sorafenib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: kinase inhibitors

High Alert

Advanced renal cell carcinoma.
Unresectable hepatocellular carcinoma.
Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine therapy.

Inhibits tumor growth by inhibiting multikinase enzyme, some of which are involved in angiogenesis.

Therapeutic effects:

Decreased growth and spread of advanced renal cell carcinoma, hepatocellular carcinoma, and differentiated thyroid carcinoma.

Absorption: 38–49% absorbed following oral administration; absorption ↓ by high-fat meals.

Distribution: Unknown.

Protein Binding: 99.5%.

Metabolism/Excretion: Primarily metabolized by the liver via the CYP3A4 isoenzyme and UGT1A9; some metabolites are pharmacologically active. Primarily excreted in feces (77%), with 51% being excreted as unchanged drug. 19% excreted in urine, primarily as metabolites.

Half-Life: 25–48 hr.

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	3 hr	12 hr

Contraindicated in:

Hypersensitivity;
Concurrent use with carboplatin and paclitaxel in patients with squamous cell lung cancer;
Congenital long QT syndrome;
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

History of cardiovascular disease;
HF, bradycardia, concurrent use of QT interval prolonging drugs, or electrolyte abnormalities (↑ risk of QT interval prolongation);
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children.

Drug-drug:

May ↑ risk of bleeding with warfarin.
CYP3A4 inducers, including rifampin, phenytoin, phenobarbital, carbamazepine, and dexamethasone, may ↓ levels and effectiveness.
Irinotecan, docetaxel, and doxorubicin may ↑ levels and risk of toxicity.
Neomycin may ↓ levels.

Drug-Natural Products:

St. John's wort may ↓ levels and effectiveness.

PO (Adults ): 400 mg twice daily until disease progression or unacceptable toxicity.

(Generic available)

Tablets: 200 mg

Monitor BP weekly during first 6 wk and then periodically during therapy. May cause hypertension. If Grade 2 (symptomatic/persistent) OR Grade 2 symptomatic increase by >20 mm Hg (diastolic) or >140/90 mm Hg if previously within normal limits OR Grade 3 hypertension occurs, hold sorafenib until symptoms resolve and diastolic BP <90 mm Hg; then resume at reduced dose by 1 dose level. If needed, reduce another dose level. If Grade 4 hypertension occurs, discontinue sorafenib permanently.
Monitor ECG in patients with HF, bradyarrhythmias, drugs known to prolong the QT interval, and electrolyte abnormalities. If Grade 3 HF occurs, hold sorafenib until Grade 1 or less; resume at reduced dose by 1 dose level. If Grade 4 HF occurs, permanently discontinue sorafenib. If QT interval >500 milliseconds OR increase from baseline of ≥60 milliseconds occurs, hold therapy and correct electrolyte abnormalities (magnesium, potassium, calcium). Consider condition of patient before restarting.
Assess for dermatologic toxicities. Treat any occurrence of Grade 1 (numbness, dysesthesia, paresthesia, tingling, painless swelling, erythema or discomfort of hands or feet that does not disrupt patient's normal activities) with topical symptomatic therapy. Treat the first occurrence of Grade 2 (painful erythema and swelling of hands or feet and/or discomfort affecting patient's normal activities) for patients with hepatocellular and renal cell carcinoma, with topical symptomatic therapy. If no improvement in 7 days or 2nd or 3rd occurrence, hold sorafenib therapy until resolves to Grade 0–1. Resume treatment with decreasing dose by one level. If 4th occurrence, discontinue therapy. For patients with hepatocellular and renal cell carcinoma,decrease sorafenib to 600 mg daily. If no improvement within 7 days at reduced dose OR 2nd and 3rd occurrence, for patients with hepatocellular and renal cell carcinoma,hold sorafenib until resolved to Grade 0 or 1. Resume therapy with decrease by 1 dose level. For patients with differentiated thyroid carcinoma,hold sorafenib until completely resolved or improved to Grade 1. When resuming therapy, decrease dose by 1 dose level for 2nd occurrence and 2 doses levels for 3rd occurrence. For 4th occurrence, discontinue sorafenib. If Grade 3 toxicity (moist desquamation, ulceration, blistering or severe pain of the hands or feet, or severe discomfort that causes the patient to be unable to work or perform activities of daily living) occurs, for 1st occurrence, for patients with hepatocellular and renal cell carcinoma,hold sorafenib therapy until resolves to Grade 0–1. Resume therapy by decreasing dose by one level. If 3rd occurrence, discontinue sorafenib therapy. For patients with differentiated thyroid carcinoma, hold sorafenib until completely resolved or improved to Grade 1. Resume therapy by decreasing dose by 1 dose level. For second occurrence, for patients with hepatocellular and renal cell carcinoma, hold sorafenib until resolved or improved to Grade 0 or 1. Resume therapy by decreasing dose by 1 dose level. For patients with differentiated thyroid carcinoma, hold sorafenib until completely resolved or improved to Grade 1. Resume therapy by decreasing dose by 2 dose levels. If 3rd occurrence, discontinue sorafenib.
Monitor for bleeding. If Grade 2 and above hemorrhage requiring medical intervention occurs, permanently discontinue sorafenib.
Assess for chest pain. If cardiac ischemia or MI occur at Grade 2 and above, permanently discontinue sorafenib.
Monitor for signs and symptoms of interstitial lung diseases (dyspnea, cough).

Lab Test Considerations:

Verify a negative pregnancy test before starting therapy.Monitor serum magnesium, potassium, and calcium periodically in patients with HF, bradyarrhythmias, and drugs known to prolong QT interval. May cause hypocalcemia and hypokalemia.
- May cause liver injury. Monitor liver function regularly during therapy. If AST and ALT significantly ↑ without alternative explanation (viral hepatitis, progressing underlying malignancy), discontinue sorafenib.
- May ↑ TSH in patients with differentiated thyroid carcinoma. Monitor TSH levels monthly.
- Commonly causes hypophosphatemia and ↑ serum lipase and amylase. Pancreatitis rarely occurs.
- Frequently causes lymphopenia, anemia, and thrombocytopenia.

Do not confuse Nexavar with Nexium. Do not confuse sorafenib with sunitinib.
May impair wound healing. Hold sorafenib for at least 10 days prior to elective surgery. Do not administer for at least 2 wk following major surgery and until adequate wound healing.
PO: Administer on an empty stomach, at least 1 hr before or 2 hr after eating. DNC: Tablets should be swallowed whole and taken with water; do not crush, break, or chew.
- If dose reduction is necessary due to adverse reactions, ↓ to 400 mg once daily. If additional dose reduction is required, ↓ to 400 mg every other day.

Instruct patient to take sorafenib as directed. If a dose is missed, skip dose and take next dose at regular time; do not double dose. Do not share medication with others; may be harmful. Advise patient to read Patient Information before starting therapy and with each Rx refill in case of changes.
Inform patient of risk of hand-foot skin reactions, hypertension, and requirement for monitoring risk of bleeding and cardiac ischemia. Advise patient to notify health care professional promptly if bleeding or chest pain occurs.
Advise patient to notify health care professional immediately if signs and symptoms of hepatotoxicity (yellow skin or white part of eyes, dark tea-colored urine, light-colored bowel movements, worsening nausea, worsening vomiting, abdominal pain), rash, blistering or peeling of skin or inside of mouth, shortness of breath, cough, dizziness, fainting, or fever occur.
Advise patient to notify health care professional of therapy prior to treatment, dental procedure, or surgery. Sorafenib therapy should be interrupted in patients undergoing major surgery.
Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new medications, especially St. John's wort.
Discuss with patient the possibility of hair loss. Explore coping strategies.
Rep: May cause fetal harm. Advise females of reproductive potential to use effective contraception during and for 6 mo after stopping therapy. Advise males with female partners of reproductive potential to use effective contraception during and for 3 mo after last dose. Advise female patients to avoid breastfeeding during and for 2 wk after last dose of therapy. May impair female and male fertility.

Decreased growth and spread of advanced renal cell, hepatocellular, and thyroid carcinoma.

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