Drug Class Description
Protein Kinase Inhibitor

Generic Name
Sorafenib

Drug Description
Each film-coated tablet contains 200 mg of sorafenib (as tosylate).

Presentation
Film-coated tablet.Red, round, biconvex film-coated tablets, debossed with Bayer cross on one side and "200" on the other side.

Indications
Hepatocellular carcinomaNexavar is indicated for the treatment of hepatocellular carcinoma.Renal cell carcinomaNexavar is indicated for the treatment of patients with advanced renal cell carcinoma who have failed prior interferon-alpha or interleukin-2 based therapy or are considered unsuitable for such therapy.

Adult Dosage
Nexavar treatment should be supervised by a physician experienced in the use of anticancer therapies. The recommended dose of Nexavar in adults is 400 mg (two tablets of 200 mg) twice daily (equivalent to a total daily dose of 800 mg). It is recommended that sorafenib should be administered without food or with a low or moderate fat meal. If the patient intends to have a high-fat meal, sorafenib tablets should be taken at least 1 hour before or 2 hours after the meal. The tablets should be swallowed with a glass of water.Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.Posology adjustments: Management of suspected adverse drug reactions may require temporary interruption or dose reduction of Nexavar therapy. When dose reduction is necessary, the Nexavar dose should be reduced to two tablets of 200 mg once daily.Paediatric patients: The safety and efficacy in children and adolescents (< 18 years) have not been studied. Nexavar is not recommended for use in children and adolescents due to a lack of data on safety and efficacy (see section 5.3).Elderly patients: No dose adjustment is required in the elderly (patients above 65 years of age).Renal impairment: No dose adjustment is required in patients with mild, moderate or severe renal impairment. No data is available in patients requiring dialysis.Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised.Hepatic impairment: No dose adjustment is required in patients with Child Pugh A and B (mild to moderate) hepatic impairment. No data is available on patients with Child Pugh C (severe) hepatic impairment.

Child Dosage
The safety and efficacy in children and adolescents (< 18 years) have not been studied. Nexavar is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.

Elderly Dosage
No dose adjustment is required in the elderly (patients above 65 years of age).

Contra Indications
Hypersensitivity to the active substance or to any of the excipients.

Special Precautions
Dermatological toxicities: Hand-foot skin reaction (palmar-plantar erythrodysaesthesia) and rash represent the most common adverse drug reactions with Nexavar. Rash and hand-foot skin reaction are usually CTC (Common Toxicity Criteria) Grade 1 and 2 and generally appear during the first six weeks of treatment with Nexavar. Management of dermatological toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of Nexavar, or in severe or persistent cases, permanent discontinuation of Nexavar.Hypertension: An increased incidence of arterial hypertension was observed in Nexavar-treated patients. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was amenable to management with standard antihypertensive therapy. Blood pressure should be monitored regularly and treated, if required, in accordance with standard medical practice. In cases of severe or persistent hypertension, or hypertensive crisis despite institution of antihypertensive therapy, permanent discontinuation of Nexavar should be considered.Haemorrhage: An increased risk of bleeding may occur following Nexavar administration. If any bleeding event necessitates medical intervention it is recommended that permanent discontinuation of Nexavar should be considered.Cardiac ischaemia and/or infarction: In a randomised, placebo-controlled, double-blind study (study 1, see section 5.1) the incidence of treatment-emergent cardiac ischaemia/infarction events was higher in the Nexavar group (2.9%) compared with the placebo group (0.4%). In study 3 (see section 5.1), the incidence of treatment-emergent cardiac ischaemia/infarction events was 2.7% in Nexavar patients compared with 1.3% in the placebo group. Patients with unstable coronary artery disease or recent myocardial infarction were excluded from these studies. Temporary or permanent discontinuation of Nexavar should be considered in patients who develop cardiac ischaemia and/or infarction.Gastrointestinal perforation: Gastrointestinal perforation is an uncommon event and has been reported in less than 1% of patients taking sorafenib. In some cases this was not associated with apparent intra-abdominal tumor. Sorafenib therapy should be discontinuedHepatic impairment: No data is available on patients with Child Pugh C (severe) hepatic impairment. Since sorafenib is mainly eliminated via the hepatic route exposure might be increased in patients with severe hepatic impairment.Warfarin co-administration: Infrequent bleeding events or elevations in the International Normalised Ratio (INR) have been reported in some patients taking warfarin while on Nexavar therapy. Patients taking concomitant warfarin or phenprocoumon should be monitored regularly for changes in prothrombin time, INR or clinical bleeding episodes.Wound healing complications: No formal studies of the effect of sorafenib on wound healing have been conducted. Temporary interruption of Nexavar therapy is recommended for precautionary reasons in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume Nexavar therapy following a major surgical intervention should be based on clinical judgement of adequate wound healing.Elderly: The experience with the use of Nexavar in elderly patients is limited. Cases of renal failure have been reported. Monitoring of renal function should be considered.Renal cell carcinoma: High Risk Patients, according to MSKCC (Memorial Sloan Kettering Cancer Center) prognostic group, were not included in the phase III clinical study in renal cell carcinoma (see study 1 in section 5.1); and benefit-risk in these patients has not been eva luated.Drug-drug interactions:Caution is recommended when administering Nexavar with compounds that are metabolised/eliminated predominantly by the UGT1A1 (e.g. irinotecan) or UGT1A9 pathways.Caution is recommended when sorafenib is co-administered with docetaxel.

Interactions
Inducers of metabolic enzymes: Administration of rifampicin for 5 days before administration of a single dose of sorafenib resulted in an average 37% reduction of sorafenib AUC. Other inducers of CYP3A4 activity and/or glucuronidation (e.g. Hypericum perforatum also known as St. John's wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) may also increase metabolism of sorafenib and thus decrease sorafenib concentrations.CYP3A4 inhibitors: Ketoconazole, a potent inhibitor of CYP3A4, administered once daily for 7 days to healthy male volunteers did not alter the mean AUC of a single 50 mg dose of sorafenib. These data suggest that clinical pharmacokinetic interactions of sorafenib with CYP3A4 inhibitors are unlikely.CYP2C9 substrates: Sorafenib inhibited CYP2C9 in vitro. It cannot be excluded that sorafenib may increase the concentrations of concomitantly administered substrates of CYP2C9. The concomitant treatment with Nexavar and warfarin, a CYP2C9 substrate, did not result in changes in mean PT-INR compared to placebo. However, patients taking warfarin or phenprocoumon should have their INR checked regularly.CYP2B6 and CYP2C8 substrates: Sorafenib inhibited CYP2B6 and CYP2C8 in vitro, but the clinical relevance of this inhibition has not been eva luated. It cannot be excluded that sorafenib may increase the concentrations of concomitantly administered substrates of CYP2B6 (e.g. bupropion, cyclophosphamide, efavirenz, ifosfamide, methadone) and CYP2C8 (e.g. paclitaxel, amodiaquine, repaglinide).UGT1A1 and UGT1A9 substrates: In vitro, sorafenib inhibited glucuronidation via UGT1A1 and UGT1A9. The clinical relevance of this finding is unknown.CYP isoforms selective substrates: Concomitant administration of sorafenib and midazolam, dextromethorphan or omeprazole, which are substrates for cytochromes CYP3A4, CYP2D6 and CYP2C19 respectively, did not alter the exposure of these agents. This indicates that sorafenib is neither an inhibitor nor an inducer of these cytochrome P450 isoenzymes. Therefore, clinical pharmacokinetic interactions of sorafenib with substrates of these enzymes are unlikely.In vitro studies of CYP enzyme induction: CYP1A2 and CYP3A4 activities were not altered after treatment of cultured human hepatocytes with sorafenib, indicating that sorafenib is unlikely to be an inducer of CYP1A2 and CYP3A4.P-gp-substrates: In vitro, sorafenib has been shown to inhibit the transport protein p-glycoprotein (P-gp). Increased plasma concentrations of P-gp substrates such as digoxin cannot be excluded with concomitant treatment with sorafenib.Combination with other anti-neoplastic agents: In clinical studies Nexavar has been administered with a variety of other anti-neoplastic agents at their commonly used dosing regimens including gemcitabine, oxaliplatin, doxorubicin, and irinotecan. Sorafenib had no effect on the pharmacokinetics of gemcitabine or oxaliplatin. Concomitant treatment with Nexavar resulted in a 21% increase in the AUC of doxorubicin. When administered with irinotecan, whose active metabolite SN-38 is further metabolised by the UGT1A1 pathway, there was a 67 - 120% increase in the AUC of SN-38 and a 26 - 42% increase in the AUC of irinotecan. The clinical significance of these findings is unknown.Docetaxel (75 or 100 mg/m2 administered once every 21 days) when co-administered with sorafenib (200 mg twice daily or 400 mg twice daily administered on Days 2 through 19 of a 21-day cycle with a 3-day break in dosing around administration of docetaxel) resulted in a 36-80% increase in docetaxel AUC and a 16-32% increase in docetaxel Cmax. Caution is recommended when sorafenib is co-administered with docetaxel.

Adverse Reactions
The most common adverse reactions were diarrhoea, rash, alopecia and hand-foot syndrome (corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRA).Table 1: Adverse reactions reported in at least 5% of patients in any treatment group – study 11213 in renal cell carcinoma (see study 1 in section 5.1).Nexavar N=451Placebo N=451System organ classPreferred termall gradesgrade 3grade 4all gradesgrade 3grade 4Metabolism and nutrition disordersanorexia9%<1%0%5%<1%0%Nervous system disordersheadache6%0%0%3%0%0%Vascular disordershypertension12%2%<1%1%<1%0%flushing6%0%0%2%0%0%Gastrointestinal disordersdiarrhoea38%2%0%9%<1%0%nausea16%<1%0%12%<1%0%vomiting10%<1%0%6%<1%0%constipation6%0%0%3%0%0%Skin and subcutaneous tissue disordersrash28%<1%0%9%<1%0%alopecia25%<1%0%3%0%0%hand foot syndrome**19%4%0%3%0%0%pruritus17%<1%0%4%0%0%erythema15%0%0%4%0%0%dry skin11%0%0%2%0%0%skin exfoliation7%<1%0%2%0%0%Musculo-skeletal and connective tissue disordersarthralgia6%<1%0%3%0%0%pain in extremity6%<1%0%2%0%0%General disorders and administration site conditionsfatigue15%2%0%11%<1%0%asthenia9%<1%0%4%<1%0%Table 2: Adverse reactions reported in at least 5% of patients in any treatment group – study 100554 in hepatocellular carcinoma (see study 3 in section 5.1).Nexavar N= 297Placebo N= 302System organ classPreferred termall grades grade 3grade 4all grades grade 3grade 4 Metabolism and nutrition disordersanorexia11%<1%0%3%<1%0%Gastrointestinal disordersdiarrhoea39%8%0%11%2%0%nausea11%<1%0%8%1%0%abdominal pain7%2%0%3%<1%0%vomiting5%1%0%3%<1%0%Skin and subcutaneous tissue disordershand foot syndrome**18%7%0%2%0%0%alopecia14%0%0%2%0%0%rash11%<1%0%8%0%0%pruritus8%0%0%7%<1%0%dry skin8%0%0%4%0%0%General disorders and administration site conditionsfatigue17%2%<1%13%3%<1%asthenia6%1%<1%2%<1%0%Investigationsweight decreased9%2%0%<1%0%0%Respiratory, thoracic and mediastinal disordershoarseness5%0%0%<1%0%0%Adverse reactions reported in multiple clinical trials are listed below in Table 3, by system organ class (in MedDRA) and frequency. Frequencies are defined as: very common (1/10), common (1/100, <1/10), uncommon (1/1,000, <1/100).Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.Table 3: All adverse reactions reported in patients in multiple clinical trials System organ classVery Common 1/10Common1/100, <1/10Uncommon1/1,000, <1/100Infections and infestationsfolliculitisinfectionBlood and lymphatic system disorderslymphopenialeucopenianeutropeniaanaemiathrombocytopeniaImmune system disordershypersensitivity reactions (including skin reactions and urticaria)Endocrine disordershypothyroidismhyperthyroidismMetabolism and nutrition disordershypophosphataemiaanorexiahyponatraemiadehydrationPsychiatric disordersdepressionNervous system disordersperipheral sensory neuropathyreversible posterior leukoencephalopathy*Ear and labyrinth disorderstinnitusCardiac disorderscongestive heart failure*myocardial ischaemia and infarction*Vascular disordershaemorrhage (inc. gastrointestinal*, respiratory tract* and cerebral haemorrhage*)hypertensionhypertensive crisis*Respiratory, thoracic and mediastinal disordershoarsenessrhinorrhoeainterstitial lung disease-like events (pneumonitits, acute respiratory distress, etc.)Gastrointestinal disordersdiarrhoeanauseavomitingconstipationstomatitis (including dry mouth and glossodynia)dyspepsiadysphagiagastro oesophageal reflux diseasepancreatitisgastritisgastrointestinal perforations*Hepatobiliary disordersincrease in bilirubin and jaundice cholecystitis cholangitisSkin and subcutaneous tissue disordersrashalopeciahand foot syndrome**erythemapruritusdry skindermatitis exfoliativeacneskin desquamationeczemaerythema multiformekeratoacanthoma/ squamous cell cancer of the skinStevens-Johnson syndromeMusculoskeletal and connective tissue and disordersarthralgiamyalgiaRenal and urinary disordersrenal failureReproductive system and breast disorderserectile dysfunctiongynaecomastiaGeneral disorders and administration site conditionsfatiguepain (including mouth, abdominal, bone, tumour pain and headache)astheniafeverinfluenza like illnessInvestigationsincreased amylase increased lipaseweight decreased transient increase in transaminasestransient increase in blood alkaline phosphatase,INR abnormal, prothrombin level abnormal* The adverse reactions may have a life-threatening or fatal outcome.** hand foot syndrome corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRAFurther information on selected adverse drug reactionsCongestive Heart Failure: In company sponsored clinical trials congestive heart failure was reported as an adverse event in 1.9% of patients treated with sorafenib (N= 2276). In study 11213 (RCC) adverse events consistent with congestive heart failure were reported in 1.7% of patients treated with sorafenib and 0.7% receiving placebo. In study 100554 (HCC), 0.99% of those treated with sorafenib and 1.1% receiving placebo were reported with these events.Laboratory test abnormalitiesIncreased lipase and amylase were very commonly reported. CTCAE Grade 3 or 4 lipase elevations occurred in 11% and 9% of patients in the Nexavar group in study 1 (RCC) and study 3 (HCC), respectively, compared to 7% and 9% of patients in the placebo group. CTCAE Grade 3 or 4 amylase elevations were reported in 1% and 2% of patients in the Nexavar group in study 1 and study 3, respectively, compared to 3% of patients in each placebo group. Clinical pancreatitis was reported in 2 of 451 Nexavar treated patients (CTCAE Grade 4) in study 1, 1 of 297 Nexavar treated patients in study 3 (CTCAE Grade 2), and 1 of 451 patients (CTCAE Grade 2) in the placebo group in study 1.Hypophosphataemia was a very common laboratory finding, observed in 45% and 35% of Nexavar treated patients compared to 12% and 11% of placebo patients in study 1 and study 3, respectively. CTCAE Grade 3 hypophosphataemia (1 – 2 mg/dl) in study 1 occurred in 13% of Nexavar treated patients and 3% of patients in the placebo group, in study 3 in 11% of Nexavar treated patients and 2% of patients in the placebo group. There were no cases of CTCAE Grade 4 hypophosphataemia (< 1 mg/dl) reported in either Nexavar or placebo patients in study 1, and 1 case in the placebo group in study 3. The aetiology of hypophosphataemia associated with Nexavar is not known.CTCAE Grade 3 or 4 laboratory abnormalities occurring in 5% of Nexavar treated patients included lymphopenia and neutropenia.

Manufacturer
Bayer

Drug Availability
(POM)

Updated
04 March 2010