Prevacid

1 INDICATIONS AND USAGE PREVACID and PREVACID SoluTab are proton pump inhibitors (PPIs) indicated for the: Treatment of active duodenal ulcer in adults. ( 1.1 ) Eradication of H. pylori to reduce the risk of duodenal ulcer recurrence in adults. ( 1.2 ) Maintenance of healed duodenal ulcers in adults. ( 1.3 ) Treatment of active benign gastric ulcer in adults. ( 1.4 ) Healing of nonsteroidal anti-inflammatory drugs (NSAID)-associated gastric ulcer in adults. ( 1.5 ) Risk reduction of NSAID-associated gastric ulcer in adults. ( 1.6 ) Treatment of symptomatic gastroesophageal reflux disease (GERD) in adults and pediatric patients 1 year of age and older. ( 1.7 ) Treatment of erosive esophagitis (EE) in adults and pediatric patients 1 year of age and older. ( 1.8 ) Maintenance of healing of EE in adults. ( 1.9 ) Pathological hypersecretory conditions, including Zollinger-Ellison syndrome (ZES) in adults. ( 1.10 ) 1.1 Treatment of Active Duodenal Ulcer PREVACID and PREVACID SoluTab are indicated in adults for short-term treatment (for four weeks) for healing and symptom relief of active duodenal ulcer [see Clinical Studies (14.1) ] . 1.2 Eradication of H. pylori to Reduce the Risk of Duodenal Ulcer Recurrence Triple Therapy: PREVACID or PREVACID SoluTab/amoxicillin/clarithromycin PREVACID or PREVACID SoluTab in combination with amoxicillin plus clarithromycin as triple therapy is indicated in adults for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or one year history of a duodenal ulcer) to eradicate H. pylori. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [see Clinical Studies (14.2) ] . Please refer to the full prescribing information for amoxicillin and clarithromycin. Dual Therapy: PREVACID or PREVACID SoluTab/amoxicillin PREVACID or PREVACID SoluTab in combination with amoxicillin as dual therapy is indicated in adults for the treatment of patients with H. pylori infection and duodenal ulcer disease (active or one year history of a duodenal ulcer) who are either allergic or intolerant to clarithromycin or in whom resistance to clarithromycin is known or suspected (see the clarithromycin prescribing information, Microbiology section). Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence [see Clinical Studies (14.2) ] . Please refer to the full prescribing information for amoxicillin. 1.3 Maintenance of Healed Duodenal Ulcers PREVACID and PREVACID SoluTab are indicated in adults to maintain healing of duodenal ulcers. Controlled studies do not extend beyond 12 months [see Clinical Studies (14.3) ] . 1.4 Treatment of Active Benign Gastric Ulcer PREVACID and PREVACID SoluTab are indicated in adults for short-term treatment (up to eight weeks) for healing and symptom relief of active benign gastric ulcer [see Clinical Studies (14.4) ] . 1.5 Healing of NSAID-Associated Gastric Ulcer PREVACID and PREVACID SoluTab are indicated in adults for the treatment of NSAID-associated gastric ulcer in patients who continue NSAID use. Controlled studies did not extend beyond eight weeks [see Clinical Studies (14.5) ] . 1.6 Risk Reduction of NSAID-Associated Gastric Ulcer PREVACID and PREVACID SoluTab are indicated in adults for reducing the risk of NSAID-associated gastric ulcers in patients with a history of a documented gastric ulcer who require the use of an NSAID. Controlled studies did not extend beyond 12 weeks [see Clinical Studies (14.6) ] . 1.7 Treatment of Symptomatic Gastroesophageal Reflux Disease (GERD) PREVACID and PREVACID SoluTab are indicated for short-term treatment in adults and pediatric patients 12 to 17 years of age (up to eight weeks) and pediatric patients one to 11 years of age (up to 12 weeks) for the treatment of heartburn and other symptoms associated with GERD [see Clinical Studies (14.7) ] . 1.8 Treatment of Erosive Esophagitis (EE) PREVACID and PREVACID SoluTab are indicated for short-term treatment…

2 DOSAGE AND ADMINISTRATION Recommended Dosage : See full prescribing information for complete dosing information for PREVACID and PREVACID SoluTab by indication and age group and dosage adjustment in patients with severe hepatic impairment. ( 2.1 , 2.2 , 2.3 ) Administration Instructions ( 2.4 ) PREVACID capsules Should be swallowed whole. See full prescribing information for alternative administration options. PREVACID SoluTab Should not be broken or cut. Should not be chewed. Place the tablet on the tongue and allow it to disintegrate, with or without water, until the particles can be swallowed. See full prescribing information for alternative administration options. 2.1 Recommended Adult Dosage by Indication Indication Recommended Dose Frequency Duodenal Ulcers Short-Term Treatment 15 mg Once daily for 4 weeks Maintenance of Healed 15 mg Once daily Eradication of H. pylori to Reduce the Risk of Duodenal Ulcer Recurrence Please refer to the amoxicillin and clarithromycin full prescribing information, Contraindications and Warnings and Precautions sections, and for information regarding dosing in elderly and renally-impaired patients. Triple Therapy: PREVACID or PREVACID SoluTab 30 mg Twice daily for 10 or 14 days Amoxicillin 1 gram Twice daily for 10 or 14 days Clarithromycin 500 mg Twice daily for 10 or 14 days Dual Therapy: PREVACID or PREVACID SoluTab 30 mg Three times daily for 14 days Amoxicillin 1 gram Three times daily for 14 days Benign Gastric Ulcer Short-Term Treatment 30 mg Once daily for up to 8 weeks NSAID-Associated Gastric Ulcer Healing 30 mg Once daily for 8 weeks Controlled studies did not extend beyond indicated duration. Risk Reduction 15 mg Once daily for up to 12 weeks Gastroesophageal Reflux Disease (GERD) Short-Term Treatment of Symptomatic GERD 15 mg Once daily for up to 8 weeks Short-Term Treatment of Erosive Esophagitis 30 mg Once daily for up to 8 weeks For patients who do not heal with PREVACID or PREVACID SoluTab for eight weeks (5 to 10%), it may be helpful to give an additional eight weeks of treatment. If there is a recurrence of erosive esophagitis, an additional eight week course of PREVACID or PREVACID SoluTab may be considered. Maintenance of Healing of Erosive Esophagitis 15 mg Once daily Controlled studies did not extend beyond 12 months. Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome 60 mg Once daily Varies with individual patient. Recommended adult starting dose is 60 mg once daily. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Dosages up to 90 mg twice daily have been administered. Daily dose of greater than 120 mg should be administered in divided doses. Some patients with Zollinger-Ellison syndrome have been treated continuously with PREVACID for more than four years. 2.2 Recommended Pediatric Dosage by Indication Pediatric Patients 1 to 11 Years of Age In clinical studies, PREVACID was not administered beyond 12 weeks in 1 to 11 year olds. It is not known if PREVACID is safe and effective if used longer than the recommended duration. Do not exceed the recommended dose and duration of use in pediatric patients as outlined below [see Use in Specific Populations (8.4) ] . Indication Recommended Dose Frequency Short-Term Treatment of Symptomatic GERD and Short-Term Treatment of Erosive Esophagitis ≤30 kg 15 mg Once daily for up to 12 weeks >30 kg 30 mg Once daily for up to 12 weeks Pediatric Patients 12 to 17 Years of Age Indication Recommended Dose Frequency Short-Term Treatment of Symptomatic GERD Non-erosive GERD 15 mg Once daily for up to 8 weeks Erosive Esophagitis 30 mg Once daily for up to 8 weeks 2.3 Hepatic Impairment The recommended dosage is 15 mg orally daily in patients with severe liver impairment (Child-Pugh C) [see Use in Specific Populations (8.6) ] . 2.4 Important Administration Information Take PREVACID or PREVACID SoluTab before meals. Do not crush or chew PREVACID capsule …

5 WARNINGS AND PRECAUTIONS Gastric Malignancy : In adults, symptomatic response with PREVACID or PREVACID SoluTab does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing. ( 5.1 ) Acute Tubulointerstitial Nephritis : Discontinue treatment and evaluate patients. ( 5.2 ) Clostridium difficile -Associated Diarrhea : PPI therapy may be associated with increased risk of Clostridium difficile -associated diarrhea. ( 5.3 ) 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. ( 5.4 ) Severe Cutaneous Adverse Reactions: Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. ( 5.5 ) Cutaneous and Systemic Lupus Erythematosus : Mostly cutaneous; new onset or exacerbation of existing disease; discontinue PREVACID and PREVACID SoluTab and refer to specialist for evaluation. ( 5.6 ) Cyanocobalamin (Vitamin B12) Deficiency : Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. ( 5.7 ) Hypomagnesemia and Mineral Metabolism : Hypomagnesemia has been reported rarely with prolonged treatment with PPIs. ( 5.8 ) Interactions with Investigations for Neuroendocrine Tumors : Increases in intragastric pH may result in hypergastrinemia and enterochromaffin-like cell hyperplasia and increased chromogranin A levels which may interfere with diagnostic investigations for neuroendocrine tumors. ( 5.9 , 7 ) Interaction with Methotrexate : Concomitant use with PPIs may elevate and/or prolong serum concentrations of methotrexate and/or its metabolite, possibly leading to toxicity. With high-dose methotrexate administration, consider a temporary withdrawal of PREVACID. ( 5.10 , 7 ) Patients with Phenylketonuria : Each 15 mg PREVACID SoluTab contains 2.5 mg and each 30 mg PREVACID SoluTab contains 5.1 mg of phenylalanine. ( 5.11 ) Fundic Gland Polyps : Risk increases with long-term use, especially beyond 1 year. Use the shortest duration of therapy. ( 5.12 ) Risk of Heart Valve Thickening in Pediatric Patients Less than One Year of Age : PREVACID is not recommended in pediatric patients less than 1 year of age. ( 5.13 , 8.4 ) 5.1 Presence of Gastric Malignancy In adults, symptomatic response to therapy with PREVACID or PREVACID SoluTab does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in adult patients who have a suboptimal response or an early symptomatic relapse after completing treatment with a PPI. In older patients, also consider an endoscopy. 5.2 Acute Tubulointerstitial Nephritis Acute tubulointerstial nephritis (TIN) has been observed in patients taking PPIs and may occur at any point during PPI therapy. Patients may present with varying signs and symptoms from symptomatic hypersensitivity reactions to non-specific symptoms of decreased renal function (e.g., malaise, nausea, anorexia). In reported case series, some patients were diagnosed on biopsy and in the absence of extra-renal manifestations (e.g., fever, rash or arthralgia). Discontinue PREVACID or PREVACID SoluTab and evaluate patients with suspected acute TIN [see Contraindications (4) ] . 5.3 Clostridium difficile -Associated Diarrhea Published observational studies suggest that PPI therapy like PREVACID and PREVACID SoluTab may be associated with an increased risk of Clostridium difficile -associated diarrhea (CDAD), 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. CDAD has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated…

4 CONTRAINDICATIONS PREVACID and PREVACID SoluTab are contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity reactions may include anaphylaxis, anaphylactic shock, angioedema, bronchospasm, acute tubulointerstitial nephritis, and urticaria [see Warnings and Precautions (5.2) , Adverse Reactions (6) ] . Proton Pump Inhibitors (PPIs), including PREVACID and PREVACID SoluTab, are contraindicated with rilpivirine-containing products [see Drug Interactions (7) ] . For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with PREVACID or PREVACID SoluTab, refer to the Contraindications section of their prescribing information. Contraindicated in patients with known hypersensitivity to any component of the PREVACID or PREVACID SoluTab formulations. ( 4 ) Patients receiving rilpivirine-containing products. ( 4 , 7 )

7 DRUG INTERACTIONS Tables 2 and 3 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with PREVACID or PREVACID SoluTab and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs. Table 2. Clinically Relevant Interactions Affecting Drugs Coadministered with PREVACID or PREVACID SoluTab and Interactions with Diagnostics Antiretrovirals Clinical Impact: The effect of PPIs on antiretroviral drugs is variable. The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with lansoprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with lansoprazole may increase toxicity of the antiretroviral drugs. There are other antiretroviral drugs which do not result in clinically relevant interactions with lansoprazole. Intervention: Rilpivirine-containing products : Concomitant use with PREVACID or PREVACID SoluTab is contraindicated [see Contraindications (4) ] . See prescribing information. Atazanavir : See prescribing information for atazanavir for dosing information. Nelfinavir : Avoid concomitant use with PREVACID or PREVACID SoluTab. See prescribing information for nelfinavir. Saquinavir : See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals : See prescribing information. Warfarin Clinical Impact: Increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Intervention: Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. Methotrexate Clinical Impact: Concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.10) ] . Intervention: A temporary withdrawal of PREVACID or PREVACID SoluTab may be considered in some patients receiving high-dose methotrexate. Digoxin Clinical Impact: Potential for increased exposure of digoxin. Intervention: Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin. Theophylline Clinical Impact: Increased clearance of theophylline [see Clinical Pharmacology (12.3) ] . Intervention: Individual patients may require additional titration of their theophylline dosage when PREVACID or PREVACID SoluTab is started or stopped to ensure clinically effective blood concentrations. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Lansoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. Intervention: Mycophenolate mofetil (MMF): Coadministration of PPIs 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 PREVACID and MMF. Use PREVACID and PREVACID SoluTab with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption.…

8.1 Pregnancy Risk Summary Available data from published observational studies overall do not indicate an association of adverse pregnancy outcomes with lansoprazole treatment (see Data ) . In animal reproduction studies, oral administration of lansoprazole to rats during organogenesis through lactation at 6.4 times the maximum recommended human dose produced reductions in the offspring in femur weight, femur length, crown-rump length and growth plate thickness (males only) on postnatal Day 21 (see Data ) . These effects were associated with reduction in body weight gain. Advise pregnant women of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. If PREVACID or PREVACID SoluTab is administered with clarithromycin, the pregnancy information for clarithromycin also applies to the combination regimen. Refer to the prescribing information for clarithromycin for more information on use in pregnancy. Data Human Data Available data from published observational studies failed to demonstrate an association of adverse pregnancy-related outcomes and lansoprazole use. Methodological limitations of these observational studies cannot definitely establish or exclude any drug-associated risk during pregnancy. In a prospective study by the European Network of Teratology Information Services, outcomes from a group of 62 pregnant women administered median daily doses of 30 mg of lansoprazole were compared to a control group of 868 pregnant women who did not take any PPIs. There was no difference in the rate of major malformations between women exposed to PPIs and the control group, corresponding to a Relative Risk (RR)=1.04, [95% Confidence Interval (CI) 0.25-4.21]. In a population-based retrospective cohort study covering all live births in Denmark from 1996 to 2008, there was no significant increase in major birth defects during analysis of first trimester exposure to lansoprazole in 794 live births. A meta-analysis that compared 1,530 pregnant women exposed to PPIs in at least the first trimester with 133,410 unexposed pregnant women showed no significant increases in risk for congenital malformations or spontaneous abortion with exposure to PPIs (for major malformations Odds Ratio (OR)=1.12, [95% CI 0.86-1.45] and for spontaneous abortions OR=1.29, [95% CI 0.84-1.97]). Animal Data No adverse effects on embryo-fetal development occurred in studies performed in pregnant rats at oral lansoprazole doses up to 150 mg/kg/day (40 times the recommended human dose [30 mg/day] based on body surface area) administered during organogenesis and pregnant rabbits at oral lansoprazole doses up to 30 mg/kg/day (16 times the recommended human dose based on body surface area) administered during organogenesis. A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with lansoprazole at oral doses of 10 to 100 mg/kg/day (0.7 to 6.4 times the maximum recommended human lansoprazole dose of 30 mg based on AUC [area under the plasma concentration-time curve]) administered during organogenesis through lactation. Maternal effects observed at 100 mg/kg/day (6.4 times the maximum recommended human lansoprazole dose of 30 mg based on AUC) included increased gestation period, decreased body weight gain during gestation, and decreased food consumption. The number of stillbirths was increased at this dose, which may have been secondary to maternal toxicity. Body weight of pups was reduced at 100 mg/kg/day starting on postnatal Day 11. Femur weight, femur length, and crown-rump length were reduced at 100 mg/kg/day on postnatal Day 21. Femur weight was …

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in labeling: Acute Tubulointerstitial 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) ] Severe Cutaneous Adverse Reactions [see Warnings and Precautions (5.5) ] Cutaneous and Systemic Lupus Erythematosus [see Warnings and Precautions (5.6) ] Cyanocobalamin (Vitamin B12) Deficiency [see Warnings and Precautions (5.7) ] Hypomagnesemia and Mineral Metabolism [see Warnings and Precautions (5.8) ] Fundic Gland Polyps [see Warnings and Precautions (5.12) ] Most commonly reported adverse reactions (≥1%): diarrhea, abdominal pain, nausea and constipation. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals America, Inc. at 1-877-TAKEDA-7 (1-877-825-3327) 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. Worldwide, over 10,000 patients have been treated with PREVACID in Phase 2 or Phase 3 clinical trials involving various dosages and durations of treatment. In general, PREVACID treatment has been well-tolerated in both short-term and long-term trials. The following adverse reactions were reported by the treating physician to have a possible or probable relationship to drug in 1% or more of PREVACID-treated patients and occurred at a greater rate in PREVACID-treated patients than placebo-treated patients in Table 1 . Table 1. Incidence of Possibly or Probably Treatment-Related Adverse Reactions in Short-Term, Placebo-Controlled PREVACID Studies Body System/Adverse Reaction PREVACID (N=2768) % Placebo (N=1023) % Body as a Whole Abdominal Pain 2.1 1.2 Digestive System Constipation 1.0 0.4 Diarrhea 3.8 2.3 Nausea 1.3 1.2 Headache was also seen at greater than 1% incidence but was more common on placebo. The incidence of diarrhea was similar between patients who received placebo and patients who received 15 and 30 mg of PREVACID, but higher in the patients who received 60 mg of PREVACID (2.9, 1.4, 4.2, and 7.4%, respectively). The most commonly reported possibly or probably treatment-related adverse event during maintenance therapy was diarrhea. In the risk reduction study of PREVACID for NSAID-associated gastric ulcers, the incidence of diarrhea for patients treated with PREVACID, misoprostol, and placebo was 5, 22, and 3%, respectively. Another study for the same indication, where patients took either a COX-2 inhibitor or lansoprazole and naproxen, demonstrated that the safety profile was similar to the prior study. Additional reactions from this study not previously observed in other clinical trials with PREVACID included contusion, duodenitis, epigastric discomfort, esophageal disorder, fatigue, hunger, hiatal hernia, hoarseness, impaired gastric emptying, metaplasia, and renal impairment. Additional adverse experiences occurring in less than 1% of patients or subjects who received PREVACID in domestic trials are shown below: Body as a Whole – abdomen enlarged, allergic reaction, asthenia, back pain, candidiasis, carcinoma, chest pain (not otherwise specified), chills, edema, fever, flu syndrome, halitosis, infection (not otherwise specified), malaise, neck pain, neck rigidity, pain, pelvic pain Cardiovascular System – angina, arrhythmia, bradycardia, cerebrovascular accident/cerebral infarction, hypertension/hypotension, migraine, myocardial infarction, palpitations, shock (circulatory failure), syncope, tachycardia, vasodilation Digestive System – abnormal stools, anorexia, bezoar, cardiospasm, cholelithiasis, colitis, dry mouth, dyspepsia, dysphagia, enteritis, eructation, esophageal stenos…