Drug Interactions between amoxicillin / clarithromycin / lansoprazole and Mudrane GG

MONITOR: Coadministration with certain macrolide antibiotics may increase the serum concentrations of methylxanthines such as theophylline, which may result in toxicity. In one case report, a pediatric patient developed seizures in association with theophylline toxicity shortly after the addition of erythromycin. The proposed mechanism is macrolide inhibition of CYP450 3A4, the isoenzyme partially responsible for the metabolic clearance of theophylline. Data from pharmacokinetic studies suggest that the magnitude of the interaction is generally greatest with troleandomycin, followed by erythromycin. The interaction with clarithromycin appears to be mild and inconsistent. Azithromycin and dirithromycin are generally believed to have little, if any, effect on CYP450 3A4, and most studies have not found a significant effect on the pharmacokinetics of theophylline. However, a case report describes an unusual interaction with azithromycin in an elderly patient whereby reduced serum theophylline levels were repeatedly observed after the discontinuation of azithromycin. The changes were transient and did not require an adjustment in the theophylline dosage. Theophylline has been reported to decrease plasma concentrations of erythromycin by increasing its renal clearance.

MANAGEMENT: Pharmacologic response and serum theophylline levels should be monitored more closely whenever a macrolide antibiotic is added to or withdrawn from therapy, and the methylxanthine dosage adjusted as necessary. For patients with theophylline levels at the upper end of the therapeutic range (15 to 20 mcg/mL), some clinicians suggest an initial reduction of the methylxanthine dosage by 25% when given with erythromycin and 50% with troleandomycin. Patients should be advised to contact their physician if they experience signs and symptoms of theophylline toxicity such as nausea, vomiting, diarrhea, headache, restlessness, insomnia, or irregular heartbeat.

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MONITOR: Barbiturates may decrease serum levels and therapeutic effects of the methylxanthines. The mechanism is barbiturate induction of CYP450 3A4 and 1A2 hepatic metabolism of methylxanthines.

MANAGEMENT: Close observation for clinical and laboratory evidence of decreased methylxanthine effect is indicated if these drugs must be used together. Patients should be advised to notify their physician if they experience a worsening of their respiratory symptoms.

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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.

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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.

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Ephedrine-methylxanthine combinations are used for the treatment of asthma but the efficacy of the combination has been questioned. This combination may lead to increased xanthine side effects. The mechanism is unknown, but may be related to synergistic pharmacologic effects. Patients using this combination should be closely monitored for side effects such as nausea, vomiting, tachycardia, nervousness, or insomnia. If side effects are noted, the dosage of the xanthine may need to be decreased.

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Coadministration with inhibitors of CYP450 2C19 may theoretically increase the plasma concentrations of phenobarbital, which is a substrate of the isoenzyme. Some studies have reported an approximately 20% decrease in the total clearance of phenobarbital in individuals who are poor metabolizers of CYP450 2C19, although an interaction with specific CYP450 2C19 inhibitors has not been reported. Other studies have found no significant difference in the pharmacokinetics of phenobarbital amongst subjects with various CYP450 2C19 genotypes, which would suggest a minor role of CYP450 2C19 in the overall clearance of phenobarbital. No precautions appear to be necessary during coadministration of phenobarbital with CYP450 2C19 inhibitors. However, dosage adjustments may be necessary if an interaction is suspected.

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Lansoprazole may cause a minor decrease in the area under the plasma concentration-time curve of theophylline and related drugs. This effect appears to be small (approximately a 13% decrease in one study) and may be related either to a reduction in absorption or to enhanced clearance caused by induction of hepatic enzymes by lansoprazole. Dosage adjustment is not believed to be necessary. However, close observation for evidence of altered methylxanthine effect is recommended.

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