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Sorafenib Tosylate Tablet

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Sorafenib tosylate, a kinase inhibitor, is the tosylate salt of sorafenib. Chemically, it is 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)N2-methylpyridine-2- carboxamide 4-methylbenzenesulfonate and its structural formula is:

Molecular formula: C21H16ClF3N4O3 • C7H8O3S - Molecular weight: 637.0 g/mole

Sorafenib tosylate is a white to yellowish or brownish solid. It is practically insoluble in aqueous media, slightly soluble in ethanol and soluble in PEG 400.

Each red, round sorafenib tosylate film-coated tablet contains sorafenib tosylate (274 mg) equivalent to 200 mg of sorafenib and the following inactive ingredients: croscarmellose sodium, microcrystalline cellulose, hypromellose, sodium lauryl sulphate, magnesium stearate, polyethylene glycol, titanium dioxide and ferric oxide red.

2. INDICATIONS AND USAGE

2.1 Hepatocellular Carcinoma

Sorafenib tosylate is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC).

2.2 Renal Cell Carcinoma

Sorafenib tosylate is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

3. DOSAGE AND ADMINISTRATION

The recommended daily dose of sorafenib tosylate is 400 mg (2 x 200 mg tablets) taken twice daily without food (at least 1 hour before or 2 hours after a meal). Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.

Management of suspected adverse drug reactions may require temporary interruption and/or dose reduction of sorafenib tosylate therapy. When dose reduction is necessary, the sorafenib tosylate dose may be reduced to 400 mg once daily. If additional dose reduction is required, sorafenib tosylate may be reduced to a single 400 mg dose every other day [see Warnings and Precautions].

Suggested dose modifications for skin toxicity are outlined in Table 1.

Table 1: Suggested Dose Modifications for Skin Toxicity

No dose adjustment is required on the basis of patient age, gender, or body weight.

Concomitant strong CYP3A4 inducers: The use of concomitant strong CYP3A4 inducers may decrease sorafenib plasma concentrations and should be avoided (for example, St. John's Wort, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital). Although a dose increase has not been studied, if a strong CYP3A4 inducer must be co-administered, a sorafenib tosylate dose increase may be considered. If the dose of sorafenib tosylate is increased, the patient should be monitored carefully for toxicity [see Drug Interactions].

4. CONTRAINDICATIONS

• Sorafenib tosylate is contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of sorafenib tosylate.

• Sorafenib tosylate in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer [see Warnings and Precautions].

5. MECHANISM OF ACTION

Sorafenib is a kinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib was shown to inhibit multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-ß). Several of these kinases are thought to be involved in tumor cell signaling, angiogenesis, and apoptosis. Sorafenib inhibited tumor growth and angiogenesis of human hepatocellular carcinoma and renal cell carcinoma, and several other human tumor xenografts in immunocompromised mice.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category D

[see ‘Warnings and Precautions’ section].

Based on its mechanism of action and findings in animals, sorafenib tosylate may cause fetal harm when administered to a pregnant woman. Sorafenib caused embryo-fetal toxicities in animals at maternal exposures that were significantly lower than the human exposures at the recommended dose of 400 mg twice daily. There are no adequate and well-controlled studies in pregnant women using sorafenib tosylate. Women of childbearing potential should be advised to avoid becoming pregnant while on sorafenib tosylate. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

When administered to rats and rabbits during the period of organogenesis, sorafenib was teratogenic and induced embryo-fetal toxicity (including increased post-implantation loss, resorptions, skeletal retardations, and retarded fetal weight). The effects occurred at doses considerably below the recommended human dose of 400 mg twice daily (approximately 500 mg/m2/day on a body surface area basis). Adverse intrauterine development effects were seen at doses ≥ 0.2 mg/kg/day (1.2 mg/m2/day) in rats and 0.3 mg/kg/ day (3.6 mg/m2/day) in rabbits. These doses result in exposures (AUC) approximately 0.008 times the AUC seen in patients at the recommended human dose. A NOAEL (no observed adverse effect level) was not defined for either species, since lower doses were not tested.

6.2 Nursing Mothers

It is not known whether sorafenib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from sorafenib tosylate, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Following administration of radiolabeled sorafenib to lactating Wistar rats, approximately 27% of the radioactivity was secreted into the milk. The milk to plasma AUC ratio was approximately 5:1.

6.3 Pediatric Use

The safety and effectiveness of sorafenib tosylate in pediatric patients have not been studied.

Repeat dosing of sorafenib to young and growing dogs resulted in irregular thickening of the femoral growth plate at daily sorafenib doses ≥ 600 mg/m2 (approximately 0.3 times the AUC at the recommended human dose), hypocellularity of the bone marrow adjoining the growth plate at 200 mg/m2/day (approximately 0.1 times the AUC at the recommended human dose), and alterations of the dentin composition at 600 mg/m2/day. Similar effects were not observed in adult dogs when dosed for 4 weeks or less.

6.4 Geriatric Use

In total, 59% of HCC patients treated with sorafenib tosylate were age 65 years or older, and 19% were 75 and older. In total, 32% of RCC patients treated with sorafenib tosylate were age 65 years or older, and 4% were 75 and older. No differences in safety or efficacy were observed between older and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

6.5 Patients with Hepatic Impairment

In vitro and in vivo data indicate that sorafenib is primarily metabolized by the liver. Comparison of data across studies suggests that patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment have sorafenib AUCs that may be 23–65% lower than subjects with normal hepatic function. Systemic exposure and safety data were comparable in HCC patients with Child-Pugh A and B hepatic impairment. Sorafenib tosylate has not been studied in patients with Child-Pugh C hepatic impairment [see Warnings and Precautions].

6.6 Patients with Renal Impairment

Sorafenib tosylate has not been studied in patients undergoing dialysis. No dosage adjustment is necessary when administering sorafenib tosylate to patients with mild, moderate or severe renal impairment not undergoing dialysis.

Monitoring of fluid balance and electrolytes in patients at risk of renal dysfunction is advised.

7. WARNINGS AND PRECAUTIONS

7.1 Risk of Cardiac Ischemia and/or Infarction

In the HCC study, the incidence of cardiac ischemia/infarction was 2.7% in sorafenib tosylate patients compared with 1.3% in the placebo group and in RCC Study 1, the incidence of cardiac ischemia/infarction was higher in the sorafenib tosylate group (2.9%) compared with the placebo group (0.4%). Patients with unstable coronary artery disease or recent myocardial infarction were excluded from this study. Temporary or permanent discontinuation of sorafenib tosylate should be considered in patients who develop cardiac ischemia and/or infarction.

7.2 Risk of Hemorrhage

An increased risk of bleeding may occur following sorafenib tosylate administration. In the HCC study, an excess of bleeding regardless of causality was not apparent and the rate of bleeding from esophageal varices was 2.4% in sorafenib tosylate patients and 4% in placebo patients. Bleeding with a fatal outcome from any site was reported in 2.4% of sorafenib tosylate patients and 4% in placebo patients. In RCC Study 1, bleeding regardless of causality was reported in 15.3% of patients in the sorafenib tosylate group and 8.2% of patients in the placebo group. The incidence of CTCAE Grade 3 and 4 bleeding was 2% and 0%, respectively, in sorafenib tosylate patients, and 1.3% and 0.2%, respectively, in placebo patients. There was one fatal hemorrhage in each treatment group in RCC Study 1. If any bleeding necessitates medical intervention, permanent discontinuation of sorafenib tosylate should be considered.

7.3 Risk of Hypertension

Blood pressure should be monitored weekly during the first 6 weeks of sorafenib tosylate therapy and thereafter monitored and treated, if required, in accordance with standard medical practice. In the HCC study, hypertension was reported in approximately 9.4% of sorafenib tosylate-treated patients and 4.3% of patients in the placebo group. In RCC Study 1, hypertension was reported in approximately 16.9% of sorafenib tosylate-treated patients and 1.8% of patients in the placebo group. Hypertension was usually mild to moderate, occurred early in the course of treatment, and was managed with standard antihypertensive therapy. In cases of severe or persistent hypertension, despite institution of antihypertensive therapy, temporary or permanent discontinuation of sorafenib tosylate should be considered. Permanent discontinuation due to hypertension occurred in 1 of 297 sorafenib tosylate patients in the HCC study and 1 of 451 sorafenib tosylate patients in RCC Study 1.

7.4 Risk of Dermatologic Toxicities

Hand-foot skin reaction and rash represent the most common adverse reactions attributed to sorafenib tosylate. Rash and hand-foot skin reaction are usually CTCAE Grade 1 and 2 and generally appear during the first six weeks of treatment with sorafenib tosylate. Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of sorafenib tosylate, or in severe or persistent cases, permanent discontinuation of sorafenib tosylate. Permanent discontinuation of therapy due to hand-foot skin reaction occurred in 4 of 297 sorafenib tosylate HCC patients and 3 of 451 sorafenib tosylate RCC patients.

There have been reports of severe dermatologic toxicities, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These cases may be life-threatening. Discontinue sorafenib if SJS or TEN are suspected.

7.5 Risk of Gastrointestinal Perforation

Gastrointestinal perforation is an uncommon adverse reaction and has been reported in less than 1% of patients taking sorafenib tosylate. In some cases this was not associated with apparent intra-abdominal tumor. In the event of a gastrointestinal perforation, sorafenib tosylate therapy should be discontinued.

7.6 Warfarin Co-Administration

Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on sorafenib tosylate therapy. Patients taking concomitant warfarin should be monitored regularly for changes in prothrombin time, INR or clinical bleeding episodes.

7.7 Wound Healing Complications

No formal studies of the effect of sorafenib tosylate on wound healing have been conducted. Temporary interruption of sorafenib tosylate therapy is recommended in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of sorafenib tosylate therapy following major surgical intervention. Therefore, the decision to resume sorafenib tosylate therapy following a major surgical intervention should be based on clinical judgment of adequate wound healing.

7.8 Increased Mortality Observed with Sorafenib Administered in Combination with Carboplatin/Paclitaxel and Gemcitabine/Cisplatin in Squamous Cell Lung Cancer

In a subset analysis of two randomized controlled trials in chemo-naive patients with Stage IIIB-IV non-small cell lung cancer, patients with squamous cell carcinoma experienced higher mortality with the addition of sorafenib compared to those treated with carboplatin/paclitaxel alone (HR 1.81, 95% CI 1.19–2.74) and gemcitabine/ cisplatin alone (HR 1.22, 95% CI 0.82-1.80). The use of sorafenib in combination with carboplatin/paclitaxel is contraindicated in patients with squamous cell lung cancer. Sorafenib in combination with gemcitabine/cisplatin is not recommended in patients with squamous cell lung cancer. The safety and effectiveness of sorafenib has not been established in patients with non-small cell lung cancer.

7.9 Risk of QT Interval Prolongation

Sorafenib can prolong the QT/QTc interval. QT/QTc interval prolongation increases the risk for ventricular arrhythmias. Avoid sorafenib in patients with congenital long QT syndrome. Monitor patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities with on-treatment electrocardiograms and electrolytes (magnesium, potassium, calcium).

7.10 Drug-Induced Hepatitis

Sorafenib-induced hepatitis is characterized by a hepatocellular pattern of liver damage with significant increases of transaminases which may result in hepatic failure and death. Increases in bilirubin and INR may also occur. Monitor liver function tests regularly. In case of significantly increased transaminases without alternative explanation such as viral hepatitis or progressing underlying malignancy, discontinue sorafenib.

7.11 Risk of Fetal Harm

There are no adequate and well-controlled studies in pregnant women using sorafenib. However, based on its mechanism of action and findings in animals, sorafenib may cause fetal harm when administered to a pregnant woman. Sorafenib caused embryo-fetal toxicities in animals at maternal exposures that were significantly lower than the human exposures at the recommended dose of 400 mg twice daily. Advise women of childbearing potential to avoid becoming pregnant while on sorafenib because of the potential hazard to the fetus [see Use in Specific Populations].

8. ADVERSE REACTIONS

The following risks are discussed in greater detail in the WARNINGS AND PRECAUTIONS section:

• Cardiac ischemia, infarction

• Hemorrhage

• Hypertension

• Hand-foot skin reaction and rash

• Gastrointestinal perforation

• Wound healing complications

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in sections 8.1 and 8.2 reflect exposure to sorafenib tosylate in 748 patients who participated in placebo controlled studies in hepatocellular carcinoma (N=297) or advanced renal cell carcinoma (N=451).

The most common adverse reactions (≥ 20%), which were considered to be related to sorafenib tosylate, in patients with HCC or RCC are fatigue, weight loss, rash/desquamation, hand-foot skin reaction, alopecia, diarrhea, anorexia, nausea and abdominal pain.

8.1 Adverse Reactions in HCC Study

Table 2 shows the percentage of HCC patients experiencing adverse reactions that were reported in at least 10% of patients and at a higher rate in the sorafenib tosylate arm than the placebo arm. CTCAE Grade 3 adverse reactions were reported in 39% of patients receiving sorafenib tosylate compared to 24% of patients receiving placebo. CTCAE Grade 4 adverse reactions were reported in 6% of patients receiving sorafenib tosylate compared to 8% of patients receiving placebo.

Table 2: Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in Sorafenib Tosylate Arm than the Placebo Arm – HCC Study

Hypertension was reported in 9% of patients treated with sorafenib tosylate and 4% of those treated with placebo. CTCAE Grade 3 hypertension was reported in 4% of sorafenib tosylate treated patients and 1% of placebo treated patients. No patients were reported with CTCAE Grade 4 reactions in either treatment group.

Hemorrhage/bleeding was reported in 18% of those receiving sorafenib tosylate and 20% of placebo patients. The rates of CTCAE Grade 3 and 4 bleeding were also higher in the placebo group (CTCAE Grade 3 - 3% sorafenib tosylate and 5% placebo and CTCAE Grade 4 - 2% sorafenib tosylate and 4% placebo). Bleeding from esophageal varices was reported in 2.4% in sorafenib tosylate treated patients and 4% of placebo treated patients.

Renal failure was reported in < 1% of patients treated with sorafenib tosylate and 3% of placebo treated patients.

The rate of adverse reactions (including those associated with progressive disease) resulting in permanent discontinuation was similar in both the sorafenib tosylate and placebo groups (32% of sorafenib tosylate patients and 35% of placebo patients).

Laboratory Abnormalities

The following laboratory abnormalities were observed in HCC patients:

Hypophosphatemia was a common laboratory finding, observed in 35% of sorafenib tosylate-treated patients compared to 11% of placebo patients; CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) occurred in 11% of sorafenib tosylate-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 sorafenib tosylate is not known.

Elevated lipase was observed in 40% of patients treated with sorafenib tosylate 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 sorafenib tosylate 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 sorafenib tosylate treatment was not interrupted. Clinical pancreatitis was reported in 1 of 297 sorafenib tosylate-treated patients (CTCAE Grade 2).

Elevations in liver function tests were comparable between the 2 arms of the study. Hypoalbuminemia was observed in 59% of sorafenib tosylate-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 sorafenib tosylate-treated patients and 34% of placebo patients; CTCAE Grade 3 INR elevations were reported in 4% of sorafenib tosylate-treated patients and 2% of placebo patients; there was no CTCAE Grade 4 INR elevation in either group.

Lymphopenia was observed in 47% of sorafenib tosylate-treated patients and 42% of placebo patients.

Thrombocytopenia was observed in 46% of sorafenib tosylate-treated patients and 41% of placebo patients; CTCAE Grade 3 or 4 thrombocytopenia was reported in 4% of sorafenib tosylate-treated patients and less than 1% of placebo patients.

8.2 Adverse Reactions in RCC Study 1

Table 3 shows the percentage of RCC patients experiencing adverse reactions that were reported in at least 10% of patients and at a higher rate in the sorafenib tosylate arm than the placebo arm. CTCAE Grade 3 adverse reactions were reported in 31% of patients receiving sorafenib tosylate compared to 22% of patients receiving placebo. CTCAE Grade 4 adverse reactions were reported in 7% of patients receiving sorafenib tosylate compared to 6% of patients receiving placebo.

Table 3: Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in Sorafenib Tosylate Arm than the Placebo Arm – RCC Study 1

The rate of adverse reactions (including those associated with progressive disease) resulting in permanent discontinuation was similar in both the sorafenib tosylate and placebo groups (10% of sorafenib tosylate patients and 8% of placebo patients).

Laboratory Abnormalities

The following laboratory abnormalities were observed in RCC patients in Study 1:

Hypophosphatemia was a common laboratory finding, observed in 45% of sorafenib tosylate-treated patients compared to 11% of placebo patients. CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) occurred in 13% of sorafenib tosylate-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 tosylate or placebo patients. The etiology of hypophosphatemia associated with sorafenib tosylate is not known.

Elevated lipase was observed in 41% of patients treated with sorafenib tosylate compared to 30% of patients in the placebo group. CTCAE Grade 3 or 4 lipase elevations occurred in 12% of patients in the sorafenib tosylate group compared to 7% of patients in the placebo group. Elevated amylase was observed in 30% of patients treated with sorafenib tosylate compared to 23% of patients in the placebo group. CTCAE Grade 3 or 4 amylase elevations were reported in 1% of patients in the sorafenib tosylate group compared to 3% of patients in the placebo group. Many of the lipase and amylase elevations were transient, and in the majority of cases sorafenib tosylate treatment was not interrupted. Clinical pancreatitis was reported in 3 of 451 sorafenib tosylate-treated patients (one CTCAE Grade 2 and two Grade 4) and 1 of 451 patients (CTCAE Grade 2) in the placebo group.

Lymphopenia was observed in 23% of sorafenib tosylate-treated patients and 13% of placebo patients. CTCAE Grade 3 or 4 lymphopenia was reported in 13% of sorafenib tosylate-treated patients and 7% of placebo patients. Neutropenia was observed in 18% of sorafenib tosylate-treated patients and 10% of placebo patients. CTCAE Grade 3 or 4 neutropenia was reported in 5% of sorafenib tosylate-treated patients and 2% of placebo patients.

Anemia was observed in 44% of sorafenib tosylate-treated patients and 49% of placebo patients. CTCAE Grade 3 or 4 anemia was reported in 2% of sorafenib tosylate-treated patients and 4% of placebo patients.

Thrombocytopenia was observed in 12% of sorafenib tosylate-treated patients and 5% of placebo patients. CTCAE Grade 3 or 4 thrombocytopenia was reported in 1% of sorafenib tosylate-treated patients and 0% of placebo patients.

8.3 Postmarketing Experience

The following adverse drug reactions have been identified during post-approval use of sorafenib tosylate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity: Angioedema.

Hepatobiliary disorders: Drug induced hepatitis, including reports of hepatic failure and death.

9. OVERDOSAGE

There is no specific treatment for sorafenib tosylate overdose.

The highest dose of sorafenib tosylate studied clinically is 800 mg twice daily. The adverse reactions observed at this dose were primarily diarrhea and dermatologic. No information is available on symptoms of acute overdose in animals because of the saturation of absorption in oral acute toxicity studies conducted in animals.

In cases of suspected overdose, sorafenib tosylate should be withheld and supportive care instituted.

10. DRUG INTERACTIONS

10.1 Carboplatin and Paclitaxel

Concomitant use of carboplatin (AUC=6 mg/ml•min) and paclitaxel (225 mg/m2) once every three weeks with sorafenib (400 mg twice daily) resulted in a 30% increase in paclitaxel AUC, a 50% increase in sorafenib AUC, and no change in carboplatin AUC. Sorafenib in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer, due to increased mortality observed with the addition of sorafenib compared to those treated with carboplatin and paclitaxel alone. No definitive cause was identified for this finding. [see Contraindications and Warnings and Precautions].

10.2 UGT1A1 and UGT1A9 Substrates

Caution is recommended when administering sorafenib with compounds that are metabolized/eliminated predominantly by the UGT1A1 pathway (for example, irinotecan). Sorafenib inhibits glucuronidation by the UGT1A1 (Ki value: 1 micromolar) and UGT1A9 pathways (Ki value: 2 micromolar). Systemic exposure to substrates of UGT1A1 and UGT1A9 may increase when co-administered with sorafenib [see Warnings and Precautions].

In clinical studies, when sorafenib was 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.

10.3 Docetaxel

Concomitant use of docetaxel (75 or 100 mg/m2 administered every 21 days) 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 and a 16–32% increase in docetaxel Cmax. Caution is recommended when sorafenib is co-administered with docetaxel [see Warnings and Precautions].

10.4 Doxorubicin

Concomitant treatment with sorafenib resulted in a 21% increase in the AUC of doxorubicin. Caution is recommended when administering doxorubicin with sorafenib. The clinical significance of these findings is unknown [see Warnings and Precautions].

10.5 Fluorouracil

Both increases (21%–47%) and decreases (10%) in the AUC of fluorouracil were observed with concomitant treatment with sorafenib. Caution is recommended when sorafenib is co-administered with fluorouracil/leucovorin.

10.6 CYP2B6 and CYP2C8 Substrates

Sorafenib inhibits CYP2B6 and CYP2C8 in vitro with Ki values of 6 and 1–2 micromolar, respectively. Systemic exposure to substrates of CYP2B6 and CYP2C8 is expected to increase when co-administered with sorafenib. Caution is recommended when administering substrates of CYP2B6 and CYP2C8 with sorafenib.

10.7 CYP3A4 Inducers

Continuous concomitant administration of sorafenib and rifampicin resulted in an average 37% reduction of sorafenib AUC. Other inducers of CYP3A4 activity (for example, 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 [see Dosage and Administration].

10.8 CYP3A4 Inhibitors and CYP Isoform Substrates

In vitro data indicate that sorafenib is metabolized by CYP3A4 and UGT1A9 pathways. Ketoconazole (400 mg), a potent inhibitor of CYP3A4, administered once daily for 7 days did not alter the mean AUC of a single oral 50 mg dose of sorafenib in healthy volunteers. Therefore, sorafenib metabolism is unlikely to be altered by CYP3A4 inhibitors.

Studies with human liver microsomes demonstrated that sorafenib is a competitive inhibitor of CYP2C19, CYP2D6, and CYP3A4 as indicated by Ki values of 17 micromolar, 22 micromolar, and 29 micromolar, respectively. Administration of sorafenib 400 mg twice daily for 28 days did not alter the exposure of concomitantly administered midazolam (CYP3A4 substrate), dextromethorphan (CYP2D6 substrate), and omeprazole (CYP2C19 substrate). This indicates that sorafenib is unlikely to alter the metabolism of substrates of these enzymes in vivo.

Studies with human liver microsomes demonstrated that sorafenib is a competitive inhibitor of CYP2C9 with a Ki value of 7– 8 micromolar. The possible effect of sorafenib on the metabolism of the CYP2C9 substrate warfarin was assessed indirectly by measuring PT-INR. The mean changes from baseline in PT-INR were not higher in sorafenib patients compared to placebo patients, suggesting that sorafenib did not inhibit warfarin metabolism in vivo [see Warnings and Precautions].

10.9 P-glycoprotein Substrates

Sorafenib is an inhibitor of P-glycoprotein in vitro, therefore may increase the concentrations of concomitant drugs that are Pglycoprotein substrates.

10.10 In Vitro Studies: CYP Enzyme Induction

CYP1A2 and CYP3A4 activities were not altered after treatment of cultured human hepatocytes with sorafenib, indicating that sorafenib is unlikely to be an inducer of CYP1A2 or CYP3A4.

10.11 Combination with Other Antineoplastic Agents

In clinical studies, sorafenib has been administered with a variety of other antineoplastic agents at their commonly used dosing regimens, including gemcitabine, oxaliplatin, doxorubicin, docetaxel, and irinotecan. Sorafenib had no effect on the pharmacokinetics of gemcitabine or oxaliplatin. [see Drug Interactions for information about interactions with irinotecan, docetaxel, doxorubicin and fluorouracil/leucovorin.]

10.12 Neomycin

The average plasma exposure (AUC) of sorafenib was decreased by 54% in healthy volunteers who first received neomycin 1 g three times daily for 5 days orally. Therefore, the coadministration of sorafenib with oral neomycin should be carefully considered. Effects of other antibiotics on sorafenib pharmacokinetics have not been studied [see Warnings & Precautions].

11. PHARMACOKINETICS

After administration of sorafenib tablets, the mean relative bioavailability is 38–49% when compared to an oral solution. The mean elimination half-life of sorafenib is approximately 25–48 hours. Multiple dosing of sorafenib for 7 days resulted 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 (30% fat; 700 calories), bioavailability was similar to that in the fasted state. With a high-fat meal (50% fat; 900 calories), sorafenib bioavailability was reduced by 29% compared to administration in the fasted state. It is recommended that sorafenib be administered without food [see Dosage and Administration].

Mean Cmax and AUC increased 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 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. This metabolite 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.

Special Populations

Age

Analyses of demographic data suggest that no dose adjustments are necessary for age.

Gender

Analyses of demographic data suggest that no dose adjustments are necessary for gender.

Race

A study of the pharmacokinetics of sorafenib indicated that the mean AUC of sorafenib in Asians (N=78) was 30% lower than in Caucasians (N=40).

Pediatric

There are no pharmacokinetic data in pediatric patients.

Hepatic Impairment

Sorafenib is cleared primarily by the liver.

Comparison of data across studies suggests that in HCC patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, 400 mg doses of sorafenib appear to be associated with AUC values that were 23 to 65% lower than those of other subjects without hepatic impairment. The AUC of sorafenib is similar between HCC patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. The pharmacokinetics of sorafenib have not been studied in patients with severe (Child-Pugh C) hepatic impairment [see Warnings and Precautions and Use in Specific Populations].

Renal Impairment

In a study of drug disposition after a single oral dose of radiolabeled sorafenib to healthy subjects, 19% of the administered dose of sorafenib was excreted in urine.

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 30–50 ml/min), or severe (CrCl < 30 ml/min) renal impairment, not undergoing 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 undergoing dialysis [see Use in Specific Populations].

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: NEXAVAR, by BAYER HEALTHCARE.

b) Generic drugs: None.

2) How Supplied:

NEXAVAR tablets are supplied as round, biconvex, red film-coated tablets, debossed with the “Bayer cross” on one side and “200” on the other side, each containing sorafenib tosylate equivalent to 200 mg of sorafenib.

Bottles of 120 tablets NDC 50419-488-58

3) Storage:

Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].

Store in a dry place.

Rx only

Rev 08/12