SUTENT® (sunitinib malate) capsules

SUTENT® (sunitinib malate) capsules

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SUTENT® (sunitinib malate) capsules

Sunitinib is a kinase inhibitor present in SUTENT capsules as the malate salt. Sunitinib malate is described chemically as (2S)-2-hydroxybutanedoic acid 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.

Indications and usage

SUTENT is a kinase inhibitor indicated for:

  • treatment of adult patients with gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate.
  • treatment of adult patients with advanced renal cell carcinoma (RCC).
  • adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy.
  • treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease

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.

Dosage and administration

Recommended Dosage for GIST and Advanced RCC: The recommended dosage of SUTENT for gastrointestinal stromal tumor (GIST) and advanced renal cell carcinoma (RCC) is 50 mg taken orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2) until disease progression or unacceptable toxicity. SUTENT may be taken with or without food.

Recommended Dosage for Adjuvant Treatment of RCC: The recommended dosage of SUTENT for the adjuvant treatment of RCC is 50 mg taken orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2), for nine 6-week cycles. SUTENT may be taken with or without food.

Recommended Dosage for pNET: The recommended dosage of SUTENT for pancreatic neuroendocrine tumors (pNET) is 37.5 mg taken orally once daily until disease progression or unacceptable toxicity. SUTENT may be taken with or without food.

Contraindications

None

Warnings and precautions

Hepatotoxicity: SUTENT can cause severe hepatotoxicity, resulting in liver failure or death. Monitor liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin) at baseline, during each cycle, and as clinically indicated. Interrupt SUTENT for Grade 3 hepatotoxicity until resolution to Grade ≤1 or baseline, then resume SUTENT at a reduced dose.

Discontinue SUTENT in patients with Grade 4 hepatotoxicity, in patients without resolution of Grade 3 hepatotoxicity, in patients who subsequently experience severe changes in liver function tests and in patients who have other signs and symptoms of liver failure. Safety in patients with ALT or AST >2.5 x upper limit of normal (ULN) or with >5 x ULN and liver metastases has not been established.

Cardiovascular Events: Cardiovascular events, including heart failure, cardiomyopathy, myocardial ischemia, and myocardial infarction, some of which were fatal, have been reported. Consider monitoring LVEF at baseline and periodically as clinically indicated. Carefully monitor patients for clinical signs and symptoms of congestive heart failure (CHF). Discontinue SUTENT in patients who experience clinical manifestations of CHF. Interrupt SUTENT and/or reduce the dose in patients without clinical evidence of CHF who have an ejection fraction of greater than 20% but less than 50% below baseline or below the lower limit of normal if baseline ejection fraction was not obtained.

QT Interval Prolongation and Torsade de Pointes: SUTENT can cause QT interval prolongation in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes. Monitor patients who are at higher risk of developing QT interval prolongation, including 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. Consider periodic monitoring of electrocardiograms and electrolytes (i.e., magnesium, potassium) during treatment with SUTENT.

Monitor blood pressure at baseline and as clinically indicated. Initiate and/or adjust antihypertensive therapy as appropriate. In cases of Grade 3 hypertension, withhold SUTENT until resolution to Grade ≤1 or baseline, then resume SUTENT at a reduced dose. Discontinue SUTENT in patients with who develop Grade 4 hypertension.

Hemorrhagic Events and Viscus Perforation: Hemorrhagic events, some of which were fatal, have involved the gastrointestinal tract, respiratory tract, tumor, urinary tract, and brain.

Tumor-related hemorrhage was 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. Pulmonary hemorrhage, some with a fatal outcome, was observed in patients treated with SUTENT for metastatic RCC, GIST, and metastatic lung cancer. SUTENT is not approved for use in patients with lung cancer.

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

Discontinue SUTENT in patients without resolution of Grade 3 or 4 hemorrhagic events.

Tumor Lysis Syndrome: Tumor Lysis Syndrome (TLS), some fatal, occurred in clinical trials and has been reported in postmarketing experience, primarily in patients with RCC or GIST. Patients generally at risk of TLS are those with high tumor burden prior to treatment. Monitor these patients for TLS and manage as appropriate.

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Thrombotic Microangiopathy: Thrombotic Microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or a fatal outcome, occurred in clinical trials and in postmarketing experience of SUTENT as monotherapy and administered in combination with bevacizumab.

SUTENT is not approved for use in combination with bevacizumab.

Discontinue SUTENT in patients developing TMA. Reversal of the effects of TMA has been observed after SUTENT was discontinued.

Proteinuria: 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 of 3 or more grams. Discontinue SUTENT for patients with nephrotic syndrome or repeat episodes of 24-hour urine protein of 3 or more grams despite dose reductions. The safety of continued SUTENT treatment in patients with moderate to severe proteinuria has not been evaluated.

Dermatologic Toxicities: Severe cutaneous adverse reactions have been reported, including erythema multiforme (EM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), some of which were fatal. Permanently discontinue SUTENT for these severe cutaneous adverse reactions

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

Thyroid Dysfunction: Monitor thyroid function at baseline, periodically during treatment and as clinically indicated. Monitor patients closely for signs and symptoms of thyroid dysfunction, including hypothyroidism, hyperthyroidism, and thyroiditis, during treatment with SUTENT. Initiate and/or adjust therapies for thyroid dysfunction as appropriate.

Hypoglycemia: Check blood glucose levels at baseline, regularly during treatment, as clinically indicated and after discontinuation of SUTENT. In patients with diabetes, assess if antidiabetic therapies need to be adjusted to minimize the risk of hypoglycemia.

Impaired Wound Healing: Withhold SUTENT for at least 3 weeks prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of SUTENT after resolution of wound healing complications has not been established.

Side effects

  • Blood and lymphatic system disorders: hemorrhage associated with thrombocytopenia*.
  • 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)*. The infections most commonly observed with SUTENT include respiratory, urinary tract, skin infections, and 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 failure*.
  • Renal and urinary disorders: renal impairment and/or failure*.
  • Respiratory disorders: pulmonary embolism*, pleural effusion*.
  • Skin and subcutaneous tissue disorders: pyoderma gangrenosum, including positive de-challenges.
  • Vascular disorders: arterial (including aortic) aneurysms, dissections*, and rupture*; arterial thromboembolic events*. The most frequent events included cerebrovascular accident, transient ischemic attack, and cerebral infarction.
  • General disorders and administration site conditions: impaired wound healing.

*including some fatalities

Drug interactions

Strong CYP3A4 Inhibitors: Co-administration with strong CYP3A4 inhibitors may increase sunitinib plasma concentrations. Select an alternate concomitant medication with no or minimal enzyme inhibition potential. Consider a dose reduction for SUTENT when it is co-administered with strong CYP3A4 inhibitors

Strong CYP3A4 Inducers: Co-administration with strong CYP3A4 inducers may decrease sunitinib plasma concentrations. Select an alternate concomitant medication with no or minimal enzyme induction potential. Consider a dose increase for SUTENT when it must be co-administered with CYP3A4 inducers

Drugs that Prolong QT Interval: SUTENT is associated with QTc interval prolongation. Monitor the QT interval with ECGs more frequently in patients who require treatment with concomitant medications known to prolong the QT interval.

Use in specific populations

Pregnancy: Based on animal reproduction studies and its mechanism of action, SUTENT can cause fetal harm when administered to a pregnant woman

Lactation: There is no information regarding the presence of sunitinib and its metabolites in human milk. Sunitinib and its metabolites were excreted in rat milk at concentrations up to 12-fold higher than in plasma. Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with SUTENT and for at least 4 weeks after the last dose.

Contraception: Advise females of reproductive potential to use effective contraception during treatment with SUTENT and for at least 4 weeks after the last dose.

Hepatic Impairment: No dose adjustment is required in patients with mild or moderate (Child-Pugh Class A or B) hepatic impairment. SUTENT was not studied in patients with severe (Child-Pugh Class C) hepatic impairment.

Renal Impairment: No dose adjustment is recommended in patients with mild (CLcr 50 to 80 mL/min), moderate (CLcr 30 to <50 mL/min), or severe (CLcr <30 mL/min) renal impairment who are not on dialysis. No dose adjustment is recommended for patients with end-stage renal disease (ESRD) on hemodialysis

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. 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. In nonclinical 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.

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