lonafarnib (Rx)

Brand and Other Names:Zokinvy
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

capsule

  • 50mg
  • 75mg

Hutchinson-Gilford Progeria Syndrome

Indicated to reduce the risk of mortality in Hutchinson-Gilford progeria syndrome (HGPS)

Initial: 115 mg/m2 PO BID with morning and evening meals

After 4 months: Increase to 150 mg/m2 PO BID

Round all total daily doses to nearest 25-mg increment

Progeroid Laminopathies

Indicated for processing-deficient progeroid laminopathies with heterozygous LMNA mutation with progerinlike protein accumulation or homozygous or compound heterozygous ZMPSTE24 mutations

Initial: 115 mg/m2 PO BID with morning and evening meals

After 4 months: Increase to 150 mg/m2 PO BID

Round all total daily doses to nearest 25-mg increment

Dosage Modifications

Renal or hepatic impairment

  • Not studied

Gastrointestinal adverse reactions

  • If patients taking 150 mg/m2 BID experience repeated episodes of vomiting and/or diarrhea resulting in dehydration or weight loss, reduce to starting dose of 115 mg/m2 BID

CYP3A inhibitors and inducers

  • Contraindicated with moderate or strong CYP3A inhibitors or inducers
  • Coadministration with weak CYP3A inhibitor
    • If unavoidable, reduce or continue at starting dose (115 mg/m2 BID)
    • Resume previous dose 14 days after discontinuing weak CYP3A inhibitor

Dosing Considerations

Limitations of use: Not indicated for other progeroid syndromes or processing-proficient progeroid laminopathies

Temporary discontinuation for midazolam use

  • Temporarily discontinue lonafarnib for 10-14 days before and 2 days after administration of midazolam

Dosage Forms & Strengths

capsule

  • 50mg
  • 75mg

Hutchinson-Gilford Progeria Syndrome

Indicated to reduce the risk of mortality in Hutchinson-Gilford progeria syndrome (HGPS) in patients aged ≥12 months with BSA >0.39 m2

Initial: 115 mg/m2 PO BID with morning and evening meals

After 4 months: Increase to 150 mg/m2 PO BID

Round all total daily doses to nearest 25-mg increment

Progeroid Laminopathies

Indicated for processing-deficient progeroid laminopathies with heterozygous LMNA mutation with progerin-like protein accumulation or homozygous or compound heterozygous ZMPSTE24 mutations in patients aged ≥12 months with BSA >0.39 m2

Initial: 115 mg/m2 PO BID with morning and evening meals

After 4 months: Increase to 150 mg/m2 PO BID

Round all total daily doses to nearest 25-mg increment

Dosage Modifications

Renal or hepatic impairment

  • Not studied

Gastrointestinal adverse reactions

  • If patients taking 150 mg/m2 BID experience repeated episodes of vomiting and/or diarrhea resulting in dehydration or weight loss, reduce to starting dose of 115 mg/m2 BID

CYP3A inhibitors and inducers

  • Contraindicated with moderate or strong CYP3A inhibitors or inducers
  • Coadministration with weak CYP3A inhibitor
    • If unavoidable, reduce or continue at starting dose (115 mg/m2 BID)
    • Resume previous dose 14 days after discontinuing weak CYP3A inhibitor

Dosing Considerations

Limitations of use: Not indicated for other progeroid syndromes or processing-proficient progeroid laminopathies

Appropriate dosage strength is not available for patients with BSA <0.39 m2

Temporary discontinuation for midazolam use

  • Temporarily discontinue lonafarnib for 10-14 days before and 2 days after administration of midazolam
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Interactions

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            Adverse Effects

            >10%

            Vomiting (90%)

            Diarrhea (81%)

            Infection (78%)

            Nausea (56%)

            Decreased appetite/anorexia (53%)

            Fatigue (51%)

            Upper respiratory tract infection (51%)

            Abdominal pain (48%)

            Musculoskeletal pain (48%)

            Electrolyte abnormalities (43%)

            Headache (37%)

            Decreased weight (37%)

            Myelosuppression (35%)

            Increased AST (35%)

            Decreased blood bicarbonate (33%)

            Cough (33%)

            Hypertension (29%)

            Increased ALT (27%)

            Ocular changes (24%)

            Constipation (22%)

            Epistaxis (21%)

            Rhinitis (19%)

            Pyrexia (14%)

            Cerebral ischemia (11%)

            Rash (11%)

            1-10%

            Pruritus (8%)

            Mucositis (8%)

            Flatulence (6%)

            Dehydration (5%)

            Depressed mood (5%)

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            Warnings

            Contraindications

            Strong or moderate CYP3A inhibitors or inducers

            Midazolam

            Lovastatin, simvastatin, or atorvastatin

            Cautions

            Laboratory abnormalities reported, including electrolyte abnormalities (eg, hyperkalemia, hypokalemia, hyponatremia, hypercalcemia), myelosuppression (eg, decreased ANC, WBC count, lymphocytes, hemoglobin, hematocrit), and increased liver enzymes; periodically monitor for these abnormalities and correct accordingly

            Nephrotoxicity observed in rats at plasma drug exposures similar to humans

            Retinal toxicity (rod-dependent, low-light vision decline) observed in monkeys at plasma drug exposures similar to humans

            Fertility impairment observed in female and male rats

            Based on animal reproduction studies, can cause embryofetal toxicity

            Drug interaction overview

            • CYP3A4 inhibitors
              • Lonafarnib is a sensitive substrate of CYP3A4
              • Strong or moderate inhibitors: Contraindicated
              • Weak inhibitors: If unable to avoid coadministration, reduce to or continue lonafarnib at the starting dose
            • CYP3A4 inducers
              • Lonafarnib is a sensitive substrate of CYP3A4
              • Strong or moderate: Contraindicated
            • CYP2C9 inhibitors
              • Lonafarnib is a CYP2C9 substrate
              • Coadministration may increase lonafarnib AUC and peak concentration
              • Avoid coadministration with CYP2C9 inhibitors
              • If unavoidable, closely monitor patients for arrhythmias and events (eg, syncope, heart palpitations); effect of increased lonafarnib systemic exposure on the QT interval is unknown
            • CYP3A4 substrates
              • Lonafarnib is a strong CYP3A inhibitor
              • HMG CoA reductase inhibitors: Coadministration is contraindicated with lovastatin, simvastatin, or atorvastatin
              • Midazolam: Coadministration is contraindicated; temporarily discontinue lonafarnib for 10-14 days before and 2 days after administration of midazolam
              • Loperamide: Loperamide is contraindicated in patients aged <2 years; when lonafarnib is coadministered with loperamide, do not exceed loperamide 1 mg qDay when first coadministered; slowly increase loperamide dosage with caution in accordance with its approved product labeling
              • Other sensitive CYP3A substrates: Avoid coadministration; if coadministration is unavoidable, monitor for adverse reactions and reduce CYP3A substrate dose in accordance with their approved product labeling
              • Certain CYP3A substrates: If coadministered with certain CYP3A substrates where minimal concentration changes may lead to serious or life-threatening toxicities, monitor for adverse reactions and reduce the CYP3A substrate dose in accordance with its approved product labeling
            • CYP2C19 substrates
              • Avoid coadministration
              • Lonafarnib may increase the AUC and peak concentration of CYP2C19 substrates
              • If coadministration unavoidable, monitor for adverse reactions and reduce the CYP2C19 substrate dose in accordance with its approved product labeling
            • P-gp substrates
              • Lonafarnib is a weak P-gp inhibitor
              • Monitor for adverse reactions if coadministered with P-gp substrates (eg, digoxin, dabigatran) where minimal concentration changes may lead to serious or life-threatening toxicities
              • Reduce the P-gp substrate dose in accordance with its approved product labeling
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            Pregnancy & Lactation

            Pregnancy

            Based on findings from animal studies, can cause embryofetal harm when administered to pregnant females

            Advise pregnant females of fetal risk

            Animal studies

            • In animal reproduction studies, administration to pregnant rats during organogenesis produced embryofetal toxicity at exposures that were 1.2-times the human exposure at the recommended dose of 150 mg/m2 BID
            • In pregnant rabbits, administration of lonafarnib during organogenesis produced skeletal malformations and variations at exposures lower than the human exposure at 150 mg/m2 BID, and maternal toxicity at 26 times the human exposure at 150 mg/m2 BID

            Fertility

            • Fertility impairment observed in female and male rats
            • Advise females and males of reproductive potential of the animal fertility findings
            • The impact on pubertal development and potential for impaired fertility in humans have not been adequately evaluated

            Lactation

            Data are unavailable on presence in human milk, effects on breastfed infants, or 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

            Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug and any potential adverse effects of the breastfed infant from lonafarnib or from the underlying maternal condition

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Oral farnesyltransferase inhibitor (FTI); farnesyltransferase is an enzyme involved in modification of proteins through a process called prenylation

            Mutation in the LMNA gene causes over-production of progerin, a farnesylated-aberrant protein; persistent farnesylation causes progerin accumulation in the inner nuclear membrane and is, at least partly, responsible for HGPS

            Accumulation of the defective lamin A protein makes the nucleus unstable, leading to the process of premature aging in children with progeria

            Absorption

            Peak plasma time

            • 115 mg/m2: 2 hr
            • 150 mg/m2: 4 hr

            Peak plasma concentration

            • 115 mg/m2: 1,777 ng/mL
            • 150 mg/m2: 2,695 ng/mL

            AUC

            • 0-8 hr
              • 115 mg/m2: 9,869 ng⋅hr/mL
              • 150 mg/m2: 16,020 ng⋅hr/mL
            • >8 hr
              • 115 mg/m2: 12,365 ng⋅hr/mL
              • 150 mg/m2: 19,539 ng⋅hr/mL

            Distribution

            Protein bound: ≥99%

            Vd: 87.8 L (100 mg PO BID): 97.4 L (75 mg PO BID)

            Metabolism

            Primarily metabolized by CYP3A

            Metabolized to a lesser extent by CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1 in vitro

            Elimination

            Half-life: ~4-6 hr

            Excretion

            • Feces ~62%; urine <1%
            • 2 most predominant metabolites were HM17 and HM21 (active metabolite) that accounted for 15% and 14% of plasma radioactivity, respectively
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            Administration

            Oral Administration

            Take BID with morning and evening meals to avoid gastrointestinal adverse effects

            Administer capsules whole with sufficient amount of water

            Do not chew capsules

            Unable to swallow capsule

            • Entire contents of capsules can be mixed with Ora-Blend SF, Ora-Plus, orange juice, or applesauce
            • Do not mix with juice containing grapefruit or Seville oranges, owing to potential drug interaction (contraindicated with moderate or strong CYP3A inhibitors or inducers)
            • Mixture must be prepared fresh for each dose and taken within ~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 container containing 5-10 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 container containing 1-2 teaspoonful of applesauce
              • Mix thoroughly with a spoon
              • Consume entire serving

            Missed dose

            • ≥8 hours before next scheduled dose: Take dose as soon as possible with food
            • <8 hours remains before next scheduled dose: Skip missed dose, and resume taking at next scheduled dose

            Storage

            Capsules: Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.