Sorafenib

Increased risk of bleeding may occur; consider permanently discontinuing with serious bleeding events (eg, requires medical intervention). Fatal bleeding events have been reported. Thyroid cancer patients with tracheal, bronchial, and esophageal infiltration should be treated with local therapy prior to administering sorafenib due to the potential bleeding risk.

May cause cardiac ischemia or infarction; consider discontinuation (temporary or permanent) in patients who develop these conditions. Use in patients with unstable coronary artery disease or recent myocardial infarction has not been studied.

Hand-foot skin reaction and rash (generally grades 1 or 2) are the most common drug-related adverse events, and typically appear within the first 6 weeks of treatment; usually managed with topical treatment, treatment delays, and/or dose reductions. Consider permanently discontinuing with severe or persistent dermatological toxicities. The risk for hand-foot skin reaction increased with cumulative doses of sorafenib (Azad 2009). Severe dermatologic toxicities, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported; may be life-threatening. Discontinue sorafenib for suspected SJS or TEN. The following treatments may be used to manage hand-foot skin reaction in addition to the recommended dosage modifications (Lacouture 2008): Prior to treatment initiation, a pedicure is recommended to remove hyperkeratotic areas/calluses, which may predispose to HFSR; avoid vigorous exercise/activities which may stress hands or feet. During therapy, patients should reduce exposure to hot water (may exacerbate hand-foot symptoms); avoid constrictive footwear and excessive skin friction. Patients may also wear thick cotton gloves or socks and should wear shoes with padded insoles. Grade 1 HFSR may be relieved with moisturizing creams, cotton gloves and socks (at night) and/or keratolytic creams such as urea (20% to 40%) or salicylic acid (6%). Apply topical steroid (eg, clobetasol ointment) twice daily to erythematous areas of grade 2 HFSR; topical anes

Gastrointestinal perforation has been reported (rare); monitor patients for signs/symptoms (abdominal pain, constipation, or vomiting); discontinue treatment if gastrointestinal perforation occurs.

May cause hypertension (generally mild-to-moderate), especially in the first 6 weeks of treatment; monitor. Use caution in patients with underlying or poorly-controlled hypertension. Consider discontinuing (temporary or permanent) in patients who develop severe or persistent hypertension while on appropriate antihypertensive therapy.

QT prolongation has been observed; may increase the risk for ventricular arrhythmia. Avoid use in patients with congenital long QT syndrome. Monitor electrolytes and ECG in patients with heart failure, bradyarrhythmias, and concurrent medications know to prolong the QT interval. Correct electrolyte (calcium, magnesium, potassium) imbalances. Interrupt treatment for QTc interval >500 msec or for ≥60 msec increase from baseline.

Sorafenib impairs exogenous thyroid suppression. TSH level elevations were commonly observed in the thyroid cancer study; monitor TSH levels monthly and as clinically necessary, and adjust thyroid replacement as needed.

May complicate wound healing; temporarily withhold treatment for patients undergoing major surgical procedures. The appropriate timing to resume sorafenib after major surgery has not been determined. Disease-related concerns:

In a scientific statement from the American Heart Association, sorafenib has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: minor) (AHA [Page 2016]).

Sorafenib levels in patients with mild-to-moderate hepatic impairment (Child-Pugh classes A and B) were similar to levels observed in patients without hepatic impairment. Not studied in patients with severe hepatic impairment (Child-Pugh class C). In a small study of Asian patients with advanced HCC, sorafenib demonstrated efficacy with adequate tolerability in a hepatitis B-endemic area (Yau 2009). There have been reports of sorafenib-induced hepatitis (including hepatic failure and death) which is characterized by hepatocellular liver damage and transaminase increases (significant); increased bilirubin and INR may also occur. Monitor hepatic function regularly; discontinue sorafenib for unexplained significant transaminase increases. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Avoid concurrent use with strong CYP3A4 inducers (eg, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, St John’s wort); may decrease sorafenib levels/effects. Use caution when administering sorafenib with compounds that are metabolized predominantly via UGT1A1 (eg, irinotecan). The incidence of hand-foot skin reaction is increased in patients treated with sorafenib plus bevacizumab in comparison to those treated with sorafenib monotherapy (Azad 2009). Use in combination with carboplatin and paclitaxel in patients with squamous cell lung cancer is contraindicated. Monitor PT/INR in patients on warfarin therapy due to potential for bleeding events to occur.