Overview
11 DESCRIPTION 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 C 27 H 31 Br 2 ClN 4 O 2 , molecular mass is 638.8 g/mol, and its chemical structure is depicted below.
Mechanism of Action
12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Lonafarnib inhibits farnesyltransferase to prevent farnesylation and subsequent accumulation of progerin and progerin-like proteins in the inner nuclear membrane. 12.2 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.
Indications
- 1 INDICATIONS AND USAGE ZOKINVY is indicated in patients 12 months of age and older with a body surface area (BSA) of 0.39 m 2 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 ZOKINVY is a farnesyltransferase inhibitor indicated in patients 12 months of age and older with a body surface area of 0.
Common Doses
- 115 mg
- 150 mg
- 25 mg
- 50 mg
Dosage
2 DOSAGE AND ADMINISTRATION Start at 115 mg/m 2 twice daily with morning and evening meals. ( 2.1 ) After 4 months, increase to 150 mg/m 2 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 ) 2.1 Recommended Dosage The starting dosage of ZOKINVY for patients with a BSA of 0.
Contraindications
- 4 CONTRAINDICATIONS 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 )] Strong CYP3A inhibitors. ( 4 ) Strong or moderate CYP3A inducers. ( 4 ) Midazolam. ( 2.3 , 4 ) Lovastatin, simvastatin, or atorvastatin. ( 4 )
Side Effects
- 6 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sentynl Therapeutics, Inc. at 1-888-507-5206 or zokinvysafety@sentynl.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.
Interactions
- 7 DRUG INTERACTIONS 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 ) 7.1 Effect of Other Drugs on ZOKINVY Table 5 presents clinically significant drug interactions involving drugs that affect ZOKINVY. Table 5: Clinically Significant Drug Interactions (Drugs that Affect ZOKINVY) CYP3A Inhibitors Clinical Impact Lonafarnib is metabolized by CYP3A.