Zokinvy (lonafarnib): Medication for Hutchinson-Gilford Progeria Syndrome

What is Zokinvy, and how does it work?

Zokinvy (lonafarnib) 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; and for treatment of processing-deficient progeroid laminopathies with either heterozygous LMNA mutation with progerin-like protein accumulation or homozygous or compound heterozygous ZMPSTE24 mutations.

Zokinvy (lonafarnib) is used to reduce the risk of mortality in Hutchinson-Gilford Progeria Syndrome. It also blocks the production of the protein Progerin, which may be responsible for the process of premature aging that characterizes the syndrome.

What are the side effects of Zokinvy?

Side effects of Zokinvy include:

vomiting,
diarrhea,
infection,
nausea,
decreased appetite,
fatigue,
upper respiratory tract infection,
abdominal pain,
musculoskeletal pain,
electrolyte abnormalities,
weight loss,
headache,
myelosuppression,
increased aspartate aminotransferase,
decreased blood bicarbonate,
cough,
high blood pressure (hypertension), and
increased alanine aminotransferase

What is the dosage for Zokinvy?

Recommended Dosage

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. An appropriate dosage strength of
Zokinvy is not available for patients with a BSA of less than 0.39 m².
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 mgMorning Dosing Number of Capsule(s)Evening Dosing Number of Capsule(s)
Zokinvy 50 mgZokinvy 75 mg
Zokinvy 50 mgZokinvy 75 mg0.39 – 0.48100110.49 – 0.59125110.6 – 0.7150110.71 – 0.8117520.82 – 0.92200220.93 – 1225112

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

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

BSA (m²)Total Daily Dosage Rounded to Nearest 25 mgMorning Dosing Number of Capsule(s)Evening Dosing Number of Capsule(s)
Zokinvy 50 mgZokinvy 75 mg
Zokinvy 50 mgZokinvy 75 mg0.39 – 0.45125110.46 – 0.54150110.55 – 0.62175210.63 – 0.7200220.71 – 0.792251120.8 – 0.8725011110.88 – 0.952752110.96 – 130022

Dosage Modifications For Gastrointestinal Adverse Reactions

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 with an adequate amount of water.

Dosage Modifications For Drug Interactions

CYP3A Inhibitors

If concomitant use of Zokinvy with a weak CYP3A inhibitor is unavoidable:

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.

Temporary Discontinuation For Midazolam Use

Temporarily discontinue Zokinvy for 10 to 14 days before and 2 days
after administration of midazolam.

Preparation And Administration Instructions

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.
The mixture must be prepared fresh for each dose and 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.

What drugs interact with Zokinvy?

Effect Of Other Drugs On Zokinvy

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

Table 4: Clinically Significant Drug Interactions (Drugs that Affect
Zokinvy)

CYP3A InhibitorsClinical Impact
Coadministration of Zokinvy with a strong CYP3A inhibitor increases
lonafarnib AUC and Cmax which may increase the risk of Zokinvy adverse reactions.Prevention or ManagementStrong or moderate CYP3A inhibitors
Use of Zokinvy with strong or moderate CYP3A inhibitors is
contraindicated. Avoid consumption of grapefruit or Seville oranges.Weak CYP3A inhibitorsAvoid coadministration of
Zokinvy with weak CYP3A inhibitors. If coadministration is unavoidable, reduce to or continue
Zokinvy at a dosage of 115 mg/m². During coadministration, closely monitor patients for arrhythmias and events such as syncope and heart palpitations because
Zokinvy exposures may be increased despite the dosage reduction and the effect on the QT interval is unknown. Resume previous
Zokinvy dosage 14 days after discontinuing the weak CYP3A inhibitor.CYP3A InducersClinical Impact
Coadministration of Zokinvy with a strong CYP3A inducer decreases lonafarnib
Cmax and AUC which may reduce Zokinvy efficacy.Prevention or ManagementStrong or moderate CYP3A inhibitors
Use of Zokinvy with strong or moderate CYP3A inducers is
contraindicated.Weak CYP3A inhibitorsNo
Zokinvy dosage adjustment is recommended.CYP2C9 InhibitorsClinical Impact
Coadministration of Zokinvy with a CYP2C9 inhibitor may increase lonafarnib
AUC and Cmax which may increase the risk of Zokinvy adverse reactions.Prevention or ManagementCYP2C9 InhibitorsAvoid coadministration of
Zokinvy with CYP2C9 inhibitors. If coadministration is unavoidable, closely monitor patients for arrhythmias and events such as syncope and heart palpitations because the effect of increased
Zokinvy exposures on the QT interval is unknown.

Zokinvy’s Effect On Other Drugs

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

Table 5: Clinically Significant Drug Interactions (Drugs Affected by
Zokinvy)

CYP3A SubstratesClinical Impact
Lonafarnib is a strong CYP3A mechanism-based inhibitor. Coadministration of
Zokinvy with a CYP3A substrate increases the AUC and Cmax of the CYP3A
substrate which may increase the risk of the CYP3A substrate’s adverse reactions, including myopathy or rhabdomyolysis (with statins), or extreme sedation or respiratory depression (with midazolam).Prevention or ManagementHMG CoA reductase inhibitors (“Statins”)
Coadministration of Zokinvy with lovastatin, simvastatin, or
atorvastatin is contraindicated.Midazolam
Coadministration of Zokinvy with midazolam is contraindicated.
Temporarily discontinue Zokinvy for 10-14 days before and 2 days after
administration of midazolam.Other sensitive CYP3A substrates
Avoid coadministration of Zokinvy with sensitive CYP3A substrates. As
noted above, use with lovastatin, simvastatin, or atorvastatin, and
midazolam is contraindicated. If coadministration of other sensitive CYP3A substrates is unavoidable, monitor for adverse reactions and reduce the dosage of those sensitive CYP3A substrate(s) in accordance with their approved product labeling.Certain CYP3A substratesWhen
Zokinvy is coadministered with certain CYP3A substrates where minimal concentration changes may lead to serious or life-threatening toxicities, monitor for adverse reactions and reduce the dosage of the CYP3A substrate in accordance with its approved product labeling.LoperamideClinical Impact
Lonafarnib is a weak inhibitor of P-gp and strong inhibitor of CYP3A.
Coadministration of Zokinvy with loperamide increases the AUC and Cmax of
loperamide which may increase the risk of loperamide’s adverse reactionsPrevention or ManagementLoperamide is contraindicated in patients less than 2 years of age. When
Zokinvy is coadministered with loperamide, do not exceed loperamide 1 mg once daily when first coadministered. Slowly increase loperamide dosage with caution in accordance with its approved product labeling.CYP2C19 SubstratesClinical Impact
Lonafarnib is a moderate CYP2C19 inhibitor. Coadministration of Zokinvy with
a CYP2C19 substrate increases the AUC and Cmax of the CYP2C19 substrate which may increase the risk of the CYP2C19 substrate’s adverse reactions.Prevention or ManagementAvoid coadministration of
Zokinvy with CYP2C19 substrates. If coadministration is unavoidable, monitor for adverse reactions and reduce the dosage of the CYP2C19 substrate in accordance with its approved product labeling.P-gp SubstratesClinical Impact
Lonafarnib is a weak P-gp inhibitor. Coadministration of Zokinvy with a P-gp
substrate increases the AUC and Cmax of the P-gp substrate, which may increase the risk of the P-gp substrate’s adverse reactions.Prevention or ManagementWhen
Zokinvy is coadministered with P-gp substrates (e.g., digoxin, dabigatran) where minimal concentration changes may lead to serious or life-threatening toxicities, monitor for adverse reactions and reduce the dosage of the P-gp substrate in accordance with its approved product labeling.

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Is Zokinvy safe to use while pregnant or breastfeeding?

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.
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.