1.1 Treatment of Active Duodenal Ulcer

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

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

Lansoprazole delayed-release capsules 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

Lansoprazole delayed-release capsules 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

Lansoprazole delayed-release capsules 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

Lansoprazole delayed-release capsules 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

Lansoprazole delayed-release capsules 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)

1.8 Treatment of Erosive Esophagitis (EE)

Lansoprazole delayed-release capsules 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 lansoprazole delayed-release capsules 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 lansoprazole delayed-release capsules may be considered [see Clinical Studies (14.8)].

1.9 Maintenance of Healing of EE

Lansoprazole delayed-release capsules are indicated in adults to maintain healing of EE. Controlled studies did not extend beyond 12 months [see Clinical Studies ( 14.9)].

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

Lansoprazole delayed-release capsules are indicated in adults for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome [see Clinical Studies (14.10)].

2.1 Recommended Adult Dosage by Indication

* Please refer to amoxicillin and clarithromycin full prescribing information for Contraindications and Warnings and Precautions sections, 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 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 lansoprazole delayed-release capsules may be considered.

¶ 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 four years.

# Controlled studies did not extend beyond 12 months

2.2 Recommended Pediatric Dosage by Indication

Pediatric patients 1 to 11 Years of Age

In clinical clinical studies, lansoprazole was not administered beyond 12 weeks in 1 to 11 year olds. It is not known if lansoprazole 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)].

Pediatric patients 12 to 17 Years of Age

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 lansoprazole delayed-release capsules before meals.
• Do not crush or chew lansoprazole delayed-release capsules.
• Take lansoprazole delayed-release capsules at least 30 minutes prior to sucralfate [see Drug Interactions (7)].
• Antacids may be used concomitantly with lansoprazole delayed-release capsules.
• 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.

Lansoprazole Delayed-Release Capsules

• Swallow whole; do not chew.
• For patients who have difficulty swallowing capsules, lansoprazole delayed-release capsules can be opened and administered orally or via a nasogastric tube in the soft foods or liquids specified below.
• Administration of lansoprazole delayed-release capsules 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.

5.1 Presence of Gastric Malignancy

In adults, symptomatic response to therapy with lansoprazole delayed-release capsules 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 Interstitial 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 extrarenal manifestations (e.g., fever, rash or arthralgia). Discontinue lansoprazole delayed-release capsules and evaluate patients with suspected acute TIN [see Contraindications (4)].

5.3 Clostridium difficile-Associated Diarrhea

Published observational studies suggest that 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 section of their prescribing information.

5.4 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) ].

5.5 Severe 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 [see Adverse Reactions ( 6.2)]. Discontinue lansoprazole delayed-release capsules at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.6 Cutaneous 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 non-drug 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 lansoprazole delayed-release capsules 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.

5.7 Cyanocobalamin (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 lansoprazole delayed-release capsules.

5.8 Hypomagnesemia 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. 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), healthcare professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions (6.2)].

5.9 Interactions 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 [see Drug Interactions (7), Clinical Pharmacology (12.2)].

5.10 Interaction 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 [see Drug Interactions (7), Clinical Pharmacology (12.3)].

5.12 Fundic 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.

5.13 Risk of Heart Valve Thickening in Pediatric Patients Less Than One Year of Age

Lansoprazole delayed-release capsules 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 [ see Use in Specific Populations (8.4)].

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 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.
• 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 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 have 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, 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; Musculoskeletal System - bone fracture, myositis; Skin and Appendages – severe dermatologic reactions including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal), cutaneous lupus erythematosus; 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 prescribing information.

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 prescribing information.

8.1 Pregnancy

8.2 Lactation

Risk Summary

There is no information regarding the presence of lansoprazole in human milk, the effects on the breastfed infant, or the effects on milk production. However, lansoprazole and its metabolites are present in rat milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for lansoprazole delayed-release capsules and any potential adverse effects on the breastfed child from lansoprazole delayed-release capsules or from the underlying maternal condition.

8.4 Pediatric Use

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

In clinical studies of symptomatic GERD and erosive esophagitis, lansoprazole was not administered beyond 12 weeks in patients one year to 11 years of age. It is not known if lansoprazole delayed-release capsules are safe and effective if used longer than the recommended duration. Do not exceed the recommended dose and duration of use in pediatric patients (see Juvenile Animal Toxicity Data).

Lansoprazole was not effective in pediatric patients with symptomatic GERD one month to less than one year of age in a multicenter, double-blind, placebo-controlled study. Therefore, safety and effectiveness have not been established in patients less than one year. Nonclinical studies in juvenile rats have demonstrated an adverse effect of heart valve thickening and bone changes at lansoprazole doses higher than the maximum recommended equivalent human dose.

8.5 Geriatric Use

Of the total number of patients (n=21,486) in clinical studies of lansoprazole delayed-release capsules, 16% of patients were aged 65 years and over, while 4% were 75 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)].

8.6 Hepatic Impairment

In patients with various degrees of chronic hepatic impairment the exposure to lansoprazole was increased compared to healthy subjects with normal hepatic function [see Clinical Pharmacology (12.3)] . No dosage adjustment for lansoprazole delayed-release capsules are necessary for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. The recommended dosage is 15 mg orally daily in patients with severe hepatic impairment (Child-Pugh Class C) [see Dosage and Administration (2.3) ].

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

Absorption:

Lansoprazole delayed-release capsules contain an enteric-coated granule formulation of lansoprazole (because lansoprazole is acid-labile), so that absorption of lansoprazole begins only after the granules leave the stomach. The mean peak plasma levels of lansoprazole occur at approximately 1.7 hours. After a single-dose administration of 15 mg to 60 mg of oral lansoprazole, the peak plasma concentrations (C max) 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.

12.4 Microbiology

Microbiology

Lansoprazole, clarithromycin and/ or amoxicillin have been shown to be active against most strains of Helicobacter pylori in vitro and in clinical infections [see Indications and Usage (1.2)].

Helicobacter pylori Pre-treatment Resistance

Clarithromycin pretreatment resistance (≥2 mcg/mL) was 9.5% (91/960) by E-test and 11.3% (12/106) by agar dilution in the dual and triple therapy clinical trials (M93-125, M93-130, M93-131, M95-392, and M95-399).

Amoxicillin pre-treatment susceptible isolates (≤0.25 mcg/mL) occurred in 97.8% (936/957) and 98% (98/100) of the patients in the dual and triple therapy clinical trials by E-test and agar dilution, respectively. Twenty one of 957 patients (2.2%) by E-test and two of 100 patients (2%) by agar dilution had amoxicillin pre-treatment MICs of greater than 0.25mcg/mL. One patient on the 14 day triple therapy regimen had an unconfirmed pre-treatment amoxicillin minimum inhibitory concentration (MIC) of greater than 256 mcg/mL by E-test and the patient was eradicated of H. pylori ( Table 8).

*Includes only patients with pre-treatment clarithromycin susceptibility test results

†Susceptible (S) MIC ≤ 0.25 mcg/mL, Intermediate (I) MIC 0.5 to1 mcg/mL, Resistant (R) MIC ≥2 mcg/mL

Patients not eradicated of H. pylori following lansoprazole/amoxicillin/clarithromycin triple therapy will likely have clarithromycin resistant H. pylori. Therefore, for those patients who fail therapy, clarithromycin susceptibility testing should be done when possible. Patients with clarithromycin resistant H. pylori should not be treated with lansoprazole/amoxicillin/clarithromycin triple therapy or with regimens which include clarithromycin as the sole antimicrobial agent.

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes: In the dual and triple therapy clinical trials, 82.6% (195/236) of the patients that had pre-treatment amoxicillin susceptible MICs (≤0.25 mcg/mL) were eradicated of H. pylori. Of those with pre-treatment amoxicillin MICs of greater than 0.25 mcg/mL, three of six had the H. pylori eradicated. A total of 30% (21/70) of the patients failed lansoprazole 30 mg three times daily /amoxicillin 1 g three times daily dual therapy and a total of 12.8% (22/172) of the patients failed the 10 and 14 day triple therapy regimens. Post-treatment susceptibility results were not obtained on 11 of the patients who failed therapy. Nine of the 11 patients with amoxicillin post-treatment MICs that failed the triple therapy regimen also had clarithromycin resistant H. pylori isolates.

Susceptibility Test for Helicobacter pylori: For susceptibility testing information about Helicobacter pylori, see Microbiology section in prescribing information for clarithromycin and amoxicillin.

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 one to 40 times the exposure on a body surface (mg/m 2) basis of a 50 kg person of average height [1.46 m 2 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 (four 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, two 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.

14.1 Duodenal Ulcer

In a U.S. multi-center, double-blind, placebo-controlled, dose-response (15, 30, and60 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 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 in duodenal ulcer is 15 mg per day (Table 9).

* p≤0.001) versus placebo.

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. multi-center 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. Although the 15 mg dose of lansoprazole delayed-release capsules was superior to ranitidine at four weeks, the lack of significant difference at two 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 10) [see Indications and Usage (1.1)].

* (p≤0.05) versus placebo and ranitidine.

+ (p≤0.05) versus placebo.

14.2 Eradication of H. pylori 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 and clarithromycin as triple 14 day therapy or in combination with amoxicillin 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 g twice daily / clarithromycin 500 mg twice daily

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

All treatments were for 14 days. H. pylori eradication was defined as two negative tests (culture and histology) at four to six 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 11 and 12) [see Indications and Usage (1.2)].

Table 11

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) vs lansoprazole /amoxicillin and lansoprazole /clarithromycin dual therapy.

§ (p<0.05) vs 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 12

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 CLO test, 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) vs lansoprazole alone.

§ (p<0.05) vs lansoprazole alone or amoxicillin alone.

14.3 Maintenance of Healed Duodenal Ulcers

Lansoprazole 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 than in patients treated with placebo over a 12 month period (Table 13) [see Indications and Usage (1.3)].

%=Life Table Estimate

* (p≤0.001) vs placebo.

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

14.4 Gastric Ulcer

In a U.S. multi-center, 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 14) [see Indications and Usage (1.4)].

* (p≤0.05) vs placebo.

Patients treated with any lansoprazole 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.

14.5 Healing of NSAID-Associated Gastric Ulcer

In two U.S. and Canadian multi-center, 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 eight 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 15) [see Indications and Usage (1.5)].

• * Actual observed ulcer(s) healed at time points ±2 days
• † Dose for healing of gastric ulcer
• ‡ (p≤0.05) vs the active control

14.6 Risk Reduction of NSAID-Associated Gastric Ulcer

In one large U.S., multi-center, 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 four, eight, 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 16) [see Indications and Usage (1.6)].

*%= Life Table Estimate

(p<0.001) Lansoprazole 15 mg daily vs placebo; lansoprazole 30 mg daily vs placebo; and misoprostol 200 mcg four times daily vs placebo.

(p<0.05) Misoprostol 200 mcg four times daily versus Lansoprazole 15 mg daily; and misoprostol 200 mcg four times daily vs lansoprazole 30 mg daily

14.7 Symptomatic Gastroesophageal Reflux Disease (GERD)

Symptomatic GERD: In a U.S. multi-center, 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 eight 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 eight week treatment period are presented in Table 17 and in Figures 1 and 2:

*(p<0.01) vs placebo.

Figure 1

Figure 2

In two U.S., multi-center 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 eight week treatment period. No significant additional benefit from lansoprazole 30 mg once daily was observed [see Indications and Usage ( 1.7)].

14.8 Erosive Esophagitis

In a U.S. multi-center, double-blind, placebo-controlled study of 269 patients entering with an endoscopic diagnosis of esophagitis with mucosal grading of two or more and grades three and four signifying erosive disease, the percentages of patients with healing are presented in Table 18.

* (p≤0.001) vs placebo.

†(p≤0.05) vs lansoprazole 15mg

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. multi-center, double-blind study to a low dose of ranitidine in 242 patients with erosive reflux esophagitis. Lansoprazole at a dose of 30 mg was significantly more effective than ranitidine 150 mg twice daily as shown below (Table 19).

* (p≤0.001) vs ranitidine.

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. multi-center, 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 H 2-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 H 2-receptor antagonists with lansoprazole, as all patients had demonstrated unresponsiveness to the histamine H 2-receptor antagonist mode of treatment. It does indicate, however, that lansoprazole may be useful in patients failing on a histamine H 2-receptor antagonist (Table 20) [see Indications and Usage ( 1.7)].

*(p<0.001) vs ranitidine.

14.9 Maintenance of Healing of Erosive Esophagitis

Two independent, double-blind, multi-center, 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 21).

%=Life Table Estimate

* (p≤0.001) versus placebo.

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 lansoprazole 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, lansoprazole was significantly more effective than ranitidine in providing complete relief of both daytime and nighttime heartburn. Patients treated with lansoprazole remained asymptomatic for a significantly longer period of time than patients treated with ranitidine [see Indications and Usage ( 1.9)].

14.10 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 ( 1.10) ].

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

Administration

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.

• Lansoprazole delayed-release capsules should be taken before eating.
• Do not crush or chew lansoprazole delayed-release capsules.
• Take lansoprazole delayed-release capsules at least 30 minutes prior to sucralfate.

Lansoprazole delayed-release capsules

• Swallow whole; do not chew.
• For patients who have difficulty swallowing capsules:
  • Lansoprazole delayed-release capsules can be opened and sprinkled on applesauce, ENSURE pudding, cottage cheese, yogurt or strained pears.
  • Lansoprazole delayed-release capsules may also be emptied into a small volume of either apple juice, orange juice or tomato juice
  • Alternatively, lansoprazole delayed-release capsules can be administered with apple juice via nasogastric tube
  • See the Instructions for Use for a description of all preparation and administration instructions