Sorafenib tablets are a kinase inhibitor indicated for the treatment of
Unresectable hepatocellular carcinoma ( 1.1 )
Advanced renal cell carcinoma ( 1.2 )
Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment ( 1.3 )
1.1Hepatocellular Carcinoma
Sorafenib tablets are indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC).
1.2Renal Cell Carcinoma
Sorafenib tablets are indicated for the treatment of patients with advanced renal cell carcinoma (RCC).
1.3Differentiated Thyroid Carcinoma
Sorafenib tablets are indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) that is refractory to radioactive iodine treatment.
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 )
Warnings 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 are suspected. ( 5.4 )
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 )
5.1Cardiovascular Events In the SHARP
(HCC) study, the incidence of cardiac ischemia/infarction was 2.7% in sorafenib-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-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-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-treated patients (N = 2276) [see Adverse Reactions (6.2) ] . Consider temporary or permanent discontinuation of sorafenib in patients who develop cardiovascular events [see Dosage and Administration (2.2) ] .
5.2Hemorrhage
An increased risk of bleeding may occur following sorafenib 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-treated patients and those receiving placebo, respectively. In the TARGET (RCC) study, bleeding was reported in 15.3% of patients in the sorafenib-treated group and 8.2% of patients receiving placebo.
The incidence of Grade 3 and 4 bleeding was 2% and 0%, respectively, in sorafenib-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-treated patients and 9.6% of those receiving placebo; however, the incidence of Grade 3 bleeding was similar (1% and 1.4%) in sorafenib-treated patients and in those receiving placebo.
If any bleeding necessitates medical intervention, consider permanent discontinuation of sorafenib [see Dosage and Administration (2.2) ] . 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.
5.3Hypertension In the SHARP
(HCC) study, hypertension was reported in 9.4% of sorafenib-treated patients and 4.3% of patients receiving placebo. In the TARGET (RCC) study, hypertension was reported in 16.9% of sorafenib-treated patients and 1.8% of patients receiving placebo. In the DECISION (DTC) study, hypertension was reported in 40.6% of sorafenib-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-treated patients in the SHARP (HCC) study, 1 of 451 sorafenib-treated patients in the TARGET (RCC) study, and 1 of 207 sorafenib-treated patients in the DECISION (DTC) study. Monitor blood pressure weekly during the first 6 weeks of sorafenib. 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 [see Dosage and Administration (2.2) ] .
5.4Dermatologic Toxicities
Hand-foot skin reaction and rash represent the most common adverse reactions attributed to sorafenib. Rash and hand-foot skin reaction are usually Grade 1 and 2 and generally appear during the first six weeks of treatment with sorafenib. Permanent discontinuation of therapy due to hand-foot skin reaction occurred in 4 (1.3%) of 297 sorafenib-treated patients with HCC, 3 (0.7%) of 451 sorafenib-treated patients with RCC, and 11 (5.3%) of 207 sorafenib-treated patients with DTC.
Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose reduction of sorafenib, or in severe or persistent cases, permanent discontinuation of sorafenib [see Dosage and Administration (2.2) ] . 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 if SJS or TEN are suspected.
5.5Gastrointestinal Perforation
Gastrointestinal perforation has been reported in less than 1% of patients taking sorafenib. In some cases this was not associated with apparent intra-abdominal tumor. In the event of a gastrointestinal perforation, permanently discontinue sorafenib.
5.6Increased 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.
5.7Risk 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 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 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
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7.1Effect of Other Drugs on Sorafenib Strong CYP3A4 Inducers
The concomitant use of sorafenib with rifampin, a strong CYP3A4 inducer decreased the mean AUC of sorafenib, which may decrease the antitumor activity [see Clinical Pharmacology (12.3) ] . Avoid concomitant use of sorafenib with strong CYP3A4 inducers, when possible, because these drugs can decrease the systemic exposure to sorafenib. Neomycin The concomitant use of sorafenib with neomycin decreased the mean AUC of sorafenib, which may decrease the antitumor activity.
Avoid concomitant use of sorafenib with neomycin. The effects of other antibiotics on the pharmacokinetics of sorafenib have not been studied [see Clinical Pharmacology (12.3) ].
7.2Concomitant Use of Warfarin
The concomitant use of sorafenib 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 [see Warnings and Precautions (5.6) ].
7.3Drugs That Prolong the QT Interval
Sorafenib is associated with QTc interval prolongation. Avoid coadministration of sorafenib with medicinal products with a known potential to prolong QT/QTc interval [see Warnings and Precautions (5.9) , Clinical Pharmacology (12.2) ] .
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary Based
on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , sorafenib may cause fetal harm when administered to a pregnant woman. There are no available data in pregnant women to inform a drug-associated risk. In animal reproduction studies, oral administration of sorafenib to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal toxicities at maternal exposures that were significantly lower than human exposures at the recommended dose of 400 mg twice daily (see Data ) .
Advise pregnant women and females of reproductive potential of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In animal reproduction studies, sorafenib was teratogenic and induced embryo-fetal toxicity (including increased post-implantation loss, resorptions, skeletal retardations, and retarded fetal weight) when administered orally to pregnant rats and rabbits during the period of organogenesis.
The effects occurred at doses considerably below the recommended human dose of 400 mg twice daily (approximately 500 mg/m 2 /day on a body surface area basis). Adverse intrauterine development effects were seen at doses > 0.2 mg/kg/day (1.2 mg/m 2 /day) in rats and ≥ 0.3 mg/kg/day (≥ 3.6 mg/m 2 /day) in rabbits. These doses result in exposures (AUC) that are approximately 0.008 times the AUC in patients at the recommended dose.
Adverse reactions
The following clinically significant adverse reactions are discussed elsewhere in the labeling:
Cardiovascular events [see Warnings and Precautions (5.1) ]
Hemorrhage [see Warnings and Precautions (5.2) ]
Hypertension [see Warnings and Precautions (5.3) ]
Dermatologic toxicities [see Warnings and Precautions (5.4) ]
Gastrointestinal perforation [see Warnings and Precautions (5.5) ]
QT interval prolongation [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.2) ]
Drug-induced liver injury [see Warnings and Precautions (5.10) ]
Impairment of TSH suppression in DTC [see Warnings and Precautions (5.12) ] The most common adverse reactions (≥ 20%) are diarrhea, fatigue, infection, alopecia, hand-foot skin reaction, rash, weight loss, decreased appetite, nausea, gastrointestinal and abdominal pains, hypertension, and hemorrhage. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Viatris at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described reflect exposure to sorafenib in 955 patients who participated in placebo-controlled studies in hepatocellular carcinoma (N = 297), advanced renal cell carcinoma (N = 451), or differentiated thyroid carcinoma (N = 207).
The most common adverse reactions (≥ 20%), which were considered to be related to sorafenib, in patients with HCC, RCC or DTC are diarrhea, fatigue, infection, alopecia, hand-foot skin reaction, rash, weight loss, decreased appetite, nausea, gastrointestinal and abdominal pains, hypertension, and hemorrhage. Hepatocellular Carcinoma Table 4 shows the percentage of patients in the SHARP (HCC) study experiencing adverse reactions that were reported in at least 10% of patients and at a higher rate in the sorafenib-treated group than in those receiving placebo.
Table 4: Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in Sorafenib Tablets Arm than the Placebo Arm – SHARP (HCC) Sorafenib Tablets N = 297 Placebo N = 302 Adverse Reaction Adverse reactions graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0). All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Any Adverse Reaction 98 39 6 96 24 8 Gastrointestinal Diarrhea 55 10 < 1 25 2 0 Anorexia 29 3 0 18 3 < 1 Nausea 24 1 0 20 3 0 Vomiting 15 2 0 11 2 0 Constipation 14 0 0 10 0 0 Constitutional symptoms Fatigue 46 9 1 45 12 2 Weight loss 30 2 0 10 1 0 Pain Pain, abdomen 31 9 0 26 5 1 Dermatology/skin Hand-foot skin reaction 21 8 0 3 < 1 0 Rash/desquamation 19 1 0 14 0 0 Alopecia 14 0 0 2 0 0 Pruritus 14 < 1 0 11 < 1 0 Dry skin 10 0 0 6 0 0 Hepatobiliary/pancreas Liver dysfunction 11 2 1 8 2 1 Hypertension was reported in 9% of patients treated with sorafenib and 4% of those receiving placebo.
Grade 3 hypertension was reported in 4% of sorafenib-treated patients and 1% of those receiving placebo. Hemorrhage/bleeding was reported in 18% of those receiving sorafenib and 20% of patients receiving placebo. The rates of Grade 3 and 4 bleeding were also higher in patients receiving placebo (Grade 3 – 3% sorafenib and 5% placebo and Grade 4 – 2% sorafenib and 4% placebo). Bleeding from esophageal varices was reported in 2.4% in sorafenib-treated patients and 4% of patients receiving placebo.
Renal failure was reported in < 1% of patients treated with sorafenib and 3% of patients receiving placebo. Clinical pancreatitis was reported in 1 of 297 sorafenib-treated patients (Grade 2). The rate of adverse reactions (including those associated with progressive disease) resulting in permanent discontinuation was similar in both the sorafenib-treated patients and those receiving placebo (32% of sorafenib-treated patients and 35% of patients receiving placebo).
Laboratory test abnormalities reported in SHARP are presented in Table 5. Table 5: Laboratory Test Abnormalities Reported in SHARP (HCC) NR = not reported Laboratory Parameter Laboratory parameters graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0). Sorafenib Tablets N = 297 Placebo N = 302 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hypoalbuminemia 59 0 47 0 Elevated Lipase 40 9 37 9 Lymphopenia 47 NR 42 NR Thrombocytopenia 46 4 41 < 1 Elevated INR 42 4 34 2 Hypophosphatemia 35 11 11 2 Elevated Amylase 34 2 29 2 Hypocalcemia 27 2.4 15 1 Hypokalemia 10 < 1 6 < 1 Renal Cell Carcinoma Table 6 shows the percentage of patients in the TARGET (RCC) study experiencing adverse reactions that were reported in at least 10% of patients and at a higher rate in sorafenib-treated patients arm than in those receiving placebo.
The rate of adverse reactions (including those associated with progressive disease) resulting in permanent discontinuation was similar in both the sorafenib-treated patients and patients receiving placebo (10% and 8%, respectively). Clinical pancreatitis was reported in 3 of 451 sorafenib-treated patients (one Grade 2 and two Grade 4). Table 6: Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in Sorafenib Tablets Arm than the Placebo Arm – TARGET (RCC) Sorafenib Tablets N = 451 Placebo N = 451 Adverse Reaction Adverse reactions graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0).
Table 7: Laboratory Test Abnormalities Reported in TARGET (RCC) Laboratory Parameter Laboratory parameters graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0). Sorafenib Tablets N = 451 Placebo N = 451 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Hypophosphatemia 45 13 11 3 Anemia 44 2 49 4 Elevated Lipase 41 12 30 7 Elevated Amylase 30 1 23 3 Lymphopenia 23 13 13 7 Neutropenia 18 5 10 2 Thrombocytopenia 12 1 5 0 Hypocalcemia 12 2 8 <1 Hypokalemia 5 1 <1 <1 Differentiated Thyroid Carcinoma The safety of sorafenib was evaluated in DECISION in 416 patients with locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine (RAI) treatment randomized to receive 400 mg twice daily sorafenib (n = 207) or matching placebo (n = 209) until disease progression or intolerable toxicity in a double-blind trial [see Clinical Studies (14.3) ].
The data described below reflect a median exposure to sorafenib for 46 weeks (range 0.3 to 135). The population exposed to sorafenib was 50% male, and had a median age of 63 years. Dose interruptions for adverse reactions were required in 66% of patients receiving sorafenib and dose reductions were required in 64% of patients. Adverse reactions that resulted in treatment discontinuation were reported in 14% of sorafenib-treated patients compared t
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Composition
Active ingredients
SORAFENIB TOSYLATE EQ 200MG BASE
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
