ESOMEPRAZOLE MAGNESIUM

The active ingredient in the proton pump inhibitor esomeprazole magnesium delayed-release capsules, USP for oral administration is 1H-Benzimidazole, 5-methoxy-2-[(S)-[(4-methoxy-3,5-dimethyl-2-pyridinyl]methyl] Sulfinyl], Magnesium Salt (2:1) Trihydrate. Esomeprazole is S-enantiomer of omeprazole. (Initial U.S. approval of esomeprazole magnesium: 2001). Its molecular formula is C34H36MgN6O6S2.3H2O with molecular weight of 767.17 as a trihydrate. The structural formula is: Figure 1 The magnesium salt is a white to slightly colored powder. It contains 3 moles of water. Slightly soluble in methanol, insoluble in water and in n-Heptane. The stability of esomeprazole magnesium is a function of pH; it rapidly degrades in acidic media, but it has acceptable stability under alkaline conditions. Esomeprazole magnesium is supplied in delayed-release capsules. Each delayed-release capsule contains 20 mg, or 40 mg of esomeprazole (present as 22.25 mg, or 44.5 mg esomeprazole magnesium trihydrate, USP) in the form of enteric-coated granules with the following inactive ingredients: glyceryl monostearate, hydroxy propyl cellulose, hypromellose, magnesium stearate, methacrylic acid ethyl acrylate copolymer, polysorbate 80, simethicone, sugar spheres (contains sucrose and starch), talc and triethyl citrate. The capsule shells have the following inactive ingredients: gelatin, titanium dioxide and sodium lauryl sulfate. The printing ink contains shellac, propylene glycol, strong ammonia solution, black iron oxide and potassium hydroxide.

Esomeprazole magnesium delayed-release capsule, is a proton pump inhibitor indicated for the following: • Treatment of gastroesophageal reflux disease (GERD) (1.1) • Risk reduction of NSAID-associated gastric ulcer (1.2) • H. pylori eradication to reduce the risk of duodenal ulcer recurrence. (1.3) • Pathological hypersecretory conditions, including Zollinger-Ellison syndrome (1.4) 1.1 Treatment of Gastroesophageal Reflux Disease (GERD) Healing of Erosive Esophagitis Esomeprazole magnesium delayed-release capsules are indicated for the short-term treatment (4 to 8 weeks) in the healing and symptomatic resolution of diagnostically confirmed erosive esophagitis. For those patients who have not healed after 4 to 8 weeks of treatment, an additional 4 to 8 week course of esomeprazole magnesium delayed-release capsules may be considered. Maintenance of Healing of Erosive Esophagitis Esomeprazole magnesium delayed-release capsules are indicated to maintain symptom resolution and healing of erosive esophagitis. Controlled studies do not extend beyond 6 months. Symptomatic Gastroesophageal Reflux Disease Esomeprazole magnesium delayed-release capsules are indicated for short-term treatment (4 to 8 weeks) of heartburn and other symptoms associated with GERD in adults and children 1 year or older. 1.2 Risk Reduction of NSAID-Associated Gastric Ulcer Esomeprazole magnesium delayed-release capsules are indicated for the reduction in the occurrence of gastric ulcers associated with continuous NSAID therapy in patients at risk for developing gastric ulcers. Patients are considered to be at risk due to their age (≥ 60) and/or documented history of gastric ulcers. Controlled studies do not extend beyond 6 months. 1.3 H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Triple Therapy (esomeprazole magnesium delayed-release capsules plus amoxicillin and clarithromycin): Esomeprazole magnesium delayed-release capsules, in combination with amoxicillin and clarithromycin, is indicated for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or history of within the past 5 years) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [see Dosage and Administration (2) and Clinical Studies (14)]. 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 Clinical Pharmacology (12.4) and the prescribing information for clarithromycin]. 1.4 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome Esomeprazole magnesium delayed-release capsules are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison Syndrome.

Esomeprazole magnesium is supplied as delayed-release capsules for oral administration. The recommended dosages are outlined in Table 1. Esomeprazole magnesium delayed-release capsules should be taken at least one hour before meals. The duration of proton pump inhibitor administration should be based on available safety and efficacy data specific to the defined indication and dosing frequency, as described in the prescribing information, and individual patient medical needs. Proton pump inhibitor treatment should only be initiated and continued if the benefits outweigh the risks of treatment. Table 1: Recommended Dosage Schedule for Esomeprazole Magnesium Delayed-Release Capsules Indication Dose Frequency Gastroesophageal Reflux Disease (GERD) Healing of Erosive Esophagitis 20 mg or 40 mg Once Daily for 4 to 8 Weeks 1 Maintenance of Healing of Erosive Esophagitis 20 mg Once Daily 2 Symptomatic Gastroesophageal Reflux Disease 20 mg Once Daily for 4 Weeks 3 Pediatric GERD 12 to 17 Year Olds Healing of Erosive Esophagitis 20 mg or 40 mg Once Daily for 4 to 8 Weeks Symptomatic GERD 20 mg Once Daily for 4 Weeks 1 to 11 Year Olds 4 Short-term Treatment of Symptomatic GERD 10 mg Once Daily for up to 8 Weeks Healing of Erosive Esophagitis weight < 20 kg 10 mg Once Daily for 8 Weeks weight ≥ 20 kg 10 mg or 20 mg Once Daily for 8 Weeks Risk Reduction of NSAID-Associated Gastric Ulcer 20 mg or 40 mg Once Daily for up to 6 months 2 H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Triple Therapy: Esomeprazole 40 mg Once Daily for 10 Day Amoxicillin 1000 mg Twice Daily for 10 Days Clarithromycin 500 mg Twice Daily for 10 Days Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome 40 mg 6 Twice Daily 7 1 [See Clinical Studies (14.1)] The majority of patients are healed within 4 to 8 weeks. For patients who do not heal after 4 to 8 weeks, an additional 4 to 8 weeks of treatment may be considered. 2 Controlled studies did not extend beyond six months. 3 If symptoms do not resolve completely after 4 weeks, an additional 4 weeks of treatment may be considered. 4 Doses over 1 mg/kg/day have not been studied. 5 . Doses over 1.33 mg/kg/day have not been studied. 6 The dosage of esomeprazole magnesium delayed-release capsules in patients with pathological hypersecretory conditions varies with the individual patient. Dosage regimens should be adjusted to individual patient needs. 7 Doses up to 240 mg daily have been administered [see Drug Interactions (7)] . Please refer to amoxicillin and clarithromycin prescribing information for Contraindications, Warnings, and dosing in elderly and renally-impaired patients. Specific Populations Hepatic Insufficiency In patients with mild to moderate liver impairment (Child-Pugh Classes A and B), no dosage adjustment is necessary. For patients with severe liver impairment (Child-Pugh Class C), a dose of 20 mg of esomeprazole magnesium delayed-release capsules should not be exceeded [see Clinical Pharmacology (12.3)] . Directions for use specific to the route and available methods of administration for each of these dosage forms are presented in Table 2. Table 2: Administration Options Administration Options (See text following table for additional instructions.) Dosage Form Route Options Delayed-Release Capsules Oral Capsule can be swallowed whole. -or- Capsule can be opened and mixed with applesauce. Delayed-Release Capsules Nasogastric Tube Capsule can be opened and the intact granules emptied into a syringe and delivered through the nasogastric tube. Esomeprazole Magnesium Delayed-Release Capsules Esomeprazole Magnesium Delayed-Release Capsules should be swallowed whole. Alternatively, for patients who have difficulty swallowing capsules, one tablespoon of applesauce can be added to an empty bowl and the esomeprazole magnesium delayed-release capsule can be opened, and the granules inside the capsule carefully emptied onto the applesauce. The granules should be mixed with the applesauce and then swallowed immediately: do not store for future use. The applesauce used should not be hot and should be soft enough to be swallowed without chewing. The granules should not be chewed or crushed. If the granules/applesauce mixture is not used in its entirety, the remaining mixture should be discarded immediately. For patients who have a nasogastric tube in place, esomeprazole magnesium delayed-release capsules can be opened and the intact granules emptied into a 60 mL catheter tipped syringe and mixed with 50 mL of water. It is important to only use a catheter tipped syringe when administering esomeprazole magnesium delayed-release capsules through a nasogastric tube. Replace the plunger and shake the syringe vigorously for 15 seconds. Hold the syringe with the tip up and check for granules remaining in the tip. Attach the syringe to a nasogastric tube and deliver the contents of the syringe through the nasogastric tube into the stomach. After administering the granules, the nasogastric tube should be flushed with additional water. Do not administer the granules if they have dissolved or disintegrated. The mixture must be used immediately after preparation. Indication Dose Frequency Gastroesophageal Reflux Disease (GERD) Adults 12 to 17 years 1 to 11 years 20 mg or 40 mg 20 mg or 40 mg 10 mg or 20 mg Once daily for 4 to 8 weeks Once daily for up to 8 weeks Once daily for up to 8 weeks Risk Reduction of NSAID-Associated Gastric Ulcer 20 mg or 40 mg Once daily for up to 6 months H. pylori Eradication (Triple Therapy): Esomeprazole 40 mg Once daily for 10 days Amoxicillin 1000 mg Twice daily for 10 days Clarithromycin 500 mg Twice daily for 10 days Pathological Hypersecretory Conditions 40 mg Twice daily See full prescribing information for administration options. (2) Patients with severe liver impairment-do not exceed dose of 20 mg. (2)

Esomeprazole magnesium 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 esomeprazole magnesium delayed-release capsules, refer to the CONTRAINDICATIONS section of their package inserts. Patients with known hypersensitivity to proton pump inhibitors (PPIs) (angioedema and anaphylaxis have occurred). (4)

The following serious adverse reactions are described below and elsewhere in labeling: • Acute Interstitial Nephritis [see Warnings and Precautions (5.2)] • Clostridium difficile -Associated Diarrhea [see Warnings and Precautions (5.3)] • Bone Fracture [see Warnings and Precautions (5.4)] • Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.5)] • Cyanocobalamin (Vitamin B-12) Deficiency [see Warnings and Precautions (5.7)] • Hypomagnesemia [see Warnings and Precautions (5.8)] • Fundic Gland Polyps [see Warnings and Precautions ( 5.12 )] Most common adverse reactions (6.1) : • Adults (≥ 18 years) (incidence > 1%) are headache, diarrhea, nausea, flatulence, abdominal pain, constipation, and dry mouth • Pediatric (1 to 17 years) (incidence > 2%) are headache, diarrhea, abdominal pain, nausea, and somnolence. To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 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 practice. Adults The safety of esomeprazole magnesium delayed-release capsules were evaluated in over 15,000 patients (aged 18 to 84 years) in clinical trials worldwide including over 8,500 patients in the United States and over 6,500 patients in Europe and Canada. Over 2,900 patients were treated in long-term studies for up to 6 to 12 months. In general, esomeprazole magnesium delayed-release capsules were well tolerated in both short and long-term clinical trials. The safety in the treatment of healing of erosive esophagitis was assessed in four randomized comparative clinical trials, which included 1,240 patients on esomeprazole magnesium delayed-release capsules 20 mg, 2,434 patients on esomeprazole magnesium delayed-release capsules 40 mg, and 3,008 patients on omeprazole 20 mg daily. The most frequently occurring adverse reactions (≥1%) in all three groups were headache (5.5, 5, and 3.8, respectively) and diarrhea (no difference among the three groups). Nausea, flatulence, abdominal pain, constipation, and dry mouth occurred at similar rates among patients taking esomeprazole magnesium delayed-release capsules or omeprazole. Additional adverse reactions that were reported as possibly or probably related to esomeprazole magnesium delayed-release capsules with an incidence <1% are listed below by body system: Body as a Whole : abdomen enlarged, allergic reaction, asthenia, back pain, chest pain, substernal chest pain, facial edema, peripheral edema, hot flushes, fatigue, fever, flu-like disorder, generalized edema, leg edema, malaise, pain, rigors; Cardiovascular : flushing, hypertension, tachycardia; Endocrine : goiter; Gastrointestinal : bowel irregularity, constipation aggravated, dyspepsia, dysphagia, dysplasia GI, epigastric pain, eructation, esophageal disorder, frequent stools, gastroenteritis, GI hemorrhage, GI symptoms not otherwise specified, hiccup, melena, mouth disorder, pharynx disorder, rectal disorder, serum gastrin increased, tongue disorder, tongue edema, ulcerative stomatitis, vomiting; Hearing : earache, tinnitus; Hematologic : anemia, anemia hypochromic, cervical lymphadenopathy, epistaxis, leukocytosis, leukopenia, thrombocytopenia; Hepatic: bilirubinemia, hepatic function abnormal, SGOT increased, SGPT increased; Metabolic/Nutritional : glycosuria, hyperuricemia, hyponatremia, increased alkaline phosphatase, thirst, vitamin B12 deficiency, weight increase, weight decrease; Musculoskeletal: arthralgia, arthritis aggravated, arthropathy, cramps, fibromyalgia syndrome, hernia, polymyalgia rheumatica; Nervous System/Psychiatric : anorexia, apathy, appetite increased, confusion, depression aggravated, dizziness, hypertonia, nervousness, hypoesthesia, impotence, insomnia, migraine, migraine aggravated, paresthesia, sleep disorder, somnolence, tremor, vertigo, visual field defect; Reproductive : dysmenorrhea, menstrual disorder, vaginitis; Respiratory : asthma aggravated, coughing, dyspnea, larynx edema, pharyngitis, rhinitis, sinusitis; Skin and Appendages : acne, angioedema, dermatitis, pruritus, pruritus ani, rash, rash erythematous, rash maculo-papular, skin inflammation, sweating increased, urticaria; Special Senses : otitis media, parosmia, taste loss, taste perversion; Urogenital: abnormal urine, albuminuria, cystitis, dysuria, fungal infection, hematuria, micturition frequency, moniliasis, genital moniliasis, polyuria; Visual : conjunctivitis, vision abnormal. The following potentially clinically significant laboratory changes in clinical trials, irrespective of relationship to esomeprazole magnesium delayed-release capsules, were reported in ≤1% of patients: increased creatinine, uric acid, total bilirubin, alkaline phosphatase, ALT, AST, hemoglobin, white blood cell count, platelets, serum gastrin, potassium, sodium, thyroxine and thyroid stimulating hormone [see Clinical Pharmacology (12) ]. Decreases were seen in hemoglobin, white blood cell count, platelets, potassium, sodium, and thyroxine. Endoscopic findings that were reported as adverse reactions include: duodenitis, esophagitis, esophageal stricture, esophageal ulceration, esophageal varices, gastric ulcer, gastritis, hernia, benign polyps or nodules, Barrett’s esophagus, and mucosal discoloration. The incidence of treatment-related adverse reactions during 6-month maintenance treatment was similar to placebo. There were no differences in types of related adverse reactions seen during maintenance treatment up to 12 months compared to short-term treatment. Two placebo-controlled studies were conducted in 710 patients for the treatment of symptomatic gastroesophageal reflux disease. The most common adverse reactions that were reported as possibly or probably related to esomeprazole magnesium delayed-release capsules were diarrhea (4.3%), headache (3.8%), and abdominal pain (3.8%). Pediatrics The safety of esomeprazole magnesium delayed-release capsules were evaluated in 316 pediatric and adolescent patients aged 1 to 17 years in four clinical trials for the treatment of symptomatic GERD [see Clinical Studies (14.2)]. In 109 pediatric patients aged 1 to 11 years, the most frequently reported (at least 1%) treatment-related adverse reactions in these patients were diarrhea (2.8%), headache (1.9%) and somnolence (1.9%). In 149 pediatric patients aged 12 to 17 years the most frequently reported (at least 2%) treatment-related adverse reactions in these patients were headache (8.1%), abdominal pain (2.7%), diarrhea (2%), and nausea (2%). No new safety concerns were identified in pediatric patients. Combination Treatment with Amoxicillin and Clarithromycin In clinical trials using combination therapy with esomeprazole magnesium delayed-release capsules plus amoxicillin and clarithromycin, no additional adverse reactions specific to these drug combinations were observed. Adverse reactions that occurred were limited to those observed when using esomeprazole magnesium delayed-release capsules, amoxicillin, or clarithromycin alone. The most frequently reported drug-related adverse reactions for patients who received triple therapy for 10 days were diarrhea (9.2%), taste perversion (6.6%), and abdominal pain (3.7%). No treatment-emergent adverse reactions were observed at higher rates with triple therapy than were observed with esomeprazole magnesium delayed-release capsules alone. For more information on adverse reactions with amoxicillin or clarithromycin, refer to their package inserts, Adverse Reactions sections. In clinical trials using combination therapy with esomeprazole magnesium delayed-release capsules plus amoxicillin and clarithromycin, no additional increased laboratory abnormalities particular to these drug combinations were observed. For more information on laboratory changes with amoxicillin or clarithromycin, refer to their package inserts, Adverse Reactions section. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of esomeprazole magnesium delayed-release capsules. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reports are listed below by body system: Blood and Lymphatic : agranulocytosis, pancytopenia; Eye : blurred vision; Gastrointestinal : pancreatitis; stomatitis; microscopic colitis; fundic gland polyps; Hepatobiliary : hepatic failure, hepatitis with or without jaundice; Immune System : anaphylactic reaction/shock; systemic lupus erythematosus; Infections and Infestations : GI candidiasis; Clostridium difficile-associated diarrhea; Metabolism and nutritional disorders : hypomagnesemia, with or without hypocalcemia and/or hypokalemia; Musculoskeletal and Connective Tissue: muscular weakness, myalgia, bone fracture; Nervous System: hepatic encephalopathy , taste disturbance; Psychiatric: aggression , agitation, depression, hallucination; Renal and Urinary : interstitial nephritis; Reproductive System and Breast : gynecomastia; Respiratory, Thoracic, and Mediastinal: bronchospasm; Skin and Subcutaneous Tissue : alopecia, erythema multiforme, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal), cutaneous lupus erythematosus.

• May affect plasma levels of antiretroviral drugs - use with atazanavir and nelfinavir is not recommended; if saquinavir is used with esomeprazole magnesium delayed-release capsules, monitor for toxicity and consider saquinavir dose reduction. (7.1) • May interfere with drugs for which gastric pH affects bioavailability (e.g., ketoconazole, iron salts, erlotinib, digoxin and mycophenolate mofetil). Patients treated with esomeprazole magnesium delayed-release capsules and digoxin may need to be monitored for digoxin toxicity. (7.2) • Combined inhibitor of CYP2C19 and 3A4 may raise esomeprazole levels. (7.3) • Clopidogrel: Esomeprazole magnesium decreases exposure to the active metabolite of clopidogrel. (7.3) • May increase systemic exposure of cilostazol and an active metabolite. Consider dose reduction. (7.3) • Tacrolimus: Esomeprazole magnesium may increase serum levels of tacrolimus. (7.5) • Methotrexate: Esomeprazole magnesium 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, of which esomeprazole is an enantiomer, 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 CYP2C19. 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 (1,250 mg, twice daily) and omeprazole (40 mg daily), AUC was decreased by 36% and 92%, C max by 37% and 89% and C min by 39% and 75% respectively for nelfinavir and M8. Following multiple doses of atazanavir (400 mg, daily) and omeprazole (40 mg, daily, 2 hours before atazanavir), AUC was decreased by 94%, C max by 96%, and C min 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 C max by 75%, and in C min by 106%, following multiple dosing of saquinavir/ritonavir (1,000/100 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 esomeprazole magnesium delayed-release capsules. 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, esomeprazole can reduce the absorption of drugs where gastric pH is an important determinant of their bioavailability. 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 esomeprazole. Esomeprazole is an enantiomer of 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 esomeprazole is expected to increase the systemic exposure of digoxin. Therefore, patients may need to be monitored when digoxin is taken concomitantly with esomeprazole. 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 esomeprazole and MMF. Use esomeprazole with caution in transplant patients receiving MMF [see Clinical Pharmacology (12.3)]. 7.3 Effects on Hepatic Metabolism/Cytochrome P-450 Pathways Esomeprazole is extensively metabolized in the liver by CYP2C19 and CYP3A4. In vitro and in vivo studies have shown that esomeprazole is not likely to inhibit CYPs 1A2, 2A6, 2C9, 2D6, 2E1, and 3A4. No clinically relevant interactions with drugs metabolized by these CYP enzymes would be expected. Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, warfarin, quinidine, clarithromycin, or amoxicillin. However, postmarketing reports of changes in prothrombin measures have been received among patients on concomitant warfarin and esomeprazole therapy. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time. Esomeprazole may potentially interfere with CYP2C19, the major esomeprazole metabolizing enzyme. Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam. Clopidogrel Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of esomeprazole 40 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition. Avoid concomitant administration of esomeprazole magnesium delayed-release capsules with clopidogrel. When using esomeprazole magnesium delayed-release capsules, consider use of alternative anti-platelet therapy [ see Clinical Pharmacology (12.3) ]. Omeprazole acts as an inhibitor of CYP2C19. Omeprazole, given in doses of 40 mg daily for one week to 20 healthy subjects in cross-over study, increased Cmax and AUC of cilostazol by 18% and 26% respectively. C max and AUC of one of its active metabolites, 3,4-dihydrocilostazol, which has 4 to 7 times the activity of cilostazol, were increased by 29% and 69%, respectively. Co-administration of cilostazol with esomeprazole 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. Concomitant administration of esomeprazole and a combined inhibitor of CYP2C19 and CYP3A4, such as voriconazole, may result in more than doubling of the esomeprazole exposure. Dose adjustment of esomeprazole is not normally required. However, in patients with Zollinger-Ellison’s Syndrome, who may require higher doses up to 240 mg/day, dose adjustment may be considered. Drugs known to induce CYP2C19 or CYP3A4 or both (such as rifampin) may lead to decreased esomeprazole serum levels. Omeprazole, of which esomeprazole is an enantiomer, has been reported to interact with St. John’s Wort, an inducer of CYP3A4. In a cross-over study in 12 healthy male subjects, St. John’s Wort (300 mg three times daily for 14 days) significantly decreased the systemic exposure of omeprazole in CYP2C19 poor metabolisers (C max and AUC decreased by 37.5% and 37.9%, respectively) and extensive metabolisers (C max and AUC decreased by 49.6 % and 43.9%, respectively). Avoid concomitant use of St. John’s Wort or rifampin with esomeprazole magnesium delayed-release capsules. 7.4 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 (12.2)]. 7.5 Tacrolimus Concomitant administration of esomeprazole and tacrolimus may increase the serum levels of tacrolimus. 7.6 Combination Therapy with Clarithromycin Co-administration of esomeprazole, clarithromycin, and amoxicillin has resulted in increases in the plasma levels of esomeprazole and 14-hydroxyclarithromycin [see Clinical Pharmacology (12.4)]. 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)].