Сорафениб геми-тозилат моногидрат

Hepatocellular Carcinoma

Сорафениб геми-тозилат моногидрат^® is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC).

Renal Cell Carcinoma

Сорафениб геми-тозилат моногидрат is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).

Differentiated Thyroid Carcinoma

Сорафениб геми-тозилат моногидрат is indicated for the treatment of patients with locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) that is refractory to radioactive iodine treatment.

Recommended Dose For Hepatocellular Carcinoma, Renal Cell Carcinoma, And Differentiated Thyroid Carcinoma

The recommended daily dose of Сорафениб геми-тозилат моногидрат 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.

Dose Modifications For Suspected Adverse Drug Reactions

Temporary interruption of Сорафениб геми-тозилат моногидрат is recommended in patients undergoing major surgical procedures.

Temporary interruption or permanent discontinuation of Сорафениб геми-тозилат моногидрат may be required for the following:

• Cardiac ischemia or infarction :
• Hemorrhage requiring medical intervention
• Severe or persistent hypertension despite adequate anti-hypertensive therapy
• Gastrointestinal perforation
• QTc prolongation
• Severe drug-induced liver injury

Dose Modifications For Hepatocellular Carcinoma And Renal Cell Carcinoma

When dose reduction is necessary, the Сорафениб геми-тозилат моногидрат dose may be reduced to 400 mg once daily. If additional dose reduction is required, Сорафениб геми-тозилат моногидрат may be reduced to a single 400 mg dose every other day.

Suggested dose modifications for dermatologic toxicities are outlined in Table 1.

Table 1: Suggested Dose Modifications for Dermatologic Toxicities in Patients with Hepatocellular or Renal Cell Carcinoma

Dose Modifications For Differentiated Thyroid Carcinoma

Table 2: Recommended Doses for Patients with Differentiated Thyroid Carcinoma Requiring Dose Reduction

When dose reduction is necessary for dermatologic toxicities, reduce the Сорафениб геми-тозилат моногидрат dose as indicated in Table 3 below.

Table 3: Recommended Dose Modifications for Dermatologic Toxicities for Patients with Differentiated Thyroid Carcinoma

Following improvement of Grade 2 or 3 dermatologic toxicity to Grade 0–1 after at least 28 days of treatment on a reduced dose of Сорафениб геми-тозилат моногидрат, the dose of Сорафениб геми-тозилат моногидрат may be increased one dose level from the reduced dose. Approximately 50% of patients requiring a dose reduction for dermatologic toxicity are expected to meet these criteria for resumption of the higher dose and roughly 50% of patients resuming the previous dose are expected to tolerate the higher dose (that is, maintain the higher dose level without recurrent Grade 2 or higher dermatologic toxicity).

• Сорафениб геми-тозилат моногидрат is contraindicated in patients with known severe hypersensitivity to sorafenib or any other component of Сорафениб геми-тозилат моногидрат.
• Сорафениб геми-тозилат моногидрат in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Risk Of Cardiac Ischemia And/Or Infarction

In the HCC study, the incidence of cardiac ischemia/infarction was 2.7% in Сорафениб геми-тозилат моногидрат-treated patients compared with 1.3% in the placebo-treated group, in RCC Study 1, the incidence of cardiac ischemia/infarction was higher in the Сорафениб геми-тозилат моногидрат-treated group (2.9%) compared with the placebo-treated group (0.4%), and in the DTC study, the incidence of cardiac ischemia/infarction was 1.9% in the Сорафениб геми-тозилат моногидрат-treated group compared with 0% in the placebo-treated group. Patients with unstable coronary artery disease or recent myocardial infarction were excluded from this study. Temporary or permanent discontinuation of Сорафениб геми-тозилат моногидрат should be considered in patients who develop cardiac ischemia and/or infarction.

Risk Of Hemorrhage

An increased risk of bleeding may occur following Сорафениб геми-тозилат моногидрат 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 Сорафениб геми-тозилат моногидрат-treated patients and 4% in placebo-treated patients. Bleeding with a fatal outcome from any site was reported in 2.4% of Сорафениб геми-тозилат моногидрат-treated patients and 4% in placebo-treated patients. In RCC Study 1, bleeding regardless of causality was reported in 15.3% of patients in the Сорафениб геми-тозилат моногидрат-treated group and 8.2% of patients in the placebo-treated group. The incidence of CTCAE Grade 3 and 4 bleeding was 2% and 0%, respectively, in Сорафениб геми-тозилат моногидрат-treated patients, and 1.3% and 0.2%, respectively, in placebo-treated patients. There was one fatal hemorrhage in each treatment group in RCC Study 1. In the DTC study, bleeding was reported in 17.4% of Сорафениб геми-тозилат моногидрат-treated patients and 9.6% of placebo-treated patients; however the incidence of CTCAE Grade 3 bleeding was 1% in Сорафениб геми-тозилат моногидрат-treated patients and 1.4% in placebo-treated patients. There was no Grade 4 bleeding reported and there was one fatal hemorrhage in a placebo-treated patient. If any bleeding necessitates medical intervention, permanent discontinuation of Сорафениб геми-тозилат моногидрат should be considered. Due to the potential risk of bleeding, tracheal, bronchial, and esophageal infiltration should be treated with local therapy prior to administering Сорафениб геми-тозилат моногидрат in patients with DTC.

Risk Of Hypertension

Monitor blood pressure weekly during the first 6 weeks of Сорафениб геми-тозилат моногидрат. Thereafter, monitor blood pressure and treat hypertension, if required, in accordance with standard medical practice. In the HCC study, hypertension was reported in approximately 9.4% of Сорафениб геми-тозилат моногидрат-treated patients and 4.3% of patients in the placebo-treated group. In RCC Study 1, hypertension was reported in approximately 16.9% of Сорафениб геми-тозилат моногидрат-treated patients and 1.8% of patients in the placebo-treated group. In the DTC study, hypertension was reported in 40.6% of Сорафениб геми-тозилат моногидрат-treated patients and 12.4% of placebo-treated patients. 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, consider temporary or permanent discontinuation of Сорафениб геми-тозилат моногидрат. Permanent discontinuation due to hypertension occurred in 1 of 297 Сорафениб геми-тозилат моногидрат-treated patients in the HCC study, 1 of 451 Сорафениб геми-тозилат моногидрат-treated patients in RCC Study 1, and 1 of 207 Сорафениб геми-тозилат моногидрат-treated patients in the DTC study.

Risk Of Dermatologic Toxicities

Hand-foot skin reaction and rash represent the most common adverse reactions attributed to Сорафениб геми-тозилат моногидрат. Rash and hand-foot skin reaction are usually CTCAE Grade 1 and 2 and generally appear during the first six weeks of treatment with Сорафениб геми-тозилат моногидрат. Management of dermatologic toxicities may include topical therapies for symptomatic relief, temporary treatment interruption and/or dose modification of Сорафениб геми-тозилат моногидрат, or in severe or persistent cases, permanent discontinuation of Сорафениб геми-тозилат моногидрат. Permanent discontinuation of therapy due to hand-foot skin reaction occurred in 4 (1.3%) of 297 Сорафениб геми-тозилат моногидрат-treated patients with HCC, 3 (0.7%) of 451 Сорафениб геми-тозилат моногидрат-treated patients with RCC, and 11 (5.3%) of 207 Сорафениб геми-тозилат моногидрат-treated patients with DTC.

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 Сорафениб геми-тозилат моногидрат if SJS or TEN are suspected.

Risk Of Gastrointestinal Perforation

Gastrointestinal perforation is an uncommon adverse reaction and has been reported in less than 1% of patients taking Сорафениб геми-тозилат моногидрат. In some cases this was not associated with apparent intra-abdominal tumor. In the event of a gastrointestinal perforation, discontinue Сорафениб геми-тозилат моногидрат.

Warfarin

Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on Сорафениб геми-тозилат моногидрат. Monitor patients taking concomitant warfarin regularly for changes in prothrombin time (PT), INR or clinical bleeding episodes.

Wound Healing Complications

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

Increased Mortality Observed With Сорафениб геми-тозилат моногидрат 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 Сорафениб геми-тозилат моногидрат 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 Сорафениб геми-тозилат моногидрат in combination with carboplatin/paclitaxel is contraindicated in patients with squamous cell lung cancer. Сорафениб геми-тозилат моногидрат in combination with gemcitabine/cisplatin is not recommended in patients with squamous cell lung cancer. The safety and effectiveness of Сорафениб геми-тозилат моногидрат has not been established in patients with non-small cell lung cancer.

Risk Of QT Interval Prolongation

Сорафениб геми-тозилат моногидрат can prolong the QT/QTc interval. QT/QTc interval prolongation increases the risk for ventricular arrhythmias. Avoid Сорафениб геми-тозилат моногидрат in patients with congenital long QT syndrome. Monitor electrolytes and electrocardiograms in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics. Correct electrolyte abnormalities (magnesium, potassium, calcium). Interrupt Сорафениб геми-тозилат моногидрат if QTc interval is greater than 500 milliseconds or for an increase from baseline of 60 milliseconds or greater.

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. The incidence of severe drug-induced liver injury, defined as elevated transaminase levels above 20 times the upper limit of normal or transaminase elevations with significant clinical sequelae (for example, elevated INR, ascites, fatal, or transplantation), was two of 3,357 patients (0.06%) in a global monotherapy database. Monitor liver function tests regularly. In case of significantly increased transaminases without alternative explanation, such as viral hepatitis or progressing underlying malignancy, discontinue Сорафениб геми-тозилат моногидрат.

Embryofetal Risk

Based on its mechanism of action and findings in animals, Сорафениб геми-тозилат моногидрат 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 Сорафениб геми-тозилат моногидрат because of the potential hazard to the fetus.

Impairment Of Thyroid Stimulating Hormone Suppression In Differentiated Thyroid Carcinoma

Сорафениб геми-тозилат моногидрат impairs exogenous thyroid suppression. In the DTC study, 99% of patients had a baseline thyroid stimulating hormone (TSH) level less than 0.5 mU/L. Elevation of TSH level above 0.5 mU/L was observed in 41% of Сорафениб геми-тозилат моногидрат-treated patients as compared with 16% of placebo-treated patients. For patients with impaired TSH suppression while receiving Сорафениб геми-тозилат моногидрат, the median maximal TSH was 1.6 mU/L and 25% had TSH levels greater than 4.4 mU/L.

Monitor TSH levels monthly and adjust thyroid replacement medication as needed in patients with DTC.

Patient Counseling Information

See FDA-approved PATIENT INFORMATION

Cardiac Ischemia; Infarction

Discuss with patients that cardiac ischemia and/or infarction has been reported during Сорафениб геми-тозилат моногидрат treatment, and that they should immediately report any episodes of chest pain or other symptoms of cardiac ischemia.

Bleeding

Inform patients that Сорафениб геми-тозилат моногидрат can increase the risk of bleeding and that they should promptly report any episodes of bleeding.

Inform patients that bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on Сорафениб геми-тозилат моногидрат and that their INR should be monitored regularly.

Hypertension

Inform patients that hypertension can develop during Сорафениб геми-тозилат моногидрат treatment, especially during the first six weeks of therapy, and that blood pressure should be monitored regularly during treatment.

Skin Reactions

Advise patients of the possible occurrence of hand-foot skin reaction and rash during Сорафениб геми-тозилат моногидрат treatment and appropriate countermeasures.

Gastrointestinal Perforation

Advise patients that cases of gastrointestinal perforation have been reported in patients taking Сорафениб геми-тозилат моногидрат.

Wound Healing Complications

Inform patients that temporary interruption of Сорафениб геми-тозилат моногидрат is recommended in patients undergoing major surgical procedures.

QT Interval Prolongation

Inform patients with a history of prolonged QT interval that Сорафениб геми-тозилат моногидрат can worsen the condition.

Drug-Induced Hepatitis

Inform patients that Сорафениб геми-тозилат моногидрат can cause hepatitis which may result in hepatic failure and death. Advise patients that liver function tests should be monitored regularly during treatment and to report signs and symptoms of hepatitis.

Birth Defects And Fetal Loss

Inform patients that Сорафениб геми-тозилат моногидрат can cause birth defects or fetal loss. Counsel both male and female patients to use effective birth control during treatment with Сорафениб геми-тозилат моногидрат and for at least 2 weeks after stopping treatment. Inform female patients to contact their healthcare provider if they become pregnant while taking Сорафениб геми-тозилат моногидрат.

Nursing Mothers

Advise mothers not to breast-feed while taking Сорафениб геми-тозилат моногидрат.

Missed Doses

Instruct patients that if a dose of Сорафениб геми-тозилат моногидрат is missed, the next dose should be taken at the regularly scheduled time, and not double the dose. Instruct patients to contact their healthcare provider immediately if they take too much Сорафениб геми-тозилат моногидрат.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been performed with sorafenib.Sorafenib was clastogenic when tested in an in vitro mammalian cell assay (Chinese hamster ovary) in the presence of metabolic activation. Sorafenib was not mutagenic in the in vitro Ames bacterial cell assay or clastogenic in an in vivo mouse micronucleus assay. 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) when tested independently.

No specific studies with sorafenib have been conducted in animals to evaluate the effect on fertility. However, results from the repeat-dose toxicity studies suggest there is a potential for sorafenib to impair reproductive function and fertility. Multiple adverse effects were observed in male and female reproductive organs, with the rat being more susceptible than mice or dogs. Typical changes in rats consisted of testicular atrophy or degeneration, degeneration of epididymis, prostate, and seminal vesicles, central necrosis of the corpora lutea and arrested follicular development. Sorafenib-related effects on the reproductive organs of rats were manifested at daily oral doses ≥ 5 mg/kg (30 mg/m²). This dose results in an exposure (AUC) that is approximately 0.5 times the AUC in patients at the recommended human dose. Dogs showed tubular degeneration in the testes at 30 mg/kg/day (600 mg/m²/day). This dose results in an exposure that is approximately 0.3 times the AUC at the recommended human dose. Oligospermia was observed in dogs at 60 mg/kg/day (1200 mg/m²/day) of sorafenib.

Adequate contraception should be used during therapy and for at least 2 weeks after completing therapy.

Use In Specific Populations

Pregnancy

Pregnancy Category D.

Based on its mechanism of action and findings in animals, Сорафениб геми-тозилат моногидрат 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 Сорафениб геми-тозилат моногидрат. Inform patients of childbearing potential that Сорафениб геми-тозилат моногидрат can cause birth defects or fetal loss. Instruct both men and women of childbearing potential to use effective birth control during treatment with Сорафениб геми-тозилат моногидрат and for at least 2 weeks after stopping treatment. Counsel female patients to contact their healthcare provider if they become pregnant while taking Сорафениб геми-тозилат моногидрат.

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.

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 Сорафениб геми-тозилат моногидрат, 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.

Pediatric Use

The safety and effectiveness of Сорафениб геми-тозилат моногидрат 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.

Geriatric Use

In total, 59% of HCC patients treated with Сорафениб геми-тозилат моногидрат were age 65 years or older and 19% were 75 and older. In total, 32% of RCC patients treated with Сорафениб геми-тозилат моногидрат 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.

Patients With Hepatic Impairment

In a trial of HCC patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, the systemic exposure (AUC) of sorafenib was within the range observed in patients without hepatic impairment. In another trial in subjects without HCC, the mean AUC was similar for subjects with mild (n=15) and moderate (n=14) hepatic impairment compared to subjects (n=15) with normal hepatic function. No dose adjustment is necessary for patients with mild or moderate hepatic impairment. The pharmacokinetics of sorafenib have not been studied in patients with severe (Child-Pugh C) hepatic impairment.

Patients With Renal Impairment

No correlation between sorafenib exposure and renal function was observed following administration of a single oral dose of Сорафениб геми-тозилат моногидрат 400 mg to subjects with normal renal function and subjects with mild (CLcr 50–80 mL/min), moderate (CLcr 30–<50 mL/min), or severe (CLcr <30 mL/min) renal impairment who are not on dialysis. No dose adjustment is necessary for patients with mild, moderate or severe renal impairment who are not on dialysis. The pharmacokinetics of sorafenib have not been studied in patients who are on dialysis.

The following serious adverse reactions are discussed elsewhere in the labeling:

• Cardiac ischemia, infarction
• Hemorrhage
• Hypertension
• Hand-foot skin reaction, rash, Stevens-Johnson syndrome, and toxic epidermal necrolysis
• Gastrointestinal perforation
• QT Interval Prolongation
• Drug-Induced Hepatitis
• Impairment of TSH suppression in DTC

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 6.1, 6.2 and 6.3 reflect exposure to Сорафениб геми-тозилат моногидрат in 955 patients who participated in placebo controlled studies in hepatocellular carcinoma (N=297), advanced renal cell carcinoma (N=451), or differentiated thyroid carcinoma (N = 207).

The most common adverse reactions (≥20%), which were considered to be related to Сорафениб геми-тозилат моногидрат, in patients with HCC, RCC or DTC are diarrhea, fatigue, infection, alopecia, hand-foot skin reaction, rash, weight loss, decreased appetite, nausea, gastrointestinal and abdominal pains, hypertension, and hemorrhage.

Adverse Reactions In HCC Study

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

Table 4: Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in Сорафениб геми-тозилат моногидрат Arm than the Placebo Arm – HCC Study

Hypertension was reported in 9% of patients treated with Сорафениб геми-тозилат моногидрат and 4% of those treated with placebo. CTCAE Grade 3 hypertension was reported in 4% of Сорафениб геми-тозилат моногидрат-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 Сорафениб геми-тозилат моногидрат and 20% of placebo-treated patients. The rates of CTCAE Grade 3 and 4 bleeding were also higher in the placebo-treated group (CTCAE Grade 3 – 3% Сорафениб геми-тозилат моногидрат and 5% placebo and CTCAE Grade 4 – 2% Сорафениб геми-тозилат моногидрат and 4% placebo). Bleeding from esophageal varices was reported in 2.4% in Сорафениб геми-тозилат моногидрат-treated patients and 4% of placebo-treated patients.

Renal failure was reported in <1% of patients treated with Сорафениб геми-тозилат моногидрат 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 Сорафениб геми-тозилат моногидрат and placebo-treated groups (32% of Сорафениб геми-тозилат моногидрат-treated patients and 35% of placebo-treated patients).

Laboratory Abnormalities

The following laboratory abnormalities were observed in patients with HCC:

Hypophosphatemia was a common laboratory finding observed in 35% of Сорафениб геми-тозилат моногидрат-treated patients compared to 11% of placebo-treated patients; CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) occurred in 11% of Сорафениб геми-тозилат моногидрат-treated patients and 2% of patients in the placebo-treated group; there was 1 case of CTCAE Grade 4 hypophosphatemia (<1 mg/dL) reported in the placebo-treated group. The etiology of hypophosphatemia associated with Сорафениб геми-тозилат моногидрат is not known.

Elevated lipase was observed in 40% of patients treated with Сорафениб геми-тозилат моногидрат compared to 37% of patients in the placebo-treated 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 Сорафениб геми-тозилат моногидрат compared to 29% of patients in the placebo-treated 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 Сорафениб геми-тозилат моногидрат treatment was not interrupted. Clinical pancreatitis was reported in 1 of 297 Сорафениб геми-тозилат моногидрат-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 Сорафениб геми-тозилат моногидрат-treated patients and 47% of placebo-treated patients; no CTCAE Grade 3 or 4 hypoalbuminemia was observed in either group.

INR elevations were observed in 42% of Сорафениб геми-тозилат моногидрат-treated patients and 34% of placebo-treated patients; CTCAE Grade 3 INR elevations were reported in 4% of Сорафениб геми-тозилат моногидрат-treated patients and 2% of placebo-treated patients; there was no CTCAE Grade 4 INR elevation in either group.

Lymphopenia was observed in 47% of Сорафениб геми-тозилат моногидрат-treated patients and 42% of placebo-treated patients.

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

Hypocalcemia was reported in 27% of Сорафениб геми-тозилат моногидрат-treated patients and 15% of placebo-treated patients. CTCAE Grade 3 hypocalcemia (6–7 mg /dL) occurred in 2% of Сорафениб геми-тозилат моногидрат-treated patients and 1% of placebo-treated patients. CTCAE Grade 4 hypocalcemia (<6 mg/dL) occurred in 0.4% of Сорафениб геми-тозилат моногидрат-treated patients and in no placebo-treated patients.

Hypokalemia was reported in 9.5% of Сорафениб геми-тозилат моногидрат-treated patients compared to 5.9% of placebo-treated patients. Most reports of hypokalemia were low grade (CTCAE Grade 1). CTCAE Grade 3 hypokalemia occurred in 0.4% of Сорафениб геми-тозилат моногидрат-treated patients and 0.7% of placebo-treated patients. There were no reports of Grade 4 hypokalemia.

Adverse Reactions In RCC Study 1

Table 5 shows the percentage of patients with RCC experiencing adverse reactions that were reported in at least 10% of patients and at a higher rate in the Сорафениб геми-тозилат моногидрат arm than the placebo arm. CTCAE Grade 3 adverse reactions were reported in 31% of patients receiving Сорафениб геми-тозилат моногидрат compared to 22% of patients receiving placebo. CTCAE Grade 4 adverse reactions were reported in 7% of patients receiving Сорафениб геми-тозилат моногидрат compared to 6% of patients receiving placebo.

Table 5: Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in Сорафениб геми-тозилат моногидрат 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 Сорафениб геми-тозилат моногидрат and placebo-treated groups (10% of Сорафениб геми-тозилат моногидрат-treated patients and 8% of placebo-treated patients).

Laboratory Abnormalities

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

Hypophosphatemia was a common laboratory finding observed in 45% of Сорафениб геми-тозилат моногидрат-treated patients compared to 11% of placebo-treated patients. CTCAE Grade 3 hypophosphatemia (1–2 mg/dL) occurred in 13% of Сорафениб геми-тозилат моногидрат-treated patients and 3% of patients in the placebo-treated group. There were no cases of CTCAE Grade 4 hypophosphatemia (<1 mg/dL) reported in either Сорафениб геми-тозилат моногидрат or placebo-treated patients. The etiology of hypophosphatemia associated with Сорафениб геми-тозилат моногидрат is not known.

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

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

Anemia was observed in 44% of Сорафениб геми-тозилат моногидрат-treated patients and 49% of placebo-treated patients. CTCAE Grade 3 or 4 anemia was reported in 2% of Сорафениб геми-тозилат моногидрат-treated patients and 4% of placebo-treated patients.

Thrombocytopenia was observed in 12% of Сорафениб геми-тозилат моногидрат-treated patients and 5% of placebo-treated patients. CTCAE Grade 3 or 4 thrombocytopenia was reported in 1% of Сорафениб геми-тозилат моногидрат-treated patients and in no placebo-treated patients.

Hypocalcemia was reported in 12% of Сорафениб геми-тозилат моногидрат-treated patients and 8% of placebo-treated patients. CTCAE Grade 3 hypocalcemia (6–7 mg/dL) occurred in 1% of Сорафениб геми-тозилат моногидрат-treated patients and 0.2% of placebo-treated patients, and CTCAE Grade 4 hypocalcemia (<6 mg/dL) occurred in 1% of Сорафениб геми-тозилат моногидрат-treated patients and 0.5% of placebo-treated patients.

Hypokalemia was reported in 5.4% of Сорафениб геми-тозилат моногидрат-treated patients compared to 0.7% of placebo-treated patients. Most reports of hypokalemia were low grade (CTCAE Grade 1). CTCAE Grade 3 hypokalemia occurred in 1.1% of Сорафениб геми-тозилат моногидрат-treated patients and 0.2% of placebo-treated patients. There were no reports of Grade 4 hypokalemia.

Adverse Reactions In DTC Study

The safety of Сорафениб геми-тозилат моногидрат was evaluated in 416 patients with locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine (RAI) treatment randomized to receive 400 mg twice daily Сорафениб геми-тозилат моногидрат (n=207) or matching placebo (n=209) until disease progression or intolerable toxicity in a double-blind trial. The data described below reflect a median exposure to Сорафениб геми-тозилат моногидрат for 46 weeks (range 0.3 to 135). The population exposed to Сорафениб геми-тозилат моногидрат was 50% male, and had a median age of 63 years.

Dose interruptions for adverse reactions were required in 66% of patients receiving Сорафениб геми-тозилат моногидрат and 64% of patients had their dose reduced. Drug-related adverse reactions that resulted in treatment discontinuation were reported in 14% of Сорафениб геми-тозилат моногидрат-treated patients compared to 1.4% of placebo-treated patients.

Table 6 shows the percentage of DTC patients experiencing adverse reactions at a higher rate in Сорафениб геми-тозилат моногидрат-treated patients than placebo-treated patients in the double-blind phase of the DTC study. CTCAE Grade 3 adverse reactions occurred in 53% of Сорафениб геми-тозилат моногидрат-treated patients compared to 23% of placebo-treated patients. CTCAE Grade 4 adverse reactions occurred in 12% of Сорафениб геми-тозилат моногидрат-treated patients compared to 7% of placebo-treated patients.

Table 6: Per-Patient Incidence of Selected Adverse Reactions Occurring at a Higher Incidence in Сорафениб геми-тозилат моногидрат-Treated Patients [Between Arm Difference of ≥ 5% (All Grades)¹ or ≥ 2% (Grades 3 and 4)]

Laboratory Abnormalities

Elevated TSH levels are discussed elsewhere in the labeling. The relative increase for the following laboratory abnormalities observed in Сорафениб геми-тозилат моногидрат-treated DTC patients as compared to placebo-treated patients is similar to that observed in the RCC and HCC studies: lipase, amylase, hypokalemia, hypophosphatemia, neutropenia, lymphopenia, anemia, and thrombocytopenia.

Serum ALT and AST elevations were observed in 59% and 54% of the Сорафениб геми-тозилат моногидрат-treated patients as compared to 24% and 15% of placebo-treated patients, respectively. High grade (≥ 3) ALT and AST elevations were observed in 4% and 2%, respectively, in the Сорафениб геми-тозилат моногидрат-treated patients as compared to none of the placebo-treated patients.

Hypocalcemia was more frequent and more severe in patients with DTC, especially those with a history of hypoparathyroidism, compared to patients with RCC or HCC. Hypocalcemia was observed in 36% of DTC patients receiving Сорафениб геми-тозилат моногидрат (with 10% ≥ Grade 3) as compared with 11% of placebo-treated patients (3% ≥ Grade 3). In the DTC study, serum calcium levels were monitored monthly.

Additional Data From Multiple Clinical Trials

The following additional drug-related adverse reactions and laboratory abnormalities were reported from clinical trials of Сорафениб геми-тозилат моногидрат (very common 10% or greater, common 1 to less than 10%, uncommon 0.1% to less than 1%, rare less than 0.1 %):

Cardiovascular: Common: congestive heart failure*^† , myocardial ischemia and/or infarction Uncommon: hypertensive crisis* Rare: QT prolongation*

Dermatologic: Very common: erythema Common: exfoliative dermatitis, acne, flushing, folliculitis, hyperkeratosis Uncommon: eczema, erythema multiforme

Digestive:Very common: increased lipase, increased amylase Common: mucositis, stomatitis (including dry mouth and glossodynia), dyspepsia, dysphagia, gastrointestinal reflux Uncommon: pancreatitis, gastritis, gastrointestinal perforations*, cholecystitis, cholangitis

Note that elevations in lipase are very common (41%, see below); a diagnosis of pancreatitis should not be made solely on the basis of abnormal laboratory values

General Disorders: Very common: infection, hemorrhage (including gastrointestinal* and respiratory tract* and uncommon cases of cerebral hemorrhage*), asthenia, pain (including mouth, bone, and tumor pain), pyrexia, decreased appetite Common: influenza-like illness

Hematologic: Very common: leukopenia, lymphopenia Common: anemia, neutropenia, thrombocytopenia Uncommon: INR abnormal

Hepatobiliary disorders: Rare: drug-induced hepatitis (including hepatic failure and death)

Metabolic and Nutritional: Very common: hypophosphatemia Common: transient increases in transaminases, hypocalcemia, hypokalemia, hyponatremia, hypothyroidism Uncommon: dehydration, transient increases in alkaline phosphatase, increased bilirubin (including jaundice), hyperthyroidism

Musculoskeletal: Very common: arthralgia Common: myalgia, muscle spasms

Nervous System and Psychiatric: Common: depression, dysgeusia Uncommon: tinnitus, reversible posterior leukoencephalopathy*

Renal and Genitourinary: Common: renal failure, proteinuria Rare: nephrotic syndrome

Reproductive: Common: erectile dysfunction Uncommon: gynecomastia

Respiratory: Common: rhinorrhea Uncommon: interstitial lung disease-like events (includes reports of pneumonitis, radiation pneumonitis, acute respiratory distress, interstitial pneumonia, pulmonitis and lung inflammation)

In addition, the following medically significant adverse reactions were uncommon during clinical trials of Сорафениб геми-тозилат моногидрат: transient ischemic attack, arrhythmia, and thromboembolism. For these adverse reactions, the causal relationship to Сорафениб геми-тозилат моногидрат has not been established.

*adverse reactions may have a life-threatening or fatal outcome.
^†reported in 1.9% of patients treated with Сорафениб геми-тозилат моногидрат (N= 2276).

Postmarketing Experience

The following adverse drug reactions have been identified during post-approval use of Сорафениб геми-тозилат моногидрат. 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.

Dermatologic: Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN)

Hypersensitivity: Angioedema

Musculoskeletal: Rhabdomyolysis, osteonecrosis of the jaw

Respiratory: Interstitial lung disease-like events (which may have a life-threatening or fatal outcome)

There is no specific treatment for Сорафениб геми-тозилат моногидрат overdose.

The highest dose of Сорафениб геми-тозилат моногидрат 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, Сорафениб геми-тозилат моногидрат should be withheld and supportive care instituted.

Cardiac Electrophysiology

The effect of Сорафениб геми-тозилат моногидрат 400 mg twice daily on the QTc interval was evaluated in a multi-center, open-label, non-randomized trial in 53 patients with advanced cancer. No large changes in the mean QTc intervals (that is, >20 ms) from baseline were detected in the trial. After one 28-day treatment cycle, the largest mean QTc interval change of 8.5 ms (upper bound of two-sided 90% confidence interval, 13.3 ms) was observed at 6 hours post-dose on day 1 of cycle 2.

The mean elimination half-life of sorafenib was approximately 25 to 48 hours. Multiple doses of Сорафениб геми-тозилат моногидрат for 7 days resulted in a 2.5- to 7-fold accumulation compared to a single dose. Steady-state plasma sorafenib concentrations were achieved within 7 days, with a peak-to-trough ratio of mean concentrations of less than 2.

The steady-state concentrations of sorafenib following administration of 400 mg Сорафениб геми-тозилат моногидрат twice daily were evaluated in DTC, RCC and HCC patients. Patients with DTC have mean steady-state concentrations that are 1.8fold higher than patients with HCC and 2.3-fold higher than those with RCC. The reason for increased sorafenib concentrations in DTC patients is unknown.

Absorption And Distribution

After administration of Сорафениб геми-тозилат моногидрат tablets, the mean relative bioavailability was 38–49% when compared to an oral solution. Following oral administration, sorafenib reached peak plasma levels in approximately 3 hours. 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), bioavailability was reduced by 29% compared to that in the fasted state. It is recommended that Сорафениб геми-тозилат моногидрат be administered without food.

Mean Cmax and AUC increased less than proportionally beyond oral doses of 400 mg administered twice daily. In vitro binding of sorafenib to human plasma proteins was 99.5%.

Metabolism And Elimination

Sorafenib undergoes oxidative metabolism by hepatic CYP3A4, as well as glucuronidation by UGT1A9. Inducers of CYP3A4 activity can decrease the systemic exposure of sorafenib.

Sorafenib accounted 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, the pyridine N-oxide that comprises approximately 9–16% of circulating analytes at steady-state, showed in vitro potency similar to that of sorafenib.

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.

Effects of Age, Gender and 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). Gender and age do not have a clinically meaningful effect on the pharmacokinetics of sorafenib.

Renal Impairment

Mild (CLcr 50-80 mL/min), moderate (CLcr 30 -<50 mL/min), and severe (CLcr <30 mL/min) renal impairment do not affect the pharmacokinetics of sorafenib. No dose adjustment is necessary.

Hepatic Impairment

Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment do not affect the pharmacokinetics of sorafenib. No dose adjustment is necessary.