Zokinvy Drug Information

Recommended Dosage

The starting dosage of ZOKINVY for patients with a BSA of 0.39 m 2 and above is 115 mg/m 2 twice daily with morning and evening meals (see Table 1 ) to reduce the risk of gastrointestinal adverse reactions. An appropriate dosage strength of ZOKINVY is not available for patients with a BSA of less than 0.39 m 2. Round all total daily dosages to the nearest 25 mg increment (see Table 1 and Table 2 ).

If a dose is missed, take the dose as soon as possible with food, up to 8 hours prior to the next scheduled dose. If less than 8 hours remain before the next scheduled dose, skip the missed dose, and resume taking ZOKINVY at the next scheduled dose. Table 1 provides the BSA-based dosage recommendations for the starting dosage of 115 mg/m 2 twice daily.

Patients Able to Swallow Capsules Administer ZOKINVY capsules whole with a sufficient amount of water. Do not chew the capsules. Patients Unable to Swallow Capsules The entire contents of ZOKINVY capsules can be mixed with Ora Blend SF ® or Ora-Plus ® or, for patients unable to access or tolerate Ora Blend SF or Ora-Plus, the contents of ZOKINVY capsules can be mixed with orange juice or applesauce (see preparation instructions below).

Do not mix with juice containing grapefruit or Seville oranges. The mixture must be prepared fresh for each dose and taken within approximately 10 minutes of mixing. Preparation of Dose in Ora Blend SF, Ora-Plus, or Orange Juice For each capsule, empty contents of the capsule into a container containing 5 mL to 10 mL of the liquid.

Mix thoroughly with a spoon. Consume entire serving. Preparation of Dose in Applesauce For each capsule, empty contents of the capsule into a container containing 1 teaspoonful to 2 teaspoonfuls of applesauce.

Consume entire serving.

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 84 subjects were treated with at least one dose of ZOKINVY with or without additional therapy, of which 8 were treated at a dosage of at least 115 mg/m 2 twice daily for greater than or equal to 10 years. In both studies, ZOKINVY was administered orally via capsules or the capsule contents were mixed with Ora Blend SF or Ora-Plus and administered orally as a suspension.

Table 4 summarizes adverse reactions reported in the clinical trials. The most common adverse reactions (≥25%) in the clinical trials were vomiting, diarrhea, infection, nausea, decreased appetite, fatigue, upper respiratory tract infection, abdominal pain, musculoskeletal pain, electrolyte abnormalities, decreased weight, headache, myelosuppression, increased aspartate aminotransferase, decreased blood bicarbonate, cough, hypertension, and increased alanine aminotransferase. Of the 35 patients who experienced nausea, 34 (97%) patients had mild nausea (defined as loss of appetite without alteration in eating habits) and 1 (3%) patient had moderate nausea (defined as oral intake decreased without significant weight loss, dehydration, or malnutrition).

By the end of therapy, 4 (14%) patients who were still on ZOKINVY required antiemetics or anti-nauseants. A total of 4 patients discontinued ZOKINVY, mostly due to nausea or vomiting. Four (8%) patients reported severe diarrhea (defined as an increase of seven or more stools per day over baseline; hospitalization indicated; severe increase in ostomy output compared to baseline; limiting self-care activities of daily living).

Twelve (43%) patients were treated with loperamide. Alanine Aminotransferase and Aspartate Aminotransferase Elevations Increased alanine aminotransferase was commonly reported (17 patients). Increased aspartate aminotransferase was also commonly reported (22 patients).

One patient with alanine and aspartate aminotransferase elevations also experienced hypertriglyceridemia and hyperglycemia resulting in discontinuation of ZOKINVY. Hypertension Increases in blood pressure have been documented in patients treated with ZOKINVY. At baseline, 22 (35%) patients had either a systolic blood pressure or a diastolic blood pressure or both above the 95th percentile.

Over the course of the trials, 18 (29%) patients had hypertension based on systolic blood pressure or diastolic blood pressure measurements above the 95th percentile on 3 or more occasions. Five (8%) patients who were normotensive at baseline had either systolic blood pressure or diastolic blood pressure above the 95th percentile at the end of treatment.

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 ), 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. Prevention or Management Strong CYP3A inhibitors Use of ZOKINVY with strong CYP3A inhibitors is contraindicated. Moderate CYP3A inhibitors No dosage adjustment for ZOKINVY is recommended when moderate CYP3A inhibitors are added to steady-state ZOKINVY.

When initiating ZOKINVY in a patient who is currently on a moderate CYP3A inhibitor, the patient may be at increased risk of adverse reactions. CYP3A Inducers Clinical Impact Coadministration of ZOKINVY with a strong CYP3A inducer decreases lonafarnib C max and AUC, which may reduce ZOKINVY efficacy. Weak CYP3A inducers No ZOKINVY dosage adjustment is recommended.

QTc Prolongation Drugs Clinical Implication ZOKINVY causes QTc interval prolongation. 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. 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.

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 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. Midazolam Coadministration of ZOKINVY with midazolam is contraindicated. Temporarily discontinue ZOKINVY for 10-14 days before and 2 days after administration of midazolam.

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. 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. Prevention or Management Loperamide is contraindicated in patients less than 2 years of age. CYP2C19 Substrates Clinical Impact Lonafarnib is a moderate CYP2C19 inhibitor.

Prevention or Management Avoid coadministration of ZOKINVY with CYP2C19 substrates.

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 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 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.

Pediatric Use The safety and effectiveness of ZOKINVY for the treatment of HGPS and processing-deficient Progeroid Laminopathies (with either heterozygous LMNA mutation with progerin-like protein accumulation or homozygous or compound heterozygous ZMPSTE24 mutations) have been established in pediatric patients 12 months of age and older. Use of ZOKINVY for these indications is supported by adequate and well-controlled studies in pediatric patients 2 years of age and older. The safety and effectiveness of ZOKINVY in pediatric patients less than 12 months of age have not been established.

ZOKINVY is contraindicated in patients taking: Strong CYP3A inhibitors Strong or moderate CYP3A inducers Midazolam Lovastatin, simvastatin, or atorvastatin Strong CYP3A inhibitors. Strong or moderate CYP3A inducers. Midazolam.

Lovastatin, simvastatin, or atorvastatin.