Lonafarnib (Monograph)

Brand name: Zokinvy
Drug class: Enzyme Inhibitors

Medically reviewed by Drugs.com on Mar 10, 2025. Written by ASHP.

Introduction

Lonafarnib is a farnesyltransferase inhibitor.

Uses for Lonafarnib

Progeroid Laminopathies

Used in patients ≥12 months of age with BSA ≥0.39 m² to reduce risk of mortality in Hutchinson-Gilford Progeria Syndrome (HGPS). Designated an orphan drug for this use.

Used for treatment of processing-deficient Progeroid Laminopathies (PL) in patients ≥12 months of age with BSA ≥0.39 m² who have either a heterozygous LMNA mutation with progerin-like protein accumulation or homozygous or compound heterozygous ZMPSTE24 mutations. Designated an orphan drug by FDA for this use.

Not indicated for other Progeroid Syndromes or processing-proficient PL. Based on its mechanism of action, the drug is not expected to be effective in these populations.

Lonafarnib Dosage and Administration

General

Pretreatment Screening

Monitor ECGs prior to therapy initiation.
Obtain serum electrolytes and correct abnormalities.

Patient Monitoring

Monitor ECGs during therapy and as clinically indicated.
Periodically monitor CBC, serum electrolytes, and liver function tests (i.e., AST, ALT), and manage abnormalities accordingly.
Perform ophthalmologic examinations at regular intervals and if any new visual changes occur during lonafarnib therapy.
Monitor renal function at regular intervals during lonafarnib therapy.

Administration

Oral Administration

Administer orally twice daily with morning and evening meals. Swallow capsules whole with a sufficient amount of water; do not chew.

If unable to swallow whole capsules, may open each capsule and empty contents into a container containing 5–10 mL of Ora Blend SF, Ora-Plus orange juice, or 1–2 teaspoonfuls of applesauce, and mix thoroughly with a spoon. Consume entire mixture immediately or within 10 minutes of mixing. Do not mix with juice containing grapefruit or Seville oranges.

If a dose is missed by 8 hours or less, the prescribed dose should be taken as soon as it is remembered. If a dose is missed by more than 8 hours, the missed dose should be skipped, and the regular dosing schedule resumed at the next scheduled time.

Dosage

Pediatric Patients

Progeroid Syndromes

HGPS and PL

Oral

Initial dosage in pediatric patients ≥12 months of age with BSA ≥0.39 m²: 115 mg/m² twice daily for 4 months (see Table 1).

Table 1. Lonafarnib Dosage and Administration Recommendations for Initial Dosage of 115 mg/m21
BSA (m²)	Total Daily Dosage (rounded to nearest 25 mg)
0.39 - 0.48	100 mg (taken as one 50 mg capsule in the morning and one 50 mg capsule in the evening)
0.49 - 0.59	125 mg (taken as one 75 mg capsule in the morning and one 50 mg capsule in the evening)
0.6 - 0.7	150 mg (taken as one 75 mg capsule in the morning and one 75 mg capsule in the evening)
0.71 - 0.81	175 mg (taken as two 50 mg capsules in the morning and one 75 mg capsule in the evening)
0.82 - 0.92	200 mg (taken as two 50 mg capsules in the morning and two 50 mg capsules in the evening)
0.93 – 1	225 mg (taken as one 50 mg capsule and one 75 mg capsule in the morning and two 50 mg capsules in the evening)

After 4 months of treatment, increase dosage to 150 mg/m² twice daily. (see Table 2.)

Table 2. Lonafarnib Dosage and Administration Recommendations for Maintenance Dosage of 150 mg/m21
BSA (m²)	Total Daily Dosage (Rounded to nearest 25 mg)
0.39 - 0.45	125 mg (taken as one 75 mg capsule in the morning and one 50 mg capsule in the evening)
0.46 - 0.54	150 mg (taken as one 75 mg capsule in the morning and one 75 mg capsule in the evening)
0.55 - 0.62	175 mg (taken as two 50 mg capsules in the morning and one 75 mg capsule in the evening)
0.63 - 0.7	200 mg (taken as two 50 mg capsules in the morning and two 50 mg capsules in the evening)
0.71 - 0.79	225 mg (taken as one 50 mg capsule and one 75 mg capsule in the morning and two 50 mg capsules in the evening)
0.8 – 0.87	250 mg (taken as one 50 mg capsule and one 75 mg capsule in the morning and one 50 mg capsule and one 75 mg capsule in the evening)
0.88 – 0.95	275 mg (taken as two 75 mg capsules in the morning and one 50 mg capsule and one 75 mg capsule in the evening)
0.96 – 1	300 mg (taken as two 75 mg capsules in the morning and two 75 mg capsules in the evening)

Adults

Progeroid Syndromes

HGPS and PL

Oral

Initial dosage: 115 mg/m² twice daily for 4 months. Refer to Table 1 for dosage and administration recommendations for initial dosage of 115 mg/m².

After 4 months of treatment, increase dosage to 150 mg/m² twice daily. Refer to Table 2 for dosage and administration recommendations for maintenance dosage of 150 mg/m².

Dosage Modification for Adverse Reactions

If the QT_c interval is ≥500 msec, withhold lonafarnib until the QT_c interval is <470 msec, then resume therapy at the same dosage.

If vomiting and/or diarrhea resulting in dehydration or weight loss occurs in patients receiving a maintenance dosage of 150 mg/m², reduce the daily dosage to 115 mg/m². See Table 1.

Dosage Modification for Drug Interactions

Inhibitors of CYP3A

When a moderate CYP3A inhibitor is added to steady state lonafarnib, no dosage adjustment of lonafarnib is recommended.

When lonafarnib is initiated in a patient who is on a moderate CYP3A inhibitor, patient may be at an increased risk for adverse reactions. Monitor patient closely for ≥7 days after therapy initiation for adverse reaction development. Consider an alternative therapy that is not a CYP3A inhibitor if the patient experiences an adverse reaction within the initial 7 days of the starting dose or thereafter.

Midazolam

Concomitant use with midazolam is contraindicated. Temporarily discontinue lonafarnib 10–14 days before and 2 days after administration of midazolam.

Concomitant use of lonafarnib with lovastatin, simvastatin, or atorvastatin is contraindicated.

Special Populations

No specific dosage recommendations for geriatric patients or for patients with renal or hepatic impairment.

Cautions for Lonafarnib

Contraindications

Concomitant use with strong CYP3A inhibitors.
Concomitant use with moderate or strong CYP3A inducers.
Concomitant use with midazolam, lovastatin, simvastatin, or atorvastatin.

Warnings/Precautions

QTc Interval Prolongation

Lonafarnib prolongs QT_c interval, which may lead to torsade de pointes, other serious arrhythmias, and sudden death. Avoid lonafarnib in patients with history of cardiac arrhythmias and other circumstances that may increase risk of torsade de pointes or sudden death including symptomatic bradycardia, hypokalemia, or hypomagnesemia. Avoid concomitant use of lonafarnib with drugs known or suspected to prolong QT_c interval.

Monitor ECGs prior to starting lonafarnib, during treatment, and as clinically indicated. If QTc interval is ≥500 msec, withhold lonafarnib until interval is <470 msec and then resume lonafarnib at the same dosage. Obtain serum electrolytes prior to starting lonafarnib and during treatment as clinically indicated; correct electrolyte abnormalities.

Risk of Reduced Efficacy or Adverse Reactions Due to Drug Interactions

Potential for clinically significant drug interactions, which can reduce drug efficacy or increase risk of adverse effects from lonafarnib or coadministered drug. Review concomitant medications and monitor for adverse reactions.

Laboratory Abnormalities

Laboratory abnormalities reported. Such abnormalities included electrolyte abnormalities (e.g., hyperkalemia, hypokalemia, hyponatremia, hypercalcemia), myelosuppression (e.g., reductions in absolute neutrophil count [ANC], white blood cell counts, lymphocytes, hemoglobin, or hematocrit), and abnormal liver function tests (e.g., increased AST or ALT). Such abnormalities generally improved during continued therapy; however, lonafarnib not excluded as a cause of these abnormalities.

Periodically monitor electrolytes, CBC, and liver enzymes (AST/ALT) during therapy, and manage abnormalities accordingly.

Nephrotoxicity

Renal toxicity, including interstitial necrosis and mineralization in the inner medulla and correlating changes in electrolytes (e.g., hyperphosphatemia, hyperkalemia), observed in animals.

Monitor renal function at regular intervals during therapy.

Retinal Toxicity

Ocular (retinal) toxicity, resulting in rod-dependent, low-light vision decline observed in animals.

Perform ophthalmological exams regularly during lonafarnib therapy and whenever there is any new visual changes.

Impaired Fertility

Lonafarnib may impair male and female fertility based on animal findings. Potential for impaired fertility not adequately evaluated in humans.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on animal findings. Embryofetal toxicity and skeletal malformations observed in animals.

Avoid pregnancy during therapy. If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.

Specific Populations

Pregnancy

Based on animal reproduction studies, may cause fetal harm. There are no adequate and well-controlled studies in pregnant women.

Lactation

Distributed into milk in rats; not known whether lonafarnib distributes into human milk, affects nursing infants, or affects milk production.

Consider developmental and health benefits of breast-feeding along with the mother's clinical need for lonafarnib and any potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.

Females and Males of Reproductive Potential

Advise females of reproductive potential to use effective contraception during therapy.

Based on animal studies, may impair male and female fertility. Effects of lonafarnib on human fertility not adequately evaluated.

Pediatric Use

Safety and efficacy not established in children <12 months of age. Safety and efficacy established in children ≥12 months of age with HGPS and processing-deficient PL; use is supported by adequate and well controlled studies in children ≥2 years of age.

Geriatric Use

Patients with HGPS and processing-deficient progeroid laminopathies do not reach geriatric age. Clinical trials for treatment of HGPS and processing-deficient PL did not include patients ≥65 years of age or older.

Hepatic Impairment

Pharmacokinetics not studied.

Renal Impairment

Pharmacokinetics not studied.

Common Adverse Effects

Adverse effects (≥25%): Vomiting, diarrhea, infection, nausea, decreased appetite, fatigue, upper respiratory tract infection, abdominal pain, musculoskeletal pain, electrolyte abnormalities, decreased weight, headache, myelosuppression, increased AST and ALT, decreased blood bicarbonate, cough, hypertension.

Drug Interactions

Metabolized primarily by CYP3A4, and to lesser extent, by CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1.

In vitro, a potent CYP3A inhibitor; also inhibits CYP2C8 and CYP2C19. Does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, or CYP2D6. Unlikely to induce CYP1A2, CYP2B6, or CYP3A.

In vitro, inhibits P-glycoprotein (P-gp), organic anion transport protein (OATP) 1B1, 1B3, and breast cancer resistant protein (BCRP). Not a substrate of OATP 1B1, 1B3, or BCRP. Marginal substrate of P-gp.

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A inhibitors: Concomitant use with strong CYP3A inhibitors is contraindicated. When a moderate CYP3A inhibitor is added to steady state lonafarnib, no dosage adjustment of lonafarnib is recommended. When lonafarnib is initiated in a patient who is on a moderate CYP3A inhibitor, patient may be at an increased risk for adverse reactions. Monitor patient closely for ≥7 days after therapy initiation for adverse reaction development. Consider alternative therapy that is not a CYP3A inhibitor if the patient experiences an adverse reaction within the initial 7 days of the starting dose or thereafter.

CYP3A inducers: Possible decreased peak plasma concentrations and AUC of lonafarnib and possible reduced therapeutic efficacy. Concomitant use with moderate or strong CYP3A inducers is contraindicated. Dosage adjustments not required if used concomitantly with a weak CYP3A inducer.

CYP2C9 inhibitors: Possible increased peak plasma concentrations and AUC of lonafarnib, which can increase risk of adverse reactions to the drug. Avoid concomitant use with CYP2C9 inhibitors. If concomitant use cannot be avoided, closely monitor patients for arrhythmias and other symptoms of QT prolongation (e.g., syncope, heart palpitations).

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP3A (e.g., certain statins, midazolam): Possible increased plasma concentrations and AUC of the CYP3A substrate, possibly increasing adverse reactions of the substrate drug. Avoid concomitant use with sensitive CYP3A substrates; if concomitant use is unavoidable, monitor for adverse effects and reduce dosage of the sensitive CYP3A substrate accordingly. Concomitant use of certain CYP3A substrates contraindicated. When lonafarnib is administered concomitantly with certain CYP3A substrates where minimal concentration changes may result in serious or life-threatening toxicities, monitor for adverse effects and reduce dosage of the CYP3A substrate accordingly.

Substrates of CYP2C19: Possible increased plasma concentrations of the CYP2C19 substrate, possibly increasing adverse reactions of the substrate drug. Avoid concomitant use with CYP2C19 substrates. If concomitant use cannot be avoided, monitor for toxicity and reduce dosage of substrate drug accordingly.

P-glycoprotein Substrates

Possible increased plasma concentrations of the P-gp substrate, possibly increasing adverse reactions of the substrate drug. If used concomitantly with P-gp substrates where minimal concentration changes may result in serious toxicity, monitor for adverse reactions and reduce dosage of the P-gp substrate accordingly.

QTc Prolongation Drugs

Avoid concomitant use of lonafarnib with drugs known or suspected to prolong the QT_c interval.

If concomitant use cannot be avoided, monitor ECGs prior to starting lonafarnib, during concomitant treatment, and as clinically indicated.

Specific Drugs and Food

Drug	Interaction	Comments
Dabigatran	Increased peak plasma concentrations and AUC of dabigatran (a P-gp substrate); possible increased risk of adverse reactions	Monitor for adverse reactions and reduce dabigatran dosage accordingly
Digoxin	Increased peak plasma concentrations and AUC of digoxin (a P-gp substrate); possible increased risk of adverse reactions	Monitor for adverse reactions and reduce digoxin dosage accordingly
Grapefruit or Seville oranges	Increased lonafarnib peak plasma concentrations and AUC; possible increased risk of lonafarnib adverse reactions	Avoid concomitant use
HMG-CoA reductase inhibitors (statins) (atorvastatin, lovastatin, simvastatin)	Concomitant use with statins that are CYP3A substrates (atorvastatin, lovastatin, simvastatin) increases plasma concentrations and AUC of the statin; possible increased risk of adverse effects of the statin including myopathy and rhabdomyolysis	Concomitant use contraindicated
Ketoconazole	Ketoconazole (a strong CYP3A inhibitor) increased lonafarnib peak plasma concentrations and AUC; possible lonafarnib toxicity	Concomitant use contraindicated
Loperamide	Increased peak plasma concentrations and AUC of loperamide (a weak inhibitor of P-gp and strong inhibitor of CYP3A), which can increase adverse reactions	Concomitant use contraindicated in patients <2 years of age If used concomitantly in patients ≥2 years of age, do not exceed loperamide dosage of 1 mg once daily when first coadministered; slowly increase loperamide dosage with caution
Midazolam	Increased peak plasma concentrations and AUC of midazolam (a CYP3A substrate), which can increase risk of adverse reactions of midazolam including extreme sedation and respiratory depression	Concomitant use contraindicated
Omeprazole	Increased omeprazole peak plasma concentrations and AUC by 28% and 60%, respectively	Avoid concomitant use; if concomitant use unavoidable, monitor for adverse effects and reduce omeprazole dosage according to product labeling
Rifampin	Rifampin (a CYP3A inducer) decreased lonafarnib peak plasma concentrations	Concomitant use contraindicated

Lonafarnib Pharmacokinetics

Absorption

Bioavailability

Absolute bioavailability following oral administration not determined.

Steady-state concentrations achieved by approximately 3 days.

Median peak plasma concentrations following twice daily dosing of 115 mg/m² and 150 mg/m² occur at 2 and 4 hours, respectively.

Food

Administration with a high-fat meal decreased peak plasma concentration and AUC by 55 and 29%, respectively, compared with fasted state. Administration with a low-fat meal decreased peak plasma concentration and AUC by 25 and 21%, respectively.

Following an oral dose with a high-fat meal (approximately 43% fat of the total 952 calories) peak plasma concentrations and AUC decreased 55% and 29%, respectively; with a low-fat meal (approximately 12% fat of the total 421 calories), peak plasma concentrations and AUC decreased 25% and 21%, respectively, compared to fasted conditions.

Special Populations

Peak plasma concentration and AUC were 26% and 44% higher in females, respectively, compared to males; however, not considered clinically relevant.

Peak plasma concentration and AUC were 27% and 59% higher in patients ≥65 years of age, respectively, compared to younger patients; however, not considered clinically relevant.

Distribution

Extent

Not known whether distributed into human milk.

Plasma Protein Binding

≥99%.

Elimination

Metabolism

Metabolized primarily by CYP3A and to a lesser extent by CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1 to inactive (i.e., HM17) and active (i.e., HM21) metabolites.

Elimination Route

Eliminated in feces (62%) and urine (<1%).

Half-life

Approximately 4–6 hours.

Stability

Storage

Oral

Capsules

20–25°C; excursions permitted between 15–30°C.

Actions

A farnesyltransferase inhibitor; prevents post-translational farnesylation, which is a necessary step in processing many cellular proteins.
In Hutchinson-Gilford Progeria Syndrome (HGPS), accumulation of these abnormal proteins results in damage to cells, including changes to nuclear structure and cellular function; pathogenic changes cause severe disease manifestations, including failure to thrive, scleroderma-like skin, lipoatrophy, alopecia, joint contractures, skeletal dysplasia, and atherosclerosis.
Lonafarnib binds to the farnesyltransferase inhibitor binding site on post-translational processing pathways and blocks accumulation of abnormal progerin and progerin-like proteins in the inner nuclear membrane.
In vitro, lonafarnib improves nuclear morphology and normalizes the structure and function of progerin-containing cells.

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (patient information and instructions for use).
Advise patients and caregivers that lonafarnib 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 lonafarnib 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 lonafarnib 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 the lonafarnib capsule can be mixed with orange juice or applesauce. Advise patients not to mix the contents of the lonafarnib capsule 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. Advise patient and caregivers to call their healthcare provider or pharmacist if they have any questions.
Inform patients and caregivers that lonafarnib 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.
Inform patients and caregivers that GI adverse reactions are common with lonafarnib. 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.
Inform patients and caregivers that BP may increase while taking lonafarnib. 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.
Inform the patient and caregiver of the risk of kidney damage.
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.
Inform patients and caregivers that lonafarnib may prolong the QT_c interval. Instruct patients and caregivers to notify their clinician if symptoms such as dizziness, lightheadedness, heart palpitations, or loss of consciousness occur.
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 lonafarnib.
Advise patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.