Zokinvy (lonafarnib) for Progeria | Sentynl Therapeutics, Inc.

INDICATION AND IMPORTANT SAFETY INFORMATION

INDICATION AND USAGE

ZOKINVY^® is indicated in adult and pediatric patients 12 months of age and older with a body surface area (BSA) of 0.39 m² and above:

To reduce the risk of mortality in Hutchinson-Gilford Progeria Syndrome (HGPS)
For the treatment of processing-deficient Progeroid Laminopathies with either:
- Heterozygous LMNA mutation with progerin-like protein accumulation
- Homozygous or compound heterozygous ZMPSTE24 mutations

Limitations of Use

ZOKINVY is not indicated for use in patients with non-HGPS Progeroid Syndromes or with Progeroid Laminopathies known to be processing-proficient. Based upon its mechanism of action, ZOKINVY would not be expected to be effective in these populations.

IMPORTANT SAFETY INFORMATION

Contraindications

ZOKINVY is contraindicated in patients taking:

Strong CYP3A inhibitors
Strong or moderate CYP3A inducers
Midazolam
Lovastatin, simvastatin, or atorvastatin

Warnings and Precautions

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 [see Drug Interactions].
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 the same dosage.
Obtain serum electrolytes prior to initiating ZOKINVY and during treatment as clinically indicated. Correct serum electrolyte abnormalities.

Laboratory Abnormalities

Some patients treated with ZOKINVY developed laboratory abnormalities. 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%) and 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.

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 reproductive potential of the animal findings and that the impact on pubertal development and the potential for impaired fertility with ZOKINVY 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.

Hypertension

Increases in blood pressure have been documented in patients treated with ZOKINVY. In clinical trials, the incidence of hypertension was 8.1%.

Drug Interactions

Strong CYP3A inhibitors

ZOKINVY administration with strong 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.

Strong or moderate CYP3A inhibitors

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

QTc Prolongation Drugs

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 arrhythmias, and sudden death.

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.

P-gp substrates

Lonafarnib is a weak P-gp inhibitor. Coadministration of ZOKINVY with a P-gp substrate increases the concentration of the P-GP substrate, which may increase the risk of the P-gp substrate’s adverse reactions.

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.

Use in Specific Populations

Patients who are pregnant or lactating: Based on findings from animal studies, ZOKINVY can cause embryofetal harm. 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 females of reproductive potential to use effective contraception during treatment with ZOKINVY. There are no data on the presence of ZOKINVY in human breast milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ZOKINVY and any potential adverse effects of the breastfed infant from ZOKINVY or from the underlying maternal condition.

You are encouraged to report side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

Please see accompanying full Prescribing Information.

References:

1. ZOKINVY [package insert]. Palo Alto, CA: Eiger BioPharmaceuticals, Inc; Revision 3/2024. 2. Gordon LB, Shappell H, Massaro J, et al. Association of lonafarnib treatment vs no treatment with mortality rate in patients with Hutchinson-Gilford progeria syndrome. JAMA. 2018;319(16):1687-1695. doi:10.1001/jama.2018.3264.

Zokinvy targets a key step in the disease pathophysiology for Progeria and PDPL^1,2

Starting and staying on Zokinvy matters

QTc Interval Prolongation

Laboratory Abnormalities

Nephrotoxicity

Retinal Toxicity

Impaired Fertility

Adverse Reactions

Gastrointestinal Adverse Reactions

Alanine Aminotransferase and Aspartate Aminotransferase Elevations

Hypertension

Drug Interactions

Zokinvy targets a key step in the disease pathophysiology for Progeria and PDPL1,2

Starting and staying on Zokinvy matters

QTc Interval Prolongation

Laboratory Abnormalities

Nephrotoxicity

Retinal Toxicity

Impaired Fertility

Adverse Reactions

Gastrointestinal Adverse Reactions

Alanine Aminotransferase and Aspartate Aminotransferase Elevations

Hypertension

Drug Interactions

Zokinvy targets a key step in the disease pathophysiology for Progeria and PDPL^1,2