Lansoprazole

1 INDICATIONS AND USAGE PREVACID and PREVACID SoluTab are proton pump inhibitors (PPIs) indicated for the: Treatment of active duodenal ulcer in adults. Eradication of H. pylori to reduce the risk of duodenal ulcer recurrence in adults. Maintenance of healed duodenal ulcers in adults. Treatment of active benign gastric ulcer in adults. Healing of nonsteroidal anti-inflammatory drugs (NSAID)-associated gastric ulcer in adults. Risk reduction of NSAID-associated gastric ulcer in adults. Treatment of symptomatic gastroesophageal reflux disease (GERD) in adults and pediatric patients 1 year of age and older. Treatment of erosive esophagitis (EE) in adults and pediatric patients 1 year of age and older. Maintenance of healing of EE in adults. Pathological hypersecretory conditions, including Zollinger-Ellison syndrome (ZES) in adults.

1.1Treatment 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 .

1.2Eradication 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 . 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 . Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence . Please refer to the full prescribing information for amoxicillin.

1.3Maintenance 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 .

1.4Treatment 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 .

1.5Healing 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 .

1.6Risk 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 .

1.7Treatment 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 .

1.8Treatment of Erosive Esophagitis

(EE) 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 healing and symptom relief of all grades of EE. For adults 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 .

1.9Maintenance of Healing of

EE PREVACID and PREVACID SoluTab are indicated in adults to maintain healing of EE. Controlled studies did not extend beyond 12 months .

1.10Pathological Hypersecretory Conditions Including Zollinger-Ellison

Syndrome (ZES) PREVACID and PREVACID SoluTab are indicated in adults for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome .

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 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.

2.1Recommended 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.

2.2Recommended 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 . 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

2.3Hepatic Impairment The

recommended dosage is 15 mg orally daily in patients with severe liver impairment (Child-Pugh C) .

2.4Important Administration Information Take

PREVACID or PREVACID SoluTab before meals. Do not crush or chew PREVACID capsule or PREVACID SoluTab. Take PREVACID or PREVACID SoluTab at least 30 minutes prior to sucralfate . Antacids may be used concomitantly with PREVACID or PREVACID SoluTab. Missed doses: If a dose is missed, administer as soon as possible.

However, if the next scheduled dose is due, do not take the missed dose, and take the next dose on time. Do not take two doses at one time to make up for a missed dose. PREVACID capsules Swallow whole; do not chew. For patients who have difficulty swallowing capsules, PREVACID capsules can be opened and administered orally or via a nasogastric tube in the soft foods or liquids specified below.

Administration of PREVACID in foods or liquids other than those discussed below have not been studied clinically and therefore are not recommended. Administration in Soft Foods (applesauce, ENSURE pudding, cottage cheese, yogurt or strained pears): Open capsule. Sprinkle intact granules on one tablespoon of either applesauce, ENSURE pudding, cottage cheese, yogurt or strained pears.

Swallow immediately. Administration in Liquids (apple juice, orange juice or tomato juice): Open capsule. Sprinkle intact granules into a small volume of either apple juice, orange juice or tomato juice (60 mL – approximately two ounces). Mix briefly. Swallow immediately. To ensure complete delivery of the dose, rinse the glass with two or more volumes of juice and swallow the contents immediately.

Administration with Apple Juice Through a Nasogastric Tube (≥16 French) Open capsule. Sprinkle intact granules into 40 mL of apple juice. Mix briefly. Using a catheter-tipped syringe, draw up the mixture. Inject through the nasogastric tube into the stomach. Flush with additional apple juice to clear the tube.

PREVACID SoluTab Do not break or cut. Place the tablet on the tongue, allow it to disintegrate, with or without water, until the microgranules can be swallowed. Do not chew the microgranules. The tablet typically disintegrates in less than one minute. Alternatively, for children or other patients who have difficulty swallowing tablets, PREVACID SoluTab can be administered with water via oral syringe or NG tube as follows: Administration with Water in an Oral Syringe Place a 15 mg tablet in oral syringe and draw up 4 mL of water, or place a 30 mg tablet in oral syringe and draw up 10 mL of water.

Shake gently to allow for a quick dispersal. After the tablet has dispersed, administer the contents within 15 minutes of mixing into the mouth. Do not save the water and microgranule mixture for later use. Refill the syringe with approximately 2 mL (5 mL for the 30 mg tablet) of water, shake gently, and administer any remaining contents.

Administration with Water via a NG Tube (≥8 French) Place a 15 mg tablet in a catheter-tip syringe and draw up 4 mL of water, or place a 30 mg tablet in a catheter-tip syringe and draw up 10 mL of water. Shake gently to allow for a quick dispersal. After the tablet has dispersed, shake the catheter-tip syringe gently in order to keep the microgranules from settling, and immediately inject the mixture through the NG tube into the stomach within 15 minutes of mixing.

Do not save the water and microgranule mixture for later use. Refill the catheter-tip syringe with approximately 5 mL of water, shake gently, and flush the tube.

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. Acute Tubulointerstitial Nephritis : Discontinue treatment and evaluate patients. Clostridium difficile -Associated Diarrhea : PPI therapy may be associated with increased risk of Clostridium difficile -associated diarrhea. 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. 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. 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. Cyanocobalamin (Vitamin B12) Deficiency : Daily long-term use (e.g., longer than 3 years) may lead to malabsorption or a deficiency of cyanocobalamin. Hypomagnesemia and Mineral Metabolism : Hypomagnesemia has been reported rarely with prolonged treatment with PPIs. 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. Fundic Gland Polyps : Risk increases with long-term use, especially beyond 1 year. Use the shortest duration of therapy. 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 )

5.1Presence 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.

5.2Acute 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 .

5.3Clostridium

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 . 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 for use in combination with PREVACID or PREVACID SoluTab, refer to Warnings and Precautions section of their prescribing information.

5.4Bone Fracture Several

published observational studies suggest that 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 .

5.5Severe Cutaneous Adverse Reactions Severe

cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with the use of PPIs . Discontinue PREVACID or PREVACID SoluTab at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.6Cutaneous and Systemic Lupus Erythematosus Cutaneous

lupus erythematosus (CLE) and systemic lupus erythematosus (SLE) have been reported in patients taking PPIs, including lansoprazole. These events have occurred as both new onset and an exacerbation of existing autoimmune disease. The majority of PPI-induced lupus erythematosus cases were CLE. The most common form of CLE reported in patients treated with PPIs was subacute CLE (SCLE) and occurred within weeks to years after continuous drug therapy in patients ranging from infants to the elderly.

Generally, histological findings were observed without organ involvement. Systemic lupus erythematosus (SLE) is less commonly reported than CLE in patients receiving PPIs. PPI-associated SLE is usually milder than nondrug induced SLE. Onset of SLE typically occurred within days to years after initiating treatment primarily in patients ranging from young adults to the elderly.

The majority of patients presented with rash; however, arthralgia and cytopenia were also reported. Avoid administration of PPIs for longer than medically indicated. If signs or symptoms consistent with CLE or SLE are noted in patients receiving PREVACID or PREVACID SoluTab, discontinue the drug and refer the patient to the appropriate specialist for evaluation.

Most patients improve with discontinuation of the PPI alone in four to 12 weeks. Serological testing (e.g., ANA) may be positive and elevated serological test results may take longer to resolve than clinical manifestations.

5.7Cyanocobalamin

(Vitamin B12) Deficiency Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than three years) may lead to malabsorption of cyanocobalamin (Vitamin B12) caused by hypo- or achlorhydria. Rare reports of cyanocobalamin deficiency occurring with acid-suppressing therapy have been reported in the literature. This diagnosis should be considered if clinical symptoms consistent with cyanocobalamin deficiency are observed in patients treated with PREVACID or PREVACID SoluTab.

5.8Hypomagnesemia and Mineral Metabolism 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. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients.

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 . Consider monitoring magnesium and calcium levels prior to initiation of PREVACID or PREVACID SoluTab and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium, as necessary. If hypocalcemia is refractory to treatment, consider discontinuing the PPI.

5.9Interactions with 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. Healthcare providers should temporarily stop lansoprazole treatment at least 14 days 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 .

5.10Interaction with Methotrexate Literature

suggests that concomitant use of PPIs with methotrexate (primarily at high dose) 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 .

5.11Patients with Phenylketonuria Phenylalanine

can be harmful to patients with phenylketonuria (PKU). PREVACID SoluTab contains phenylalanine, a component of aspartame. Each 15 mg tablet contains 2.5 mg and each 30 mg tablet contains 5.1 mg of phenylalanine. Before prescribing PREVACID SoluTab to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including PREVACID SoluTab.

5.12Fundic Gland Polyps

PPI use is associated with an increased risk of fundic gland polyps that increases with long-term use, especially beyond one year. Most PPI users who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of PPI therapy appropriate to the condition being treated.

5.13Risk of Heart Valve Thickening in Pediatric

Patients Less Than One Year of Age PREVACID and PREVACID SoluTab are not approved in pediatric patients less than one year of age. Nonclinical studies in juvenile rats with lansoprazole have demonstrated an adverse effect of heart valve thickening. The risk of heart valve injury does not appear to be relevant to patients one year of age and older .

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 . Proton Pump Inhibitors (PPIs), including PREVACID and PREVACID SoluTab, are contraindicated with rilpivirine-containing products . 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.

Patients receiving rilpivirine-containing products. ( 4 , 7 )

8.1Pregnancy Risk Summary Available

data from published observational studies overall do not indicate an association of adverse pregnancy outcomes with lansoprazole treatment . 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 . 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 still decreased in the 100 mg/kg/day group at age 17 to 18 weeks. Growth plate thickness was decreased in the 100 mg/kg/day males on postnatal Day 21, and was increased in the 30 and 100 mg/kg/day males at age 17 to 18 weeks.

The effects on bone parameters were associated with reduction in body weight gain.

The following serious adverse reactions are described below and elsewhere in labeling: Acute Tubulointerstitial Nephritis Clostridium difficile -Associated Diarrhea Bone Fracture Severe Cutaneous Adverse Reactions Cutaneous and Systemic Lupus Erythematosus Cyanocobalamin (Vitamin B12) Deficiency Hypomagnesemia and Mineral Metabolism Fundic Gland Polyps Most commonly reported adverse reactions (≥1%): diarrhea, abdominal pain, nausea and constipation. 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 .

6.1Clinical 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

1.2Digestive System Constipation

1.0

0.4Diarrhea

3.8

2.3Nausea

1.3

1.2Headache

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 stenosis, esophageal ulcer, esophagitis, fecal discoloration, flatulence, gastric nodules/fundic gland polyps, gastritis, gastroenteritis, gastrointestinal anomaly, gastrointestinal disorder, gastrointestinal hemorrhage, glossitis, gum hemorrhage, hematemesis, increased appetite, increased salivation, melena, mouth ulceration, nausea and vomiting, nausea and vomiting and diarrhea, gastrointestinal moniliasis, rectal disorder, rectal hemorrhage, stomatitis, tenesmus, thirst, tongue disorder, ulcerative colitis, ulcerative stomatitis Endocrine System – diabetes mellitus, goiter, hypothyroidism Hemic and Lymphatic System – anemia, hemolysis, lymphadenopathy Metabolism and Nutritional Disorders – avitaminosis, gout, dehydration, hyperglycemia/hypoglycemia, peripheral edema, weight gain/loss Musculoskeletal System – arthralgia, arthritis, bone disorder, joint disorder, leg cramps, musculoskeletal pain, myalgia, myasthenia, ptosis, synovitis Nervous System – abnormal dreams, agitation, amnesia, anxiety, apathy, confusion, convulsion, dementia, depersonalization, depression, diplopia, dizziness, emotional lability, hallucinations, hemiplegia, hostility aggravated, hyperkinesia, hypertonia, hypesthesia, insomnia, libido decreased/increased, nervousness, neurosis, paresthesia, sleep disorder, somnolence, thinking abnormality, tremor, vertigo Respiratory System – asthma, bronchitis, cough increased, dyspnea, epistaxis, hemoptysis, hiccup, laryngeal neoplasia, lung fibrosis, pharyngitis, pleural disorder, pneumonia, respiratory disorder, upper respiratory inflammation/infection, rhinitis, sinusitis, stridor Skin and Appendages – acne, alopecia, contact dermatitis, dry skin, fixed eruption, hair disorder, maculopapular rash, nail disorder, pruritus, rash, skin carcinoma, skin disorder, sweating, urticaria Special Senses – abnormal vision, amblyopia, blepharitis, blurred vision, cataract, conjunctivitis, deafness, dry eyes, ear/eye disorder, eye pain, glaucoma, otitis media, parosmia, photophobia, retinal degeneration/disorder, taste loss, taste perversion, tinnitus, visual field defect Urogenital System – abnormal menses, breast enlargement, breast pain, breast tenderness, dysmenorrhea, dysuria, gynecomastia, impotence, kidney calculus, kidney pain, leukorrhea, menorrhagia, menstrual disorder, penis disorder, polyuria, testis disorder, urethral pain, urinary frequency, urinary retention, urinary tract infection, urinary urgency, urination impaired, vaginitis

6.2Postmarketing Experience Additional

adverse experiences have been reported since PREVACID and PREVACID SoluTab have been marketed. The majority of these cases are foreign-sourced and a relationship to PREVACID or PREVACID SoluTab has not been established. Because these reactions were reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

These events are listed below by COSTART body system. Body as a Whole – anaphylactic/anaphylactoid reactions, systemic lupus erythematosus; Digestive System – hepatotoxicity, pancreatitis, vomiting; Hemic and Lymphatic System – agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, neutropenia, pancytopenia, thrombocytopenia, and thrombotic thrombocytopenic purpura; Infections and Infestations – Clostridium difficile -associated diarrhea; Metabolism and Nutritional Disorders – hypomagnesemia, hypocalcemia, hypokalemia, hyponatremia; Musculoskeletal System – bone fracture, myositis; Skin and Appendages – severe dermatologic reactions including erythema multiforme, SJS/TEN (some fatal), DRESS, AGEP, cutaneous lupus erythematosus; Special Senses – speech disorder; Urogenital System – interstitial nephritis, urinary retention.

6.3Combination Therapy with Amoxicillin and Clarithromycin In

clinical trials using combination therapy with PREVACID plus amoxicillin and clarithromycin, and PREVACID plus amoxicillin, no adverse reactions peculiar to these drug combinations were observed. Adverse reactions that have occurred have been limited to those that had been previously reported with PREVACID, amoxicillin, or clarithromycin. Triple Therapy: PREVACID/amoxicillin/clarithromycin The most frequently reported adverse reactions for patients who received triple therapy for 14 days were diarrhea (7%), headache (6%), and taste perversion (5%).

There were no statistically significant differences in the frequency of reported adverse reactions between the 10 and 14 day triple therapy regimens. No treatment-emergent adverse reactions were observed at significantly higher rates with triple therapy than with any dual therapy regimen. Dual Therapy: PREVACID/amoxicillin The most frequently reported adverse reactions for patients who received PREVACID three times daily plus amoxicillin three times daily dual therapy were diarrhea (8%) and headache (7%).

No treatment-emergent adverse reactions were observed at significantly higher rates with PREVACID three times daily plus amoxicillin three times daily dual therapy than with PREVACID alone. For information about adverse reactions with antibacterial agents (amoxicillin and clarithromycin) indicated in combination with PREVACID or PREVACID SoluTab, refer to the Adverse Reactions section of their prescribing information.

6.4Laboratory Values The

following changes in laboratory parameters in patients who received PREVACID were reported as adverse reactions: Abnormal liver function tests, increased SGOT (AST), increased SGPT (ALT), increased creatinine, increased alkaline phosphatase, increased globulins, increased GGTP, increased/decreased/abnormal WBC, abnormal AG ratio, abnormal RBC, bilirubinemia, blood potassium increased, blood urea increased, crystal urine present, eosinophilia, hemoglobin decreased, hyperlipemia, increased/decreased electrolytes, increased/decreased cholesterol, increased glucocorticoids, increased LDH, increased/decreased/abnormal platelets, increased gastrin levels and positive fecal occult blood. Urine abnormalities such as albuminuria, glycosuria, and hematuria were also reported. Additional isolated laboratory abnormalities were reported.

In the placebo-controlled studies, when SGOT (AST) and SGPT (ALT) were evaluated, 0.4% (4/978) and 0.4% (11/2677) patients, who received placebo and PREVACID, respectively, had enzyme elevations greater than three times the upper limit of normal range at the final treatment visit. None of these patients who received PREVACID reported jaundice at any time during the study. In clinical trials using combination therapy with PREVACID plus amoxicillin and clarithromycin, and PREVACID plus amoxicillin, no increased laboratory abnormalities particular to these drug combinations were observed.

For information about laboratory value changes with antibacterial agents (amoxicillin and clarithromycin) indicated in combination with PREVACID or PREVACID SoluTab, refer to the Adverse Reactions section of their prescribing information.