Lonafarnib b
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alara Ece Dagsali, M.D.
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Overview
Lonafarnib b is a direct farnesyl transferase inhibitor that is FDA approved for the {{{indicationType}}} of 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. Common adverse reactions include Vomiting, Diarrhea, Nausea, Abdominal Pain, Constipation, Fatigue, Infection,.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
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
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lonafarnib b in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lonafarnib b in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Lonafarnib b FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Lonafarnib b in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Lonafarnib b in pediatric patients.
Contraindications
ZOKINVY is contraindicated in patients taking:
- Strong CYP3A inhibitors
- Strong or moderate CYP3A inducers
- Midazolam
- Lovastatin, simvastatin, or atorvastatin
Warnings
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.
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.
Risk of Reduced Efficacy or Adverse Reactions Due to Drug Interactions Coadministration of ZOKINVY with other drugs may result in clinically significant drug interactions.These drug interactions can lead to:
- Reduced efficacy of ZOKINVY
- Increased risk of adverse reactions from ZOKINVY or co-administered drugs
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%), 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.
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 Lonafarnib caused impaired fertility in female rats at 1.2 times the human dose based on plasma drug exposure.
Lonafarnib caused impaired fertility and testicular toxicity in male rats at 1.5 times the human dose based on plasma drug exposureand toxicity in the male reproductive tract in monkeys at doses lower than the human dose based on plasma drug exposure.
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
Embryo-Fetal Toxicity 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
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
A total of 84 subjects were treated with at least one dose of ZOKINVY with or without additional therapy, of which 8 were treated at a dosage of at least 115 mg/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.
Postmarketing Experience
There is limited information regarding Lonafarnib b Postmarketing Experience in the drug label.
Drug Interactions
Risk of Reduced Efficacy or Adverse Reactions Due to Drug Interactions Coadministration of ZOKINVY with other drugs may result in clinically significant drug interactions.These drug interactions can lead to:
- Reduced efficacy of ZOKINVY
- Increased risk of adverse reactions from ZOKINVY or co-administered drugs
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Lonafarnib b in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Lonafarnib b in women who are pregnant.
Labor and Delivery
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.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.
Nursing Mothers
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. 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.
Pediatric Use
The safety and effectiveness of ZOKINVY for the treatment of HGPS and processing-deficient Progeroid Laminopathies (with either heterozygous LMNA mutation with progerin-like protein accumulation or homozygous or compound heterozygous ZMPSTE24 mutations) have been established in pediatric patients 12 months of age and older. Use of ZOKINVY for these indications is supported by adequate and well-controlled studies in pediatric patients 2 years of age and older. The safety and effectiveness of ZOKINVY in pediatric patients less than 12 months of age have not been established.
Geriatic Use
There is no FDA guidance on the use of Lonafarnib b in geriatric settings.
Gender
Female Contraception ZOKINVY can cause embryo-fetal harm when administered to pregnant women. 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
Race
There is no FDA guidance on the use of Lonafarnib b with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Lonafarnib b in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Lonafarnib b in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Lonafarnib b in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Lonafarnib b in patients who are immunocompromised.
Adult Use
The safety and effectiveness of ZOKINVY for the treatment of HGPS and processing-deficient Progeroid Laminopathies (with either heterozygous LMNA mutation with progerin-like protein accumulation or homozygous or compound heterozygous ZMPSTE24 mutations) have been established in 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
Administration and Monitoring
Administration
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
- Do not mix with juice containing grapefruit or Seville oranges
- The mixture must be prepared fresh for each dose and be taken within approximately 10 minutes of mixing.
Monitoring
- Withhold ZOKINVY until QTc interval is less than 470 msec, then resume ZOKINVY at same dosage.
Monitor electrocardiograms (ECGs) prior to initiating ZOKINVY, during treatment, and as clinically indicated.
- 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. The dose of ZOKINVY can be reduced to the starting dose of 115 mg/m2 twice daily
- When initiating ZOKINVY in a patient who is concurrently on a moderate CYP3A inhibitor. The patient may be at increased risk of adverse reactions.
Monitor the patient closely for adverse reactions for at least the first 7 days after initiating ZOKINVY. If the patient experiences an adverse reaction during the first 7 days of the starting dose or thereafter, consider an alternative therapy that is not a moderate CYP3A inhibitor.
IV Compatibility
There is limited information regarding the compatibility of Lonafarnib b and IV administrations.
Overdosage
There is limited information regarding Lonafarnib b overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Lonafarnib b Pharmacology in the drug label.
Mechanism of Action
Lonafarnib inhibits farnesyltransferase to prevent farnesylation and subsequent accumulation of progerin and progerin-like proteins in the inner nuclear membrane.
Structure
There is limited information regarding Lonafarnib b Structure in the drug label.
Pharmacodynamics
Cardiac Electrophysiology The effect of lonafarnib on the QTc interval was evaluated in a randomized, double-blind, placebo- and positive-controlled (moxifloxacin 400 mg single dose), multiple-dose, QTc study in 64 healthy subjects. Subjects received 200 mg lonafarnib twice daily for 9 consecutive days and a single 200 mg dose in the morning on Day 10, with food.
The largest mean increase in QTc interval was 19 msec (upper bound of 90% confidence interval = 27 msec) on Day 10 at 48 hours after administration of the morning dose of lonafarnib 200 mg. The Cmax on Day 10 was 2233 ng/mL, which is similar to the mean Cmax of 2695 ng/mL observed in the HGPS patient population.
Pharmacokinetics
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.
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.
Nonclinical Toxicology
Nonclinical toxi: 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
Clinical Studies
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.
How Supplied
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)
Storage
Store at 20°C-25°C (68°F-77°F), excursions permitted to 15°C-30ºC (59°F-86°F)
Images
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Patient Counseling Information
Dosing
- 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
- 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
QTc Interval Prolongation
- Inform patients and caregivers that ZOKINVY causes QTc interval prolongation and may increase the risk of Torsades de pointes, other ventricular arrhythmias, and sudden death.
- Instruct patients or caregivers to notify their healthcare provider if they experience symptoms such as dizziness, lightheadedness, heart palpitations, or loss of consciousness.
- Instruct patients to inform their healthcare provider if they are taking any other medications that may prolong the QTc interval.
Drug Interactions Inform patients and caregivers that ZOKINVY may interact with several drugs. Advise patients and their caregivers to inform their healthcare provider before starting or discontinuing a prescription or non-prescription drug, supplement, or strong CYP3A inhibitor.
Nephrotoxicity Inform the patient and caregiver of the risk of kidney damage.
Retinal Toxicity 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.
Gastrointestinal Adverse Reactions 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 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.
Impaired Fertility Inform females and males of reproductive potential that ZOKINVY may impact pubertal development and impair fertility.
Embryo-Fetal Toxicity 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.
Precautions with Alcohol
Alcohol-Lonafarnib b interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
ZOKINVY
Look-Alike Drug Names
There is limited information regarding Lonafarnib b Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.