Fintepla Drug Interactions

Pharmacodynamic interactions: Pharmacodynamic interactions with other central nervous system depressants increase the risk of aggravated central nervous system depression. Examples of such depressants are other serotonergic agents (including SSRIs, SNRIs, tricyclic antidepressants, or triptans); agents that impair metabolism of serotonin such as MAOIs; or antipsychotics that may affect the serotonergic neurotransmitter systems (see Contraindications and Precautions).
Pharmacokinetic interactions: Clinical studies: Effect of steady state stiripentol plus clobazam and/or valproate on fenfluramine: At steady state in the Phase 3 studies, the co-administration of 0.2 mg/kg twice daily (0.4 mg/kg/day), maximum 17 mg/day, fenfluramine with a standard anti-epileptic medicine regimen of stiripentol plus clobazam and/or valproate, resulted in a 130% increase in fenfluramine AUC_0-24 and a 60% decrease in norfenfluramine AUC_0-24, as compared to 0.35 mg/kg twice daily (0.7 mg/kg/day), maximum 26 mg/day, fenfluramine without stiripentol (see Dosage & Administration).
Effect of steady state cannabidiol on fenfluramine: Co-administration of a single 0.35 mg/kg dose of fenfluramine with repeated doses of cannabidiol increased the AUC_0-INF of fenfluramine by 59% and the C_max by 10%, and decreased the AUC_0-INF of norfenfluramine by 22% and the C_max by 33%, as compared to fenfluramine administered alone. Co-administration of a single 0.35 mg/kg dose of fenfluramine, with repeated doses of cannabidiol, did not affect the pharmacokinetics of cannabidiol, as compared to cannabidiol alone. No dose adjustment is necessary when fenfluramine is co-administered with cannabidiol.
Effect of rifampicin (a strong inducer of CYP3A and 2C19 and a moderate inducer of CYP1A2, 2B6, 2C8 and 2C9), or strong CYP1A2 or CYP2B6 inducers: Rifampicin induces multiple CYP enzymes which metabolize fenfluramine and norfenfluramine. Coadministration of a single 0.35 mg/kg dose of fenfluramine with rifampicin at steady state (600 mg once daily) in healthy volunteers decreased the AUC0-t of fenfluramine by 58% and the Cmax by 40%, and decreased the AUC0-t of norfenfluramine by 50%, and increased the Cmax of norfenfluramine by 13%, as compared to fenfluramine administered alone. An increase in fenfluramine dose may be necessary when coadministered with rifampicin or a strong CYP1A2 or CYP2B6 inducer (see Precautions).
Effect of CYP1A2 or CYP2D6 inhibitors: Coadministration of a single 0.35 mg/kg dose of fenfluramine with fluvoxamine (a strong CYP1A2 inhibitor) at steady state (50 mg once daily) in healthy volunteers increased the AUC0-t of fenfluramine by a ratio of 2.1-fold and the Cmax by a ratio of 1.2-fold, and decreased the AUC0-t of norfenfluramine by a ratio of 1.3-fold and the Cmax by a ratio of 1.4-fold, as compared to fenfluramine administered alone.
Coadministration of a single 0.35 mg/kg dose of fenfluramine with paroxetine (a strong CYP2D6 inhibitor) at steady state (30 mg once daily) in healthy volunteers increased the AUC0-t of fenfluramine by a ratio of 1.8-fold and the Cmax by a ratio of 1.1-fold, and decreased the AUC0-t of norfenfluramine by a ratio of 1.2-fold and the Cmax by a ratio of 1.3-fold, as compared to fenfluramine administered alone.
In vitro studies: Effect of fenfluramine on other medicinal products: Co-administration of a single 0.7 mg/kg dose of fenfluramine, with a single dose of a stiripentol, clobazam, and valproic acid combination, did not affect the pharmacokinetics of stiripentol, nor the pharmacokinetics of clobazam or its Ndesmethyl-metabolite norclobazam, nor the pharmacokinetics of valproic acid, as compared to the stiripentol, clobazam, and valproic acid combination alone.
Effect of fenfluramine on CYP2D6 substrates: In vitro studies indicate that fenfluramine may inhibit CYP2D6. It has been reported that steady-state desipramine concentrations increase approximately 2-fold with concomitant administration of fenfluramine. Co-administration of fenfluramine with CYP2D6 substrates may increase their plasma concentrations.
Effect of fenfluramine on CYP2B6 and CYP3A4 substrates: In vitro studies indicate that fenfluramine may induce CYP2B6 and may induce intestinal CYP3A4. Co-administration of fenfluramine with CYP2B6 substrates or CYP3A4 substrates may decrease their plasma concentrations.
Effect of fenfluramine on MATE1 substrates: In vitro studies indicate that norfenfluramine (major and pharmacologically active metabolite) may inhibit MATE1 at clinically relevant concentrations. Co-administration of fenfluramine with MATE1 substrates may increase their plasma concentrations.