Pronunciation: soe-RAF-e-nib
Class: Multikinase inhibitor

Trade Names

Nexavar
- Tablets 200 mg

Pharmacology

Decreases tumor cell proliferation in vitro.

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Pharmacokinetics

Absorption

Bioavailability is 38% to 49%. T _max is 3 h. Steady state plasma levels occur within 7 days. Administration with high-fat meals reduced sorafenib bioavailability 29%.

Distribution

In vitro protein binding is 99.5%.

Metabolism

Metabolism occurs primarily in the liver by CYP3A4 and UGT1A9-mediated glucuronidation. Eight metabolites have been identified, of which pyridine N-oxide has shown in vitro potency similar to the parent drug.

Elimination

Mean elimination t _½ is about 25 to 48 h. After oral administration of a sorafenib 100 mg oral solution, 96% was recovered within 14 days (77% in the feces and 19% in the urine).

Special Populations

Renal Function Impairment

No dose adjustments are necessary for mild, moderate, or severe renal function impairment in patients not undergoing dialysis.

Hepatic Function Impairment

Mild (Child-Pugh class A) and moderate (Child-Pugh class B) hepatic function impairment decreased AUC by 23% and 65%, respectively. Not studied in severe (Child-Pugh class C) hepatic function impairment.

Gender

No dose adjustments are necessary for gender.

Race

Mean AUC in Asians is 30% lower than in white patients.

Age

No dose adjustments are necessary for age.

Indications and Usage

Treatment of advanced renal cell carcinoma; treatment of unresectable hepatocellular carcinoma.

Contraindications

Standard considerations.

Dosage and Administration

Adults

PO 400 mg (two 200 mg tablets) twice daily. Continue treatment until patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

Dosage Adjustment

Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction. When dose reduction is necessary, sorafenib dosage may be reduced to 400 mg once daily; if additional dose reduction is required, dosage may be reduced to 400 mg every other day.

Skin toxicity grade 1

Continue treatment and consider topical therapy for symptomatic relief.

Skin toxicity grade 2 First occurrence

Continue treatment and consider topical therapy for symptomatic relief. If no relief occurs in 7 days, interrupt treatment until toxicity resolves to grade 0 to 1. When resuming treatment, decrease dosage by one dose level (400 mg twice daily to 400 mg once daily; 400 mg once daily to 400 mg every other day).

Second or third occurrence

Interrupt treatment until toxicity resolves to grade 0 to 1. When resuming treatment, decrease dosage by one dose level (400 mg once daily to 400 mg every other day).

Fourth occurrence

Discontinue sorafenib.

Skin toxicity grade 3 First or second occurrence

Interrupt treatment until toxicity resolves to grade 0 to 1. When resuming treatment, decrease dosage by one dose level (400 mg twice daily to 400 mg once daily; 400 mg once daily to 400 mg every other day).

Third occurrence

Discontinue sorafenib.

General Advice

• Administer each dose with a full glass of water on an empty stomach, at least 1 h before or 2 h after eating.
• Caution patient not to chew, crush, or break tablets.
• If a dose is missed, skip that dose and administer the next dose at the regularly scheduled time. Never administer 2 doses at the same time to catch up.

Storage/Stability

Store tablets at controlled room temperature (59° to 86°F). Keep in a dry place.

Drug Interactions

CYP2B6 and CYP2C8 substrates (eg, bupropion, rosiglitazone)

Plasma levels of drugs metabolized by these isozymes are expected to be elevated by sorafenib.

CYP3A4 inducers (eg, carbamazepine, dexamethasone, phenobarbital, rifampin, St. John's wort)

Sorafenib plasma levels may be reduced.

Docetaxel

Use with caution; docetaxel plasma levels may be increased.

Doxorubicin

Use with caution; a 21% increase in doxorubicin AUC has been reported.

Drugs metabolized by UGT1A1 (eg, irinotecan)

Use with caution.

Fluorouracil

Use with caution; increases and decreases in fluorouracil AUC have been reported.

Warfarin

Infrequent bleeding events and elevated INR have been reported.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypertension (17%).

CNS

Fatigue (46%); sensory neuropathy (13%); asthenia (at least 10%); headache (10%); depression (1% to less than 10%).

Dermatologic

Rash/desquamation (40%); hand-foot reaction (30%); alopecia (27%); pruritus (19%); dry skin (11%); erythema (at least 10%); acne, exfoliative dermatitis, flushing (1% to less than 10%).

GI

Diarrhea (55%); anorexia (29%); nausea (24%); vomiting (16%); constipation (15%); decreased appetite, dyspepsia, dysphagia, mucositis, stomatitis (1% to less than 10%).

Genitourinary

Erectile dysfunction (1% to less than 10%).

Hematologic-Lymphatic

Thrombocytopenia, lymphopenia (47%); anemia (44%); neutropenia (18%); hemorrhage (15%); leukopenia (at least 10%).

Hepatic

Liver dysfunction (11%).

Lab Tests

Hypoalbuminemia (59%); hypophosphatemia (45%); elevated INR (42%); elevated lipase (41%); elevated amylase (34%).

Metabolic-Nutritional

Weight loss (30%); transient increases in transaminases (1% to less than 10%).

Musculoskeletal

Joint pain (10%); arthralgia, myalgia (1% to less than 10%).

Respiratory

Dyspnea (14%); hoarseness (1% to less than 10%).

Miscellaneous

Abdominal pain (30%); pain (at least 10%); influenza-like illness, pyrexia (1% to less than 10%).

Precautions

Monitor Monitor BP weekly during first 6 wk of therapy and monitor and treat thereafter if necessary.

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Hepatic Function

No dose adjustment necessary in patients with Child-Pugh class A and B hepatic function impairment. Sorafenib has not been studied in patients with Child-Pugh class C hepatic function impairment.

Cardiac effects

Treatment-emergent cardiac ischemia/infarction has been reported. Consider temporary or permanent discontinuation of sorafenib in patients who develop cardiac ischemia and/or infarction.

Dermatologic toxicities

Hand-foot skin reactions and rash are the most common adverse reactions.

GI perforation

An uncommon adverse reaction, which warrants discontinuation of therapy.

Hemorrhage

May increase risk of bleeding. If any bleeding event necessitates medical intervention, consider permanent discontinuation of sorafenib.

Hypertension

Treatment-emergent mild to moderate hypertension has been reported, usually early in the course of therapy.

Wound healing

Temporarily interrupt therapy in patients undergoing major surgical procedures.

Overdosage

Symptoms

No data available. Diarrhea and dermatologic events have been associated with dosages of 800 mg twice daily.

Patient Information

• Advise patient or caregiver to read patient information leaflet carefully before starting therapy, and to read and check for new information each time the medication is refilled.
• Advise patient that usual dosage is 2 tablets taken twice daily but that the dose may be reduced, or the medication temporarily withheld, if bothersome adverse reactions develop.
• Advise patient to take each dose with a full glass of water on an empty stomach, 1 h before or 2 h after eating. Caution patient to swallow tablets whole and not to chew, crush, or break.
• Advise patient that if a dose is missed to skip that dose and take the next dose at the regularly scheduled time. Caution patient not to take 2 doses at the same time to catch up.
• Advise patient that sorafenib can cause BP to become elevated and to check BP at least once a week for the first 6 wk of therapy and periodically thereafter. Advise patient that medications may be needed to control elevated BP.
• Instruct patient to immediately notify health care provider if any of the following occur: chest pain, chest pressure, or unexplained shortness of breath on exertion or with activity; redness, pain, swelling, or blistering of palms of hands or soles of feet; unexplained bleeding.
• Advise patient to notify health care provider if rash; persistent diarrhea; persistent nausea and/or vomiting; weakness; mouth sores; or numbness, tingling, or pain in hands or feet develops.
• Advise patient to use effective contraception during treatment and for 2 wk after stopping therapy.
• Caution women of childbearing potential to avoid becoming pregnant while using sorafenib and for 2 wk after stopping therapy.

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