Class: Antineoplastic Agents
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
Introduction
Antineoplastic agent; inhibitor of several serine/threonine and receptor tyrosine kinases.1 2 4 5 6 7 8 9 10 11 12 13 15 16 17
Uses for Sorafenib Tosylate
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
Sorafenib Tosylate 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.1 (See Cardiovascular Effects 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
Renal Cell Carcinoma
General Dosage
Oral
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 Modification for Toxicity
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
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 | 1st 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 2nd or 3rd 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) |
| 4th 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 | 1st or 2nd 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) |
| 3rd occurrence | Discontinue sorafenib therapy |
Prescribing Limits
Adults
Renal Cell Carcinoma
Oral
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 specific dosage recommendations for patients with renal impairment.1 14 (See Renal Impairment under Cautions.)
Geriatric Patients
No dosage adjustment is required on the basis of patient age.1 (See Geriatric Use under Cautions.)
Cautions for Sorafenib Tosylate
Contraindications
Known hypersensitivity to sorafenib or any ingredient in the formulation.1
Warnings/Precautions
Warnings
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.)
Major Toxicities
Dermatologic Effects
Palmar-plantar erythrodysesthesia (i.e., hand-foot syndrome) and rash occur frequently.1 2 4 5 8 9 10 11 12 15
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
Cardiovascular Effects
Mild or moderate treatment-emergent 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
Treatment-emergent cardiac ischemia or infarction reported; consider temporary or permanent discontinuance of therapy if cardiac ischemia and/or infarction occurs.1
GI Perforation
GI perforation, sometimes associated with intra-abdominal tumor, reported rarely; discontinue therapy if GI perforation occurs.1
Hemorrhage
Increased risk of bleeding;1 15 consider permanent discontinuance of therapy if any bleeding episode requiring medical attention occurs.1
Monitor patients receiving concomitant therapy with warfarin and sorafenib for increased risk of bleeding episodes or INR elevations.1 Assess for changes in PT or INR regularly and monitor for clinical bleeding episodes.1
General Precautions
Japanese Populations
Reduction in systemic exposure to sorafenib reported in Japanese patients (see Special Populations under Pharmacokinetics); clinical importance is not known.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
Specific Populations
Pregnancy
Category D.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Lactation
Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing because of potential risk to nursing infants.1
Pediatric Use
Safety and efficacy not established in children <18 years of age.1 14
Geriatric Use
No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1
Hepatic Impairment
Systemic exposure and safety data in patients with mild or moderate hepatic impairment (Child-Pugh class A or B) similar to these data in patients without hepatic impairment.1 14 Safety and efficacy not established in patients with severe (Child-Pugh class C) hepatic impairment.1
Renal Impairment
Systemic exposure data in patients with mild or moderate renal impairment (Clcr 30–80 mL/minute) similar to such data in patients without renal impairment.1 Safety and efficacy not established in patients with severe renal impairment (Clcr <30 mL/minute) or in those undergoing peritoneal dialysis or hemodialysis.1 14
Common Adverse Effects
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 (all sites, including GI and respiratory tract),1 15 dyspnea,1 15 cough,1 15 sensory neuropathy,1 15 dry skin,1 pain (abdominal, joint, headache, mouth, bone, and tumor),1 15 weight loss,1 15 erythema,1 asthenia,1 leukopenia.1
Interactions for Sorafenib Tosylate
Metabolized by CYP3A4 and uridine diphosphate-glucuronosyltransferase (UGT) 1A9.1 7
Inhibits CYP isoenzymes 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4 in vitro.1 Unlikely to induce CYP1A2 or CYP3A4.1
Inhibits glucuronidation by UGT1A1 and UGT1A9.1
Drugs Affecting Hepatic Microsomal Enzymes
CYP3A4 inhibitors: Unlikely to alter metabolism of sorafenib based on drug interaction studies with ketoconazole.1
CYP3A4 inducers: Potential pharmacokinetic interaction (decreased plasma concentrations of sorafenib).1
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP isoenzymes 2C19, 2D6, or 3A4: Pharmacokinetic interaction (alteration of substrate metabolism) unlikely.1
Substrates of CYP2B6 or CYP2C8: Possible pharmacokinetic interaction (increased systemic exposure to the substrate); caution is advised during concomitant use.1
Drugs Metabolized by Uridine Diphosphate-glucuronosyltransferase
Substrates of UGT1A1 or UGT1A9: Potential pharmacokinetic interaction (increased systemic exposure to the substrate).1 Caution is advised with concomitant use of sorafenib and substrates of UGT1A1 (e.g., irinotecan).1
Specific Drugs
Drug | Interaction | Comments |
---|---|---|
Anticonvulsants (carbamazepine, phenobarbital, phenytoin) | Possible decreased plasma sorafenib concentrations1 | |
Dexamethasone | Possible decreased plasma sorafenib concentrations1 | |
Dextromethorphan | Pharmacokinetic interaction unlikely1 | |
Doxorubicin | Possible increased AUC of doxorubicin1 | Caution is advised1 |
Gemcitabine | Sorafenib does not appear to affect gemcitabine pharmacokinetics1 | |
Irinotecan | Possible increased AUC of irinotecan and its active metabolite, SN-381 | Caution is advised1 |
Ketoconazole | Pharmacokinetic interaction unlikely 1 | |
Midazolam | Pharmacokinetic interaction unlikely1 | |
Omeprazole | Pharmacokinetic interaction unlikely1 | |
Oxaliplatin | Sorafenib does not appear to affect oxaliplatin pharmacokinetics1 | |
Rifampin | Possible decreased plasma sorafenib concentrations1 | |
St. John's wort (Hypericum perforatum) | Possible decreased plasma sorafenib concentrations1 | |
Warfarin | Increased risk of bleeding episodes or INR elevations; sorafenib does not appear to affect warfarin metabolism1 | Monitor regularly for changes in PT or INR and for clinical bleeding episodes1 |
Sorafenib Tosylate Pharmacokinetics
Absorption
Bioavailability
Mean relative bioavailability is 38–49% when compared with oral solution.1 Peak plasma concentrations attained in approximately 3 hours.1
Food
High-fat meal reduces bioavailability by about 29%.1
Special Populations
AUC in Japanese patients receiving sorafenib 400 mg twice daily reduced by 45% compared with data from phase 1 studies in Caucasian patients.1 (See Japanese Populations under Cautions.)
Distribution
Extent
Not known whether sorafenib is distributed into milk.1
Plasma Protein Binding
99.5%.1
Elimination
Metabolism
Metabolized mainly in the liver via oxidation by CYP3A4 and glucuronidation by UGT1A9.1 7
At least 8 metabolites identified.1 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.1
Elimination Route
Excreted in feces (77%) and urine (19%).1
51% of a dose recovered in feces as unchanged drug; unchanged drug not recovered in urine.1
Half-life
Approximately 25–48 hours.1
Stability
Storage
Oral
Tablets
25°C (may be exposed to 15–30°C).1 Store in a dry place.1
ActionsActions
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, vascular endothelial growth factor receptors 2 and 3, platelet-derived growth factor receptor-β) in vitro.1 2 4 5 6 7 8 9 10 11 12 13 15 16 17
Advice to Patients
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 potential GI perforation.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 and/or infarction.1
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Oral | Tablets, film-coated | 200 mg (of sorafenib) | Nexavar | Bayer , (comarketed by Onyx) |
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions November 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
References
1. Bayer. Nexavar (sorafenib tosylate) tablets prescribing information. West Haven, CT: 2007 Feb.
2. Ahmad T, Eisen T. Kinase inhibition with BAY 43-9006 in renal cell carcinoma. Clin Cancer Res. 2004; 10:6388S-92S. [PubMed 15448036]
3. Food and Drug Administration. Cumulative list of all orphan designated products that have received marketing approval. Available at: . Accessed 2006 Feb 10.
4. Escudier B, Szczylik C, Eisen T et al. Randomized phase III trial of the raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). Presented at the 41st Annual Meeting of the American Society of Clinical Oncology (ASCO). Orlando, FL. 2005 13–17 May. Abstract LBA 4510.
5. Ratain MJ, Eisen T, Stadler WM et al. Final findings from a phase II, placebo-controlled, randomized discontinuation trial (RDT) of sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). Presented at the 41st Annual Meeting of the American Society of Clinical Oncology (ASCO). Orlando, FL. 2005 13–17 May. Abstract LBA 4544.
6. Favaro JP, George DJ. Targeted therapy in renal cell carcinoma. Expert Opin Investig Drugs. 2005; 14:1251-8. [PubMed 16185167]
7. Beeram M, Patnaik A, Rowinsky EK. Raf: a strategic target for therapeutic development against cancer. J Clin Oncol. 2005; 23:6771-90. [IDIS 543417] [PubMed 16170185]
8. Cooney MM, Remick SC, Vogelzang NJ. Promising systemic therapy for renal cell carcinoma. Curr Treat Options Oncol. 2005; 6:357-65. [PubMed 16107239]
9. Arora A, Scholar EM. Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther. 2005; 315:971-9. [PubMed 16002463]
10. Schöffski P, Dumez H, Clement P et al. Emerging role of tyrosine kinase inhibitors in the treatment of advanced renal cell cancer: a review. Ann Oncol . 2006 (Advance access [doi:10.1093/annonc/mdj133]); :.
11. Zakarija A, Soff G. Update on angiogenesis inhibitors. Curr Opin Oncol. 2005; 17:578-83. [PubMed 16224236]
12. Gollob JA. Sorafenib: scientific rationales for single-agent and combination therapy in clear-cell renal cell carcinoma. Clin Genitourin Cancer. 2005; 4:167-74. [PubMed 16425993]
13. Wilhelm SM, Carter C, Tang L et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004; 64:7099-109. [PubMed 15466206]
14. Bayer, West Haven, CT: Personal communication.
15. Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007; 356:125-34. [PubMed 17215530]
16. Brugarolas J. Renal-cell carcinoma—molecular pathways and therapies. N Engl J Med. 2007; 356:185-7. [PubMed 17215538]
17. Govindarajan R, Adusumilli J, Baxter DL et al. Reversible posterior leukoencephalopathy syndrome induced by RAF kinase inhibitor BAY 43-9006. J Clin Oncol. 2006; 24:e48. [PubMed 17008686]
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