may require an additional four weeks of therapy. 2.2 H. pylori Eradication for the Reduction of the Risk of Duodenal Ulcer Recurrence Triple Therapy (omeprazole/clarithromycin/amoxicillin) — The recommended adult oral regimen is omeprazole delayed-release capsules 20 mg plus clarithromycin 500 mg plus amoxicillin 1000 mg each given twice daily for 10 days. In patients with an ulcer present at the time of initiation of therapy, an additional 18 days of omeprazole delayed-release capsules 20 mg once daily is recommended for ulcer healing and symptom relief. Dual Therapy (omeprazole/clarithromycin) — The recommended adult oral regimen is omeprazole delayed-release capsuels 40 mg once daily plus clarithromycin 500 mg three times daily for 14 days. In patients with an ulcer present at the time of initiation of therapy, an additional 14 days of omeprazole delayed-release capsules 20 mg once daily is recommended for ulcer healing and symptom relief. 2.3 Gastric Ulcer The recommended adult oral dose is 40 mg once daily for 4 to 8 weeks. 2.4 Gastroesophageal Reflux Disease (GERD) The recommended adult oral dose for the treatment of patients with symptomatic GERD and no esophageal lesions is 20 mg daily for up to 4 weeks. The recommended adult oral dose for the treatment of patients with erosive esophagitis and accompanying symptoms due to GERD is 20 mg daily for 4 to 8 weeks. 2.5 Maintenance of Healing of Erosive Esophagitis The recommended adult oral dose is 20 mg daily. Controlled studies do not extend beyond 12 months. [See Clinical Studies (14.4) ] 2.6 Pathological Hypersecretory Conditions The dosage of omeprazole delayed-release capsules in patients with pathological hypersecretory conditions varies with the individual patient. The recommended adult oral starting dose is 60 mg once daily. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Doses up to 120 mg three times daily have been administered. Daily dosages of greater than 80 mg should be administered in divided doses. Some patients with Zollinger-Ellison syndrome have been treated continuously with omeprazole delayed-release capsules for more than 5 years. 2.7 Pediatric Patients For the treatment of GERD and maintenance of healing of erosive esophagitis, the recommended daily dose for pediatric patients 2 to 16 years of age is as follows: Patient Weight Omeprazole Daily Dose 10 < 20 kg 10 mg ≥ 20 kg 20 mg On a per kg basis, the doses of omeprazole required to heal erosive esophagitis in pediatric patients are greater than those for adults. Alternative administrative options can be used for pediatric patients unable to swallow an intact capsule [See Dosage and Administration (2.8 ) ]. 2.8 Alternative Administration Options Omeprazole is available as a delayed-release capsule. For patients who have difficulty swallowing capsules, the contents of an omeprazole delayed-release capsule can be added to applesauce. One tablespoon of applesauce should be added to an empty bowl and the capsule should be opened. All of the pellets inside the capsule should be carefully emptied on the applesauce. The pellets should be mixed with the applesauce and then swallowed immediately with a glass of cool water to ensure complete swallowing of the pellets. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. The pellets should not be chewed or crushed. The pellets/applesauce mixture should not be stored for future use.
                                              • Clinical_pharmacology_table ::
                                                  • 0 :
                                                    Omeprazole 20 mg Omeprazole 40 mg
                                                    Parameter Max Min Max Min
                                                    % Decrease in Basal Acid Output 78* 58 to 80 94* 80 to 93
                                                    % Decrease in Peak Acid Output 79* 50 to 59 88* 62 to 68
                                                    % Decrease in 24–hr Intragastric Acidity 80 to 97 92 to 94
                                                    • 1 :
                                                      Tissue Clarithromycin Clarithromycin + Omeprazole
                                                      Antrum 10.48 ± 2.01 (n = 5) 19.96 ± 4.71 (n=5)
                                                      Fundus 20.81 ± 7.64 (n = 5) 24.25 ± 6.37 (n= 5)
                                                      Mucus 4.15 ± 7.74 (n = 4) 39.29 ± 32.79 (n=4)
                                                      • 2 :
                                                        Single or Repeated Oral Dosing /Parameter Children† ≤ 20 kg 2 to 5 years Children†> 20 kg 6 to 16 years Adults‡(mean 76 kg) 23 to 29 years(n=12)
                                                        10 mg 20 mg
                                                        Single Dosing
                                                        Cmax* (ng/mL) 288 (n=10) 495 (n=49) 668
                                                        AUC* (ng h/mL) 511 (n=7) 1140 (n=32) 1220
                                                        Repeated Dosing
                                                        Cmax* (ng/mL) 539 (n=4) 851 (n=32) 1458
                                                        AUC * (ng h/mL) 1179 (n=2) 2276 (n=23) 3352
                                                        • 3 :
                                                          Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomesa
                                                          Clarithromycin Pretreatment Results Clarithromycin Post-treatment Results
                                                          H. pylori negative – eradicated H. pylori positive – not eradicated Post-treatment susceptibility results
                                                          S b I b R b No MIC
                                                          Dual Therapy – (omeprazole 40 mg once daily/clarithromycin 500 three times daily for 14 days followed by omeprazole 20 mg once daily for another 14 days) (Studies 4,5)
                                                          Susceptible b 108 72 1 26 9
                                                          Intermediate b 1 1
                                                          Resistant b 4 4
                                                          Triple Therapy – (omeprazole 20 mg twice daily/clarithromycin 500 mg twice daily/amoxicillin 1 g twice daily for 10 days – Studies 1, 2,3; followed by omeprazole 20 mg once daily for another 18 days – Studies 1,2)
                                                          Susceptible b 171 153 7 3 8
                                                          Intermediate b
                                                          Resistant b 14 4 1 6 3
                                                      • Effective_time : 20150204
                                                        • Mechanism_of_action ::
                                                            • 0 : 12.1 Mechanism of Action Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, omeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Animal studies indicate that after rapid disappearance from plasma, omeprazole can be found within the gastric mucosa for a day or more.
                                                          • Geriatric_use ::
                                                              • 0 : 8.5 Geriatric Use Omeprazole was administered to over 2000 elderly individuals (≥ 65 years of age) in clinical trials in the U.S. and Europe. There were no differences in safety and effectiveness between the elderly and younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have shown the elimination rate was somewhat decreased in the elderly and bioavailability was increased. The plasma clearance of omeprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers. However, no dosage adjustment is necessary in the elderly. [See Clinical Pharmacology (12.3) ]
                                                            • Adverse_reactions ::
                                                                • 0 : 6 ADVERSE REACTIONS Adults: Most common adverse reactions (incidence >2%) are Headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence. (6) Pediatric patients (2 to 16 years of age): Safety profile similar to that in adults, except that respiratory system events and fever were the most frequently reported reactions in pediatric studies. (8.4) To report SUSPECTED ADVERSE REACTIONS, contact Dr. Reddy’s Laboratories Inc., at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience with Omeprazole Monotherapy Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below reflects exposure to omeprazole delayed-release capsules in 3096 patients from worldwide clinical trials (465 patients from US studies and 2,631 patients from international studies). Indications clinically studied in US trials included duodenal ulcer, resistant ulcer, and Zollinger-Ellison syndrome. The international clinical trials were double blind and open-label in design. The most common adverse reactions reported (i.e., with an incidence rate ≥ 2%) from omeprazole-treated patients enrolled in these studies included headache (6.9%), abdominal pain (5.2%), nausea (4%), diarrhea (3.7%), vomiting (3.2%), and flatulence (2.7%). Additional adverse reactions that were reported with an incidence ≥1% included acid regurgitation (1.9%), upper respiratory infection (1.9%), constipation (1.5%), dizziness (1.5%), rash (1.5%), asthenia (1.3%), back pain (1.1%), and cough (1.1%). The clinical trial safety profile in patients greater than 65 years of age was similar to that in patients 65 years of age or less. The clinical trial safety profile in pediatric patients who received omeprazole delayed-release capsules was similar to that in adult patients. Unique to the pediatric population, however, adverse reactions of the respiratory system were most frequently reported in the 2 to 16 year age group (18.5%). Similarly, accidental injuries were reported frequently in the 2 to 16 year age group (3.8%). [See Use in Specific Populations (8.4) ] 6.2 Clinical Trials Experience with Omeprazole in Combination Therapy for H. pylori Eradication In clinical trials using either dual therapy with omeprazole and clarithromycin, or triple therapy with omeprazole, clarithromycin, and amoxicillin, no adverse reactions unique to these drug combinations were observed. Adverse reactions observed were limited to those previously reported with omeprazole, clarithromycin, or amoxicillin alone. Dual Therapy (omeprazole/clarithromycin) Adverse reactions observed in controlled clinical trials using combination therapy with omeprazole and clarithromycin (n = 346) that differed from those previously described for omeprazole alone were taste perversion (15%), tongue discoloration (2%), rhinitis (2%), pharyngitis (1%) and flu-syndrome (1%). (For more information on clarithromycin, refer to the clarithromycin prescribing information, Adverse Reactions section). Triple Therapy (omeprazole/clarithromycin/amoxicillin) The most frequent adverse reactions observed in clinical trials using combination therapy with omeprazole, clarithromycin, and amoxicillin (n = 274) were diarrhea (14%), taste perversion (10%), and headache (7%). None of these occurred at a higher frequency than that reported by patients taking antimicrobial agents alone. (For more information on clarithromycin or amoxicillin, refer to the respective prescribing information, Adverse Reactions sections). 6.3 Post-marketing Experience The following adverse reactions have been identified during post-approval use of omeprazole delayed-release capsules. Because these reactions are voluntarily reported from a population of uncertain size, it is not always possible to reliably estimate their actual frequency or establish a causal relationship to drug exposure. Body As a Whole: Hypersensitivity reactions including anaphylaxis, anaphylactic shock, angioedema, bronchospasm, interstitial nephritis, urticaria, (see also Skin below); fever; pain; fatigue; malaise; Cardiovascular: Chest pain or angina, tachycardia, bradycardia, palpitations, elevated blood pressure, peripheral edema Endocrine: Gynecomastia Gastrointestinal: Pancreatitis (some fatal), anorexia, irritable colon, fecal discoloration, esophageal candidiasis, mucosal atrophy of the tongue, stomatitis, abdominal swelling, dry mouth, microscopic colitis. During treatment with omeprazole, gastric fundic gland polyps have been noted rarely. These polyps are benign and appear to be reversible when treatment is discontinued. Gastroduodenal carcinoids have been reported in patients with ZE syndrome on long-term treatment with omeprazole. This finding is believed to be a manifestation of the underlying condition, which is known to be associated with such tumors. Hepatic: Liver disease including hepatic failure (some fatal), liver necrosis (some fatal), hepatic encephalopathy hepatocellular disease, cholestatic disease, mixed hepatitis, jaundice, and elevations of liver function tests [ALT, AST, GGT, alkaline phosphatase, and bilirubin] Infections and Infestations: Clostridium difficile associated diarrhea Metabolism and Nutritional disorders: Hypoglycemia, hypomagnesemia, hyponatremia, weight gain Musculoskeletal: Muscle weakness, myalgia, muscle cramps, joint pain, leg pain, bone fracture Nervous System/Psychiatric: Psychiatric and sleep disturbances including depression, agitation, aggression, hallucinations, confusion, insomnia, nervousness, apathy, somnolence, anxiety, and dream abnormalities; tremors, paresthesia; vertigo Respiratory: Epistaxis, pharyngeal pain Skin: Severe generalized skin reactions including toxic epidermal necrolysis (some fatal), Stevens-Johnson syndrome, and erythema multiforme; photosensitivity; urticaria; rash; skin inflammation; pruritus; petechiae; purpura; alopecia; dry skin; hyperhidrosis Special Senses: Tinnitus, taste perversion Ocular: Optic atrophy, anterior ischemic optic neuropathy, optic neuritis, dry eye syndrome, ocular irritation, blurred vision, double vision Urogenital: Interstitial nephritis, hematuria, proteinuria, elevated serum creatinine, microscopic pyuria, urinary tract infection, glycosuria, urinary frequency, testicular pain Hematologic: Agranulocytosis (some fatal), hemolytic anemia, pancytopenia, neutropenia, anemia, thrombocytopenia, leukopenia, leucocytosis
                                                              • Clinical_pharmacology ::
                                                                  • 0 : 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Omeprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the H+/K+ ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the gastric mucosa, omeprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated acid secretion irrespective of the stimulus. Animal studies indicate that after rapid disappearance from plasma, omeprazole can be found within the gastric mucosa for a day or more. 12.2 Pharmacodynamics Antisecretory Activity After oral administration, the onset of the antisecretory effect of omeprazole occurs within one hour, with the maximum effect occurring within two hours. Inhibition of secretion is about 50% of maximum at 24 hours and the duration of inhibition lasts up to 72 hours. The antisecretory effect thus lasts far longer than would be expected from the very short (less than one hour) plasma half-life, apparently due to prolonged binding to the parietal H+/K+ ATPase enzyme. When the drug is discontinued, secretory activity returns gradually, over 3 to 5 days. The inhibitory effect of omeprazole on acid secretion increases with repeated once-daily dosing, reaching a plateau after four days. Results from numerous studies of the antisecretory effect of multiple doses of 20 mg and 40 mg of omeprazole in normal volunteers and patients are shown below. The “max” value represents determinations at a time of maximum effect (2 to 6 hours after dosing), while “min” values are those 24 hours after the last dose of omeprazole. Table 1 Range of Mean Values from Multiple Studies of the Mean Antisecretory Effects of Omeprazole After Multiple Daily Dosing Omeprazole 20 mg Omeprazole 40 mg Parameter Max Min Max Min % Decrease in Basal Acid Output 78* 58 to 80 94* 80 to 93 % Decrease in Peak Acid Output 79* 50 to 59 88* 62 to 68 % Decrease in 24–hr Intragastric Acidity 80 to 97 92 to 94 * Single Studies Single daily oral doses of omeprazole ranging from a dose of 10 mg to 40 mg have produced 100% inhibition of 24-hour intragastric acidity in some patients. Serum Gastrin Effects In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks of once-daily administration of therapeutic doses of omeprazole in parallel with inhibition of acid secretion. No further increase in serum gastrin occurred with continued treatment. In comparison with histamine H2-receptor antagonists, the median increases produced by 20 mg doses of omeprazole were higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold increase). Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy. Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors. Enterochromaffin-like (ECL) Cell Effects Human gastric biopsy specimens have been obtained from more than 3000 patients treated with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients. [See Clinical Pharmacology (12) ] However, these studies are of insufficient duration and size to rule out the possible influence of long-term administration of omeprazole on the development of any premalignant or malignant conditions. Other Effects Systemic effects of omeprazole in the CNS, cardiovascular and respiratory systems have not been found to date. Omeprazole, given in oral doses of 30 or 40 mg for 2 to 4 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin. No effect on gastric emptying of the solid and liquid components of a test meal was demonstrated after a single dose of omeprazole 90 mg. In healthy subjects, a single I.V. dose of omeprazole (0.35 mg/kg) had no effect on intrinsic factor secretion. No systematic dose-dependent effect has been observed on basal or stimulated pepsin output in humans. However, when intragastric pH is maintained at 4 or above, basal pepsin output is low, and pepsin activity is decreased. As do other agents that elevate intragastric pH, omeprazole administered for 14 days in healthy subjects produced a significant increase in the intragastric concentrations of viable bacteria. The pattern of the bacterial species was unchanged from that commonly found in saliva. All changes resolved within three days of stopping treatment. The course of Barrett’s esophagus in 106 patients was evaluated in a U.S. double-blind controlled study of omeprazole 40 mg twice daily for 12 months followed by 20 mg twice daily for 12 months or ranitidine 300 mg twice daily for 24 months. No clinically significant impact on Barrett’s mucosa by antisecretory therapy was observed. Although neosquamous epithelium developed during antisecretory therapy, complete elimination of Barrett’s mucosa was not achieved. No significant difference was observed between treatment groups in development of dysplasia in Barrett’s mucosa and no patient developed esophageal carcinoma during treatment. No significant differences between treatment groups were observed in development of ECL cell hyperplasia, corpus atrophic gastritis, corpus intestinal metaplasia, or colon polyps exceeding 3 mm in diameter [See Clinical Pharmacology (12) ]. 12.3 Pharmacokinetics Absorption Omeprazole delayed-release capsules contain an enteric-coated granule formulation of omeprazole (because omeprazole is acid-labile), so that absorption of omeprazole begins only after the granules leave the stomach. Absorption is rapid, with peak plasma levels of omeprazole occurring within 0.5 to 3.5 hours. Peak plasma concentrations of omeprazole and AUC are approximately proportional to doses up to 40 mg, but because of a saturable first-pass effect, a greater than linear response in peak plasma concentration and AUC occurs with doses greater than 40 mg. Absolute bioavailability (compared with intravenous administration) is about 30 to 40% at doses of 20 to 40 mg, due in large part to presystemic metabolism. In healthy subjects the plasma half-life is 0.5 to 1 hour, and the total body clearance is 500 to 600 mL/min. The bioavailability of omeprazole increases slightly upon repeated administration of omeprazole delayed-release capsules. Omeprazole delayed-release capsule 40 mg was bioequivalent when administered with and without applesauce. However, Omeprazole delayed-release capsule 20 mg was not bioequivalent when administered with and without applesauce. When administered with applesauce, a mean 25% reduction in Cmax was observed without a significant change in AUC for Omeprazole delayed-release capsule 20 mg. The clinical relevance of this finding is unknown. Distribution Protein binding is approximately 95%. Metabolism Omeprazole is extensively metabolized by the cytochrome P450 (CYP) enzyme system. Excretion Following single dose oral administration of a buffered solution of omeprazole, little if any unchanged drug was excreted in urine. The majority of the dose (about 77%) was eliminated in urine as at least six metabolites. Two were identified as hydroxyomeprazole and the corresponding carboxylic acid. The remainder of the dose was recoverable in feces. This implies a significant biliary excretion of the metabolites of omeprazole. Three metabolites have been identified in plasma — the sulfide and sulfone derivatives of omeprazole, and hydroxyomeprazole. These metabolites have very little or no antisecretory activity. Combination Therapy with Antimicrobials Omeprazole 40 mg daily was given in combination with clarithromycin 500 mg every 8 hours to healthy adult male subjects. The steady state plasma concentrations of omeprazole were increased (Cmax, AUC0-24, and T1/2 increases of 30%, 89% and 34% respectively) by the concomitant administration of clarithromycin. The observed increases in omeprazole plasma concentration were associated with the following pharmacological effects. The mean 24-hour gastric pH value was 5.2 when omeprazole was administered alone and 5.7 when co-administered with clarithromycin. The plasma levels of clarithromycin and 14-hydroxy-clarithromycin were increased by the concomitant administration of omeprazole. For clarithromycin, the mean Cmax was 10% greater, the mean Cmin was 27% greater, and the mean AUC0-8 was 15% greater when clarithromycin was administered with omeprazole than when clarithromycin was administered alone. Similar results were seen for 14-hydroxy-clarithromycin, the mean Cmax was 45% greater, the mean Cmin was 57% greater, and the mean AUC0-8 was 45% greater. Clarithromycin concentrations in the gastric tissue and mucus were also increased by concomitant administration of omeprazole. Table 2 Clarithromycin Tissue Concentrations 2 hours after Dose1 Tissue Clarithromycin Clarithromycin + Omeprazole Antrum 10.48 ± 2.01 (n = 5) 19.96 ± 4.71 (n=5) Fundus 20.81 ± 7.64 (n = 5) 24.25 ± 6.37 (n= 5) Mucus 4.15 ± 7.74 (n = 4) 39.29 ± 32.79 (n=4) 1mean ± SD (mcg/g) Concomitant Use with Clopidogrel In a crossover clinical study, 72 healthy subjects were administered clopidogrel (300 mg loading dose followed by 75 mg per day) alone and with omeprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when clopidogrel and omeprazole were administered together. Results from another crossover study in healthy subjects showed a similar pharmacokinetic interaction between clopidogrel (300 mg loading dose/75 mg daily maintenance dose) and omeprazole 80 mg daily when co-administered for 30 days. Exposure to the active metabolite of clopidogrel was reduced by 41% to 46% over this time period. In another study, 72 healthy subjects were given the same doses of clopidogrel and 80 mg omeprazole but the drugs were administered 12 hours apart; the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction. Concomitant Use with Mycophenolate Mofetil Administration of omeprazole 20 mg twice daily for 4 days and a single 1000 mg dose of MMF approximately one hour after the last dose of omeprazole to 12 healthy subjects in a cross-over study resulted in a 52% reduction in the Cmax and 23% reduction in the AUC of MPA. Special Populations Geriatric Population The elimination rate of omeprazole was somewhat decreased in the elderly, and bioavailability was increased. Omeprazole was 76% bioavailable when a single 40 mg oral dose of omeprazole (buffered solution) was administered to healthy elderly volunteers, versus 58% in young volunteers given the same dose. Nearly 70% of the dose was recovered in urine as metabolites of omeprazole and no unchanged drug was detected. The plasma clearance of omeprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers. Pediatric Use The pharmacokinetics of omeprazole have been investigated in pediatric patients 2 to 16 years of age: Table 3 Pharmacokinetic Parameters of Omeprazole Following Single and Repeated Oral Administration in Pediatric Populations Compared with Adults Single or Repeated Oral Dosing /Parameter Children† ≤ 20 kg 2 to 5 years Children†> 20 kg 6 to 16 years Adults‡(mean 76 kg) 23 to 29 years(n=12) 10 mg 20 mg Single Dosing Cmax* (ng/mL) 288 (n=10) 495 (n=49) 668 AUC* (ng h/mL) 511 (n=7) 1140 (n=32) 1220 Repeated Dosing Cmax* (ng/mL) 539 (n=4) 851 (n=32) 1458 AUC * (ng h/mL) 1179 (n=2) 2276 (n=23) 3352 Note: * = plasma concentration adjusted to an oral dose of 1 mg/kg. † Data from single and repeated dose studies ‡ Data from a single and repeated dose study Doses of 10, 20 and 40 mg omeprazole as enteric-coated granules Following comparable mg/kg doses of omeprazole, younger children (2 to 5 years of age) have lower AUCs than children 6 to16 years of age or adults; AUCs of the latter two groups did not differ. [See Dosage and Administration (2) ] Hepatic Impairment In patients with chronic hepatic disease, the bioavailability increased to approximately 100% compared with an I.V. dose, reflecting decreased first-pass effect, and the plasma half-life of the drug increased to nearly 3 hours compared with the half-life in normals of 0.5 to 1 hour. Plasma clearance averaged 70 mL/min, compared with a value of 500 to 600 mL/min in normal subjects. Dose reduction, particularly where maintenance of healing of erosive esophagitis is indicated, for the hepatically impaired should be considered. Renal Impairment In patients with chronic renal impairment, whose creatinine clearance ranged between 10 and 62 mL/min/1.73 m2, the disposition of omeprazole was very similar to that in healthy volunteers, although there was a slight increase in bioavailability. Because urinary excretion is a primary route of excretion of omeprazole metabolites, their elimination slowed in proportion to the decreased creatinine clearance. No dose reduction is necessary in patients with renal impairment. Asian Population In pharmacokinetic studies of single 20 mg omeprazole doses, an increase in AUC of approximately four-fold was noted in Asian subjects compared with Caucasians. Dose reduction, particularly where maintenance of healing of erosive esophagitis is indicated, for Asian subjects should be considered. 12.4 Microbiology Omeprazole and clarithromycin dual therapy and omeprazole, clarithromycin and amoxicillin triple therapy have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections as described in the Indications and Usage section 1.1 . Helicobacter Helicobacter pylori- Pretreatment Resistance Clarithromycin pretreatment resistance rates were 3.5% (4/113) in the omeprazole/clarithromycin dual therapy studies (4 and 5) and 9.3% (41/439) in omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2, and 3). Amoxicillin pretreatment susceptible isolates (≤ 0.25 mcg/mL) were found in 99.3% (436/439) of the patients in the omeprazole/clarithromycin/amoxicillin triple therapy studies (1, 2, and 3). Amoxicillin pretreatment minimum inhibitory concentrations (MICs) > 0.25 mcg/mL occurred in 0.7% (3/439) of the patients, all of whom were in the clarithromycin and amoxicillin study arm. One patient had an unconfirmed pretreatment amoxicillin minimum inhibitory concentration (MIC) of > 256 mcg/mL by Etest®. Table 4 Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomesa Clarithromycin Pretreatment Results Clarithromycin Post-treatment Results H. pylori negative – eradicated H. pylori positive – not eradicated Post-treatment susceptibility results S b I b R b No MIC Dual Therapy – (omeprazole 40 mg once daily/clarithromycin 500 three times daily for 14 days followed by omeprazole 20 mg once daily for another 14 days) (Studies 4,5) Susceptible b 108 72 1 26 9 Intermediate b 1 1 Resistant b 4 4 Triple Therapy – (omeprazole 20 mg twice daily/clarithromycin 500 mg twice daily/amoxicillin 1 g twice daily for 10 days – Studies 1, 2,3; followed by omeprazole 20 mg once daily for another 18 days – Studies 1,2) Susceptible b 171 153 7 3 8 Intermediate b Resistant b 14 4 1 6 3 a Includes only patients with pretreatment clarithromycin susceptibility test results b Susceptible (S) MIC ≤ 0.25 mcg/mL, Intermediate (I) MIC 0.5 to 1 mcg/mL, Resistant (R) MIC ≥ 2 mcg/mL Patients not eradicated of H. pylori following omeprazole/clarithromycin/amoxicillin triple therapy or omeprazole/clarithromycin dual therapy will likely have clarithromycin resistant H. pylori isolates. Therefore, clarithromycin susceptibility testing should be done, if possible. Patients with clarithromycin resistant H. pylori should not be treated with any of the following: omeprazole/clarithromycin dual therapy, omeprazole/clarithromycin/amoxicillin triple therapy, or other regimens which include clarithromycin as the sole antimicrobial agent. Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes In the triple therapy clinical trials, 84.9% (157/185) of the patients in the omeprazole/clarithromycin/amoxicillin treatment group who had pretreatment amoxicillin susceptible MICs (≤ 0.25 mcg/mL) were eradicated of H. pylori and 15.1% (28/185) failed therapy. Of the 28 patients who failed triple therapy, 11 had no post-treatment susceptibility test results and 17 had post-treatment H. pylori isolates with amoxicillin susceptible MICs. Eleven of the patients who failed triple therapy also had post-treatment H. pylori isolates with clarithromycin resistant MICs. Susceptibility Test for Helicobacter pylori For susceptibility testing information about Helicobacter pylori, see Microbiology section in prescribing information for clarithromycin and amoxicillin. Effects on Gastrointestinal Microbial Ecology Decreased gastric acidity due to any means including proton pump inhibitors, increases gastric counts of bacteria normally present in the gastrointestinal tract. Treatment with proton pump inhibitors may lead to slightly increased risk of gastrointestinal infections such as Salmonella and Campylobacter and, in hospitalized patients, possibly Clostridium difficile.
                                                                • Clinical_studies ::
                                                                    • 0 : 14 CLINICAL STUDIES 14.1 Duodenal Ulcer Disease Active Duodenal Ulcer— In a multicenter, double-blind, placebo-controlled study of 147 patients with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 2 and 4 weeks was significantly higher with omeprazole 20 mg once daily than with placebo (p ≤ 0.01). Treatment of Active Duodenal Ulcer % of Patients Healed Omeprazole 20 mg a.m. Placebo a.m. (n=99) (n=48) Week 2 *41 13 Week 4 *75 27 *(p ≤ 0.01) Complete daytime and nighttime pain relief occurred significantly faster (p ≤ 0.01) in patients treated with omeprazole 20 mg than in patients treated with placebo. At the end of the study, significantly more patients who had received omeprazole had complete relief of daytime pain (p ≤ 0.05) and nighttime pain (p ≤ 0.01). In a multicenter, double-blind study of 293 patients with endoscopically documented duodenal ulcer, the percentage of patients healed (per protocol) at 4 weeks was significantly higher with omeprazole 20 mg once daily than with ranitidine 150 mg b.i.d. (p < 0.01). Treatment of Active Duodenal Ulcer % of Patients Healed Omeprazole Ranitidine 20 mg a.m. 150 mg twice daily (n = 145) (n = 148) Week 2 42 34 Week 4 *82 63 *(p < 0.01) Healing occurred significantly faster in patients treated with omeprazole than in those treated with ranitidine 150 mg b.i.d. (p < 0.01). In a foreign multinational randomized, double-blind study of 105 patients with endoscopically documented duodenal ulcer, 20 mg and 40 mg of omeprazole were compared with 150 mg b.i.d. of ranitidine at 2, 4 and 8 weeks. At 2 and 4 weeks both doses of omeprazole were statistically superior (per protocol) to ranitidine, but 40 mg was not superior to 20 mg of omeprazole, and at 8 weeks there was no significant difference between any of the active drugs. Treatment of Active Duodenal Ulcer % of Patients Healed Omeprazole Ranitidine 20 mg (n=34) 40 mg (n=36) 150 mg twice daily (n=35) Week 2 *83 *83 53 Week 4 *97 *100 82 Week 8 100 100 94 *(p ≤ 0.01) H. pylori Eradication in Patients with Duodenal Ulcer Disease Triple Therapy(omeprazole/clarithromycin/amoxicillin)— Three U.S., randomized, double-blind clinical studies in patients with H. pylori infection and duodenal ulcer disease (n=558) compared omeprazole plus clarithromycin plus amoxicillin with clarithromycin plus amoxicillin. Two studies (1 and 2) were conducted in patients with an active duodenal ulcer, and the other study (3) was conducted in patients with a history of a duodenal ulcer in the past 5 years but without an ulcer present at the time of enrollment. The dose regimen in the studies was omeprazole 20 mg twice daily plus clarithromycin 500 mg twice daily plus amoxicillin 1 g twice daily for 10 days; or clarithromycin 500 mg twice daily, plus amoxicillin 1 g twice daily for 10 days. In studies 1 and 2, patients who took the omeprazole regimen also received an additional 18 days of omeprazole 20 mg once daily. Endpoints studied were eradication of H. pylori and duodenal ulcer healing (studies 1 and 2 only). H. pylori status was determined by CLOtest®, histology and culture in all three studies. For a given patient, H. pylori was considered eradicated if at least two of these tests were negative, and none was positive. The combination of omeprazole plus clarithromycin plus amoxicillin was effective in eradicating H. pylori. Table 5 Per-Protocol and Intent-to-Treat H. pylori Eradication Rates % of Patients Cured [95% Confidence Interval] Omeprazole +clarithromycin+amoxicillin Clarithromycin +amoxicillin Per-Protocol † Intent-to-Treat ‡ Per-Protocol † Intent-to-Treat ‡ Study 1 *77 [64, 86] *69 [57, 79] 43 [31, 56] 37 [27, 48] (n = 64) (n = 80) (n = 67) (n = 84) Study 2 *78 [67, 88] *73 [61, 82] 41 [29, 54] 36 [26, 47] (n = 65) (n = 77) (n = 68) (n = 83) Study 3 *90 [80, 96] *83 [74, 91] 33 [24, 44] 32 [23, 42] (n = 69) (n = 84) (n = 93) (n = 99) † Patients were included in the analysis if they had confirmed duodenal ulcer disease (active ulcer, studies 1 and 2; history of ulcer within 5 years, study 3) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest®, histology, and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy. The impact of eradication on ulcer recurrence has not been assessed in patients with a past history of ulcer. ‡ Patients were included in the analysis if they had documented H. pylori infection at baseline and had confirmed duodenal ulcer disease. All dropouts were included as failures of therapy. *(p < 0.05) versus clarithromycin plus amoxicillin. Dual Therapy (omeprazole /clarithromycin) Four randomized, double-blind, multi-center studies (4, 5, 6, and 7) evaluated omeprazole 40 mg once daily plus clarithromycin 500 mg three times daily for 14 days, followed by omeprazole 20 mg once daily, (studies 4, 5, and 7) or by omeprazole 40 mg once daily (Study 6) for an additional 14 days in patients with active duodenal ulcer associated with H. pylori. Studies 4 and 5 were conducted in the U.S. and Canada and enrolled 242 and 256 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 219 patients in Study 4 and 228 patients in Study 5. These studies compared the combination regimen to omeprazole and clarithromycin monotherapies. Studies 6 and 7 were conducted in Europe and enrolled 154 and 215 patients, respectively. H. pylori infection and duodenal ulcer were confirmed in 148 patients in Study 6 and 208 patients in Study 7. These studies compared the combination regimen with omeprazole monotherapy. The results for the efficacy analyses for these studies are described below. H. pylori eradication was defined as no positive test (culture or histology) at 4 weeks following the end of treatment, and two negative tests were required to be considered eradicated of H. pylori. In the per-protocol analysis, the following patients were excluded: dropouts, patients with missing H. pylori tests post-treatment, and patients that were not assessed for H. pylori eradication because they were found to have an ulcer at the end of treatment. The combination of omeprazole and clarithromycin was effective in eradicating H. pylori. Table 6 H. pylori Eradication Rates (Per-Protocol Analysis at 4 to 6 Weeks) % of Patients Cured [95% Confidence Interval] Omeprazole+Clarithromycin Omeprazole Clarithromycin U.S. Studies Study 4 74 [60, 85] †‡ 0 [0, 7] 31 [18, 47] (n = 53) (n=54) (n = 42) Study 5 64 [51, 76] †‡ 0 [0, 6] 39 [24, 55] (n = 61) (n = 59) (n = 44) Non U.S. Studies Study 6 83 [71, 92] ‡ 1 [0, 7] N/A (n = 60) (n = 74) Study 7 74 [64, 83] ‡ 1 [0,6] N/A † Statistically significantly higher than clarithromycin monotherapy (p < 0.05) ‡ Statistically significantly higher than omeprazole monotherapy (p < 0.05) Ulcer healing was not significantly different when clarithromycin was added to omeprazole therapy compared with omeprazole therapy alone. The combination of omeprazole and clarithromycin was effective in eradicating H. pylori and reduced duodenal ulcer recurrence. Table 7 Duodenal Ulcer Recurrence Rates by H. pylori Eradication Status % of Patients with Ulcer Recurrence H. pylori eradicated# H. pylori not eradicated# U.S. Studies † 6 months post-treatment Study 4 *35 60 (n = 49) (n = 88) Study 5 *8 60 (n = 53) (n = 106) Non U.S. Studies ‡ 6 months post-treatment Study 6 *5 46 (n=43) (n=78) Study 7 *6 43 (n=53) (n=107) 12 months post-treatment Study 6 *5 68 (n=39) (n=71) # H. pylori eradication status assessed at same time point as ulcer recurrence † Combined results for omeprazole + clarithromycin, omeprazole, and clarithromycin treatment arms ‡ Combined results for omeprazole + clarithromycin and omeprazole treatment arms * (p ≤ 0.01) versus proportion with duodenal ulcer recurrence who were not H. pylori eradicated 14.2 Gastric Ulcer In a U.S. multicenter, double-blind, study of omeprazole 40 mg once daily, 20 mg once daily, and placebo in 520 patients with endoscopically diagnosed gastric ulcer, the following results were obtained. Treatment of Gastric Ulcer % of Patients Healed (All Patients Treated) Omeprazole Omeprazole 20 mg once daily 40 mg once daily Placebo (n=202) (n=214) (n=104) Week 4 47.5 ** 55.6 ** 30.8 Week 8 74.8 ** 82.7 **,+ 48.1 **(p < 0.01) omeprazole 40 mg or 20 mg versus placebo +(p < 0.05) omeprazole 40 mg versus 20 mg For the stratified groups of patients with ulcer size less than or equal to 1 cm, no difference in healing rates between 40 mg and 20 mg was detected at either 4 or 8 weeks. For patients with ulcer size greater than 1 cm, 40 mg was significantly more effective than 20 mg at 8 weeks. In a foreign, multinational, double-blind study of 602 patients with endoscopically diagnosed gastric ulcer, omeprazole 40 mg once daily, 20 mg once daily, and ranitidine 150 mg twice a day were evaluated. Treatment of Gastric Ulcer % of Patients Healed (All Patients Treated) Omeprazole Omeprazole Ranitidine 20 mg once daily 40 mg once daily 150 twice daily (n=200) (n=187) (n=199) Week 4 63.5 78.1**,++ 56.3 Week 8 81.5 91.4 **,++ 78.4 ** (p < 0.01) omeprazole 40 mg versus ranitidine ++ (p < 0.01) omerpazole 40 mg versus 20 mg 14.3 Gastroesophageal Reflux Disease (GERD) Symptomatic GERD A placebo-controlled study was conducted in Scandinavia to compare the efficacy of omeprazole 20 mg or 10 mg once daily for up to 4 weeks in the treatment of heartburn and other symptoms in GERD patients without erosive esophagitis. Results are shown below. % Successful Symptomatic Outcomea Omeprazole Omeprazole Placebo 20 mg a.m. 10 mg a.m. a.m. All patients 46*,† 31† 13 (n=205) (n=199) (n=105) Patients with confirmed GERD 56*,† 36† 14 (n=115) (n=109) (n=59) a Defined as complete resolution of heartburn *(p < 0.005) versus 10 mg †(p < 0.005) versus placebo 14.4 Erosive Esophagitis In a U.S. multicenter double-blind placebo controlled study of 20 mg or 40 mg of omeprazole delayed-release capsules in patients with symptoms of GERD and endoscopically diagnosed erosive esophagitis of grade 2 or above, the percentage healing rates (per protocol) were as follows: Week 20 mg Omeprazole 40 mg Omeprazole Placebo (n=83) (n=87) (n=43) 4 39** 45** 7 8 74** 75** 14 **(p < 0.01) omeprazole versus placebo In this study, the 40 mg dose was not superior to the 20 mg dose of omeprazole in the percentage healing rate. Other controlled clinical trials have also shown that omeprazole is effective in severe GERD. In comparisons with histamine H2-receptor antagonists in patients with erosive esophagitis, grade 2 or above, omeprazole in a dose of 20 mg was significantly more effective than the active controls. Complete daytime and nighttime heartburn relief occurred significantly faster (p < 0.01) in patients treated with omeprazole than in those taking placebo or histamine H2- receptor antagonists. In this and five other controlled GERD studies, significantly more patients taking 20 mg omeprazole (84%) reported complete relief of GERD symptoms than patients receiving placebo (12%). Long Term Maintenance of Healing of Erosive Esophagitis In a U.S. double-blind, randomized, multicenter, placebo controlled study, two dose regimens of omeprazole were studied in patients with endoscopically confirmed healed esophagitis. Results to determine maintenance of healing of erosive esophagitis are shown below. Life Table Analysis Omeprazole Omeprazole 20 mg once daily 20 mg 3 days per week Placebo (n=138) (n = 137) (n = 131) Percent in endoscopic remission at 6 months *70 34 11 *(p < 0.01) omeprazole 20 mg once daily versus omeprazole 20 mg 3 consecutive days per week or placebo. In an international multicenter double-blind study, omeprazole 20 mg daily and 10 mg daily were compared with ranitidine 150 mg twice daily in patients with endoscopically confirmed healed esophagitis. The table below provides the results of this study for maintenance of healing of erosive esophagitis. Life Table Analysis Omeprazole Omeprazole Ranitidine 20 mg once daily 10 mg once daily 150 mg twice daily (n=131) (n = 133) (n = 128) Percent in endoscopic remission at 12 months *77 ‡58 46 * (p = 0.01) omeprazole 20 mg once daily. versus omeprazole 10 mg once daily or ranitidine. ‡ (p = 0.03) omepazole 10 mg once daily. versus ranitidine. In patients who initially had grades 3 or 4 erosive esophagitis, for maintenance after healing 20 mg daily of omeprazole was effective, while 10 mg did not demonstrate effectiveness. 14.5 Pathological Hypersecretory Conditions In open studies of 136 patients with pathological hypersecretory conditions, such as Zollinger-Ellison (ZE) syndrome with or without multiple endocrine adenomas, omeprazole delayed-release capsules significantly inhibited gastric acid secretion and controlled associated symptoms of diarrhea, anorexia, and pain. Doses ranging from 20 mg every other day to 360 mg per day maintained basal acid secretion below 10 mEq/hr in patients without prior gastric surgery, and below 5 mEq/hr in patients with prior gastric surgery. Initial doses were titrated to the individual patient need, and adjustments were necessary with time in some patients [See D osage and Administration (2) ]. Omeprazole was well tolerated at these high dose levels for prolonged periods (> 5 years in some patients). In most ZE patients, serum gastrin levels were not modified by omeprazole. However, in some patients serum gastrin increased to levels greater than those present prior to initiation of omeprazole therapy. At least 11 patients with ZE syndrome on long-term treatment with omeprazole developed gastric carcinoids. These findings are believed to be a manifestation of the underlying condition, which is known to be associated with such tumors, rather than the result of the administration of omeprazole. [See Adverse Reactions (6) ] 14.6 Pediatric GERD Symptomatic GERD The effectiveness of omeprazole for the treatment of nonerosive GERD in pediatric patients 2 to 16 years of age is based in part on data obtained from 125 pediatric patients in an uncontrolled Phase III study. [See Use in Specific Populations (8.4) ] The study enrolled 113 pediatric patients 2 to 16 years of age with a history of symptoms suggestive of nonerosive GERD. Patients were administered a single dose of omeprazole (10 mg or 20 mg, based on body weight) for 4 weeks either as an intact capsule or as an open capsule in applesauce. Successful response was defined as no moderate or severe episodes of either pain-related symptoms or vomiting/regurgitation during the last 4 days of treatment. Results showed success rates of 60% (9/15; 10 mg omeprazole) and 59% (58/98; 20 mg omeprazole), respectively. Healing of Erosive Esophagitis In an uncontrolled, open-label dose-titration study, healing of erosive esophagitis in pediatric patients 1 to 16 years of age required doses that ranged from 0.7 to 3.5 mg/kg/day (80 mg/day). Doses were initiated at 0.7 mg/kg/day. Doses were increased in increments of 0.7 mg/kg/day (if intraesophageal pH showed a pH of < 4 for less than 6% of a 24-hour study). After titration, patients remained on treatment for 3 months. Forty-four percent of the patients were healed on a dose of 0.7 mg/kg body weight; most of the remaining patients were healed with 1.4 mg/kg after an additional 3 months’ treatment. Erosive esophagitis was healed in 51 of 57 (90%) children who completed the first course of treatment in the healing phase of the study. In addition, after 3 months of treatment, 33% of the children had no overall symptoms, 57% had mild reflux symptoms, and 40% had less frequent regurgitation/vomiting. Maintenance of Healing of Erosive Esophagitis In an uncontrolled, open-label study of maintenance of healing of erosive esophagitis in 46 pediatric patients, 54% of patients required half the healing dose. The remaining patients increased the healing dose (0.7 to a maximum of 2.8 mg/kg/day) either for the entire maintenance period, or returned to half the dose before completion. Of the 46 patients who entered the maintenance phase, 19 (41%) had no relapse. In addition, maintenance therapy in erosive esophagitis patients resulted in 63% of patients having no overall symptoms.
                                                                  • Use_in_specific_populations ::
                                                                      • 0 : 8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data may cause fetal harm (8.1) Patients with hepatic impairment: Consider dose reduction, particularly for maintenance of healing erosive esophagitis (12.3) 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies with omeprazole in pregnant women. Available epidemiologic data fail to demonstrate an increased risk of major congenital malformations or other adverse pregnancy outcomes with first trimester omeprazole use. Teratogenicity was not observed in animal reproduction studies with administration of oral esomeprazole magnesium in rats and rabbits with doses about 68 times and 42 times, respectively, an oral human dose of 40 mg (based on a body surface area basis for a 60 kg person). However, changes in bone morphology were observed in offspring of rats dosed through most of pregnancy and lactation at doses equal to or greater than approximately 34 times an oral human dose of 40 mg (see Animal Data). Because of the observed effect at high doses of esomeprazole magnesium on developing bone in rat studies, omeprazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Human Data Four published epidemiological studies compared the frequency of congenital abnormalities among infants born to women who used omeprazole during pregnancy with the frequency of abnormalities among infants of women exposed to H2-receptor antagonists or other controls. A population-based retrospective cohort epidemiological study from the Swedish Medical Birth Registry, covering approximately 99% of pregnancies, from 1995-99, reported on 955 infants (824 exposed during the first trimester with 39 of these exposed beyond first trimester, and 131 exposed after the first trimester) whose mothers used omeprazole during pregnancy. The number of infants exposed in utero to omeprazole that had any malformation, low birth weight, low Apgar score, or hospitalization was similar to the number observed in this population. The number of infants born with ventricular septal defects and the number of stillborn infants was slightly higher in the omeprazole-exposed infants than the expected number in this population. A population-based retrospective cohort study covering all live births in Denmark from 1996-2009, reported on 1,800 live births whose mothers used omeprazole during the first trimester of pregnancy and 837,317 live births whose mothers did not use any proton pump inhibitor. The overall rate of birth defects in infants born to mothers with first trimester exposure to omeprazole was 2.9% and 2.6% in infants born to mothers not exposed to any proton pump inhibitor during the first trimester. A retrospective cohort study reported on 689 pregnant women exposed to either H2-blockers or omeprazole in the first trimester (134 exposed to omeprazole) and 1,572 pregnant women unexposed to either during the first trimester. The overall malformation rate in offspring born to mothers with first trimester exposure to omeprazole, an H2-blocker, or were unexposed was 3.6%, 5.5% and 4.1% respectively. A small prospective observational cohort study followed 113 women exposed to omeprazole during pregnancy (89% first trimester exposures). The reported rates of major congenital malformations was 4% for the omeprazole group, 2% for controls exposed to non-teratogens, and 2.8% in disease-paired controls. Rates of spontaneous and elective abortions, preterm deliveries, gestational age at delivery, and mean birth weight were similar among the groups. Several studies have reported no apparent adverse short-term effects on the infant when single dose oral or intravenous omeprazole was administered to over 200 pregnant women as premedication for cesarean section under general anesthesia. Animal Data Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis) did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 3.4 to 34 times an oral human dose of 40 mg on a body surface area basis) produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138 mg/kg/day (about 3.4 to 34 times an oral human doses of 40 mg on a body surface area basis). Reproduction studies have been performed with esomeprazole magnesium in rats at oral doses up to 280 mg/kg/day (about 68 times an oral human dose of 40 mg on a body surface area basis) and in rabbits at oral doses up to 86 mg/kg/day (about 42 times an oral human dose of 40 mg on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to esomeprazole magnesium. A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with esomeprazole magnesium at oral doses of 14 to 280 mg/kg/day (about 3.4 to 68 times an oral human dose of 40 mg on a body surface area basis). Neonatal/early postnatal (birth to weaning) survival was decreased at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). Body weight and body weight gain were reduced and neurobehavioral or general developmental delays in the immediate postweaning timeframe were evident at doses equal to or greater than 69 mg /kg/day (about 17 times an oral human dose of 40 mg on a body surface area basis). In addition, decreased femur length, width and thickness of cortical bone, decreased thickness of the tibial growth plate and minimal to mild bone marrow hypocellularity were noted at doses equal to or greater than 14 mg/kg/day (about 3.4 times an oral human dose of 40 mg on a body surface area basis). Physeal dysplasia in the femur was observed in offspring of rats treated with oral doses of esomeprazole magnesium at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). Effects onmaternal bone were observed in pregnant and lactating rats in the pre- and postnatal toxicity study when esomeprazole magnesiumwas administered at oral doses of 14 to 280 mg /kg/day (about 3.4 to 68 times an oral human dose of 40 mg on a body surface area basis). When rats were dosed from gestational day 7 through weaning on postnatal day 21, a statistically significant decrease in maternal femur weight of up to 14% (as compared to placebo treatment) was observed at doses equal to or greater than 138 mg/kg/day (about 34 times an oral human dose of 40 mg on a body surface area basis). A pre- and postnatal development study in rats with esomeprazole strontium (using equimolar doses compared to esomeprazole magnesium study) produced similar results in dams and pups as described above. 8.3 Nursing Mothers Omeprazole is present in human milk. Omeprazole concentrations were measured in breast milk of a woman following oral administration of 20 mg. The peak concentration of omeprazole in breast milk was less than 7% of the peak serum concentration. This concentration would correspond to 0.004 mg of omperazole in 200 mL of milk. Caution should be exercised when omperazole is administered to a nursing woman. 8.4 Pediatric Use Use of omeprazole in pediatric and adolescent patients 2 to 16 years of age for the treatment of GERD and maintenance of healing of erosive esophagitis is supported by a) extrapolation of results from adequate and well-controlled studies that supported the approval of omeprazole for adults, and b) safety and pharmacokinetic studies performed in pediatric and adolescent patients. [See Clinical Pharmacology, Pharmacokinetics, Pediatric for pharmacokinetic information (12.3) and Dosage and Administration (2) . Adverse Reactions (6.1) and Clinical Studies (14.6) ]. The safety and effectiveness of omeprazole for the treatment of GERD in patients < 1 year of age have not been established. The safety and effectiveness of omeprazole for other pediatric uses have not been established. Juvenile Animal Data In a juvenile rat toxicity study, esomeprazole was administered with both magnesium and strontium salts at oral doses about 34 to 57 times a daily human dose of 40 mg based on body surface area. Increases in death were seen at the high dose, and at all doses of esomeprazole, there were decreases in body weight, body weight gain, femur weight and femur length, and decreases in overall growth [see Nonclinical Toxicology ( 13.2 )]. 8.5 Geriatric Use Omeprazole was administered to over 2000 elderly individuals (≥ 65 years of age) in clinical trials in the U.S. and Europe. There were no differences in safety and effectiveness between the elderly and younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger subjects, but greater sensitivity of some older individuals cannot be ruled out. Pharmacokinetic studies have shown the elimination rate was somewhat decreased in the elderly and bioavailability was increased. The plasma clearance of omeprazole was 250 mL/min (about half that of young volunteers) and its plasma half-life averaged one hour, about twice that of young healthy volunteers. However, no dosage adjustment is necessary in the elderly. [See Clinical Pharmacology (12.3) ] 8.6 Hepatic Impairment Consider dose reduction, particularly for maintenance of healing of erosive esophagitis. [See Clinical Pharmacology (12.3) ] 8.7 Renal Impairment No dosage reduction is necessary. [See Clinical Pharmacology (12.3) ] 8.8 Asian Population Consider dose reduction, particularly for maintenance of healing of erosive esophagitis. [See Clinical Pharmacology (12.3) ]
                                                                    • Nonclinical_toxicology ::
                                                                        • 0 : 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility In two 24-month carcinogenicity studies in rats, omeprazole at daily doses of 1.7, 3.4, 13.8, 44 and 140.8 mg/kg/day (about 0.4 to 34 times a human dose of 40 mg/day, as expressed on a body surface area basis) produced gastric ECL cell carcinoids in a dose-related manner in both male and female rats; the incidence of this effect was markedly higher in female rats, which had higher blood levels of omeprazole. Gastric carcinoids seldom occur in the untreated rat. In addition, ECL cell hyperplasia was present in all treated groups of both sexes. In one of these studies, female rats were treated with 13.8 mg omeprazole/kg/day (about 3.4 times a human dose of 40 mg/day, based on body surface area) for one year, and then followed for an additional year without the drug. No carcinoids were seen in these rats. An increased incidence of treatment-related ECL cell hyperplasia was observed at the end of one year (94% treated vs 10% controls). By the second year the difference between treated and control rats was much smaller (46% vs 26%) but still showed more hyperplasia in the treated group. Gastric adenocarcinoma was seen in one rat (2%). No similar tumor was seen in male or female rats treated for two years. For this strain of rat no similar tumor has been noted historically, but a finding involving only one tumor is difficult to interpret. In a 52-week toxicity study in Sprague-Dawley rats, brain astrocytomas were found in a small number of males that received omeprazole at dose levels of 0.4, 2, and 16 mg/kg/day (about 0.1 to 3.9 times the human dose of 40 mg/day, based on a body surface area basis). No astrocytomas were observed in female rats in this study. In a 2-year carcinogenicity study in Sprague-Dawley rats, no astrocytomas were found in males or females at the high dose of 140.8 mg/kg/day (about 34 times the human dose of 40 mg/day on a body surface area basis). A 78-week mouse carcinogenicity study of omeprazole did not show increased tumor occurrence, but the study was not conclusive. A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive. Omeprazole was positive for clastogenic effects in an in vitro human lymphocyte chromosomal aberration assay, in one of two in vivo mouse micronucleus tests, and in an in vivo bone marrow cell chromosomal aberration assay. Omeprazole was negative in the in vitro Ames test, an in vitro mouse lymphoma cell forward mutation assay, and an in vivo rat liver DNA damage assay. Omeprazole at oral doses up to 138 mg/kg/day in rats (about 34 times an oral human dose of 40 mg on a body surface area basis) was found to have no effect on fertility and reproductive performance. In 24-month carcinogenicity studies in rats, a dose-related significant increase in gastric carcinoid tumors and ECL cell hyperplasia was observed in both male and female animals [See Warnings and Precautions (5) ] Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with other proton pump inhibitors or high doses of H2-receptor antagonists. 13.2 Animal Toxicology and/or Pharmacology Reproduction Studies Reproductive Toxicology Studies Reproductive studies conducted with omeprazole in rats at oral doses up to 138 mg/kg/day (about 34 times the human dose of 40 mg/day on a body surface area basis) and in rabbits at doses up to 69 mg/kg/day (about 34 times the human dose on a body surface area basis) did not disclose any evidence for a teratogenic potential of omeprazole. In rabbits, omeprazole in a dose range of 6.9 to 69.1 mg/kg/day (about 3.4 to 34 times the human dose of 40 mg/day on a body surface area basis) produced dose-related increases in embryo-lethality, fetal resorptions, and pregnancy disruptions. In rats, dose-related embryo/fetal toxicity and postnatal developmental toxicity were observed in offspring resulting from parents treated with omeprazole at 13.8 to 138 mg/kg/day (about 3.4 to 34 times the human dose of 40 mg/day on a body surface area basis) [see Pregnancy, Animal Data ( 8.1 )]. Juvenile Animal Study A 28-day toxicity study with a 14-day recovery phase was conducted in juvenile rats with esomeprazole magnesium at doses of 70 to 280 mg /kg/day (about 17 to 68 times a daily oral human dose of 40 mg on a body surface area basis). An increase in the number of deaths at the high dose of 280 mg /kg/day was observed when juvenile rats were administered esomeprazole magnesium from postnatal day 7 through postnatal day 35. In addition, doses equal to or greater than 140 mg/kg/day (about 34 times a daily oral human dose of 40 mg on a body surface area basis), produced treatment-related decreases in body weight (approximately 14%) and body weight gain, decreases in femur weight and femur length, and affected overall growth. Comparable findings described above have also been observed in this study with another esomeprazole salt, esomeprazole strontium, at equimolar doses of esomeprazole.
                                                                      • Spl_product_data_elements ::
                                                                          • 0 : Omeprazole Omeprazole Omeprazole omeprazole crospovidone hypromelloses magnesium stearate mannitol meglumine methacrylic acid - ethyl acrylate copolymer (1:1) type A shellac poloxamer 407 povidone triethyl citrate D&C Red No. 28 FD&C Blue No. 1 FD&C Red No. 40 FD&C Yellow No. 6 ferric oxide yellow gelatin silicon dioxide sodium lauryl sulfate titanium dioxide butyl alcohol propylene glycol off-white to pale yellow Omepraole;20mg;R158 container1 carton1 container2 carton2 container3 carton3 structure DContainer DCarton
                                                                        • Overdosage ::
                                                                            • 0 : 10 OVERDOSAGE Reports have been received of overdosage with omeprazole in humans. Doses ranged up to 2400 mg (120 times the usual recommended clinical dose). Manifestations were variable, but included confusion, drowsiness, blurred vision, tachycardia, nausea, vomiting, diaphoresis, flushing, headache, dry mouth, and other adverse reactions similar to those seen in normal clinical experience. [See Adverse Reactions (6) ] Symptoms were transient, and no serious clinical outcome has been reported when omeprazole was taken alone. No specific antidote for omeprazole overdosage is known. Omeprazole is extensively protein bound and is, therefore, not readily dialyzable. In the event of overdosage, treatment should be symptomatic and supportive. As with the management of any overdose, the possibility of multiple drug ingestion should be considered. For current information on treatment of any drug overdose, contact your local Poison Control Center. Single oral doses of omeprazole at 1350, 1339, and 1200 mg/kg were lethal to mice, rats, and dogs, respectively. Animals given these doses showed sedation, ptosis, tremors, convulsions, and decreased activity, body temperature, and respiratory rate and increased depth of respiration.
                                                                          • Pharmacodynamics ::
                                                                              • 0 : 12.2 Pharmacodynamics Antisecretory Activity After oral administration, the onset of the antisecretory effect of omeprazole occurs within one hour, with the maximum effect occurring within two hours. Inhibition of secretion is about 50% of maximum at 24 hours and the duration of inhibition lasts up to 72 hours. The antisecretory effect thus lasts far longer than would be expected from the very short (less than one hour) plasma half-life, apparently due to prolonged binding to the parietal H+/K+ ATPase enzyme. When the drug is discontinued, secretory activity returns gradually, over 3 to 5 days. The inhibitory effect of omeprazole on acid secretion increases with repeated once-daily dosing, reaching a plateau after four days. Results from numerous studies of the antisecretory effect of multiple doses of 20 mg and 40 mg of omeprazole in normal volunteers and patients are shown below. The “max” value represents determinations at a time of maximum effect (2 to 6 hours after dosing), while “min” values are those 24 hours after the last dose of omeprazole. Table 1 Range of Mean Values from Multiple Studies of the Mean Antisecretory Effects of Omeprazole After Multiple Daily Dosing Omeprazole 20 mg Omeprazole 40 mg Parameter Max Min Max Min % Decrease in Basal Acid Output 78* 58 to 80 94* 80 to 93 % Decrease in Peak Acid Output 79* 50 to 59 88* 62 to 68 % Decrease in 24–hr Intragastric Acidity 80 to 97 92 to 94 * Single Studies Single daily oral doses of omeprazole ranging from a dose of 10 mg to 40 mg have produced 100% inhibition of 24-hour intragastric acidity in some patients. Serum Gastrin Effects In studies involving more than 200 patients, serum gastrin levels increased during the first 1 to 2 weeks of once-daily administration of therapeutic doses of omeprazole in parallel with inhibition of acid secretion. No further increase in serum gastrin occurred with continued treatment. In comparison with histamine H2-receptor antagonists, the median increases produced by 20 mg doses of omeprazole were higher (1.3 to 3.6 fold vs. 1.1 to 1.8 fold increase). Gastrin values returned to pretreatment levels, usually within 1 to 2 weeks after discontinuation of therapy. Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum Chromogranin A (CgA) levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors. Enterochromaffin-like (ECL) Cell Effects Human gastric biopsy specimens have been obtained from more than 3000 patients treated with omeprazole in long-term clinical trials. The incidence of ECL cell hyperplasia in these studies increased with time; however, no case of ECL cell carcinoids, dysplasia, or neoplasia has been found in these patients. [See Clinical Pharmacology (12) ] However, these studies are of insufficient duration and size to rule out the possible influence of long-term administration of omeprazole on the development of any premalignant or malignant conditions. Other Effects Systemic effects of omeprazole in the CNS, cardiovascular and respiratory systems have not been found to date. Omeprazole, given in oral doses of 30 or 40 mg for 2 to 4 weeks, had no effect on thyroid function, carbohydrate metabolism, or circulating levels of parathyroid hormone, cortisol, estradiol, testosterone, prolactin, cholecystokinin or secretin. No effect on gastric emptying of the solid and liquid components of a test meal was demonstrated after a single dose of omeprazole 90 mg. In healthy subjects, a single I.V. dose of omeprazole (0.35 mg/kg) had no effect on intrinsic factor secretion. No systematic dose-dependent effect has been observed on basal or stimulated pepsin output in humans. However, when intragastric pH is maintained at 4 or above, basal pepsin output is low, and pepsin activity is decreased. As do other agents that elevate intragastric pH, omeprazole administered for 14 days in healthy subjects produced a significant increase in the intragastric concentrations of viable bacteria. The pattern of the bacterial species was unchanged from that commonly found in saliva. All changes resolved within three days of stopping treatment. The course of Barrett’s esophagus in 106 patients was evaluated in a U.S. double-blind controlled study of omeprazole 40 mg twice daily for 12 months followed by 20 mg twice daily for 12 months or ranitidine 300 mg twice daily for 24 months. No clinically significant impact on Barrett’s mucosa by antisecretory therapy was observed. Although neosquamous epithelium developed during antisecretory therapy, complete elimination of Barrett’s mucosa was not achieved. No significant difference was observed between treatment groups in development of dysplasia in Barrett’s mucosa and no patient developed esophageal carcinoma during treatment. No significant differences between treatment groups were observed in development of ECL cell hyperplasia, corpus atrophic gastritis, corpus intestinal metaplasia, or colon polyps exceeding 3 mm in diameter [See Clinical Pharmacology (12) ].
                                                                            • Warnings_and_cautions ::
                                                                                • 0 : 5 WARNINGS AND PRECAUTIONS Symptomatic response does not preclude the presence of gastric malignancy (5.1) Atrophic gastritis: has been noted with long-term therapy (5.2) Acute interstitial nephritis has been observed in patients taking PPIs. (5.3) Cyanocobalamin (vitamin B-12) Deficiency: Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. (5.4) PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea. (5.5) Avoid concomitant use of omeprazole with clopidogrel. (5.6) Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. (5.7) Hypomagnesemia has been reported rarely with prolonged treatment with PPIs. (5.8) Avoid concomitant use of omeprazole with St.John’s Wort or rifampin due to the potential reduction in omeprazole concentrations. (5.9, 7.3) Interactions with diagnostic investigations for Neuroendocrine Tumors: Increases in intragastric pH may result in hypergastrinemia and enterochromaffin-like cell hyperplasia and increased Choromogranin A levels which may interfere with diagnostic investigations for neuroendocrine tumors. (5.10, 12.2) 5.1 Concomitant Gastric Malignancy Symptomatic response to therapy with omeprazole does not preclude the presence of gastric malignancy. 5.2 Atrophic Gastritis Atrophic gastritis has been noted occasionally in gastric corpus biopsies from patients treated long-term with omeprazole. 5.3 Acute Interstitial Nephritis Acute interstitial nephritis has been observed in patients taking PPIs including omeprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue omeperazole if acute interstitial nephritis develops [see Contraindications (4)]. 5.4 Cyanocobalamin (vitamin B-12) Deficiency Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin B-12) caused by hypo-or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acidsuppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed. 5.5 Clostridium difficile associated diarrhea Published observational studies suggest that PPI therapy like omeprazole may be associated with an increased risk of Clostridium difficile associated diarrhea, especially in hospitalized patients. This diagnosis should be considered for diarrhea that does not improve [see Adverse Reactions (6.2)]. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Clostridium diffficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with omeprazole, refer to WARNINGS and PRECAUTIONS sections of those package inserts. 5.6 Interaction with Clopidogrel Avoid concomitant use of omeprazole with clopidogrel. Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by use with concomitant medications, such as omeprazole, that inhibit CYP2C19 activity. Concomitant use of clopidogrel with 80 mg omeprazole reduces the pharmacological activity of clopidogrel, even when administered 12 hours apart. When using omeprazole, consider alternative anti-platelet therapy [see Drug Interactions (7.3) and Pharmacokinetics (12.3)]. 5.7 Bone Fracture Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines. [see Dosage and Administration (2) and Adverse Reactions (6.3) ] 5.8 Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically. [See Adverse Reactions ( 6 .3) ] 5.9 Comcomitant Use of Omeprazole with St John’s Wort or rifampin Drugs which induce CYP2C19 or CYP3A4 (such as St John’s Wort or rifampin) can substantially decrease omeprazole concentrations. [See Drug Interactions (7.3) ]. Avoid concomitant use of omeprazole with St John’s Wort or rifampin. 5.10 Interactions with Diagnostic Investigations for Neuroendocrine Tumors Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Providers should temporarily stop omeprazole treatment before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g. for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. 5.11 Concomitant use of NEXIUM with Methotrexate Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration a temporary withdrawal of the PPI may be considered in some patients. [see Drug Interactions (7.6) ]
                                                                              • Dosage_and_administration_table ::
                                                                                  • 0 :
                                                                                    Indication Omeprazole Dose Frequency
                                                                                    Treatment of Active Duodenal Ulcer (2.1) 20 mg Once daily for 4 weeks. Some patients may require an additional 4 weeks
                                                                                    H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence (2.2)
                                                                                    Triple Therapy:
                                                                                    Omeprazole 20 mg Each drug twice daily for 10 days
                                                                                    Amoxicillin 1000 mg
                                                                                    Clarithromycin 500 mg
                                                                                    Dual Therapy:
                                                                                    Omeprazole 40 mg Once daily for 14 days
                                                                                    Clarithromycin 500 mg Three times daily for 14 days
                                                                                    Gastric Ulcer (2.3) 40 mg Once daily for 4 to 8 weeks
                                                                                    GERD (2.4) 20 mg Once daily for 4 to 8 weeks
                                                                                    Maintenance of Healing of Erosive Esophagitis (2.5) 20 mg Once daily
                                                                                    Pathological Hypersecretory Conditions (2.6) 60 mg (varies with individual patient) Once daily
                                                                                    Pediatric Patients (2 to 16 years of age) (2.7) Weight Dose
                                                                                    GERD 10 < 20 kg 10 mg Once daily
                                                                                    And Maintenance of ≥ 20 kg 20 mg
                                                                                    Healing of Erosive Esophagitis
                                                                                    • 1 :
                                                                                      Patient Weight Omeprazole Daily Dose
                                                                                      10 < 20 kg 10 mg
                                                                                      ≥ 20 kg 20 mg
                                                                                  • How_supplied ::
                                                                                      • 0 : 16 HOW SUPPLIED/STORAGE AND HANDLING Omeprazole delayed-release capsules, USP 10 mg are off-white to pale yellow, elliptical to spherical pellets filled in size ‘3’ hard gelatin capsules with opaque lavender coloured cap and opaque yellow coloured body, imprinted on cap ‘OMEPRAZOLE’ 10 mg and on body ‘R157’ with black ink. The capsules are supplied in bottles of 30, 100, 1000 and unit-dose packages of 100 (10 x 10). Bottles of 30 NDC 55111-157-30 Bottles of 100 NDC 55111-157-01 Bottles of 1000 NDC 55111-157-10 Unit-dose packages of 100 (10 x 10) NDC 55111-157-78 Omeprazole delayed-release capsules, USP 20 mg are off-white to pale yellow, elliptical to spherical pellets filled in size ‘2’ hard gelatin capsules with opaque lavender coloured cap and opaque iron grey coloured body, imprinted on cap ‘OMEPRAZOLE’ 20 mg and on body ‘R158’ with black ink. The capsules are supplied in bottles of 30, 90, 100, 1000 and unit-dose packages of 100 (10 x 10). Bottles of 30 NDC 55111-158-30 NDC 55111-158-34 Bottles of 90 NDC 55111-158-90 Bottles of 100 NDC 55111-158-01 Bottles of 1000 NDC 55111-158-10 Unit-dose packages of 100 (10 x 10) NDC 55111-158-78 Omeprazole delayed-release capsules, USP 40 mg are off-white to pale yellow, elliptical to spherical pellets filled in size ‘Oel’ hard gelatin capsules with opaque yellow coloured cap and opaque lavender coloured body, imprinted on cap ‘OMEPRAZOLE’ 40 mg and on body ‘R159’ with black ink. The capsules are supplied in bottles of 30, 100, 500 and unit-dose packages of 100 (10 x 10). Bottles of 30 NDC 55111-159-30 Bottles of 100 NDC 55111-159-01 Bottles of 500 NDC 55111-159-05 Unit-dose packages of 100 (10 x 10) NDC 55111-159-78 Storage Store omeprazole delayed-release capsules in a tight container protected from light and moisture. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
                                                                                    • Nursing_mothers ::
                                                                                        • 0 : 8.3 Nursing Mothers Omeprazole is present in human milk. Omeprazole concentrations were measured in breast milk of a woman following oral administration of 20 mg. The peak concentration of omeprazole in breast milk was less than 7% of the peak serum concentration. This concentration would correspond to 0.004 mg of omperazole in 200 mL of milk. Caution should be exercised when omperazole is administered to a nursing woman.
                                                                                      • Set_id : ed5e0d81-0c1a-4548-bde3-03fff123f12e

Drug Labelling

  • 3 ::
      • Active_ingredient ::
          • 0 : Active ingredient (in each capsule) Solubilized ibuprofen equal to 200 mg ibuprofen (NSAID)* (present as the free acid and potassium salt) *nonsteroidal anti-inflammatory drug
        • Ask_doctor ::
            • 0 : Ask a doctor before use if the stomach bleeding warning applies to you you have problems or serious side effects from taking pain relievers or fever reducers you have a history of stomach problems, such as heartburn you have high blood pressure, heart disease, liver cirrhosis, kidney disease or asthma you are taking a diuretic
          • Package_label_principal_display_panel ::
              • 0 : Product Label Ibuprofen softgels 200 mg Healthy Accents DZA Brands
            • Stop_use ::
                • 0 : Stop use and ask a doctor if you experience any of the following signs of stomach bleeding: feel faint have bloody or black stools vomit blood have stomach pain that does not get better pain gets worse or lasts more than 10 days fever gets worse or lasts more than 3 days redness or swelling is present in the painful area any new symptoms appear
              • Questions ::
                  • 0 : Questions or Comments ? Call toll free 1-866-322-2439
                • When_using ::
                    • 0 : When using this product take with food or milk if stomach upset occurs the risk of heart attack or stroke may increase if you use more than directed or for longer than directed
                  • Id : ec5b32ef-f68d-48f8-9838-cc26d6ce4de0
                    • Indications_and_usage ::
                        • 0 : Uses temporarily relieves minor aches and pains due to: headache muscular aches minor pain of arthritis toothache backache the common cold menstrual cramps temporarily reduces fever
                      • Pregnancy_or_breast_feeding ::
                          • 0 : If pregnant or breast-feeding, ask a health professional before use. It is especially important not to use ibuprofen during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery
                        • Spl_unclassified_section ::
                            • 0 : Principal Display Panel Compare to Advil® Liqui-Gels® active ingredient † SOFTGELS** **(LIQUID FILLED CAPSULES) Ibuprofen Softgels Solubilized Ibuprofen Capsules, 200 mg Pain reliever & fever reducer (NSAID) KEEP OUTER CARTON FOR COMPLETE WARNINGS AND PRODUCT INFORMATION Do not use if tamper-evident seal under bottle cap imprinted with "SEALED for YOUR PROTECTION" is broken or missing †This product is not manufactured or distributed by Pfizer Consumer Healthcare, owner of the registered trademark Advil® Liqui-Gels®
                          • Inactive_ingredient ::
                              • 0 : Inactive ingredients FD&C blue #1, gelatin, pharmaceutical ink, polyethylene glycol, potassium hydroxide, purified water, sorbitan, sorbitol
                            • Do_not_use ::
                                • 0 : Do not use if you have ever had an allergic reaction to any other pain reliever/fever reducer right before or after heart surgery
                              • Openfda ::
                                  • Manufacturer_name ::
                                      • 0 : Healthy Accents (DZA Brands, LLC)
                                    • Unii ::
                                        • 0 : WK2XYI10QM
                                      • Product_type ::
                                          • 0 : HUMAN OTC DRUG
                                        • Rxcui ::
                                            • 0 : 310964
                                          • Spl_set_id ::
                                              • 0 : 190638ee-7cc9-412d-8b69-c1bcbbf96778
                                            • Route ::
                                                • 0 : ORAL
                                              • Generic_name ::
                                                  • 0 : IBUPROFEN
                                                • Upc ::
                                                    • 0 : 0725439978460
                                                  • Pharm_class_cs ::
                                                      • 0 : Nonsteroidal Anti-inflammatory Compounds [Chemical/Ingredient]
                                                    • Brand_name ::
                                                        • 0 : Ibuprofen
                                                      • Product_ndc ::
                                                          • 0 : 55316-198
                                                        • Pharm_class_epc ::
                                                            • 0 : Nonsteroidal Anti-inflammatory Drug [EPC]
                                                          • Substance_name ::
                                                              • 0 : IBUPROFEN
                                                            • Spl_id ::
                                                                • 0 : ec5b32ef-f68d-48f8-9838-cc26d6ce4de0
                                                              • Pharm_class_moa ::
                                                                  • 0 : Cyclooxygenase Inhibitors [MoA]
                                                                • Application_number ::
                                                                    • 0 : ANDA078682
                                                                  • Is_original_packager ::
                                                                      • 0 : 1
                                                                    • Nui ::
                                                                        • 0 : N0000000160
                                                                          • 1 : N0000175722
                                                                            • 2 : N0000175721
                                                                          • Package_ndc ::
                                                                              • 0 : 55316-198-80
                                                                        • Version : 1
                                                                          • Warnings ::
                                                                              • 0 : Warnings Allergy alert: Ibuprofen may cause a severe allergic reaction, especially in people allergic to aspirin. Symptoms may include: hives facial swelling asthma (wheezing) shock skin reddening rash blisters If an allergic reaction occurs, stop use and seek medical help right away. Stomach bleeding warning: This product contains an NSAID, which may cause severe stomach bleeding. The chance is higher if you: are age 60 or older have had stomach ulcers or bleeding problems take a blood thinning (anticoagulant) or steroid drug take other drugs containing prescription or nonprescription NSAIDs [aspirin, ibuprofen, naproxen, or others] have 3 or more alcoholic drinks every day while using this product take more or for a longer time than directed Do not use if you have ever had an allergic reaction to any other pain reliever/fever reducer right before or after heart surgery Ask a doctor before use if the stomach bleeding warning applies to you you have problems or serious side effects from taking pain relievers or fever reducers you have a history of stomach problems, such as heartburn you have high blood pressure, heart disease, liver cirrhosis, kidney disease or asthma you are taking a diuretic Ask a doctor or pharmacist before use if you are under a doctor's care for any serious condition taking aspirin for heart attack or stroke, because ibuprofen may decrease this benefit of aspirin taking any other drug When using this product take with food or milk if stomach upset occurs the risk of heart attack or stroke may increase if you use more than directed or for longer than directed Stop use and ask a doctor if you experience any of the following signs of stomach bleeding: feel faint have bloody or black stools vomit blood have stomach pain that does not get better pain gets worse or lasts more than 10 days fever gets worse or lasts more than 3 days redness or swelling is present in the painful area any new symptoms appear If pregnant or breast-feeding, ask a health professional before use. It is especially important not to use ibuprofen during the last 3 months of pregnancy unless definitely directed to do so by a doctor because it may cause problems in the unborn child or complications during delivery Keep out of reach of children In case of overdose, get medical help or contact a Poison Control Center right away right away.
                                                                            • Effective_time : 20130405
                                                                              • Other_safety_information ::
                                                                                  • 0 : Other information each capsule contains: potassium 20 mg read all warnings and directions before use. store at 20° - 25°C (68°- 77°F) avoid excessive heat above 40°C (104°F). Protect from light.
                                                                                • Spl_product_data_elements ::
                                                                                    • 0 : Ibuprofen Ibuprofen IBUPROFEN IBUPROFEN FD&C BLUE NO. 1 GELATIN POLYETHYLENE GLYCOLS POTASSIUM HYDROXIDE WATER SORBITOL SORBITAN light IB200
                                                                                  • Dosage_and_administration ::
                                                                                      • 0 : Directions do not take more than directed the smallest effective dose should be used adults and children 12 years and over: take 1 capsule every 4 to 6 hours while symptoms persist if pain or fever does not respond to 1 capsule, 2 capsules may be used do not exceed 6 capsules in 24 hours, unless directed by a doctor children under 12 years: ask a doctor
                                                                                    • Purpose ::
                                                                                        • 0 : Purpose Pain reliever/ fever reducer
                                                                                      • Ask_doctor_or_pharmacist ::
                                                                                          • 0 : Ask a doctor or pharmacist before use if you are under a doctor's care for any serious condition taking aspirin for heart attack or stroke, because ibuprofen may decrease this benefit of aspirin taking any other drug
                                                                                        • Keep_out_of_reach_of_children ::
                                                                                            • 0 : Keep out of reach of children In case of overdose, get medical help or contact a Poison Control Center right away right away.
                                                                                          • Set_id : 190638ee-7cc9-412d-8b69-c1bcbbf96778

Drug Labelling

  • 4 ::
      • Package_label_principal_display_panel ::
          • 0 : Testosterone Tablets Homeopathic 50 tablets Testosterone Tablets
        • Active_ingredient ::
            • 0 : ACTIVE INGREDIENTS Testosterone 30X
          • Warnings ::
              • 0 : WARNINGS Not intended for persons under the age of 18. If pregnant or breast-feeding, do not use. Consult a health professional prior to use if you ahve any pre-existing medical conditions or take any prescription medications. Do not consume with any caffeine or stimulants. Improper use will not improve results and is potentially hazardous to a person's health. Use only as directed. Keep out of reach of children. In case of overdose, get medical help or contact a Poison Control Center right away. Do not use if tamper evident seal is broken or missing. To report a serious adverse event or obtain product information, please call 1-866-607-2768
            • Inactive_ingredient ::
                • 0 : INACTIVE INGREDIENTS Creatine Monohydrate, Croscarmellose Sodium, Magnesium Stearate, Microcrystalline Cellulose, Silicon Dioxide, Stearic Acid
              • Effective_time : 20130403
                • Openfda ::
                    • Manufacturer_name ::
                        • 0 : Zoe Processing
                      • Unii ::
                          • 0 : 3XMK78S47O
                        • Product_type ::
                            • 0 : HUMAN OTC DRUG
                          • Spl_set_id ::
                              • 0 : 45750272-3581-4e2a-a9f7-d2d0a91e3cc0
                            • Route ::
                                • 0 : ORAL
                              • Generic_name ::
                                  • 0 : TESTOSTERONE
                                • Brand_name ::
                                    • 0 : Testosterone
                                  • Pharm_class_cs ::
                                      • 0 : Androstanes [Chemical/Ingredient]
                                    • Product_ndc ::
                                        • 0 : 44117-0001
                                      • Pharm_class_epc ::
                                          • 0 : Androgen [EPC]
                                        • Substance_name ::
                                            • 0 : TESTOSTERONE
                                          • Spl_id ::
                                              • 0 : f7c97c4f-7542-445a-96b4-5d2d8617b5c0
                                            • Pharm_class_moa ::
                                                • 0 : Androgen Receptor Agonists [MoA]
                                              • Is_original_packager ::
                                                  • 0 : 1
                                                • Nui ::
                                                    • 0 : N0000175824
                                                      • 1 : N0000008241
                                                        • 2 : N0000000146
                                                      • Package_ndc ::
                                                          • 0 : 44117-0001-1
                                                    • Keep_out_of_reach_of_children ::
                                                        • 0 : KEEP OUT OF REACH OF CHILDREN In case of overdose, get medical help or contact a Poison Control Center right away.
                                                      • Spl_product_data_elements ::
                                                          • 0 : Testosterone Testosterone TESTOSTERONE TESTOSTERONE CREATINE MONOHYDRATE CROSCARMELLOSE SODIUM MAGNESIUM STEARATE CELLULOSE, MICROCRYSTALLINE SILICON DIOXIDE STEARIC ACID oblong
                                                        • Set_id : 45750272-3581-4e2a-a9f7-d2d0a91e3cc0
                                                          • Dosage_and_administration ::
                                                              • 0 : DIRECTIONS Adults take 1-2 tablets daily. Read warnings and use only as directed.
                                                            • Version : 1
                                                              • Purpose ::
                                                                  • 0 : INDICATIONS For temporary relief of sexual debility from nervous prostration, for enhancing sexual function, nervous exhaustion causing lack of sexual desire.
                                                                • Questions ::
                                                                    • 0 : QUESTIONS Developed by and manufactured for: Zoe Processing P.O. Box 487 Avon, OH 44011 WWW.TESTOSTERONERX.COM
                                                                  • Id : f7c97c4f-7542-445a-96b4-5d2d8617b5c0
                                                                    • Indications_and_usage ::
                                                                        • 0 : INDICATIONS AND USAGE For temporary relief of sexual debility from nervous prostration, for enhancing sexual function, nervous exhaustion causing lack of sexual desire.