Drug Interaction Report

MONITOR: Coadministration with weak inhibitors of CYP450 3A4 may increase the plasma concentrations 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. An analysis of population pharmacokinetic data from clinical trials in adult pulmonary hypertension patients indicated a reduction in sildenafil clearance of approximately 30% when coadministered with mild CYP450 3A4 inhibitors. Sildenafil labeling does not currently report study data involving concurrent use with weak CYP450 3A4 inhibitors in pediatric pulmonary hypertension patients. Likewise, sildenafil products indicated for erectile dysfunction also focus on study data with more potent CYP450 3A4 inhibitors.

MANAGEMENT: Caution is advised if sildenafil is coadministered with weak CYP450 3A4 inhibitors. The significance of this interaction may be less for intravenous formulations of sildenafil and greater in patients with risk factors for adverse effects, such as those with renal impairment, hepatic impairment, and/or elderly patients. The presence of renal and/or hepatic dysfunction may necessitate adjustments of sildenafil's dose. If concurrent administration is necessary, patients should be monitored closely for adverse reactions and may benefit from initiating sildenafil at the lowest recommended dosage with slow, careful titration. Dosage adjustments may be necessary for sildenafil whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy based on efficacy and side effects. Patients should be advised to promptly notify their physician if they experience pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, visual disturbances, syncope, or prolonged erection (greater than 4 hours).

GENERALLY AVOID: Coadministration with grapefruit juice may slightly increase the oral bioavailability and delay the onset of action of sildenafil. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. In a randomized, crossover study with 24 healthy male volunteers, ingestion of 250 mL of grapefruit juice one hour before and concurrently with a 50 mg dose of sildenafil increased the mean area under the plasma concentration-time curve (AUC) of sildenafil and its pharmacologically active N-desmethyl metabolite by 23% and 24%, respectively, compared to water. Peak plasma concentrations (Cmax) were unaltered, but the time to reach sildenafil Cmax was prolonged by 0.25 hour. The observed increase in sildenafil bioavailability is unlikely to be of clinical significance in most individuals. However, pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability and may be significant in the occasional susceptible patient. Indeed, one subject in the study had a 2.6-fold increase in sildenafil concentrations.

MANAGEMENT: It may be advisable to avoid administration of sildenafil with grapefruit juice to prevent potential toxicity and delay in onset of action.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of ivacaftor. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Elexacaftor and tezacaftor are also CYP450 3A4 substrates in vitro and may interact similarly with grapefruit juice, whereas lumacaftor is not expected to interact.

ADJUST DOSING INTERVAL: According to prescribing information, systemic exposure to ivacaftor increased approximately 2.5- to 4-fold, systemic exposure to elexacaftor increased approximately 1.9- to 2.5-fold, and systemic exposure to lumacaftor increased approximately 2-fold following administration with fat-containing foods relative to administration in a fasting state. Tezacaftor exposure is not significantly affected by administration of fat-containing foods.

MANAGEMENT: Patients treated with ivacaftor-containing medications should avoid consumption of grapefruit juice and any food that contains grapefruit or Seville oranges. All ivacaftor-containing medications should be administered with fat-containing foods such as eggs, avocados, nuts, meat, butter, peanut butter, cheese pizza, and whole-milk dairy products. A typical cystic fibrosis diet will satisfy this requirement.