LONAFARNIB Drug Interactions: What You Need to Know

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.

ZOKINVY is contraindicated in patients taking: Strong CYP3A inhibitors [see Drug Interactions ( 7.1 )] Strong or moderate CYP3A inducers [see Drug Interactions ( 7.1 )] Midazolam [see Drug Interactions ( 7.2 )] Lovastatin, simvastatin, or atorvastatin [see Drug Interactions ( 7.2 )] Strong CYP3A inhibitors. ( 4 ) Strong or moderate CYP3A inducers. ( 4 ) Midazolam. ( 2.3 , 4 ) Lovastatin, simvastatin, or atorvastatin. ( 4 )

AND PRECAUTIONS QTc Interval Prolongation : Increases the QTc interval. Avoid use in patients with symptomatic bradycardia, hypokalemia, or hypomagnesemia, and in combination with other drugs known to prolong the QTc interval. ( 5.1 ) Risk of Reduced Efficacy or Adverse Reactions Due to Drug Interactions : Prior to and during treatment, consider potential for drug interactions and review concomitant medications; monitor for adverse reactions. ( 5.2 , 7 )

Laboratory

Abnormalities: Monitor for changes in electrolytes, complete blood counts, and liver enzymes. ( 5.3 ) Nephrotoxicity: Caused nephrotoxicity in rats. Monitor renal function at regular intervals. ( 5.4 , 13.2 )

Retinal

Toxicity: Caused rod-dependent, low-light vision decline in monkeys. Perform ophthalmological evaluation at regular intervals and at the onset of any new visual changes. ( 5.5 , 13.2 )

Impaired

Fertility: Caused impaired fertility in female rats, impaired fertility and testicular toxicity in male rats, and toxicity in the male reproductive tract in monkeys. Advise females and males of reproductive potential of the animal fertility findings. ( 5.6 , 13.1 , 13.2 ) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the risk to a fetus and to use effective contraception. ( 5.7 , 8.1 , 8.3 )

5.1 QTc Interval Prolongation ZOKINVY prolongs the QTc interval. Prolongation of the QTc interval increases the risk of Torsade de pointes, other serious arrhythmias, and sudden death. Avoid use of ZOKINVY in patients with a history of cardiac arrhythmias, as well as in other circumstances that may increase the risk of the occurrence of Torsade de pointes or sudden death, including symptomatic bradycardia, hypokalemia, or hypomagnesemia. Avoid use of ZOKINVY in combination with other drugs known or suspected to prolong the QTc interval <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span> . Monitor ECGs prior to initiating ZOKINVY, during treatment, and as clinically indicated. If QTc interval is greater than 500 msec, withhold ZOKINVY until QTc interval is less than 470 msec, then resume ZOKINVY at same dosage. Obtain serum electrolytes prior to initiating ZOKIVNY and during treatment as clinically indicated. Correct serum electrolyte abnormalities.

5.2 Risk of Reduced Efficacy or Adverse Reactions Due to Drug Interactions Coadministration of ZOKINVY with other drugs may result in clinically significant drug interactions <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 , 2.3 ), Contraindications ( 4 ), Drug Interactions ( 7.1 , 7.2 )]</span> . These drug interactions can lead to: Reduced efficacy of ZOKINVY Increased risk of adverse reactions from ZOKINVY or co-administered drugs See Table 5 and Table 6 for steps to prevent or manage these clinically significant drug interactions, including dosage recommendations <span class="opacity-50 text-xs">[see Drug Interactions (7.1, 7.2 ) ]</span> . Consider the potential for drug interactions prior to and during ZOKINVY therapy; review concomitant medications during ZOKINVY therapy; and monitor for adverse reactions.

5.3 Laboratory Abnormalities Some patients treated with ZOKINVY developed laboratory abnormalities <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . These included: Electrolyte abnormalities (43%), such as hyperkalemia, hypokalemia, hyponatremia, or hypercalcemia Myelosuppression (35%), such as reductions in absolute neutrophil count, white blood cell counts, lymphocytes, hemoglobin, or hematocrit Increased liver enzymes, such as aspartate aminotransferase (35%), or alanine aminotransferase (27%) These laboratory abnormalities often improved while continuing ZOKINVY, but it is not possible to exclude ZOKINVY as a cause of the abnormalities. Periodically monitor electrolytes, complete blood counts, and liver enzymes, and manage abnormalities accordingly.

5.4 Nephrotoxicity Lonafarnib caused nephrotoxicity in rats at plasma drug exposures approximately equal to that achieved with the human dose [ see Nonclinical Toxicology ( 13.2 )] . Monitor renal function at regular intervals during ZOKINVY therapy.

5.5 Retinal Toxicity Lonafarnib caused rod-dependent, low-light vision decline in monkeys at plasma drug exposures similar to that achieved with the human dose <span class="opacity-50 text-xs">[see Nonclinical Toxicology ( 13.2 )]</span> . Perform ophthalmological evaluation at regular intervals and at the onset of any new visual changes during ZOKINVY therapy.

5.6 Impaired Fertility Lonafarnib caused impaired fertility in female rats at 1.2 times the human dose based on plasma drug exposure <span class="opacity-50 text-xs">[see Nonclinical Toxicology ( 13.1 )]</span> . Lonafarnib caused impaired fertility and testicular toxicity in male rats at 1.5 times the human dose based on plasma drug exposure <span class="opacity-50 text-xs">[see Nonclinical Toxicology ( 13.1 )]</span> , and toxicity in the male reproductive tract in monkeys at doses lower than the human dose based on plasma drug exposure <span class="opacity-50 text-xs">[see Nonclinical Toxicology ( 13.2 )]</span> . Advise females and males of reproductive potential of the animal fertility findings, and that the impact on pubertal development and the potential for impaired fertility with ZOKINVY therapy in humans have not been adequately evaluated <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.3 )]</span> .

5.7 Embryo-Fetal Toxicity Based on findings from animal reproduction studies, ZOKINVY can cause embryo-fetal harm when administered to pregnant women. In animal reproduction studies, oral administration of lonafarnib in pregnant rats during organogenesis produced embryo-fetal toxicity at plasma drug exposures that were approximately equal to the recommended human dose. In pregnant rabbits, oral administration of lonafarnib during organogenesis produced skeletal malformations and variations at exposures lower than the human exposure. Advise pregnant women of the risk to a fetus. Advise females of reproductive potential to avoid becoming pregnant and to use appropriate effective contraception during treatment with ZOKINVY <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span> .