These Highlights Do Not Include All The Information Needed To Use Zokinvy Safely And Effectively. See Full Prescribing Information For Zokinvy.

Limitations of Use

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

Principal Display Panel - 50 mg Carton Label

NDC 42358-450-30

Zokinvy

(lonafarnib) capsules

50 mg

30 capsules

Rx only

INSTRUCTIONS FOR USE

ZOKINVY® (ZO-kinvy) (lonafarnib)

capsules, for oral use

This Instructions for Use contains information on how to mix and give or take a dose of ZOKINVY if the capsules cannot be swallowed whole.

Read this Instructions for Use before you start giving or taking ZOKINVY and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about you or your child's medical condition or treatment

Supplies needed to prepare and give or take a dose of ZOKINVY

Before mixing a dose of ZOKINVY, gather the following supplies:

• the prescribed number of ZOKINVY capsules for you or your child's dose. Place the capsule or capsules on a clean flat surface.
• either Ora-Blend SF, Ora-Plus, orange juice or applesauce for mixing. Do not mix with juice that contains grapefruit or Seville oranges. Seville oranges may also be called bitter or sour oranges.
• if mixing with Ora-Blend SF, Ora-Plus or orange juice: a clean medicine cup with 5 milliliter (mL) and 10 mL measurement levels, OR if mixing with applesauce: a clean teaspoon.
• clean cup(s) for each ZOKINVY capsule to be mixed.
• a clean spoon for stirring the mixture.

How to open ZOKINVY capsules and mix the capsule contents

Step 1:

If mixing with Ora-Blend SF, Ora-Plus or orange juice: Use a clean medicine cup to measure either 5 mL or 10 mL of Ora-Blend SF, Ora-Plus or orange juice.

If mixing with applesauce: measure either 1 or 2 teaspoonfuls of applesauce.

You can choose to use 5 mL or 10 mL of liquid or 1 or 2 teaspoonfuls of applesauce (See Figure A).

Step 2:

Place the Ora-Blend SF, Ora-Plus, orange juice or applesauce measured in Step 1 into a clean cup (See Figure B).

Step 3:

Hold a ZOKINVY capsule above the clean cup containing the liquid or applesauce. Hold the ZOKINVY capsule on both sides between your thumb and forefinger. Gently twist and pull apart the capsule (See Figure C). Empty the contents of the capsule directly into the clean cup (See Figure D).

Step 4:

Using a clean spoon, mix the ZOKINVY capsule contents well (See Figure E). If only 1 capsule is to be taken, skip to Step 6. If 2 capsules are to be taken, go to Step 5.

Step 5:

If 2 capsules will be taken, repeat Steps 1 through 4 for the second capsule. After completing the mixing process for the second capsule, the 2 servings can either be placed together in a single cup or remain in 2 serving cups for you or your child to take the full dose of ZOKINVY. After you finish, go to Step 6.

Step 6:

Give or take all of the ZOKINVY mixture with morning and evening meals within about 10 minutes of preparing.

How should I store ZOKINVY?

• Store at room temperature between 68°F to 77°F (20°C to 25°C)

Keep ZOKINVY and all medicines out of reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured for:

Sentynl Therapeutics, Inc.,

420 Stevens Ave., Suite 200

Solana Beach, CA 92075

©2024 Sentynl Therapeutics, Inc.

Revised: 7/2025

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 adults. Use of ZOKINVY in adults for these indications is based on adequate and well-controlled studies in pediatric patients 2 years of age and older [see Clinical Studies (14)].

ZOKINVY (lonafarnib) is a farnesyltransferase inhibitor. The chemical name for lonafarnib is 4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H- benzo[1,2] cyclohepta [2,4-b]pyridin-11-yl]piperidin-1-yl]-2- oxoethyl]piperidine-1-carboxamide. Its molecular formula is C₂₇H₃₁Br₂ClN₄O₂, molecular mass is 638.8 g/mol, and its chemical structure is depicted below.

ZOKINVY (lonafarnib) capsules for oral administration contain 50 mg or 75 mg of lonafarnib as the active ingredient and the following inactive ingredients: croscarmellose sodium, magnesium stearate, poloxamer 188, povidone, and silicon dioxide. The capsule shells of both strengths contain gelatin, titanium dioxide, and yellow iron oxide; the 75 mg capsule also contains red iron oxide. The imprinting ink contains ammonia solution, black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, and shellac.

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 [see Clinical Studies (14)].

The safety and effectiveness of ZOKINVY in pediatric patients less than 12 months of age have not been established.

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.

The efficacy of ZOKINVY is based on results from the Observational Cohort Survival Study, which retrospectively compared survival data from two Phase 2 studies in patients with HGPS to those from a natural history cohort.

Study 1 (NCT00425607) was a Phase 2 open-label, single-arm trial that evaluated the efficacy of ZOKINVY in 28 patients (26 with classic HGPS, one with non-classic HGPS, and one with processing-deficient Progeroid Laminopathy with LMNA heterozygous mutation with progerin-like protein accumulation). Patients received ZOKINVY for 24 to 30 months. Patients initiated treatment with ZOKINVY 115 mg/m² twice daily. After 4 months of treatment, patients who tolerated treatment had an increase in dose to 150 mg/m² twice daily. Among the 28 patients treated, 27 patients with HGPS (16 females, 11 males) were included in the survival assessment. The median age at treatment initiation for the 27 patients was 7.5 years (range: 3 to 16 years). The body weight range was 6.6 to 17.6 kg and the BSA range was 0.38 to 0.75 m² (ZOKINVY is not indicated in patients with a BSA less than 0.39 m² because the appropriate dosage strength is not available for this population).

Following completion of Study 1, 26 patients enrolled in a second Phase 2 open label, single-arm trial (Study 2, NCT00916747) which consisted of two study phases. In the first phase of Study 2, patients received ZOKINVY with additional therapies for about 5 years. In the second phase of Study 2, patients received ZOKINVY 150 mg/m² twice daily for a period of up to 3 years.

There were 35 treatment naïve patients with HGPS enrolled into the second phase of Study 2. Among the 35 treated patients (22 males, 13 females), 34 (97.1%) patients had classic HGPS and 1 (2.9%) patient had non-classic HGPS. The median age was 6 years (range: 2 to 17 years). The body weight range was 6.7 to 22 kg and the BSA range was 0.42 to 0.90 m².

Throughout Study 1 and Study 2, 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.

The retrospective survival analysis was based on the mortality data from 62 treated patients (27 patients in Study 1 and 35 treatment-naïve patients in Study 2) and data from matched, untreated patients in a separate natural history cohort. The mean lifespan of HGPS patients treated with ZOKINVY increased by an average of 3 months through the first three years of follow-up and 2.5 years through the last follow-up time (11 years) compared to untreated patients. The survival analysis summary is provided in Table 8 and Figure 1.

Figure 1: Kaplan-Meier Survival Curves for Follow-up Time Censored at Last Follow-up for Patients with HGPS

Note: The Kaplan-Meier (KM) survival curve for the ZOKINVY-treated patients is indicated with a solid line; the curve for the untreated patients is indicated with a dashed line. The shaded regions in blue and red represent the 95% confidence bands for the treated and untreated KM survival curves, respectively.

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)]

The most common adverse reactions (incidence ≥25%) are 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. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sentynl Therapeutics, Inc. at 1-888-507-5206 or [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• 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)

Lonafarnib caused rod-dependent, low-light vision decline in monkeys at plasma drug exposures similar to that achieved with the human dose [see Nonclinical Toxicology (13.2)]. Perform ophthalmological evaluation at regular intervals and at the onset of any new visual changes during ZOKINVY therapy.

The pharmacokinetics of lonafarnib at steady state in patients with HGPS following oral administration of lonafarnib twice daily with food are summarized in Table 7.

• The starting dosage of ZOKINVY for patients with a BSA of 0.39 m² and above is 115 mg/m² twice daily with morning and evening meals (see Table 1) to reduce the risk of gastrointestinal adverse reactions [see Adverse Reactions (6.1)]. An appropriate dosage strength of ZOKINVY is not available for patients with a BSA of less than 0.39 m² [see Indications and Usage (1)].
• After 4 months of treatment, increase the dosage to 150 mg/m² twice daily with morning and evening meals (see Table 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/m² twice daily.

Table 2 provides the BSA-based dosage recommendations for the dosage of 150 mg/m² twice daily.

Lonafarnib caused impaired fertility in female rats at 1.2 times the human dose based on plasma drug exposure [see Nonclinical Toxicology (13.1)].

Lonafarnib caused impaired fertility and testicular toxicity in male rats at 1.5 times the human dose based on plasma drug exposure [see Nonclinical Toxicology (13.1)], and toxicity in the male reproductive tract in monkeys at doses lower than the human dose based on plasma drug exposure [see Nonclinical Toxicology (13.2)].

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 [see Use in Specific Populations (8.3)].

ZOKINVY is indicated in 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

Lonafarnib inhibits farnesyltransferase to prevent farnesylation and subsequent accumulation of progerin and progerin-like proteins in the inner nuclear membrane.

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 [see Use in Specific Populations (8.1, 8.3)].

• 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)

• Start at 115 mg/m² twice daily with morning and evening meals. (2.1)
• After 4 months, increase to 150 mg/m² twice daily. (2.1)
• Round all total daily doses to nearest 25 mg increment. (2.1)
• See full prescribing information for dosage modifications due to adverse reactions. (2.2)
• See full prescribing information for preparation and administration instructions. (2.4)

Capsules:

• 50 mg, opaque yellow with “LNF” and “50” printed in black
• 75 mg, opaque light orange with “LNF” and “75” printed in black

Some patients treated with ZOKINVY developed laboratory abnormalities [see Adverse Reactions (6.1)]. 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.

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 (7.1)].

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.

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/m² twice daily for greater than or equal to 10 years.

The safety profile of ZOKINVY is based on 128 patient-years of treatment exposure (62 patients with HGPS and 1 patient with processing-deficient Progeroid Laminopathy with LMNA heterozygous mutation) and pooled results from two Phase 2 open-label, single-arm trials (n=63: 28 patients from Study 1 and 35 treatment naïve patients from Study 2). In Study 1, ZOKINVY treatment was initiated at 115 mg/m² twice daily and increased to 150 mg/m² twice daily after approximately 4 months for a total treatment duration of 24 to 30 months. Treatment naïve patients in Study 2 received ZOKINVY 150 mg/m² twice daily for up to 36 months. 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.

In these two studies, a total of 63 patients received ZOKINVY for a median duration of 2.2 years, with approximately 1.9 years at the recommended dose of 150 mg/m² twice daily. The population was 2 to 17 years old, with a similar proportion of males (33 [52%] patients) and females (30 [48%] patients). Most patients had classic HGPS (60 [95%] patients) compared to non-classic HGPS (2 [3%] patients) and 1 (2%) patient had Progeroid Laminopathy with LMNA heterozygous mutation.

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.

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Table 6 presents clinically significant drug interactions involving drugs affected by ZOKINVY.

ZOKINVY is supplied as:

• 50 mg capsules: Size 4 hard capsule, opaque yellow with “LNF” and “50” printed in black.
  
  Bottles of 30 capsules each (NDC 42358-450-30)
• 75 mg capsules: Size 3 hard capsule, opaque light orange with “LNF and “75” printed in black.
  
  Bottles of 30 capsules each (NDC 42358-475-30)

Store at 20°C-25°C (68°F-77°F), excursions permitted to 15°C-30ºC (59°F-86ºF) [see USP Controlled Room Temperature].

Table 5 presents clinically significant drug interactions involving drugs that affect ZOKINVY.

Renal toxicity occurred in a 6-month oral toxicity study of lonafarnib in rats, with kidney lesions (interstitial necrosis and mineralization in the inner medulla) and correlating changes in clinical chemistry (e.g., hyperphosphatemia, hyperkalemia) and urinalysis parameters observed at systemic exposures approximately equal to the AUC in humans at the recommended dose of 150 mg/m² twice daily. No evidence of renal toxicity was observed at systemic exposures lower than the human AUC at 150 mg/m² twice daily [see Warnings and Precautions (5.4)].

Toxicity in the male reproductive tract occurred in a 1-year oral toxicity study in monkeys at 10 mg/kg/day or higher (AUC lower than the human AUC at the recommended dose of 150 mg/m² twice daily). The lesions in the male reproductive tract included aspermia in the epididymis and atrophy of seminiferous tubules, seminal vesicle, and prostate gland. Testicular toxicity was also observed in rats, where severe impairment of male fertility occurred [see Warnings and Precautions (5.6), Nonclinical Toxicology (13.1)].

Ocular (retinal) toxicity occurred in a 1-year oral toxicity study in monkeys at 40 mg/kg/day (3.7 times the human AUC at the recommended dose of 150 mg/m² twice daily). The retinal injury involved single cell necrosis of photoreceptor cells in the layer of rods and cones and the outer nuclear layer. No retinal toxicity was observed at 20 mg/kg/day (2.1 times the human AUC at 150 mg/m² twice daily). However, in a follow-up study of lonafarnib effects on visual function in monkeys as evaluated by electroretinography, oral administration of 15 mg/kg/day for 13 weeks or 60 mg/kg/day for 6 weeks produced adverse effects on rod-dependent, low-light vision. The effects were observed at several time-points throughout the treatment period. No histological changes in the retina were observed at study termination [see Warnings and Precautions (5.5)].

Temporarily discontinue ZOKINVY for 10 to 14 days before and 2 days after administration of midazolam [see Contraindications (4), Drug Interactions (7.2)].

Administer ZOKINVY orally with the morning and evening meals.

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 [see Contraindications (4) , Drug Interactions (7.1)].
• 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.
• Mix thoroughly with a spoon.
• Consume entire serving.

Coadministration of ZOKINVY with other drugs may result in clinically significant drug interactions [see Dosage and Administration (2.2, 2.3), Contraindications (4), Drug Interactions (7.1, 7.2)]. 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 [see Drug Interactions (7.1, 7.2)]. Consider the potential for drug interactions prior to and during ZOKINVY therapy; review concomitant medications during ZOKINVY therapy; and monitor for adverse reactions.

Limitations of Use

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

Principal Display Panel - 50 mg Carton Label

NDC 42358-450-30

Zokinvy

(lonafarnib) capsules

50 mg

30 capsules

Rx only

INSTRUCTIONS FOR USE

ZOKINVY® (ZO-kinvy) (lonafarnib)

capsules, for oral use

This Instructions for Use contains information on how to mix and give or take a dose of ZOKINVY if the capsules cannot be swallowed whole.

Read this Instructions for Use before you start giving or taking ZOKINVY and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about you or your child's medical condition or treatment

Supplies needed to prepare and give or take a dose of ZOKINVY

Before mixing a dose of ZOKINVY, gather the following supplies:

• the prescribed number of ZOKINVY capsules for you or your child's dose. Place the capsule or capsules on a clean flat surface.
• either Ora-Blend SF, Ora-Plus, orange juice or applesauce for mixing. Do not mix with juice that contains grapefruit or Seville oranges. Seville oranges may also be called bitter or sour oranges.
• if mixing with Ora-Blend SF, Ora-Plus or orange juice: a clean medicine cup with 5 milliliter (mL) and 10 mL measurement levels, OR if mixing with applesauce: a clean teaspoon.
• clean cup(s) for each ZOKINVY capsule to be mixed.
• a clean spoon for stirring the mixture.

How to open ZOKINVY capsules and mix the capsule contents

Step 1:

If mixing with Ora-Blend SF, Ora-Plus or orange juice: Use a clean medicine cup to measure either 5 mL or 10 mL of Ora-Blend SF, Ora-Plus or orange juice.

If mixing with applesauce: measure either 1 or 2 teaspoonfuls of applesauce.

You can choose to use 5 mL or 10 mL of liquid or 1 or 2 teaspoonfuls of applesauce (See Figure A).

Step 2:

Place the Ora-Blend SF, Ora-Plus, orange juice or applesauce measured in Step 1 into a clean cup (See Figure B).

Step 3:

Hold a ZOKINVY capsule above the clean cup containing the liquid or applesauce. Hold the ZOKINVY capsule on both sides between your thumb and forefinger. Gently twist and pull apart the capsule (See Figure C). Empty the contents of the capsule directly into the clean cup (See Figure D).

Step 4:

Using a clean spoon, mix the ZOKINVY capsule contents well (See Figure E). If only 1 capsule is to be taken, skip to Step 6. If 2 capsules are to be taken, go to Step 5.

Step 5:

If 2 capsules will be taken, repeat Steps 1 through 4 for the second capsule. After completing the mixing process for the second capsule, the 2 servings can either be placed together in a single cup or remain in 2 serving cups for you or your child to take the full dose of ZOKINVY. After you finish, go to Step 6.

Step 6:

Give or take all of the ZOKINVY mixture with morning and evening meals within about 10 minutes of preparing.

How should I store ZOKINVY?

• Store at room temperature between 68°F to 77°F (20°C to 25°C)

Keep ZOKINVY and all medicines out of reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured for:

Sentynl Therapeutics, Inc.,

420 Stevens Ave., Suite 200

Solana Beach, CA 92075

©2024 Sentynl Therapeutics, Inc.

Revised: 7/2025

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 adults. Use of ZOKINVY in adults for these indications is based on adequate and well-controlled studies in pediatric patients 2 years of age and older [see Clinical Studies (14)].

ZOKINVY (lonafarnib) is a farnesyltransferase inhibitor. The chemical name for lonafarnib is 4-[2-[4-[(11R)-3,10-dibromo-8-chloro-6,11-dihydro-5H- benzo[1,2] cyclohepta [2,4-b]pyridin-11-yl]piperidin-1-yl]-2- oxoethyl]piperidine-1-carboxamide. Its molecular formula is C₂₇H₃₁Br₂ClN₄O₂, molecular mass is 638.8 g/mol, and its chemical structure is depicted below.

ZOKINVY (lonafarnib) capsules for oral administration contain 50 mg or 75 mg of lonafarnib as the active ingredient and the following inactive ingredients: croscarmellose sodium, magnesium stearate, poloxamer 188, povidone, and silicon dioxide. The capsule shells of both strengths contain gelatin, titanium dioxide, and yellow iron oxide; the 75 mg capsule also contains red iron oxide. The imprinting ink contains ammonia solution, black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, purified water, and shellac.

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 [see Clinical Studies (14)].

The safety and effectiveness of ZOKINVY in pediatric patients less than 12 months of age have not been established.

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.

The efficacy of ZOKINVY is based on results from the Observational Cohort Survival Study, which retrospectively compared survival data from two Phase 2 studies in patients with HGPS to those from a natural history cohort.

Study 1 (NCT00425607) was a Phase 2 open-label, single-arm trial that evaluated the efficacy of ZOKINVY in 28 patients (26 with classic HGPS, one with non-classic HGPS, and one with processing-deficient Progeroid Laminopathy with LMNA heterozygous mutation with progerin-like protein accumulation). Patients received ZOKINVY for 24 to 30 months. Patients initiated treatment with ZOKINVY 115 mg/m² twice daily. After 4 months of treatment, patients who tolerated treatment had an increase in dose to 150 mg/m² twice daily. Among the 28 patients treated, 27 patients with HGPS (16 females, 11 males) were included in the survival assessment. The median age at treatment initiation for the 27 patients was 7.5 years (range: 3 to 16 years). The body weight range was 6.6 to 17.6 kg and the BSA range was 0.38 to 0.75 m² (ZOKINVY is not indicated in patients with a BSA less than 0.39 m² because the appropriate dosage strength is not available for this population).

Following completion of Study 1, 26 patients enrolled in a second Phase 2 open label, single-arm trial (Study 2, NCT00916747) which consisted of two study phases. In the first phase of Study 2, patients received ZOKINVY with additional therapies for about 5 years. In the second phase of Study 2, patients received ZOKINVY 150 mg/m² twice daily for a period of up to 3 years.

There were 35 treatment naïve patients with HGPS enrolled into the second phase of Study 2. Among the 35 treated patients (22 males, 13 females), 34 (97.1%) patients had classic HGPS and 1 (2.9%) patient had non-classic HGPS. The median age was 6 years (range: 2 to 17 years). The body weight range was 6.7 to 22 kg and the BSA range was 0.42 to 0.90 m².

Throughout Study 1 and Study 2, 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.

The retrospective survival analysis was based on the mortality data from 62 treated patients (27 patients in Study 1 and 35 treatment-naïve patients in Study 2) and data from matched, untreated patients in a separate natural history cohort. The mean lifespan of HGPS patients treated with ZOKINVY increased by an average of 3 months through the first three years of follow-up and 2.5 years through the last follow-up time (11 years) compared to untreated patients. The survival analysis summary is provided in Table 8 and Figure 1.

Figure 1: Kaplan-Meier Survival Curves for Follow-up Time Censored at Last Follow-up for Patients with HGPS

Note: The Kaplan-Meier (KM) survival curve for the ZOKINVY-treated patients is indicated with a solid line; the curve for the untreated patients is indicated with a dashed line. The shaded regions in blue and red represent the 95% confidence bands for the treated and untreated KM survival curves, respectively.

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)]

The most common adverse reactions (incidence ≥25%) are 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. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sentynl Therapeutics, Inc. at 1-888-507-5206 or [email protected] or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

• 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)

Lonafarnib caused rod-dependent, low-light vision decline in monkeys at plasma drug exposures similar to that achieved with the human dose [see Nonclinical Toxicology (13.2)]. Perform ophthalmological evaluation at regular intervals and at the onset of any new visual changes during ZOKINVY therapy.

The pharmacokinetics of lonafarnib at steady state in patients with HGPS following oral administration of lonafarnib twice daily with food are summarized in Table 7.

• The starting dosage of ZOKINVY for patients with a BSA of 0.39 m² and above is 115 mg/m² twice daily with morning and evening meals (see Table 1) to reduce the risk of gastrointestinal adverse reactions [see Adverse Reactions (6.1)]. An appropriate dosage strength of ZOKINVY is not available for patients with a BSA of less than 0.39 m² [see Indications and Usage (1)].
• After 4 months of treatment, increase the dosage to 150 mg/m² twice daily with morning and evening meals (see Table 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/m² twice daily.

Table 2 provides the BSA-based dosage recommendations for the dosage of 150 mg/m² twice daily.

Lonafarnib caused impaired fertility in female rats at 1.2 times the human dose based on plasma drug exposure [see Nonclinical Toxicology (13.1)].

Lonafarnib caused impaired fertility and testicular toxicity in male rats at 1.5 times the human dose based on plasma drug exposure [see Nonclinical Toxicology (13.1)], and toxicity in the male reproductive tract in monkeys at doses lower than the human dose based on plasma drug exposure [see Nonclinical Toxicology (13.2)].

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 [see Use in Specific Populations (8.3)].

ZOKINVY is indicated in 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

Lonafarnib inhibits farnesyltransferase to prevent farnesylation and subsequent accumulation of progerin and progerin-like proteins in the inner nuclear membrane.

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 [see Use in Specific Populations (8.1, 8.3)].

• 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)

• Start at 115 mg/m² twice daily with morning and evening meals. (2.1)
• After 4 months, increase to 150 mg/m² twice daily. (2.1)
• Round all total daily doses to nearest 25 mg increment. (2.1)
• See full prescribing information for dosage modifications due to adverse reactions. (2.2)
• See full prescribing information for preparation and administration instructions. (2.4)

Capsules:

• 50 mg, opaque yellow with “LNF” and “50” printed in black
• 75 mg, opaque light orange with “LNF” and “75” printed in black

Some patients treated with ZOKINVY developed laboratory abnormalities [see Adverse Reactions (6.1)]. 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.

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 (7.1)].

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.

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/m² twice daily for greater than or equal to 10 years.

The safety profile of ZOKINVY is based on 128 patient-years of treatment exposure (62 patients with HGPS and 1 patient with processing-deficient Progeroid Laminopathy with LMNA heterozygous mutation) and pooled results from two Phase 2 open-label, single-arm trials (n=63: 28 patients from Study 1 and 35 treatment naïve patients from Study 2). In Study 1, ZOKINVY treatment was initiated at 115 mg/m² twice daily and increased to 150 mg/m² twice daily after approximately 4 months for a total treatment duration of 24 to 30 months. Treatment naïve patients in Study 2 received ZOKINVY 150 mg/m² twice daily for up to 36 months. 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.

In these two studies, a total of 63 patients received ZOKINVY for a median duration of 2.2 years, with approximately 1.9 years at the recommended dose of 150 mg/m² twice daily. The population was 2 to 17 years old, with a similar proportion of males (33 [52%] patients) and females (30 [48%] patients). Most patients had classic HGPS (60 [95%] patients) compared to non-classic HGPS (2 [3%] patients) and 1 (2%) patient had Progeroid Laminopathy with LMNA heterozygous mutation.

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.

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Table 6 presents clinically significant drug interactions involving drugs affected by ZOKINVY.

ZOKINVY is supplied as:

• 50 mg capsules: Size 4 hard capsule, opaque yellow with “LNF” and “50” printed in black.
  
  Bottles of 30 capsules each (NDC 42358-450-30)
• 75 mg capsules: Size 3 hard capsule, opaque light orange with “LNF and “75” printed in black.
  
  Bottles of 30 capsules each (NDC 42358-475-30)

Store at 20°C-25°C (68°F-77°F), excursions permitted to 15°C-30ºC (59°F-86ºF) [see USP Controlled Room Temperature].

Table 5 presents clinically significant drug interactions involving drugs that affect ZOKINVY.

Renal toxicity occurred in a 6-month oral toxicity study of lonafarnib in rats, with kidney lesions (interstitial necrosis and mineralization in the inner medulla) and correlating changes in clinical chemistry (e.g., hyperphosphatemia, hyperkalemia) and urinalysis parameters observed at systemic exposures approximately equal to the AUC in humans at the recommended dose of 150 mg/m² twice daily. No evidence of renal toxicity was observed at systemic exposures lower than the human AUC at 150 mg/m² twice daily [see Warnings and Precautions (5.4)].

Toxicity in the male reproductive tract occurred in a 1-year oral toxicity study in monkeys at 10 mg/kg/day or higher (AUC lower than the human AUC at the recommended dose of 150 mg/m² twice daily). The lesions in the male reproductive tract included aspermia in the epididymis and atrophy of seminiferous tubules, seminal vesicle, and prostate gland. Testicular toxicity was also observed in rats, where severe impairment of male fertility occurred [see Warnings and Precautions (5.6), Nonclinical Toxicology (13.1)].

Ocular (retinal) toxicity occurred in a 1-year oral toxicity study in monkeys at 40 mg/kg/day (3.7 times the human AUC at the recommended dose of 150 mg/m² twice daily). The retinal injury involved single cell necrosis of photoreceptor cells in the layer of rods and cones and the outer nuclear layer. No retinal toxicity was observed at 20 mg/kg/day (2.1 times the human AUC at 150 mg/m² twice daily). However, in a follow-up study of lonafarnib effects on visual function in monkeys as evaluated by electroretinography, oral administration of 15 mg/kg/day for 13 weeks or 60 mg/kg/day for 6 weeks produced adverse effects on rod-dependent, low-light vision. The effects were observed at several time-points throughout the treatment period. No histological changes in the retina were observed at study termination [see Warnings and Precautions (5.5)].

Temporarily discontinue ZOKINVY for 10 to 14 days before and 2 days after administration of midazolam [see Contraindications (4), Drug Interactions (7.2)].

Administer ZOKINVY orally with the morning and evening meals.

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 [see Contraindications (4) , Drug Interactions (7.1)].
• 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.
• Mix thoroughly with a spoon.
• Consume entire serving.

Coadministration of ZOKINVY with other drugs may result in clinically significant drug interactions [see Dosage and Administration (2.2, 2.3), Contraindications (4), Drug Interactions (7.1, 7.2)]. 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 [see Drug Interactions (7.1, 7.2)]. Consider the potential for drug interactions prior to and during ZOKINVY therapy; review concomitant medications during ZOKINVY therapy; and monitor for adverse reactions.