Sorafenib Tosylate

Hepatocellular Carcinoma

Treatment of unresectable hepatocellular carcinoma (designated an orphan drug by FDA for this use).1 3 18 20 21 22

Renal Cell Carcinoma

Treatment of advanced renal cell carcinoma (designated an orphan drug by FDA for this use).1 3 4 5 14 15 16 17

General

• Monitor BP weekly during the first 6 weeks of therapy; thereafter, monitor and treat, if required, in accordance with established medical practice.1 (See Hypertension under Cautions.)

Administration

Oral Administration

Administer ≥1 hour before or 2 hours after a meal, since administration with a high-fat meal may decrease oral bioavailability.1

Dosage

Available as sorafenib tosylate; dosage expressed in terms of sorafenib.1

Adults

400 mg twice daily.1

Continue therapy for as long as the patient derives clinical benefit from the drug or until unacceptable toxicity occurs.1

400 mg twice daily.1 2 4 5 15

Continue therapy for as long as the patient derives clinical benefit from the drug or until unacceptable toxicity occurs.1

Dosage may be reduced or therapy temporarily interrupted if adverse effects, such as cutaneous toxicity, occur.1

If dosage reduction is necessary, dosage may be decreased to 400 mg once daily.1 If further dosage reduction is required, dosage may be decreased to 400 mg every other day.1

Prescribing Limits

Adults

Highest dosage evaluated clinically was 800 mg twice daily.1

Special Populations

Hepatic Impairment

No dosage adjustment required in patients with mild or moderate (Child-Pugh class A or B) hepatic impairment.1 Not studied in patients with severe (Child-Pugh class C) hepatic impairment.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

No dosage adjustment required in patients with mild to severe renal impairment.1 Not studied in patients with renal impairment requiring dialysis.1

Geriatric Patients

No specific dosage recommendations.1 (See Geriatric Use under Cautions.)

Contraindications

• Known hypersensitivity to sorafenib or any ingredient in the formulation.1

• In combination with carboplatin and paclitaxel in patients with squamous cell lung cancer.1 (See Increased Mortality in Squamous Cell Carcinoma of the Lung under Cautions.)

Warnings/Precautions

Hypertension

Mild or moderate hypertension reported early in the course of treatment;1 2 4 5 6 8 9 10 11 12 15 17 generally managed with standard antihypertensive therapy.1 12 15 (See General under Dosage and Administration.)

If hypertension is severe or persistent despite use of antihypertensive therapy, consider temporary or permanent discontinuance of sorafenib.1

Cardiac Ischemia

Cardiac ischemia or infarction reported; consider temporary or permanent discontinuance of therapy if cardiac ischemia and/or infarction occurs.1 15 18

QT-Interval Prolongation

Prolongation of QT interval may occur.1

Avoid use in patients with congenital long QT syndrome.1

Monitor ECG and serum electrolytes (calcium, potassium, magnesium) in patients with CHF, bradyarrhythmias, or electrolyte abnormalities, and in those receiving drugs known to prolong the QT interval (e.g., class IA and III antiarrhythmic agents).1

Hemorrhage

Increased risk of bleeding;1 15 18 consider permanent discontinuance of therapy if any bleeding episode requiring medical attention occurs.1

Monitor patients receiving concomitant therapy with warfarin and sorafenib for changes in PT or INR regularly and monitor for clinical bleeding episodes.1

Dermatologic Effects

Palmar-plantar erythrodysesthesia (i.e., hand-foot syndrome) and rash occur frequently.1 2 4 5 8 9 10 11 12 15 18

Reactions (generally grade 1 or 2) typically appear during the first 6 weeks of therapy.1 15

Management includes topical symptomatic therapy, temporary interruption of therapy, and/or dosage modification; consider permanent discontinuance of therapy in severe or persistent cases.1

Severe, possibly life-threatening dermatologic toxicities (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) reported; discontinue therapy if Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected.1

GI Effects

GI perforation, sometimes associated with intra-abdominal tumor, reported rarely; discontinue therapy if GI perforation occurs.1

Wound-healing Complications

Effect on wound healing not established; manufacturer recommends that therapy be temporarily interrupted in patients undergoing major surgery.1 Decision to resume therapy should be based on clinical assessment of adequacy of wound healing.1

Increased Mortality in Squamous Cell Carcinoma of the Lung

Increased risk of mortality reported in patients with previously untreated, advanced squamous cell carcinoma of the lung receiving sorafenib in combination with carboplatin and paclitaxel or in combination with gemcitabine and cisplatin.1

Contraindicated in combination with carboplatin and paclitaxel in patients with squamous cell carcinoma of the lung.1

Not recommended for use in combination with gemcitabine and cisplatin in patients with squamous cell carcinoma of the lung.1

Safety and efficacy not established in patients with non-small cell lung cancer (NSCLC).1

Hepatic Effects

Drug-induced hepatitis (serious or fatal), increased serum concentrations of bilirubin, or increased INR may occur.1 Drug-induced hepatitis is characterized by a hepatocellular pattern of injury with substantially elevated serum aminotransferase concentrations.1

Monitor liver function tests regularly.1 Discontinue therapy if substantially elevated serum aminotransferase concentrations occur and other possible causes (i.e., viral hepatitis, malignancy progression) have been ruled out.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.1

Pregnancy should be avoided during and for ≥2 weeks following completion of therapy.1 If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.1 (See Advice to Patients.)

Specific Populations

Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or drug.1

Safety and efficacy not established in children <18 years of age.1 14

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Systemic exposure in patients with mild or moderate (Child-Pugh class A or B) hepatic impairment, with or without hepatocellular carcinoma, similar to that in individuals without hepatic impairment.1 (See Special Populations under Pharmacokinetics.)

Limited safety and efficacy data in patients with hepatocellular carcinoma and moderate hepatic impairment;18 20 some data suggest shorter overall survival in patients with moderate hepatic impairment compared with those with mild hepatic impairment.23 25 26 27

Safety and efficacy not established in patients with severe (Child-Pugh class C) hepatic impairment.1

Common Adverse Effects

Patients with hepatocellular carcinoma: Hypoalbuminemia,1 diarrhea,1 18 20 lymphopenia,1 fatigue,1 18 20 thrombocytopenia,1 increased INR,1 increased lipase concentrations,1 hypophosphatemia,1 increased amylase concentrations,1 abdominal pain,1 weight loss,1 anorexia,1 18 20 hypocalcemia,1 nausea,1 18 20 hand-foot syndrome,1 18 20 rash/desquamation,1 18 20 vomiting,1 alopecia,1 18 20 constipation,1 pruritus,1 hepatic impairment,1 dry skin,1 hypertension.20

Patients with renal cell carcinoma: Hypophosphatemia,1 15 diarrhea,1 10 15 increased lipase concentrations,1 15 rash/desquamation,1 15 fatigue,1 10 15 hand-foot syndrome,1 10 15 increased amylase concentrations,1 alopecia,1 15 nausea,1 15 lymphopenia,1 15 pruritus,1 15 neutropenia,1 hypertension,1 10 15 anorexia,1 15 vomiting,1 15 constipation,1 15 hemorrhage,1 15 dyspnea,1 15 sensory neuropathy,1 15 hypocalcemia,1 thrombocytopenia,1 dry skin,1 pain (abdominal, joint, headache),1 15 weight loss.1 15

Metabolized by CYP3A4 and uridine diphosphate-glucuronosyltransferase (UGT) 1A9.1 7

Inhibits CYP isoenzymes 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 in vitro.1 24 Unlikely to induce CYP1A2 or CYP3A4.1 24

Inhibits glucuronidation by UGT1A1 and UGT1A9 in vitro.1 24 28

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Unlikely to alter metabolism of sorafenib.1 28

CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma concentrations of sorafenib).1 24 When possible, avoid concomitant use of potent CYP3A4 inducers.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP isoenzymes 2B6 or 2C8: At recommended sorafenib dosage, clinically important inhibition of CYP2B6 or CYP2C8 may be unlikely.28

Substrates of CYP isoenzymes 2C19, 2D6, or 3A4: Clinically important pharmacokinetic interactions unlikely.1 24 28

CYP2C9 substrates: Risk for clinically important inhibition of CYP2C9 by sorafenib may be low.24 28

Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase

Substrates of UGT1A1 or UGT1A9: Potential pharmacokinetic interaction (increased systemic exposure to the substrate).1 Caution is advised.1 28

Drugs Affecting Gastric Acidity

Potential pharmacokinetic interaction (decreased solubility of sorafenib) with drugs that increase gastric pH.1 However, manufacturer states adjustment of sorafenib dosage is not necessary.1

Substrates of P-glycoprotein Transport System

Substrates of P-gp: Potential pharmacokinetic interaction (increased systemic exposure to the substrate).1 24

Specific Drugs

• If a dose is missed, importance of administering the next dose at the regularly scheduled time; do not administer a double dose to make up for a missed dose.1

• Importance of reading the manufacturer’s patient information prior to beginning therapy and rereading it each time the prescription is renewed.1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Necessity of advising women to avoid pregnancy during therapy and for ≥2 weeks following completion of sorafenib therapy, as well as advising women to discontinue nursing while receiving therapy.1 Necessity of advising women and men to use effective contraceptive methods during sorafenib therapy and for ≥2 weeks following completion of therapy.1 Advise women of the potential risk to the fetus (e.g., birth defects) and/or the potential risk for loss of the pregnancy.1

• Risk of hand-foot syndrome and rash.1 Importance of advising patient about appropriate countermeasures.1

• Risk of hypertension, particularly during the first 6 weeks of sorafenib therapy.1 Importance of monitoring BP regularly during therapy.1

• Risk of bleeding.1 Importance of patients promptly informing clinicians of any episodes of bleeding.1

• Risk of bleeding or INR elevation in patients receiving concomitant therapy with warfarin and sorafenib.1 Importance of monitoring INR regularly during concomitant therapy.1

• Risk of potential GI perforation.1 Importance of informing clinician immediately if high fever, nausea, vomiting, or severe stomach or abdominal pain occurs.1

• Risk of potential cardiac ischemia and/or infarction.1 Importance of patients immediately informing clinicians of any episodes of chest pain or other symptoms of cardiac ischemia.1

• Risk of wound healing complications.1 Importance of informing clinician of any scheduled surgery.1

• Risk of QT-interval prolongation.1 Importance of informing clinicians immediately if an abnormal heartbeat or feelings of dizziness or faintness occur.1

• Risk of hepatitis and importance of regular liver function test monitoring.1 Importance of informing clinician if signs and symptoms of hepatitis (e.g., jaundice, dark tea-colored urine, light-colored stool, worsening nausea or vomiting, abdominal pain) occur.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John’s wort), as well as any concomitant illnesses (e.g., cardiovascular disease [including congenital long QT syndrome]).1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)