1 INDICATIONS AND USAGE 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 ) 1.1 Hepatocellular Carcinoma Sorafenib tablets are indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC).

1.2 Renal Cell Carcinoma Sorafenib tablets are indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

1.3 Differentiated 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.

6 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.

6.1 Clinical 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).

All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Any Adverse Reactions 95 31 7 86 22 6 Gastrointestinal symptoms Diarrhea 43 2 0 13 < 1 0 Nausea 23 < 1 0 19 < 1 0 Anorexia 16 < 1 0 13 1 0 Vomiting 16 < 1 0 12 1 0 Constipation 15 < 1 0 11 < 1 0 Dermatology/skin Rash/desquamation 40 < 1 0 16 < 1 0 Hand-foot skin reaction 30 6 0 7 0 0 Alopecia 27 < 1 0 3 0 0 Pruritus 19 < 1 0 6 0 0 Dry skin 11 0 0 4 0 0 Constitutional symptoms Fatigue 37 5 < 1 28 3 < 1 Weight loss 10 < 1 0 6 0 0 Cardiovascular, General Hypertension 17 3 < 1 2 < 1 0 Hemorrhage/bleeding Hemorrhage – all sites 15 2 0 8 1 < 1 Pulmonary Dyspnea 14 3 < 1 12 2 < 1 Neurology Neuropathy-sensory 13 < 1 0 6 < 1 0 Pain Pain, abdomen 11 2 0 9 2 0 Pain, headache 10 < 1 0 6 < 1 0 Pain, joint 10 2 0 6 < 1 0 Laboratory test abnormalities reported in TARGET are presented in Table 7.

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 to 1.4% of patients receiving placebo.

Table 8 shows the percentage of DTC patients experiencing adverse reactions at a higher rate in sorafenib-treated patients than in patients receiving placebo in the double-blind phase of the DECISION study.

Grade 3 adverse reactions occurred in 53% of sorafenib-treated patients compared to 23% of patients receiving placebo.

Grade 4 adverse reactions occurred in 12% of sorafenib-treated patients compared to 7% of patients receiving placebo.

Table 8: Selected Adverse Reactions Occurring at a Higher Incidence in Sorafenib-Treated Patients [Between Arm Difference of ≥ 5% (All Grades) National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 or ≥ 2% (Grades 3 and 4)] Adverse Reaction Sorafenib Tablets N = 207 Placebo N = 209 All Grades (%) Grades 3 and 4 (%) All Grades (%) Grades 3 and 4 (%) Skin and subcutaneous tissue disorders PPES Palmar-plantar erythrodysesthesia syndrome (Hand-foot skin reaction) 69 19 8 0 Alopecia 67 0 8 0 Rash 35 5 7 0 Pruritus 20 0.5 11 0 Dry skin 13 0.5 5 0 Erythema 10 0 0.5 0 Hyperkeratosis 7 0 0 0 Gastrointestinal disorders Diarrhea 68 6 15 1 Stomatitis Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation 24 2 3 0 Nausea 21 0 12 0 Abdominal pain Includes the following terms: abdominal pain, abdominal discomfort, hepatic pain, esophageal pain, esophageal discomfort, abdominal pain lower, abdominal pain upper, abdominal tenderness, abdominal rigidity 20 1 7 1 Constipation 16 0 8 0.5 Oral pain Includes the following terms: oral pain, oropharyngeal discomfort, glossitis, burning mouth syndrome, glossodynia 14 0.5 6 0 Vomiting 11 0 3 0 Investigations Weight loss 49 6 14 1 General disorders and administration site conditions Fatigue 41 5 20 1 Asthenia 12 0 7 0 Pyrexia 11 1 5 0 Vascular disorders Hypertension Includes the following terms: hypertension, blood pressure increased, blood pressure systolic increased 41 10 12 2 Metabolism and nutrition disorders Decreased appetite 30 2 5 0 Nervous system disorders Headache 17 0 6 0 Dysgeusia 6 0 0 0 Musculoskeletal and connective tissue disorders Pain in extremity 15 1 7 0 Muscle spasms 10 0 3 0 Respiratory, thoracic and mediastinal disorders Dysphonia 13 0.5 3 0 Epistaxis 7 0 1 0 Neoplasms benign, malignant and unspecified Squamous cell carcinoma of skin 3 3 0 0 The relative increase for the following laboratory abnormalities observed in sorafenib-treated patients as compared to patients receiving placebo in the DECISION study is similar to that observed in the RCC and HCC studies: lipase, amylase, hypokalemia, hypophosphatemia, neutropenia, lymphopenia, anemia, and thrombocytopenia.

Hypocalcemia was more frequent and more severe in patients with DTC, especially those with a history of hypoparathyroidism, compared to patients with RCC or HCC.

Other laboratory test abnormalities reported in DECISION are presented in Table 9 Table 9: Laboratory Test Abnormalities Reported in DECISION (DTC) 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 = 207 Placebo N = 209 All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Elevated ALT 59 4 24 0 Elevated AST 54 2 15 0 Hypocalcemia 36 10 11 3 Additional Data from Multiple Clinical Trials The following additional drug-related adverse reactions and laboratory abnormalities were reported from clinical trials of sorafenib ( very common 10% or greater, common 1 to less than 10%, uncommon 0.1% to less than 1%, rare less than 0.1%): Cardiovascular: Common : congestive heart failure *† , myocardial ischemia and/or infarction Uncommon : hypertensive crisis* Rare : QT prolongation * Dermatologic: Very common : erythema Common : exfoliative dermatitis, acne, flushing, folliculitis, hyperkeratosis Uncommon : eczema, erythema multiforme Digestive: Very common : increased lipase, increased amylase Common : mucositis, stomatitis (including dry mouth and glossodynia), dyspepsia, dysphagia, gastrointestinal reflux Uncommon : pancreatitis, gastritis, gastrointestinal perforations * , cholecystitis, cholangitis Note that elevations in lipase are very common (41%, see below); a diagnosis of pancreatitis should not be made solely on the basis of abnormal laboratory values General Disorders: Very common : infection, hemorrhage (including gastrointestinal * and respiratory tract * and uncommon cases of cerebral hemorrhage * ), asthenia, pain (including mouth, bone, and tumor pain), pyrexia, decreased appetite Common : influenza-like illness Hematologic: Very common : leukopenia, lymphopenia Common : anemia, neutropenia, thrombocytopenia Uncommon : INR abnormal Hepatobiliary Disorders: Rare : drug-induced liver injury (including hepatic failure and death) Hypersensitivity: Uncommon : hypersensitivity reactions (including skin reactions and urticaria), anaphylactic reaction Metabolic and Nutritional: Very common : hypophosphatemia Common : transient increases in transaminases, hypocalcemia, hypokalemia, hyponatremia, hypothyroidism Uncommon : dehydration, transient increases in alkaline phosphatase, increased bilirubin (including jaundice), hyperthyroidism Musculoskeletal: Very common : arthralgia Common : myalgia, muscle spasms Nervous System and Psychiatric: Common : depression, dysgeusia Uncommon : tinnitus, reversible posterior leukoencephalopathy* Renal and Genitourinary: Common : renal failure, proteinuria Rare : nephrotic syndrome Reproductive: Common : erectile dysfunction Uncommon : gynecomastia Respiratory: Common : rhinorrhea Uncommon : interstitial lung disease-like events (includes reports of pneumonitis, radiation pneumonitis, acute respiratory distress, interstitial pneumonia, pulmonitis and lung inflammation) In addition, the following medically significant adverse reactions were uncommon during clinical trials of sorafenib: transient ischemic attack, arrhythmia, and thromboembolism.

For these adverse reactions, the causal relationship to sorafenib has not been established.

* adverse reactions may have a life-threatening or fatal outcome.

† reported in 1.9% of patients treated with sorafenib (N = 2276).

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of sorafenib.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and Lymphatic Disorders: Thrombotic microangiopathy (TMA) Dermatologic: Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) Hypersensitivity: Angioedema Musculoskeletal: Rhabdomyolysis, osteonecrosis of the jaw Respiratory: Interstitial lung disease-like events (which may have a life-threatening or fatal outcome) Vascular: Arterial (including aortic) aneurysms, dissections, and rupture