Drug Interactions between amoxicillin / clarithromycin / lansoprazole and Viagra

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations and effects of sildenafil, which is primarily metabolized by the isoenzyme. Pharmacokinetic models predict that this interaction may be more significant for oral rather than intravenous formulations of sildenafil, due at least partly to effects from first pass metabolism. In healthy adult volunteers (n=14), administration of a single dose of sildenafil (100 mg) during treatment with ritonavir (500 mg twice a day for 7 days) increased the mean sildenafil peak plasma concentration (Cmax) and systemic exposure (AUC) by 300% and 1000%, respectively, compared to administration alone. At 24 hours, sildenafil plasma levels were approximately 200 ng/mL as opposed to about 5 ng/mL with sildenafil alone. In a parallel study of healthy adult volunteers (n=14), un-boosted saquinavir (soft gelatin capsule 1200 mg three times a day for 7 days) increased single-dose sildenafil's (100 mg) Cmax and AUC by 140% and 210%, respectively. No change in safety or tolerability of sildenafil was observed with either CYP450 3A4 inhibitor. However, other studies of sildenafil in combination with potent inhibitors have observed increases in AUC and adverse effects (headache, flushing, dyspepsia, rhinitis, hypotension). Potent CYP450 3A4 inhibitors like clarithromycin, telithromycin, and nefazodone are generally assumed to increase sildenafil's exposure by 7-fold, an effect in between that of ritonavir and saquinavir. Despite the potential risks, there are a few case studies available in the literature which describe the successful use of sildenafil in combination with ritonavir and 1 case study of use in combination with cobicistat in HIV-infected patients being treated for pulmonary arterial hypertension (PAH). These cases report the use of therapeutic drug monitoring for sildenafil. Data regarding this drug interaction in pediatric patients has not been reported by the manufacturers of sildenafil.

MANAGEMENT: Coadministration with potent CYP450 3A4 inhibitors should generally be avoided when sildenafil is indicated for pulmonary arterial hypertension (PAH). When indicated for erectile dysfunction, the initial dose of sildenafil should not exceed 25 mg, and in some situations should be limited to 25 mg in a 48-hour time frame, if coadministration is required. Recommendations vary according to the indication of sildenafil, the patient's age, the presence of renal and/or hepatic impairment, and the specific potency of the CYP450 3A4 inhibitor(s) in question. For example, when indicated for PAH, some authorities consider the administration of inhibitors similar in potency to itraconazole, ketoconazole, or ritonavir to be contraindicated with sildenafil. If coadministration with inhibitors considered slightly less potent (e.g., clarithromycin, telithromycin, or nefazodone) is required in adult patients with PAH, they suggest reducing sildenafil's dose to 20 mg orally (10 mg IV) once daily. Consult the product labeling for both sildenafil and the potent CYP450 3A4 inhibitor for more detailed guidance and recommendations. Clinical literature regarding therapeutic drug monitoring of sildenafil may also be helpful if the combination is clinically necessary. In addition, if concomitant use is in the best interests of the patient, all patients, regardless of indication, should be monitored closely for adverse effects and advised to promptly notify their doctor if they experience pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, hypotension, sudden decrease or loss of hearing, visual disturbances, syncope, or prolonged erection (greater than 4 hours).

Switch to consumer interaction data

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.

Switch to consumer interaction data

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.

Switch to consumer interaction data