Drug Interactions between amoxicillin / clarithromycin / omeprazole and atorvastatin

ADJUST DOSE: Some macrolide antibiotics inhibit CYP450 3A4 and may elevate the plasma concentrations of HMG-CoA reductase inhibitors that are metabolized by the isoenzyme. Macrolides that may significantly inhibit CYP450 3A4 include troleandomycin, erythromycin, and clarithromycin. There have been case reports of patients treated with lovastatin or simvastatin who developed severe myopathy or rhabdomyolysis following the addition of a macrolide, usually erythromycin. Plasma levels of HMG-CoA reductase inhibitory activity were significantly elevated in these patients, up to severalfold in many cases. Similar pharmacokinetic changes have been reported in studies with erythromycin and simvastatin and, to a lesser extent, with clarithromycin or erythromycin and atorvastatin. The interaction was also suspected in a patient treated with atorvastatin (more than 1 year) and esomeprazole (6 weeks) who developed rhabdomyolysis with AV block two days after the addition of clarithromycin. The patient reported experiencing symptoms of increased fatigue, mild chest pain, and shortness of breath that coincided with the initiation of esomeprazole approximately six weeks prior to admission.

MANAGEMENT: The benefits of using HMG-CoA reductase inhibitors that are metabolized by CYP450 3A4 in combination with medications that can inhibit the isoenzyme such as clarithromycin and erythromycin should be carefully weighed against the potentially increased risk of myopathy including rhabdomyolysis. A lower dosage of the HMG-CoA reductase inhibitor should be considered if concomitant use is required. Atorvastatin labeling recommends that the dosage not exceed 20 mg/day when used in combination with clarithromycin. Fluvastatin, pitavastatin, and rosuvastatin may be safer alternatives, since they are not metabolized by CYP450 3A4. All patients receiving statin therapy should be advised to promptly report any unexplained muscle pain, tenderness or weakness, particularly if accompanied by fever, malaise and/or dark colored urine. Therapy should be discontinued if creatine kinase is markedly elevated in the absence of strenuous exercise or if myopathy is otherwise suspected or diagnosed.

MONITOR: A case report suggests that coadministration with esomeprazole may increase the plasma concentrations of atorvastatin and the associated risk of myopathy. The proposed mechanism is competitive inhibition of intestinal P-glycoprotein, resulting in decreased drug secretion into the intestinal lumen and increased drug bioavailability. Another, perhaps minor mechanism is competitive inhibition of CYP450 3A4 metabolism. The interaction was suspected in a patient treated with atorvastatin (more than 1 year) and esomeprazole (6 weeks) who developed rhabdomyolysis with AV block two days after the addition of clarithromycin. The patient reported experiencing symptoms of increased fatigue, mild chest pain, and shortness of breath that coincided with the initiation of esomeprazole approximately six weeks prior to admission. Theoretically, the interaction may also occur with other proton pump inhibitors like lansoprazole, omeprazole, and pantoprazole and HMG-CoA reductase inhibitors like lovastatin and simvastatin, since these drugs are all substrates of P-glycoprotein and CYP450 3A4.

MANAGEMENT: Because of the increased risk of musculoskeletal toxicity associated with high levels of HMG-CoA reductase inhibitory activity in plasma, patients treated with atorvastatin, lovastatin, simvastatin, and red yeast rice (which contains lovastatin) should be monitored more closely during concomitant use of proton pump inhibitors. All patients treated with HMG-CoA reductase inhibitors should be advised to promptly report to their physician any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Therapy should be discontinued if creatine kinase is markedly elevated or if myopathy is suspected or diagnosed.

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.