Nexavar

Nexavar

sorafenib

Manufacturer:

Bayer Indonesia
Full Prescribing Info
Contents
Sorafenib.
Description
Each Nexavar film-coated tablet contains 274 mg sorafenib tosylate correspond to 200 mg of sorafenib.
Action
Pharmacotherapeutic group: Protein kinase inhibitors.
Pharmacology: Pharmacodynamics: Sorafenib is a multikinase inhibitor which has demonstrated both anti-proliferative and anti-angiogenic properties in vitro and in vivo.
Mechanism of Action and Pharmacodynamic effects: Sorafenib is a multikinase inhibitor that decreases tumor cell proliferation in vitro.
Sorafenib inhibits tumor growth of human tumor xenografts in athymic mice accompanied by a reduction of tumor angiogenesis.
Sorafenib inhibits the activity of targets present in the tumor cell (CRAF, BRAF, V600E BRAF, c-KIT, and FLT-3) and in the tumor vasculature (CRAF, VEGFR-2, VEGFR-3, and PDGFR-β). RAF kinases are serine/threonine kinases whereas, c-KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-β are receptor tyrosine kinases.
Clinical efficacy: The clinical safety and efficacy of Nexavar have been studied in patients with hepatocellular carcinoma (HCC) and in patients with advanced renal cell carcinoma (RCC).
Hepatocellular Carcinoma: Study 3 (study 100554) was a Phase III, international, multi centre, randomized, double blind, placebo controlled study in 602 patients with hepatocellular carcinoma. Demographics and baseline disease characteristics were comparable between the Nexavar and the placebo group with regard to ECOG status (status 0: 54% vs. 54%; status 1: 38% vs. 39%; status 2: 8% vs. 7%), TNM stage (stage 1: <1% vs. <1%; stage II: 10.4% vs. 8.3%; stage III: 37.8% vs. 43.6%; stage IV: 50.8% vs. 46.9%), and BCLC stage (stage B: 18.1% vs. 16.8%; stage C: 81.6% vs. 83.2%; stage D: <1% vs. 0%).
The study was stopped after a planned interim analysis of OS had crossed the prespecified efficacy boundary. This OS analysis showed a statistically significant advantage for Nexavar over placebo for OS (HR: 0.69, P = 0.00058, See Table 1). In the prespecified stratification factors (ECOG status, presence or absence of macroscopic vascular invasion and/or extrahepatic tumor spread) the hazard ratio consistently favoured Nexavar over placebo. The descriptive subgroup analysis suggested a potentially less pronounced treatment effect for the subgroups of patients below 65 years of age and those with metastatic disease. There are limited data from this study in patients with Child Pugh B liver impairment and only one patient with Child Pugh C had been included. (See Table 1.)


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Renal Cell Carcinoma: The safety and efficacy of Nexavar in the treatment of advanced renal cell carcinoma (RCC) were investigated in two clinical studies: Study 1 was a Phase III, international, multi-centre, randomized, double blind, placebo-controlled study in 903 patients. Primary study endpoints included overall survival and progression-free survival (PFS). Tumor response rate was a secondary endpoint.
Patients were randomized to Nexavar 400 mg twice daily (N=451) or to placebo (N=452). Baseline demographics and patient characteristics were well balanced for both treatment groups. Approximately half of the patients had an ECOG performance Status of 0, and half of the patients were in the low MSKCC (Memorial Sloan Kettering Cancer Center) prognostic group.
In a planned interim analysis of survival based on 220 deaths, there was an estimated 39% improvement in overall survival for patients receiving Nexavar vs. placebo. The estimated hazard ratio (risk of death With Nexavar compared to placebo) was 0.72 (95% CI, 0.55-0.95; p=0.018. The threshold for statistical significance of the interim analysis was p<0.0005).
The PFS analysis included 769 patients randomised to Nexavar 400 mg twice daily (N=384) or to placebo (N=385). PFS was evaluated by blinded independent radiological review using RECIST criteria. The median PFS was double for patients randomized to Nexavar (167 days) compared to placebo patients (84 days) (HR=0.44; 95% CI: 0.35-0.55; p<0.000001).
The effect on PFS was also explored across different patient subsets. The subsets included age above or below 65 years, ECOG PS 0 or 1, MSKCC prognostic risk category 1, whether the prior therapy was for progressive metastatic disease or for an earlier disease setting, and time from diagnosis of less than or greater than 1.5 years. The effect of Nexavar on PFS was consistent across these subsets, including patients with no prior IL-2 or interferon therapy (n=137; 65 patients receiving Nexavar and 72 placebo), for whom the median PFS was 172 days on Nexavar compared to 85 days on placebo.
Best overall tumor response was determined by investigator radiological review according to RECIST criteria. In the Nexavar group 1 patient (0.2%) had a complete response, 43 patients (9.5%) had a partial response, and 333 patients (73.8%) had stable disease. In the placebo group O patients (0%) had complete response, 8 patients (1.8%) had partial response, and 239 patients (52.9%) had stable disease.
Nexavar demonstrated no overall deterioration in kidney-cancer specific symptoms (FKSI-10) or health-related quality of life compared to placebo. At 18 and 24 weeks of treatment, more patients receiving Nexavar reported improvement in total FKSI-10 score (55 and 44%, respectively) and the physical well-being (FACT-G PWB) score (57 and 47%, respectively) versus placebo (FKSI-10, 33 and 21% and FACT-G PWB 37 and 21%, respectively).
Study 2 was a Phase II randomized discontinuation trial in patients with metastatic malignancies, including RCC. The primary endpoint of the study was the percentage of randomized patients (N=65) remaining progression-free at 24 weeks. Progression-free survival was significantly longer in the Nexavar group (163 days) than in the placebo group (41 days) (p=0.0001, HR=0.29). The progression-free rate was significantly higher in patients randomized to Nexavar (50%) than in the placebo patients (18%) (p=0.0077).
Pharmacokinetics: After administration of sorafenib tablets, the mean relative bioavailability is 38-49% when compared to an oral solution.
The elimination half-life of sorafenib is approximately 25-48 hours. Multiple dosing of sorafenib for 7 days results in a 2.5 to 7 fold accumulation compared to single dose administration.
Steady state plasma sorafenib concentrations are achieved within 7 days, with a peak to trough ratio of mean concentrations of less than 2.
Absorption and Distribution: Following oral administration, sorafenib reaches peak plasma levels in approximately 3 hours. When given with a moderate-fat meal, bioavailability is similar to that in the fasted state, with a high-fat meal, sorafenib bioavailability is reduced by 29% compared to administration in the fasted state. It is recommended that sorafenib be administered without food (at least 1 hour before or 2 hours after eating).
Mean Cmax and AUC increase less than proportionally beyond doses of 400 mg administered orally twice daily.
In vitro binding of sorafenib to human plasma proteins is 99.5%.
Metabolism and Elimination: Sorafenib is metabolized primarily in the liver undergoing oxidative metabolism mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9. Sorafenib conjugates may be cleaved in the GI tract by bacterial glucuronidase activity, allowing reabsorption of unconjugated drug. Co-administration of neomycin interferes with this process, decreasing the mean bioavailability of sorafenib by 54%.
Sorafenib accounts for approximately 70-85% of the circulating analytes in plasma at steady state. Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The main circulating metabolite of sorafenib in plasma, the pyridine N-oxide, shows in vitro potency similar to that of sorafenib and comprises approximately 9-16% of circulating analytes at steady state.
Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in feces, and 19% of the dose excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51% of the dose, was found in feces but not in urine.
Studies on enzyme inhibition: Studies with human liver microsomes demonstrated that sorafenib is a competitive inhibitor of CYP2C19, CYP2D6, and CYP3A4. Sorafenib may increase the blood level of drugs that are substrates of these enzymes.
In vitro data show that Sorafenib inhibits glucuronidation by the UGT1A1 and UGT1A9 pathways. Systemic exposure to substrates of UGT1A1 and UGT1A9 may be increased when co-administered with sorafenib.
Sorafenib inhibits CYP2B6 and CYP2C8 in vitro with Ki values of 6 and 1-2 μM, respectively. Systemic exposure to substrates of CYP2B6 and CYP2C8 may increase when co-administered with sorafenib.
Concomitant administration of sorafenib with cyclophosphamide resulted in a small decrease in cyclophosphamide exposure, but no decrease in the systemic exposure of 4-OH cyclophosphamide, the active metabolite of cyclophosphamide that is formed primarily by CYP2B6. These data suggest that sorafenib may not be an in vivo inhibitor of CYP2B6.
Studies with human liver microsomes demonstrated that sorafenib is a competitive inhibitor of CYP2C9 with a Ki value of 7-8 μM. The possible effect of sorafenib on a CYP2C9 substrate was assessed in patients receiving sorafenib or placebo in combination with warfarin. The mean changes from baseline in PT-INR were not higher in sorafenib patients compared to placebo patients, suggesting that sorafenib may not be an in vivo inhibitor of CYP2C9.
Effect of CYP3A4 inhibitors: Ketoconazole (400 mg), 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.
Effect of CYP inducers: 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.
Combination with other anti-neoplastic agents: In clinical studies, sorafenib has been administered together with a variety of other anti-neoplastic agents at their commonly used dosing regimens, including gemcitabine, cisplatin, oxaliplatin, paclitaxel. carboplatin, capecitabine, doxorubicin, irinotecan, and docetaxel, and cyclophosphamide. Sorafenib had no clinically relevant effect on the pharmacokinetics of gemcitabine, cisplatin, carboplatin, oxaliplatin, or cyclophosphamide.
Paclitaxel/Carboplatin: Administration of paclitaxel (225 mg/m2) and carboplatin (AUC = 6) with sorafenib (≤400 mg twice daily) administered with a 3-day break in sorafenib dosing around administration of paclitaxel/carboplatin, resulted in no significant effect on the pharmacokinetics of paclitaxel.
Co-administration of paclitaxel (225 mg/m2, once every 3 weeks) and carboplatin (AUC=6) with sorafenib (400 mg twice daily, without a break in sorafenib dosing) resulted in a 35% increase in sorafenib exposure, a 29% increase in paclitaxel exposure and a 50% increase in 6-OH paclitaxel exposure. The pharmacokinetics of carboplatin were unaffected.
These data indicate no need for dose adjustments when paclitaxel and carboplatin are co-administered with sorafenib with a 3-day break in sorafenib dosing. The clinical significance of the small increases in sorafenib and paclitaxel exposure, upon co-administration of sorafenib without a break in dosing, is unknown.
Capecitabine: Co-administration of capecitabine (750-1050 mg/m2, Days 1-14 every 21 days) and sorafenib (200 or 400 mg twice daily, continuous uninterrupted administration) resulted in no significant change in sorafenib exposure, but a 15-50% increase in capecitabine exposure and a 0-52% increase in 5-FU exposure. The clinical significance of these small to modest increases in capecitabine and 5-FU exposure upon co-administered with sorafenib is unknown.
Doxorubicin/Irinotecan: Concomitant treatment with sorafenib resulted in a 21% increase in the AUC of doxorubicin. When administered with irinotecan, whose active metabolite SN-38 is further metabolized by the UGT 1A1 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 (see Precautions).
Docetaxel: 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 Day 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. (See Precautions).
Combination with antibiotics: Neomycin: Co-administration of neomycin, a non-systemic antimicrobial agent used to eradicate GI flora microbes with the enterohepatic recycling of sorafenib (see previously mentioned), resulting in decreased sorafenib exposure. In healthy volunteers treated with a 5-day regimen of neomycin the average bioavailability of sorafenib decreased by 54%. The clinical significance of these findings for is unknown. Effects of other antibiotics have not been studied, but will likely depend on their ability to decrease glucuronidase activity.
Combination with proton pump Inhibitors: Omeprazole: Co-administration of omeprazole has no impact on the pharmacokinetics of sorafenib. No dose adjustment for sorafenib is necessary.
Pharmacokinetics in Special Populations: Elderly (above 65 years) and gender: Analyses Of demographic data suggest that no dose adjustments are necessary for age or gender.
Pediatric patients: There are no pharmacokinetic data in pediatric patients.
Hepatic impairment: Sorafenib is cleared primarily by the liver.
In HCC patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, exposure values were within the range observed in patients without hepatic impairment. The pharmacokinetics (PK) of sorafenib in Child-Pugh A and Child-Pugh B non-HCC patients were similar to the PK in healthy volunteers. The pharmacokinetics of sorafenib has not been studied in patients with severe (Child-Pugh C) hepatic impairment. (See Precautions).
Sorafenib is mainly eliminated via the liver, and exposure might be increased in this patient population.
Renal impairment: In four Phase I clinical trials, steady state exposure to sorafenib was similar in patients with mild or moderate renal impairment compared to the exposures in patients with normal renal function. In a clinical pharmacology study (single dose of 400 mg of sorafenib), no relationship was observed between sorafenib exposure and renal function in subjects with normal renal function, mild, moderate or severe renal impairment. No data is available in patients requiring dialysis.
Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: The preclinical safety profile of sorafenib was assessed in mice, rats, dogs and rabbits.
Repeat-dose toxicity studies revealed changes (degenerations and regenerations) in various organs at exposures below the anticipated clinical exposure (based on AUC comparisons).
After repeated dosing to young and growing dogs effects on bone and teeth were observed at exposures below the clinical exposure. Changes consisted in irregular thickening of the femoral growth plate at a daily sorafenib dose of 600 mg/m2 body surface area (equivalent to 1.2 times the recommended clinical dose of 500 mg/m2 on a body surface area basis), hypocellularity of the bone marrow next to the altered growth plate at 200 mg/m2/day, and alterations of the dentin composition at 600 mg/m2/day. Similar effects were not induced in adult dogs.
Positive genotoxic effects were obtained for sorafenib in an in vitro mammalian cell assay (Chinese hamster ovary) for clastogenicity (chromosome aberrations) in the presence of metabolic activation. One intermediate in the manufacturing process, which is also present in the final drug substance (<0.15%), was positive for mutagenesis in an in vitro bacterial cell assay (Ames test). Sorafenib was not genotoxic in the Ames test (the material contained the intermediate at 0.34%), and in an in vivo mouse micronucleus assay.
Carcinogenicity studies have not been performed with sorafenib.
No specific studies with sorafenib have been conducted in animals to evaluate the effect on fertility. An adverse effect on male and female fertility can however be expected because repeat-dose studies in animals have shown changes in male and female reproductive organs at exposure below the anticipated clinical exposure (based on AUC). Typical changes consisted of signs of degeneration and retardation in testes, epididymides, prostate, and seminal vesicles of rats. Female rats showed central necrosis of the corpora lutea and arrested follicular development in the ovaries. Dogs showed tubular degeneration in the testes and oligospermia. Sorafenib has been shown to be embryotoxic and teratogenic when administered to rats and rabbits at exposures below the clinical exposure. Observed effects included decreases in maternal and fetal body weights, an increased number of fetal resorptions and an increased number of external and visceral malformations. Adverse fetal outcomes were observed at an oral dose of 6 mg/m2/day in rats and 36 mg/m2/day in rabbits (see Precautions and Use in Pregnancy & Lactation).
Indications/Uses
NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma.
NEXAVAR is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC).
Dosage/Direction for Use
Recommended dose: The recommended daily dose of sorafenib is 400 mg (2 x 200 mg tablets) taken twice a day, without food (at least 1 hour before or 2 hours after eating).
Method of administration: For oral use. To be swallowed with a glass of water.
Duration of treatment: Treatment should be continued until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.
Dose titration, dose adjustment, special monitoring advice: Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of sorafenib therapy. When dose reduction is necessary, the sorafenib dose should be reduced to two tablets of 200 mg once daily (see Precautions).
Suggested dose modifications for skin toxicity are outlined in Table 2. (See Table 2.)


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Special populations: Pediatric Patients: The safety and effectiveness of sorafenib in children and adolescents (<18 years) have not been established. Nexavar is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.
Elderly (above 65 years), Gender and Body Weight: No dose adjustment is required on the basis of patient age (above 65 years), gender, or body weight.
Hepatic impairment: No dose adjustment is required in patients with Child-Pugh A or B hepatic impairment. Sorafenib has not been studied in patients with Child-Pugh C hepatic impairment (see Pharmacology: Pharmacokinetics: Special populations: Hepatic Impairment under Actions).
Renal impairment: No dose adjustment is required in patients with mild, moderate or severe renal impairment not requiring dialysis. Sorafenib has not been studied in patients undergoing dialysis. (See Pharmacology: Pharmacokinetics: Special Populations: Renal Impairment under Actions).
Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised.
Overdosage
There is no specific treatment for sorafenib overdose.
The highest dose of sorafenib studied clinically is 800 mg twice daily. The adverse reactions observed at this dose were primarily diarrhea and dermatologic events.
In the event of suspected overdose, sorafenib should be withheld and supportive care instituted.
Contraindications
Sorafenib is contraindicated in patients with known severe hypersensitivity to sorafenib or 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 sorafenib. Rash and hand-foot skin reaction are usually CTC (National Cancer Institute Common Toxicity Criteria) Grade 1 and 2 and generally appear during the first six weeks of treatment with sorafenib.
Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of sorafenib, or in severe or persistent cases, permanent discontinuation of sorafenib (see Adverse Reactions).
Hypertension: An increased incidence of hypertension was observed in sorafenib-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 of persistent hypertension, or hypertensive crisis despite adequate antihypertensive therapy, permanent discontinuation of sorafenib should be considered (see Adverse Reactions).
Hemorrhage: An increase in the risk of bleeding may occur following sorafenib administration. The incidence of severe bleeding events is uncommon. If any bleeding event necessitates medical intervention, it is recommended that permanent discontinuation of sorafenib should be considered (see Adverse Reactions).
Warfarin: Infrequent bleeding events or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on sorafenib therapy. Patients taking warfarin concomitantly should be monitored regularly for changes in prothrombin time, INR and for clinical bleeding episodes (see Adverse Reactions).
Wound healing complications: No formal studies of the effect of sorafenib on wound healing have been conducted. In patients undergoing major surgical procedures, temporary interruption of sorafenib therapy is recommended for precautionary reasons. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume sorafenib therapy following a major surgical intervention should be based on clinical judgment of adequate wound healing.
Cardiac Ischemia and/or Infarction: In Study 11213, the incidence of treatment-emergent cardiac ischemia/infarction events was higher in the NEXAVAR group (2.9%) compared with the placebo group (0.4%). In Study 100554, the incidence of treatment-emergent cardiac ischemia/infarction events was 2.7% in sorafenib 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 ischemia and/or infarction (see Pharmacology: Pharmacodynamics: Clinical Efficacy under Actions and Adverse Reactions).
Gastrointestinal perforation: Gastrointestinal perforation is an uncommon adverse reaction and has been reported in less than 1% of patients taking sorafenib. In some cases this was not associated with apparent intra-abdominal tumor. In the event of a gastrointestinal perforation, sorafenib therapy should be discontinued.
Hepatic 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 (see Pharmacology: Pharmacokinetics under Actions).
Drug-Drug Interactions: UGT1A1 pathway: Caution is recommended when administering sorafenib together with compounds that are metabolized/eliminated predominantly by the UGT1A1 pathway (e.g. irinotecan). (See interactions.)
Docetaxel: Concomitant use Of docetaxel (75 or 100 mg/m2 administered every 21 days) With sorafenib (200 mg or 400 mg twice daily), administered 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 (see Interactions).
Doxorubicin: Concomitant treatment with Nexavar resulted in a 21% increase in the AUC of doxorubicin. Caution is recommended when administering doxorubicin with Nexavar. (See Interactions).
Neomycin: Co-administration of neomycin may cause a decrease in sorafenib bioavailability (see Interactions).
QT Interval prolongation: NEXAVAR has been shown to prolong the QT/QTc interval (see Pharmacology: Pharmacodynamics under Actions), which may lead to an increased risk for ventricular arrhythmias. Use sorafenib with caution in patients who have, or may develop prolongation of QTc, such as patients with a congenital long QT syndrome, patients treated with a high cumulative dose of anthracycline therapy, patients taking certain anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, or hypomagnesemia. When using NEXAVAR in these patients, periodic monitoring with on-treatment electrocardiograms and electrolytes (magnesium, potassium, calcium) should be considered.
Effects on Ability to Drive and Use Machines: No studies on the effects of sorafenib on the ability to drive or use machines have been performed. There is no evidence that sorafenib affects the ability to drive or operate machinery.
Use in Pregnancy: Women should avoid becoming pregnant while on therapy.
Women of childbearing potential must be apprised of the potential hazard to the fetus, which includes severe malformation (teratogenicity), failure to thrive and fetal death (embryotoxicity).
Sorafenib should not be used during pregnancy. Prescribers may only consider it to be used, if the potential benefits justify the potential risks to the fetus.
Based on the proposed mechanism of multikinase inhibition and multiple adverse effects seen in animals at exposure levels significantly below the clinical dose, sorafenib should be assumed to cause fetal harm when administered to a pregnant woman.
Breastfeeding should be discontinued during sorafenib therapy. (See Use in Pregnancy & Lactation).
Use In Pregnancy & Lactation
Pregnancy: There are no adequate and well-controlled studies in pregnant women using sorafenib. Studies in animals have shown reproductive toxicity including malformations. In rats, sorafenib and its metabolites were demonstrated to cross the placenta and sorafenib is anticipated to inhibit angiogenesis in the fetus.
Women should avoid becoming pregnant while on therapy. Women of childbearing potential must be apprised of the potential hazard to the fetus, which includes severe malformation (teratogenicity), failure to thrive and fetal death (embryotoxicity).
Sorafenib should not be used during pregnancy. Prescribers may only consider it to be used, if the potential benefits justify the potential risks to the fetus (see Precautions).
Women of childbearing-potential: In animals, sorafenib has been shown to be teratogenic and embryotoxic. Adequate contraception should be used during therapy and for at least 2 weeks after completion of therapy.
Lactation: It is not known whether sorafenib is excreted in human milk. In animals, sorafenib and/or its metabolites were excreted in milk. Because many drugs are excreted in human milk and because the effects of sorafenib on infants have not been studied, woman should discontinue breastfeeding during sorafenib treatment.
Fertility: Results from animal studies indicate that sorafenib can impair male and female fertility.
Adverse Reactions
The most common adverse reactions were diarrhoea, rash, alopecia and hand-foot skin syndrome (corresponds to palmar plantar erythrodysaesthesia syndrome in MedDRA). (See Table 3 and Table 4.)


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Adverse reactions that occurred either during clinical studies or have been identified through postmarketing use 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), rare (≥1/10,000, <1/1,000), not known (cannot be estimated from the data available).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See Table 5.)


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Further information on selected adverse drug reactions: Congestive 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 1.7% of those 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.
Two randomized placebo-controlled trials comparing safety and efficacy of sorafenib in combination with doublet platinum-based chemotherapies (carboplatin/paclitaxel and separately gemcitabine/cisplatin) versus the respective doublet platinum-based chemotherapies alone as first-line treatment for patients with advanced Non-Small Cell Lung Cancer (NSCLC) did not meet their primary endpoint of improved overall survival. Safety events were generally consistent with those previously reported. However, in both trials, higher mortality was observed in the subset of patients with squamous cell carcinoma of the lung treated with sorafenib and doublet platinum-based chemotherapies versus those treated with doublet platinum-based chemotherapies alone (paclitaxel/carboplatin: HR 1.81, 95% CI 1.19-2.74; gemcitabine/cisplatin: HR 1.22, 95% CI 0.82-1.80). No definitive cause was identified for the findings.
Laboratory test abnormalities in RCC patients (study 11213): Elevated lipase and amylase levels were very commonly reported. In Study 1, CTCAE grade 3 or 4 lipase elevations occurred in 12% of patients in the soraferub group compared to 7% of patients in the placebo group. CTCAE grade 3 or 4 amylase elevations were reported in 1% of patients in the sorafenib group compared to 3% grade of patients in the placebo group. Clinical pancreatitis was reported in 2 of 451 sorafenib treated patients (CTCAE grade 4) and 1 of 451 patients (CTCAE grade 2) in the placebo group in Study 1.
Hypophosphataemia was a common laboratory finding, observed in 45% of sorafenib treated patients compared to 11% of placebo patients. CTCAE grade 3 hypophosphataemia (1-2 mg/dl) occurred in 13% on sorafenib treated patients and 3% of patients in the placebo group. There were no cases of CTCAE grade 4 hypophosphataemia (<1 mg/dl) reported in either sorafenib or placebo patients. The aetiology of hypophosphataemia associated with sorafenib is not known.
CTCAE grade 3 or 4 were reported for lymphopenia in 13% of sorafenib treated patients and 7% of placebo patients, for neutropenia in 5% of sorafenib treated patients and 2% of placebo patients, for anaemia in 2% of sorafenib treated patients and 4% of placebo patients and for thrombocytopenia in 1% of sorafenib treated patients and 0% of placebo patients.
Laboratory abnormalities in HCC patients (study 100554): Elevated lipase was observed in 40% of patients treated with NEXAVAR compared to 37% of patients in the placebo group. CTCAE Grade 3 or 4 lipase elevations occurred in 9% of patients in each group. Elevated amylase was observed in 34% of patients treated with NEXAVAR compared to 29% of patients in the placebo group. CTCAE Grade 3 or 4 amylase elevations were reported in 2% of patients in each group. Many of the lipase and amylase elevations were transient, and in the majority of cases NEXAVAR treatment was not interrupted. Clinical pancreatitis was reported in 1 of 297 NEXAVAR-treated patients (CTCAE Grade 2).
Hypophosphataemia was a common laboratory finding, observed in 35% of NEXAVAR-treated patients compared to 11% of placebo patients; CTCAE grade 3 hypophosphataemia (1-2 mg/dl) occurred in 11% of NEXAVAR treated patients and 2% of patients in the placebo group; There was 1 case of CTCAE Grade 4 hypophosphataemia (<1 mg/dl) reported in the placebo group. The etiology of hypophosphataemia associated with NEXAVAR is not known.
Elevations in liver function tests were comparable between the 2 arms of the study. Hypoalbuminemia was observed in 59% of NEXAVAR-treated patients and 47% of placebo patients; no CTCAE Grade 3 or 4 hypoalbuminemia was observed in either group.
INR elevations were observed in 42% of NEXAVAR-treated patients; CTCAE Grade 3 INR elevations were reported in 4% of NEXAVAR-treated patients and 2% of placebo patients; there was no CTCAE Grade 4 INR elevation in either group.
Lymphopenia was observed in 47% of NEXAVAR-treated patients and 42% of placebo patients.
Thrombocytopenia was observed in 46% of NEXAVAR-treated patients and 41% of placebo patients; CTCAE Grade 3 or 4 thrombocytopenia was reported in 4% of NEXAVAR-treated patients and less than 1% of placebo patients.
Drug Interactions
CYP3A4 Inducers: Continuous concomitant administration of sorafenib and rifampicin resulted in an average 37% reduction of sorafenib AUC. Other inducers of CYP3A4 activity (e.g. Hypericum perforatum also known as St. John's wort, phenytoin, carbamazepine, phenobarbital, and dexamethasone) may 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. Therefore, clinical pharmacokinetic interactions of sorafenib with CYP3A4 inhibitors are unlikely.
CYP2C9 substrates: The possible effect of sorafenib on warfarin, a CYP2C9 substrate, was assessed in sorafenib-treated patients compared to placebo treated patients. The concomitant treatment with sorafenib and warfarin did not result in changes in mean PT-INR compared to placebo. However, patients taking warfarin should have their INR checked regularly (see Precautions).
CYP isoform-selective substrates: Concomitant administration of midazolam, dextromethorphan and omeprazole, which are substrates of cytochromes CYP3A4, CYP2D6 and CYP2C19, respectively, following 4 weeks of sorafenib administration did not alter the exposure of these agents. This indicates that sorafenib is neither an inhibitor nor an inducer of these cytochrome P450 isoenzymes. In a separate clinical study, concomitant administration of sorafenib with paclitaxel resulted in an increase, instead of a decrease, in the exposure of 6-OH paclitaxel, the active metabolite of paclitaxel that is formed by CYP2C8. These data suggest that sorafenib may not be an in vivo inhibitor of CYP2C8. In another clinical study, concomitant administration of sorafenib with cyclophosphamide resulted in a small decrease in cyclophosphamide exposure, but no decrease in the systemic exposure of 4-OH cyclophosphamide, the active metabolite of cyclophosphamide that is formed primarily by CYP2B6. These data suggest that sorafenib may not be an in vivo inhibitor of CYP2B6.
Combination with other anti-neoplastic agents: In clinical studies, sorafenib has been administered together with a variety of other anti-neoplastic agents at their commonly used dosing regimens, including gemcitabine, cisplatin, oxaliplatin, paclitaxel, carboplatin, capecitabine, doxorubicin, irinotecan, and docetaxel, and cyclophosphamide. Sorafenib had no clinically relevant effect on the pharmacokinetics of gemcitabine, cisplatin, carboplatin, oxaliplatin, or cyclophosphamide.
Paclitaxel/Carboplatin: Administration of paclitaxel (225 mg/m2) and carboplatin (AUC=6) with sorafenib (≤400 mg twice daily), administered with a 3-day break in sorafenib dosing around administration of paclitaxel/carboplatin, resulted in no significant effect on the pharmacokinetics of paclitaxel.
Co-administration of paclitaxel (225 mg/m2, once every 3 weeks) and carboplatin (AUC=6) with sorafenib (400 mg twice daily, without a break in sorafenib dosing) resulted in a 47% increase in sorafenib exposure, a 29% increase in paclitaxel exposure and a 50% increase in 6-OH paclitaxel exposure. The pharmacokinetics of carboplatin were unaffected.
These data indicate no need for dose adjustments when paclitaxel and carboplatin are co-administered with sorafenib with a 3-day break in sorefenib dosing. The clinical significance of the small increases in sorefenib and paclitaxel exposure, upon co-administration of sorafenib without a break in dosing, is unknown.
Capecitabine: Co-administration Of capecitabine (750-1050 mg/m2 twice daily, Days 1-14 every 21 days) and sorafenib (200 or 400 mg twice daily, continuous uninterrupted administration) resulted in no significant change in sorafenib exposure, but a 15-50% increase in capecitabine exposure and a 0-52% increase in 5-FU exposure. The clinical significance of these small to modest increases in capecitabine and 5-FU exposure when co-administered with sorafenib is unknown.
Doxorubicin/Irinotecan: Concomitant treatment with sorafenib resulted in a 21% increase in the AUC of doxorubicin. When administered with irinotecan, whose active metabolite SN-38 is further metabolized 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 (see Precautions).
Docotaxel: 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 Day 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 (see Precautions).
Combination with antibiotics: Neomycin: Co-administration of neomycin, a non-systemic antimicrobial agent used to eradicate GI flora, interferes with the enterohepatic recycling of sorafenib (see Pharmacology: Pharmacokinetics: Metabolism and Elimination under Actions), resulting in decreased sorafenib exposure. In healthy volunteers treated with a 5-day regimen of neomycin the average bioavailability of sorafenib decreased by 54%. The clinical significance of these findings is unknown. Effects of other antibiotics have not been studied, but will likely depend on their ability to decrease glucuronidase activity.
Combination with proton pump inhibitors: Omeprazole: Co-administration of omeprazole has no impact on the the pharmacokinetics of sorafenib. No dose adjustment for sorafenib is necessary.
Storage
Store below 30°C.
Self life: 36 months.
ATC Classification
L01XE05 - sorafenib ; Belongs to the class of protein kinase inhibitors, other antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
FC tab 200 mg x 6 x 10's.
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