lonafarnib

Contraindicated in:

Cardiac arrhythmias, symptomatic bradycardia, hypokalemia, hypomagnesemia, or concurrent use of QT interval prolonging medications;
Concurrent use of strong CYP3A inhibitors or inducers;
Concurrent use of atorvastatin, lovastatin, midazolam, or simvastatin;
OB: Pregnancy.

Use Cautiously in:

Lactation: Safety not established in breastfeeding;
Rep: Women and men of reproductive potential;
Pedi: Children <1 yr (safety and effectiveness not established).

Adv. Reactions/Side Effects ⬆ ⬇

CV: hypertension, QT interval prolongation

Derm: rash, pruritus

EENT: epistaxis, rhinitis, vision abnormalities

F and E: hypercalcemia, hyperkalemia, hypokalemia, hyponatremia, metabolic acidosis, dehydration

GI: ↑liver enzymes, abdominal pain, constipation, diarrhea, nausea, vomiting, flatulence, mucositis

GU: ↓fertility, renal impairment

Hemat: anemia, leukopenia, lymphocytopenia, neutropenia

Metab: anorexia, weight loss

MS: pain

Neuro: fatigue, headache, cerebral ischemia, depression

Resp: cough

Misc: fever, infection

Interactions ⬆ ⬇

Drug-drug:

QT interval prolonging medications may ↑ risk of QT interval prolongation and torsades de pointes; concurrent use contraindicated.
Strong CYP3A inhibitors, including ketoconazole, may significantly ↑ levels and risk of toxicity; concurrent use contraindicated.
Strong CYP3A inducers, including rifampin or moderate CYP3A inducers, may significantly ↓ levels and effectiveness; concurrent use contraindicated.
May significantly ↑ levels and risk of myopathy and/or rhabdomyolysis with atorvastatin, lovastatin, and simvastatin; concurrent use contraindicated.
May significantly ↑ levels and risk of sedation and/or respiratory depression with midazolam; concurrent use contraindicated. Must temporarily discontinue lonafarnib for 10–14 days before and 2 days after receiving midazolam.
Moderate CYP3A inhibitors, including fluconazole, may ↑ levels and risk of toxicity.
CYP2C9 inhibitors may ↑ levels and risk of toxicity; avoid concurrent use. If concurrent use unavoidable, monitor closely.
May ↑ levels and risk of toxicity of CYP3A substrates; avoid concurrent use. If concurrent use unavoidable, monitor closely.
May ↑ levels and risk of toxicity of loperamide; do not exceed initial loperamide dose of 1 mg once daily (contraindicated in children <2 yr), and then slowly titrate, if needed.
May ↑ levels and risk of toxicity of CYP2C19 substrates; avoid concurrent use. If concurrent use unavoidable, monitor closely.
May ↑ levels and risk of toxicity of P-glycoprotein substrates, including digoxin and dabigatran; monitor closely.

Drug-Natural Products:

St. John's wort may significantly ↓ levels and effectiveness; concurrent use contraindicated.

Drug-Food:

Grapefruit or Seville oranges may ↑ levels and risk of toxicity; avoid concurrent use

Availability ⬆ ⬇

Capsules: 50 mg; 75 mg

Route/Dosage ⬆ ⬇

PO (Adults and Children with body surface area ≥0.39 m²): 115 mg/m² (rounded to nearest 25-mg increment) twice daily with morning and evening meal; after 4 mo, ↑ to 150 mg/m² (rounded to nearest 25-mg increment) twice daily with morning and evening meal. Moderate CYP3A inhibitor initiated in patient already receiving lonafarnib: No dosage adjustment needed for lonafarnib. Lonafarnib initiated in patient already receiving moderate CYP3A inhibitor: Monitor patient for adverse reactions for ≥7 days after initiating therapy; if adverse reaction develops, consider alternative to moderate CYP3A inhibitor.

US Brand Names ⬆ ⬇

Action ⬆ ⬇

Inhibits farnesyltransferase, which prevents accumulation of progerin and progerin-like proteins in the inner nuclear membrane.

Therapeutic effects:

Improved survival in patients with Hutchinson-Gilford progeria syndrome.

Classifications ⬆ ⬇

Therapeutic Classification: none assigned

Pharmacologic Classification: Farnesyltransferase inhibitors

Pharmacokinetics ⬆ ⬇

Absorption: Extent of absorption following oral administration unknown.

Distribution: Extensively distributed to extravascular tissues.

Protein Binding: ≥99%.

Metabolism/Excretion: Primarily metabolized in the liver via the CYP3A4 isoenzyme (also by CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1 to a lesser extent). Primarily excreted in feces (62%), with <1% being excreted in urine.

Half-Life: 4–6 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	2–4 hr	12 hr

Patient/Family Teaching ⬆ ⬇

Explain purpose and side effects of medication. Advise patient to take as directed. Tell patient to swallow capsule whole with water and to not chew. Tell patient and caregiver that if a dose is missed, the next dose should be taken as soon as possible, up to 8 hr prior to the next scheduled dose. If <8 hr remain before the next scheduled dose, tell patient to skip the missed dose and resume therapy at the next scheduled dose. Advise patient to read Patient Information before starting therapy.
Inform patient unable to swallow capsules that contents of capsule may be mixed with Ora Blend SF or Ora-Plus, orange juice, or applesauce and must be prepared fresh for each dose and taken within approximately 10 min of mixing. Advise patient and caregiver to avoid any products or juices containing grapefruit or Seville oranges during treatment.
Advise patient to immediately report symptoms of QT interval prolongation and torsades de pointes (dizziness, trouble breathing, chest pain, palpitations, fainting).
Advise patient and caregiver to report persistent abdominal pain, diarrhea, loss of appetite, nausea, and vomiting.
Advise patient and caregiver to report symptoms of retinal toxicities (central visual loss, reading difficulties, reduced color vision).
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult health care professional before taking other medications.
Rep: May cause fetal harm. Advise women of reproductive potential to notify health care professional if pregnancy is planned or suspected or if breastfeeding. Effective contraception is recommended for women of reproductive potential during therapy. May impair fertility.

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Indications ⬇

Contraind./Precautions ⬆ ⬇