Sutent 50 mg

Co-administration of SUTENT with inducers of the CYP3A4 family may decrease SUTENT concentrations (see Action and Clinical Pharmacology). Concomitant administration of SUTENT with CYP3A4 inducers should be avoided. CYP3A4 inducers include, but are not limited to: barbiturates (e.g. phenobarbital); anticonvulsants (e.g. carbamazepine, phenytoin); rifampin; glucocorticoids; pioglitazone; and some HIV antivirals (e.g. efavirenz, nevirapine).

Grapefruit juice has CYP3A4 inhibitory activity. Therefore, ingestion of grapefruit juice while on SUTENT therapy may lead to decreased SUTENT metabolism and increased SUTENT plasma concentrations (see Drug-Drug Interactions). Concomitant administration of SUTENT with grapefruit juice should be avoided.

Caution should be used if SUTENT is prescribed to patients in combination with other drugs that also cause PR interval prolongation, such as beta blockers, calcium channel blockers, digitalis, or HIV protease inhibitors (see Warnings and Precautions, Cardiovascular, QT Interval Prolongation).

The above list of potentially interacting drugs is not comprehensive. Current scientific literature should be consulted for more information.

Co-administration of SUTENT (sunitinib malate) with inhibitors of the CYP3A4 family may increase SUTENT concentrations (see Action and Clinical Pharmacology). Concomitant administration of SUTENT with CYP3A4 inhibitors should be avoided. These include, but are not limited to: non-dihydropyridine calcium channel blockers (e.g. diltiazem, verapamil); antifungals (e.g. ketoconazole, fluconazole, itraconazole, voriconazole); macrolide antibiotics (e.g. erythromycin, clarithromycin, telithromycin); fluoroquinolone antibiotics (e.g. ciprofloxacin, norfloxacin); and some HIV antivirals (e.g. ritonavir, indinavir).

St. John’s Wort is a potent CYP3A4 inducer. Co-administration with SUTENT may lead to increased SUTENT metabolism and decreased SUTENT plasma concentrations (see Drug-Drug Interactions). Patients receiving SUTENT should not take St. John’s Wort concomitantly.

The concomitant use of SUTENT with another QT/QTc-prolonging drug is discouraged. However, if it is necessary, particular care should be used. Drugs that have been associated with QT/QTc interval prolongation and/or torsade de pointes include, but are not limited to, the examples in the following list. Chemical/pharmacological classes are listed if some, although not necessarily all, class members have been implicated in QT/QTc prolongation and/or torsade de pointes:

• Antiarrhythmics (Class IA, e.g., quinidine, procainamide, disopyramide; Class III, e.g. amiodarone, sotalol, ibutilide; Class IC, e.g. flecainide, propafenone)

  
  

• Antipsychotics (e.g. thioridazine, chlorpromazine, pimozide, haloperidol, droperidol)

  
  

• Antidepressants (e.g. amitriptyline, imipramine, maprotiline, fluoxetine, venlafaxine)

  
  

• Opioids (e.g. methadone)

  
  

• Macrolide antibiotics (e.g. erythromycin, clarithromycin, telithromycin)

  
  

• Quinolone antibiotics (e.g. moxifloxacin, gatifloxacin, ciprofloxacin)

  
  

• Antimalarials (e.g. quinine)

  
  

• Pentamidine

  
  

• Azole antifungals (e.g. ketoconazole, fluconazole, voriconazole)

  
  

• Gastrointestinal drugs (e.g. domperidone, 5HT3 antagonists, such as granisetron, ondansetron, dolasetron)

  
  

• Βeta 2-adrenoreceptor agonists (e.g. salmeterol, formoterol)

  
  

• Tacrolimus

Sunitinib is metabolized primarily by CYP3A4. Potential interactions may occur with drugs/foods/herbs that are inhibitors or inducers of this enzyme system.

Concurrent administration of sunitinib malate with the CYP3A4 inhibitor, ketoconazole, resulted in 49% and 51% increases in combined (sunitinib + active metabolite) C_max and AUC_0-∞ values, respectively, after a single dose of sunitinib malate in healthy volunteers. Doses of SUTENT may need to be reduced to a minimum of 25 mg daily, and clinical response and tolerability should be carefully monitored, in patients receiving a potent CYP3A4 inhibitor such as ketoconazole (see Drug Interactions and Action and Clinical Pharmacology). Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential should be considered. Note: This recommendation is based on pharmacokinetic data from healthy volunteers. In clinical trials conducted to date, the safety and efficacy of SUTENT with concomitant use of CYP3A4 inhibitors has not been established. In the 2 cytokine-refractory MRCC studies, 14 of the 169 patients used a potent CYP 3A4 inhibitor concomitantly with SUTENT with no modification of the starting dose of SUTENT.

No dose adjustment is required on the basis of patient age, body weight, creatine clearance, race, gender or ECOG score. (See Action And Clinical Pharmacology, Special Populations and Conditions.)

Concurrent administration of sunitinib malate with the potent CYP3A4 inducer, rifampin, resulted in a more than 23% and 46% reduction in combined (sunitinib + active metabolite) C_max and AUC_0-∞ values, respectively, after a single dose of SUTENT in healthy volunteers. The dose of SUTENT may need to be increased (maximum 50 mg), and clinical response and tolerability should be carefully monitored, in patients receiving SUTENT with a potent CYP3A4 inducer, such as rifampin (see Drug Interactions and Action and Clinical Pharmacology). Selection of an alternate concomitant medication with no or minimal enzyme induction potential should be considered. Note: This recommendation is based on pharmacokinetic data from healthy volunteers. In clinical trials conducted to date, the safety and efficacy of SUTENT with concomitant use of CYP3A4 inducers has not been established. In the two cytokine-refractory MRCC studies, 33 of the 169 patients received a potent CYP3A4 inducer concomitantly with SUTENT with no modification of the starting dose of SUTENT.

Daily doses should not exceed 50 mg nor be decreased below 25 mg. Dose modification of 12.5-mg is recommended based on individual safety and tolerability.

Rare cases of hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through post-marketing experience (see Warnings and Precautions, Thyroid Dysfunction).

Grade 3 or 4 treatment-emergent laboratory abnormalities were seen in 68 SUTENT patients (34%) versus 22 placebo patients (22%). Elevated liver function tests, pancreatic enzymes and creatinine were all more common in SUTENT patients than placebo patients. Decreased LVEF, myelosuppression and electrolyte disturbances were all more common in SUTENT patients than placebo patients. Treatment-emergent acquired hypothyroidism was noted in 4% of GIST patients on SUTENT versus 1% on placebo.

Cases of proteinuria and rare cases of nephrotic syndrome have been reported. Baseline urinalysis is recommended, and patients should be monitored for the development or worsening of proteinuria. The safety of continued sunitinib treatment in patients with moderate to severe proteinuria has not been systematically evaluated. Discontinue sunitinib in patients with nephrotic syndrome.

Rare cases of myopathy and/or rhabdomyolysis, some with acute renal failure, have been reported. Most of these patients had pre-existing risk factors and/or were receiving concomitant medications known to be associated with these adverse reactions. Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice. (See Warnings and Precautions.)

Cases of serious infection (with or without neutropenia), in some cases with fatal outcome, have been reported.

See Warnings and Precautions.

Rhabdomyolysis has been reported in some cases from non-pivotal clinical trials (see Warnings and Precautions and Post-Marketing Experience).

See Warnings and Precautions.

The following adverse reactions have been identified during postapproval use of SUTENT. 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.

Two thousand, two hundred and eight (2208) patients with solid tumours, including 853 (39%) patients with GIST and 927 (42%) patients with MRCC, have been treated with SUTENT (sunitinib malate) in 25 completed and ongoing clinical trials. Most of these patients received SUTENT (sunitinib malate) once daily as a 50-mg oral capsule, as a starting dose, on Schedule 4/2. One hundred two (102) patients received placebo in the randomized, double-blind, placebo-controlled clinical trial conducted in patients with GIST. Three hundred and sixty (360) patients received IFN-α in the randomized clinical trial in patients with treatment-naïve MRCC. Most adverse events are reversible and do not need to result in discontinuation. If necessary, these events can be managed through dose adjustments or interruptions.

Treatment-Emergent Laboratory Abnormalities Reported in at Least 10% of Treatment-Naïve MRCC Patients Who Received SUTENT or IFN-α

Rare cases of thrombotic microangiopathy have been reported. Temporary suspension of sunitinib is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.

See Warnings and Precautions.

See Warnings and Precautions.

Of the 450 patients with solid tumours reported from clinical studies of SUTENT, 115 (25.6%) were 65 and over. No overall differences in safety or effectiveness were observed between younger and older patients.

The safety and efficacy of SUTENT in pediatric patients have not been established (see Warnings and Precautions).

Each hard gelatin capsule with caramel cap and caramel body, printed with white ink “Pfizer” on the cap, “STN 50 mg” on the body, contains: sunitinib malate equivalent to sunitinib 50 mg. Nonmedicinal ingredients: croscarmellose sodium, magnesium stearate, mannitol and povidone (K-25); orange capsule shell: gelatin, red iron oxide and titanium dioxide; caramel capsule shell also contain: black iron oxide and yellow iron oxide; imprinting ink: povidone, propylene glycol, shellac, sodium hydroxide and titanium dioxide. Bottles of 28.

Each hard gelatin capsule with orange cap and orange body, printed with white ink “Pfizer” on the cap, “STN 12.5 mg” on the body, contains: sunitinib malate equivalent to sunitinib 12.5 mg. Nonmedicinal ingredients: croscarmellose sodium, magnesium stearate, mannitol and povidone (K-25); orange capsule shell: gelatin, red iron oxide and titanium dioxide; imprinting ink: povidone, propylene glycol, shellac, sodium hydroxide and titanium dioxide. Bottles of 28.

Each hard gelatin capsule with caramel cap and orange body, printed with white ink “Pfizer” on the cap, “STN 25 mg” on the body, contains: sunitinib malate equivalent to sunitinib 25 mg. Nonmedicinal ingredients: croscarmellose sodium, magnesium stearate, mannitol and povidone (K-25); orange capsule shell: gelatin, red iron oxide and titanium dioxide; caramel capsule shell also contain: black iron oxide and yellow iron oxide; imprinting ink: povidone, propylene glycol, shellac, sodium hydroxide and titanium dioxide. Bottles of 28.

Each hard gelatin capsule with standard yellow cap and standard yellow body, printed with black ink “Pfizer” on the cap, “STN 37.5 mg” on the body, contains: sunitinib malate equivalent to sunitinib 37.5 mg. Nonmedicinal ingredients: Nonmedicinal ingredients: croscarmellose sodium, magnesium stearate, mannitol and povidone (K-25); yellow capsule shell: gelatin, titanium dioxide and yellow iron oxide; imprinting ink: black iron oxide, butyl alcohol, dehydrated alcohol, isopropyl alcohol, potassium hydroxide, propylene glycol, strong ammonia solution, and shellac. Bottles of 28.

SUTENT has not been studied in patients with renal impairment.

Sunitinib is metabolized primarily by CYP3A4. Potential interactions may occur with drugs that are inhibitors or inducers of this enzyme system (see Drug Interactions).

Carcinogenicity studies with sunitinib have not been performed.

Sunitinib has been tested for genotoxicity in a series of in vitro assays (bacterial mutation, human lymphocyte chromosome aberration) and an in vivo rat bone marrow micronucleus test and did not cause genetic damage.

There have been no cases of myocardial ischemia or myocardial infarction in patients with GIST exposed to either SUTENT or placebo. Two (2) patients with treatment-naïve MRCC experienced myocardial infarction (1 Grade 2 and 1 Grade 3), while 1 patient had Grade 3 myocardial ischaemia. Two (2) patients with cytokine-refractory MRCC experienced Grade 3 myocardial ischemia, 1 had Grade 2 “cardiovascular toxicity” reported as an adverse event and 1 patient experienced a fatal myocardial infarction while on treatment.

Treatment-emergent acquired hypothyroidism was noted in 4% of GIST patients on SUTENT versus 1% on placebo. Although not prospectively studied in clinical trials, hypothyroidism was reported as an adverse event in 2% of patients on SUTENT in the treatment-naïve MRCC study and one patient (<1%) in the IFN-α arm, and in 4% of patients across the two cytokine-refractory MRCC studies. Additionally, TSH elevations were reported in 2% of cytokine-refractory MRCC patients. Overall, 7% of the MRCC population had either clinical or laboratory evidence of treatment-emergent hypothyroidism.

All patients should be observed closely for signs and symptoms of thyroid dysfunction on sunitinib treatment. Patients with signs and/or symptoms suggestive of hypothyroidism thyroid dysfunction, such as fatigue, should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice.

Rare cases of hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through post-marketing experience.

Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation, (likely linked to tumour necrosis) have occurred rarely in patients with intra-abdominal malignancies treated with SUTENT.

Adrenal toxicity was noted in pre-clinical repeat dose studies of 14 days to 9 months in rats and monkeys at plasma exposures as low as 1.1 times the AUC observed in clinical studies. Histological changes of the adrenal gland were characterized as hemorrhage, necrosis, congestion, hypertrophy and inflammation. In clinical studies, CT or MRI scanning performed on 336 patients treated with SUTENT demonstrated no evidence of adrenal gland hemorrhage or necrosis. ACTH stimulation testing was conducted in over 400 patients across multiple clinical trials of SUTENT. In the GIST studies, 13 patients with normal baseline testing had abnormalities at post-baseline testing consisting of: peak cortisol levels post-stimulation less than normal (497 nmol/L, or 18 μg/dL); failure of stimulation to increase cortisol level by a normal amount (193 nmol/L, or 7 μg/dL); or failure of ACTH Gel test to detect doubling of cortisol level post-stimulation. None of these patients were reported to have clinical evidence of adrenal insufficiency. In the cytokine-refractory MRCC studies, 28 patients with normal baseline testing had abnormalities at post-baseline testing and 3 patients had a treatment-emergent adverse event of adrenal insufficiency, which were not considered by the investigator to be related to SUTENT.

Patients treated with SUTENT should be monitored for adrenal insufficiency when they experience stress such as surgery, trauma, or severe infection.

The safety and efficacy of SUTENT in pediatric patients have not been established (see Indications and Clinical Use). However, physeal dysplasia was observed in Cynomolgus monkeys with open growth plates treated for 3 months with sunitinib at doses that were approximately 0.4 times the recommended human dose (RHD) based on systemic exposure (AUC). The incidence and severity of physeal dysplasia were dose-related and were reversible upon cessation of treatment.

There are no adequate and well-controlled studies of SUTENT in pregnant women. Repeat-dose studies in animals have shown effects in reproductive organs. SUTENT should not be used during pregnancy or in any woman not employing adequate contraception. If the drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with SUTENT.

Grade 3 and 4 increases in serum lipase have been observed in 20 SUTENT patients (10%) versus 7 placebo patients (7%) with GIST. Grade 3 and 4 increases in amylase have been observed in 10 SUTENT patients (5%) versus 3 placebo patients (3%) with GIST. In patients with treatment-naïve MRCC, Grade 3 or 4 increases in amylase and lipase have been observed in 5% and 16% of SUTENT-treated patients and in 3% and 6% of patients receiving IFN-α. In the cytokine-refractory MRCC studies, grade 3 or 4 increases in amylase and lipase have been observed in 4.8% and 16.9% of SUTENT-treated patients, respectively. Increases in lipase levels were transient and were generally not accompanied by signs or symptoms of pancreatitis in subjects receiving SUTENT for GIST or MRCC. Pancreatitis was observed in 2 solid tumour patients (0.4%). Hepatic failure was observed in <1% of solid tumour patients treated with SUTENT. If symptoms of pancreatitis or hepatic failure are present, patients should have SUTENT discontinued and be provided with appropriate medical care.

Decreased absolute neutrophil counts of Grade 3 and 4 severity were reported in 13.1% and 0.9% patients, respectively. One (1) case of febrile neutropenia was reported in a patient receiving SUTENT on the GIST pivotal trial (Study A). Decreased platelet counts of grade 3 and 4 severity were reported in 4% and 0.5% of patients respectively. The above events were not cumulative, were typically reversible and generally did not result in treatment discontinuation. Complete blood counts should be performed at the beginning of each treatment cycle for patients receiving treatment with SUTENT. Supportive care for hematologic events may include colony stimulating factors.

In the GIST pivotal trial (Study A), bleeding events occurred in 20% of patients (41/202) receiving SUTENT, compared to 11% (11/102) receiving placebo. In GIST Study A, 14/202 patients (7%) receiving SUTENT and 9/102 patients (9%) on placebo had Grade 3 or 4 bleeding events. In addition, 1 patient in Study A taking placebo had a fatal gastrointestinal bleeding event during cycle 2.

In patients receiving SUTENT for treatment-naïve MRCC, 28% of patients had bleeding events compared with 7% of patients receiving IFN-α. Seven (1.9%) patients on SUTENT versus 0% of patients on IFN-α experienced Grade 3 or greater treatment-related bleeding events.

Bleeding events occurred in 50/169 (26%) patients receiving SUTENT for cytokine-refractory MRCC. Most events in cytokine-refractory MRCC patients were Grade 1 or 2; there was one Grade 3 event (bleeding foot wound). Two (2) cytokine-refractory MRCC study patients with pulmonary metastases experienced hemoptysis considered to be related to SUTENT administration.

Epistaxis was the most common hemorrhagic adverse event reported. Less common bleeding events in MRCC or GIST patients included rectal, gingival, upper GI, genital and wound bleeding.

Treatment-related tumour hemorrhage has been observed in patients receiving SUTENT. These events may occur suddenly, and in the case of pulmonary tumours, may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Fatal pulmonary hemorrhage occurred in 2 patients receiving SUTENT in a clinical trial of patients with metastatic non-small cell lung cancer (NSCLC). Both patients had squamous cell histology. SUTENT is not approved for use in patients with NSCLC. Treatment-related Grade 3 and 4 tumour hemorrhage occurred in 4/257 (approximately 2%) of GIST patients treated with SUTENT. One (1) patient with tumour hemorrhage had the SUTENT dose temporarily delayed. No patients discontinued treatment due to tumour hemorrhage.

Routine assessment of this event should include serial complete blood counts (CBCs) and physical examination.

SUTENT has not been studied in patients with known brain metastases. In clinical studies of SUTENT, seizures have been observed in <1% of subjects with radiological evidence of brain metastases.

In addition, there have been rare (<1%) reports of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). None of these subjects had a fatal outcome to the event. Patients with seizures and signs/symptoms consistent with RPLS, such as hypertension, headache, decreased alertness, altered mental functioning and visual loss, including cortical blindness should be controlled with medical management including control of hypertension. Discontinuation of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating physician, although the evidence to support this recommendation (restarting treatment) is extremely limited.

CBCs and serum chemistries (including liver function tests, creatinine, electrolytes, magnesium, calcium, phosphate, amylase, and lipase) should be performed at the beginning of each treatment cycle for patients receiving treatment with SUTENT. In the event of an electrolyte abnormality, there should be prompt correction of the imbalance. Thyroid testing should be considered periodically.

Baseline ECG should be conducted prior to starting SUTENT, and ECGs should be performed periodically during therapy. SUTENT should generally not be prescribed to patients with abnormally long baseline QT/QTc intervals or AV block. If there are symptoms suggestive of arrhythmia or if the QT/QTc interval becomes markedly prolonged while the patient is on SUTENT, the drug should be discontinued.

Skin discoloration, possibly due to the active substance color (yellow) is a common treatment-related adverse event occurring in approximately 30% of patients. Patients should be advised that depigmentation of the hair or skin may also occur during treatment with SUTENT. Other possible dermatologic effects may include dryness, thickness or cracking of the skin, blisters or occasional rash on the palms of the hands and soles of the feet.

The above events were not cumulative, were typically reversible, generally did not result in treatment discontinuation and may include topical therapies for symptomatic relief.

Blood pressure was monitored on a routine basis in the clinical studies. In the treatment-naïve study, one patient was discontinued due to treatment-related grade 4 hypertension.

In the GIST trial (Study A), hypertension (all grades) was reported as an adverse event in 51/257 (19%) patients on SUTENT and 7/102 (7%) patients on placebo. Severe hypertension (>200 mmHg systolic or >110 mmHg diastolic) occurred in 9/237 (4%) patients on SUTENT and no patients on placebo. SUTENT dosing was neither delayed nor reduced due to hypertension in any of the GIST patients in the GIST pivotal trial.

Treatment-related hypertension was reported in approximately 24% of patients receiving SUTENT for treatment-naïve MRCC compared to 1% of patients receiving interferon-alfa (IFN-α). Severe hypertension (>200 mmHg systolic or >110 mmHg diastolic) occurred in 5% of treatment-naïve patients on SUTENT and 1% of patients on IFN-α.

In the cytokine-refractory metastatic RCC (MRCC) trials, hypertension (all grades) was reported as an adverse event in 47/169 (28%) patients on SUTENT. Hypertension (>150 mmHg systolic or >100 mmHg diastolic) occurred at least once during the study for 86/165 (52%) patients on SUTENT; severe hypertension (>200 mmHg systolic or >110 mmHg diastolic) occurred in 10/165 (6%) patients on SUTENT. SUTENT dosing was delayed or reduced due to hypertension in 8/165 (4%) cytokine-refractory MRCC patients.

Patients should be monitored for hypertension and treated as appropriate with standard antihypertensive therapy. Temporary suspension of SUTENT is recommended in patients with severe hypertension. Treatment may be resumed once hypertension is controlled.

Patients with hypertension that is not controlled by medications should not be treated with SUTENT.

Decreases in left ventricular ejection fraction (LVEF) of ≥20% and below the lower limit of normal (LLN) occurred in approximately 2% of SUTENT-treated GIST patients, 4% of SUTENT-treated cytokine-refractory MRCC patients and 2% of placebo-treated patients.

In GIST Study A, 22 patients (11%) on SUTENT and 3 patients (3%) on placebo had treatment-emergent LVEF values below LLN. Nine (9) of 22 GIST patients on SUTENT with LVEF changes recovered without intervention. Five (5) patients had documented LVEF recovery following intervention (dose reduction- 1 patient; addition of antihypertensive or diuretic medications- 4 patients). Six (6) patients went off study without documented recovery. Additionally, 3 patients (1%) on SUTENT had Grade 3 reductions in left ventricular systolic function to LVEF <40%; 2 of these patients died without receiving further study drug.

In the treatment-naïve MRCC study, 21% and 12% of patients on SUTENT and IFN-α, respectively, had an LVEF value below the LLN. One (<1%) patient who received SUTENT was diagnosed with congestive heart failure (CHF).

In cytokine-refractory MRCC Studies 1 and 2, a total of 24 patients (14%) had treatment-emergent LVEF values below the LLN. Five (5) of 24 patients on SUTENT with LVEF changes recovered without intervention. Five (5) patients had documented LVEF recovery following intervention (dose reduction- 3 patients; addition of antihypertensive or diuretic medications- 2 patients). Eight (8) patients went off study without documented recovery and 6 patients are ongoing on study without recovery.

Patients who presented with cardiac events within 12 months prior to SUTENT administration, such as myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass graft, symptomatic CHF, cerebrovascular accident or transient ischemic attack, or pulmonary embolism were excluded from SUTENT clinical studies. It is unknown whether patients with these concomitant conditions may be at a higher risk of developing drug-related left ventricular dysfunction. Physicians are advised to weigh this risk against the potential benefits of the drug. These patients should be carefully monitored for clinical signs and symptoms of CHF while receiving SUTENT. Baseline and periodic evaluations of LVEF should also be considered while the patient is receiving SUTENT. In patients without cardiac risk factors, a baseline evaluation of ejection fraction should be considered.

In the presence of clinical manifestations of CHF, discontinuation of SUTENT is recommended. The dose of SUTENT should be interrupted and/or reduced in patients without clinical evidence of CHF but with an ejection fraction <50% and >20% below baseline.

Male patients should be surgically sterile or agree to use effective contraception during the period of therapy with SUTENT. SUTENT may cause embryonal and fetal developmental effects should the female partner of a male taking SUTENT become pregnant as the drug may be present in the semen.

Seven (7) patients (3%) on SUTENT and none on placebo in a Phase 3 GIST study experienced venous thromboembolic events; 5 of the 7 were Grade 3 deep vein thrombosis (DVT), and 2 were Grade 1 or 2. Four (4) of these 7 GIST patients discontinued treatment following first observation of DVT. Four (4) GIST patients receiving SUTENT experienced a Grade 3/4 pulmonary embolism. All 4 GIST patients had a dose interruption or delay, but were able to continue on SUTENT. Two (2) patients receiving placebo experienced pulmonary embolism. No fatalities related to pulmonary embolism were reported.

Seven (2%) patients receiving SUTENT for treatment-naïve MRCC and 4 (2%) patients on the 2 cytokine-refractory MRCC studies had venous thromboembolic events reported. Six (6) of these patients had pulmonary embolism, 1 was Grade 3 and 5 were Grade 4. Five (5) patients had DVT, 1 each with Grade 1 and 4, and 3 with Grade 3. Dose interruption occurred in 1 of these cases. In treatment-naïve MRCC patients receiving IFN-α , 6 (2%) venous thromboembolic events occurred; 1 patient (<1%) experienced a Grade 3 DVT and 5 patients (1%) had pulmonary embolism, 1 Grade 1 and 4 with Grade 4.

Sunitinib and/or its metabolites are excreted in rat milk. It is not known whether sunitinib or its primary active metabolite are excreted in human milk. Because drugs are commonly excreted in human milk and, because of the potential for serious adverse reactions in nursing infants, women should be advised against breastfeeding while taking SUTENT.

There is clinical evidence that SUTENT prolongs QT interval, PR interval, and decreases the heart rate. Patients with QTc interval prolongation, atrioventricular (AV) block, and those taking concomitant drugs with dysrhythmic potential were excluded from the pivotal trials, therefore there is no information regarding safety of SUTENT therapy in this group. Because excessive prolongation of the PR interval can result in AV block, caution should be used if SUTENT is prescribed to patients in combination with other drugs that also cause PR interval prolongation, such as beta-blockers, calcium channel blockers, digitalis, or HIV protease inhibitors.

Pre-clinical data (in vitro and in vivo) demonstrate SUTENT causes QT interval prolongation.

Particular care should be exercised when administering SUTENT to patients who are at an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging drug, or who are taking concomitant drugs with potential to cause QTc interval prolongation (see Drug Interactions).

Bradycardia and AV block are recognized risk factors for torsade de pointes. For this reason, because SUTENT causes QTc prolongation in association with prolongation of the PR and RR intervals, this raises particular concern with respect to proarrhythmic potential. QT interval prolongation may lead to an increased risk of torsade de pointes. Torsade de pointes has been observed in <0.1% of SUTENT-exposed patients.

SUTENT therapy should be discontinued if symptoms suggestive of arrhythmia occur.

A single 50 mg dose of SUTENT was administered to patients with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment, and to control group of patients with normal hepatic function. The pharmacokinetic parameters evaluated demonstrated that dose adjustments might not be necessary for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. However, SUTENT was not studied in subjects with severe (Child-Pugh Class C) hepatic impairment. In addition, repeated administration of SUTENT was not studied in subjects with hepatic impairment.

A single 50 mg dose of SUTENT was administered to patients with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment, and to control group of patients with normal hepatic function. The pharmacokinetic parameters evaluated demonstrated that dose adjustments might not be necessary for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. However, SUTENT was not studied in subjects with severe (Child-Pugh Class C) hepatic impairment. In addition, repeated administration of SUTENT was not studied in subjects with hepatic impairment.

The pharmacokinetics of sunitinib and its primary active metabolite have been evaluated in 135 healthy volunteers and in 266 patients with solid tumours.

Concurrent administration of SUTENT with the potent CYP3A4 inducer, rifampin, resulted in a 23% and 46% reduction in the combined (sunitinib + active metabolite) C_max and AUC_0-∞ values, respectively, after a single dose of SUTENT in healthy volunteers.

Administration of SUTENT with potent inducers of CYP3A4 may decrease SUTENT concentrations. Concomitant administration of SUTENT should be avoided or selection of an alternate concomitant medication with no or minimal potential to induce CYP3A4 should be considered. If this is not possible, the dose of SUTENT may need to be increased (see Dosage and Administration). Note: In clinical trials conducted to date, the safety and efficacy of SUTENT with concomitant use of CYP3A4 inducers have not been established.

Population pharmacokinetic analyses of demographic data suggest that there are no clinically relevant effects of age, body weight, creatinine clearance, race, gender or ECOG score on the pharmacokinetics of sunitinib or the active metabolite.

There are no pharmacokinetic data available in pediatric patients.

Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4. The primary active metabolite comprises 23 to 37% of the total exposure. Elimination is primarily via feces. In a human mass balance study of [¹⁴C] sunitinib, 61% of the radioactive dose was eliminated in feces, with renal elimination of drug and metabolites accounting for 16% of the administered radioactive dose. Sunitinib and its primary active metabolite are the major drug-related compounds identified in plasma, urine and feces, representing 91.5 %, 86.4 % and 73.8% of radioactivity in pooled samples, respectively. Minor metabolites were identified in urine and feces, but were generally not found in plasma. Total oral clearance (CL/F) was 34-62 L/hr with an inter-patient variability of 40%.

No clinical studies were conducted in patients with impaired renal function. Studies that were conducted excluded patients with serum creatinine >2.0×ULN. No relationship was observed between renal function (as measured by calculated creatinine clearance, range 42-347 mL/min) and sunitinib pharmacokinetics in a population pharmacokinetic analysis.

In a phase I clinical QT study, patients with advanced solid tumours received SUTENT 150 mg on Days 3 and 9, and SUTENT 50 mg daily Days 4 to 8 (positive control given Day 1 and placebo given Day 2). Manual serial ECG readings were conducted in accordance with current guidelines. At approximately twice therapeutic concentrations, SUTENT was associated with QTc prolongation. On both Day 3 and Day 9, SUTENT was associated with a progressive increase in the QTc interval that continued throughout the 24-hour observation period, without reaching any obvious peak, plateau, or offset. Because of this, the peak effect could not be characterized with confidence. At the last observation (24 h), the maximum mean placebo-adjusted increase from baseline was 9.6 (90% CI 4.1, 15.1) msec for Day 3 and 15.4 (90% CI 8.4, 22.4) msec for Day 9 using a time-matched baseline and Fridericia’s heart rate correction. The magnitude of these increases is considered to justify cause for concern. However, no subjects experienced an effect on the QTc interval greater than grade 2 (CTCAE version 3.0). No patient presented with a cardiac arrhythmia (see Warnings and Precautions).

Concurrent administration of SUTENT with the potent CYP3A4 inhibitor, ketoconazole, resulted in a 49% and 51% increase in the combined (sunitinib + active metabolite) C_max and AUC_0-∞ values, respectively, after a single dose of SUTENT in healthy volunteers.

Administration of SUTENT with potent inhibitors of the CYP3A4 family may increase SUTENT concentrations. Concomitant administration of SUTENT with inhibitors should be avoided or the selection of an alternate concomitant medication with no, or minimal potential to inhibit CYP3A4 should be considered. If this is not possible, the dose of SUTENT may need to be reduced (see Dosage and Administration). Note: In clinical trials conducted to date, the safety and efficacy of SUTENT with concomitant use of CYP3A4 inhibitors has not been established.

In vitro studies indicate that sunitinib does not induce or inhibit major CYP enzymes.

At baseline, the incidence of patients with T wave abnormalities and the proportion of ECGs with abnormal T waves was high in this population of cancer patients. After 7 days of SUTENT therapy, however, these incidences had increased.

QTc prolongation in association with changes in T wave morphology has been suggested to merit intensified concern with respect to proarrhythmic potential.

The in vitro studies in human liver microsomes and hepatocytes of the activity of CYP isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 indicated that sunitinib and its primary active metabolite are unlikely to have any clinically relevant drug-drug interactions with drugs that may be metabolized by these enzymes.

Maximum plasma concentrations (C_max) of sunitinib are generally observed from 6 to 12 hours (T_max) post-dose. Food has no effect on the bioavailability of sunitinib. Following administration of a single oral dose in healthy volunteers, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 hours, respectively. After repeated daily administration, in the dosing ranges of 25 to 100 mg, the area under the plasma concentration-time curve (AUC) and C_max for sunitinib and total drug increases proportionally with dose. With repeated daily administration, sunitinib accumulates 3- to 4-fold while the primary metabolite accumulates 7- to 10-fold. Steady-state concentrations of sunitinib and its primary active metabolite, are achieved within 10 to 14 days. By Day 14, combined trough plasma concentrations of sunitinib and its active metabolite are 62.9-101 ng/mL. No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite are observed with repeated daily administration or with repeated cycles in the dosing regimens tested. The apparent volume of distribution (Vd/F) for sunitinib was 2230 L.

The pharmacokinetics were similar in healthy volunteers and in the solid tumour patient populations tested, including patients with GIST or MRCC.

Binding of sunitinib and its primary active metabolite to human plasma protein in vitro was 95% and 90%, respectively, with no apparent concentration dependence.

Mean placebo-adjusted changes in the PR interval were positive at all time points, with the maximum increase occurring 7 to 12 hours post-dosing, followed by a decline at 24 hours. Outlier analyses for the PR interval (>200 msec) were consistent with a shift toward a higher proportion of outliers in patients treated with SUTENT. Excessive PR interval prolongation can result in AV block. Progressive levels of AV block are associated with increasing morbidity and mortality.

On Days 3 and 9, heart rate decreased progressively over the 24 hours period following SUTENT dosing, but was not affected by the positive control. During the study, an event of bradycardia occurred that was considered treatment-related, and dizziness was experienced by 7 of 48 patients.

Bradycardia and AV block are recognized risk factors for torsade de pointes. For this reason, a drug that causes QTc prolongation in associated with prolongation of the PR and RR intervals raises particular concerns with respect to proarrhythmic potential.