Sunitinib

Sunitinib
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]

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Black Box Warning

HEPATOTOXICITY See full prescribing information for complete Boxed Warning. Hepatotoxicity has been observed in clinical trials and post-marketing experience. This hepatotoxicity may be severe, and deaths have been reported.

Overview

Sunitinib is a tyrosine kinase inhibitor that is FDA approved for the treatment of gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate, advanced renal cell carcinoma (RCC) and Progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with unresectable locally advanced or metastatic disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, hand-foot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia and bleeding.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Gastrointestinal Stromal Tumor (GIST)

• Sunitinib is indicated for the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate.
• Dosage: one 50 mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2).
• Sunitinib malate may be taken with or without food

Advanced Renal Cell Carcinoma (RCC)

• Sunitinib malate is indicated for the treatment of advanced renal cell carcinoma.
• Dosage: one 50 mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2).
• Sunitinib malate may be taken with or without food

Advanced Pancreatic Neuroendocrine Tumors (pNET)

• Sunitinib malate is indicated for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors in patients with unresectable locally advanced or metastatic disease.
• Dosage: 37.5 mg taken orally once daily continuously without a scheduled off-treatment period.
• Sunitinib malate may be taken with or without food.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Sunitinib in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Sunitinib in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Sunitinib FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Sunitinib in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Sunitinib in pediatric patients.

Contraindications

None

Warnings

HEPATOTOXICITY See full prescribing information for complete Boxed Warning. Hepatotoxicity has been observed in clinical trials and post-marketing experience. This hepatotoxicity may be severe, and deaths have been reported.

Hepatotoxicity

Sunitinib malate has been associated with hepatotoxicity, which may result in liver failure or death. Liver failure has been observed in clinical trials (7/2281 [0.3%]) and post-marketing experience. Liver failure signs include jaundice, elevated transaminases and/or hyperbilirubinemia in conjunction with encephalopathy, coagulopathy, and/or renal failure. Monitor liver function tests (ALT, AST, bilirubin) before initiation of treatment, during each cycle of treatment, and as clinically indicated. SUTENT should be interrupted for Grade 3 or 4 drug-related hepatic adverse events and discontinued if there is no resolution. Do not restart SUTENT if patients subsequently experience severe changes in liver function tests or have other signs and symptoms of liver failure.

Safety in patients with ALT or AST >2.5 × ULN or, if due to liver metastases, >5.0 × ULN has not been established.

Pregnancy

Sunitinib malate can cause fetal harm when administered to a pregnant woman. As angiogenesis is a critical component of embryonic and fetal development, inhibition of angiogenesis following administration of SUTENT should be expected to result in adverse effects on pregnancy. In animal reproductive studies in rats and rabbits, sunitinib was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of SUTENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with SUTENT.

Left Ventricular Dysfunction

In the presence of clinical manifestations of congestive heart failure (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.

Cardiovascular events, including heart failure, myocardial disorders and cardiomyopathy, some of which were fatal, have been reported through post-marketing experience. For GIST and RCC, more patients treated with SUTENT experienced decline in left ventricular ejection fraction (LVEF) than patients receiving either placebo or interferon-α (IFN-α). In the double-blind treatment phase of GIST Study A, 22/209 patients (11%) on SUTENT and 3/102 patients (3%) on placebo had treatment-emergent LVEF values below the lower limit of normal (LLN). Nine of 22 GIST patients on SUTENT with LVEF changes recovered without intervention. Five patients had documented LVEF recovery following intervention (dose reduction: one patient; addition of antihypertensive or diuretic medications: four patients). Six patients went off study without documented recovery. Additionally, three patients on SUTENT had Grade 3 reductions in left ventricular systolic function to LVEF <40%; two of these patients died without receiving further study drug. No GIST patients on placebo had Grade 3 decreased LVEF. In the double-blind treatment phase of GIST Study A, 1 patient on SUTENT and 1 patient on placebo died of diagnosed heart failure; 2 patients on SUTENT and 2 patients on placebo died of treatment-emergent cardiac arrest.

In the treatment-naïve RCC study, 103/375 (27%) and 54/360 (15%) patients on SUTENT and IFN-α, respectively, had an LVEF value below the LLN. Twenty-six patients on SUTENT (7%) and seven on IFN-α (2%) experienced declines in LVEF to >20% below baseline and to below 50%. Left ventricular dysfunction was reported in four patients (1%) and CHF in two patients (<1%) who received SUTENT.

In the Phase 3 pNET study, cardiac failure leading to death was reported in 2/83 (2%) patients on SUTENT and no patients on placebo.

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 these patients are receiving SUTENT. In patients without cardiac risk factors, a baseline evaluation of ejection fraction should be considered.

QT Interval Prolongation and Torsade de Pointes

Sunitinib malate has been shown to prolong the QT interval in a dose dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes. Torsade de Pointes has been observed in <0.1% of SUTENT-exposed patients.

Sunitinib malate should be used with caution in patients with a history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. When using SUTENT, periodic monitoring with on-treatment electrocardiograms and electrolytes (magnesium, potassium) should be considered. Concomitant treatment with strong CYP3A4 inhibitors, which may increase sunitinib plasma concentrations, should be used with caution and dose reduction of SUTENT should be considered [see DOSAGE AND ADMINISTRATION (2.2)].

Hypertension

Patients should be monitored for hypertension and treated as needed with standard anti-hypertensive therapy. In cases of severe hypertension, temporary suspension of SUTENT is recommended until hypertension is controlled.

Of patients receiving SUTENT for treatment-naïve RCC, 127/375 patients (34%) receiving SUTENT compared with 13/360 patients (4%) on IFN-α experienced hypertension. Grade 3 hypertension was observed in 50/375 treatment-naïve RCC patients (13%) on SUTENT compared to 1/360 patients (<1%) on IFN-α. While all-grade hypertension was similar in GIST patients on SUTENT compared to placebo, Grade 3 hypertension was reported in 9/202 GIST patients on SUTENT (4%), and none of the GIST patients on placebo. Of patients receiving SUTENT in the Phase 3 pNET study, 22/83 patients (27%) on SUTENT and 4/82 patients (5%) on placebo experienced hypertension. Grade 3 hypertension was reported in 8/83 pNET patients (10%) on SUTENT, and 1/82 patient (1%) on placebo. No Grade 4 hypertension was reported. SUTENT dosing was reduced or temporarily delayed for hypertension in 21/375 patients (6%) on the treatment-naive RCC study and 7/83 pNET patients (8%). Four treatment-naïve RCC patients, including one with malignant hypertension, one patient with pNET, and no GIST patients discontinued treatment due to hypertension. Severe hypertension (>200 mmHg systolic or 110 mmHg diastolic) occurred in 8/202 GIST patients on SUTENT (4%), 1/102 GIST patients on placebo (1%), in 32/375 treatment-naïve RCC patients (9%) on SUTENT, in 3/360 patients (1%) on IFN-α, and in 8/80 pNET patients (10%) on SUTENT and 2/76 pNET patients (3%) on placebo.

Hemorrhagic Events

Hemorrhagic events reported through post-marketing experience, some of which were fatal, have included GI, respiratory, tumor, urinary tract and brain hemorrhages. In patients receiving SUTENT in a clinical trial for treatment-naïve RCC, 140/375 patients (37%) had bleeding events compared with 35/360 patients (10%) receiving IFN-α. Bleeding events occurred in 37/202 patients (18%) receiving SUTENT in the double-blind treatment phase of GIST Study A, compared to 17/102 patients (17%) receiving placebo. Epistaxis was the most common hemorrhagic adverse event reported. Bleeding events, excluding epistaxis, occurred in 18/83 patients (22%) receiving SUTENT in the Phase 3 pNET study, compared to 8/82 patients (10%) receiving placebo. Epistaxis was reported in 17/83 patients (20%) receiving SUTENT for pNET and 4 patients (5%) receiving placebo. Less common bleeding events in GIST, RCC and pNET patients included rectal, gingival, upper gastrointestinal, genital, and wound bleeding. In the double-blind treatment phase of 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, one patient in GIST Study A taking placebo had a fatal gastrointestinal bleeding event during Cycle 2. Most events in RCC patients were Grade 1 or 2; there was one Grade 5 event of gastric bleed in a treatment-naïve patient. In the pNET study, 1/83 patients (1%) receiving SUTENT had Grade 3 epistaxis, and no patients had other Grade 3 or 4 bleeding events. In pNET patients receiving placebo, 3/82 patients (4%) had Grade 3 or 4 bleeding events.

Tumor-related hemorrhage has been observed in patients treated with SUTENT. These events may occur suddenly, and in the case of pulmonary tumors may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Cases of pulmonary hemorrhage, some with a fatal outcome, have been observed in clinical trials and have been reported in post-marketing experience in patients treated with SUTENT for MRCC, GIST and metastatic lung cancer. SUTENT is not approved for use in patients with lung cancer. Treatment-emergent Grade 3 and 4 tumor hemorrhage occurred in 5/202 patients (3%) with GIST receiving SUTENT on Study A. Tumor hemorrhages were observed as early as Cycle 1 and as late as Cycle 6. One of these five patients received no further drug following tumor hemorrhage. None of the other four patients discontinued treatment or experienced dose delay due to tumor hemorrhage. No patients with GIST in the Study A placebo arm were observed to undergo intratumoral hemorrhage. Clinical assessment of these events should include serial complete blood counts (CBCs) and physical examinations.

Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation, have occurred rarely in patients with intra-abdominal malignancies treated with SUTENT.

Osteonecrosis of the Jaw (ONJ)

ONJ has been observed in clinical trials and has been reported in post-marketing experience in patients treated with sunitinib. Concomitant exposure to other risk factors, such as bisphosphonates or dental disease, may increase the risk of osteonecrosis of the jaw.

Tumor Lysis Syndrome (TLS)

Cases of TLS, some fatal, have been observed in clinical trials and have been reported in post-marketing experience, primarily in patients with RCC or GIST treated with SUTENT. Patients generally at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and treated as clinically indicated.

Thyroid Dysfunction

Baseline laboratory measurement of thyroid function is recommended and patients with hypothyroidism or hyperthyroidism should be treated as per standard medical practice prior to the start of SUTENT treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, on SUTENT treatment. Patients with signs and/or symptoms suggestive of thyroid dysfunction should have laboratory monitoring of thyroid function performed and be treated as per standard medical practice.

Treatment-emergent acquired hypothyroidism was noted in eight GIST patients (4%) on SUTENT versus one (1%) on placebo. Hypothyroidism was reported as an adverse reaction in sixty-one patients (16%) on SUTENT in the treatment-naïve RCC study and in three patients (1%) in the IFN-α arm. Hypothyroidism was reported as an adverse reaction in 6/83 patients (7%) on SUTENT in the Phase 3 pNET study and in 1/82 patients (1%) in the placebo arm.

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

Wound Healing

Cases of impaired wound healing have been reported during SUTENT therapy. Temporary interruption of SUTENT therapy is recommended for precautionary reasons in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume SUTENT therapy following a major surgical intervention should be based upon clinical judgment of recovery from surgery.

Proteinuria

Proteinuria and nephrotic syndrome have been reported. Some of these cases have resulted in renal failure and fatal outcomes. Monitor patients for the development or worsening of proteinuria. Perform baseline and periodic urinalyses during treatment, with follow up measurement of 24-hour urine protein as clinically indicated. Interrupt SUTENT and dose reduce for 24-hour urine protein ≥ 3 grams. Discontinue SUTENT for patients with nephrotic syndrome or repeat episodes of urine protein ≥ 3 grams despite dose reductions. The safety of continued SUTENT treatment in patients with moderate to severe proteinuria has not been systematically evaluated.

Dermatologic Toxicities

Severe cutaneous reactions have been reported, including cases of erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of which were fatal. If signs or symptoms of SJS, TEN, or EM (e.g., progressive skin rash often with blisters or mucosal lesions) are present, SUTENT treatment should be discontinued. If a diagnosis of SJS or TEN is suspected, SUTENT treatment must not be re-started.

Necrotizing fasciitis, including fatal cases, has been reported in patients treated with Sutent, including of the perineum and secondary to fistula formation. Discontinue Sutent in patients who develop necrotizing fasciitis.

Adrenal Function

Physicians prescribing SUTENT are advised to monitor for adrenal insufficiency in patients who experience stress such as surgery, trauma or severe infection.

Adrenal toxicity was noted in non-clinical repeat dose studies of 14 days to 9 months in rats and monkeys at plasma exposures as low as 0.7 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/MRI obtained in 336 patients after exposure to one or more cycles of SUTENT demonstrated no evidence of adrenal hemorrhage or necrosis. ACTH stimulation testing was performed in approximately 400 patients across multiple clinical trials of SUTENT. Among patients with normal baseline ACTH stimulation testing, one patient developed consistently abnormal test results during treatment that are unexplained and may be related to treatment with SUTENT. Eleven additional patients with normal baseline testing had abnormalities in the final test performed, with peak cortisol levels of 12–16.4 mcg/dL (normal >18 mcg/dL) following stimulation. None of these patients were reported to have clinical evidence of adrenal insufficiency.

Laboratory Tests

CBCs with platelet count and serum chemistries including phosphate should be performed at the beginning of each treatment cycle for patients receiving treatment with SUTENT.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Sunitinib Clinical Trials Experience in the drug label.

Postmarketing Experience

The following adverse reactions have been identified during post-approval 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.

Blood and lymphatic system disorders

• Thrombotic microangiopathy; hemorrhage associated with thrombocytopenia1.
• Suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.

Gastrointestinal disorders

• Esophagitis

Hepatobiliary disorders

• Cholecystitis, particularly acalculous cholecystitis.

Immune system disorders

• Hypersensitivity reactions, including angioedema.

Infections and infestations

• Serious infection (with or without neutropenia)1.
• The infections most commonly observed with sunitinib treatment include respiratory, urinary tract, skin infections, sepsis/septic shock.

Musculoskeletal and connective tissue disorders

• Fistula formation, sometimes associated with tumor necrosis and/or regression; myopathy and/or rhabdomyolysis with or without acute renal failure1.
• Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice.

Renal and urinary disorders

• Renal impairment and/or failure

Respiratory disorders

• Pulmonary embolism

Skin and subcutaneous tissue disorders

• Pyoderma gangrenosum, including positive dechallenges.

Vascular disorders

• Arterial thromboembolic events.
• The most frequent events included cerebrovascular accident, transient ischemic attack and cerebral infarction.

Drug Interactions

CYP3A4 Inhibitors

Strong CYP3A4 inhibitors such as ketoconazole may increase sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme inhibition potential is recommended. Concurrent administration of SUTENT with the strong CYP3A4 inhibitor, ketoconazole, resulted in 49% and 51% increases in the combined (sunitinib + primary active metabolite) Cmax and AUC0–∞ values, respectively, after a single dose of SUTENT in healthy volunteers. Co-administration of SUTENT with strong inhibitors of the CYP3A4 family (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase sunitinib concentrations. Grapefruit may also increase plasma concentrations of sunitinib. A dose reduction for SUTENT should be considered when it must be co-administered with strong CYP3A4 inhibitors.

CYP3A4 Inducers

CYP3A4 inducers such as rifampin may decrease sunitinib plasma concentrations. Selection of an alternate concomitant medication with no or minimal enzyme induction potential is recommended. Concurrent administration of SUTENT with the strong CYP3A4 inducer, rifampin, resulted in a 23% and 46% reduction in the combined (sunitinib + primary active metabolite) Cmax and AUC0–∞ values, respectively, after a single dose of SUTENT in healthy volunteers. Co-administration of SUTENT with inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's Wort) may decrease sunitinib concentrations. St. John's Wort may decrease sunitinib plasma concentrations unpredictably. Patients receiving SUTENT should not take St. John's Wort concomitantly. A dose increase for SUTENT should be considered when it must be co-administered with CYP3A4 inducers.

In Vitro Studies of CYP Inhibition and Induction

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

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): D Sunitinib malate can cause fetal harm when administered to a pregnant woman. As angiogenesis is a critical component of embryonic and fetal development, inhibition of angiogenesis following administration of SUTENT should be expected to result in adverse effects on pregnancy. In animal reproductive studies in rats and rabbits, sunitinib was teratogenic, embryotoxic, and fetotoxic. There are no adequate and well-controlled studies of SUTENT in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with SUTENT.

Sunitinib was evaluated in pregnant rats (0.3, 1.5, 3.0, 5.0 mg/kg/day) and rabbits (0.5, 1, 5, 20 mg/kg/day) for effects on the embryo. Significant increases in the incidence of embryolethality and structural abnormalities were observed in rats at the dose of 5 mg/kg/day (approximately 5.5 times the systemic exposure [combined AUC of sunitinib + primary active metabolite] in patients administered the recommended daily doses [RDD]). Significantly increased embryolethality was observed in rabbits at 5 mg/kg/day while developmental effects were observed at ≥1 mg/kg/day (approximately 0.3 times the AUC in patients administered the RDD of 50 mg/day). Developmental effects consisted of fetal skeletal malformations of the ribs and vertebrae in rats. In rabbits, cleft lip was observed at 1 mg/kg/day and cleft lip and cleft palate were observed at 5 mg/kg/day (approximately 2.7 times the AUC in patients administered the RDD). Neither fetal loss nor malformations were observed in rats dosed at ≤3 mg/kg/day (approximately 2.3 times the AUC in patients administered the RDD).

Sunitinib (0.3, 1.0, 3.0 mg/kg/day) was evaluated in a pre- and postnatal development study in pregnant rats. Maternal body weight gains were reduced during gestation and lactation at doses ≥1 mg/kg/day but no maternal reproductive toxicity was observed at doses up to 3 mg/kg/day (approximately 2.3 times the AUC in patients administered the RDD). At the high dose of 3 mg/kg/day, reduced body weights were observed at birth and persisted for offspring of both sexes during the pre-weaning period and in males during post-weaning period. No other developmental toxicity was observed at doses up to 3 mg/kg/day (approximately 2.3 times the AUC in patients administered the RDD).
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Sunitinib in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Sunitinib during labor and delivery.

Nursing Mothers

Sunitinib and its metabolites are excreted in rat milk. In lactating female rats administered 15 mg/kg, sunitinib and its metabolites were extensively excreted in milk at concentrations up to 12-fold higher than in plasma. It is not known whether this drug or its primary active metabolite are 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 SUTENT, 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.

Pediatric Use

The safety and efficacy of SUTENT in pediatric patients have not been established.

Physeal dysplasia was observed in cynomolgus monkeys with open growth plates treated for ≥3 months (3 month dosing 2, 6, 12 mg/kg/day; 8 cycles of dosing 0.3, 1.5, 6.0 mg/kg/day) with sunitinib at doses that were >0.4 times the RDD based on systemic exposure (AUC). In developing rats treated continuously for 3 months (1.5, 5.0 and 15.0 mg/kg) or 5 cycles (0.3, 1.5, and 6.0 mg/kg/day), bone abnormalities consisted of thickening of the epiphyseal cartilage of the femur and an increase of fracture of the tibia at doses ≥5 mg/kg (approximately 10 times the RDD based on AUC). Additionally, caries of the teeth were observed in rats at >5 mg/kg. The incidence and severity of physeal dysplasia were dose-related and were reversible upon cessation of treatment; however, findings in the teeth were not. A no effect level was not observed in monkeys treated continuously for 3 months, but was 1.5 mg/kg/day when treated intermittently for 8 cycles. In rats the no effect level in bones was ≤2 mg/kg/day.

Geriatic Use

Of 825 GIST and RCC patients who received SUTENT on clinical studies, 277 (34%) were 65 and over. In the Phase 3 pNET study, 22 (27%) patients who received SUTENT were 65 and over. No overall differences in safety or effectiveness were observed between younger and older patients.

Gender

There is no FDA guidance on the use of Sunitinib with respect to specific gender populations.

Race

There is no FDA guidance on the use of Sunitinib with respect to specific racial populations.

Renal Impairment

No adjustment to the starting dose is required when administering SUTENT to patients with mild, moderate, and severe renal impairment. Subsequent dose modifications should be based on safety and tolerability. In patients with end-stage renal disease (ESRD) on hemodialysis, no adjustment to the starting dose is required. However, compared to subjects with normal renal function, the sunitinib exposure is 47% lower in subjects with ESRD on hemodialysis. Therefore, the subsequent doses may be increased gradually up to 2 fold based on safety and tolerability.

Hepatic Impairment

No dose adjustment to the starting dose is required when administering SUTENT to patients with Child-Pugh Class A or B hepatic impairment. Sunitinib and its primary metabolite are primarily metabolized by the liver. Systemic exposures after a single dose of SUTENT were similar in subjects with mild or moderate (Child-Pugh Class A and B) hepatic impairment compared to subjects with normal hepatic function. SUTENT was not studied in subjects with severe (Child-Pugh Class C) hepatic impairment. Studies in cancer patients have excluded patients with ALT or AST >2.5 × ULN or, if due to liver metastases, >5.0 × ULN.

Females of Reproductive Potential and Males

Effects on the female reproductive system were identified in a 3-month repeat dose monkey study (2, 6, 12 mg/kg/day), where ovarian changes (decreased follicular development) were noted at 12 mg/kg/day (≥5.1 times the AUC in patients administered the RDD), while uterine changes (endometrial atrophy) were noted at ≥2 mg/kg/day (≥0.4 times the AUC in patients administered the RDD). With the addition of vaginal atrophy, the uterine and ovarian effects were reproduced at 6 mg/kg/day in the 9-month monkey study (0.3, 1.5 and 6 mg/kg/day administered daily for 28 days followed by a 14 day respite; the 6 mg/kg dose produced a mean AUC that was ≥0.8 times the AUC in patients administered the RDD). A no effect level was not identified in the 3 month study; 1.5 mg/kg/day represents a no effect level in monkeys administered sunitinib for 9 months.

Although fertility was not affected in rats, SUTENT may impair fertility in humans. In female rats, no fertility effects were observed at doses of ≤5.0 mg/kg/day [(0.5, 1.5, 5.0 mg/kg/day) administered for 21 days up to gestational day 7; the 5.0 mg/kg dose produced an AUC that was ≥5 times the AUC in patients administered the RDD], however significant embryolethality was observed at the 5.0 mg/kg dose. No reproductive effects were observed in male rats dosed (1, 3 or 10 mg/kg/day) for 58 days prior to mating with untreated females. Fertility, copulation, conception indices, and sperm evaluation (morphology, concentration, and motility) were unaffected by sunitinib at doses ≤10 mg/kg/day (the 10 mg/kg/day dose produced a mean AUC that was ≥25.8 times the AUC in patients administered the RDD).

Immunocompromised Patients

There is no FDA guidance one the use of Sunitinib in patients who are immunocompromised.

Administration and Monitoring

Administration

Oral

Monitoring

There is limited information regarding Sunitinib Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Sunitinib and IV administrations.

Overdosage

Treatment of overdose with SUTENT should consist of general supportive measures. There is no specific antidote for overdosage with SUTENT. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage. A few cases of accidental overdose have been reported; these cases were associated with adverse reactions consistent with the known safety profile of SUTENT, or without adverse reactions. A case of intentional overdose involving the ingestion of 1,500 mg of SUTENT in an attempted suicide was reported without adverse reaction. In non-clinical studies mortality was observed following as few as 5 daily doses of 500 mg/kg (3000 mg/m2) in rats. At this dose, signs of toxicity included impaired muscle coordination, head shakes, hypoactivity, ocular discharge, piloerection and gastrointestinal distress. Mortality and similar signs of toxicity were observed at lower doses when administered for longer durations.

Pharmacology

There is limited information regarding Sunitinib Pharmacology in the drug label.

Mechanism of Action

Sunitinib is a small molecule that inhibits multiple receptor tyrosine kinases (RTKs), some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases (>80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity of these RTKs has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays.

Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFRβ, VEGFR2, KIT) in tumor xenografts expressing RTK targets in vivo and demonstrated inhibition of tumor growth or tumor regression and/or inhibited metastases in some experimental models of cancer. Sunitinib demonstrated the ability to inhibit growth of tumor cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFRβ- and VEGFR2-dependent tumor angiogenesis in vivo.

Structure

Sunitinib malate is described chemically as Butanedioic acid, hydroxy-, (2S)-, compound with N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide (1:1). The molecular formula is C22H27FN4O2 • C4H6O5 and the molecular weight is 532.6 Daltons.

The chemical structure of sunitinib malate is:

Pharmacodynamics

There is limited information regarding Sunitinib Pharmacodynamics in the drug label.

Pharmacokinetics

The pharmacokinetics of sunitinib and sunitinib malate have been evaluated in 135 healthy volunteers and in 266 patients with solid tumors.

Maximum plasma concentrations (Cmax) of sunitinib are generally observed between 6 and 12 hours (Tmax) following oral administration. Food has no effect on the bioavailability of sunitinib. SUTENT may be taken with or without food.

Binding of sunitinib and its primary active metabolite to human plasma protein in vitro was 95% and 90%, respectively, with no concentration dependence in the range of 100 – 4000 ng/mL. The apparent volume of distribution (Vd/F) for sunitinib was 2230 L. In the dosing range of 25 – 100 mg, the area under the plasma concentration-time curve (AUC) and Cmax increase proportionately with dose.

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 dose was eliminated in feces, with renal elimination accounting for 16% of the administered dose. Sunitinib and its primary active metabolite were 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 generally not found in plasma. Total oral clearance (CL/F) ranged from 34 to 62 L/hr with an inter-patient variability of 40%.

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. 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 plasma concentrations of sunitinib and its active metabolite ranged from 62.9 – 101 ng/mL. No significant changes in the pharmacokinetics of sunitinib or the primary active metabolite were observed with repeated daily administration or with repeated cycles in the dosing regimens tested.

The pharmacokinetics were similar in healthy volunteers and in the solid tumor patient populations tested, including patients with GIST and RCC.

Nonclinical Toxicology

Carcinogenesis and Mutagenesis

The carcinogenic potential of sunitinib has been evaluated in two species: rasH2 transgenic mice and Sprague-Dawley rats. There were similar positive findings in both species. In rasH2 transgenic mice gastroduodenal carcinomas and/or gastric mucosal hyperplasia, as well as an increased incidence of background hemangiosarcomas were observed at doses of ≥25 mg/kg/day following daily dose administration of sunitinib in studies of 1 or 6 months duration. No proliferative changes were observed in rasH2 transgenic mice at 8 mg/kg/day. Similarly, in a 2-year rat carcinogenicity study, administration of sunitinib in 28-day cycles followed by 7-day dose-free periods resulted in findings of duodenal carcinoma at doses as low as 1 mg/kg/day (approximately 0.9 times the AUC in patients given the RDD of 50 mg/day).At the high dose of 3 mg/kg/day (approximately 7.8 times the AUC in patients at the RDD of 50 mg/day) the incidence of duodenal tumors was increased and was accompanied by findings of gastric mucous cell hyperplasia and by an increased incidence of pheochromocytoma and hyperplasia of the adrenal. Sunitinib did not cause genetic damage when tested in in vitro assays (bacterial mutation [AMES Assay], human lymphocyte chromosome aberration) and an in vivo rat bone marrow micronucleus test.

Clinical Studies

There is limited information regarding Sunitinib Clinical Studies in the drug label.

How Supplied

• 12.5 mg Capsules

• Bottles of 28
• NDC 0069-0550-38

• 25 mg Capsules

• Bottles of 28
• NDC 0069-0770-38

• 37.5 mg Capsules

• Bottles of 28
• NDC 0069-0830-38

• 50 mg Capsules

• Bottles of 28
• NDC 0069-0980-38

Storage

Store at 25°C (77°F)

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

Gastrointestinal Disorders

Gastrointestinal disorders such as diarrhea, nausea, stomatitis, dyspepsia, and vomiting were the most commonly reported gastrointestinal events occurring in patients who received SUTENT. Supportive care for gastrointestinal adverse events requiring treatment may include anti-emetic or anti-diarrheal medication.

Skin Effects

Skin discoloration possibly due to the drug color (yellow) occurred in approximately one third of patients. Patients should be advised that depigmentation of the hair or skin may occur during treatment with SUTENT. Other possible dermatologic effects may include dryness, thickness or cracking of skin, blister or rash on the palms of the hands and soles of the feet. Severe dermatologic toxicities including Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis have been reported. Patients should be advised to immediately inform their healthcare provider if severe dermatologic reactions occur.

Other Common Events

Other commonly reported adverse events included fatigue, high blood pressure, bleeding, swelling, mouth pain/irritation and taste disturbance.

Musculoskeletal Disorders

Prior to treatment with SUTENT, a dental examination and appropriate preventive dentistry should be considered. In patients being treated with SUTENT, who have previously received or are receiving bisphosphonates, invasive dental procedures should be avoided, if possible.

Concomitant Medications

Patients should be advised to inform their healthcare providers of all concomitant medications, including over-the-counter medications and dietary supplements

Precautions with Alcohol

Alcohol-Sunitinib interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Sunitinib Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Sunitinib Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

Sunitinib

File:Sunitinib.svg
Clinical data
[[Regulation of therapeutic goods |Template:Engvar data]]	EU EMA: by INN US FDA: Sunitinib
Pregnancy category	AU: D US: D (Evidence of risk)
Routes of administration	Oral
ATC code	L01XE04 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Bioavailability	Unaffected by food
Protein binding	95%
Metabolism	Hepatic (CYP3A4-mediated)
Elimination half-life	40 to 60 hours (sunitinib) 80 to 110 hours (metabolite)
Excretion	Fecal (61%) and renal (16%)
Identifiers
IUPAC name N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-1,2- dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4- dimethyl-1H-pyrrole-3-carboxamide
CAS Number	341031-54-7
PubChem CID	5329102
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C22H27FN4O2
Molar mass	398.474 g/mol 532.561 g/mol (malate)

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Overview

Sunitinib (marketed as Sutent, and previously known as SU11248) is an oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST) on January 26, 2006. Sunitinib was the first cancer drug simultaneously approved for two different indications. Sunitinib has become the standard of care for both of these cancers, and is currently being studied for the treatment of many others.

Mechanism of action

Sunitinib inhibits cellular signaling by targeting multiple RTKs. These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R), which play a role in both tumor angiogenesis and tumor cell proliferation. The simultaneous inhibition of these targets therefore leads to both reduced tumor vascularization and cancer cell death, and ultimately tumor shrinkage. Sunitinib also inhibits KIT (CD117), the RTK that drives the majority of GISTs. In addition, sunitinib inhibits other RTKs including RET, CSF-1R, and flt3.

Indications

Renal cell carcinoma

Sunitinib has become the new standard of care in the first-line treatment of metastatic RCC.

RCC is generally resistant to chemotherapy or radiation. Prior to RTKs, metastatic disease could only be treated with the cytokines interferon alpha (IFNa) or Interleukin 2 (IL-2). However, these agents demonstrated low rates of efficacy (5%-20%) and are associated with severe infusion-related adverse events.

In two separate Phase II studies, sunitinib demonstrated consistent response rates of approximately 40% in patients who had already failed cytokine therapy. Although these were Phase II studies, these results were impressive enough for the FDA to approve sunitinib for first-line use even before Phase III data were available.

The results of the Phase III study, published in the New England Journal of Medicine in 2007, proved that sunitinib offers superior efficacy compared with IFNa. Progression-free survival (primary endpoint) was more than doubled: 11 months for sunitinib compared with 5 months for IFNa (P<.000001). The benefit for sunitinib was significant across all major patient subgroups, including those with a poor prognosis at baseline.

Secondary endpoints also favored sunitinib. 28% of sunitinib patients had significant tumor shrinkage (objective response) compared with only 5% of patients who received IFNa (P<.001). Although overall survival data are not yet mature, there is a clear trend toward improved survival with sunitinib. Patients receiving sunitinib also reported a significantly better quality of life than those treated with IFNa (P<.001).

Sunitinib was generally better tolerated than IFNa. Significantly more patients discontinued IFN due to adverse events (P=.05), withdrawal of consent (P<.001), or disease progression (P<.001). Serious fatigue was significantly more common with IFNa (P<.05), while diarrhea was reported more commonly with sunitinib.

Based on these results, lead investigator Dr. Robert Motzer announced at ASCO 2006 that “Sunitinib is the new reference standard for the first-line treatment of mRCC.”

Gastrointestinal stromal tumor

Like RCC, GIST does not generally respond to standard chemotherapy or radiation. Imatinib was the first cancer agent proven effective for metastatic GIST and represented a major development in the treatment of this rare but challenging disease. However, approximately 20% of patients do not respond to imatinib (early or primary resistance), and among those who do respond initially, 50% develop secondary imatinib resistance and disease progression within 2 years. Prior to sunitinib, patients had no therapeutic option once they became resistant to imatinib.

Sunitinib offers patients with imatinib-resistant GIST a new treatment option to stop further disease progression and, in some cases, even reverse it. This was proven in a large, Phase III clinical trial in which patients who failed imatinib therapy (due to primary resistance, secondary resistance, or intolerance) were treated in a randomized and blinded fashion with either sunitinib or placebo.

The study was unblinded early, at the very first interim analysis, due to the clearly emerging benefit of sunitinib. At that time, patients receiving placebo were offered to switch over to sunitinib. In the primary endpoint of this study, median time to tumor progression (TTP) was more than 4-fold longer with sunitinib (27 weeks) compared with placebo (6 weeks, P<.0001). These are based on the assessments of an independent radiology lab assessment. The benefit of sunitinib remained statistically significant when stratified for a multitude of prespecified baseline factors, including:

• Prior dose of imatinib
• Prior duration of imatinib therapy
• ECOG Performance status
• Age
• Weight
• Race
• Pain score
• Time since initial diagnosis
• Study location
• ITT vs PP analysis
• Investigator vs independent radiology lab assessment

Among the secondary endpoints, the difference in PFS was similar to that in TTP (24 weeks vs 6 weeks, P<.0001). 7% of sunitinib patients had significant tumor shrinkage (objective response) compared with 0% of placebo patients (P=.006). Another 58% of sunitinib patients had disease stabilization vs. 48% of patients receiving placebo. The median time to response with sunitinib was 10.4 weeks. Sunitinib reduced the relative risk of disease progression or death by 67%, and the risk of death alone by 51%. The difference in survival benefit may be diluted by the fact that placebo patients crossed over to sunitinib upon disease progression, and most of these patients subsequently responded to sunitinib.

Sunitinib was relatively well tolerated. 83% of sunitinib patients experienced a treatment-related adverse event of any severity, as did 59% of patients who received placebo. Serious adverse events were reported in 20% of sunitinib patients and 5% of placebo patients. Adverse events were generally moderate and easily managed by dose reduction, dose interruption, or other treatment. 9% of sunitinib patients and 8% of placebo patients discontinued therapy due to an adverse event.

Fatigue is the adverse event most commonly associated with sunitinib therapy. In this study, 34% of sunitinib patients reported any grade of fatigue, compared with 22% for placebo. The incidence of grade 3 (severe) fatigue was similar between the two groups, and there was no grade 4 fatigue reported.

Other solid tumors

The efficacy of sunitinib is currently being evaluated in a broad range of solid tumors, including breast, lung, and colorectal cancers. Early studies have shown single-agent efficacy in a number of different areas.

• A Phase II study in previously-treated patients with metastatic breast cancer found that sunitinib “has significant single agent activity”
• A Phase II study of refractory non-small-cell lung cancer found that “Sunitinib has provocative single-agent activity in previously treated pts with recurrent and advanced NSCLC, with the level of activity similar to currently approved agents.”
• In a Phase II study of patients with nonresectable neuroendocrine tumors (NET), 91% of patients responded to sunitinib (9% partial response + 82% stable disease)

Safety

An oral agent, sunitinib is generally well tolerated. Adverse events are manageable and the incidence of serious adverse events is low.

The most common adverse events associated with sunitinib therapy include fatigue, diarrhea, nausea, anorexia, hypertension, and skin discoloration. In the placebo-controlled Phase III GIST study, adverse events which occurred more often with sunitinib than placebo included diarrhea, anorexia, skin discoloration, mucositis/stomatitis, asthenia, altered taste, and constipation.

Serious (grade 3 or 4) adverse events occur in ≤10% of patients and include hypertension, fatigue, asthenia, diarrhea, and hand-foot syndrome. Lab abnormalities associated with sunitinib therapy include lipase, amylase, neutrophils, lymphocytes, and platelets. Hypothyroidism has also been associated with sunitinib.

Most adverse events can be managed through supportive care, dose interruption, or dose reduction.

External links

• Sutent.com — Manufacturer's site
• GIST Support International — An international organization for the support of GIST patients, families, and friends. Includes detailed information from some of the foremost experts on GIST, links to research, treatment options, and GIST registry.
• Kidney Cancer Association — An organization that educates physicians and patients about kidney cancer; funds, promotes, and collaborates on research projects; and advocates at the federal and state levels on behalf of patient interests.
• [http//mpablog.typepad.com/david_foster] Cancer veteran's blog with two years experience with Sutent, Nexavar and chemo.