Lonafarnib

7 DRUG INTERACTIONS QTc Interval Prolongation Drugs : Avoid concomitant use with ZOKINVY. ( 2.2 , 5.2 , 7.1 , 12.3 ) See full prescribing information for additional clinically significant drug interactions with ZOKINVY and recommended dosage modifications for drug interactions. ( 2.2 , 7 )

7.1 Effect of Other Drugs on ZOKINVY Table 5 presents clinically significant drug interactions involving drugs that affect ZOKINVY. Table 5: Clinically Significant Drug Interactions (Drugs that Affect ZOKINVY) CYP3A Inhibitors Clinical Impact Lonafarnib is metabolized by CYP3A. Concomitant use of ZOKINVY with a strong CYP3A inhibitor may increase lonafarnib area under curve (AUC) and maximum concentration (C max ) [see Clinical Pharmacology ( 12.3 )] , which may increase the incidence and severity of adverse reactions, including QTc interval prolongation.

Prolongation of the QTc interval increases the risk of Torsade de pointes, other serious arrhythmias, and sudden death [see Warnings and Precautions ( 5.1 )] . Prevention or Management Strong CYP3A inhibitors Use of ZOKINVY with strong CYP3A inhibitors is contraindicated [see Contraindications ( 4 )] . Avoid consumption of grapefruit or Seville oranges. Moderate CYP3A inhibitors No dosage adjustment for ZOKINVY is recommended when moderate CYP3A inhibitors are added to steady-state ZOKINVY [see Dosage and Administration ( 2.2 )] .

When initiating ZOKINVY in a patient who is currently on a moderate CYP3A inhibitor, the patient may be at increased risk of adverse reactions [see Dosage and Administration ( 2.2 )]. CYP3A Inducers Clinical Impact Coadministration of ZOKINVY with a strong CYP3A inducer decreases lonafarnib C max and AUC [see Clinical Pharmacology ( 12.3 )] , which may reduce ZOKINVY efficacy. Prevention or Management Strong or moderate CYP3A inducers Use of ZOKINVY with strong or moderate CYP3A inducers is contraindicated [see Contraindications ( 4 )] . Weak CYP3A inducers No ZOKINVY dosage adjustment is recommended.

QTc Prolongation Drugs Clinical Implication ZOKINVY causes QTc interval prolongation [see Clinical Pharmacology ( 12.2 )] . Concomitant use of ZOKINVY with other products that prolong the QTc interval may result in a greater increase of the QTc interval and adverse reactions associated with QTc interval prolongation, including Torsade de pointes, other serious arrythmias, and sudden death [see Warnings and Precautions ( 5.1 )] . Prevention or Management Avoid concomitant use of ZOKINVY with other drugs with a known potential to prolong the QTc interval.

If concomitant use cannot be avoided, obtain ECGs when initiating, during concomitant use, and as clinically indicated [see Warnings and Precautions ( 5.1 )] .

7.2 ZOKINVY's Effect on Other Drugs Table 6 presents clinically significant drug interactions involving drugs affected by ZOKINVY. Table 6: Clinically Significant Drug Interactions (Drugs Affected by ZOKINVY) CYP3A Substrates Clinical Impact Lonafarnib is a strong CYP3A mechanism-based inhibitor. Coadministration of ZOKINVY with a CYP3A substrate increases the AUC and C max of the CYP3A substrate [see Clinical Pharmacology ( 12.3 )] which may increase the risk of the CYP3A substrate's adverse reactions, including myopathy or rhabdomyolysis (with statins), or extreme sedation or respiratory depression (with midazolam).

Prevention or Management HMG CoA reductase inhibitors (“Statins”) Coadministration of ZOKINVY with lovastatin, simvastatin, or atorvastatin is contraindicated [see Contraindications ( 4 )] . Midazolam Coadministration of ZOKINVY with midazolam is contraindicated [see Contraindications ( 4 )] . Temporarily discontinue ZOKINVY for 10-14 days before and 2 days after administration of midazolam [see Dosage and Administration ( 2.3 )] . Other sensitive CYP3A substrates Avoid coadministration of ZOKINVY with sensitive CYP3A substrates. As noted above, use with lovastatin, simvastatin, or atorvastatin, and midazolam is contraindicated [see Contraindications ( 4 )] ).

If coadministration of other sensitive CYP3A substrates is unavoidable, monitor for adverse reactions and reduce the dosage of those sensitive CYP3A substrate(s) in accordance with their approved product labeling. Certain CYP3A substrates When ZOKINVY is coadministered with certain CYP3A substrates where minimal concentration changes may lead to serious or life-threatening toxicities, monitor for adverse reactions and reduce the dosage of the CYP3A substrate in accordance with its approved product labeling. Loperamide Clinical Impact Lonafarnib is a weak inhibitor of P-gp and strong inhibitor of CYP3A.

Coadministration of ZOKINVY with loperamide increases the AUC and C max of loperamide [see Clinical Pharmacology ( 12.3 )] which may increase the risk of loperamide's adverse reactions. Prevention or Management Loperamide is contraindicated in patients less than 2 years of age. When ZOKINVY is coadministered with loperamide, do not exceed loperamide 1 mg once daily when first coadministered. Slowly increase loperamide dosage with caution in accordance with its approved product labeling. CYP2C19 Substrates Clinical Impact Lonafarnib is a moderate CYP2C19 inhibitor.

Coadministration of ZOKINVY with a CYP2C19 substrate increases the AUC and C max of the CYP2C19 substrate [see Clinical Pharmacology ( 12.3 )] which may increase the risk of the CYP2C19 substrate's adverse reactions. Prevention or Management Avoid coadministration of ZOKINVY with CYP2C19 substrates. If coadministration is unavoidable, monitor for adverse reactions and reduce the dosage of the CYP2C19 substrate in accordance with its approved product labeling. P-gp Substrates Clinical Impact Lonafarnib is a weak P-gp inhibitor.

Coadministration of ZOKINVY with a P-gp substrate increases the AUC and C max of the P-gp substrate [see Clinical Pharmacology ( 12.3 )] , which may increase the risk of the P-gp substrate's adverse reactions. Prevention or Management When ZOKINVY is coadministered with P-gp substrates (e.g., digoxin, dabigatran) where minimal concentration changes may lead to serious or life-threatening toxicities, monitor for adverse reactions and reduce the dosage of the P-gp substrate in accordance with its approved product labeling.

8.1 Pregnancy Risk Summary Based on findings from animal studies, ZOKINVY can cause embryofetal harm when administered to a pregnant woman. There are no human data on ZOKINVY use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Advise pregnant women of the risk to a fetus. In animal reproduction studies, oral administration of lonafarnib to pregnant rats during organogenesis produced embryo-fetal toxicity at exposures that were 1.2-times the human exposure at the recommended dose of 150 mg/m 2 twice daily.

In pregnant rabbits, oral administration of lonafarnib during organogenesis produced skeletal malformations and variations at exposures lower than the human exposure at 150 mg/m 2 twice daily, and maternal toxicity at 26 times the human exposure at 150 mg/m 2 twice daily (see Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data Animal Data In an embryo-fetal development study in rats, oral administration of lonafarnib during organogenesis produced an increase in post-implantation loss (resorptions) and decreases in fetal body weight and number of live fetuses at 30 mg/kg/day (1.2 times the AUC [area under the plasma concentration-time curve] in humans at the recommended dose of 150 mg/m 2 twice daily). No effects on embryo-fetal development in rats were observed at systemic exposures lower than the human AUC at 150 mg/m 2 twice daily.

In rabbits, oral administration of lonafarnib during organogenesis resulted in skeletal malformations and variations at systemic exposures lower than the human AUC at the recommended dose of 150 mg/m 2 twice daily, and maternal toxicity (body weight loss and abortion) at 120 mg/kg/day (26 times the human AUC at 150 mg/m 2 twice daily). No effects in offspring were observed in a pre- and postnatal development study in rats with maternal administration of up to 20 mg/kg/day orally (AUC lower than the human AUC at 150 mg/m 2 twice daily) during organogenesis through lactation.