Sunitinib Malate (sunitinib 50 mg) Dailymed

Recent Major Changes Section

Dosage and Administration, Dosage Modifications for Adverse Reactions (2.4)     8/2021

Dosage and Administration, Dosage Modification for Drug Interactions (2.5)     8/2021

Warnings and Precautions, Hepatotoxicity (5.1)     8/2021

Warnings and Precautions, Hypertension (5.4)     8/2021

Warnings and Precautions, Hemorrhagic Events and Viscous Perforation (5.5)     8/2021

Warnings and Precautions, Reversible Posterior Leukoencephalopathy Syndrome (5.10)     8/2021

Warnings and Precautions, Hypoglycemia (5.12)     8/2021

Warnings and Precautions, Osteonecrosis of the Jaw (5.13)     8/2021

Warning: Hepatotoxicity

Hepatotoxicity may be severe, and in some cases, fatal. Monitor hepatic function and interrupt, dose reduce, or discontinue sunitinib malate capsules as recommended [see Warnings and Precautions (5.1)].


WARNING: HEPATOTOXICITY

See full prescribing information for complete boxed warning.

Hepatotoxicity may be severe, and in some cases fatal. Monitor hepatic function and interrupt, dose reduce, or discontinue sunitinib malate capsules as recommended [see Warnings and Precautions (5.1)].

GIST and Advanced RCC:

• •The recommended dosage is 50 mg orally once daily for the first 4 weeks of each 6-week cycle (Schedule 4/2). (2.1)

Adjuvant Treatment of RCC:

• •The recommended dosage is 50 mg orally once daily for the first 4 weeks of a 6-week cycle (Schedule 4/2) for a maximum of 9 cycles. (2.2)

pNET:

• •The recommended dosage is 37.5 mg orally once daily. (2.3)

2.1Recommended Dosage for GIST and Advanced RCC

The recommended dosage of sunitinib malate capsules 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. Sunitinib malate capsules may be taken with or without food.

2.2Recommended Dosage for Adjuvant Treatment of RCC

The recommended dosage of sunitinib malate capsules 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. Sunitinib malate capsules may be taken with or without food.

2.3Recommended Dosage for pNET

The recommended dosage of sunitinib malate capsules for pancreatic neuroendocrine tumors (pNET) is 37.5 mg taken orally once daily until disease progression or unacceptable toxicity. Sunitinib malate capsules may be taken with or without food.

2.4Dosage Modifications for Adverse Reactions

To manage adverse reactions, the recommended dosage modifications are provided in Table 1. Table 2 provides the recommended dosage reductions of sunitinib malate capsules for adverse reactions.

Table 1. Recommended Dosage Reductions of Sunitinib Malate Capsules for Adverse Reactions

Indications	GIST	RCC		pNET
		Advanced RCC	Adjuvant RCC
First dose reduction	37.5 mg once daily	37.5 mg once daily	37.5 mg once daily	25 mg once daily
Second dose reduction	25 mg once daily	25 mg once daily	NA	NA

 
Withhold until resolution to Grade 0 to 1 or baseline.

Resume at a reduced dose.

For recurring Grade 3 permanently discontinue. Permanently discontinue. Withhold until resolution to Grade 0 to 1 or baseline.

Resume at reduced dose. Permanently discontinue. Withhold until resolution to Grade 0 to 1 or baseline.

Resume at a reduced dose. Permanently discontinue. Withhold until resolution to Grade 0 to 1 or baseline.

Either resume at a reduced dose or discontinue depending on the severity and persistence of adverse reaction. Permanently discontinue. Withhold until resolution to Grade 0 to 1 or baseline.

Resume at a reduced dose. Permanently discontinue. Permanently discontinue. Permanently discontinue. The safety of resumption of sunitinib malate capsules after osteonecrosis has not been established.

Either resume at a reduced dose or discontinue depending on the severity and persistence of the adverse reaction. The safety of resumption of sunitinib malate capsules after resolution of wound healing has not been established.

Either resume at a reduced dose or discontinue depending on the severity and persistence of the adverse reaction.

Table 2. Recommended Dosage Modifications for Sunitinib Malate Capsules for Adverse Reactions

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Adverse Reaction	Severity	Dosage Modifications for Sunitinib Malate Capsules
Hepatotoxicity [see Warnings and Precautions (5.1) ]	Grade 3
	Grade 4
Cardiovascular events [see Warnings and Precautions (5.2) ]	Asymptomatic cardiomyopathy (left ventricular ejection fraction greater than 20% but less than 50% below baseline or below the lower limit of normal if baseline was not obtained)
	Clinically manifested congestive heart failure (CHF)
Hypertension [see Warnings and Precautions (5.4) ]	Grade 3
	Grade 4
Hemorrhagic events [see Warnings and Precautions (5.5) ]	Grade 3 or 4
Thrombotic microangiopathy [see Warnings and Precautions (5.7) ]	Any Grade
Proteinuria or Nephrotic syndrome [see Warnings and Precautions (5.8) ]	3 or more grams proteinuria in 24 hours in the absence of nephrotic syndrome
	Nephrotic syndrome or recurrent proteinuria of 3 or more grams per 24 hours despite dose reductions
Dermatological toxicities Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Necrotizing fasciitis [see Warnings and Precautions (5.9) ]	Any Grade
Reversible posterior leukoencephalopathy syndrome [see Warnings and Precautions (5.10) ]	Any Grade
Osteonecrosis of the jaw [see Warnings and Precautions (5.13) ]	Any Grade
Impaired wound healing [see Warnings and Precautions (5.14) ]	Any Grade

2.5Dosage Modification for Drug Interactions

Select an alternate concomitant medication with no or minimal enzyme inhibition potential. If coadministration of sunitinib malate capsules with a strong CYP3A4 inhibitor cannot be avoided, consider a dose reduction for sunitinib malate capsules to a minimum dosage as follows [see Drug Interactions (7.1) ]:

• • GIST and RCC: 37.5 mg orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2)
• • pNET: 25 mg orally once daily

Select an alternate concomitant medication with no or minimal enzyme induction potential. If coadministration of sunitinib malate capsules with a strong CYP3A4 inducer cannot be avoided, consider a dose increase for sunitinib malate capsules to a maximum dosage as follows:

• •GIST and RCC: 87.5 mg orally once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off (Schedule 4/2)
• •pNET: 62.5 mg orally once daily

If the dose of sunitinib malate capsules is increased, monitor patients carefully for adverse reactions [see Drug Interactions (7.1)].

2.6Dosage Modification for End-Stage Renal Disease Patients on Hemodialysis

No starting dose adjustment is required in patients with end-stage renal disease (ESRD) on hemodialysis. However, given the decreased exposure compared to patients with normal renal function, subsequent doses may be increased gradually up to 2-fold based on safety and tolerability [see Clinical Pharmacology (12.3)].

3 Dosage Forms And Strengths

Sunitinib Malate Capsules are available containing 12.5 mg, 25 mg, 37.5 mg or 50 mg of sunitinib equivalent to 16.7 mg, 33.4 mg, 50.1 mg or 66.8 mg of sunitinib malate, respectively.

• •The 12.5 mg capsules are hard-shell gelatin capsules with a pink-brown opaque cap and pink-brown opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 12.5 in black ink on cap and body.
• •The 25 mg capsules are hard-shell gelatin capsules with a yellow opaque cap and pink-brown opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 25 in black ink on cap and body.
• •The 37.5 mg capsules are hard-shell gelatin capsules with an ivory opaque cap and ivory opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 37.5 in black ink on cap and body.
• •The 50 mg capsules are hard-shell gelatin capsules with a yellow opaque cap and yellow opaque body filled with yellow to orange powder. The capsules are axially printed with MYLAN over SM 50 in black ink on cap and body.

• •Capsules: 12.5 mg, 25 mg, 37.5 mg, 50 mg sunitinib (3)

4 Contraindications

None.

• •None (4)

5 Warnings And Precautions

• • Hepatotoxicity: Fatal liver failure has been observed. Monitor liver function tests at baseline, during each cycle, and as clinically indicated. Interrupt sunitinib malate capsules for Grade 3 hepatotoxicity until resolution to Grade ≤ 1 or baseline and resume sunitinib malate capsules at a reduced dose; discontinue if no resolution. Discontinue sunitinib malate capsules in patients with Grade 4 hepatotoxicity, in patients who have subsequent severe changes in liver function tests or other signs and symptoms of liver failure. (2.4, 5.1)
• • Cardiovascular Events: Myocardial ischemia, myocardial infarction, heart failure, cardiomyopathy, and decreased left ventricular ejection fraction (LVEF) to below the lower limit of normal including death have occurred. Monitor for signs and symptoms of congestive heart failure and consider monitoring LVEF at baseline and periodically during treatment. Discontinue sunitinib malate capsules for clinical manifestations of congestive heart failure. Interrupt and/or dose reduce for decreased LVEF. (5.2)
• • QT Interval Prolongation and Torsade de Pointes: Monitor patients at higher risk for developing QT interval prolongation. Consider monitoring of electrocardiograms and electrolytes. (5.3)
• • Hypertension: Monitor blood pressure at baseline and as clinically indicated. Initiate and/or adjust antihypertensive therapy as appropriate. Interrupt sunitinib malate capsules for Grade 3 hypertension until resolution to Grade ≤ 1 or baseline, then resume sunitinib malate capsules at a reduced dose. Discontinue sunitinib malate capsules in patients who develop Grade 4 hypertension. (5.4)
• • Hemorrhagic Events: Tumor-related hemorrhage and viscus perforation (both with fatal events) have occurred. Perform serial complete blood counts and physical examinations. Interrupt sunitinib malate capsules for Grade 3 or 4 hemorrhagic events until resolution to Grade ≤ 1 or baseline, then resume at a reduced dose; discontinue if no resolution. (5.5)
• • Tumor Lysis Syndrome (TLS): TLS (some fatal) has been reported primarily in patients with RCC and GIST. Monitor these patients and treat as clinically indicated. (5.6)
• • Thrombotic Microangiopathy (TMA): TMA, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, sometimes leading to renal failure or a fatal outcome, has been reported. Discontinue sunitinib malate capsules for TMA. (5.7)
• • Proteinuria: Renal failure or a fatal outcome has occurred. Monitor urine protein. Interrupt treatment for 24-hour urine protein of 3 or more grams. Discontinue for repeat episodes of 24-hour urine protein of 3 or more grams despite dose reductions or nephrotic syndrome. (5.8)
• • Dermatologic Toxicities: Necrotizing fasciitis, erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) (some fatal) have occurred. Discontinue sunitinib malate capsules for these events. (5.9)
• • Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS (some fatal) has been reported. Monitor for signs and symptoms of RPLS. Withhold sunitinib malate capsules until resolution. (5.10)
• • Thyroid Dysfunction: Monitor thyroid function at baseline, periodically during treatment, and as clinically indicated. Initiate and/or adjust therapy for thyroid dysfunction as appropriate. (5.11)
• • Hypoglycemia: Check blood glucose levels regularly and assess if antidiabetic drug dose modifications are required. (5.12)
• • Osteonecrosis of the Jaw (ONJ): Withhold sunitinib malate capsules for at least 3 weeks prior to invasive dental procedure and for development of ONJ until complete resolution. (5.13)
• • Impaired Wound Healing: 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. (5.14)
• • Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. (5.15, 8.1, 8.3)

5.1Hepatotoxicity

Sunitinib malate capsules can cause severe hepatotoxicity, resulting in liver failure or death. In the pooled safety population, liver failure occurred in < 1% of patients in clinical trials. Liver failure include jaundiced, elevated transaminases and/or hyperbilirubinemia in conjunction with encephalopathy, coagulopathy, and/or renal failure.

Monitor liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and bilirubin) at baseline, during each cycle, and as clinically indicated. Interrupt sunitinib malate capsules for Grade 3 hepatotoxicity until resolution to Grade ≤ 1 or baseline, then resume sunitinib malate capsules at a reduced dose.

Discontinue sunitinib malate capsules 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.

5.2Cardiovascular Events

Cardiovascular events, including heart failure, cardiomyopathy, myocardial ischemia, and myocardial infarction, some of which were fatal, have been reported.

In pooled safety population, 3% of patients experienced heart failure; 71% of the patients with heart failure were reported as recovered. Fatal cardiac failure was reported in < 1% of patients.

In the adjuvant treatment of RCC study, 11 patients experienced Grade 2 decreased ejection fraction (left ventricular ejection fraction [LVEF] 40% to 50% and a 10% to 19% decrease from baseline). In 3 of these 11 patients, the ejection fractions arm did not return to ≥ 50% or baseline by the time of last measurement. No patients who received sunitinib malate capsules were diagnosed with CHF.

Patients who presented with cardiac events within 12 months prior to sunitinib malate capsules 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 sunitinib malate capsules clinical studies. Patients with prior anthracycline use or cardiac radiation were also excluded from some studies. It is unknown whether patients with these concomitant conditions may be at a higher risk of developing left ventricular dysfunction.

Consider monitoring LVEF at baseline and periodically as clinically indicated. Carefully monitor patients for clinical signs and symptoms of congestive heart failure (CHF). Discontinue sunitinib malate capsules in patients who experience clinical manifestations of CHF. Interrupt sunitinib malate capsules 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.

5.3QT Interval Prolongation and Torsade de Pointes

Sunitinib malate capsules can cause QT interval prolongation in a dose-dependent manner, which may lead to an increased risk for ventricular arrhythmias including Torsade de Pointes. Torsade de Pointes was observed in < 0.1% of patients.

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 sunitinib malate capsules.

Monitor QT interval more frequently when sunitinib malate capsules are concomitantly administered with strong CYP3A4 inhibitors or drugs known to prolong QT interval. Consider dose reducing sunitinib malate capsules [see Dosage and Administration (2.5), Drug Interactions (7.2)].

5.4Hypertension

In the pooled safety population, 29% of patients experienced hypertension. Grade 3 hypertension was reported in 7% of patients, and Grade 4 hypertension was reported in 0.2%.

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

5.5Hemorrhagic 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.

5.6Tumor 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.

5.8Proteinuria

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.

5.9Dermatologic 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.

5.10Reversible 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.

5.11Thyroid 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.

5.12Hypoglycemia

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.

5.13Osteonecrosis 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.

5.14Impaired 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.

5.15Embryo-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)]

• •The most common adverse reactions (≥ 25%) are fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia/altered taste, dyspepsia, and thrombocytopenia. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The pooled safety population described in the Warnings and Precautions reflect exposure to sunitinib malate in 7527 patients with GIST, RCC (advanced and adjuvant), or pNET. In this pooled safety population, the most common adverse reactions (≥ 25%) were fatigue/asthenia, diarrhea, mucositis/stomatitis, nausea, decreased appetite/anorexia, vomiting, abdominal pain, hand-foot syndrome, hypertension, bleeding events, dysgeusia/altered taste, dyspepsia, and thrombocytopenia.

The safety of sunitinib malate capsules was evaluated in Study 1, a randomized, double-blind, placebo-controlled trial in which previously treated patients with GIST received sunitinib malate capsules 50 mg daily on Schedule 4/2 (n = 202) or placebo (n = 102). Median duration of blinded study treatment was 2 cycles for patients on sunitinib malate capsules (mean: 3.0; range: 1-9) and 1 cycle (mean; 1.8; range: 1-6) for patients on placebo at the time of the interim analysis.

Permanent discontinuation due to an adverse reaction occurred in 7% of patients in the sunitinib malate capsules arm. Dose reductions occurred in 11% and dose interruptions occurred in 29% of patients who received sunitinib malate capsules.

Table 3 summarizes the adverse reactions for Study 1.

Table 3. Adverse Reactions Reported in ≥ 10% of GIST Patients Who Received Sunitinib Malate Capsules in the Double-Blind Treatment Phase and More Commonly Than in Patients Given PlaceboCommon Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 1

Abbreviations: GIST = gastrointestinal stromal tumor; N = number of patients.
Adverse Reaction	GIST
	Sunitinib Malate Capsules (N = 202)		Placebo (N = 102)
	All Grades %	Grade 3-4%	All Grades %	Grade 3-4%
Any Adverse Reaction	94	56	97	51
Gastrointestinal
Diarrhea	40	4	27	0
Mucositis/stomatitis	29	1	18	2
Constipation	20	0	14	2
Metabolism/Nutrition
AnorexiaIncludes decreased appetite.	33	1	29	5
Asthenia	22	5	11	3
Dermatology
Skin discoloration	30	0	23	0
Rash	14	1	9	0
Hand-foot syndrome	14	4	10	3
Neurology
Altered taste	21	0	12	0
Cardiac
Hypertension	15	4	11	0
Musculoskeletal
Myalgia/limb pain	14	1	9	1

Other clinically relevant adverse reactions included oral pain other than mucositis/stomatitis in 6%; hair color changes in 7%; alopecia in 5% of patients who received sunitinib malate capsules.

Table 4 summarizes the laboratory abnormalities in Study 1.

Table 4. Laboratory Abnormalities Reported in ≥ 10% of GIST Patients Who Received Sunitinib Malate Capsules or Placebo in the Double-Blind Treatment PhaseCommon Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 1

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; GIST = gastrointestinal stromal tumor; LVEF = left ventricular ejection fraction; N = number of patients.
Laboratory Abnormality	GIST
	Sunitinib Malate Capsules (N = 202)		Placebo (N = 102)
	All Grades %	Grade 3-4 , Grade 4 laboratory abnormalities in patients on sunitinib malate capsules included alkaline phosphatase (1%), lipase (2%), creatinine (1%), potassium decreased (1%), neutrophils (2%), hemoglobin (2%), and platelets (1%). %	All Grades %	Grade 3-4 , Grade 4 laboratory abnormalities in patients on placebo included amylase (1%), lipase (1%), and hemoglobin (2%). %
Any Laboratory Abnormality		34		22
Hematology
Neutrophils decreased	53	10	4	0
Lymphocytes decreased	38	0	16	0
Platelets decreased	38	5	4	0
Hemoglobin decreased	26	3	22	2
Gastrointestinal
AST/ALT increased	39	2	23	1
Lipase increased	25	10	17	7
Alkaline phosphatase increased	24	4	21	4
Amylase increased	17	5	12	3
Total bilirubin increased	16	1	8	0
Indirect bilirubin increased	10	0	4	0
Renal/Metabolic
Creatinine increased	12	1	7	0
Potassium decreased	12	1	4	0
Sodium increased	10	0	4	1
Cardiac
Decreased LVEF	11	1	3	0

After an interim analysis, the study was unblinded and patients on the placebo arm were given the opportunity to receive open-label sunitinib malate capsules [see Clinical Studies (14.1)]. For 241 patients randomized to the sunitinib malate capsules arm, including 139 who received sunitinib malate capsules in both the double-blind and open-label phases, the median duration of sunitinib malate capsules treatment was 6 cycles (mean: 8.5; range: 1–44). For the 255 patients who ultimately received open-label sunitinib malate capsules treatment, median duration of treatment was 6 cycles (mean: 7.8; range: 1–37) from the time of the unblinding.

Permanent discontinuation due to an adverse reaction occurred in 20% of patients who received sunitinib malate capsules. Dosage interruption occurred in 46% and dose reduction occurred in 28% of patients who received sunitinib malate capsules.

The most common Grade 3 or 4 adverse reactions in patients who received sunitinib malate capsules in the open-label phase were fatigue (10%), hypertension (8%), asthenia (5%), diarrhea (5%), hand-foot syndrome (5%), nausea (4%), abdominal pain (3%), anorexia (3%), mucositis (2%), vomiting (2%), and hypothyroidism (2%).

The safety of sunitinib malate capsules was evaluated in Study 3, a double-blind, active-controlled trial in which previously untreated patients with locally advanced or metastatic RCC received sunitinib malate capsules 50 mg daily on Schedule 4/2 (n = 375) or interferon alfa 9 million International Units (MIU) (n = 360). The median duration of treatment was 11.1 months (range: 0.4 to 46.1) for sunitinib malate capsules treatment and 4.1 months (range: 0.1 to 45.6) for interferon alfa treatment.

Permanent discontinuation due to an adverse reaction occurred in 20% of patients in the sunitinib malate capsules arm. Dose interruptions occurred in 54% and dose reductions occurred in 52% of patients who received sunitinib malate capsules.

Table 5 summarizes the adverse reactions for Study 3.

Table 5. Adverse Reactions Reported in ≥ 10% of Patients With RCC Who Received Sunitinib Malate Capsules or Interferon AlfaCommon Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 3

Abbreviations: ARs = adverse reactions; N = number of patients; RCC = renal cell carcinoma.
Adverse Reaction	Treatment-Naïve RCC
	Sunitinib Malate Capsules (N = 375)		Interferon Alfa (N = 360)
	All Grades %	Grade 3-4 Grade 4 ARs in patients on sunitinib malate capsules included back pain (1%), arthralgia (< 1%), dyspnea (< 1%), asthenia (< 1%), fatigue (< 1%), limb pain (< 1%), and rash (< 1%). %	All Grades %	Grade 3-4 Grade 4 ARs in patients on interferon alfa included dyspnea (1%), fatigue (1%), abdominal pain (< 1%), and depression (< 1%). %
Any Adverse Reaction	99	77	99	55
Gastrointestinal
Diarrhea	66	10	21	< 1
Nausea	58	6	41	2
Mucositis/stomatitis	47	3	5	< 1
Vomiting	39	5	17	1
Dyspepsia	34	2	4	0
Abdominal painIncludes flank pain.	30	5	12	1
Constipation	23	1	14	< 1
Dry mouth	13	0	7	< 1
Oral pain	14	< 1	1	0
Flatulence	14	0	2	0
GERD/reflux esophagitis	12	< 1	1	0
Glossodynia	11	0	1	0
Hemorrhoids	10	0	2	0
Constitutional
Fatigue	62	15	56	15
Asthenia	26	11	22	6
Fever	22	1	37	< 1
Weight decreased	16	< 1	17	1
Chills	14	1	31	0
Chest Pain	13	2	7	1
Influenza like illness	5	0	15	< 1
Metabolism/Nutrition
AnorexiaIncludes decreased appetite.	48	3	42	2
Neurology
Altered tasteIncludes ageusia, hypogeusia, and dysgeusia.	47	< 1	15	0
Headache	23	1	19	0
Dizziness	11	< 1	14	1
Hemorrhage/Bleeding
Bleeding, all sites	37	4Includes 1 patient with Grade 5 gastric hemorrhage.	10	1
Cardiac
Hypertension	34	13	4	< 1
Edema peripheral	24	2	5	1
Ejection fraction decreased	16	3	5	2
Dermatology
Rash	29	2	11	< 1
Hand-foot syndrome	29	8	1	0
Skin discoloration/yellow skin	25	< 1	0	0
Dry skin	23	< 1	7	0
Hair color changes	20	0	< 1	0
Alopecia	14	0	9	0
Erythema	12	< 1	1	0
Pruritus	12	< 1	7	< 1
Musculoskeletal
Pain in extremity/limb discomfort	40	5	30	2
Arthralgia	30	3	19	1
Back pain	28	5	14	2
Respiratory
Cough	27	1	14	< 1
Dyspnea	26	6	20	4
Nasopharyngitis	14	0	2	0
Oropharyngeal pain	14	< 1	2	0
Upper respiratory tract infection	11	< 1	2	0
Endocrine
Hypothyroidism	16	2	1	0
Psychiatric
Insomnia	15	< 1	10	0
DepressionIncludes depressed mood.	11	0	14	1

Table 6 summarizes the laboratory abnormalities in Study 3.

Table 6. Laboratory Abnormalities Reported in ≥ 10% of RCC Patients Who Received Sunitinib Malate Capsules or Interferon Alfa in Study 3

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; N = number of patients; RCC = renal cell carcinoma.
Laboratory Abnormality	Treatment-Naïve RCC
	Sunitinib Malate Capsules (N = 375)		Interferon Alfa (N = 360)
	All Grades Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. %	Grade 3/4 , Grade 4 laboratory abnormalities in patients on sunitinib malate capsules included uric acid (14%), lipase (3%), neutrophils (2%), lymphocytes (2%), hemoglobin (2%), platelets (1%), amylase (1%), ALT (< 1%), creatine kinase (< 1%), creatinine (< 1%), glucose increased (< 1%), calcium decreased (< 1%), phosphorous (< 1%), potassium increased (< 1%), and sodium decreased (< 1%). %	All Grades %	Grade 3/4 , Grade 4 laboratory abnormalities in patients on interferon alfa included uric acid (8%), lymphocytes (2%), lipase (1%), neutrophils (1%), amylase (< 1%), calcium increased (< 1%), glucose decreased (< 1%), potassium increased (< 1%), and hemoglobin (< 1%). %
Hematology
Hemoglobin decreased	79	8	69	5
Neutrophils decreased	77	17	49	9
Platelets decreased	68	9	24	1
Lymphocytes decreased	68	18	68	26
Renal/Metabolic
Creatinine increased	70	< 1	51	< 1
Creatine kinase increased	49	2	11	1
Uric acid increased	46	14	33	8
Calcium decreased	42	1	40	1
Phosphorus decreased	31	6	24	6
Albumin decreased	28	1	20	0
Glucose increased	23	6	15	6
Sodium decreased	20	8	15	4
Glucose decreased	17	0	12	< 1
Potassium increased	16	3	17	4
Calcium increased	13	< 1	10	1
Potassium decreased	13	1	2	< 1
Sodium increased	13	0	10	0
Gastrointestinal
AST increased	56	2	38	2
Lipase increased	56	18	46	8
ALT increased	51	3	40	2
Alkaline phosphatase increased	46	2	37	2
Amylase increased	35	6	32	3
Total bilirubin increased	20	1	2	0
Indirect bilirubin increased	13	1	1	0

The long-term safety of sunitinib malate capsules in patients with metastatic RCC was analyzed across 9 completed clinical studies conducted in the first-line, bevacizumab-refractory, and cytokine-refractory treatment settings. The analysis included 5739 patients, of whom 807 (14%) were treated for at least 2 years and 365 (6%) for at least 3 years. Prolonged treatment with sunitinib malate capsules did not appear to be associated with new types of adverse reactions. There appeared to be no increase in the yearly incidence of adverse reactions at later time points. Hypothyroidism increased during the second year of treatment with new cases reported up to year 4.

The safety of sunitinib malate capsules was evaluated in S-TRAC, a randomized, double-blind, placebo-controlled trial in which patients who had undergone nephrectomy for RCC received sunitinib malate capsules 50 mg daily on Schedule 4/2 (n = 306) or placebo (n = 304). The median duration of treatment was 12.4 months (range: 0.13 to 14.9) for sunitinib malate capsules and 12.4 months (range: 0.03 to 13.7) for placebo.

Permanent discontinuation due to an adverse reaction occurred in 28% of patients in the sunitinib malate capsules arm. Adverse reactions leading to permanent discontinuation in > 2% of patients include hand-foot syndrome and fatigue/asthenia. Dosing interruptions occurred in 54% and dose reductions occurred in 46% of patients who received sunitinib malate capsules.

Table 7 summarizes the adverse reactions in S-TRAC.

Table 7. Adverse Reactions Reported in ≥ 10% of Patients With RCC Who Received Sunitinib Malate Capsules and More Commonly Than in Patients Given PlaceboCommon Terminology Criteria for Adverse Events (CTCAE), version 3.0. in S-TRAC

Abbreviations: ARs = adverse reactions; N = number of patients; RCC = renal cell carcinoma.
Adverse Reaction	Adjuvant Treatment of RCC
	Sunitinib Malate Capsules (N = 306)		Placebo (N = 304)
	All Grades %	Grade 3-4 %	All Grades %	Grade 3-4 %
Any Adverse Reaction	99	60	88	15
Gastrointestinal
Mucositis/StomatitisIncludes mucosal inflammation, stomatitis aphthous ulcer, mouth ulceration, tongue ulceration, oropharyngeal pain, and oral pain.	61	6	15	0
Diarrhea	57	4	22	< 1
Nausea	34	2	15	0
Dyspepsia	27	1	7	0
Abdominal painIncludes abdominal pain, abdominal pain lower, and abdominal pain upper.	25	2	9	< 1
Vomiting	19	2	7	0
Constipation	12	0	11	0
Constitutional
Fatigue/Asthenia	57	8	34	2
Localized edemaIncludes edema localized, face edema, eyelid edema, periorbital edema, swelling face, and eye edema.	18	< 1	< 1	0
Pyrexia	12	< 1	6	0
Dermatology
Hand-foot syndrome	50	16	10	< 1
RashIncludes dermatitis, dermatitis psoriasiform, exfoliative rash, genital rash, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, and rash pruritic.	24	2	12	0
Hair color changes	22	0	2	0
Skin discoloration/ Yellow skin	18	0	1	0
Dry skin	14	0	6	0
Cardiac
HypertensionIncludes hypertension, blood pressure increased, blood pressure systolic increased, blood pressure diastolic increased, and hypertensive crisis.	39	8	14	1
Edema/Peripheral edema	10	< 1	7	0
Neurology
Altered tasteIncludes ageusia, hypogeusia, and dysgeusia.	38	< 1	6	0
Headache	19	< 1	12	0
Endocrine
Hypothyroidism/TSH increased	24	< 1	4	0
Hemorrhage/Bleeding
Bleeding events, all sitesIncludes epistaxis, gingival bleeding, rectal hemorrhage, hemoptysis, anal hemorrhage, upper gastrointestinal hemorrhage, and hematuria.	24	< 1	5	< 1
Metabolism/Nutrition
Anorexia/Decreased appetite	19	< 1	5	0
Musculoskeletal
Pain in extremity	15	< 1	7	0
Arthralgia	11	< 1	10	0

Grade 4 adverse reactions in patients on sunitinib malate capsules included hand-foot syndrome (1%), fatigue (< 1%), abdominal pain (< 1%), stomatitis (< 1%), and pyrexia (< 1%).

Grade 3-4 laboratory abnormalities that occurred in ≥ 2% of patients receiving sunitinib malate capsules include neutropenia (13%), thrombocytopenia (5%), leukopenia (3%), lymphopenia (3%), elevated alanine aminotransferase (2%), elevated aspartate aminotransferase (2%), hyperglycemia (2%), and hyperkalemia (2%).

The safety of sunitinib malate capsules was evaluated in Study 6, a randomized, double-blind, placebo-controlled trial in which patients with progressive pNET received sunitinib malate capsules 37.5 mg once daily (n = 83) or placebo (n = 82). The median number of days on treatment was 139 days (range: 13-532 days) for patients on sunitinib malate capsules and 113 days (range: 1-614 days) for patients on placebo. Nineteen patients (23%) on sunitinib malate capsules and 4 patients (5%) on placebo were on study for > 1 year.

Permanent discontinuation due to an adverse reaction occurred in 22% in the sunitinib malate capsules arm. Dose interruptions occurred in 30% and dose reductions occurred in 31% of patients who received sunitinib malate capsules.

Table 8 summarizes the adverse reactions in Study 6.

Table 8. Adverse Reactions Reported in ≥ 10% of Patients With pNET Who Received Sunitinib Malate Capsules and More Commonly Than in Patients Given PlaceboCommon Terminology Criteria for Adverse Events (CTCAE), version 3.0. in Study 6

Abbreviations: N = number of patients; pNET = pancreatic neuroendocrine tumors.
Adverse Reaction	pNET
	Sunitinib Malate Capsules (N = 83)		Placebo (N = 82)
	All Grades %	Grade 3-4 Grade 4 adverse reactions in patients on sunitinib malate capsules included fatigue (1%). %	All Grades %	Grade 3-4 %
Any Adverse Reaction	99	54	95	50
Gastrointestinal
Diarrhea	59	5	39	2
Stomatitis/oral syndromesIncludes aphthous stomatitis, gingival pain, gingivitis, glossitis, glossodynia, mouth ulceration, oral discomfort, oral pain, tongue ulceration, mucosal dryness, mucosal inflammation, and dry mouth.	48	6	18	0
Nausea	45	1	29	1
Abdominal painIncludes abdominal discomfort, abdominal pain, and abdominal pain upper.	39	5	34	10
Vomiting	34	0	31	2
Dyspepsia	15	0	6	0
Constitutional
Asthenia	34	5	27	4
Fatigue	33	5	27	9
Weight decreased	16	1	11	0
Dermatology
Hair color changes	29	1	1	0
Hand-foot syndrome	23	6	2	0
Rash	18	0	5	0
Dry skin	15	0	11	0
Cardiac
Hypertension	27	10	5	1
Hemorrhage/Bleeding
Bleeding eventsIncludes hematemesis, hematochezia, hematoma, hemoptysis, hemorrhage, melena, and metrorrhagia.	22	0	10	4
Epistaxis	21	1	5	0
Neurology
Dysgeusia	21	0	5	0
Headache	18	0	13	1
Psychiatric
Insomnia	18	0	12	0
Musculoskeletal
Arthralgia	15	0	6	0

Table 9 summarizes the laboratory abnormalities in Study 6.

Table 9. Laboratory Abnormalities Reported in ≥ 10% of Patients With pNET Who Received Sunitinib Malate Capsules in Study 6

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; N = number of patients; pNET = pancreatic neuroendocrine tumors.
Laboratory Abnormality	pNET
	Sunitinib Malate Capsules		Placebo
	All Grades The denominator used to calculate the rate varied from 52 to 82 for sunitinib malate capsules and 39 to 80 for Placebo based on the number of patients with a baseline value and at least one post-treatment value. Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. %	Grade 3-4 , Grade 4 laboratory abnormalities in patients on sunitinib malate capsules included creatinine (4%), lipase (4%), glucose decreased (2%), glucose increased (2%), neutrophils (2%), ALT (1%), AST (1%), platelets (1%), potassium increased (1%), and total bilirubin (1%). %	All Grades %	Grade 3-4 , Grade 4 laboratory abnormalities in patients on placebo included creatinine (3%), alkaline phosphatase (1%), glucose increased (1%), and lipase (1%). %
Gastrointestinal
AST increased	72	5	70	3
Alkaline phosphatase increased	63	10	70	11
ALT increased	61	4	55	3
Total bilirubin increased	37	1	28	4
Amylase increased	20	4	10	1
Lipase increased	17	5	11	4
Hematology
Neutrophils decreased	71	16	16	0
Hemoglobin decreased	65	0	55	1
Platelets decreased	60	5	15	0
Lymphocytes decreased	56	7	35	4
Renal/Metabolic
Glucose increased	71	12	78	18
Albumin decreased	41	1	37	1
Phosphorus decreased	36	7	22	5
Calcium decreased	34	0	19	0
Sodium decreased	29	2	34	3
Creatinine increased	27	5	28	5
Glucose decreased	22	2	15	4
Potassium decreased	21	4	14	0
Magnesium decreased	19	0	10	0
Potassium increased	18	1	11	1

In pooled safety population, 3.5% of patients experienced a venous thromboembolic event, including Grade 3-4 in 2.2% of patients.

Pancreatitis was observed in 1 patient (1%) in the pNET study, 5 patients (1%) in the treatment-naïve RCC study, and 1 patient (< 1%) in the adjuvant treatment for RCC study on sunitinib malate capsules.

6.2Postmarketing Experience

The following adverse reactions have been identified during postapproval use of sunitinib malate capsules. 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:  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 sunitinib malate capsules 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