SORAFENIB Drug Interactions: What You Need to Know

Strong CYP3A Inducers: Avoid strong CYP3A4 inducers.(7.1)

7.1 Effect of Other Drugs on Sorafenib Tablets Strong CYP3A4 Inducers The concomitant use of sorafenib tablets with rifampin, a strong CYP3A4 inducer decreased the mean AUC of sorafenib, which may decrease the antitumor activity <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span>. Avoid concomitant use of sorafenib tablets with strong CYP3A4 inducers, when possible, because these drugs can decrease the systemic exposure to sorafenib.

Neomycin

The concomitant use of sorafenib tablets with neomycin decreased the mean AUC of sorafenib, which may decrease the antitumor activity. Avoid concomitant use of sorafenib tablets with neomycin. The effects of other antibiotics on the pharmacokinetics of sorafenib have not been studied [see Clinical Pharmacology (12.3)].

7.2 Concomitant Use of Warfarin The concomitant use of sorafenib tablets and warfarin may increase the risk of bleeding or increased the INR. Monitor INR and for clinical bleeding episodes in patients taking warfarin while receiving sorafenib tablets <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6)]</span>.

7.3 Drugs That Prolong the QT Interval Sorafenib tablets are associated with QTc interval prolongation. Avoid coadministration of sorafenib tablets with medicinal products with a known potential to prolong QT/QTc interval <span class="opacity-50 text-xs">[see Warnings and Precautions (5.9), Clinical Pharmacology (12.2)]</span>.

8.7 Hepatic Impairment No dose adjustment is necessary for patients with mild or moderate hepatic impairment. The pharmacokinetics of sorafenib have not been studied in patients with severe (Child-Pugh C) hepatic impairment <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span>.

4 CONTRAINDICATIONS

• Sorafenib tablets are contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of sorafenib tablets.
• Sorafenib tablets in combination with carboplatin and paclitaxel are contraindicated in patients with squamous cell lung cancer [see Warnings and Precautions (5.8) ] .
• Sorafenib tablets are contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of sorafenib tablets. ( 4 )
• Sorafenib tablets in combination with carboplatin and paclitaxel are contraindicated in patients with squamous cell lung cancer. ( 4 )

AND PRECAUTIONS

• Cardiovascular Events : Consider temporary or permanent discontinuation of sorafenib tablets. ( 2.2 , 5.1 )
• Hemorrhage: Discontinue sorafenib tablets if needed. ( 5.2 )
• Hypertension: Monitor blood pressure weekly during the first 6 weeks and periodically thereafter. Consider temporary or permanent discontinuation for severe or persistent hypertension despite antihypertensive therapy. ( 5.3 )
• Dermatologic Toxicities : Interrupt and/or decrease dose. Discontinue for severe or persistent reactions, or if Stevens-Johnson syndrome and toxic epidermal necrolysis is suspected. ( 5.4 )
• Gastrointestinal Perforation : Discontinue sorafenib tablets. ( 5.5 )
• Risk of Impaired Wound Healing : Withhold sorafenib tablets for at least 10 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of Sorafenib tablets after resolution of wound healing complications has not been established. ( 5.7 )
• QT Prolongation : Monitor electrocardiograms and electrolytes in patients at increased risk for ventricular arrhythmias. Correct electrolytes. Interrupt if QTc greater than 500 msec or increases greater than 60 msec from baseline. ( 2.2 , 5.9 , 12.2 )
• Drug-Induced Liver Injury : Monitor liver function tests regularly; discontinue for unexplained transaminase elevations. ( 5.10 )
• Embryo-Fetal Toxicity : Sorafenib may cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.11 , 8.1 , 8.3 )
• Impairment of Thyroid Stimulating Hormone Suppression (TSH) in DTC : Monitor TSH monthly and adjust thyroid replacement therapy in patients with thyroid cancer. ( 5.12 )

5.1 Cardiovascular Events In the SHARP (HCC) study, the incidence of cardiac ischemia/infarction was 2.7% in sorafenib tablets-treated patients compared with 1.3% in those receiving placebo; in the TARGET (RCC) study, the incidence of cardiac ischemia/infarction was higher in the sorafenib tablets-treated group (2.9%) compared with patients receiving placebo (0.4%), and in the DECISION (DTC) study, the incidence of cardiac ischemia/infarction was 1.9% in the sorafenib tablets-treated group compared with 0% in patients receiving placebo. Patients with unstable coronary artery disease or recent myocardial infarction were excluded from this study. In multiple clinical trials, congestive heart failure has been reported in 1.9% of sorafenib tablets-treated patients (N=2,276) <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . Consider temporary or permanent discontinuation of sorafenib tablets in patients who develop cardiovascular events <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span>.

5.2 Hemorrhage An increased risk of bleeding may occur following sorafenib tablets administration. In the SHARP (HCC) study, the rates of bleeding from esophageal varices (2.4% and 4%) and of bleeding with a fatal outcome from any site (2.4% and 4%) were similar in sorafenib tablets-treated patients and those receiving placebo, respectively . In the TARGET (RCC) study, bleeding was reported in 15.3% of patients in the sorafenib tablets-treated group and 8.2% of patients receiving placebo. The incidence of Grade 3 and 4 bleeding was 2% and 0%, respectively, in sorafenib tablets-treated patients, and 1.3% and 0.2%, respectively, in those receiving placebo. There was one fatal hemorrhage in each treatment group in the TARGET (RCC) study. In the DECISION (DTC) study, bleeding was reported in 17.4% of sorafenib tablets-treated patients and 9.6% of those receiving placebo; however, the incidence of Grade 3 bleeding was similar (1% and 1.4%) in sorafenib tablets-treated patients and in those receiving placebo. If any bleeding necessitates medical intervention, consider permanent discontinuation of sorafenib tablets <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> . Due to the potential risk of bleeding, treat tracheal, bronchial, and esophageal infiltration with local therapy prior to administering sorafenib tablets in patients with DTC.

5.3 Hypertension In the SHARP (HCC) study, hypertension was reported in 9.4% of sorafenib tablets-treated patients and 4.3% of patients receiving placebo. In the TARGET (RCC) study, hypertension was reported in 16.9% of sorafenib tablets-treated patients and 1.8% of patients receiving placebo. In the DECISION (DTC) study, hypertension was reported in 40.6% of sorafenib tablets-treated patients and 12.4% of patients receiving placebo. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was managed with standard antihypertensive therapy. Permanent discontinuation due to hypertension occurred in 1 of 297 sorafenib tablets-treated patients in the SHARP (HCC) study, 1 of 451 sorafenib tablets-treated patients in the TARGET (RCC) study, and 1 of 207 sorafenib tablets-treated patients in the DECISION (DTC) study. Monitor blood pressure weekly during the first 6 weeks of sorafenib tablets. Thereafter, monitor blood pressure and treat hypertension, if required, in accordance with standard medical practice. In cases of severe or persistent hypertension despite institution of antihypertensive therapy, consider temporary or permanent discontinuation of sorafenib tablets <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> .

5.4 Dermatologic Toxicities Hand-foot skin reaction and rash represent the most common adverse reactions attributed to sorafenib tablets. Rash and hand-foot skin reaction are usually Grade 1 and 2 and generally appear during the first six weeks of treatment with sorafenib tablets. Permanent discontinuation of therapy due to hand-foot skin reaction occurred in 4 (1.3%) of 297 sorafenib tablets-treated patients with HCC, 3 (0.7%) of 451 sorafenib tablets-treated patients with RCC, and 11 (5.3%) of 207 sorafenib tablets-treated patients with DTC. Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose reduction of sorafenib tablets, or in severe or persistent cases, permanent discontinuation of sorafenib tablets <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> . There have been reports of severe dermatologic toxicities, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These cases may be life-threatening. Discontinue sorafenib tablets if SJS or TEN are suspected.

5.5 Gastrointestinal Perforation Gastrointestinal perforation has been reported in less than 1% of patients taking sorafenib tablets. In some cases this was not associated with apparent intra-abdominal tumor. In the event of a gastrointestinal perforation, permanently discontinue sorafenib tablets.

5.6 Increased Risk of Bleeding with Concomitant Use of Warfarin Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on sorafenib. Monitor patients taking concomitant warfarin regularly for changes in prothrombin time (PT), INR or clinical bleeding episodes.

5.7 Risk of Impaired Wound Healing Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, sorafenib has the potential to adversely affect wound healing. Withhold sorafenib tablets for at least 10 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of sorafenib tablets after resolution of wound healing complications has not been established.

5.8 Increased Mortality Observed with Sorafenib Administered in Combination with Carboplatin/Paclitaxel and Gemcitabine/Cisplatin in Squamous Cell Lung Cancer In a subset analysis of two randomized controlled trials in chemo-naive patients with Stage IIIB-IV non- small cell lung cancer, patients with squamous cell carcinoma experienced higher mortality with the addition of sorafenib compared to those treated with carboplatin/paclitaxel alone (HR 1.81; 95% CI 1.19, 2.74) and gemcitabine/cisplatin alone (HR 1.22; 95% CI 0.82, 1.80). The use of sorafenib in combination with carboplatin/paclitaxel is contraindicated in patients with squamous cell lung cancer. Sorafenib in combination with gemcitabine/cisplatin is not recommended in patients with squamous cell lung cancer. The safety and effectiveness of sorafenib has not been established in patients with non-small cell lung cancer.

5.9 QT Interval Prolongation Sorafenib can prolong the QT/QTc interval. QT/QTc interval prolongation increases the risk for ventricular arrhythmias. Avoid sorafenib tablets in patients with congenital long QT syndrome. Monitor electrolytes and electrocardiograms in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Correct electrolyte abnormalities (magnesium, potassium, calcium). Interrupt sorafenib tablets if QTc interval is greater than 500 milliseconds or for an increase from baseline of 60 milliseconds or greater <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> .

5.10 Drug-Induced Liver Injury Sorafenib-induced hepatitis is characterized by a hepatocellular pattern of liver damage with significant increases of transaminases which may result in hepatic failure and death. Increases in bilirubin and INR may also occur. The incidence of severe drug-induced liver injury, defined as elevated transaminase levels above 20 times the upper limit of normal or transaminase elevations with significant clinical sequelae (for example, elevated INR, ascites, fatal, or transplantation), was two of 3,357 patients (0.06%) in a global monotherapy database. Monitor liver function tests regularly. In case of significantly increased transaminases without alternative explanation, such as viral hepatitis or progressing underlying malignancy, discontinue sorafenib tablets <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span>.

5.11 Embryo-Fetal Toxicity Based on its mechanism of action and findings in animals, sorafenib tablets may cause fetal harm when administered to a pregnant woman. Sorafenib caused embryo-fetal toxicities in animals at maternal exposures that were significantly lower than the human exposures at the recommended dose of 400 mg twice daily. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of sorafenib tablets. Advise male patients with female partners of reproductive potential and pregnant partners to use effective contraception during treatment and for 3 months following the last dose of sorafenib tablets <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 )]</span>.

5.12 Impairment of Thyroid Stimulating Hormone Suppression in Differentiated Thyroid Carcinoma Sorafenib impairs exogenous thyroid suppression. In the DECISION (DTC) study, 99% of patients had a baseline thyroid stimulating hormone (TSH) level less than 0.5 mU/L. Elevation of TSH level above 0.5 mU/L was observed in 41% of sorafenib tablets-treated patients as compared with 16% of those receiving placebo patients. For patients with impaired TSH suppression while receiving sorafenib, the median maximal TSH was 1.6 mU/L and 25% had TSH levels greater than 4.4 mU/L. Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC.