Drug Interactions between Kisqali Femara Co-Pack and Mudrane

GENERALLY AVOID: Coadministration with potent CYP450 3A4 inducers may significantly decrease the plasma concentrations and therapeutic effects of ribociclib, which is a substrate of the isoenzyme. In healthy study subjects, administration of a single 600 mg dose of ribociclib with multiple 600 mg daily doses of rifampin, a potent CYP450 3A4 inducer, resulted in an 81% and 89% decrease in ribociclib peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to ribociclib administered alone. In addition, administration of efavirenz, a moderate CYP450 3A4 inducer, is predicted to decrease ribociclib Cmax and AUC by 37% and 60%, respectively.

MANAGEMENT: Concomitant use of ribociclib with potent CYP450 3A4 inducers should generally be avoided. Alternative agents with no or minimal CYP450 3A4 induction potential are recommended whenever possible. If coadministration is necessary, dosage adjustments as well as clinical and laboratory monitoring should be considered whenever a potent CYP450 3A4 inducer is added to or withdrawn from therapy. Patients should be monitored for therapeutic failure.

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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 ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

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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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