The data described below reflect exposure to SUTENT in 577 patients who participated
in a placebo-controlled trial (n=202) for the treatment of GIST or an active-controlled
trial (n=375) for the treatment of MRCC. In these two studies, 225 patients were
exposed to SUTENT for at least 6 months and 16 were exposed for greater than one
year. The population was 23 - 87 years of age and 69% male and 31% female. The race
distribution was 92% White, 3% Asian, 2% Black and 3% not reported. The patients
received a starting oral dose of 50 mg daily on Schedule 4/2 in repeated cycles.
The most common adverse reactions (≥20%) in patients with GIST or MRCC are fatigue,
asthenia, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal
pain, constipation, hypertension, rash, hand-foot syndrome, skin discoloration,
altered taste, anorexia, and bleeding. The potentially serious adverse reactions
of left ventricular dysfunction, QT interval prolongation, hemorrhage, hypertension,
and adrenal function are discussed in Warnings and Precautions. Other adverse
reactions occurring in GIST and MRCC studies are described below.
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.
Adverse Reactions in GIST Study A
Median duration of blinded study treatment was two cycles for patients on SUTENT
(mean 3.0, range 1-9) and one cycle (mean 1.8, range 1-6) for patients on placebo.
Dose reductions occurred in 23 patients (11%) on SUTENT and none on placebo. Dose
interruptions occurred in 59 patients (29%) on SUTENT and 31 patients (30%) on placebo.
The rates of treatment-emergent, non-fatal adverse reactions resulting in permanent
discontinuation were 7% and 6% in the SUTENT and placebo groups, respectively.
Most treatment-emergent adverse reactions in both study arms were Grade 1 or 2 in
severity. Grade 3 or 4 treatment-emergent adverse reactions were reported in 56%
versus 51% of patients on SUTENT versus placebo, respectively. Table 1 compares
the incidence of common (≥10%) treatment-emergent adverse reactions for patients
receiving SUTENT and reported more commonly in patients receiving SUTENT than in
patients receiving placebo.
Table 1. Adverse Reactions Reported in Study A in at least 10% of GIST Patients who
Received SUTENT and More Commonly Than in Patients Given Placebo*
Oral pain other than mucositis/stomatitis occurred in 12 patients (6%) on SUTENT
versus 3 (3%) on placebo. Hair color changes occurred in 15 patients (7%) on SUTENT
versus 4 (4%) on placebo. Alopecia was observed in 10 patients (5%) on SUTENT versus
2 (2%) on placebo.
Table 2 provides common (≥10%) treatment-emergent laboratory abnormalities.
Table 2. Laboratory Abnormalities Reported in Study A in at least 10% of GIST Patients
who Received SUTENT or Placebo*
Adverse Reactions in the Treatment-Naïve MRCC Study
The as-treated patient population for the interim safety analysis of the treatment-naïve
MRCC study included 735 patients, 375 randomized to SUTENT and 360 randomized to
IFN-α. The median duration of treatment was 5.6 months (range: 0.4-15.6) for SUTENT
treatment and 4.1 months (range: 0.1-13.7) on IFN-α treatment. Dose reductions occurred
in 121 patients (32%) on SUTENT and 77 patients (21%) on IFN-α. Dose interruptions
occurred in 142 patients (38%) on SUTENT and 115 patients (32%) on IFN-α. The rates
of treatment-emergent, non-fatal adverse reactions resulting in permanent discontinuation
were 9% and 12% in the SUTENT and IFN-α groups, respectively. Most treatment-emergent
adverse reactions in both study arms were Grade 1 or 2 in severity. Grade 3 or 4
treatment-emergent adverse reactions were reported in 67% versus 51% of patients
on SUTENT versus IFN-α, respectively.
Table 3 compares the incidence of common (≥10%) treatment-emergent adverse reactions
for patients receiving SUTENT versus IFN-α.
Table 3. Adverse Reactions Reported in at Least 10% of Patients with MRCC who Received
SUTENT or IFN-α*
Treatment-emergent Grade 3/4 laboratory abnormalities are presented in Table 4.
Table 4. Laboratory Abnormalities Reported in at Least 10% of Treatment-Naïve MRCC
Patients who Received SUTENT or IFN-α*
Venous Thromboembolic Events
Seven patients (3%) on SUTENT and none on placebo in GIST Study A experienced venous
thromboembolic events; five of the seven were Grade 3 deep venous thrombosis (DVT),
and two were Grade 1 or 2. Four of these seven GIST patients discontinued treatment
following first observation of DVT.
Eight (2%) patients receiving SUTENT for treatment-naïve MRCC had venous thromboembolic
events reported. Four (1%) of these patients had pulmonary embolism, one was Grade
3 and three were Grade 4, and four (1%) patients had DVT, including one Grade 3.
One patient was permanently withdrawn from SUTENT due to pulmonary embolism; dose
interruption occurred in two patients with pulmonary embolism and one with DVT.
In treatment-naïve MRCC patients receiving IFN-α, six (2%) venous thromboembolic
events occurred; one patient (<1%) experienced a Grade 3 DVT and five patients
(1%) had pulmonary embolism, one Grade 1 and four with Grade 4.
Reversible Posterior Leukoencephalopathy Syndrome
There have been rare (<1%) reports of subjects presenting with seizures and radiological
evidence of reversible posterior leukoencephalopathy syndrome (RPLS). None of these
subjects had a fatal outcome to the event. Patients with seizures and signs/symptoms
consistent with RPLS, such as hypertension, headache, decreased alertness, altered
mental functioning, and visual loss, including cortical blindness should be controlled
with medical management including control of hypertension. Temporary suspension
of SUTENT is recommended; following resolution, treatment may be resumed at the
discretion of the treating physician.
Pancreatic and Hepatic Function
If symptoms of pancreatitis or hepatic failure are present, patients should have
SUTENT discontinued. Pancreatitis was observed in 5 (1%) patients receiving SUTENT
for treatment-naïve MRCC compared to 1 (<1%) patient receiving IFN-α. Hepatic
failure was observed in <1% of solid tumor patients treated with SUTENT.
Post-marketing 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.
Cases of serious infection (with or without neutropenia), in some cases with fatal outcome, have been reported.
Cases of myopathy and/or rhabdomyolysis, some with acute renal failure, have been reported. Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice.
Thrombotic microangiopathy has been reported in patients on SUTENT. Suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.
Cases of renal impairment and/or failure, in some cases with fatal outcome, have been reported.
Cases of proteinuria and rare cases of nephrotic syndrome have been reported. Baseline urinalysis is recommended, and patients should be monitored for the development or worsening of proteinuria. The safety of continued SUTENT treatment in patients with moderate to severe proteinuria has not been systematically evaluated. Discontinue SUTENT in patients with nephrotic syndrome.
Hypersensitivity reactions, including angioedema, have been reported.
Cases of fistula formation, sometimes associated with tumor necrosis and/or regression, in some cases with fatal outcome, have been reported.
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 [see Dosage and Administration].
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 [see Dosage and Administration].
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 enzymes.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category D [see Warnings and Precautions].
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
sunitinib or its primary active metabolite are excreted in human milk. Because drugs
are commonly excreted in human milk and because of the potential for serious adverse
reactions in nursing infants, 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 [see Nonclinical Toxicology].
Pediatric Use
The safety and efficacy of SUTENT in pediatric patients have not been studied in
clinical trials.
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.
Geriatric Use
Of 825 GIST and MRCC patients who received SUTENT on clinical studies, 277 (34%)
were 65 and over. No overall differences in safety or effectiveness were observed
between younger and older patients.
Hepatic Impairment
No dose adjustment 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 x ULN or, if due to liver metastases,
>5.0 x ULN.