sorafenib (Nexavar)

Dosing and uses of Nexavar (sorafenib)

• Adult
• Pediatric

 

Adult dosage forms and strengths

tablet

• 200mg

 

Renal Cell Carcinoma

Indicated for advanced renal cell carcinoma

400 mg PO q12hr

If skin toxicity, discontinue/decrease dose frequency to qDay or every other day as recommended by Manufacturer

 

Hepatocellular Carcinoma

Indicated for unresectable hepatocellular carcinoma

400 mg PO q12hr

If skin toxicity, discontinue/decrease dose frequency to qDay or every other day as recommended by Manufacturer

 

Thyroid Cancer

Indicated for locally recurrent or metastatic, progressive, differentiated thyroid cancer (DTC) that is refractory to radioactive iodine treatment

400 mg PO q12hr

Dosage modification for DTC

• Dose reduction for dermatologic toxicities (see prescribing information for specific toxicity grades 2 or 3 dosage modifications)
• First dose reduction: 600 mg/day (divided as 2 doses of 400 mg and 200 mg 12 hr apart)
• Second dose reduction: 200 mg q12hr
• Third dose reduction: 200 mg qDay

 

Melanoma (Orphan)

Treatment of stage IIB through stage IV melanoma

Orphan indication sponsor

• EMD Serono, Inc; One Technology Plc; Rockland, MA 02370

 

Renal Impairment

Mild to moderate: Dose adjustment not necessary

Severe renal impairment: Not studied

 

Hepatic Impairment

Mild to moderate: Dose adjustment not necessary

Severe renal impairment: Not studied

 

Administration

Take 1 hr before or 2 hr after meals

Although partially metabolized by CYP3A4, dose modification appears to be unnecessary if coadministered with CYP3A4 inhibitors

Monitor: Bp

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Nexavar (sorafenib) adverse (side) effects

>10%

Thrombocytopenia (12-46%)

Anemia (44%)

Diarrhea (43%)

Rash/desquamation (40%)

Fatigue (37%)

Abd pain (31%)

Hand-foot skin reaction (30%)

Weight loss (30%)

Anorexia (29%)

Alopecia (27%)

Nausea (24%)

Lymphopenia (23%)

Neutropenia (18%)

Hemorrhage (15-18%)

Hypertension (9-17%)

Vomiting (16%)

Constipation (15%)

Neuropathy (13%)

Dry skin (11%)

 

1-10%

Headache (10%)

Joint pain (10%)

Congestive heart failure, MI (1.9%)

QT prolonation (rare)

 

<1%

Acute renal failure

Angioedema and arrhythmia may occur

Bone pain reported

 

Frequency not defined

Stevens-Johnson Syndrome

Hyperthyroidism

Interstitial lung disease

 

Postmarketing Reports

Hypersensitivity: Angioedema, anaphylactic reaction

Hepatobiliary disorders: Drug-induced hepatitis, including reports of hepatic failure and death

Dermatologic: Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN)

Musculoskeletal: Rhabdomyolysis, osteonecrosis of the jaw

Respiratory: Interstitial lung disease-like events

 

Warnings

Contraindications

Hypersensitivity

Coadministration with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer; a randomized controlled trial comparing safety and efficacy of carboplatin and paclitaxel with or without sorafenib stopped early because overall survival was not improved with addition of sorafeniB

 

Cautions

Osteonecrosis of jaw reported

Increased risk of cardiac ischemia/HTN/hemorrhage

Hepatitis reported; characterized by a hepatocellular pattern of liver damage with significant increases of transaminases which may result in hepatic failure and death

QT Prolongation: Monitor for prolonged QT intervals with CHF, bradyarrhythmias, drugs known to prolong QT interval, and electrolyte abnormalities; avoid with congenital long QT syndrome

Avoid pregnancy

High incidence of skin toxicity and rash

Severe dermatologic toxicities, including Stevens-Johnson syndrome and toxic epidermal necrolysis reported

Impairs exogenous thyroid suppression; for patients with impaired TSH suppression while receiving sorafenib, the median maximal TSH was 1.6 mU/L and 25% had TSH levels >4.4 mU/L; monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with disseminated thyroid cancer

Temporarily discontinue before surgery, resumption should be based on adequate wound healing

 

Pregnancy and lactation

Pregnancy category: d

Lactation: not known whether distributed in breast milk, discouraged

 

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.

 

Pharmacology of Nexavar (sorafenib)

Mechanism of action

Multikinase inhibitor (including VEGF and PDGF receptor kinases), reduces tumor cell proliferation in vitro, may act at least partially by inhibiting tumor angiogenesis

 

Absorption

Bioavailability: 38-49%, reduced by high fat diet

Peak Plasma Time: 3 hr

 

Distribution

Protein Bound: 99.5%

 

Metabolism

Metabolism: in liver by CYP3A4 & UGT1A9

 

Elimination

Half-Life, Elimination: 25-48 hr

Excretion: Feces 77%; urine 19%