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

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may decrease the plasma concentrations of sunitinib and its pharmacologically active metabolite, both of which are substrates of the isoenzyme. In healthy volunteers, administration of a single dose of sunitinib with the potent CYP450 3A4 inducer, rifampin, decreased the combined (i.e., sunitinib plus its primary active metabolite) peak plasma concentration (Cmax) and systemic exposure (AUC) values by 23% and 46%, respectively, compared to administration of sunitinib alone. In addition, when two or more medications with similar adverse effect profiles are given concurrently, the likelihood of experiencing these adverse reactions may be increased. For example, coadministration with other agents that can prolong the QT interval (e.g., apalutamide, encorafenib, enzalutamide) may result in additive effects and an increased risk of ventricular arrhythmias like torsade de pointes.

MANAGEMENT: Concomitant use of sunitinib with potent CYP450 3A4 inducers should generally be avoided. Alternative therapeutic agents with minimal or no enzyme induction potential should be considered whenever possible. If coadministration with a potent CYP450 3A4 inducer is required, a dose increase for sunitinib in 12.5 mg increments up to a maximum of 87.5 mg daily for gastrointestinal stromal tumor (GIST) and renal cell carcinoma (RCC) or 62.5 mg daily for pancreatic neuroendocrine tumors (pNET) may be considered based on careful monitoring of clinical response and tolerability. (Note: This recommendation is based on pharmacokinetic data from healthy volunteers as described above. The safety and efficacy of sunitinib with concomitant CYP450 3A4 inducers have not been established. In two cytokine-refractory metastatic RCC studies, 33 of the 169 patients received sunitinib with a potent CYP450 3A4 inducer with no modification of the starting dose of sunitinib.) If the CYP450 3A4 inducer also carries a risk of prolonging the QT interval, then obtaining more frequent electrocardiograms (ECGs) to monitor the QT interval may be advisable. Patients should be counseled to seek immediate medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, syncope, palpitations, irregular heartbeat, and/or shortness of breath.

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.