Pregnancy
Pregnancy Category D
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. There are no adequate and well-controlled studies
of SUTENT in pregnant women. If the drug is used during pregnancy, or if the patient
becomes pregnant while receiving this drug, the patient should be apprised of the
potential hazard to the fetus. Women of childbearing potential should be advised
to avoid becoming pregnant while receiving treatment with SUTENT.
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).
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.
More patients treated with SUTENT experienced decline in left ventricular ejection
fraction (LVEF) than patients receiving either placebo or interferon-α (IFN-α).
In 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 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 MRCC study, 78/375 (21%) and 44/360 (12%) patients on SUTENT
and IFN-α, respectively, had an LVEF value below the LLN. Thirteen patients on SUTENT
(4%) and four on IFN-α (1%) experienced declines in LVEF of >20% from baseline
and to below 50%. Left ventricular dysfunction was reported in three patients (1%)
and CHF in one patient (<1%) who received SUTENT.
Patients who presented with cardiac events within 12 months prior to SUTENT administration,
such as myocardial infarction (including severe/unstable angina), coronary/peripheral
artery bypass graft, symptomatic CHF, cerebrovascular accident or transient ischemic
attack, or pulmonary embolism were excluded from SUTENT clinical studies. It is
unknown whether patients with these concomitant conditions may be at a higher risk
of developing drug-related left ventricular dysfunction. Physicians are advised
to weigh this risk against the potential benefits of the drug. These patients should
be carefully monitored for clinical signs and symptoms of CHF while receiving SUTENT.
Baseline and periodic evaluations of LVEF should also be considered while the patient
is receiving SUTENT. In patients without cardiac risk factors, a baseline evaluation
of ejection fraction should be considered.
QT Interval Prolongation and Torsade de Pointes
SUTENT 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.
SUTENT 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].
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 MRCC, 111/375 patients (30%) receiving
SUTENT compared with 13/360 patients (4%) on IFN-α experienced hypertension. Grade
3 hypertension was observed in 36/375 treatment-naïve MRCC patients (10%) on SUTENT
compared to 1/360 patient (<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.
No Grade 4 hypertension was reported. SUTENT dosing was reduced or temporarily delayed
for hypertension in 18/375 patients ( 5%) on the treatment-naïve MRCC study. Two
treatment-naïve MRCC patients, including one with malignant hypertension, 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%), and in 20/375 treatment-naïve MRCC patients
(5%) on SUTENT and 2/360 patients (1%) on IFN-α.
Hemorrhagic Events
In patients receiving SUTENT for treatment-naïve MRCC, 112/375 patients (30%) had
bleeding events compared with 27/360 patients (8%) receiving IFN-α. Bleeding events
occurred in 37/202 patients (18%) receiving SUTENT in GIST Study A, compared to
17/102 patients (17%) receiving placebo. Epistaxis was the most common hemorrhagic
adverse event reported. Less common bleeding events in GIST or MRCC patients included
rectal, gingival, upper gastrointestinal, genital, and wound bleeding. In GIST Study
A, 14/202 patients (7%) receiving SUTENT and 9/102 patients (9%) on placebo had
Grade 3 or 4 bleeding events. In addition, one patient in Study A taking placebo
had a fatal gastrointestinal bleeding event during Cycle 2. Most events in MRCC
patients were Grade 1 or 2; there was one Grade 5 event of gastric bleed in a treatment-naïve
patient.
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. Fatal pulmonary hemorrhage
occurred in 2 patients receiving SUTENT on a clinical trial of patients with metastatic
non-small cell lung cancer (NSCLC). Both patients had squamous cell histology. SUTENT
is not approved for use in patients with NSCLC. Treatment-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. Tumor hemorrhage has not been observed in patients
with MRCC. 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.
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 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 eleven patients (3%) on SUTENT in the treatment-naïve MRCC study and
in one patient (<1%) in the IFN-α arm. An additional seven patients (2%) with
no prior history of hypothyroidism were started on thyroid replacement therapy while
on study.
Cases of hyperthyroidism, some followed by hypothyroidism, have been reported in
clinical trials and through post-marketing experience.
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.
PATIENT COUNSELING INFORMATION
See FDA-Approved Patient Labeling.
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.
Other Common Events
Other commonly reported adverse events included fatigue, high blood pressure, bleeding,
swelling, mouth pain/irritation and taste disturbance.
Concomitant Medications
Patients should be advised to inform their health care providers of all concomitant
medications, including over-the-counter medications and dietary supplements [see
Drug Interactions].