Sunitinib Malate (Page 3 of 15)

5.5 Hemorrhagic Events and Viscus Perforation

Hemorrhagic events, some of which were fatal, have involved the gastrointestinal tract, respiratory tract, tumor, urinary tract, and brain. In the pooled safety population, 30% of patients experienced hemorrhagic events, including Grade 3 or 4 in 4.2% of patients. Epistaxis was the most common hemorrhagic event and gastrointestinal hemorrhage was the most common Grade 3-5 event .

Tumor-related hemorrhage was observed in patients treated with sunitinib malate capsules. 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 sunitinib malate capsules for metastatic RCC, GIST, and metastatic lung cancer. Sunitinib malate capsules are 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 sunitinib malate capsules.

Include serial complete blood counts (CBCs) and physical examinations with the clinical assessment of hemorrhagic events. Interrupt sunitinib malate capsules for Grade 3 or 4 hemorrhagic events until resolution to Grade ≤ 1 or baseline, then resume sunitinib malate capsules at a reduced dose.

Discontinue sunitinib malate capsules in patients without resolution of Grade 3 or 4 hemorrhagic events.

5.6 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.

5.7 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 sunitinib malate capsules as monotherapy and administered in combination with bevacizumab. Sunitinib malate capsules are not approved for use in combination with bevacizumab.

Discontinue sunitinib malate capsules in patients developing TMA. Reversal of the effects of TMA has been observed after sunitinib malate capsules were discontinued.

5.8 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 sunitinib malate capsules and dose reduce for 24-hour urine protein of 3 or more grams. Discontinue sunitinib malate capsules 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 sunitinib malate capsules treatment in patients with moderate to severe proteinuria has not been evaluated.

5.9 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 sunitinib malate capsules for these severe cutaneous adverse reactions.

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

5.10 Reversible Posterior Leukoencephalopathy Syndrome

Reversible posterior leukoencephalopathy syndrome (RPLS) has been reported in < 1% of patients, some of which were fatal. Patients can present with hypertension, headache, decreased alertness, altered mental functioning, and visual loss, including cortical blindness. Magnetic resonance imaging is necessary to confirm the diagnosis. Discontinue sunitinib malate capsules in patients developing RPLS.

5.11 Thyroid Dysfunction

Hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through postmarketing experience of sunitinib malate capsules.

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 sunitinib malate capsules. Initiate and/or adjust therapies for thyroid dysfunction as appropriate.

5.12 Hypoglycemia

Sunitinib malate capsules can result in symptomatic hypoglycemia, which may lead to loss of consciousness, or require hospitalization. In the pooled safety population, hypoglycemia occurred in 2% of the patients treated with sunitinib malate capsules. Hypoglycemia has occurred in clinical trials in 2% of the patients treated with sunitinib malate capsules for advanced RCC (Study 3) and GIST (Study 1) (n = 577) and in approximately 10% of the patients treated with sunitinib malate capsules for pNET (Study 6) (n = 83). For patients being treated with sunitinib malate capsules for pNET, pre-existing abnormalities in glucose homeostasis were not present in all patients who experienced hypoglycemia. Reductions in blood glucose levels may be worse in patients with diabetes .

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

5.13 Osteonecrosis of the Jaw

Osteonecrosis of the Jaw (ONJ) occurred in patients treated with sunitinib malate capsules. Concomitant exposure to other risk factors, such as bisphosphonates or dental disease/invasive dental procedures, may increase the risk of ONJ. Perform an oral examination prior to initiation of sunitinib malate capsules and periodically during sunitinib malate capsules therapy. Advise patients regarding good oral hygiene practices. Withhold sunitinib malate capsules treatment for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold sunitinib malate capsules for development of ONJ until complete resolution. The safety of resumption of sunitinib malate capsules after resolution of osteonecrosis of the jaw has not been established.

5.14 Impaired Wound Healing

Impaired wound healing has been reported in patients who received sunitinib malate capsules [see Adverse Reactions (6.2)].

Withhold sunitinib malate capsules 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 sunitinib malate capsules after resolution of wound healing complications has not been established.

5.15 Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, sunitinib malate capsules can cause fetal harm when administered to a pregnant woman. Administration of sunitinib to pregnant rats and rabbits during the period of organogenesis resulted in teratogenicity at approximately 5.5 and 0.3 times the combined systemic exposure [combined area under the curve (AUC) of sunitinib plus its active metabolite] in patients administered the recommended daily dose (RDD) of 50 mg, respectively.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with sunitinib malate capsules and for 4 weeks following the final dose [see Use in Specific Populations (8.1, 8.3)].

6 ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling.

Hepatotoxicity [see Warnings and Precautions (5.1)]
Cardiovascular Events [see Warnings and Precautions (5.2)]
QT Interval Prolongation and Torsade de Pointes [see Warnings and Precautions (5.3)]
Hypertension [see Warnings and Precautions (5.4)]
Hemorrhagic Events [see Warnings and Precautions (5.5)]
Tumor Lysis Syndrome [see Warnings and Precautions (5.6)]
Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]
Proteinuria [see Warnings and Precautions (5.8)]
Dermatologic Toxicities [see Warnings and Precautions (5.9)]
Reversible Posterior Leukoencephalopathy Syndrome [see Warnings and Precautions (5.10)]
Thyroid Dysfunction [see Warnings and Precautions (5.11)]
Hypoglycemia [see Warnings and Precautions (5.12)]
Osteonecrosis of the Jaw [see Warnings and Precautions (5.13)]
Impaired Wound Healing [see Warnings and Precautions (5.14)]

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