sorafenib (Nexavar)
Classes: Antineoplastics, Tyrosine Kinase Inhibitor; Antineoplastics, VEGF Inhibitor
Dosing and uses of Nexavar (sorafenib)
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%
