Sorafenib
- Dosage: 200 mg q12h, taken 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. Temporary interruption of Sorafenib is recommended in patients undergoing major surgical procedures.
Temporary interruption or permanent discontinuation of Sorafenib 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
- Temporary interruption or permanent discontinuation of Sorafenib 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
- 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
When dose reduction is necessary, the Sorafenib dose may be reduced to 400 mg once daily. If additional dose reduction is required, Sorafenib may be reduced to a single 400 mg dose every other day. If dermatological toxicity presented, the following scheme should be followed:
Following improvement of Grade 2 or 3 dermatologic toxicity to Grade 01 after at least 28 days of treatment on a reduced dose of Sorafenib, the dose of Sorafenib 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)
- Sorafenib in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer.
- In the HCC study, the incidence of cardiac ischemia/infarction was 2.7% in Sorafenib-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 Sorafenib-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 Sorafenib-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 Sorafenib should be considered in patients who develop cardiac ischemia and/or infarction.
- An increased risk of bleeding may occur following Sorafenib 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-treated patients and 4% in placebo-treated patients. Bleeding with a fatal outcome from any site was reported in 2.4% of Sorafenib-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 Sorafenib-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 Sorafenib-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 Sorafenib-treated patients and 9.6% of placebo-treated patients; however the incidence of CTCAE Grade 3 bleeding was 1% in Sorafenib-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 Sorafenib should be considered. Due to the potential risk of bleeding, tracheal, bronchial, and esophageal infiltration should be treated with local therapy prior to administering Sorafenib in patients with DTC.
- Monitor blood pressure weekly during the first 6 weeks of Sorafenib. 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 Sorafenib-treated patients and 4.3% of patients in the placebo-treated group. In RCC Study 1, hypertension was reported in approximately 16.9% of Sorafenib-treated patients and 1.8% of patients in the placebo-treated group. In the DTC study, hypertension was reported in 40.6% of Sorafenib-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 Sorafenib. Permanent discontinuation due to hypertension occurred in 1 of 297 Sorafenib-treated patients in the HCC study, 1 of 451 Sorafenib-treated patients in RCC Study 1, and 1 of 207 Sorafenib-treated patients in the DTC study.
- Hand-foot skin reaction and rash represent the most common adverse reactions attributed to Sorafenib. 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. 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. Permanent discontinuation of therapy due to hand-foot skin reaction occurred in 4 (1.3%) of 297 Sorafenib-treated patients with HCC, 3 (0.7%) of 451 Sorafenib-treated patients with RCC, and 11 (5.3%) of 207 Sorafenib-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 Sorafenib if SJS or TEN are suspected.
- Gastrointestinal perforation is an uncommon adverse reaction and has been reported in less than 1% of patients taking Sorafenib. In some cases this was not associated with apparent intra-abdominal tumor. In the event of a gastrointestinal perforation, discontinue Sorafenib.
- Infrequent bleeding or elevations in the International Normalized Ratio (INR) have been reported in some patients taking warfarin while on Sorafenib. Monitor patients taking concomitant warfarin regularly for changes in prothrombin time (PT), INR or clinical bleeding episodes.
- No formal studies of the effect of Sorafenib on wound healing have been conducted. Temporary interruption of Sorafenib is recommended in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of Sorafenib following major surgical intervention. Therefore, the decision to resume Sorafenib following a major surgical intervention should be based on clinical judgment of adequate wound healing.
- 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 1.192.74) 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.
- 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 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 Sorafenib if QTc interval is greater than 500 milliseconds or for an increase from baseline of 60 milliseconds or greater.
- 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 Sorafenib.
- 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.
- Sorafenib 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 Sorafenib-treated patients as compared with 16% of placebo-treated patients. For patients with impaired TSH suppression while receiving Sorafenib, 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.
Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in Sorafenib Arm than the Placebo Arm  HCC Study:
- Fatigue
- Weight loss
- Rash/Desquamation
- Pruritus
- Hand-Foot skin reaction
- Dry skin
- Alopecia
- Diarrhea
- Anorexia
- Nausea
- Vomiting
- Constipation
- Liver dysfunction
- Abdominal pain
Hypertension was reported in 9% of patients treated with Sorafenib and 4% of those treated with placebo. CTCAE Grade 3 hypertension was reported in 4% of Sorafenib-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 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% Sorafenib and 5% placebo and CTCAE Grade 4  2% Sorafenib and 4% placebo). Bleeding from esophageal varices was reported in 2.4% in Sorafenib-treated patients and 4% of placebo-treated patients. Renal failure was reported in <1% of patients treated with Sorafenib 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 and placebo-treated groups (32% of Sorafenib-treated patients and 35% of placebo-treated patients).
The following laboratory abnormalities were observed in patients with HCC:
- Hypophosphatemia was a common laboratory finding, observed in 35% of Sorafenib-treated patients compared to 11% of placebo-treated patients; CTCAE Grade 3 hypophosphatemia (12 mg/dL) occurred in 11% of Sorafenib-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 Sorafenib is not known.
- Elevated lipase was observed in 40% of patients treated with Sorafenib 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 Sorafenib 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 Sorafenib treatment was not interrupted. Clinical pancreatitis was reported in 1 of 297 Sorafenib-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-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 Sorafenib-treated patients and 34% of placebo-treated patients; CTCAE Grade 3 INR elevations were reported in 4% of Sorafenib-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 Sorafenib-treated patients and 42% of placebo-treated patients.
- Thrombocytopenia was observed in 46% of Sorafenib-treated patients and 41% of placebo-treated patients; CTCAE Grade 3 or 4 thrombocytopenia was reported in 4% of Sorafenib-treated patients and less than 1% of placebo-treated patients.
- Hypocalcemia was reported in 27% of Sorafenib-treated patients and 15% of placebo-treated patients. CTCAE Grade 3 hypocalcemia (67 mg /dL) occurred in 2% of Sorafenib-treated patients and 1% of placebo-treated patients. CTCAE Grade 4 hypocalcemia (<6 mg/dL) occurred in 0.4% of Sorafenib-treated patients and in no placebo-treated patients.
- Hypokalemia was reported in 9.5% of Sorafenib- 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 Sorafenib-treated patients and 0.7% of placebo-treated patients. There were no reports of Grade 4 hypokalemia.

# Adverse Reactions in RCC Study 1
Adverse Reactions Reported in at Least 10% of Patients and at a Higher Rate in Sorafenib Arm than the Placebo Arm  RCC Study 1:
- Hypertension
- Fatigue
- Weight loss
- Rash/Desquamation
- Hand-foot skin reaction
- Alopecia
- Pruritus
- Dry skin
- Diarrhea
- Nausea
- Anorexia
- Vomiting
- Constipation
- Hemorrhage - All sites
- Sensory neuropathy
- Abdominal Pain
- Joint Pain
- Headache
- Dyspnea
The following laboratory abnormalities were observed in patients with RCC in Study 1:
- Hypophosphatemia was a common laboratory finding, observed in 45% of Sorafenib-treated patients compared to 11% of placebo-treated patients. CTCAE Grade 3 hypophosphatemia (12 mg/dL) occurred in 13% of Sorafenib-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 Sorafenib or placebo-treated patients. The etiology of hypophosphatemia associated with Sorafenib is not known.
- Elevated lipase was observed in 41% of patients treated with Sorafenib compared to 30% of patients in the placebo-treated group. CTCAE Grade 3 or 4 lipase elevations occurred in 12% of patients in the Sorafenib-treated group compared to 7% of patients in the placebo-treated group. Elevated amylase was observed in 30% of patients treated with Sorafenib 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 Sorafenib-treated group compared to 3% of patients in the placebo-treated group. Many of the Sorafenib and amylase elevations were transient, and in the majority of cases Sorafenib treatment was not interrupted. Clinical pancreatitis was reported in 3 of 451 Sorafenib-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 Sorafenib-treated patients and 13% of placebo-treated patients. CTCAE Grade 3 or 4 lymphopenia was reported in 13% of Sorafenib-treated patients and 7% of placebo-treated patients. Neutropenia was observed in 18% of Sorafenib-treated patients and 10% of placebo-treated patients. CTCAE Grade 3 or 4 neutropenia was reported in 5% of Sorafenib-treated patients and 2% of placebo-treated patients.
- Anemia was observed in 44% of Sorafenib-treated patients and 49% of placebo-treated patients. CTCAE Grade 3 or 4 anemia was reported in 2% of Sorafenib-treated patients and 4% of placebo-treated patients.
- Thrombocytopenia was observed in 12% of Sorafenib-treated patients and 5% of placebo-treated patients. CTCAE Grade 3 or 4 thrombocytopenia was reported in 1% of Sorafenib-treated patients and in no placebo-treated patients.
- Hypocalcemia was reported in 12% of Sorafenib-treated patients and 8% of placebo-treated patients. CTCAE Grade 3 hypocalcemia (67 mg/dL) occurred in 1% of Sorafenib-treated patients and 0.2% of placebo-treated patients, and CTCAE Grade 4 hypocalcemia (<6 mg/dL) occurred in 1% of Sorafenib-treated patients and 0.5% of placebo-treated patients.
- Hypokalemia was reported in 5.4% of Sorafenib-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 Sorafenib-treated patients and 0.2% of placebo-treated patients. There were no reports of Grade 4 hypokalemia.

# Adverse Reactions in DTC Study
Per-Patient Incidence of Selected Adverse Reactions Occurring at a Higher Incidence in Sorafenib-Treated Patients :
- Diarrhea
- Nausea
- Abdominal pain
- Constipation
- Stomatitis
- Vomiting
- Oral pain
- Fatigue
- Asthenia
- Pyrexia
- Weight loss
- Decreased appetite
- Pain in extremities
- Muscle spasms
- Squamous cell carcinoma of skin
- Headache
- Dysgeusia
- Epistaxis
- Dysphonia
- PPES
- Alopecia
- Rash
- Pruritus
- Dry skin
- Erythema
- Hyperkeratosis
- Hypertension
- Elevated TSH levels are discussed elsewhere in the labeling. The relative increase for the following laboratory abnormalities observed in Sorafenib-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 Sorafenib-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 Sorafenib-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 Sorafenib (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 Sorafenib (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
- 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 and multiform.
- Very common: erythema
- Common: exfoliative dermatitis, acne, flushing, folliculitis, hyperkeratosis
- Uncommon: eczema, erythema and multiform.
- 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
- 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
- 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.
- 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
- Very common: leukopenia, lymphopenia
- Common: anemia, neutropenia, thrombocytopenia
- Uncommon: INR abnormal
- Hepatobiliary disorders:
Rare: drug-induced hepatitis (including hepatic failure and death)
- Hypersensitivity
Uncommon: hypersensitivity reactions (including skin reactions and urticaria), anaphylactic reaction
- Uncommon: hypersensitivity reactions (including skin reactions and urticaria), anaphylactic reaction
- 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
- 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
- Very common: arthralgia
- Common: myalgia, muscle spasms
- Nervous System and Psychiatric
Common: depression, dysgeusia
Uncommon: tinnitus, reversible posterior leukoencephalopathy
- Common: depression, dysgeusia
- Uncommon: tinnitus, reversible posterior leukoencephalopathy
- Renal and Genitourinary
Common: renal failure, proteinuria
Rare: nephrotic syndrome
- Common: renal failure, proteinuria
- Rare: nephrotic syndrome
- Reproductive
Common: erectile dysfunction
Uncommon: gynecomastia
- 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)
- 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 Sorafenib: transient ischemic attack, arrhythmia, and thromboembolism. For these adverse reactions, the causal relationship of Sorafenib has not been established.
- 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)
- Rifampin, a strong CYP3A4 inducer, administered at a dose of 600 mg once daily for 5 days with a single oral dose of Sorafenib 400 mg in healthy volunteers resulted in a 37% decrease in the mean AUC of sorafenib. Avoid concomitant use of strong CYP3A4 inducers (such as, carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, rifabutin, St. Johns wort), when possible, because these drugs can decrease the systemic exposure to sorafenib.
- Ketoconazole, a strong inhibitor of CYP3A4 and P-glycoprotein, administered at a dose of 400 mg once daily for 7 days did not alter the mean AUC of a single oral dose of Sorafenib 50 mg in healthy volunteers.
- Sorafenib 400 mg twice daily for 28 days did not increase the systemic exposure of concomitantly administered midazolam (CYP3A4 substrate), dextromethorphan (CYP2D6 substrate), and omeprazole (CYP2C19 substrate)
- Neomycin administered as an oral dose of 1 g three times daily for 5 days decreased the mean AUC of sorafenib by 54% in healthy volunteers administered a single oral dose of Sorafenib 400 mg. The effects of other antibiotics on the pharmacokinetics of sorafenib have not been studied.
- The aqueous solubility of sorafenib is pH dependent, with higher pH resulting in lower solubility. However, omeprazole, a proton pump inhibitor, administered at a dose of 40 mg once daily for 5 days, did not result in a clinically meaningful change in sorafenib single dose exposure. No dose adjustment for Sorafenib is necessary.
- 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.
- 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.
- 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.
- After administration of Sorafenib tablets, the mean relative bioavailability was 3849% 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 Sorafenib 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%.
- 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 7085% 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 916% 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.
- 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.
- 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.
- Mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment do not affect the pharmacokinetics of sorafenib. No dose adjustment is necessary.
Studies in human liver microsomes demonstrated that sorafenib competitively inhibited CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. However, Sorafenib 400 mg twice daily for 28 days with substrates of CYP3A4, CYP2D6 and CYP2C19 did not increase the systemic exposure of these substrates. Studies with cultured human hepatocytes demonstrated that sorafenib did not increase CYP1A2 and CYP3A4 activities, suggesting that sorafenib is unlikely to induce CYP1A2 or CYP3A4 in humans. Sorafenib inhibits glucuronidation by UGT1A1 and UGT1A9 in vitro. Sorafenib could increase the systemic exposure of concomitantly administered drugs that are UGT1A1 or UGT1A9 substrates. Sorafenib inhibited P-glycoprotein in vitro. Sorafenib could increase the concentrations of concomitantly administered drugs that are P-glycoprotein substrates.
- 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.
- The HCC Study was a Phase 3, international, multicenter, randomized, double blind, placebo-controlled trial in patients with unresectable hepatocellular carcinoma. Overall survival was the primary endpoint. A total of 602 patients were randomized; 299 to Sorafenib 400 mg twice daily and 303 to matching placebo. Demographics and baseline disease characteristics were similar between the Sorafenib and placebo-treated 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. 30.0%), and Barcelona Clinic Liver Cancer stage (stage B: 18.1% vs. 16.8%; stage C: 81.6% vs. 83.2%; stage D: <1% vs. 0%). Liver impairment by Child-Pugh score was comparable between the Sorafenib and placebo-treated groups (Class A: 95% vs. 98%; B: 5% vs. 2%). Only one patient with Child-Pugh class C was entered. Prior treatments included surgical resection procedures (19.1% vs. 20.5%), locoregional therapies (including radiofrequency ablation, percutaneous ethanol injection and transarterial chemoembolization; 38.8% vs. 40.6%), radiotherapy (4.3% vs. 5.0%) and systemic therapy (3.0% vs. 5.0%).
- The trial was stopped for efficacy following a pre-specified second interim analysis for survival showing a statistically significant advantage for Sorafenib over placebo for overall survival (HR: 0.69, p= 0.00058) (see Table 4 and Figure 1). This advantage was consistent across all subsets analyzed. Final analysis of time to tumor progression (TTP) based on data from an earlier time point (by independent radiologic review) also was significantly longer in the Sorafenib arm (HR: 0.58, p=0.000007).
- The safety and efficacy of Sorafenib in the treatment of advanced renal cell carcinoma (RCC) were studied in the following two randomized controlled clinical trials. RCC Study 1 was a Phase 3, international, multicenter, randomized, double blind, placebo-controlled trial in patients with advanced renal cell carcinoma who had received one prior systemic therapy. Primary study endpoints included overall survival and progression-free survival (PFS). Tumor response rate was a secondary endpoint. The PFS analysis included 769 patients stratified by MSKCC (Memorial Sloan Kettering Cancer Center) prognostic risk category (low or intermediate) and country and randomized to Sorafenib 400 mg twice daily (N=384) or to placebo (N=385). Table 8 summarizes the demographic and disease characteristics of the study population analyzed. Baseline demographics and disease characteristics were well balanced for both treatment groups. The median time from initial diagnosis of RCC to randomization was 1.6 and 1.9 years for the Sorafenib and placebo-treated groups, respectively.
- The safety and effectiveness of Sorafenib was established in a multicenter, randomized (1:1), double-blind, placebo-controlled trial conducted in 417 patients with locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine] (RAI) treatment]. Randomization was stratified by age (< 60 years versus  60 years) and geographical region (North America, Europe, and Asia).
- All patients were required to have actively progressing disease defined as progression within 14 months of enrollment. RAI-refractory disease was defined based on four criteria that were not mutually exclusive. All RAI treatments and diagnostic scans were to be performed under conditions of a low iodine diet and adequate TSH stimulation. Following are the RAI-refractory criteria and the proportion of patients in the study that met each one: a target lesion with no iodine uptake on RAI scan (68%); tumors with iodine uptake and progression after RAI treatment within 16 months of enrollment (12%); tumors with iodine uptake and multiple RAI treatments with the last treatment greater than 16 months prior to enrollment, and disease progression after each of two RAI treatments administered within 16 months of each other (7%); cumulative RAI dose  600 mCi administered (34%). The major efficacy outcome measure was progression-free survival (PFS) as determined by a blinded, independent radiological review using a modified Response Evaluation Criteria in Solid Tumors v. 1.0 (RECIST). RECIST was modified by inclusion of clinical progression of bone lesions based on the need for external beam radiation (4.4% of progression events). Additional efficacy outcomes measures included overall survival (OS), tumor response rate, and duration of response.
- Patients were randomized to receive Sorafenib 400 mg twice daily (n=207) or placebo (n=210). Of the 417 patients randomized, 48% were male, the median age was 63 years, 61% were 60 years or older, 60% were white, 62% had an ECOG performance status of 0, and 99% had undergone thyroidectomy. The histological diagnoses were papillary carcinoma in 57%, follicular carcinoma (including Hurthle cell) in 25%, and poorly differentiated carcinoma in 10%, and other in 8% of the study population. Metastases were present in 96% of the patients: lungs in 86%, lymph nodes in 51%, and bone in 27%. The median cumulative RAI activity administered prior to study entry was 400 mCi. A statistically significant prolongation in PFS was demonstrated among Sorafenib-treated patients compared to those receiving placebo. Following investigator-determined disease progression, 157 (75%) patients randomized to placebo crossed over to open-label Sorafenib, and 61 (30%) patients randomized to Sorafenib received open-label Sorafenib  There was no statistically significant difference in overall survival between the two treatment arms (see Table 9 and Figure 3).
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