Lansoprazole, amoxicillin, and clarithromycin

Drug Interactions No drug interaction studies have been conducted specifically with lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets. The following drug interactions are for the individual drug components: lansoprazole, amoxicillin, and clarithromycin. Therefore, the decision to adjust dosage should depend on the clinician’s assessment of among other things, the cumulative or net effect of the drug components of lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets.

Lansoprazole Delayed-Release Capsules Tables 5 and 6 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with lansoprazole delayed-release capsules and instructions for preventing or managing them. Consult the labeling of concomitantly used drugs to obtain further information about interactions with PPIs. Table 5. Clinically Relevant Interactions Affecting Drugs Coadministered with Lansoprazole Delayed-release Capsules and Interactions with Diagnostics Antiretrovirals Clinical Impact: The effect of PPIs on antiretroviral drugs is variable.

The clinical importance and the mechanisms behind these interactions are not always known. Decreased exposure of some antiretroviral drugs (e.g., rilpivirine, atazanavir, and nelfinavir) when used concomitantly with lansoprazole may reduce antiviral effect and promote the development of drug resistance. Increased exposure of other antiretroviral drugs (e.g., saquinavir) when used concomitantly with lansoprazole may increase toxicity of the antiretroviral drugs. There are other antiretroviral drugs which do not result in clinically relevant interactions with lansoprazole.

Intervention: Rilpivirine-containing products: Concomitant use with lansoprazole is contraindicated (see CONTRAINDICATIONS ). See prescribing information. Atazanavir : See prescribing information for atazanavir for dosing information. Nelfinavir : Avoid concomitant use with lansoprazole. See prescribing information for nelfinavir. Saquinavir : See the prescribing information for saquinavir and monitor for potential saquinavir toxicities. Other antiretrovirals : See prescribing information. Warfarin Clinical Impact: 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.

Intervention: Monitor INR and prothrombin time. Dose adjustment of warfarin may be needed to maintain target INR range. See prescribing information for warfarin. Methotrexate Clinical Impact: Concomitant use of PPIs with methotrexate (primarily at high dose) may elevate and prolong serum concentrations of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. No formal drug interaction studies of high-dose methotrexate with PPIs have been conducted (see WARNINGS ). Intervention: A temporary withdrawal of lansoprazole may be considered in some patients receiving high-dose methotrexate.

Digoxin Clinical Impact: Potential for increased exposure of digoxin. Intervention: Monitor digoxin concentrations. Dose adjustment of digoxin may be needed to maintain therapeutic drug concentrations. See prescribing information for digoxin. Theophylline Clinical Impact: Increased clearance of theophylline (see CLINICAL PHARMACOLOGY ). Intervention: Individual patients may require additional titration of their theophylline dosage when lansoprazole is started or stopped to ensure clinically effective blood concentrations.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Lansoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. Intervention: Mycophenolate mofetil (MMF): Coadministration of PPIs in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH.

The clinical relevance of reduced MPA exposure on organ rejection has not been established in transplant patients receiving lansoprazole delayed-release capsules and MMF. Use lansoprazole delayed-release capsules with caution in transplant patients receiving MMF. See the prescribing information for other drugs dependent on gastric pH for absorption. Combination Therapy with Clarithromycin and Amoxicillin Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.

Intervention: See CONTRAINDICATIONS , WARNINGS and PRECAUTIONS in prescribing information for clarithromycin. See Drug Interactions in prescribing information for amoxicillin. Tacrolimus Clinical Impact: Potentially increased exposure of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19. Intervention: Monitor tacrolimus whole blood trough concentrations. Dose adjustment of tacrolimus may be needed to maintain therapeutic drug concentrations. See prescribing information for tacrolimus. Interactions with Investigations of Neuroendocrine Tumors Clinical Impact: CgA levels increase secondary to PPI-induced decreases in gastric acidity.

The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors (see WARNINGS , CLINICAL PHARMACOLOGY ). Intervention: Temporarily stop lansoprazole treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary. Interaction with Secretin Stimulation Test Clinical Impact: Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.

Intervention: Temporarily stop lansoprazole treatment at least 28 days before assessing to allow gastrin levels to return to baseline (see CLINICAL PHARMACOLOGY ). False Positive Urine Tests for THC Clinical Impact: There have been reports of false positive urine screening tests for tetrahydrocannabinol (THC) in patients receiving PPIs. Intervention: An alternative confirmatory method should be considered to verify positive results. Table 6.

Clinically Relevant Interactions Affecting Lansoprazole Delayed-release Capsules When Coadministered with Other Drugs CYP2C19 OR CYP3A4 Inducers Clinical Impact: Decreased exposure of lansoprazole when used concomitantly with strong inducers (see CLINICAL PHARMACOLOGY ). Intervention: St John's Wort, rifampin : Avoid concomitant use with lansoprazole. Ritonavir-containing products : See prescribing information. CYP2C19 or CYP3A4 Inhibitors Clinical Impact: Increased exposure of lansoprazole is expected when used concomitantly with strong inhibitors (see CLINICAL PHARMACOLOGY ). Intervention: Voriconazole : See prescribing information.

Sucralfate Clinical Impact: Decreased and delayed absorption of lansoprazole (see CLINICAL PHARMACOLOGY ). Intervention: Take lansoprazole delayed-release capsules at least 30 minutes prior to sucralfate (see CLINICAL PHARMACOLOGY ). Amoxicillin Probenecid Probenecid decreases the renal tubular secretion of amoxicillin. Concurrent use of amoxicillin and probenecid may result in increased and prolonged blood levels of amoxicillin. Antibiotics Chloramphenicol, macrolides, sulfonamides, and tetracyclines may interfere with bactericidal effects of penicillin. This has been demonstrated in vitro ; however, the clinical significance of this interaction is not well documented.

Amoxicillin may affect the gut flora, leading to lower estrogen reabsorption and reduced efficacy of combined oral estrogen/progesterone contraceptives. Table 7. Clinically Significant Drug Interactions with Clarithromycin Tablets Drugs That Are Affected By Clarithromycin tablets Drug(s) with Pharmacokinetics Affected by Clarithromycin tablets Recommendation Comments Antiarrhythmics: Disopyramide Quinidine Dofetilide Amiodarone Sotalol Procainamide Not Recommended Disopyramide, Quinidine : There have been postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine or disopyramide.

Electrocardiograms should be monitored for QTc prolongation during coadministration of clarithromycin with these drugs (see WARNINGS ). Serum concentrations of these medications should also be monitored. There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with disopyramide and quinidine. There have been postmarketing reports of hypoglycemia with the concomitant administration of clarithromycin and disopyramide. Therefore,…

Pregnancy Teratogenic Effects Pregnancy Category C Category C is based on the pregnancy category for clarithromycin. There are no adequate and well-controlled studies of lansoprazole, clarithromycin or amoxicillin (used separately or together) in pregnant women. Lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus and there is no appropriate alternative therapy (see WARNINGS ).

Lansoprazole No adverse effects on embryo-fetal development occurred in studies performed in pregnant rats at oral lansoprazole doses up to 150 mg/kg/day (40 times the recommended human dose [30 mg/day] based on body surface area) administered during organogenesis and pregnant rabbits at oral lansoprazole doses up to 30 mg/kg/day (16 times the recommended human dose based on body surface area) administered during organogenesis.

A pre- and postnatal developmental toxicity study in rats with additional endpoints to evaluate bone development was performed with lansoprazole at oral doses of 10 to 100 mg/kg/day (0.7 to 6.4 times the maximum recommended human lansoprazole dose of 30 mg based on AUC [area under the plasma concentration-time curve]) administered during organogenesis through lactation. Maternal effects observed at 100 mg/kg/day (6.4 times the maximum recommended human lansoprazole dose of 30 mg based on AUC) included increased gestation period, decreased body weight gain during gestation, and decreased food consumption.

The number of stillbirths was increased at this dose, which may have been secondary to maternal toxicity. Body weight of pups was reduced at 100 mg/kg/day starting on postnatal Day 11. Femur weight, femur length, and crown-rump length were reduced at 100 mg/kg/day on postnatal Day 21. Femur weight was still decreased in the 100 mg/kg/day group at age 17 to 18 weeks. Growth plate thickness was decreased in the 100 mg/kg/day males on postnatal Day 21, and was increased in the 30 and 100 mg/kg/day males at age 17 to 18 weeks. The effects on bone parameters were associated with reduction in body weight gain.

Amoxicillin Reproduction studies with amoxicillin have been performed in mice and rats at doses up to ten times the human dose and revealed no evidence of impaired fertility or harm to the fetus. Clarithromycin Four teratogenicity studies in rats with clarithromycin (three with oral doses and one with intravenous doses up to 160 mg/kg/day administered during the period of major organogenesis) and two in rabbits at oral…

Nursing Mothers Lansoprazole and its metabolites are excreted in the milk of rats. It is not known whether lansoprazole is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets, and the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies, a decision should be made whether to discontinue nursing or to discontinue lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets, taking into account the importance of the therapy to the mother. Penicillins have been shown to be excreted in human milk.

Amoxicillin use by nursing mothers may lead to sensitization of infants. Caution should be exercised when amoxicillin is administered to a nursing woman. Clarithromycin and its active metabolite 14-hydroxy clarithromycin are excreted in human milk. Serum and milk samples were obtained after three days of treatment, at steady state, from one published study of 12 lactating women who were taking clarithromycin 250 mg orally twice daily. Based on the limited data from this study, and assuming milk consumption of 150 mL/kg/day, an exclusively human milk-fed infant would receive an estimated average of 136 mcg/kg/day of clarithromycin and its active metabolite, with this maternal dosage regimen.

This is less than 2% of the maternal weight-adjusted dose (7.8 mg/kg/day, based on the average maternal weight of 64 kg), and less than 1% of the pediatric dose (15 mg/kg/day) for children greater than six months of age. A prospective observational study of 55 breastfed infants of mothers taking a macrolide antibiotic (six were exposed to clarithromycin) were compared to 36 breastfed infants of mothers taking amoxicillin. Adverse reactions were comparable in both groups. Adverse reactions occurred in 12.7% of infants exposed to macrolides and included rash, diarrhea, loss of appetite, and somnolence. Caution should be exercised when clarithromycin is administered to nursing women.

The development and health benefits of human milk feeding should be considered along with the mother's clinical…