Drug Interactions between aminophylline / ephedrine / guaifenesin / phenobarbital and sildenafil

ADJUST DOSE: Coadministration with moderate to potent CYP450 3A4 inducers may significantly decrease the plasma concentrations and effects of sildenafil, which is primarily metabolized by CYP450 3A4 and, to a lesser extent, by CYP450 2C9. This interaction has been demonstrated in studies using bosentan, a moderate CYP450 3A4 inducer and weak CYP450 2C9 inducer in vivo as well as an in vitro inducer of CYP450 2C19. Coadministration of oral sildenafil (80 mg three times daily) at steady state with bosentan (125 mg twice daily) at steady state over 6 days in healthy adult volunteers decreased the systemic exposure (AUC) and peak plasma concentration (Cmax) of sildenafil by 62.6% and 55.4%, respectively. The same effect was also observed with lower doses of oral sildenafil (20 mg three times daily) added to bosentan therapy (62.5 mg - 125 mg twice daily). The labeling for some sildenafil formulations used for pulmonary arterial hypertension (PAH) reported a population pharmacokinetic analysis of data from patients in clinical trials which indicated an approximately 3-fold increase in sildenafil clearance when co-administered with mild CYP450 3A4 inducers. However, this increased clearance was not reflected in a population pharmacokinetic analysis described in the labeling of some sildenafil formulations indicated for erectile dysfunction. More potent CYP450 3A4 inducers are expected to have greater effects than those observed with bosentan or mild inducers; however, data are not available. Likewise, clinical data regarding this interaction in pediatric patients are also unavailable.

MANAGEMENT: In adult patients being treated for pulmonary arterial hypertension (PAH), the dose of sildenafil may need to be increased when initiating treatment with moderate to potent CYP450 3A4 inducers. Conversely, the manufacturer recommends reducing the dose of sildenafil to 20 mg orally three times daily when discontinuing treatment with moderate to potent CYP450 3A4 inducers. Patients being treated for erectile dysfunction should be monitored closely and may require a dose adjustment of sildenafil if a moderate or strong CYP450 3A4 inducer is initiated or discontinued. Dosing should be guided by the patient's symptoms, ability to tolerate sildenafil, and recommendations provided in the product labeling.

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.

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.