Interactions : אינטראקציות

7           DRUG INTERACTIONS
7.1         Effect of Other Drugs on ZOKINVY
Table 4 presents clinically significant drug interactions involving drugs that affect ZOKINVY.

Table 4: Clinically Significant Drug Interactions (Drugs that Affect ZOKINVY) CYP3A Inhibitors
Coadministration of ZOKINVY with a strong CYP3A inhibitor increases
Clinical Impact       lonafarnib AUC and Cmax [see Clinical Pharmacology (12.3)] which may increase the risk of ZOKINVY adverse reactions.

Use of ZOKINVY with strong or moderate CYP3A
Strong or moderate         inhibitors is contraindicated [see Contraindications Prevention or       CYP3A inhibitors           (4)]. Avoid consumption of grapefruit or Seville Management                                     oranges.
Weak CYP3A                 Avoid coadministration of ZOKINVY with weak inhibitors                 CYP3A inhibitors. If coadministration is unavoidable, reduce to or continue ZOKINVY at a dosage of 115 mg/m2 [see Dosage and Administration (2.3)]. During coadministration, closely monitor patients for arrhythmias and events such as syncope and heart palpitations because ZOKINVY exposures may be increased despite the dosage reduction and the effect on the QT interval is unknown. Resume previous
ZOKINVY dosage 14 days after discontinuing the weak CYP3A inhibitor.
CYP3A Inducers
Coadministration of ZOKINVY with a strong CYP3A inducer decreases
Clinical Impact     lonafarnib Cmax and AUC [see Clinical Pharmacology (12.3)] which may reduce ZOKINVY efficacy.
Use of ZOKINVY with strong or moderate CYP3A
Strong or moderate
Prevention or                                inducers is contraindicated [see Contraindications CYP3A inducers
Management                                   (4)].
Weak CYP3A inducers No ZOKINVY dosage adjustment is recommended.
CYP2C9 Inhibitors
Coadministration of ZOKINVY with a CYP2C9 inhibitor may increase
Clinical Impact     lonafarnib AUC and Cmax [see Clinical Pharmacology (12.3)] which may increase the risk of ZOKINVY adverse reactions.
Avoid coadministration of ZOKINVY with CYP2C9 inhibitors. If coadministration is unavoidable, closely
Prevention or                                 monitor patients for arrhythmias and events such as CYP2C9 Inhibitors
Management                                    syncope and heart palpitations because the effect of increased ZOKINVY exposures on the QT interval is unknown.

7.2        ZOKINVY’s Effect on Other Drugs
Table 5 presents clinically significant drug interactions involving drugs affected by ZOKINVY.

Table 5: 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 Cmax 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        HMG CoA reductase           Coadministration of ZOKINVY with lovastatin, Management           inhibitors (“Statins”)      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 (2.4)].
Other sensitive CYP3A    Avoid coadministration of ZOKINVY with substrates               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 Cmax of loperamide [see Clinical Pharmacology (12.3)] which may increase the risk of loperamide’s adverse reactions

Prevention or         Loperamide is contraindicated in patients less than 2 years of age. When Management            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 Cmax of the CYP2C19 substrate [see Clinical Pharmacology (12.3)] which may increase the risk of the CYP2C19 substrate’s adverse reactions.

Prevention or         Avoid coadministration of ZOKINVY with CYP2C19 substrates. If Management            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 Cmax 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         When ZOKINVY is coadministered with P-gp substrates (e.g., digoxin, Management            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.