Zokinvy
FDA Label NDC 73079-050

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

  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.

• 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 remains 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 1: Recommended Dosage and Administration for 115 mg/m² Body Surface Area-Based Dosing

BSA(m2)	Total Daily Dosage Rounded to Nearest 25 mg	Morning Dosing Number of Capsule(s)		Evening Dosing Number of Capsule(s)
		ZOKINVY 50 mg	ZOKINVY 75 mg	ZOKINVY 50 mg	ZOKINVY 75 mg
0.39 - 0.48	100	1		1
0.49 - 0.59	125		1	1
0.6 - 0.7	150		1		1
0.71 - 0.81	175	2			1
0.82 - 0.92	200	2		2
0.93 – 1	225	1	1	2

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

Table 2: Recommended Dosage and Administration for 150 mg/m² Body Surface Area-Based Dosing

BSA(m2)	Total Daily Dosage Rounded to Nearest 25 mg	Morning Dosing Number of Capsule(s)		Evening Dosing Number of Capsule(s)
		ZOKINVY 50 mg	ZOKINVY 75 mg	ZOKINVY 50 mg	ZOKINVY 75 mg
0.39 - 0.45	125		1	1
0.46 - 0.54	150		1		1
0.55 - 0.62	175	2			1
0.63 - 0.7	200	2		2
0.71 - 0.79	225	1	1	2
0.8 - 0.87	250	1	1	1	1
0.88 - 0.95	275		2	1	1
0.96 – 1	300		2		2

For patients who have increased their dose of ZOKINVY to 150 mg/m² twice daily and are experiencing repeated episodes of vomiting and/or diarrhea resulting in dehydration or weight loss, ZOKINVY can be dose reduced to the starting dose of 115 mg/m² twice daily (see Table 1). Ensure ZOKINVY is taken with the morning and evening meals and an adequate amount of water.

CYP3A Inhibitors
If concomitant use of ZOKINVY with a weak CYP3A inhibitor is unavoidable [see Warnings and Precautions (5.1), Drug Interactions (7.1)]:

• Reduce to or continue ZOKINVY at the starting dosage of 115 mg/m² twice daily (see Table 1).
• Resume the previous ZOKINVY dosage 14 days after discontinuing the concomitant use of the weak CYP3A inhibitor.

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 be 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.

Capsules:

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

ZOKINVY is contraindicated in patients taking:

• Strong or moderate CYP3A inhibitors or inducers [see Drug Interactions (7.1)]
• Midazolam [see Drug Interactions (7.2)]
• Lovastatin, simvastatin, or atorvastatin [see Drug Interactions (7.2)]

Coadministration of ZOKINVY with other drugs may result in clinically significant drug interactions [see Dosage and Administration (2.3, 2.4), 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 4 and Table 5 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 the adverse reactions.

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.

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.

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.

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)].

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)].

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 3 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.

Gastrointestinal Adverse Reactions
As noted in Table 3, gastrointestinal adverse reactions were the most frequently reported adverse reactions. Of the 57 patients who experienced vomiting, 30 (53%) patients had mild vomiting (defined as no intervention required), 26 (46%) patients had moderate vomiting (defined as outpatient intravenous hydration; medical intervention required), and 1 (2%) patient had severe vomiting (defined as tube feeding, total parental nutrition, or hospitalization indicated). 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). During the first four months of treatment in Study 1, 19 (68%) patients had vomiting and 10 (36%) patients had nausea. 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.

Of the 51 patients who experienced diarrhea, the majority of patients (approximately 92%) experienced mild or moderate diarrhea; 38 (75%) patients reported mild diarrhea (defined as an increase of less than 4 stools per day over baseline) and 9 (18%) patients reported moderate diarrhea (defined as increase of 4 to 6 stools per day over baseline; limiting instrumental activities of daily living). Four (8%) patients reported severe diarrhea (defined as 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). During the first four months of treatment in Study 1, 23 (82%) patients had diarrhea; by the end of therapy, 3 (11%) patients had diarrhea. Twelve (43%) patients were treated with loperamide.

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 (defined as greater than upper limit of normal (ULN) to 3.0 times ULN if baseline was normal; 1.5 to 3.0 times ULN if baseline was abnormal), 1 (6%) patient had moderate increases (defined as greater than 3.0 to 5.0 times ULN if baseline was normal or abnormal), and 2 (12%) patients had severe increases (defined as greater than 5.0 to 20.0 times ULN if baseline was normal or abnormal). Increased aspartate aminotransferase was also commonly reported (22 [35%] patients). Of the 22 patients with increased aspartate aminotransferase, 21 (95%) patients had mild increases (defined as greater than ULN to 3.0 times ULN if baseline was normal; 1.5 to 3.0 times ULN if baseline was abnormal) and 1 (5%) patient had a severe increase (defined as greater than 5.0 to 20.0 times ULN if baseline was normal or abnormal). 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.

Table 4 presents clinically significant drug interactions involving drugs that affect ZOKINVY.

Table 5 presents clinically significant drug interactions involving drugs affected by ZOKINVY.

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/m² 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/m² twice daily, and maternal toxicity at 26 times the human exposure at 150 mg/m² 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 2 to 4% and 15 to 20%, 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 [area under the plasma concentration-time curve] in humans at the recommended dose of 150 mg/m² twice daily). No effects on embryo-fetal development in rats were observed at systemic exposures lower than the human AUC at 150 mg/m² 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/m² twice daily, and maternal toxicity (body weight loss and abortion) at 120 mg/kg/day (26 times the human AUC at 150 mg/m² 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/m² twice daily) during organogenesis through lactation.

Risk Summary
There are no data on the presence of ZOKINVY in human milk, the effects on the breastfed infant, or the effects on milk production. Lonafarnib is excreted in rat milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk.

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.

Data
Lonafarnib is excreted in milk following oral administration in lactating rats, with a mean milk to plasma concentration ratio of 1.5 at 12 hours.

Contraception
ZOKINVY can cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use appropriate effective contraception during treatment with ZOKINVY.

Infertility
Based on findings in rats, ZOKINVY may reduce fertility in females and males of reproductive potential [see Warnings and Precautions (5.5), Nonclinical Toxicology (13.1)].

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.

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 C₂₇H₃₁B_r2ClN₄O₂, molecular mass is 638.8 g/mol, and its chemical structure is depicted below.

Chemical Structure (Lonafarnib 01)

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.

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

No formal pharmacodynamic studies have been conducted with ZOKINVY.

The pharmacokinetics of lonafarnib at steady state in patients with HGPS following oral administration of lonafarnib twice daily with food are summarized in Table 6.

Absorption
The absolute bioavailability of lonafarnib following oral administration has not been determined. Following oral administration of lonafarnib 75 mg and 100 mg twice daily in healthy subjects under fasted conditions, the geometric mean (CV%) maximum peak plasma concentrations of lonafarnib were 834 (32%) ng/mL and 964 (32%) ng/mL, respectively.

Effect of Food
Following a single oral dose of 75 mg lonafarnib in healthy subjects, the C_max decreased 55% and AUC decreased 29% with a high-fat meal (approximately 43% fat of the total 952 calories) compared to fasted conditions. C_max decreased 25% and AUC decreased 21% with a low-fat meal (approximately 12% fat of the total 421 calories) compared to fasted conditions.

Distribution
In vitro plasma protein binding of lonafarnib was greater than or equal to 99% over the concentration range between 0.5 to 40.0 μg/mL. The apparent volumes of distribution were 87.8 L and 97.4 L, respectively, at steady state following oral administration of lonafarnib 100 mg and 75 mg twice daily in healthy subjects.

Elimination
The mean half-life was approximately 4 to 6 hours following oral administration of lonafarnib 100 mg twice daily in healthy subjects.

Metabolism
Lonafarnib is primarily metabolized by CYP3A and to a lesser extent by CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1 in vitro.

Excretion
Following an oral administration of 104 mg [¹⁴C]-lonafarnib under fasted conditions in healthy subjects, approximately 62% of the total radiolabeled dose was recovered in feces and <1% of the total radiolabeled dose was recovered in urine up to 240 hours post-dose. The two most predominant metabolites were HM17 and HM21 (an active metabolite) accounting for 15% and 14% of plasma radioactivity, respectively.

Specific Populations

Patients with Renal Impairment or Hepatic Impairment
ZOKINVY has not been studied in patients with renal impairment or in patients with hepatic impairment.

Male and Female Patients
Following a single oral dose of 100 mg lonafarnib in healthy subjects, the plasma lonafarnib AUC and C_max were 44% and 26% higher in female subjects, respectively, compared to male subjects. The observed exposure difference by sex in healthy subjects is not considered clinically meaningful.

Geriatric Patients
Following a single oral dose of 100 mg lonafarnib in healthy subjects, the plasma lonafarnib exposure AUC and C_max were 59% and 27% higher in subjects ≥65 years, respectively, compared to subjects 18 to 45 years of age. The observed higher exposure in geriatric subjects is not considered clinically relevant.

Drug Interaction Studies

In Vitro Studies
Lonafarnib is a CYP3A substrate and a potent CYP3A time-dependent and mechanism-based inhibitor. Lonafarnib is an inhibitor of CYP2C8 and CYP2C19. Lonafarnib is not considered an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, or CYP2D6. Lonafarnib is unlikely to be an inducer of CYP1A2, CYP2B6, and CYP3A.

Lonafarnib is not a substrate of transporters OATP1B1, OATP1B3, or BCRP, but is likely a marginal substrate of P-gp. Lonafarnib is an inhibitor of P-gp, OATP1B1, OATP1B3, and BCRP.

Clinical Studies: Effects of other Drugs on Lonafarnib

CYP3A inhibitors
Lonafarnib is a sensitive substrate for CYP3A. With coadministration of a single oral dose of 50 mg lonafarnib following 200 mg ketoconazole (a strong CYP3A inhibitor) once daily for 5 days, the C_max and AUC of lonafarnib were increased by 270% and 425%, respectively, as compared to lonafarnib administered alone in healthy subjects [see Dosage and Administration (2.3), Contraindications (4), Drug Interactions (7.1)].

CYP2C9 inhibitors
Coadministration with CYP2C9 inhibitors may increase lonafarnib AUC and C_max. A drug-drug interaction study of ZOKINVY with CYP2C9 inhibitors has not been conducted [see Drug Interactions (7.1)].

CYP3A inducers
With coadministration of a single oral dose of 50 mg lonafarnib (combined with a single oral dose of 100 mg ritonavir) following 600 mg rifampin once daily for 8 days, the C_max of lonafarnib was reduced by 92% and the AUC was reduced by 98%, as compared to without rifampin coadministration in healthy subjects [see Contraindications (4), Drug Interactions (7.1)].

Clinical Studies: Effects of Lonafarnib on other Drugs

CYP3A Substrates
Lonafarnib is a strong inhibitor of CYP3A. With coadministration of a single oral dose of 3 mg midazolam with multiple oral doses of 100 mg lonafarnib twice daily for 5 days in healthy subjects, the C_max and AUC of midazolam were increased by 180% and 639%, respectively [see Dosage and Administration (2.4), Contraindications (4), Drug Interactions (7.2)].

Loperamide
With coadministration of a single oral 2 mg dose of loperamide (primarily metabolized by CYP2C8 and CYP3A and a substrate of P-gp) with multiple oral doses of lonafarnib 100 mg twice daily for 5 days in healthy subjects, the C_max and AUC of loperamide were increased by 214% and 299%, respectively [see Drug Interactions (7.2)].

CYP2C19 Substrates
Lonafarnib is a moderate CYP2C19 inhibitor. With coadministration of a single oral dose of 40 mg omeprazole with multiple oral doses of lonafarnib 75 mg twice daily for 5 days in healthy subjects, the C_max and AUC of omeprazole were increased by 28% and 60%, respectively [see Drug Interactions (7.2)].

P-gp and OATP1B Substrates
With coadministration of a single oral dose of 180 mg fexofenadine (a P-gp and OATP1B substrate) with multiple oral doses of 100 mg lonafarnib twice daily for 5 days in healthy subjects, the C_max and AUC of fexofenadine were increased by 21% and 24%, respectively [see Drug Interactions (7.2)].

Carcinogenesis
Carcinogenicity studies have not been conducted with lonafarnib.

Mutagenesis
Lonafarnib was not genotoxic in the bacterial mutagenicity (Ames) assay, in vitro chromosomal aberration assay in mammalian cells, or in vivo micronucleus assay in mice.

Impairment of Fertility
Lonafarnib produced impaired fertility in male rats at 90 mg/kg/day or higher (1.5 times the AUC in humans at the recommended dose of 150 mg/m² twice daily), with a nearly complete loss of fertility at 180 mg/kg/day (3 times the AUC in humans). Male rats treated with 180 mg/kg/day exhibited small testes, flaccid testes, and discolored epididymis (84%, 56%, and 24% of males, respectively). No effects on fertility occurred in males at systemic exposures lower than the human AUC at 150 mg/m² twice daily.

Female rats treated with 30 mg/kg/day lonafarnib or higher (1.2 times the human AUC at the recommended human dose of 150 mg/m² twice daily) showed a decrease in fertility, as indicated by reductions in the number of corpora lutea and implantation sites, and increases in pre- and post-implantation loss. No effects on fertility occurred in females at systemic exposures lower than the human AUC at 150 mg/m² twice daily [see Warnings and Precautions (5.5)].

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 (5.3)].

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 (5.5), 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 (5.4)].

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 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 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 7 and Figure 1.

Table 7: Survival Analysis Summary for Patients with HGPS

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

Chemical Structure (Lonafarnib 02)

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 supplied as:

• 50 mg capsules: Size 4 hard capsule, opaque yellow with “LNF” and “50” printed in black.
  Bottles of 30 capsules each (NDC 73079-050-30)
• 75 mg capsules: Size 3 hard capsule, opaque light orange with “LNF and “75” printed in black.
  Bottles of 30 capsules each (NDC 73079-075-30)

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

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

Dosing [see Dosage and Administration (2.1)]

• Advise patients and caregivers that ZOKINVY should be taken twice daily with the morning and evening meals.
• Inform patients and caregivers that if a dose is missed, the next dose should be given as soon as possible up to 8 hours prior to the next scheduled dose. If less than 8 hours remain before the next scheduled dose, the patient should skip the missed dose and resume taking ZOKINVY at the next scheduled dose

Preparation and Administration [see Dosage and Administration (2.5), Drug Interactions (7)]

• Advise patients to swallow the capsule whole with water. The capsules should not be chewed.
• For patients unable to swallow capsules, advise patients and caregivers that the contents of ZOKINVY can be mixed with Ora Blend SF or Ora-Plus. For patients unable to access or tolerate Ora Blend SF or Ora-Plus, the contents of ZOKINVY can be mixed with orange juice or applesauce. Advise patients not to mix the contents of ZOKINVY with juice containing grapefruit or Seville oranges. Advise patients and caregivers that the mixture must be prepared fresh for each dose and taken within approximately 10 minutes of mixing.
• Advise patients and caregivers to read and carefully follow the instructions for administering the capsule contents in Ora Blend SF, Ora-Plus, orange juice or applesauce [see Instructions for Use]. Advise patient and caregivers to call their healthcare provider or pharmacist if they have any questions.

Drug Interactions [see Dosage and Administration (2.3, 2.4), Contraindications (4), Warnings and Precautions (5.1), Drug Interactions (7)]
Inform patients and caregivers that ZOKINVY may interact with many drugs. Advise patients and their caregivers to report the patient’s use of all prescription and nonprescription medications, including nutritional supplements and vitamins.

Gastrointestinal Adverse Reactions [see Dosage and Administration (2.2), Adverse Reactions (6.1)]
Inform patients and caregivers that gastrointestinal adverse reactions are common with ZOKINVY. These include, but are not limited to, vomiting, diarrhea, and nausea. Advise patients and caregivers to contact their healthcare provider if these adverse reactions persist.

Hypertension [see Adverse Reactions (6.1)]
Inform patients and caregivers that blood pressure may increase while taking ZOKINVY. Symptoms of hypertension may include headaches, shortness of breath, nosebleeds, flushing, dizziness, or chest pain. Advise patients and caregivers to contact their healthcare provider if these adverse reactions occur.

Nephrotoxicity [see Warnings and Precautions (5.3), Nonclinical Toxicology (13.2)]
Inform the patient and caregiver of the risk of kidney damage.

Retinal Toxicity [see Warnings and Precautions (5.4), Nonclinical Toxicology (13.2)]
Inform the patient and caregiver of the risk of developing difficulty with night vision. Advise patients and caregivers to contact their healthcare provider if they experience a change in vision.

Impaired Fertility [see Warnings and Precautions (5.5), Nonclinical Toxicology (13.1)]
Inform females and males of reproductive potential that ZOKINVY may impact pubertal development and impair fertility.

Embryo-Fetal Toxicity [see Warnings and Precautions (5.6), Use in Specific Populations (8.1, 8.3)]
Inform pregnant women and female patients of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZOKINVY.





Manufactured for:
Eiger BioPharmaceuticals, Inc., 2155 Park Boulevard Palo Alto, CA 94306
ZOKINVY is a trademark of Eiger BioPharmaceuticals, Inc.