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Nephrotoxicity

• Lonafarnib caused nephrotoxicity in rats at plasma drug exposures approximately equal to that achieved with the human dose. Monitor renal function at regular intervals during ZOKINVY therapy.

Retinal Toxicity

• Lonafarnib caused rod-dependent, low-light vision decline in monkeys at plasma drug exposures similar to that achieved with the human dose. Perform ophthalmological evaluation at regular intervals and at the onset of any new visual changes during ZOKINVY therapy.

Impaired Fertility

• Based on findings in rats Zokinvy may reduce fertility. Advise males and females of reproducitve potential of the animal findings and that the impact on pubertal development and the potential for impaired fertility with Zonkivy have not been adequately evaluated.

Adverse Reactions

• The most common adverse reactions were vomiting (90%), diarrhea (81%), infection (78%), nausea (56%), decreased appetite (53%), fatigue (51%), upper respiratory tract infection (51%), abdominal pain (48%), musculoskeletal pain (48%), electrolyte abnormalities (43%), headache (37%), decreased weight (37%), increased aspartate aminotransferase (35%), myelosuppression (35%), cough (33%), decreased blood bicarbonate (33%), hypertension (29%), and increased alanine aminotransferase (27%).

Gastrointestinal Adverse Reactions

• Gastrointestinal adverse reactions were the most frequently reported adverse reactions. Of the 57 patients (90%) that experienced vomiting, 30 (53%) patients had mild vomiting, 26 (46%) patients had moderate vomiting, and 1 (2%) patient had severe vomiting.
• Of the 35 patients (56%) that experienced nausea, 34 (97%) patients had mild nausea and 1 (3%) patient had moderate nausea.
• Of the 51 patients (81%) that experienced diarrhea, the majority of patients (92%) experienced mild or moderate diarrhea; 38 (75%) patients reported mild diarrhea and 9 (18%) patients reported moderate diarrhea. Four (8%) patients reported severe diarrhea.
• Loss of fluids and dehydration can be severe, leading to hospitalization. As a result, patients should receive therapy for diarrhea at the earliest signs in order to avoid possible severe complications.

Alanine Aminotransferase and Aspartate Aminotransferase Elevations

• Increased alanine aminotransferase was commonly reported (17 [27%] patients). Of the 17 patients with increased alanine aminotransferase, 14 (82%) patients had mild increases, 1 (6%) patient had moderate increases, and 2 (12%) patients had severe increases.
• Increased aspartate aminotransferase was also commonly reported (22 [35%] patients). Of the 22 patients with increased aspartate aminotransferase, 21 (95%) patients had mild increases and 1 (5%) patient had a severe increase.

Drug Interactions

• Strong or moderate CYP3A inhibitors
• ZOKINVY administration with strong or moderate CYP3A inhibitors, including herbal supplements can increase exposures of ZOKINVY resulting in risk of clinically significant adverse events.
• Do not mix the contents of ZOKINVY with any food or juice containing grapefruit or Seville oranges.

• Weak CYP3A inhibitors
• Avoid coadmistration of Zokinvy with weak CYP3A inhibitors. If coadministration is unavoidable, reduce ZOKINVY dosage. Resume previous dosage 14 days after discontinuing the weak CYP3A inhibitor. Closely monitor patients for arrhythmias and events such as syncope and heart palpitations.

• Strong or moderate CYP3A inducers
• ZOKINVY administration with CYP3A inducers, including herbal supplements, can decrease exposure of ZOKINVY, which may impact efficacy.

• CYP2C9 Inhibitors
• Avoid coadministration of Zokinvy with CYP2C9 inhibitors. If coadminstration is unavoidable, closely monitor patients for arrhythmias and events such as syncope and heart palpitations because the effect of increased Zokinvy exposures on the QT interval is unknown.

• 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
• Lonafarnib is a weak inhibitor of P-gp and strong inhibitor of CYP3A. Do not exceed loperamide 1 mg once daily when first coadministered with ZOKINVY. Slowly increase loperamide dosage with caution as needed to treat diarrhea in accordance with its approved product labeling.

• CYP2C19 substrates
• Lonafarnib is a moderate CYP2C19 inhibitor. 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.