Lonafarnib- Zokinvy- (Nov 2020)- To treat rare condition of premature aging
Drug Name:Lonafarnib- Zokinvy- (Nov 2020)- To treat rare condition of premature aging
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS- summary
• Reduce to or continue at 115 mg/m2 twice daily with concomitant use of weak CYP3A inhibitors
• See Full Prescribing Information for additional information regarding drug interactions
Indication:
U.S. FDA APPROVED DRUGS DURING 2020
Sr.No- 43
Name of the Drug- ZOKINVY
Active Ingredient - Lonafarnib
Pharmacological Classification-
To treat rare conditions of premature aging
Date of Approval- 11/20/2020
(Ref- FDA approved List 2020)
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
ZOKINVY safely and effectively.
See full prescribing information for ZOKINVY. ZOKINVYTM (lonafarnib) capsules, for oral use
Initial U.S. Approval: 2020
INDICATIONS AND USAGE
ZOKINVY is a farnesyltransferase inhibitor indicated in patients 12 months of age and older with a body surface area of 0.39 m2 and above
• To reduce risk of mortality in Hutchinson-Gilford Progeria Syndrome
• For treatment of processing-deficient Progeroid Laminopathies with either:
o Heterozygous LMNA mutation with progerin-like protein accumulation
o Homozygous or compound heterozygous ZMPSTE24 mutations
Limitations of Use- 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
DOSAGE AND ADMINISTRATION
• Start at 115 mg/m2 twice daily with morning and evening meals
• After 4 months, increase to 150 mg/m2 twice daily
• Round all total daily doses to nearest 25 mg increment
• Swallow capsules whole. If unable to swallow capsules, mix contents with Ora Blend SF®, Ora-Plus®, orange juice, or applesauce
• See Full Prescribing Information for additional instructions on dosing, preparation and administration
DOSAGE FORMS AND STRENGTHS-
Capsules: 50 mg and 75 mg
CONTRAINDICATIONS-
• Strong or moderate CYP3A inhibitors or inducers
• Midazolam
• Lovastatin, simvastatin, and atorvastatin
Adverse Reaction:
ADVERSE REACTIONS-
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
Contra-Indications:
CONTRAINDICATIONS-
• Strong or moderate CYP3A inhibitors or inducers
• Midazolam
• Lovastatin, simvastatin, and atorvastatin
WARNINGS AND PRECAUTIONS-
• 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
• Laboratory Abnormalities: Monitor for changes in electrolytes, complete blood counts, and liver enzymes
• Nephrotoxicity: Caused nephrotoxicity in rats. Monitor renal function at regular intervals
• 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
• 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
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the risk to a fetus and to use effective contraception
Dosages/ Overdosage Etc:
DOSAGE AND ADMINISTRATION
• Start at 115 mg/m2 twice daily with morning and evening meals
• After 4 months, increase to 150 mg/m2 twice daily
• Round all total daily doses to nearest 25 mg increment
• Swallow capsules whole. If unable to swallow capsules, mix contents with Ora Blend SF®, Ora-Plus®, orange juice, or applesauce
• See Full Prescribing Information for additional instructions on dosing, preparation and administration
DOSAGE FORMS AND STRENGTHS-
Capsules: 50 mg and 75 mg
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).
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
• 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 -
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 -
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.
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.
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.
Manufactured for:
Eiger BioPharmaceuticals, Inc., 2155 Park Boulevard Palo Alto
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action- Lonafarnib inhibits farnesyltransferase to prevent farnesylation and subsequent accumulation of progerin and progerin-like proteins in the inner nuclear membrane.
2. Pharmacodynamics- No formal pharmacodynamic studies have been conducted with ZOKINVY.
3. Pharmacokinetics- The pharmacokinetics of lonafarnib at steady state in patients with HGPS following oral administration of lonafarnib twice daily with food are summarized beow.
Summary of Pharmacokinetic Parameters of Lonafarnib- at Steady State after Oral Administration Twice Daily to Patients with HGPS Lonafarnib
Dose Median (range) tmax (hr) Mean (SD) Cmax (ng/mL) Mean (SD) AUC0-8hr (ng*hr/mL) Mean (SD) AUCtau (ng*hr/mL) 115 mg/m2 N 23 23 23 15 Results 2 (0, 6) 1777 (1083) 9869 (6327) 12365 (9135) 150 mg/m2 N 18 18 18 8 Results 4 (0, 12) 2695 (1090) 16020 (4978) 19539 (6434)
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 Cmax decreased 55% and AUC decreased 29% with a high-fat meal (approximately 43% fat of the total 952 calories) compared to fasted conditions. Cmax 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 Cmax 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 AUC and Cmax 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 Cmax and AUC of lonafarnib were increased by 270% and 425%, respectively, as compared to lonafarnib administered alone in healthy subjects [
Drug Interactions-
CYP2C9 inhibitors Coadministration with CYP2C9 inhibitors may increase lonafarnib AUC and Cmax. A drug-drug interaction study of ZOKINVY with CYP2C9 inhibitors has not been conducted
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 Cmax of lonafarnib was reduced by 92% and the AUC was reduced by 98%, as compared to without rifampin coadministration in healthy subjects
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 Cmax and AUC of midazolam were increased by 180% and 639%, respectively.
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
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy Risk Summary- Based on findings from animal studies, ZOKINVY can cause embryofetal harm when administered to a pregnant woman.
There are no human data on ZOKINVY use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Advise pregnant women of the risk to a fetus.
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.
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.
2.Females and Males of Reproductive Potential- 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 .
3.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.
4.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.
