Lansoprazole

Actavis Inc
Natco Pharma Limited

HIGHLIGHTS OF PRESCRIBING INFORMATION       RECENT MAJOR CHANGESWARNINGS AND PRECAUTIONS Clostridium difficile Associated Diarrhea (5.2)    9/2012 Concomitant Use of  lansoprazole delayed release capsules with Methotrexate (5.5)   5/2012 INDICATIONS AND USAGELansoprazole is a proton pump inhibitor (PPI). Refer to DOSAGE AND ADMINISTRATION table (below) for indications and usage. (1)DOSAGE AND ADMINISTRATION Indication Dose Frequency Duodenal Ulcers (1.1, 1.3) Short-Term TreatmentMaintenance of Healed 15 mg15 mg Once daily for 4 wksOnce daily H. Pylori Eradication to Reduce Recurrence of Duodenal Ulcer (1.2) Triple Therapy: Lansoprazole       delayed-release capsules 30 mg    Twice daily for 10 or 14 days                           Amoxicillin 1 gram                         Clarithromycin 500 mg Dual Therapy: Lansoprazole       delayed-release capsules 30 mg Three times daily for 14 days Amoxicillin 1 gram Benign Gastric Ulcer (1.4) Short-Term Treatment 30 mg Once daily up to 8 wks NSAID-associated Gastric Ulcer (1.6) Healing Risk Reduction 30 mg 15 mg Once daily for 8 wksOnce daily up to 12 wks GERD (1.7) Short-Term Treatment of Symptomatic GERD 15 mg Once daily up to 8 wks Short-Term Treatment of EE 30 mg Once daily up to 8 wks Pediatric (8.4) (1 to 11 years of age) Short-Term Treatment of Symptomatic GERD and Short-Term Treatment of EE     ≤ 30 kg 15mg Once daily up to 12 wks     > 30 kg 30 mg Once daily up to 12 wks (12 to 17 years of age) Short-Term Treatment of Symptomatic GERD  Nonerosive  GERD EE 15 mg 30 mg Once daily up to 8 wksOnce daily up to 8 wks Maintenance of Healing of EE (1.8) 15 mg Once daily Pathological Hypersecretory Conditions (i.e.,  ZES)  (1.9) 60 mg Once daily DOSAGE FORMS AND STRENGTHSCapsules: 15 mg and 30 mg.  (3)CONTRAINDICATIONS4WARNINGS AND PRECAUTIONS Symptomatic response with lansoprazole delayed-release capsules does not preclude the presence of gastric malignancy. (5.1) PPI therapy may be associated with increased risk of Clostridium difficile associated diarrhea. (5.2) Bone Fracture: Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine.   (5.3) Hypomagnesemia has been reported rarely with prolonged treatment with PPIs. (5.4) Side Effects6To report SUSPECTED ADVERSE REACTIONS, contact Actavis Inc. atFDA at 1-800-FDA-1088www.fda.gov/medwatch.DRUG INTERACTIONS Atazanavir: Do not co-administer with atazanavir. (7.1) Drugs with pH-Dependent Absorption: May interfere with the absorption of drugs where gastric pH is important for bioavailability. (7.1) Warfarin: Concomitant warfarin use may require monitoring for increases in INR and prothrombin time. (7.2) Tacrolimus: Concomitant tacrolimus use may increase tacrolimus whole blood concentrations. (7.3) Theophylline: Titration of theophylline dosage may be required when concomitant lansoprazole delayed-release capsules use is started or stopped. (7.4) Methotrexate: Lansoprazole delayed release capsules may increase serum levels of methotrexate. (7.6) USE IN SPECIFIC POPULATIONS·         Consider dose adjustment in patients with severe liver impairment. (8.7)·         Lansoprazole delayed-release capsules are not effective in patients with symptomatic GERD 1 month to less than 1 year of age. (8.4)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 LANSOPRAZOLE INDICATIONS AND USAGE
  • 1.1 Short-Term Treatment of Active Duodenal Ulcer
  • 1.2 H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence
  • 1.3 Maintenance of Healed Duodenal Ulcers
  • 1.4 Short-Term Treatment of Active Benign Gastric Ulcer
  • 1.5 Healing of NSAID-Associated Gastric Ulcer
  • 1.6 Risk Reduction of NSAID-Associated Gastric Ulcer
  • 1.7 Gastroesophageal Reflux Disease (GERD)
  • 1.8 Maintenance of Healing of Erosive Esophagitis (EE)
  • 1.9 Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome (ZES)
• 2 LANSOPRAZOLE DOSAGE AND ADMINISTRATION
  • 2.1 Recommended Dose
  • 2.2 Special Populations
  • 2.3 Important Administration Information
• 3 DOSAGE FORMS & STRENGTHS
• 4 LANSOPRAZOLE CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Gastric Malignancy
  • 5.2 Clostridium difficile Associated Diarrhea
  • 5.3 Bone Fracture
  • 5.4 Hypomagnesemia
  • 5.5 Concomitant use of Lansoprazole Delayed-Release capsules with methotrexate
• 6 LANSOPRAZOLE ADVERSE REACTIONS
  • 6.1 Clinical
  • 6.2 Postmarketing Experience
  • 6.3 Combination Therapy with Amoxicillin and Clarithromycin
  • 6.4 Laboratory Values
• 7 DRUG INTERACTIONS
  • 7.1 Drugs with pH-Dependent Absorption Kinetics
  • 7.2 Warfarin
  • 7.3 Tacrolimus
  • 7.4 Theophylline
  • 7.5 Clopidogrel
  • 7.6 Methotrexate
  • 7.7 Combination Therapy with Clarithromycin
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
  • 8.7 Hepatic Impairment
  • 8.8 Gender
  • 8.9 Race
• 10 OVERDOSAGE
• 11 LANSOPRAZOLE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility
  • 13.2 Animal Pharmacology & OR Toxicology
• 14 CLINICAL STUDIES
• 15 REFERENCES
• 17 PATIENT COUNSELING INFORMATION
• MEDICATION GUIDE
• Lansoprazole Delayed-Release Capsules USP, 15mg-Bottle of 30 capsules
• Lansoprazole Delayed-Release Capsules USP, 30mg-Bottle of 30 caspules
• Lansoprazole Delayed-Release Capsules USP, 30mg-Bottle of 100 caspules

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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

Lansoprazole 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)

Short-Term Treatment of Symptomatic GERD

Lansoprazole delayed-release capsules are indicated for the treatment of heartburn and other symptoms associated with GERD [see Clinical Studies (14)].

Short-Term Treatment of Erosive Esophagitis

Lansoprazole delayed-release capsules are indicated for short-term treatment (up to 8 weeks) for healing and symptom relief of all grades of erosive esophagitis. For patients who do not heal with lansoprazole delayed-release capsules for 8 weeks (5 to10%), 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 [see Clinical Studies (14)].

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 DOSAGE AND ADMINISTRATION

Lansoprazole is available as a capsule, in 15 mg and 30 mg strengths. Directions for use specific to the route and available methods of administration for each of these dosage forms is presented below. Lansoprazole delayed-release capsules should be taken before eating. Lansoprazole products SHOULD NOT BE CRUSHED OR CHEWED. In the clinical trials, antacids were used concomitantly with lansoprazole delayed-release capsules.

2.1 Recommended 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

Administration Options

Lansoprazole delayed-release capsules - Oral Administration

·         Lansoprazole delayed-release capsules should be swallowed whole.

·     Alternatively, for patients who have difficulty swallowing capsules, lansoprazole delayed-release capsules can be opened and administered as follows:

o  Open capsule.

o  Sprinkle intact granules on one tablespoon of either applesauce, ENSURE pudding, cottage cheese, yogurt or strained pears.

o  Swallow immediately.

·         Lansoprazole delayed-release capsules may also be emptied into a small volume of either apple juice, orange juice or tomato juice and administered as follows:

o  Open capsule.

o  Sprinkle intact granules into a small volume of either apple juice, orange juice or tomato juice (60 mL – approximately 2 ounces).

o  Mix briefly.

o  Swallow immediately.

·         For patients who have a nasogastric tube in place, lansoprazole delayed-release capsules can be administered as follows:

o  Open capsule.

o  Mix intact granules into 40 mL of apple juice. DO NOT USE OTHER LIQUIDS.

o  Inject through the nasogastric tube into the stomach.

o  Flush with additional apple juice to clear the tube.

USE IN OTHER FOODS AND LIQUIDS HAS NOT BEEN STUDIED CLINICALLY AND IS THEREFORE NOT RECOMMENDED.

3 DOSAGE FORMS & STRENGTHS

• 15 mg capsules contains white to off white coloured spherical shaped pellets filled in size ‘3’ capsules with green colour body and pink colour cap, printed NATCO on cap and 15 on body  with white ink.
• 30 mg capsules contains white to off white coloured spherical shaped pellets filled in size ‘1’ capsules with dark blue colour body and pink colour cap, printed NATCO on cap and 30 on body  with white ink.

4 CONTRAINDICATIONS

Lansoprazole delayed-release capsules are contraindicated in patients with known severe hypersensitivity to any component of the formulation of lansoprazole delayed-release capsules.

For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with lansoprazole delayed-release capsules, refer to the CONTRAINDICATIONS section of their packaging inserts.

5 WARNINGS AND PRECAUTIONS

5.1 Gastric Malignancy

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

5.2 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.

5.3 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 conditions 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)].

5.4 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)].

5.5 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 ADVERSE REACTIONS

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 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

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; 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 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 DRUG INTERACTIONS

7.1 Drugs with pH-Dependent Absorption Kinetics

Lansoprazole delayed-release capsule causes long-lasting inhibition of gastric acid secretion. Lansoprazole delayed-release capsules and other PPIs 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 and other PPIs should not be co-administered with atazanavir [see Clinical Pharmacology (12.3)].

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 (5.5)].

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 about drug interactions of antibacterial agents (amoxicillin and clarithromycin) indicated in combination with lansoprazole delayed-release capsules, refer to the DRUG INTERACTIONS section of their package inserts.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.1 Pregnancy

Teratogenic effects

Pregnancy Category B. Reproduction studies have been performed in pregnant rats at oral doses up to 40 times the recommended human dose and in pregnant rabbits at oral doses up to 16 times the recommended human dose and have revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole. There are, however, no adequate or well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed [see Nonclinical Toxicology(13.2)].

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 pharmacokinetics of lansoprazole were studied in pediatric patients with GERD aged less than 28 days and 1 to 11 months. Compared to healthy adults receiving 30 mg, neonates had higher exposure (mean weight-based normalized AUC values 2.04- and 1.88-fold higher at doses of 0.5 mg/kg/day and 1 mg/kg/day, respectively). Infants aged ≤ 10 weeks had clearance and exposure values that were similar to neonates. Infants aged greater than 10 weeks who received 1 mg/kg/day had mean AUC values that were similar to adults who received a 30 mg dose.

Lansoprazole was not found to be effective in a U.S. and Polish 4 week multicenter, double-blind, placebo-controlled, parallel-group study of 162 patients between one month and less than 12 months of age with symptomatic GERD based on a medical history of crying/fussing/irritability associated with feedings who had not responded to conservative GERD management (i.e., non-pharmacologic intervention) for 7 to 14 days. Patients received lansoprazole as a suspension daily (0.2 to 0.3 mg/kg/day in infants ≤10 weeks of age or 1.0 to 1.5 mg/kg/day in infants greater than 10 weeks or placebo) for up to 4 weeks of double-blind treatment.

There was no difference in the percentage of responders between the lansoprazole pediatric suspension group and placebo group (54% in both groups). 

There were no adverse events reported in pediatric clinical studies (1 month to less than 12 months of age) that were not previously observed in adults.

In an uncontrolled, open-label, U.S. multicenter study, 66 pediatric patients (1 to 11 years of age) with GERD were assigned, based on body weight, to receive an initial dose of either lansoprazole delayed-release capsules 15 mg daily if ≤30 kg or lansoprazole delayed-release capsules 30 mg daily if greater than 30 kg administered for 8 to 12 weeks. The lansoprazole delayed-release capsules dose was increased (up to 30 mg twice daily) in 24 of 66 pediatric patients after 2 or more weeks of treatment if they remained symptomatic. At baseline 85% of patients had mild to moderate overall GERD symptoms (assessed by investigator interview), 58% had non-erosive GERD and 42% had erosive esophagitis (assessed by endoscopy). 

In a study of 66 pediatric patients in the age group 1 year to 11 years old after treatment with lansoprazole delayed-release capsules given orally in doses of 15 mg daily to 30 mg twice daily, increases in serum gastrin levels were similar to those observed in adult studies. Median fasting serum gastrin levels increased 89% from 51 pg/mL at baseline to 97 pg/mL [interquartile range (25^th to 75^th percentile) of 71 to 130 pg/mL] at the final visit.

The pediatric safety of lansoprazole delayed-release capsules has been assessed in 66 pediatric patients aged 1 to 11 years of age. Of the 66 patients with GERD 85% (56/66) took lansoprazole delayed-release capsules for 8 weeks and 15% (10/66) took it for 12 weeks.

In an uncontrolled, open-label, U.S. multicenter study, 87 adolescent patients (12 to 17 years of age) with symptomatic GERD were treated with lansoprazole delayed-release capsules for 8 to 12 weeks. Baseline upper endoscopies classified these patients into two groups: 64 (74%) nonerosive GERD and 23 (26%) erosive esophagitis (EE). The nonerosive GERD patients received lansoprazole delayed-release capsules 15 mg daily for 8 weeks and the EE patients received lansoprazole delayed-release capsules 30 mg daily for 8 to 12 weeks. At baseline, 89% of these patients had mild to moderate overall GERD symptoms (assessed by investigator interviews). During 8 weeks of lansoprazole delayed-release capsules treatment, adolescent patients experienced a 63% reduction in frequency and a 69% reduction in severity of GERD symptoms based on diary results.

In these 87 adolescent patients, increases in serum gastrin levels were similar to those observed in adult studies, median fasting serum gastrin levels increased 42% from 45 pg/mL at baseline to 64 pg/mL [interquartile range (25^th to 75^th percentile) of 44 to 88 pg/mL] at the final visit. (Normal serum gastrin levels are 25 to 111 pg/mL).

The safety of lansoprazole delayed-release capsules has been assessed in these 87 adolescent patients. Of the 87 adolescent patients with GERD, 6% (5/87) took lansoprazole delayed-release capsules for less than 6 weeks, 93% (81/87) for 6 to 10 weeks, and 1% (1/87) for greater than 10 weeks.

The most frequently reported (at least 3%) treatment-related adverse reactions in these patients were headache (7%), abdominal pain (5%), nausea (3%) and dizziness (3%). Treatment-related dizziness, reported in this package insert as occurring in less than 1% of adult patients, was reported in this study by 3 adolescent patients with nonerosive GERD, who had dizziness concurrently with other reactions (such as migraine, dyspnea, and vomiting).

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 C_max values were comparable.

10 OVERDOSAGE

Lansoprazole delayed-release capsules are not removed from the circulation by hemodialysis. In one reported overdose, a patient consumed 600 mg of lansoprazole delayed-release capsules with no adverse reaction. Oral lansoprazole delayed-release capsule doses up to 5000 mg/kg in rats [approximately 1300 times the 30 mg human dose based on body surface area (BSA)] and in mice (about 675.7 times the 30 mg human dose based on BSA) did not produce deaths or any clinical signs.

11 DESCRIPTION

_1614332

Lansoprazole is a white to brownish-white odorless crystalline powder which melts with decomposition at approximately 166°C. Lansoprazole is freely soluble in dimethylformamide; soluble in methanol; sparingly soluble in ethanol; slightly soluble in ethyl acetate, dichloromethane and acetonitrile; very slightly soluble in ether; and practically insoluble in hexane and water.

 

Lansoprazole is stable when exposed to light for up to two months. The rate of degradation of the compound in aqueous solution increases with decreasing pH. The degradation half-life of the drug substance in aqueous solution at 25°C is approximately 0.5 hour at pH 5.0 and approximately 18 hours at pH 7.0.

 

Lansoprazole is supplied in delayed-release capsule form, for oral administration in two strengths 15 mg and 30 mg.

 

Lansoprazole delayed-release capsules are available in two strengths: 15 mg and 30 mg of lansoprazole per capsule. Each delayed-release capsule contains lansoprazole delayed-release pellets 8.5% consisting of 15 mg or 30 mg of lansoprazole (active ingredient) and the following inactive ingredients: acetone, hypromellose, isopropyl alcohol, light magnesium carbonate, methacrylic acid copolymer, polyethylene glycol, polysorbate 80, sugar spheres, talc and titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Lansoprazole delayed-release capsules 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

Antisecretory Activity: After oral administration, lansoprazole was shown to significantly decrease the basal acid output and significantly increase the mean gastric pH and percent of time the gastric pH was greater than 3 and greater than 4. Lansoprazole also significantly reduced meal-stimulated gastric acid output and secretion volume, as well as pentagastrin-stimulated acid output. In patients with hypersecretion of acid, lansoprazole significantly reduced basal and pentagastrin-stimulated gastric acid secretion. Lansoprazole inhibited the normal increases in secretion volume, acidity and acid output induced by insulin.

NOTE: An intragastric pH of greater than 4 reflects a reduction in gastric acid by 99%. * (p<0.05) versus baseline only. †(p<0.05) versus baseline and lansoprazole 15 mg.
Table 4: Mean Antisecretory Effects After Single and Multiple Daily Lansoprazole Delayed-Release Capsules Dosing
		Lansoprazole delayed-release capsules
Parameter	Baseline Value	15 mg		30 mg
		Day 1	Day 5	Day 1	Day 5
Mean 24 Hour pH	2.1	2.7 *	4.0 *	3.6 †	4.9 †
Mean Nighttime pH	1.9	2.4	3.0 *	2.6	3.8†
% Time Gastric pH>3	18	33 *	59 *	51 †	72 †
% Time Gastric pH>4	12	22 *	49 *	41 †	66 †

Helicobacter pyloriH. pylori

* (p<0.05) versus lansoprazole delayed-release capsules 30 mg daily † (p<0.05) versus lansoprazole delayed-release capsules 30 mg daily, 15 mg twice daily and 30 mgtwice daily.
Table 5: Mean Antisecretory Effects After 5 Days of Twice Daily and Three Times Daily Dosing
	Lansoprazole delayed-release capsules
Parameter	30 mg daily	15 mg twice daily	30 mg twice daily	30 mg three times daily
% Time Gastric pH>5	43	47	59 *	77 †
% Time Gastric pH>6	20	23	28	45 †

Enterochromaffin-like (ECL) Cell Effects

[see Nonclinical Toxicology (13.1)]

Other Gastric Effects in Humans



Serum Gastrin Effects



Endocrine Effects

₃₄

Other Effects



Microbiology

Helicobacter pylori in vitro[see Indications and Usage (1.2)].

Helicobacter pylori Pretreatment Resistance



H. pylori .

*Includes only patients with pretreatment clarithromycin susceptibility test results †Susceptible (S) MIC ≤0.25 mcg/mL, Intermediate (I) MIC 0.5 - 1.0 mcg/mL, Resistant (R) MIC ≥2 mcg/mL
Table 6: Clarithromycin Susceptibility Test Results and Clinical/Bacteriological Outcomes*
Clarithromycin Pretreatment Results		Clarithromycin Post-treatment Results
		H. pylori negative – eradicated		H. pylori positive – not eradicated Post-treatment susceptibility results
				S †	I †			R †			No MIC
Triple Therapy 14-Day (lansoprazole 30 mg twice daily /amoxicillin 1 gtwice daily/clarithromycin 500 mg twice daily)(M95-399, M93-131, M95-392)
Susceptible †	112	105									7
Intermediate †	3	3
Resistant †	17	6						7			4
Triple Therapy 10-Day (lansoprazole 30 mg twice daily /amoxicillin 1 g twice daily/clarithromycin 500 mg twice daily) (M95-399)
Susceptible †	42	40	1					1
Intermediate †
Resistant †	4	1						3

H. pyloriH. pylori.H. pylori

Amoxicillin Susceptibility Test Results and Clinical/Bacteriological Outcomes: H. pyloriH. pyloriH. pylori

Susceptibility Test for Helicobacter pylori: Helicobacter pylori,

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 (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.

Absorption: The absorption of lansoprazole is rapid, with the mean C_max occurring approximately 1.7 hours after oral dosing, and the absolute bioavailability is over 80%. In healthy subjects, the mean (±SD) plasma half-life was 1.5 (±1.0) hours. Both the C_max and AUC are diminished by about 50% to 70% if lansoprazole is given 30 minutes after food, compared to the fasting condition. There is no significant food effect if lansoprazole is given before meals.

Distribution:

Metabolism:⁺⁺

Elimination:¹⁴

Specific Populations

Pediatric Use:

One to 17 years of age

The pharmacokinetics of lansoprazole were studied in pediatric patients with GERD aged 1 to 11 years and 12 to 17 years in two separate clinical studies. In children aged 1 to 11 years, lansoprazole was dosed 15 mg daily for subjects weighing ≤30 kg and 30 mg daily for subjects weighing greater than 30 kg. Mean C_max and AUC values observed on Day 5 of dosing were similar between the two dose groups and were not affected by weight or age within each weight-adjusted dose group used in the study. In adolescent subjects aged 12 to 17 years, subjects were randomized to receive lansoprazole at 15 mg or 30 mg daily. Mean C_max and AUC values of lansoprazole were not affected by body weight or age; and nearly dose-proportional increases in mean C_max and AUC values were observed between the two dose groups in the study. Overall, lansoprazole pharmacokinetics in pediatric patients aged 1 to 17 years were similar to those observed in healthy adult subjects.

Neonate to less than one year of age

Refer to Section 8.4 for the pharmacokinetics of lansoprazole in pediatric patients with GERD aged less than 28 days and 1 to 11 months.

Geriatric Use: The clearance of lansoprazole is decreased in the elderly, with elimination half-life increased approximately 50% to 100%. Because the mean half-life in the elderly remains between 1.9 to 2.9 hours, repeated once daily dosing does not result in accumulation of lansoprazole. Peak plasma levels were not increased in the elderly. No dosage adjustment is necessary in the elderly [see Use in Specific Populations (8.5)].

Renal Impairment: In patients with severe renal impairment, plasma protein binding decreased by 1.0% to1.5% after administration of 60 mg of lansoprazole. Patients with renal impairment had a shortened elimination half-life and decreased total AUC (free and bound). The AUC for free lansoprazole in plasma, however, was not related to the degree of renal impairment; and the C_max and T_max (time to reach the maximum concentration) were not different than the C_max and T_max from subjects with normal renal function. No dosage adjustment is necessary in patients with renal impairment [see Use in Specific Populations (8.6)].

Hepatic Impairment: In patients with various degrees of chronic hepatic impairment, the mean plasma half-life of lansoprazole was prolonged from 1.5 hours to 3.2 to 7.2 hours. An increase in the mean AUC of up to 500% was observed at steady state in hepatically-impaired patients compared to healthy subjects. Consider dose reduction in patients with severe hepatic impairment [see Use in Specific Populations (8.7)].

Gender: In a study comparing 12 male and 6 female human subjects who received lansoprazole, no gender differences were found in pharmacokinetics and intragastric pH results [see Use in Specific Populations (8.8)].

Drug-Drug Interactions

Lansoprazole delayed-release capsules may interfere with the absorption of other drugs where gastric pH is an important determinant of bioavailability (e.g., ketoconazole, ampicillin esters, iron salts, digoxin).

Lansoprazole delayed-release capsules are metabolized through the cytochrome P₄₅₀ system, specifically through the CYP3A and CYP2C19 isozymes. Studies have shown that lansoprazole delayed-release capsules does not have clinically significant interactions with other drugs metabolized by the cytochrome P₄₅₀ system, such as warfarin, antipyrine, indomethacin, ibuprofen, phenytoin, propranolol, prednisone, diazepam, or clarithromycin in healthy subjects. These compounds are metabolized through various cytochrome P₄₅₀ isozymes including CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A.

Atazanavir: Lansoprazole delayed-release capsule causes long-lasting inhibition of gastric acid secretion. Lansoprazole delayed-release capsules substantially decreases 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, or other proton pump inhibitors, should not be co-administered with atazanavir.

Theophylline: When lansoprazole delayed-release capsules were administered concomitantly with theophylline (CYP1A2, CYP3A), a minor increase (10%) in the clearance of theophylline was seen. Because of the small magnitude and the direction of the effect on theophylline clearance, this interaction is unlikely to be of clinical concern. Nonetheless, individual patients may require additional titration of their theophylline dosage when lansoprazole delayed-release capsules are started or stopped to ensure clinically effective blood levels.

Warfarin: In a study of healthy subjects neither the pharmacokinetics of warfarin enantiomers nor prothrombin time were affected following single or multiple 60 mg doses of lansoprazole. However, there have been reports of increased International Normalized Ratio (INR) and prothrombin time in patients receiving proton pump inhibitors, including lansoprazole delayed-release capsules, and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with proton pump inhibitors and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.

Methotrexate and 7-hydromethotrexate: In an open-label, single-arm, eight-day, pharmacokinetic study of 28 adult rheumatoid arthritis patients (who required the chronic use of 7.5 to 15 mg of methotrexate given weekly), administration of 7 days of naproxen 500 mg twice daily and lansoprazole delayed-release capsules 30 mg daily had no effect on the pharmacokinetics of methotrexate and 7-hydroxymethotrexate. While this study was not designed to assess the safety of this combination of drugs, no major adverse reactions were noted. However, this study was conducted with low doses of methotrexate. A drug interaction study with high doses of methotrexate has not been conducted.

Amoxicillin: Lansoprazole delayed-release capsules have also been shown to have no clinically significant interaction with amoxicillin.

Sucralfate: In a single-dose crossover study examining lansoprazole delayed-release capsules 30 mg and omeprazole 20 mg each administered alone and concomitantly with sucralfate 1 gram, absorption of the proton pump inhibitors was delayed and their bioavailability was reduced by 17% and 16%, respectively, when administered concomitantly with sucralfate. Therefore, proton pump inhibitors should be taken at least 30 minutes prior to sucralfate. In clinical trials, antacids were administered concomitantly with lansoprazole delayed-release capsules and there was no evidence of a change in the efficacy of lansoprazole delayed-release capsules.

Clopidogrel:

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

²²

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 assays. 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 Pharmacology & OR Toxicology

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.

14 CLINICAL STUDIES

Duodenal Ulcer

* (p≤0.001) versus placebo.
Table 7: Duodenal Ulcer Healing Rates
Week	Lansoprazole delayed-release capsules			Placebo   (N=72)
	15 mg daily (N=68)	30 mg daily (N=74)	60 mg daily (N=70)
2	42.4% *	35.6% *	39.1% *	11.3%
4	89.4% *	91.7% *	89.9% *	46.1%

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

[see Indications and Usage (1.1)].

* (p≤0.05) versus placebo and ranitidine. †(p≤0.05) versus placebo
Table 8: Duodenal Ulcer Healing Rates
Week	Lansoprazole delayed-release capsules		Ranitidine	Placebo (N=41)
	15 mg daily (N=80)	30 mg daily (N=77)	300 mg h. s. (N=82)
2	35.0%	44.2%	30.5%	34.2%
4	92.3% *	80.3%†	70.5%†	47.5%

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

H. pyloriH. pylori.

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 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 delayed-release capsules 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)].

* 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 delayed-release capsules/amoxicillin and lansoprazole delayed-release capsules /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 9 H. pylori Eradication Rates – Triple Therapy (Lansoprazole delayed-release capsules/amoxicillin/clarithromycin) Percent of Patients Cured [95% Confidence Interval]  (Number of patients)
Study	Duration	Triple Therapy Evaluable Analysis *	Triple Therapy Intent-to-Treat Analysis†
M93-131	14 days	92‡ [80.0-97.7] (N=48)	86‡ [73.3-9 3.5] (N=55)
M95-392	14 days	86§ [75.7-93.6] (N=66)	83§ [72.0-90.8] (N=70)
M95-399¶	14 days	85 [77.0-91.0] (N=113)	82 [73.9-88.1] (N=126)
	10 days	84 [76.0-89.8] (N=123)	81 [73.9-87.6] (N=135)

* 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 delayed-release capsules alone. §  (p<0.05) versus lansoprazole delayed-release capsules alone or amoxicillin alone.
Table 10 H. pylori Eradication Rates – 14-Day Dual Therapy (Lansoprazole delayed-release capsules /amoxicillin) Percent of Patients Cured [95% Confidence Interval] (Number of patients)
Study	Dual Therapy Evaluable Analysis *	Dual Therapy Intent-to-Treat Analysis†
M93-131	77‡ [62.5-87.2] (N=51)	70‡ [56.8-81.2] (N=60)
M93-125	66§ [51.9-77.5] (N=58)	61§ [48.5-72.9] (N=67)

Long-Term Maintenance Treatment of Duodenal Ulcers

[see Indications and Usage (1.3)].

%=Life Table Estimate * (p≤0.001) versus placebo.
Table 11: Endoscopic Remission Rates
Trial	Drug	No. of   Pts.	Percent in Endoscopic Remission
			0-3 mo.	0-6 mo.	0-12 mo.
#1	Lansoprazole delayed-release capsules 15 mg daily	86	90% *	87% *	84% *
	Placebo	83	49%	41%	39%
#2	Lansoprazole delayed-release capsules 30 mg daily	18	94% *	94% *	85% *
	Lansoprazole delayed-release capsules 15 mg daily	15	87% *	79% *	70% *
	Placebo	15	33%	0%	0%

Gastric Ulcer
[see Indications and Usage (1.4)].

* (p≤0.05) versus placebo.
Table 12: Gastric Ulcer Healing Rates
	Lansoprazole delayed-release capsules			Placebo (N=64)
Week	15 mg daily (N=65)	30 mg daily (N=63)	60 mg daily (N=61)
4	64.6% *	58.1% *	53.3% *	37.5%
8	92.2% *	96.8% *	93.2% *	76.7%

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.

 

Healing of NSAID-Associated Gastric Ulcer

[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) versus the active control
Table 13: NSAID-Associated Gastric Ulcer Healing Rates*
Study #1
	Lansoprazole delayed-release capsules 30 mg daily	Active Control†
Week 4	60% (53/88) ‡	28% (23/83)
Week 8	79% (62/79) ‡	55% (41/74)
Study #2
	Lansoprazole delayed-release capsules 30 mg daily	Active Control†
Week 4	53% (40/75)	38% (31/82)
Week 8	77% (47/61) ‡	50% (33/66)

Risk Reduction of NSAID-Associated Gastric Ulcer

[see Indications and Usage (1.6)].

*% = Life Table Estimate.
Table 14: Proportion of Patients Remaining Free of Gastric Ulcers*
Week	Lansoprazole delayed-release capsules 15 mg daily (N=121)	Lansoprazole delayed-release capsules 30 mg daily (N=116)		Misoprostol 200 mcg four times daily (N=106)	Placebo (N=112)
4	90%	92%		96%	66%
8	86%	88%		95%	60%
12	80%	82%		93%	51%

(p<0.001) Lansoprazole delayed-release capsules 15 mg daily versus placebo; Lansoprazole delayed-release capsules 30 mg daily versus placebo; and misoprostol 200 mcg four times daily versus placebo.

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:

* (p<0.01) versus placebo.
Table 15: Frequency of Heartburn
Variable	Placebo (n=43)	Lansoprazole delayed-release capsules 15 mg (n=80)	Lansoprazole delayed-release capsules 30 mg (n=86)
	Median
% 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%*

[see Indications and Usage (1.7)].

Erosive Esophagitis

* (p≤0.001) versus placebo. † (p≤0.05) versus lansoprazole delayed-release capsules 15 mg.
Table 16: Erosive Esophagitis Healing Rates
Week	Lansoprazole delayed-release capsules			Placebo (N=63)
	15 mg daily (N=69)	30 mg daily (N=65)	60 mg daily (N=72)
4	67.6% *	81.3% * †	80.6% * †	32.8%
6	87.7% *	95.4% *	94.3%*	52.5%
8	90.9% *	95.4% *	94.4%*	52.5%

 

Lansoprazole delayed-release capsules were also compared in a U.S. multicenter, double-blind study to a low dose of ranitidine in 242 patients with erosive reflux esophagitis.

*(p≤0.001) versus ranitidine.
Table 17: Erosive Esophagitis Healing Rates
Week	Lansoprazole delayed-release capsules 30 mg daily (N=115)	Ranitidine 150 mg twice daily (N=127)
2	66.7% *	38.7%
4	82.5% *	52.0%
6	93.0% *	67.8%
8	92.1% *	69.9%

In addition, patients treated with lansoprazole delayed-release capsules 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 delayed-release capsules 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 delayed-release capsules produced healing rates similar to those shown above.

 

₂₂₂₂ [see Indications and Usage (1.7)].

* (p≤0.001) versus ranitidine.
Table 18: Reflux Esophagitis Healing Rates in Patients Poorly Responsive to Histamine H2-Receptor Antagonist Therapy
Week	Lansoprazole delayed-release capsules 30 mg daily (N=100)	Ranitidine 150 mg twice daily (N=51)
4 8	74.7% * 83.7% *	42.6% 32.0%

Long-Term Maintenance Treatment of Erosive Esophagitis

%=Life Table Estimate * (p≤0.001) versus placebo.
Table 19: Endoscopic Remission Rates
			Percent in Endoscopic Remission
Trial	Drug	No. of Pts.	0-3 mo.	0-6 mo.	0-12 mo.
#1	Lansoprazole delayed-release capsules 15 mg daily	59	83% *	81% *	79% *
	Lansoprazole delayed-release capsules 30 mg daily	56	93% *	93% *	90% *
	Placebo	55	31%	27%	24%
#2	Lansoprazole delayed-release capsules 15 mg daily	50	74% *	72% *	67% *
	Lansoprazole delayed-release capsules30 mg daily	49	75% *	72% *	55% *
	Placebo	47	16%	13%	13%

 

[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 delayed-release capsules 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 delayed-release capsules were 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 delayed-release capsules. 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)].

15 REFERENCES

1.  National Committee for Clinical Laboratory Standards. Summary Minutes, Subcommittee on Antimicrobial Susceptibility Testing, Tampa, FL, January 11-13, 1998.

17 PATIENT COUNSELING INFORMATION

[See FDA-Approved Medication Guide and Patient Instructions for Use]

• Advise patients to immediately report and seek care for diarrhea that does not improve. This may be sign of Clostridium difficile associated diarrhea [see Warnings and Precautions (5.2)].
• Advise patients to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures, and tetany as these may be signs of hypomagnesemia [see Warnings and Precautions (5.4)].

Information for Patients

Lansoprazole delayed-release capsules are available as a capsule, and are available in 15 mg and 30 mg strengths. Directions for use specific to the route and available methods of administration for each of these dosage forms is presented below [see Dosage and Administration (2.3)].

• Lansoprazole delayed-release capsules should be taken before eating.
• Lansoprazole delayed-release capsules SHOULD NOT BE CRUSHED OR CHEWED.

Administration Options

Lansoprazole Delayed-Release Capsules – Oral Administration

• Lansoprazole delayed-release capsules should be swallowed whole.
• Alternatively, for patients who have difficulty swallowing capsules, lansoprazole delayed-release capsules can be opened and administered as follows:

o  Open capsule.

o  Sprinkle intact granules on one tablespoon of applesauce, ENSURE pudding, cottage cheese, yogurt or strained pears.

o  Swallow immediately.

• Lansoprazole delayed-release capsules may also be emptied into a small volume of either apple juice, orange juice or tomato juice and administered as follows:

o  Open capsule.

o  Sprinkle intact granules into a small volume of either apple juice, orange juice or tomato juice (60 mL – approximately 2 ounces).

o  Mix briefly.

o  Swallow immediately.

o  To ensure complete delivery of the dose, the glass should be rinsed with two or more volumes of juice and the contents swallowed immediately.

Lansoprazole Delayed-Release Capsules – Nasogastric Tube (≥16 French) Administration

• For patients who have a nasogastric tube in place,lansoprazole delayed-release capsules can be administered as follows:

o  Open capsule.

o  Mix intact granules into 40 ml of apple juice. DO NOT USE OTHER LIQUIDS.

o  Inject through the nasogastric tube into the stomach.

o  Flush with additional apple juice to clear the tube.

USE IN OTHER FOODS AND LIQUIDS HAS NOT BEEN STUDIED CLINICALLY AND IS THEREFORE NOT RECOMMENDED.

MEDICATION GUIDE

Lansoprazole delayed-release capsules

What is the most important information that I should know about lansoprazole delayed-release capsules ?

Lansoprazole delayed-release capsules may help your acid-related symptoms, but you could still have serious stomach problems. Talk with your doctor.

Lansoprazole delayed-release capsules can cause serious side effects, including:

· Diarrhea. Lansoprazole delayed-release capsules may increase your risk of getting severe diarrhea. This diarrhea may be caused by an infection (Clostridium difficile) in your intestines.

Call your doctor right away if you have watery stool, stomach pain, and fever that does not go away.

· Bone fractures. People who take multiple daily doses of proton pump inhibitor medicines for a long period of time (a year or longer) may have an increased risk of fractures of the hip, wrist or spine. You should take lansoprazole delayed-release capsules exactly as prescribed, at the lowest dose possible for your treatment and for the shortest time needed. Talk to your doctor about your risk of bone fracture if you take lansoprazole delayed-release capsules.

Lansoprazole delayed-release capsules can have other serious side effects. See “What are the possible side effects of Lansoprazole delayed-release capsules?”

What are lansoprazole delayed-release capsules?

Lansoprazole delayed-release capsule is a prescription medicine called a proton pump inhibitor (PPI). Lansoprazole delayed-release capsules reduce the amount of acid in your stomach.

Lansoprazole delayed-release capsules are used in adults:

• for 4 weeks for the healing and symptom  relief of duodenal ulcers. The duodenal area is the area where food passes when it leaves the stomach.
• with certain antibiotics to treat an infection called H. pylori. Sometimes H. pylori bacteria can cause duodenal ulcers. The infection needs to be treated to prevent ulcers from coming back.
• for continued healing of duodenal ulcers.
• for up to 8 weeks to heal stomach ulcers.
• for up to 8 weeks to heal stomach  ulcers in some people taking pain medicines called non-steroidal anti-inflammatory drugs (NSAIDs).
• for reducing the risk of stomach ulcers in some people taking NSAIDs.
• for up to 8 weeks for the relief of heartburn and other symptoms of gastroesophageal reflux disease (GERD).

GERD happens when acid in your stomach backs up into the tube (esophagus) that connects your mouth to your stomach. This may cause a burning feeling in your chest or throat, sour taste or burping.

• for 8 weeks to heal the acid-related damage to the lining of the esophagus (called erosive esophagitis) and to relieve symptoms. If needed, your doctor may prescribe another 8 weeks of lansoprazole delayed-release capsules.
• for continued healing of erosive esophagitis.
•  for the long-term treatment of conditions where your stomach makes too much acid. This includes a condition called Zollinger-Ellison syndrome.

Lansoprazole delayed-release capsules are used in children and adolescents (ages 1 to 17):

• for up to 12 weeks to treat GERD and erosive esophagitis in children 1 to 11 years old.
• for up to 8 weeks to treat GERD and erosive esophagitis in adolescents 12 to17 years old.

Lansoprazole delayed-release capsules are not effective for symptoms of GERD in children under the age of 1 year.

Who should not take lansoprazole delayed-release capsules?

• Do not take lansoprazole delayed-release capsules if you are allergic to lansoprazole or any of the other ingredients in lansoprazole delayed-release capsules. See the end of this Medication Guide for a complete list of ingredients in lansoprazole delayed-release capsules.

What should I tell my doctor before taking lansoprazole delayed-release capsules?

Before you take lansoprazole delayed-release capsules, tell your doctor if you:

• have been told that you have low magnesium levels in your blood.
• have liver problems
• have any other medical conditions
• are pregnant or plan to become pregnant. It is not known if lansoprazole delayed-release capsules will harm your unborn baby.
• are breastfeeding or plan to breastfeed. It is not known if lansoprazole delayed-release capsules passes into your breast milk. You and your doctor should decide if you will take lansoprazole delayed-release capsules or breastfeed. You should not do both. Talk to your doctor about the best way to feed your baby if you take lansoprazole delayed-release capsules.

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Lansoprazole delayed-release capsules may affect how other medicines work, and other medicines may affect how lansoprazole delayed-release capsules works.

Especially tell your doctor if you take:

• atazanavir (Reyataz)
• digoxin (Lanoxin)
• a product that contains iron
• ketoconazole (Nizoral)
• warfarin (Coumadin, Jantoven)
• tacrolimus (Prograf)
• theophylline (Theo-24, Elixophyllin, Theochron, Theolair)
• an antibiotic that contains ampicillin or clarithromycin
• methotrexate

Ask your doctor or pharmacist for a list of these medicines if you are not sure.

Know the medicines that you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.

How should I take lansoprazole delayed-release capsules?

• Take lansoprazole delayed-release capsules exactly as prescribed by your doctor.
• Do not change your dose or stop taking lansoprazole delayed-release capsules without talking to your doctor.
• You should take lansoprazole delayed-release capsules before eating.
• Lansoprazole delayed-release capsules:

o   You shouldswallow lansoprazole delayed-release capsules whole.

o   Do not crush or chew lansoprazole delayed-release capsules.

o   If you have trouble swallowing a whole capsule, you can open the capsule and take the contents with certain foods or juices. See the “Instructions for Use” at the end of this Medication Guide for instructions on how to take lansoprazole delayed-release capsules with certain foods and juices.

o   See the “Instructions for Use” at the end of this Medication Guide for instructions on how to mix and give lansoprazole delayed-release capsules through a nasogastric tube.

• If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Just take the next dose at your regular time. Do not take 2 doses at the same time.
• If you take too much lansoprazole delayed-release capsules, call your doctor right away.

What are the possible side effects of lansoprazole delayed-release capsules?

Lansoprazole delayed-release capsules can cause serious side effects, including:

• See “What is the most important information that I should know about lansoprazole delayed-release capsules ?”
• Low magnesium levels in your body. This problem can be serious. Low magnesium can happen  in some people who take a proton pump inhibitor medicine for at least 3 months. If low magnesium levels happen, it is usually after a year of treatment. You may or may not have symptoms of low magnesium.

Tell your doctor right away if you develop any of these symptoms:

• seizures
• dizziness
• abnormal or fast heartbeat
• jitteriness
• jerking movements or shaking (tremors)
• muscle weakness
• spasms of the hands and feet
• cramps or muscle aches
• spasm of the voice box

Your doctor may check the level of magnesium in your body before you start taking lansoprazole delayed-release capsules, or during treatment; if you will be taking lansoprazole delayed-release capsules for a long period of time.

The most common side effects of lansoprazole delayed-release capsules in adults and children include:

• diarrhea
• stomach pain
• nausea
• constipation
• headache                                                                      

Other side effects:

• Serious allergic reactions. Tell your doctor if you get any of the following symptoms with lansoprazole delayed-release capsules.
• rash
• face swelling
• throat tightness
• difficulty breathing

Your doctor may stop lansoprazole delayed-release capsules if these symptoms happen.

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of lansoprazole delayed-release capsules. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

How should I store lansoprazole delayed-release capsule?

• Store lansoprazole delayed-release capsules at room temperature between 68°F to 77°F (20°C to 25°C).

Keep lansoprazole delayed-release capsules and all medicines out of the reach of children.

General information about lansoprazole delayed-release capsules

Medicines are sometimes prescribed for conditions other than those listed in a Medication Guide. Do not use lansoprazole delayed-release capsules for conditions for which it was not prescribed. Do not give lansoprazole delayed-release capsules to other people, even if they have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important information about lansoprazole delayed-release capsules. If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about lansoprazole delayed-release capsules that is written for healthcare professionals.

For more information, call Actavis Inc. at 1-800-432-8534.

What are ingredients in lansoprazole delayed-release capsules?

Active ingredient: lansoprazole.

Inactive ingredients in lansoprazole delayed-release capsules:

Acetone, hypromellose, isopropyl alcohol, light magnesium carbonate, methacrylic acid copolymer, polyethylene glycol, polysorbate 80, sugar spheres, talc and titanium dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by:

NATCO PHARMA LIMITED,

Kothur- 509228,

AP, India.

Distributed by:

Actavis Inc.
60 Columbia Road, Bldg. B
Morristown, NJ 07960 USA 

Lansoprazole Delayed-Release Capsules USP, 15mg-Bottle of 30 capsules

Each capsule is printed with NATCO and 15 for product identification.

Store at 25°C (77°F); excursions permitted to15-30°C (59-86°F) [See USP Controlled Room Temperature].

PHARMACIST:

Lansoprazole Delayed-Release Capsules USP, 30mg-Bottle of 30 caspules

Each capsule is printed with NATCO and 30 for product identification.

Store at 25°C (77°F); excursions permitted to15-30°C (59-86°F) [See USP Controlled Room Temperature].

Do not accept if seal over bottle opening is broken or missing.

PHARMACIST:

Lansoprazole Delayed-Release Capsules USP, 30mg-Bottle of 100 caspules

Each capsule is printed with NATCO and 30 for product identification.

Store at 25°C (77°F); excursions permitted to15-30°C (59-86°F) [See USP Controlled Room Temperature].

PHARMACIST:

 

Lansoprazole Lansoprazole CAPSULE, DELAYED RELEASE Product Information Product Type Human prescription drug label Item Code (Source) NDC:45963-460 Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength lansoprazole LANSOPRAZOLE 15 mg Inactive Ingredients Ingredient Name Strength acetone HYPROMELLOSES ISOPROPYL ALCOHOL MAGNESIUM CARBONATE METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A POLYETHYLENE GLYCOL 4000 polysorbate 80 STARCH, CORN SUCROSE talc titanium dioxide Product Characteristics Color Size Imprint Code Shape PINK 3 mm NATCO;15 CAPSULE Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:45963-460-03 30 in 1 BOTTLE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA201921 2012-12-18

Lansoprazole Lansoprazole CAPSULE, DELAYED RELEASE Product Information Product Type Human prescription drug label Item Code (Source) NDC:45963-461 Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength lansoprazole LANSOPRAZOLE 30 mg Inactive Ingredients Ingredient Name Strength acetone HYPROMELLOSES ISOPROPYL ALCOHOL MAGNESIUM CARBONATE METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A POLYETHYLENE GLYCOL 4000 polysorbate 80 STARCH, CORN SUCROSE talc titanium dioxide Product Characteristics Color Size Imprint Code Shape PINK 1 mm NATCO;30 CAPSULE Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:45963-461-03 30 in 1 BOTTLE 2 NDC:45963-461-10 100 in 1 BOTTLE 3 NDC:45963-461-96 1000 in 1 BOTTLE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA201921 2012-12-18