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Indications/Uses
Treatment of patients with hepatocellular and advanced renal cell carcinoma.
Dosage/Direction for Use
Recommended Daily Dose: 400 mg (2 x 200 mg tablets) taken twice a day, either without food or together with a low fat or moderate fat meal.
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 2 tablets of 200 mg once daily (see Precautions).
Suggested dose modifications for skin toxicity are shown in Table 2.
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 2 tablets of 200 mg once daily (see Precautions).
Suggested dose modifications for skin toxicity are shown in Table 2.
Special Populations: Pediatric Patients: The safety and effectiveness of sorafenib in pediatric patients has not been established.
Elderly (>65 years), Gender and Body Weight: No dose adjustment is required on the basis of patient age (>65 years), gender or body weight.
Hepatic Impairment: No dose adjustment is required in patients with Child-Pugh A and B hepatic impairment. Sorafenib has not been studied in patients with Child-Pugh C hepatic impairment (see Hepatic Impairment in Special Populations 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 Renal Impairment in Special Populations under Actions).
Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised.
Administration: For oral use. To be swallowed with a glass of water.
Elderly (>65 years), Gender and Body Weight: No dose adjustment is required on the basis of patient age (>65 years), gender or body weight.
Hepatic Impairment: No dose adjustment is required in patients with Child-Pugh A and B hepatic impairment. Sorafenib has not been studied in patients with Child-Pugh C hepatic impairment (see Hepatic Impairment in Special Populations 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 Renal Impairment in Special Populations under Actions).
Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised.
Administration: For oral use. To be swallowed with a glass of water.
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.
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.
Administration
Should be taken on an empty stomach: Take on an empty stomach or w/ a low or moderate fat meal. If the patient intends to have a high fat meal, take at least 1 hr before or 2 hr after meals. Swallow whole, do not chew/crush.
Contraindications
Patients with known severe hypersensitivity to sorafenib or any of the excipients.
Special Precautions
Dermatological Toxicities: Hand-foot skin reaction (palmar-plantar erythrodysesthesia) and rash represent the most common adverse reactions with sorafenib. Rash and hand-foot skin reaction are usually National Cancer Institute Common Toxicity Criteria (CTC) grade 1 and 2 and generally appear during the first 6 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 or 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 normal 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 sorafenib group (4.9%) 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 this study. Temporary or permanent discontinuation of Nexavar should be considered in patients who develop cardiac ischemia and/or infarction (see Pharmacology: Clinical Efficacy and Safety under Actions and Adverse Reactions).
QT Interval Prolongation: Nexavar has been shown to prolong the QT/QTc interval (see Pharmacology 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 eg, patients with a congenital long QT syndrome, patients treated with a high cumulative dose of anthracycline therapy, patients taking certain antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances eg, hypokalemia, hypocalcemia, or hypomagnesemia. When using Nexavar in these patients, periodic monitoring with on-treatment electrocardiograms and electrolytes (magnesium, potassium, calcium) should be considered.
Gastrointestinal Perforation: Gastrointestinal perforation is an uncommon event and has been reported in <1% of patients taking sorafenib. In some cases, this was not associated with apparent intra-abdominal tumor. Sorafenib therapy should be discontinued (see Adverse Reactions).
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 Pharmacokinetics under Actions).
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 (see Toxicology: Preclinical Safety Data under Actions).
Drug-Drug Interactions: UGT1A Pathway: Caution is recommended when administering sorafenib together with compounds that are metabolized/eliminated predominantly by the UGT1A1 pathway (eg, irinotecan) (see Interactions).
Docetaxel: Concomitant use of docetaxel (75 or 100 mg/m2) with sorafenib (200 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. Caution is recommended when sorafenib is co-administered with docetaxel.
Neomycin: Co-administration of neomycin may cause a decrease in sorafenib concentration.
Effects on the Ability to Drive or Operate Machinery: 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.
Impairment of Fertility: Results from animal studies indicate that sorafenib can impair male and female fertility (see Toxicology: Preclinical Safety Data under Actions).
Use in Pregnancy: 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.
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 Toxicology: Preclinical Safety Data under Actions).
Use in 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.
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 or 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 normal 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 sorafenib group (4.9%) 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 this study. Temporary or permanent discontinuation of Nexavar should be considered in patients who develop cardiac ischemia and/or infarction (see Pharmacology: Clinical Efficacy and Safety under Actions and Adverse Reactions).
QT Interval Prolongation: Nexavar has been shown to prolong the QT/QTc interval (see Pharmacology 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 eg, patients with a congenital long QT syndrome, patients treated with a high cumulative dose of anthracycline therapy, patients taking certain antiarrhythmic medicines or other medicinal products that lead to QT prolongation, and those with electrolyte disturbances eg, hypokalemia, hypocalcemia, or hypomagnesemia. When using Nexavar in these patients, periodic monitoring with on-treatment electrocardiograms and electrolytes (magnesium, potassium, calcium) should be considered.
Gastrointestinal Perforation: Gastrointestinal perforation is an uncommon event and has been reported in <1% of patients taking sorafenib. In some cases, this was not associated with apparent intra-abdominal tumor. Sorafenib therapy should be discontinued (see Adverse Reactions).
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 Pharmacokinetics under Actions).
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 (see Toxicology: Preclinical Safety Data under Actions).
Drug-Drug Interactions: UGT1A Pathway: Caution is recommended when administering sorafenib together with compounds that are metabolized/eliminated predominantly by the UGT1A1 pathway (eg, irinotecan) (see Interactions).
Docetaxel: Concomitant use of docetaxel (75 or 100 mg/m2) with sorafenib (200 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. Caution is recommended when sorafenib is co-administered with docetaxel.
Neomycin: Co-administration of neomycin may cause a decrease in sorafenib concentration.
Effects on the Ability to Drive or Operate Machinery: 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.
Impairment of Fertility: Results from animal studies indicate that sorafenib can impair male and female fertility (see Toxicology: Preclinical Safety Data under Actions).
Use in Pregnancy: 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.
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 Toxicology: Preclinical Safety Data under Actions).
Use in 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.
Use In Pregnancy & Lactation
Use in Pregnancy: 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.
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 Toxicology: Preclinical Safety Data under Actions).
Use in 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.
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 Toxicology: Preclinical Safety Data under Actions).
Use in 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.
Adverse Reactions
The most important serious adverse reactions were myocardial infarction/ischemia, gastrointestinal perforation, drug-induced hepatitis, hemorrhage, and hypertension/hypertensive crisis.
The most common adverse reactions were diarrhea, rash, alopecia and hand-foot skin syndrome (corresponds to palmar-plantar erythrodysesthesia syndrome in MedDRA).
Adverse reactions reported in multiple clinical trials or through post-marketing use are listed in Tables 3 and 4, by system organ class (in MedDRA) and frequency. Frequencies are defined as: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), not known (cannot be estimated from the data available).
Within each frequency grouping, adverse effects are presented in order of decreasing seriousness. (See Tables 3 and 4.)
The most common adverse reactions were diarrhea, rash, alopecia and hand-foot skin syndrome (corresponds to palmar-plantar erythrodysesthesia syndrome in MedDRA).
Adverse reactions reported in multiple clinical trials or through post-marketing use are listed in Tables 3 and 4, by system organ class (in MedDRA) and frequency. Frequencies are defined as: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), not known (cannot be estimated from the data available).
Within each frequency grouping, adverse effects are presented in order of decreasing seriousness. (See Tables 3 and 4.)
Palmar-plantar erythrodysesthesia syndrome in MedDRA.
Adverse reactions that occurred either during clinical studies or have been identified through post-marketing use are listed in Table 5, by system organ class (in MedDRA) and frequency. Frequencies are defined as: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), not known (cannot be estimated from the data available).
Within each frequency grouping, adverse effects are presented in order of decreasing seriousness. (See Table 5.)
Adverse reactions that occurred either during clinical studies or have been identified through post-marketing use are listed in Table 5, by system organ class (in MedDRA) and frequency. Frequencies are defined as: Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), not known (cannot be estimated from the data available).
Within each frequency grouping, adverse effects are presented in order of decreasing seriousness. (See Table 5.)
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 in 1.1% receiving placebo were reported with these events.
Special Populations: 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 1st 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 0.82-1.8). No definitive cause was identified for the findings.
Safety was also assessed in a phase 2 study pool comprised of 638 sorafenib-treated patients, including 202 patients with RCC, 137 patients with hepatocellular carcinoma, and 299 patients with other cancers. The most common drug-related adverse events reported in sorafenib-treated patients in this pool were rash (38%), diarrhea (37%), hand-foot skin reaction (35%), and fatigue (33%). The respective rates of CTC (v 2.0) grade 3 and 4 drug-related adverse events in sorafenib-treated patients were 37% and 3%, respectively.
Laboratory Test Abnormalities in RCC Patients (Study 11213): Elevated lipase and amylase levels were very commonly reported. In Study 11213, Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 lipase elevations occurred in 12% of patients in the sorafenib 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% of patients in the placebo group. Clinical pancreatitis was reported in 2/451 sorafenib-treated patients (CTCAE grade 4) and 1/451 patients (CTCAE grade 2) in the placebo group in Study 1.
Hypophosphatemia was a common laboratory finding, observed in 45% of sorafenib treated patients compared to 11% of placebo patients. CTCAE grade 3 hypophosphatemia (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 hypophosphatemia (<1 mg/dL) reported in either sorafenib or placebo patients. The etiology of hypophosphatemia 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 anemia 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.
Hypocalcemia was reported in 12% of sorafenib treated patients compared to 7.5% of placebo patients. Most reports of hypocalcemia were low grade (CTCAE grade 1 and 2). CTCAE grade 3 hypocalcemia (6-7 mg/dL) occurred in 1.1% of sorafenib treated patients and 0.2% of patients in the placebo group, and CTCAE grade 4 hypocalcemia (<6 mg/dL) occurred in 1.1% of sorafenib treated patients and 0.5% of patients in the placebo group. The etiology of hypocalcemia associated with sorafenib is not known.
Laboratory Test 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).
Hypophosphatemia was a common laboratory finding, observed in 35% of Nexavar-treated patients compared to 11% of placebo patients; CTCAE grade 3 hypophosphatemia (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 hypophosphatemia (<1 mg/dL) reported in the placebo group. The etiology of hypophosphatemia associated with Nexavar is not known.
Elevations in liver function tests were comparable between the 2 arms of the study. Elevated AST was observed in 94% of Nexavar-treated patients and 91% of placebo patients; CTCAE grade 3 or 4 AST elevations were reported in 16% of Nexavar-treated patients and 17% of patients in the placebo group. ALT elevations were observed in 69% of Nexavar-treated patients and 68% of placebo patients; CTCAE grade 3 or 4 ALT elevations were reported in 3% of Nexavar-treated patients and 8% of placebo treated patients. Elevated bilirubin was observed in 47% of Nexavar-treated patients and 45% of placebo patients; CTCAE grade 3 or 4 bilirubin elevations were reported in 10% of Nexavar-treated patients and 11% of placebo treated patients. 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.
Alkaline phosphatase elevations were observed in 82.2% of Nexavar-treated patients and 82.5% of placebo patients; CTCAE grade 3 alkaline phosphatase elevations were reported in 6.2% of Nexavar-treated patients and 8.2% of placebo treated patients; no CTCAE grade 4 alkaline phosphatase elevation was observed in either group.
International normalized ratio elevations were observed in 42% of Nexavar-treated patients and 34% of placebo 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; CTCAE grade 3 or 4 lymphopenia was reported in 6% of patients in each group. Neutropenia was observed in 11% of Nexavar-treated patients and 14% of placebo patients; CTCAE grade 3 or 4 neutropenia was reported in 1% of patients in each group.
Anemia was observed in 59% of Nexavar-treated patients and 64% of placebo patients; CTCAE grade 3 or 4 anemia was reported in 3% of patients in each group.
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 <1% of placebo patients.
Hypocalcaemia was reported in 26.5% of sorafenib-treated patients compared to 14.8% of placebo patients. Most reports of hypocalcemia were low grade (CTCAE grade 1 and 2). CTCAE grade 3 hypocalcemia (6-7 mg /dL) occurred in 1.8% of sorafenib-treated patients and 1.1% of patients in the placebo group, and CTCAE grade 4 hypocalcemia (<6 mg/dL) occurred in 0.4% of sorafenib-treated patients and 0% of patients in the placebo group. The etiology of hypocalcemia associated with sorafenib is not known.
Special Populations: 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 1st 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 0.82-1.8). No definitive cause was identified for the findings.
Safety was also assessed in a phase 2 study pool comprised of 638 sorafenib-treated patients, including 202 patients with RCC, 137 patients with hepatocellular carcinoma, and 299 patients with other cancers. The most common drug-related adverse events reported in sorafenib-treated patients in this pool were rash (38%), diarrhea (37%), hand-foot skin reaction (35%), and fatigue (33%). The respective rates of CTC (v 2.0) grade 3 and 4 drug-related adverse events in sorafenib-treated patients were 37% and 3%, respectively.
Laboratory Test Abnormalities in RCC Patients (Study 11213): Elevated lipase and amylase levels were very commonly reported. In Study 11213, Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 lipase elevations occurred in 12% of patients in the sorafenib 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% of patients in the placebo group. Clinical pancreatitis was reported in 2/451 sorafenib-treated patients (CTCAE grade 4) and 1/451 patients (CTCAE grade 2) in the placebo group in Study 1.
Hypophosphatemia was a common laboratory finding, observed in 45% of sorafenib treated patients compared to 11% of placebo patients. CTCAE grade 3 hypophosphatemia (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 hypophosphatemia (<1 mg/dL) reported in either sorafenib or placebo patients. The etiology of hypophosphatemia 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 anemia 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.
Hypocalcemia was reported in 12% of sorafenib treated patients compared to 7.5% of placebo patients. Most reports of hypocalcemia were low grade (CTCAE grade 1 and 2). CTCAE grade 3 hypocalcemia (6-7 mg/dL) occurred in 1.1% of sorafenib treated patients and 0.2% of patients in the placebo group, and CTCAE grade 4 hypocalcemia (<6 mg/dL) occurred in 1.1% of sorafenib treated patients and 0.5% of patients in the placebo group. The etiology of hypocalcemia associated with sorafenib is not known.
Laboratory Test 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).
Hypophosphatemia was a common laboratory finding, observed in 35% of Nexavar-treated patients compared to 11% of placebo patients; CTCAE grade 3 hypophosphatemia (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 hypophosphatemia (<1 mg/dL) reported in the placebo group. The etiology of hypophosphatemia associated with Nexavar is not known.
Elevations in liver function tests were comparable between the 2 arms of the study. Elevated AST was observed in 94% of Nexavar-treated patients and 91% of placebo patients; CTCAE grade 3 or 4 AST elevations were reported in 16% of Nexavar-treated patients and 17% of patients in the placebo group. ALT elevations were observed in 69% of Nexavar-treated patients and 68% of placebo patients; CTCAE grade 3 or 4 ALT elevations were reported in 3% of Nexavar-treated patients and 8% of placebo treated patients. Elevated bilirubin was observed in 47% of Nexavar-treated patients and 45% of placebo patients; CTCAE grade 3 or 4 bilirubin elevations were reported in 10% of Nexavar-treated patients and 11% of placebo treated patients. 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.
Alkaline phosphatase elevations were observed in 82.2% of Nexavar-treated patients and 82.5% of placebo patients; CTCAE grade 3 alkaline phosphatase elevations were reported in 6.2% of Nexavar-treated patients and 8.2% of placebo treated patients; no CTCAE grade 4 alkaline phosphatase elevation was observed in either group.
International normalized ratio elevations were observed in 42% of Nexavar-treated patients and 34% of placebo 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; CTCAE grade 3 or 4 lymphopenia was reported in 6% of patients in each group. Neutropenia was observed in 11% of Nexavar-treated patients and 14% of placebo patients; CTCAE grade 3 or 4 neutropenia was reported in 1% of patients in each group.
Anemia was observed in 59% of Nexavar-treated patients and 64% of placebo patients; CTCAE grade 3 or 4 anemia was reported in 3% of patients in each group.
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 <1% of placebo patients.
Hypocalcaemia was reported in 26.5% of sorafenib-treated patients compared to 14.8% of placebo patients. Most reports of hypocalcemia were low grade (CTCAE grade 1 and 2). CTCAE grade 3 hypocalcemia (6-7 mg /dL) occurred in 1.8% of sorafenib-treated patients and 1.1% of patients in the placebo group, and CTCAE grade 4 hypocalcemia (<6 mg/dL) occurred in 0.4% of sorafenib-treated patients and 0% of patients in the placebo group. The etiology of hypocalcemia associated with sorafenib is not known.
Drug Interactions
CYP3A4 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. Continuous concomitant administration of sorafenib and rifampicin resulted in an average 37% reduction of sorafenib AUC. Other inducers of CYP3A4 activity (eg, 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. 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 P-450 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 Antineoplastic Agents: In clinical studies, sorafenib has been administered together with a variety of other antineoplastic agents at their commonly used dosing regimens, including gemcitabine, cisplatin, oxaliplatin, paclitaxel, carboplatin, capecitabine, doxorubicin, docetaxel, irinotecan 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 sorafenib dosing. The clinical significance of the 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 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).
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: Co-administration of neomycin, a non-systemic antimicrobial agent used to eradicate gastrointestinal flora, interferes with the enterohepatic recycling of sorafenib (see Pharmacokinetics 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 pharmacokinetics of sorafenib. No dose adjustment for sorafenib is necessary.
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 P-450 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 Antineoplastic Agents: In clinical studies, sorafenib has been administered together with a variety of other antineoplastic agents at their commonly used dosing regimens, including gemcitabine, cisplatin, oxaliplatin, paclitaxel, carboplatin, capecitabine, doxorubicin, docetaxel, irinotecan 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 sorafenib dosing. The clinical significance of the 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 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).
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: Co-administration of neomycin, a non-systemic antimicrobial agent used to eradicate gastrointestinal flora, interferes with the enterohepatic recycling of sorafenib (see Pharmacokinetics 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 pharmacokinetics of sorafenib. No dose adjustment for sorafenib is necessary.
Storage
Store at temperatures not exceeding 30°C.
Action
Pharmacotherapeutic Group: Protein kinase inhibitor. ATC Code: L01XE05.
Pharmacology: Mechanism of Action: Sorafenib is a multikinase inhibitor that decreases tumor cell proliferation in vitro.
Sorafenib was shown to inhibit multiple intracellular (c-CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3 and PDGFR-β). Several of these kinases are thought to be involved in tumor cell signaling, angiogenesis and apoptosis. Sorafenib inhibited tumor growth of the human hepatocellular carcinoma and renal cell carcinoma, and several other human tumor xenografts in immunocompromised mice. A reduction in tumor angiogenesis and increases in tumor apoptosis was seen in models of human hepatocellular and renal cell carcinoma. Additionally a reduction in tumor cell signaling was seen in a model of human hepatocellular carcinoma.
Clinical Efficacy and Safety: 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, multicenter, randomized, double-blind, placebo-controlled trial in 602 patients with hepatocellular carcinoma. Overall survival (OS) was a primary endpoint of this study, time to progression (TTP) a secondary endpoint.
Demographics and baseline disease characteristics were comparable between Nexavar and placebo groups with regard to age, gender, race, performance status, etiology (including hepatitis B, hepatitis C and alcoholic liver disease), TNM stage (stage I: <1% vs <1%; stage II: 10.4% vs 8.3%; stage III: 37.8% vs 43.6%; stage IV: 50.8% vs 46.9%), absence of both macroscopic vascular invasion and extrahepatic tumor spread (30.1% vs 30%), and BCLC stage (stage B: 18.1% vs 16.8%; stage C: 81.6% vs 83.2%; stage D: <1% vs 0%). Liver function Child-Pugh status was comparable between Nexavar and placebo groups (A: 95% vs 98%; B: 5% vs 2%). Only 1 patient with Child-Pugh C liver dysfunction was treated in the study. Prior treatment included surgical resection procedures (19.1% vs 20.5%), locoregional therapies (including radiofrequency ablation, percutaneous ethanol injection and transarterial chemoembolisation; 38.8% vs 40.6%), radiotherapy (4.3% vs. 5%) and systemic therapy (3% vs. 5%).
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 and figure). This advantage was consistent across almost all subsets analyzed. In the prespecified stratification factors [Eastern Cooperative Oncology Group (ECOG) status, presence or absence of macroscopic vascular invasion and/or extrahepatic tumor spread and region] the hazard ratio consistently favored Nexavar over placebo. The time to tumor progression (TTP, by independent radiological review) was significantly larger in the Nexavar Arm (HR: 0.58, p=0.000007, see Table 1). (See Table 1 and figure.)
Pharmacology: Mechanism of Action: Sorafenib is a multikinase inhibitor that decreases tumor cell proliferation in vitro.
Sorafenib was shown to inhibit multiple intracellular (c-CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3 and PDGFR-β). Several of these kinases are thought to be involved in tumor cell signaling, angiogenesis and apoptosis. Sorafenib inhibited tumor growth of the human hepatocellular carcinoma and renal cell carcinoma, and several other human tumor xenografts in immunocompromised mice. A reduction in tumor angiogenesis and increases in tumor apoptosis was seen in models of human hepatocellular and renal cell carcinoma. Additionally a reduction in tumor cell signaling was seen in a model of human hepatocellular carcinoma.
Clinical Efficacy and Safety: 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, multicenter, randomized, double-blind, placebo-controlled trial in 602 patients with hepatocellular carcinoma. Overall survival (OS) was a primary endpoint of this study, time to progression (TTP) a secondary endpoint.
Demographics and baseline disease characteristics were comparable between Nexavar and placebo groups with regard to age, gender, race, performance status, etiology (including hepatitis B, hepatitis C and alcoholic liver disease), TNM stage (stage I: <1% vs <1%; stage II: 10.4% vs 8.3%; stage III: 37.8% vs 43.6%; stage IV: 50.8% vs 46.9%), absence of both macroscopic vascular invasion and extrahepatic tumor spread (30.1% vs 30%), and BCLC stage (stage B: 18.1% vs 16.8%; stage C: 81.6% vs 83.2%; stage D: <1% vs 0%). Liver function Child-Pugh status was comparable between Nexavar and placebo groups (A: 95% vs 98%; B: 5% vs 2%). Only 1 patient with Child-Pugh C liver dysfunction was treated in the study. Prior treatment included surgical resection procedures (19.1% vs 20.5%), locoregional therapies (including radiofrequency ablation, percutaneous ethanol injection and transarterial chemoembolisation; 38.8% vs 40.6%), radiotherapy (4.3% vs. 5%) and systemic therapy (3% vs. 5%).
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 and figure). This advantage was consistent across almost all subsets analyzed. In the prespecified stratification factors [Eastern Cooperative Oncology Group (ECOG) status, presence or absence of macroscopic vascular invasion and/or extrahepatic tumor spread and region] the hazard ratio consistently favored Nexavar over placebo. The time to tumor progression (TTP, by independent radiological review) was significantly larger in the Nexavar Arm (HR: 0.58, p=0.000007, see Table 1). (See Table 1 and figure.)
Renal Cell Carcinoma: The safety and efficacy of Nexavar in the treatment of advanced RCC were studied in the following 2 randomized controlled clinical studies: Study 1 (11213) was a phase III, international, multicenter, 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 Memorial Sloan Kettering Cancer Center (MSKCC) 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 sorafenib versus placebo. The estimated hazard ratio (risk of death with sorafenib 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 randomized 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 sorafenib (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 >1.5 years. The effect of sorafenib on PFS was consistent across these subsets, including patients with no prior IL-2 or interferon therapy (n=137; 65 patients receiving sorafenib and 72 placebo), for whom the median PFS was 172 days on Sorafenib compared to 85 days on placebo.
Best overall tumor response was determined by investigator radiological review according to RECIST criteria. In the sorafenib 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, 0 patients (0%) had complete response, 8 patients (1.8%) had partial response, and 239 patients (52.9%) had stable disease. Sorafenib 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 Sorafenib 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 sorafenib 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 sorafenib (50%) than in the placebo patients (18%) (p=0.0077).
QT Interval Prolongation: In a clinical pharmacology study, QT/QTc measurements were recorded in 31 patients at baseline (pre-treatment) and post-treatment. After one 28-day treatment cycle, at the time of maximum concentration of sorafenib, QTcB was prolonged by 4±19 msec and QTcF by 9±18 msec, as compared to placebo treatment at baseline. No subject showed a QTcB or QTcF >500 msec during the post-treatment ECG monitoring (see Precautions).
Pharmacokinetics: After administration of sorafenib tablets, the mean relative bioavailability is 38-49% when compared to an oral solution.
The elimination t½ of sorafenib is approximately 25-48 hrs. 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 <2.
Absorption and Distribution: Following oral administration, sorafenib reaches peak plasma levels in approximately 3 hrs. 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.
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 gastrointestinal 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 5 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. Concomitant clinical 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 P-450 isoenzymes.
In vitro data show that sorafenib inhibits glucuronidation by the UGT1A1 (Ki=1 microM) and UGT1A9 (Ki=2 microM) pathways. Concomitant clinical administration of sorafenib with irinotecan, whose active metabolite SN-38 is further metabolized by the UGT1A1 pathway, resulted in a 67-120% increase in the AUC of SN-38. 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 microM, respectively. Concomitant clinical 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. 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 microM. 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.
Special Populations: Elderly (>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 of sorafenib in Child-Pugh A and Child-Pugh B non-HCC patients were similar to the pharmacokinetics in healthy volunteers. The pharmacokinetics of sorafenib has not been studied in patients with severe (Child-Pugh C) hepatic impairment (see Dosage & Administration and Precautions).
Renal Impairment: In a clinical pharmacology study, the pharmacokinetics of sorafenib were evaluated following administration of a single 400 mg dose to subjects with normal renal function, and in subjects with mild (CrCl 50-80 mL/min), moderate (CrCl 30 to <50 mL/min), or severe (CrCl <30 mL/min) renal impairment, not requiring dialysis. There was no relationship observed between sorafenib exposure and renal function. No dosage adjustment is necessary based on mild, moderate or severe renal impairment not requiring dialysis (see Dosage & Administration).
Toxicology: Preclinical Safety Data: Systemic Toxicity: Repeat-dose toxicity studies revealed mild to moderate changes (degenerations and regenerations) in various organs.
After repeated dosing to young and growing dogs, effects on bone and teeth were observed. 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.
Genotoxicity and Carcinogenicity: 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. Typical changes consisted of signs of degeneration and retardation in testes, epididymides, prostate and seminal vesicles of rats, with clear effects at a daily sorafenib dose of 150 mg/m2 body surface area (equivalent to approximately 0.3 times the recommended clinical dose of 500 mg/m2 on a body surface area basis). Female rats showed central necrosis of the corpora lutea and arrested follicular development in the ovaries with a lowest observed effect at 30 mg/m2/day. Dogs showed tubular degeneration in the testes at 600 mg/m2/day and oligospermia at 1200 mg/m2/day.
Reproduction Toxicity: Sorafenib has been shown to be embryotoxic and teratogenic when administered to rats and rabbits. 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 Use in pregnancy and Use in lactation under Precautions).
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 Memorial Sloan Kettering Cancer Center (MSKCC) 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 sorafenib versus placebo. The estimated hazard ratio (risk of death with sorafenib 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 randomized 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 sorafenib (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 >1.5 years. The effect of sorafenib on PFS was consistent across these subsets, including patients with no prior IL-2 or interferon therapy (n=137; 65 patients receiving sorafenib and 72 placebo), for whom the median PFS was 172 days on Sorafenib compared to 85 days on placebo.
Best overall tumor response was determined by investigator radiological review according to RECIST criteria. In the sorafenib 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, 0 patients (0%) had complete response, 8 patients (1.8%) had partial response, and 239 patients (52.9%) had stable disease. Sorafenib 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 Sorafenib 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 sorafenib 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 sorafenib (50%) than in the placebo patients (18%) (p=0.0077).
QT Interval Prolongation: In a clinical pharmacology study, QT/QTc measurements were recorded in 31 patients at baseline (pre-treatment) and post-treatment. After one 28-day treatment cycle, at the time of maximum concentration of sorafenib, QTcB was prolonged by 4±19 msec and QTcF by 9±18 msec, as compared to placebo treatment at baseline. No subject showed a QTcB or QTcF >500 msec during the post-treatment ECG monitoring (see Precautions).
Pharmacokinetics: After administration of sorafenib tablets, the mean relative bioavailability is 38-49% when compared to an oral solution.
The elimination t½ of sorafenib is approximately 25-48 hrs. 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 <2.
Absorption and Distribution: Following oral administration, sorafenib reaches peak plasma levels in approximately 3 hrs. 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.
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 gastrointestinal 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 5 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. Concomitant clinical 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 P-450 isoenzymes.
In vitro data show that sorafenib inhibits glucuronidation by the UGT1A1 (Ki=1 microM) and UGT1A9 (Ki=2 microM) pathways. Concomitant clinical administration of sorafenib with irinotecan, whose active metabolite SN-38 is further metabolized by the UGT1A1 pathway, resulted in a 67-120% increase in the AUC of SN-38. 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 microM, respectively. Concomitant clinical 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. 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 microM. 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.
Special Populations: Elderly (>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 of sorafenib in Child-Pugh A and Child-Pugh B non-HCC patients were similar to the pharmacokinetics in healthy volunteers. The pharmacokinetics of sorafenib has not been studied in patients with severe (Child-Pugh C) hepatic impairment (see Dosage & Administration and Precautions).
Renal Impairment: In a clinical pharmacology study, the pharmacokinetics of sorafenib were evaluated following administration of a single 400 mg dose to subjects with normal renal function, and in subjects with mild (CrCl 50-80 mL/min), moderate (CrCl 30 to <50 mL/min), or severe (CrCl <30 mL/min) renal impairment, not requiring dialysis. There was no relationship observed between sorafenib exposure and renal function. No dosage adjustment is necessary based on mild, moderate or severe renal impairment not requiring dialysis (see Dosage & Administration).
Toxicology: Preclinical Safety Data: Systemic Toxicity: Repeat-dose toxicity studies revealed mild to moderate changes (degenerations and regenerations) in various organs.
After repeated dosing to young and growing dogs, effects on bone and teeth were observed. 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.
Genotoxicity and Carcinogenicity: 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. Typical changes consisted of signs of degeneration and retardation in testes, epididymides, prostate and seminal vesicles of rats, with clear effects at a daily sorafenib dose of 150 mg/m2 body surface area (equivalent to approximately 0.3 times the recommended clinical dose of 500 mg/m2 on a body surface area basis). Female rats showed central necrosis of the corpora lutea and arrested follicular development in the ovaries with a lowest observed effect at 30 mg/m2/day. Dogs showed tubular degeneration in the testes at 600 mg/m2/day and oligospermia at 1200 mg/m2/day.
Reproduction Toxicity: Sorafenib has been shown to be embryotoxic and teratogenic when administered to rats and rabbits. 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 Use in pregnancy and Use in lactation under Precautions).
MedsGo Class
Targeted Cancer Therapy
Features
Dosage
200 mg
Ingredients
- Sorafenib
Packaging
Film-Coated Tablet 1's
Generic Name
Sorafenib Tosylate
Registration Number
DR-XY32442
Classification
Prescription Drug (RX)
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Product Questions
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