Drug Interactions between amoxicillin / clarithromycin / lansoprazole and bromocriptine

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of bromocriptine. Orally administered bromocriptine is extensively metabolized in the gastrointestinal tract and liver by CYP450 3A4, with approximately 93% of the absorbed dose undergoing first-pass metabolism and only the remaining 7% reaching systemic circulation. As such, inhibitors of CYP450 3A4 may markedly reduce the metabolic clearance of bromocriptine. The interaction has been studied with erythromycin, a moderate CYP450 3A4 inhibitor. When a single 5 mg oral dose of bromocriptine was given following a 4-day treatment of erythromycin estolate 250 mg four times a day in five male volunteers, mean bromocriptine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 4.6- and 3.7-fold, respectively, compared to administration of bromocriptine alone. An even greater magnitude of interaction should be expected with more potent inhibitors. High bromocriptine plasma levels may increase the frequency and/or severity of adverse effects such as nausea, headache, dizziness, somnolence (e.g., episodes of sudden sleep onset), hypotension, syncope, and impulse control problems or compulsive behaviors (e.g., gambling or sexual urges; uncontrolled spending).

MANAGEMENT: Concomitant use of bromocriptine with potent CYP450 3A4 inhibitors should be avoided when possible. In patients who have been treated with a potent CYP450 3A4 inhibitor, an adequate washout of the inhibitor (approximately 3 to 5 elimination half-lives) is recommended prior to initiation of bromocriptine. If coadministration with a potent CYP450 3A4 inhibitor is required, bromocriptine dosage should be reduced to avoid toxicity. Caution and close monitoring for development of adverse effects are advisable, and the bromocriptine dosage further adjusted if necessary.

MONITOR: Coadministration with clarithromycin may increase the plasma concentrations of lansoprazole. The proposed mechanism is clarithromycin inhibition of intestinal (first-pass) and hepatic metabolism of lansoprazole via CYP450 3A4. Although lansoprazole is primarily metabolized by CYP450 2C19 in the liver, 3A4-mediated metabolism is the predominant pathway in individuals who are 2C19-deficient (approximately 3% to 5% of the Caucasian and 17% to 20% of the Asian population). Additionally, inhibition of P-glycoprotein intestinal efflux transporter by clarithromycin may also contribute to the interaction, resulting in increased bioavailability of lansoprazole. In 18 healthy volunteers--six each of homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs) of CYP450 2C19--clarithromycin (400 mg orally twice a day for 6 days) increased the peak plasma concentration (Cmax) of a single 60 mg oral dose of lansoprazole by 1.47, 1.71- and 1.52-fold, respectively, and area under the concentration-time curve (AUC) by 1.55-, 1.74- and 1.80-fold, respectively, in each of these groups compared to placebo. The AUC ratio of lansoprazole to lansoprazole sulphone, which is considered an index of CYP450 3A4 activity, was significantly increased by clarithromycin in all three groups. However, elimination half-life of lansoprazole was prolonged by 1.54-fold only in PMs. Mild diarrhea was reported in two subjects and mild abdominal disturbance in six subjects during clarithromycin coadministration. These side effects continued until day 6 and ameliorated the day after discontinuation of clarithromycin, whereas no adverse events were reported during placebo administration or after lansoprazole plus placebo. In another study, clarithromycin induced dose-dependent increases in the plasma concentration of lansoprazole in a group of 20 patients receiving treatment for H. pylori eradication. Mean 3-hour plasma lansoprazole concentration was 385 ng/mL for the control subjects who received lansoprazole 30 mg and amoxicillin 750 mg twice a day for 7 days; 696 ng/mL for patients coadministered clarithromycin 200 mg twice a day; and 947 ng/mL for patients coadministered clarithromycin 400 mg twice a day.

MANAGEMENT: Although lansoprazole is generally well tolerated, caution may be advised during coadministration with clarithromycin, particularly if higher dosages of one or both drugs are used. Dosage adjustment may be necessary in patients who experience excessive adverse effects of lansoprazole.

MONITOR: The concomitant administration of lansoprazole may decrease the antiparkinsonian effects of bromocriptine. The mechanism is unknown but may involve competitive inhibition of p-glycoprotein transport. In a single case report, a 73-year-old patient with Parkinson's disease experienced acute exacerbation of his symptoms after lansoprazole 15 mg/day was added to his stable regimen of bromocriptine and levodopa/benserazide. The symptoms improved within 1 day after lansoprazole was discontinued and did not recur when omeprazole was substituted.

MANAGEMENT: Until more information is available, it may be advisable to monitor patients for altered efficacy when lansoprazole is added to a regimen. Patients and/or their caregivers should be advised to notify their physician if worsening of symptoms occurs.

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.