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Sorafenib Tosylate

Pronunciation

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

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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

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

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

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, 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.

Sorafenib Tosylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

200 mg (of sorafenib)

Nexavar

Bayer , (comarketed by Onyx)

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 1, 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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