A-Z Drug Facts > Sorafenib

Sorafenib

Pronouncation: (sore-ah-FEE-nib)
Class: Multikinase inhibitor

Trade Names:
Nexavar
- Tablets 200 mg

Pharmacology

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Decreases tumor cell proliferation in vitro.

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 UGTiA9-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

Race

Compared with white patients, Japanese patients showed 45% lower systemic exposure following administration of sorafenib 400 mg twice daily.

Indications and Usage

Treatment of advanced renal cell 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 dose may be reduced to 400 mg once daily; if additional dose reduction is required, may reduce 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 in 7 days, interrupt treatment until toxicity resolves to grade 0 to 1. When resuming treatment, decrease dose 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 dose 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 dose 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

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

Doxorubicin

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

Drugs metabolized by UGT1A1 (eg, irinotecan)

Use with caution.

Warfarin

Infrequent bleeding events and elevated INR have been reported.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypertension (17%).

CNS

Fatigue (37%); sensory neuropathy (13%); headache (10%); asthenia (at least 10%); depression, pyrexia (1% to less than 10%).

Dermatologic

Rash/desquamation (40%); hand-food skin reaction (35%); alopecia (27%); pruritus (19%); dry skin (11%); erythema (at least 10%); acne, exfoliative dermatitis, flushing (1% to less than 10%).

GI

Diarrhea (43%); nausea (23%); anorexia, 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

Hemorrhage (15%); leukopenia (at least 10%); anemia, neutropenia, thrombocytopenia (1% to less than 10%).

Lab Tests

Hypophosphatemia (45%); anemia (44%); elevated lipase (41%); elevated amylase (30%); lymphopenia (23%); neutropenia (18%); thrombocytopenia (12%).

Metabolic-Nutritional

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

Musculoskeletal

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

Respiratory

Dyspnea (14%); cough (13%); hoarseness (1% to less than 10%).

Miscellaneous

Abdominal pain (11%); pain (at least 10%); influenza-like illness (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 A and B hepatic impairment. Sorafenib has not been studied in patients with Child-Pugh C hepatic 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 most common adverse effects.

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 doses 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 dose is 2 tablets taken twice daily but that the dose may be reduced, or the medication temporarily withheld, if bothersome side effects 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.
• Instruct patient not to change the dose or stop taking unless advised by health care provider.
• 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 develop.
• Advise patients 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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