Drug Interactions between amoxicillin / clarithromycin / omeprazole and methotrexate

MONITOR CLOSELY: Concomitant use of large doses of penicillins may elevate serum methotrexate concentrations. The mechanism may involve competitive inhibition of renal tubular secretion of methotrexate. In one study, methotrexate clearance reductions were 35%, 40%, and 66% with penicillin, ticarcillin, and piperacillin, respectively. Serious adverse effects, primarily hematologic, have been described with concurrent penicillins and high or low-dose methotrexate regimens. Fatalities have occurred with both types of methotrexate regimens.

MANAGEMENT: If a penicillin must be used concurrently, close monitoring of methotrexate serum concentrations and of the patient for evidence of serious methotrexate toxicity are recommended. Leucovorin rescue should be available. Methotrexate dose reductions may be necessary. If broad-spectrum antibiotic coverage is needed during high-dose methotrexate therapy, use of other antimicrobials may be preferable. Patients should be advised to promptly report symptoms including fever, chills, sore throat, bruising, bleeding, stomatitis, or malaise to their physician.

MONITOR CLOSELY: Coadministration with proton pump inhibitors (PPIs) may increase the serum concentrations of methotrexate (MTX) and its potentially active 7-hydroxy metabolite. The proposed mechanism is PPI inhibition of the active tubular secretion of MTX and 7-hydroxymethotrexate via renal H+/K+ ATPase pumps. Inhibition of the breast cancer resistance protein (BCRP)-mediated transport of methotrexate and 7-hydroxymethotrexate by the proton pump inhibitors has also been suggested. The interaction was suspected in 2 case reports involving omeprazole and high-dose MTX cycles, where elimination of MTX was significantly delayed during cycles with omeprazole but became normal during subsequent cycles after omeprazole was discontinued or substituted with ranitidine. In another case, coadministration of pantoprazole and low-dose pulse MTX (15 mg IM once a week) resulted in severe myalgia and bone pain for several days following each of five MTX injections. The symptoms subsided dramatically and eventually disappeared after pantoprazole was replaced with ranitidine. A subsequent rechallenge led to reappearance of symptoms. Although the pharmacokinetics of MTX were not affected, systemic exposure (AUC) of 7-hydroxymethotrexate was significantly increased by 70% and half-life was doubled in the presence of pantoprazole.

MANAGEMENT: Proton pump inhibitor therapy should preferably be stopped several days prior to administration of methotrexate. In addition, it is not generally recommended to use proton pump inhibitors with high-dose methotrexate therapy, particularly in the presence of renal impairment. If concomitant use is necessary, clinicians should consider the potential for interaction and closely monitor methotrexate serum levels and toxicity. Use of an H2 antagonist may also be an appropriate alternative. It is not known if the interaction occurs with low, oral doses of methotrexate used to treat rheumatoid arthritis.

GENERALLY AVOID: Coadministration of methotrexate with other agents known to induce hepatotoxicity may potentiate the risk of liver injury. Methotrexate, especially at higher dosages or during prolonged treatment, has been associated with severe hepatotoxicity including acute hepatitis, chronic fibrosis, cirrhosis, and fatal liver failure.

MANAGEMENT: The risk of hepatic injury should be considered when methotrexate is used with other potentially hepatotoxic agents (e.g., acetaminophen; alcohol; androgens and anabolic steroids; antituberculous agents; azole antifungal agents; ACE inhibitors; cyclosporine (high dosages); disulfiram; endothelin receptor antagonists; interferons; ketolide and macrolide antibiotics; kinase inhibitors; minocycline; nonsteroidal anti-inflammatory agents; nucleoside reverse transcriptase inhibitors; proteasome inhibitors; retinoids; sulfonamides; tamoxifen; thiazolidinediones; tolvaptan; vincristine; zileuton; anticonvulsants such as carbamazepine, hydantoins, felbamate, and valproic acid; lipid-lowering medications such as fenofibrate, lomitapide, mipomersen, niacin, and statins; herbals and nutritional supplements such as black cohosh, chaparral, comfrey, DHEA, kava, pennyroyal oil, and red yeast rice). Baseline and periodic monitoring of hepatic function is recommended, while liver biopsy may be warranted during long-term use of methotrexate. Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, itching, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, pale stools, and jaundice.

Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.