1.1 Short-Term Treatment of Active Duodenal Ulcer

Lansoprazole delayed-release capsules are indicated for short-term treatment (for 4 weeks) for healing and symptom relief of active duodenal ulcer. [See Clinical Studies (14)]

1.2 H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Triple Therapy: Lansoprazole delayed-release capsules /amoxicillin /clarithromycin

Lansoprazole delayed-release capsules in combination with amoxicillin plus clarithromycin as triple therapy is indicated 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)] 

Please refer to the full prescribing information for amoxicillin and clarithromycin.

Dual Therapy: Lansoprazole delayed-release capsules /amoxicillin 

Dual Therapy: Lansoprazole delayed-release capsules /amoxicillinLansoprazole delayed-release capsules in combination with amoxicillin as dual therapy is indicated 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 package insert, MICROBIOLOGY section). Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence. [See Clinical Studies (14)]

Please refer to the full prescribing information for amoxicillin.

1.3 Maintenance of Healed Duodenal Ulcers

Lansoprazole delayed-release capsules are indicated to maintain healing of duodenal ulcers. Controlled studies do not extend beyond 12 months. [See Clinical Studies (14)]

1.4 Short-Term Treatment of Active Benign Gastric Ulcer

Lansoprazole delayed-release capsules are indicated for short-term treatment (up to 8 weeks) for healing and symptom relief of active benign gastric ulcer. [See Clinical Studies (14)]

1.5 Healing of NSAID-Associated Gastric Ulcer

Lansoprazole delayed-release capsules are indicated for the treatment of NSAID-associated gastric ulcer in patients who continue NSAID use. Controlled studies did not extend beyond 8 weeks. [See Clinical Studies (14)]

1.6 Risk Reduction of NSAID-Associated Gastric Ulcer

Lansoprazole delayed-release capsules are indicated 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)]

1.7 Gastroesophageal Reflux Disease (GERD)

1.8 Maintenance of Healing of Erosive Esophagitis (EE)

Lansoprazole delayed-release capsules are indicated to maintain healing of erosive esophagitis. Controlled studies did not extend beyond 12 months. [See Clinical Studies (14)]

1.9 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome (ZES)

Lansoprazole delayed-release capsules are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome. [See Clinical Studies (14)]

2.1 Recommended Dose

*  Please refer to amoxicillin and clarithromycin full prescribing information for CONTRAINDICATIONS and WARNINGS, and for information regarding dosing in elderly and renally-impaired patients.

† Controlled studies did not extend beyond indicated duration.

‡ For patients who do not heal with lansoprazole delayed-release capsules for 8 weeks (5 to 10%), it may be helpful to give an additional 8 weeks of treatment. If there is a recurrence of erosive esophagitis, an additional 8 week course of lansoprazole delayed-release capsules may be considered.

§The lansoprazole delayed-release capsules dose was increased (up to 30 mg twice daily) in some pediatric patients after 2 or more weeks of treatment if they remained symptomatic. For pediatric patients unable to swallow an intact capsule please see Administration Options.

¶  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 lansoprazole delayed-release capsules for more than 4 years.

# Controlled studies did not extend beyond 12 months

Patients should be instructed that if a dose is missed, it should be taken as soon as possible. However, if the next scheduled dose is due, the patient should not take the missed dose, and should be instructed to take the next dose on time. Patients should be instructed not to take 2 doses at one time to make up for a missed dose.

2.2 Special Populations

Renal impairment patients and geriatric patients do not require dosage adjustment. However, consider dose adjustment in patients with severe liver impairment. [See Use in Specific Populations (8.5, 8.6 and 8.7]

2.3 Important Administration Information

5.1 Gastric Malignancy

Symptomatic response to therapy with lansoprazole does not preclude the presence of gastric malignancy.

5.2 Acute Interstitial Nephritis

Acute interstitial nephritis has been observed in patients taking PPIs including lansoprazole. Acute interstitial nephritis may occur at any point during PPI therapy and is generally attributed to an idiopathic hypersensitivity reaction. Discontinue lansoprazole delayed-release capsules if acute interstitial nephritis develops [see Contraindications (4)].

5.3 Cyanocobalamin (vitamin B12) Deficiency

Daily treatment with any acid-suppressing medications over a long period of time (e.g., longer than 3 years) may lead to malabsorption of cyanocobalamin (vitamin 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.

5.4 Clostridium difficile Associated Diarrhea

Published observational studies suggest that proton pump inhibitor (PPI) therapy like lansoprazole delayed-release capsules 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 for use in combination with lansoprazole delayed release capsules, refer to WARNINGS and PRECAUTIONS sections of those package inserts.

5.5 Bone 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 [see Dosage and Administration (2) and Adverse Reactions (6.2)].  

5.6 Hypomagnesemia

Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI.  

For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2)].

5.7 Concomitant use of lansoprazole delayed-release capsules with Methotrexate

Literature suggests that concomitant use of PPIs with methotrexate (primarily at high dose; see methotrexate prescribing information) may elevate and prolong serum levels of methotrexate and/or its metabolite, possibly leading to methotrexate toxicities. In high-dose methotrexate administration, a temporary withdrawal of the PPI may be considered in some patients [see Drug Interactions (7.6) and Clinical Pharmacology (12.3)].

6.1 Clinical

Worldwide, over 10,000 patients have been treated with lansoprazole delayed-release capsules in Phase 2 or Phase 3 clinical trials involving various dosages and durations of treatment. In general, lansoprazole delayed-release capsules treatment has been well-tolerated in both short-term and long-term trials.

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.

The following adverse reactions were reported by the treating physician to have a possible or probable relationship to drug in 1% or more of lansoprazole delayed-release capsules-treated patients and occurred at a greater rate in lansoprazole delayed-release capsules-treated patients than placebo-treated patients in Table 1.

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 mg and 30 mg of lansoprazole delayed-release capsules, but higher in the patients who received 60 mg of lansoprazole delayed-release capsules (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 lansoprazole delayed-release capsules for NSAID-associated gastric ulcers, the incidence of diarrhea for patients treated with lansoprazole delayed-release capsules, 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 lansoprazole delayed-release capsules 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 lansoprazole delayed-release capsules 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.

6.2 Postmarketing Experience

Additional adverse experiences have been reported since lansoprazole delayed-release capsules has been marketed. The majority of these cases are foreign-sourced and a relationship to lansoprazole delayed-release capsules 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; 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; Musculoskeletal System - bone fracture,myositis; Skin and Appendages – severe dermatologic reactions including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal); Special Senses - speech disorder; Urogenital System – interstitial nephritis, urinary retention.

6.3 Combination Therapy with Amoxicillin and Clarithromycin

In clinical trials using combination therapy with lansoprazole delayed-release capsules plus amoxicillin and clarithromycin, and lansoprazole delayed-release capsules 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 lansoprazole delayed-release capsules, amoxicillin, or clarithromycin.  

Triple Therapy: Lansoprazole delayed-release capsules /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: Lansoprazole delayed-release capsules /amoxicillin

The most frequently reported adverse reactions for patients who received lansoprazole delayed-release capsules 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 lansoprazole delayed-release capsules three times daily plus amoxicillin three times daily dual therapy than with lansoprazole delayed-release capsules alone.

For information about adverse reactions with antibacterial agents (amoxicillin and clarithromycin) indicated in combination with lansoprazole delayed-release capsules, refer to the ADVERSE REACTIONS section of their package inserts.

6.4 Laboratory Values

The following changes in laboratory parameters in patients who received lansoprazole delayed-release capsules 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 lansoprazole delayed-release capsules, 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 lansoprazole delayed-release capsules reported jaundice at any time during the study.

In clinical trials using combination therapy with lansoprazole delayed-release capsules plus amoxicillin and clarithromycin, and lansoprazole delayed-release capsules 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 lansoprazole delayed-release capsules, refer to the ADVERSE REACTIONS section of their package inserts.

7.1 Drugs with pH-Dependent Absorption Kinetics

Due to its effects on gastric acid secretion, lansoprazole 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 ampicillin esters, ketoconazole, atazanavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) can decrease, while the absorption of drugs such as digoxin can increase during treatment with lansoprazole delayed-release capsules [see Clinical Pharmacology (12.3)]. 

Lansoprazole delayed-release capsules are likely to substantially decrease the systemic concentrations of the HIV protease inhibitor atazanavir, which is dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir and the development of HIV resistance. Therefore, lansoprazole delayed-release capsules should not be co-administered with atazanavir [see Clinical Pharmacology (12.3)].

Co-administration 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 PPIs and MMF. Use lansoprazole delayed-release capsules with caution in transplant patients receiving MMF. 

7.2 Warfarin

In a study of healthy subjects, co-administration of single or multiple 60 mg doses of lansoprazole delayed-release capsules and warfarin did not affect the pharmacokinetics of warfarin nor prothrombin time (see Clinical Pharmacology (12.3). However, there have been reports of 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. Patients treated with PPIs and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time. [See Clinical Pharmacology (12.3)]

7.3 Tacrolimus

Concomitant administration of lansoprazole and tacrolimus may increase whole blood levels of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.

7.4 Theophylline

A minor increase (10%) in the clearance of theophylline was observed following the administration of lansoprazole delayed-release capsules concomitantly with theophylline. Although the magnitude of the effect on theophylline clearance is small, individual patients may require additional titration of their theophylline dosage when lansoprazole delayed-release capsules is started or stopped to ensure clinically effective blood levels. [See Clinical Pharmacology (12.3)]

7.5 Clopidogrel

Concomitant administration of lansoprazole and clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition [see Clinical Pharmacology (12.3)]. No dose adjustment of clopidogrel is necessary when administered with an approved dose of lansoprazole delayed-release capsules.

7.6 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 high dose methotrexate with PPIs have been conducted [see Warnings and Precautions (5.7)]. 

In a study of rheumatoid arthritis patients receiving low-dose methotrexate, lansoprazole delayed-release capsules and naproxen, no effect on pharmacokinetics of methotrexate was observed [see Clinical Pharmacology (12.3)].

7.7 Combination Therapy with Clarithromycin

Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions [see Warnings and Precautions in prescribing information for clarithromycin]. Because of these drug interactions, clarithromycin is contraindicated for co-administration with certain drugs [see Contraindications in prescribing information for clarithromycin].

For information on drug interactions for amoxicillin or clarithromycin, refer to their full prescribing information, DRUG INTERACTIONS sections.

8.1 Pregnancy

8.3 Nursing Mothers

Lansoprazole or its metabolites are excreted in the milk of rats. It is not known whether lansoprazole is excreted in human milk. Because many drugs are excreted in human milk, because of the potential for serious adverse reactions in nursing infants from lansoprazole, and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue lansoprazole, taking into account the importance of lansoprazole to the mother.

8.4 Pediatric Use

The safety and effectiveness of lansoprazole delayed-release capsules have been established in pediatric patients 1 to 17 years of age for short-term treatment of symptomatic GERD and erosive esophagitis.

8.5 Geriatric Use

No dosage adjustment of lansoprazole delayed-release capsules is necessary in geriatric patients. The incidence rates of lansoprazole delayed-release capsules-associated adverse reactions and laboratory test abnormalities are similar to those seen in younger patients. [See Clinical Pharmacology (12.3)]

8.6 Renal Impairment

No dosage adjustment of lansoprazole delayed-release capsules is necessary in patients with renal impairment. The pharmacokinetics of lansoprazole in patients with various degrees of renal impairment were not substantially different compared to those in subjects with normal renal function. [See Clinical Pharmacology (12.3)]

8.7 Hepatic Impairment

In patients with various degrees of chronic hepatic impairment, an increase in the mean AUC of up to 500% was observed at steady state compared to healthy subjects. Consider dose reduction in patients with severe hepatic impairment. [See Clinical Pharmacology (12.3)]

8.8 Gender

Over 4,000 women were treated with lansoprazole delayed-release capsules. Ulcer healing rates in females were similar to those in males. The incidence rates of adverse reactions in females were similar to those seen in males. [See Clinical Pharmacology (12.3)]

8.9 Race

The pooled mean pharmacokinetic parameters of lansoprazole delayed-release capsules from twelve U.S. Phase 1 studies (N=513) were compared to the mean pharmacokinetic parameters from two Asian studies (N=20). The mean AUCs of lansoprazole delayed-release capsules in Asian subjects were approximately twice those seen in pooled U.S. data; however, the inter-individual variability was high. The Cmax values were comparable.

12.1 Mechanism of Action

Lansoprazole belongs to a class of antisecretory compounds, the substituted benzimidazoles, that suppress gastric acid secretion by specific inhibition of the (H+, K+)-ATPase enzyme system at the secretory surface of the gastric parietal cell. Because this enzyme system is regarded as the acid (proton) pump within the parietal cell, lansoprazole has been characterized as a gastric acid-pump inhibitor, in that it blocks the final step of acid production. This effect is dose-related and leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. Lansoprazole does not exhibit anticholinergic or histamine type-2 antagonist activity.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Lansoprazole delayed-release capsules contain an enteric-coated granule formulation of lansoprazole. Absorption of lansoprazole begins only after the granules leave the stomach. Absorption is rapid, with mean peak plasma levels of lansoprazole occurring after approximately 1.7 hours. After a single-dose administration of 15 mg to 60 mg of oral lansoprazole, the peak plasma concentrations (Cmax) of lansoprazole and the area under the plasma concentration curves (AUCs) of lansoprazole were approximately proportional to the administered dose. Lansoprazole does not accumulate and its pharmacokinetics are unaltered by multiple dosing.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated with oral lansoprazole doses of 5 to 150 mg/kg/day –about 1 to 40 times the exposure on a body surface (mg/m2) basis of a 50 kg person of average height [1.46 m2 body surface area (BSA)] given the recommended human dose of 30 mg/day. Lansoprazole produced dose-related gastric enterochromaffin-like (ECL) cell hyperplasia and ECL cell carcinoids in both male and female rats. It also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg/kg/day (4 to 40 times the recommended human dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat.

In a 24-month carcinogenicity study, CD-1 mice were treated with oral lansoprazole doses of 15 to 600 mg/kg/day, 2 to 80 times the recommended human dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 and 600 mg/kg/day (40 to 80 times the recommended human dose based on BSA) and female mice treated with 150 to 600 mg/kg/day (20 to 80 times the recommended human dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg/kg/day (10 to 80 times the recommended human dose based on BSA).

A 26-week p53 (+/-) transgenic mouse carcinogenicity study was not positive.

Lansoprazole was positive in the Ames test and the in vitro human lymphocyte chromosomal aberration assay.Lansoprazole was not genotoxic in the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus test, or the rat bone marrow cell chromosomal aberration test.

Lansoprazole at oral doses up to 150 mg/kg/day (40 times the recommended human dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats.

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies

Reproduction studies have been 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 (BSA)] and pregnant rabbits at oral lansoprazole doses up to 30 mg/kg/day (16 times the recommended human dose based on BSA) and have revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole.

Duodenal Ulcer

In a U.S. multicenter, double-blind, placebo-controlled, dose-response (15, 30, and 60 mg of lansoprazole delayed-release capsules once daily) study of 284 patients with endoscopically documented duodenal ulcer, the percentage of patients healed after two and four weeks was significantly higher with all doses of lansoprazole delayed-release capsules than with placebo. There was no evidence of a greater or earlier response with the two higher doses compared with lansoprazole delayed-release capsules 15 mg. Based on this study and the second study described below, the recommended dose of lansoprazole delayed-release capsules in duodenal ulcer is 15 mg per day (Table 7).

Lansoprazole delayed-release capsules 15 mg was significantly more effective than placebo in relieving day and nighttime abdominal pain and in decreasing the amount of antacid taken per day.

In a second U.S. multicenter study, also double-blind, placebo-controlled, dose-comparison (15 and 30 mg of lansoprazole delayed-release capsules once daily), and including a comparison with ranitidine, in 280 patients with endoscopically documented duodenal ulcer, the percentage of patients healed after four weeks was significantly higher with both doses of lansoprazole delayed-release capsules than with placebo. There was no evidence of a greater or earlier response with the higher dose of lansoprazole delayed-release capsules. Although the 15 mg dose of lansoprazole delayed-release capsules was superior to ranitidine at 4 weeks, the lack of significant difference at 2 weeks and the absence of a difference between 30 mg of lansoprazole delayed-release capsules and ranitidine leaves the comparative effectiveness of the two agents undetermined (Table 8). [See Indications and Usage (1.1)]

H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence

Randomized, double-blind clinical studies performed in the U.S. in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) evaluated the efficacy of lansoprazole delayed-release capsules in combination with amoxicillin capsules and clarithromycin tablets as triple 14 day therapy or in combination with amoxicillin capsules as dual 14 day therapy for the eradication of H. pylori. Based on the results of these studies, the safety and efficacy of two different eradication regimens were established:  

Triple therapy: Lansoprazole delayed-release capsules 30 mg twice daily / amoxicillin 1 gm twice daily / clarithromycin 500 mg twice daily

Dual therapy: Lansoprazole delayed-release capsules 30 mg three times daily / amoxicillin 1 gm three times daily  

All treatments were for 14 days. H. pylori eradication was defined as two negative tests (culture and histology) at 4 to 6 weeks following the end of treatment.  Triple therapy was shown to be more effective than all possible dual therapy combinations. Dual therapy was shown to be more effective than both monotherapies. Eradication of H. pylori has been shown to reduce the risk of duodenal ulcer recurrence.  A randomized, double-blind clinical study performed in the U.S. in patients with H. pylori and duodenal ulcer disease (defined as an active ulcer or history of an ulcer within one year) compared the efficacy of lansoprazole triple therapy for 10 and 14 days. This study established that the 10-day triple therapy was equivalent to the 14-day triple therapy in eradicating H. pylori (Tables 9 and 10). [See Indications and Usage (1.2)]  

Table 9 H. pylori Eradication Rates – Triple Therapy (Lansoprazole/ amoxicillin/clarithromycin) Percent of Patients Cured

[95% Confidence Interval]

(Number of patients)

*Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest, histology and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the evaluable analysis as failures of therapy.

#Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy.

†(p<0.05) versus lansoprazole /amoxicillin and lansoprazole /clarithromycin dual therapy.

‡(p<0.05) versus clarithromycin/amoxicillin dual therapy. 

+The 95% confidence interval for the difference in eradication rates, 10-day minus 14-day is (-10.5, 8.1) in the evaluable analysis and (-9.7, 9.1) in the intent-to-treat analysis.  

Table 10 H. pylori Eradication Rates – 14-Day Dual Therapy (lansoprazole /amoxicillin) Percent of Patients Cured

[95% Confidence Interval]

(Number of patients)

* Based on evaluable patients with confirmed duodenal ulcer (active or within one year) and H. pylori infection at baseline defined as at least two of three positive endoscopic tests from CLOtest, histology and/or culture. Patients were included in the analysis if they completed the study. Additionally, if patients dropped out of the study due to an adverse event related to the study drug, they were included in the analysis as failures of therapy.

# Patients were included in the analysis if they had documented H. pylori infection at baseline as defined above and had a confirmed duodenal ulcer (active or within one year). All dropouts were included as failures of therapy.

† (p<0.05) versus lansoprazole alone.

‡ (p<0.05) versus lansoprazole alone or amoxicillin alone.

Long-Term Maintenance Treatment of Duodenal Ulcers

lansoprazole delayed-release capsules has been shown to prevent the recurrence of duodenal ulcers. Two independent, double-blind, multicenter, controlled trials were conducted in patients with endoscopically confirmed healed duodenal ulcers. Patients remained healed significantly longer and the number of recurrences of duodenal ulcers was significantly less in patients treated with lansoprazole delayed-release capsules than in patients treated with placebo over a 12-month period (Table 11). [See Indications and Usage (1.3)]

In trial #2, no significant difference was noted between lansoprazole delayed-release capsules 15 mg and 30 mg in maintaining remission.

Gastric Ulcer

In a U.S. multicenter, double-blind, placebo-controlled study of 253 patients with endoscopically documented gastric ulcer, the percentage of patients healed at four and eight weeks was significantly higher with lansoprazole delayed-release capsules 15 mg and 30 mg once a day than with placebo (Table 12). [See Indications and Usage (1.4)]

Patients treated with any lansoprazole delayed-release capsules dose reported significantly less day and night abdominal pain along with fewer days of antacid use and fewer antacid tablets used per day than the placebo group.

Independent substantiation of the effectiveness of lansoprazole delayed-release capsules 30 mg was provided by a meta-analysis of published and unpublished data.

Healing of NSAID-Associated Gastric Ulcer

In two U.S. and Canadian multicenter, double-blind, active-controlled studies in patients with endoscopically confirmed NSAID-associated gastric ulcer who continued their NSAID use, the percentage of patients healed after 8 weeks was statistically significantly higher with 30 mg of lansoprazole delayed-release capsules than with the active control. A total of 711 patients were enrolled in the study, and 701 patients were treated. Patients ranged in age from 18 to 88 years (median age 59 years), with 67% female patients and 33% male patients. Race was distributed as follows: 87% Caucasian, 8% Black, 5% Other. There was no statistically significant difference between lansoprazole delayed-release capsules 30 mg daily and the active control on symptom relief (i.e., abdominal pain) (Table 13). [See Indications and Usage (1.5)]

Risk Reduction of NSAID-Associated Gastric Ulcer

In one large U.S., multicenter, double-blind, placebo- and misoprostol-controlled (misoprostol blinded only to the endoscopist) study in patients who required chronic use of an NSAID and who had a history of an endoscopically documented gastric ulcer, the proportion of patients remaining free from gastric ulcer at 4, 8, and 12 weeks was significantly higher with 15 or 30 mg of lansoprazole than placebo. A total of 537 patients were enrolled in the study, and 535 patients were treated. Patients ranged in age from 23 to 89 years (median age 60 years), with 65% female patients and 35% male patients. Race was distributed as follows: 90% Caucasian, 6% Black, 4% other. The 30 mg dose of lansoprazole demonstrated no additional benefit in risk reduction of the NSAID-associated gastric ulcer than the 15 mg dose (Table 14). [See Indications and Usage (1.6)]

Gastroesophageal Reflux Disease (GERD)

Symptomatic GERD: In a U.S. multicenter, double-blind, placebo-controlled study of 214 patients with frequent GERD symptoms, but no esophageal erosions by endoscopy, significantly greater relief of heartburn associated with GERD was observed with the administration of lansoprazole 15 mg once daily up to 8 weeks than with placebo. No significant additional benefit from lansoprazole 30 mg once daily was observed.

The intent-to-treat analyses demonstrated significant reduction in frequency and severity of day and night heartburn. Data for frequency and severity for the 8-week treatment period are presented in Table 15 and in Figures 1 and 2:

Table 12: Frequency of Heartburn

Variable	Placebo (n=43)	Lansoprazole 15 mg (n=80)	Lansoprazole 30 mg (n=86)
	Median
* (p<0.01) versus placebo.
% of Days without Heartburn
Week 1	0%	71%*	46%*
Week 4	11%	81%*	76%*
Week 8	13%	84%*	82%*
% of Nights without Heartburn
Week 1	17%	86%*	57%*
Week 4	25%	89%*	73%*
Week 8	36%	92%*	80%*

Figure 1

Figure 2

In two U.S., multicenter double-blind, ranitidine-controlled studies of 925 total patients with frequent GERD symptoms, but no esophageal erosions by endoscopy, lansoprazole 15 mg was superior to ranitidine 150 mg (twice daily) in decreasing the frequency and severity of day and night heartburn associated with GERD for the 8-week treatment period. No significant additional benefit from lansoprazole 30 mg once daily was observed. [See Indications and Usage (1.7)]

Erosive Esophagitis

In a U.S. multicenter, double-blind, placebo-controlled study of 269 patients entering with an endoscopic diagnosis of esophagitis with mucosal grading of 2 or more and grades 3 and 4 signifying erosive disease, the percentages of patients with healing are presented in Table 16:

In this study, all lansoprazole groups reported significantly greater relief of heartburn and less day and night abdominal pain along with fewer days of antacid use and fewer antacid tablets taken per day than the placebo group.

Although all doses were effective, the earlier healing in the higher two doses suggests 30 mg daily as the recommended dose.

Lansoprazole was also compared in a U.S. multicenter, double-blind study to a low dose of ranitidine in 242 patients with erosive reflux esophagitis.Lansoprazoles at a dose of 30 mg was significantly more effective than ranitidine 150 mg twice daily as shown below (Table 17).

In addition, patients treated with lansoprazole reported less day and nighttime heartburn and took less antacid tablets for fewer days than patients taking ranitidine 150 mg twice daily.

Although this study demonstrates effectiveness of lansoprazole in healing erosive esophagitis, it does not represent an adequate comparison with ranitidine because the recommended ranitidine dose for esophagitis is 150 mg four times daily, twice the dose used in this study.

In the two trials described and in several smaller studies involving patients with moderate to severe erosive esophagitis, lansoprazole produced healing rates similar to those shown above.

In a U.S. multicenter, double-blind, active-controlled study, 30 mg of lansoprazole was compared with ranitidine 150 mg twice daily in 151 patients with erosive reflux esophagitis that was poorly responsive to a minimum of 12 weeks of treatment with at least one H2-receptor antagonist given at the dose indicated for symptom relief or greater, namely, cimetidine 800 mg/day, ranitidine 300 mg/day, famotidine 40 mg/day or nizatidine 300 mg/day. Lansoprazole 30 mg was more effective than ranitidine 150 mg twice daily in healing reflux esophagitis, and the percentage of patients with healing were as follows. This study does not constitute a comparison of the effectiveness of histamine H2-receptor antagonists with lansoprazole , as all patients had demonstrated unresponsiveness to the histamine H2-receptor antagonist mode of treatment. It does indicate, however, that lansoprazole may be useful in patients failing on a histamine H2-receptor antagonist (Table 18). [See Indications and Usage (1.7)]

Long-Term Maintenance Treatment of Erosive Esophagitis

Two independent, double-blind, multicenter, controlled trials were conducted in patients with endoscopically confirmed healed esophagitis. Patients remained in remission significantly longer and the number of recurrences of erosive esophagitis was significantly less in patients treated with lansoprazole than in patients treated with placebo over a 12-month period (Table 19).

Regardless of initial grade of erosive esophagitis, lansoprazole 15 mg and 30 mg were similar in maintaining remission.

In a U.S., randomized, double-blind, study, lansoprazole 15 mg daily (n = 100) was compared with ranitidine 150 mg twice daily (n = 106), at the recommended dosage, in patients with endoscopically-proven healed erosive esophagitis over a 12-month period. Treatment with lansoprazoles resulted in patients remaining healed (Grade 0 lesions) of erosive esophagitis for significantly longer periods of time than those treated with ranitidine (p<0.001). In addition, lansoprazoles was significantly more effective than ranitidine in providing complete relief of both daytime and nighttime heartburn. Patients treated with lansoprazoles remained asymptomatic for a significantly longer period of time than patients treated with ranitidine. [See Indications and Usage (1.8)]

Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome

In open studies of 57 patients with pathological hypersecretory conditions, such as Zollinger-Ellison syndrome (ZES) with or without multiple endocrine adenomas, lansoprazole significantly inhibited gastric acid secretion and controlled associated symptoms of diarrhea, anorexia and pain. Doses ranging from 15 mg every other day to 180 mg per day maintained basal acid secretion below 10 mEq/hr in patients without prior gastric surgery and below 5 mEq/hr in patients with prior gastric surgery.

Initial doses were titrated to the individual patient need, and adjustments were necessary with time in some patients. [See Dosage and Administration (2.1)] lansoprazole was well tolerated at these high dose levels for prolonged periods (greater than four years in some patients). In most ZES patients, serum gastrin levels were not modified by lansoprazole. However, in some patients, serum gastrin increased to levels greater than those present prior to initiation of lansoprazole therapy. [See Indications and Usage (1.9)]

Store at 20°–25° C (68°–77° F); [See USP Controlled Room Temperature].

Information for Patients

Lansoprazole is available as a capsule and is available in 15 mg and 30 mg strengths. Directions for use specific to the route and available methods of administration is presented below. [See Dosage and Administration (2.3)]

•

Lansoprazole should be taken before eating.

•

Lansoprazole products SHOULD NOT BE CRUSHED OR CHEWED.