SORAfenib

Class: Antineoplastic Agents
- Kinase Inhibitors
- Receptor Tyrosine Kinase Inhibitors
- Tyrosine Kinase Inhibitors
VA Class: AN900
Chemical Name: 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide
Molecular Formula: C₂₁H₁₆ClF₃N₄O₃
CAS Number: 284461-73-0
Brands: NexAVAR

Medically reviewed by Drugs.com on Aug 16, 2021. Written by ASHP.

Introduction

Antineoplastic agent; inhibitor of several serine/threonine and receptor tyrosine kinases.

Uses for SORAfenib

Hepatocellular Carcinoma

Treatment of unresectable hepatocellular carcinoma (designated an orphan drug by FDA for this use).

Renal Cell Carcinoma

Treatment of advanced renal cell carcinoma (designated an orphan drug by FDA for this use).

SORAfenib Dosage and Administration

General

Monitor BP weekly during the first 6 weeks of therapy; thereafter, monitor and treat, if required, in accordance with established medical practice. (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.

Dosage

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

Adults

Hepatocellular Carcinoma

Oral

400 mg twice daily.

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

Renal Cell Carcinoma

Oral

400 mg twice daily.

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

Dosage Modification for Toxicity (in Hepatocellular or Renal Cell Carcinoma)

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

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

Suggested Dosage Modification for Cutaneous Toxicity 1
Cutaneous Toxicity Grade	Occurrence	Suggested Dosage Modification
Grade 1: numbness, dysesthesia, paresthesia, tingling, painless swelling, erythema, and/or discomfort of the hands or feet that does not disrupt the patient’s normal activities	Any occurrence	Continue therapy with sorafenib and consider topical therapy for symptomatic relief
Grade 2: painful erythema and swelling of the hands or feet and/or discomfort affecting the patient’s normal activities	1^st occurrence	Continue therapy with sorafenib and consider topical therapy for symptomatic relief If improvement is not evident within 7 days, see below
	No improvement within 7 days or 2^nd or 3^rd occurrence	Interrupt sorafenib therapy until toxicity resolves to grade 0 or 1 When resuming therapy, decrease sorafenib dosage by one dose level (e.g., to 400 mg once daily or 400 mg every other day)
	4^th occurrence	Discontinue sorafenib therapy
Grade 3: moist desquamation, ulceration, blistering or severe pain of the hands or feet, and/or severe discomfort that causes the patient to be unable to work or perform activities of daily living	1^st or 2^nd occurrence	Interrupt sorafenib therapy until toxicity resolves to grade 0 or 1 When resuming therapy, decrease sorafenib dosage by one dose level (e.g., to 400 mg once daily or 400 mg every other day)
	3^rd occurrence	Discontinue sorafenib therapy

Prescribing Limits

Adults

Renal Cell Carcinoma

Oral

Highest dosage evaluated clinically was 800 mg twice daily.

Special Populations

Hepatic Impairment

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

Renal Impairment

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

Geriatric Patients

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

Cautions for SORAfenib

Contraindications

Known hypersensitivity to sorafenib or any ingredient in the formulation.
In combination with carboplatin and paclitaxel in patients with squamous cell lung cancer. (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; generally managed with standard antihypertensive therapy. (See General under Dosage and Administration.)

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

Cardiac Ischemia

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

QT-Interval Prolongation

Prolongation of QT interval may occur.

Avoid use in patients with congenital long QT syndrome.

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).

Hemorrhage

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

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

Dermatologic Effects

Palmar-plantar erythrodysesthesia (i.e., hand-foot syndrome) and rash occur frequently.

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

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

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.

GI Effects

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

Wound-healing Complications

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

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.

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

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

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

Hepatic Effects

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

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

Fetal/Neonatal Morbidity and Mortality

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

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

Specific Populations

Pregnancy

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

Lactation

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

Pediatric Use

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

Geriatric Use

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

Hepatic Impairment

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. (See Special Populations under Pharmacokinetics.)

Limited safety and efficacy data in patients with hepatocellular carcinoma and moderate hepatic impairment; some data suggest shorter overall survival in patients with moderate hepatic impairment compared with those with mild hepatic impairment.

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

Common Adverse Effects

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

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

Interactions for SORAfenib

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

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

Inhibits glucuronidation by UGT1A1 and UGT1A9 in vitro.

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A4 inhibitors: Unlikely to alter metabolism of sorafenib.

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

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.

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

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

Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase

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

Drugs Affecting Gastric Acidity

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

Substrates of P-glycoprotein Transport System

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

Specific Drugs

Drug	Interaction	Comments
Anticonvulsants (carbamazepine, phenobarbital, phenytoin)	Possible decreased plasma sorafenib concentrations	Avoid concomitant use when possible
Antimycobacterials, rifamycins (e.g., rifampin, rifabutin)	Possible decreased plasma sorafenib concentrations Rifampin: Decreased sorafenib AUC	Avoid concomitant use when possible
Capecitabine	Increased AUC of capecitabine and its active metabolite fluorouracil No effect on AUC of sorafenib
Carboplatin	No apparent effect on carboplatin pharmacokinetics Increased mortality reported in patients with advanced NSCLC receiving sorafenib in combination with carboplatin and paclitaxel	Sorafenib in combination with carboplatin and paclitaxel contraindicated in patients with squamous cell lung cancer
Cisplatin	Sorafenib does not appear to affect cisplatin pharmacokinetics Increased mortality reported in patients with advanced NSCLC receiving sorafenib in combination with gemcitabine and cisplatin	Sorafenib in combination with cisplatin and gemcitabine not recommended in patients with squamous cell lung cancer
Cyclophosphamide	Sorafenib does not appear to affect cyclophosphamide pharmacokinetics
Dexamethasone	Possible decreased plasma sorafenib concentrations	Avoid concomitant use when possible
Dextromethorphan	Pharmacokinetic interaction unlikely
Digoxin	Possible increased systemic exposure of digoxin
Docetaxel	Increased peak concentration and AUC of docetaxel	Caution advised
Doxorubicin	Increased AUC of doxorubicin
Gemcitabine	Sorafenib does not appear to affect gemcitabine pharmacokinetics Increased mortality reported in patients with advanced NSCLC receiving sorafenib in combination with gemcitabine and cisplatin	Sorafenib in combination with gemcitabine and cisplatin not recommended in patients with squamous cell lung cancer
Irinotecan	Increased AUC of irinotecan and its active metabolite, SN-38	Caution advised
Ketoconazole	No substantial effect on sorafenib exposure
Midazolam	Pharmacokinetic interaction unlikely
Neomycin	Decreased sorafenib AUC
Omeprazole	No substantial effect on systemic exposure of sorafenib	Dosage adjustment of sorafenib not necessary
Oxaliplatin	Sorafenib does not appear to affect oxaliplatin pharmacokinetics
Paclitaxel	Increased AUC of paclitaxel, 6-hydroxypaclitaxel, and sorafenib in patients receiving paclitaxel, carboplatin, and sorafenib Increased mortality reported in patients with advanced NSCLC receiving sorafenib in combination with carboplatin and paclitaxel	Sorafenib in combination with paclitaxel and carboplatin contraindicated in patients with squamous cell lung cancer

St. John's wort (Hypericum perforatum)	Possible decreased plasma sorafenib concentrations	Avoid concomitant use when possible
Warfarin	No apparent effect on PT/INR compared with placebo, but infrequent bleeding events or INR elevations reported	Monitor regularly for changes in PT or INR and for bleeding

SORAfenib Pharmacokinetics

Absorption

Bioavailability

Mean relative bioavailability is 38–49% when compared with oral solution. Peak plasma concentrations attained in approximately 3 hours.

Food

High-fat meal reduces bioavailability by about 29%.

Special Populations

Mild or moderate hepatic impairment (Child-Pugh class A or B) does not substantially affect pharmacokinetics; peak concentration and AUC slightly higher in moderate than in mild hepatic impairment, but differences are not clinically meaningful. Not studied in patients with severe (Child-Pugh class C) hepatic impairment.

Mild to severe renal impairment (Cl_cr ≤80 mL/minute) does not affect pharmacokinetics; not studied in patients with renal impairment requiring dialysis.

Age and gender do not substantially affect pharmacokinetics.

AUC is 30% lower in Asians than in Caucasians.

Distribution

Extent

Not known whether sorafenib is distributed into milk.

Plasma Protein Binding

99.5%.

Elimination

Metabolism

Metabolized mainly in the liver via oxidation by CYP3A4 and glucuronidation by UGT1A9.

At least 8 metabolites identified. The main circulating metabolite, a pyridine N-oxide derivative, is pharmacologically active and accounts for approximately 9–16% of total plasma concentrations of the drug.

Elimination Route

Excreted in feces (77%) and urine (19%).

51% of a dose recovered in feces as unchanged drug; unchanged drug not recovered in urine.

Half-life

Approximately 25–48 hours.

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C). Store in a dry place.

Actions

Mechanism of action not fully elucidated; appears to inhibit signal transduction pathways involving multiple intracellular (e.g., c-Raf, b-Raf, mutant b-Raf) and cell surface kinases (e.g., c-Kit, Flt-3, RET, vascular endothelial growth factor receptors 1, 2 and 3, platelet-derived growth factor receptor-β) in vitro.

Advice to Patients

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.
Importance of reading the manufacturer’s patient information prior to beginning therapy and rereading it each time the prescription is renewed.
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. 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. Necessity of advising women and men to use effective contraceptive methods during sorafenib therapy and for ≥2 weeks following completion of therapy. Advise women of the potential risk to the fetus (e.g., birth defects) and/or the potential risk for loss of the pregnancy.
Risk of hand-foot syndrome and rash. Importance of advising patient about appropriate countermeasures.

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

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

Risk of bleeding or INR elevation in patients receiving concomitant therapy with warfarin and sorafenib. Importance of monitoring INR regularly during concomitant therapy.
Risk of potential GI perforation. Importance of informing clinician immediately if high fever, nausea, vomiting, or severe stomach or abdominal pain occurs.

Risk of potential cardiac ischemia and/or infarction. Importance of patients immediately informing clinicians of any episodes of chest pain or other symptoms of cardiac ischemia.
Risk of wound healing complications. Importance of informing clinician of any scheduled surgery.
Risk of QT-interval prolongation. Importance of informing clinicians immediately if an abnormal heartbeat or feelings of dizziness or faintness occur.
Risk of hepatitis and importance of regular liver function test monitoring. 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.

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]).

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

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.