LANSOPRAZOLE

The active ingredient in lansoprazole delayed-release capsules USP is lansoprazole, USP, a substituted benzimidazole, 2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl]sulfinyl] benzimidazole, a compound that inhibits gastric acid secretion. Lansoprazole, USP has the following structure: C 16 H 14 F 3 N 3 O 2 S M.W. 369.36 Lansoprazole, USP is a white to brownish-white odorless crystalline powder which melts with decomposition at approximately 166°C. Lansoprazole, USP 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, USP 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 and approximately 18 hours at pH 7. The lansoprazole delayed-release capsules USP for oral administration are available in two dosage strengths: 15 mg and 30 mg of lansoprazole, USP per capsule. Each delayed-release capsule contains enteric-coated granules consisting of 15 mg or 30 mg of lansoprazole, USP (active ingredient) and the following inactive ingredients: black iron oxide, gelatin, hypromellose, magnesium carbonate, methacrylic acid copolymer dispersion, propylene glycol, red iron oxide, shellac, sugar spheres (which contain sucrose and corn starch), talc, titanium dioxide, and triethyl citrate. Additionally, 15 mg capsule contains brilliant blue FCF - FD&C blue 1. The imprinting ink may contain potassium hydroxide. lansoprazole structural formula

Lansoprazole is a proton pump inhibitor (PPI). Refer to DOSAGE AND ADMINISTRATION table (below) for indications and usage. ( 1 ) 1.1 Short-Term Treatment of Active Duodenal Ulcer Lansoprazole delayed-release capsules USP 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 USP/amoxicillin/clarithromycin Lansoprazole delayed-release capsules USP 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 USP/amoxicillin Lansoprazole delayed-release capsules USP 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 USP 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 USP 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 USP 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 USP 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 USP 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 USP 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 USP for 8 weeks (5 to 10%), it may be helpful to give an additional 8 weeks of treatment. If there is a recurrence of erosive esophagitis an additional 8 week course of lansoprazole delayed-release capsules USP may be considered [ see Clinical Studies ( 14 ) ]. 1.8 Maintenance of Healing of Erosive Esophagitis (EE) Lansoprazole delayed-release capsules USP 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 USP are indicated for the long-term treatment of pathological hypersecretory conditions, including Zollinger-Ellison syndrome [ see Clinical Studies ( 14 ) ].

Lansoprazole delayed-release capsules are available in 15 mg and 30 mg strengths. Directions for use specific to the route and available methods of administration for this dosage form is presented below. Lansoprazole delayed-release capsules should be taken before eating. Lansoprazole delayed-release capsules SHOULD NOT BE CRUSHED OR CHEWED. In the clinical trials, antacids were used concomitantly with lansoprazole. Indication Dose Frequency Duodenal Ulcers ( 1.1 , 1.3 ) Short-Term Treatment 15 mg Once daily for 4 wks Maintenance of Healed 15 mg Once 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 30 mg Once daily for 8 wks Risk Reduction 15 mg Once 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 15 mg 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 15 mg Once daily up to 8 wks EE 30 mg Once 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 2.1 Recommended Dose Indication Recommended Dose Frequency Duodenal Ulcers Short-Term Treatment 15 mg Once daily for 4 weeks Maintenance of Healed 15 mg Once daily H. pylori Eradication to Reduce the Risk of Duodenal Ulcer Recurrence Please refer to amoxicillin and clarithromycin full prescribing information for CONTRAINDICATIONS and WARNINGS, and for information regarding dosing in elderly and renally-impaired patients. Triple Therapy: Lansoprazole Delayed-Release Capsules 30 mg Twice daily (q12h) for 10 or 14 days Amoxicillin 1 gram Twice daily (q12h) for 10 or 14 days Clarithromycin 500 mg Twice daily (q12h) for 10 or 14 days Dual Therapy: Lansoprazole Delayed-Release Capsules 30 mg Three times daily (q8h) for 14 days Amoxicillin 1 gram Three times daily (q8h) for 14 days Benign Gastric Ulcer Short-Term Treatment 30 mg Once daily for up to 8 weeks NSAID-associated Gastric Ulcer Healing 30 mg Once daily for 8 weeks Controlled studies did not extend beyond indicated duration. Risk Reduction 15 mg Once daily for up to 12 weeks Gastroesophageal Reflux Disease (GERD) Short-Term Treatment of Symptomatic GERD 15 mg Once daily for up to 8 weeks Short-Term Treatment of Erosive Esophagitis 30 mg Once daily for up to 8 weeks For patients who do not heal with lansoprazole delayed-release capsules for 8 weeks (5 to 10%), it may be helpful to give an additional 8 weeks of treatment. If there is a recurrence of erosive esophagitis, an additional 8 week course of lansoprazole delayed-release capsules may be considered. Pediatric (1 to 11 years of age) Short-Term Treatment of Symptomatic GERD and Short-Term Treatment of Erosive Esophagitis ≤ 30 kg 15 mg Once daily for up to 12 weeks The lansoprazole dose was increased (up to 30 mg twice daily) in some pediatric patients after 2 or more weeks of treatment if they remained symptomatic. For pediatric patients unable to swallow an intact capsule please see Administration Options. > 30 kg 30 mg Once daily for up to 12 weeks (12 to 17 years of age) Short-Term Treatment of Symptomatic GERD Nonerosive GERD 15 mg Once daily for up to 8 weeks Erosive Esophagitis 30 mg Once daily for up to 8 weeks Maintenance of Healing of Erosive Esophagitis 15 mg Once daily Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome 60 mg Once daily Varies with individual patient. Recommended adult starting dose is 60 mg once daily. Doses should be adjusted to individual patient needs and should continue for as long as clinically indicated. Dosages up to 90 mg twice daily have been administered. Daily dose of greater than 120 mg should be administered in divided doses. Some patients with Zollinger-Ellison syndrome have been treated continuously with lansoprazole for more than 4 years. Patients should be instructed that if a dose is missed, it should be taken as soon as possible. However, if the next scheduled dose is due, the patient should not take the missed dose, and should be instructed to take the next dose on time. Patients should be instructed not to take 2 doses at one time to make up for a missed dose. 2.2 Special Populations Renal impairment patients and geriatric patients do not require dosage adjustment. However, consider dose adjustment in patients with severe liver impairment [ see Use in Specific Populations ( 8.5 , 8.6 and 8.7 ) ]. 2.3 Important Administration Information 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: • Open capsule. • Sprinkle intact granules on one tablespoon of either applesauce, ENSURE ® pudding, cottage cheese, yogurt or strained pears. • 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: • Open capsule. • Sprinkle intact granules into a small volume of either apple juice, orange juice or tomato juice (60 mL — approximately 2 ounces). • Mix briefly. • Swallow immediately. • 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: • Open capsule. • Mix intact granules into 40 mL of apple juice. DO NOT USE OTHER LIQUIDS. • Inject through the nasogastric tube into the stomach. • 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.

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 package inserts. Contraindicated in patients with known severe hypersensitivity to any component of the lansoprazole delayed-release capsule formulation. ( 4 )

Most commonly reported adverse reactions (≥ 1%): diarrhea, abdominal pain, nausea and constipation. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or [email protected]; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Worldwide, over 10,000 patients have been treated with lansoprazole in Phase 2 or Phase 3 clinical trials involving various dosages and durations of treatment. In general, lansoprazole treatment has been well-tolerated in both short-term and long-term trials. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The following adverse reactions were reported by the treating physician to have a possible or probable relationship to drug in 1% or more of lansoprazole-treated patients and occurred at a greater rate in lansoprazole-treated patients than placebo-treated patients in Table 1 . Table 1: Incidence of Possibly or Probably Treatment-Related Adverse Reactions in Short-Term, Placebo-Controlled Lansoprazole Studies Body System/Adverse Event Lansoprazole Placebo (N = 2768) (N = 1023) % % Body as a Whole Abdominal Pain 2.1 1.2 Digestive System Constipation 1 0.4 Diarrhea 3.8 2.3 Nausea 1.3 1.2 Headache was also seen at greater than 1% incidence but was more common on placebo. The incidence of diarrhea was similar between patients who received placebo and patients who received 15 mg and 30 mg of lansoprazole, but higher in the patients who received 60 mg of lansoprazole (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 for NSAID-associated gastric ulcers, the incidence of diarrhea for patients treated with lansoprazole, 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 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 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 has been marketed. The majority of these cases are foreign-sourced and a relationship to lansoprazole 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 plus amoxicillin and clarithromycin, and lansoprazole 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, amoxicillin, or clarithromycin. Triple Therapy: Lansoprazole/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/amoxicillin The most frequently reported adverse reactions for patients who received lansoprazole 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 three times daily plus amoxicillin three times daily dual therapy than with lansoprazole alone. For information about adverse reactions with antibacterial agents (amoxicillin and clarithromycin) indicated in combination with lansoprazole delayed-release capsules, refer to the ADVERSE REACTIONS section of their package inserts. 6.4 Laboratory Values The following changes in laboratory parameters in patients who received lansoprazole 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, 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 reported jaundice at any time during the study. In clinical trials using combination therapy with lansoprazole plus amoxicillin and clarithromycin, and lansoprazole 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.

• Atazanavir: Do not coadminister 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 use is started or stopped. ( 7.4 ) • Methotrexate: Lansoprazole may increase serum levels of methotrexate. ( 7.6 ) 7.1 Drugs With pH-Dependent Absorption Kinetics Lansoprazole causes long-lasting inhibition of gastric acid secretion. Lansoprazole 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 and other PPIs should not be coadministered with atazanavir [ see Clinical Pharmacology ( 12.3 ) ]. Lansoprazole and other PPIs may interfere with the absorption of other drugs where gastric pH is an important determinant of oral bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole) [ see Clinical Pharmacology ( 12.3 ) ]. 7.2 Warfarin In a study of healthy subjects, coadministration of single or multiple 60 mg doses of lansoprazole 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 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 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. 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 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, refer to the DRUG INTERACTIONS section of their package inserts.