PITOLISANT Drug Interactions: What You Need to Know

INTERACTIONS Strong CYP2D6 Inhibitors: Maximum recommended dosage is 17.8 mg once daily ( 2.5 , 7.1 ) Strong CYP3A4 Inducers: Decreased exposure of WAKIX; consider dosage adjustment ( 2.5 , 7.1 ) Sensitive CYP3A4 Substrates (including hormonal contraceptives): WAKIX may reduce effectiveness of sensitive CYP3A4 substrates. Use an alternative non-hormonal contraceptive method during treatment with WAKIX and for at least 21 days after discontinuation of treatment ( 7.1 , 8.3 )

7.1 Drugs Having Clinically Important Interactions with WAKIX Table 2: Clinically Significant Drug Interactions with WAKIX Effect of Other Drugs on WAKIX Strong CYP2D6 Inhibitors Clinical Implication: Concomitant administration of WAKIX with strong CYP2D6 inhibitors increases pitolisant exposure by 2.2-fold. Prevention or Management: Reduce the dose of WAKIX by half <span class="opacity-50 text-xs">[see see Dosage and Administration ( 2.5 ), Clinical Pharmacology ( 12.3 )]</span> . Strong CYP3A4 Inducers Clinical Implication: Concomitant use of WAKIX with strong CYP3A4 inducers decreases exposure of pitolisant by 50%. Prevention or Management: Assess for loss of efficacy after initiation of a strong CYP3A4 inducer. For patients stable on WAKIX 8.9 mg or 17.8 mg once daily, increase the dose of WAKIX to reach double the original daily dose (i.e., 17.8 mg or 35.6 mg, respectively) over 7 days. If concomitant dosing of a strong CYP3A4 inducer is discontinued, decrease WAKIX dosage by half <span class="opacity-50 text-xs">[see see Dosage and Administration ( 2.5 ), Clinical Pharmacology ( 12.3 )]</span> . Histamine-1 (H1)

Receptor Antagonists Clinical

Implication: WAKIX increases the levels of histamine in the brain; therefore, H1 receptor antagonists that cross the blood-brain barrier may reduce the effectiveness of WAKIX. Prevention or Management: Avoid centrally acting H1 receptor antagonists. QT Interval Prolongation Clinical Implication: Concomitant use of drugs that prolong the QT interval may add to the QT effects of WAKIX and increase the risk of cardiac arrhythmia. Prevention or Management: Avoid the use of WAKIX in combination with other drugs known to prolong the QT interval [see Warnings and Precautions ( 5.1 )] . Effect of WAKIX on Other Drugs Sensitive CYP3A4 Substrates Clinical Implication: WAKIX is a borderline/weak inducer of CYP3A4. Therefore, reduced effectiveness of sensitive CYP3A4 substrates may occur when used concomitantly with WAKIX [see Clinical Pharmacology ( 12.3 )] . The effectiveness of hormonal contraceptives (e.g., ethinyl estradiol) may be reduced when used with WAKIX and effectiveness may be reduced for 21 days after discontinuation of therapy. Prevention or Management: Patients using hormonal contraception should be advised to use an alternative non-hormonal contraceptive method during treatment with WAKIX and for at least 21 days after discontinuation of treatment [see Use in Specific Populations ( 8.3 )].

7.2 Drugs Having No Clinically Important Interactions with WAKIX A clinical study was conducted to evaluate the concomitant use of WAKIX with modafinil or sodium oxybate. This study demonstrated no clinically relevant effect of modafinil or sodium oxybate on the pharmacokinetics of WAKIX and no effect of WAKIX on the pharmacokinetics of modafinil or sodium oxybate <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . A clinical study showed that strong CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice) have no effect on the pharmacokinetics of WAKIX <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

WAKIX is contraindicated in patients with: known hypersensitivity to pitolisant or any component of the formulation. Anaphylaxis has been reported in patients treated with WAKIX [see Adverse Reactions ( 6.2 )] . severe hepatic impairment. WAKIX is extensively metabolized by the liver and there is a significant increase in WAKIX exposure in patients with moderate hepatic impairment [see Use in Specific Populations ( 8.6 )] . Known hypersensitivity to pitolisant or any component of the formulation ( 4 ) Severe hepatic impairment ( 4 )

AND PRECAUTIONS QT Interval Prolongation : Increases in QT interval. Avoid use with drugs that also increase the QT interval and in patients with risk factors for prolonged QT interval. Monitor patients with hepatic or renal impairment for increased QTc ( 5.1 )

5.1 QT Interval Prolongation WAKIX prolongs the QT interval. The use of WAKIX should be avoided in patients with known QT prolongation or in combination with other drugs known to prolong the QT interval <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span>. WAKIX should also be avoided in patients with a history of cardiac arrhythmias, as well as other circumstances that may increase the risk of the occurrence of torsade de pointes or sudden death, including symptomatic bradycardia, hypokalemia or hypomagnesemia, and the presence of congenital prolongation of the QT interval <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span>. The risk of QT prolongation may be greater in patients with hepatic or renal impairment due to higher concentrations of pitolisant. Monitor patients with hepatic or renal impairment for increased QTc. Dosage modification is recommended in patients with moderate hepatic impairment and moderate or severe renal impairment <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 , 2.4 )]</span> . WAKIX is contraindicated in patients with severe hepatic impairment <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span> . WAKIX is not recommended in patients with end-stage renal disease (ESRD) <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ), Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )]</span> .