Sorafenib

FDA Drug Information • Also known as: Nexavar, Sorafenib, Sorafenib Tosylate

Brand Names: Nexavar, Sorafenib, Sorafenib Tosylate
Drug Class: Kinase Inhibitor [EPC]
Route: ORAL
Dosage Form: TABLET, FILM COATED
Product Type: HUMAN PRESCRIPTION DRUG

Description

DESCRIPTION Sorafenib, a kinase inhibitor, is the tosylate salt of sorafenib. Sorafenib tosylate has the chemical name 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)N2-methylpyridine-2-carboxamide 4 methylbenzenesulfonate. The molecular formula of sorafenib tosylate is C21H16ClF3N4O3 x C7H8O3S and the molecular weight of sorafenib tosylate is 637.0 g/mole. Its structural formula is: : Sorafenib tosylate is a white to yellowish or brownish solid. Sorafenib tosylate is practically insoluble in aqueous media, slightly soluble in ethanol and soluble in PEG 400. Sorafenib Tablets, USP for oral use is supplied as film-coated tablets containing 200 mg sorafenib equivalent to 274 mg sorafenib tosylate and the following inactive ingredients: croscarmellose sodium, ferric oxide red, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium lauryl sulphate, and titanium dioxide. FDA approved dissolution test specifications differ from USP. structural formula of Sorafenib tosylate

What Is Sorafenib Used For?

Sorafenib tablets are a kinase inhibitor indicated for the treatment of Unresectable hepatocellular carcinoma(1.1) 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). 1.3 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.

Dosage and Administration

2.1 Recommended Dosage The recommended dosage of sorafenib tablets is 400 mg orallytwice daily without food (at least 1 hourbefore or 2 hours after a meal) until the patient is no longer clinically benfiting from therapy or until unacceptable toxicity.

The recommended dosage is 400 mg orally twice daily without food. (2.1) 2.2 Dose Modifications for Adverse Reactions Recommended Dosage Modifications The recommended dosage modifications for adverse reactions are provided in Tables 1, 2, and 3. Table 1: Recommended Dose Reductions forAdverse Reactions Dose Reduction Hepatocellular Carcinoma Differentiated Thyroid Carcinoma First Dose Reduction 400 mg orally once daily 400 mg orally in the morning and 200 mg orally in the evening about 12 hours apart OR 200 mg orally in the morning and 400 mg orally in the evening about 12 hours apart Second Dose Reduction 200 mg orally once daily OR 400 every other day 200 mg orally twice daily Third Dose Reduction None 200 mg orally once daily Table 2: Recommended Dosage Modifications of Sorafenib Tablets for Adverse Reactions Adverse Reaction Severity 1 Sorafenib T ablets Dosage M odification Cardiovascular Events [see Warnings and Precautions (5.1)] Cardiac Ischemia and/or Infarction Grade 2 and above Permanently discontinue. Congestive Heart Failure Grade 3 Interrupt2 until Grade 1 or less, resume at reduced dose by 1 dose level.3 Grade 4 Permanently discontinue. Hemorrhage [see Warnings and Precautions (5.2)] Grade 2 and above requiring medical intervention Permanently discontinue. Hypertension [see Warnings and Precautions (5.3)] Grade 2 (symptomatic/persistent) OR Grade 2 symptomatic increase by greater than 20 mm Hg (diastolic) or greater than 140/90 mm Hg if previously within normal limits OR Grade 3 Interrupt until symptoms resolve and diastolic blood pressure less than 90 mm Hg, then resume at reduced dose by 1 dose level.3 If needed, reduce another dose level.3 Grade 4 Permanently discontinue. G astrointestinal Perforation [see Warnings and Precautions (5.5)] Any grade Permanently discontinue. QT Interval Prolongation [see Warnings and Precautions (5.9)] Greater than 500 milliseconds OR Increase from baseline of 60 milliseconds or greater Interrupt and correct electrolyte abnormalities (magnesium, potassium, calcium). Use medical judgement before restarting. Drug-Induced Liver Injury [see Warnings and Precautions (5.10)] Grade 3 ALT or higher in the absence of another cause4 OR AST/ALT greater than 3 × upper limit normal (ULN) with bilirubin greater than 2 × ULN in the absence of another cause4 Permanently discontinue. Non-hematological toxicities [see Adverse Reactions (6.1)] Grade 2 Continue treatment at reduced dose by 1 dose level. Grade 3 1st occurrence Interrupt until Grade 2 or less, then resume at reduced dose by 1 dose level. No improvement within 7 days OR 2nd or 3rd occurrence Interrupt until Grade 2 or less, then resume at reduced dose by 2 dose levels. 4th occurrence Interrupt until Grade...

Side Effects (Adverse Reactions)

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 Upsher-Smith Laboratories, LLC at 1-855-899-9180 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 tablets in 504 patients who participated in placebo-controlled studies in hepatocellular carcinoma N=297), or differentiated thyroid carcinoma (N = 207). The most common adverse reactions (≥20%), which were considered to be related to sorafenib tablets, in patients with HCC 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 Tablets -treated group than in those eceiving 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) Adverse Reaction 1 Sorafenib Tablets N = 297 Placebo N = 302 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 1Adverse reactions graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI CTCAE v3.0). Hypertension was reported in 9% of patients treated with sorafenib tablets and 4% of those receiving placebo. Grade 3 hypertension was reported in 4% of sorafenib tablets -treated patients and 1% of those receiving placebo. Hemorrhage/bleeding was reported in 18% of those receiving sorafenib tablets 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 tablets and 5% placebo and Grade 4 – 2% sorafenib tablets and 4% placebo). Bleeding from esophageal varices was reported in 2.4% in sorafenib tablets -treated patients and 4% of patients receiving placebo. Renal failure was reported in <1% of patients treated with sorafenib tablets and 3% of patients receiving placebo. Clinical pancreatitis was reported in 1 of 297 sorafenib tablets -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...

Drug Interactions

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 [see Clinical Pharmacology (12.3)]. 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 [see Warnings and Precautions (5.6)]. 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 [see Warnings and Precautions (5.9), Clinical Pharmacology (12.2)]. 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 [see Clinical Pharmacology (12.3)].

Contraindications

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 is contraindicated in patients with squamous cell lung cancer. (4) 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)].

Overdosage

OVERDOSAGE The adverse reactions observed at a dose of 800 mg twice daily (2 times the recommended dose) were primarily diarrhea and dermatologic. No information is available on symptoms of acute overdose in animals because of the saturation of absorption in oral acute toxicity studies conducted in animals. In cases of suspected overdose, withhold sorafenib tablets and institute supportive care.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING Sorafenib Tablets, USP are supplied as round, pink, film-coated tablets, debossed with “YB” on one side and “201” on the other side. Bottles of 120 tablets NDC 24979-715-44 Bottles of 60 tablets NDC 24979-715-04 Store at 20 to 25°C (68 to 77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP controlled room temperature]. Store in a dry place.

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.