human milk and because of the potential for serious adverse reactions in nursing infants from

Sunitinib, 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.

Pediatric Use
The safety and efficacy of Sunitinib in pediatric patients have not been established. 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
COMPOSITION and an increase of fracture of the tibia at doses > _ 5 mg/kg (approximately 10 times the RDD
Sunitix Capsule: Each capsule contains Sunitinib Malate INN equivalent to Sunitinib 50 mg. based on AUC). Additionally, caries of the teeth were observed in rats at >5 mg/kg. The incidence
Sunitix 12.5 Capsule: Each capsule contains Sunitinib Malate INN equivalent to Sunitinib 12.5 mg. and severity of physeal dysplasia were dose-related and were reversible upon cessation of
Sunitix 25 Capsule: Each capsule contains Sunitinib Malate INN equivalent to Sunitinib 25 mg. 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
CLINICAL PHARMACOLOGY cycles. In rats the no effect level in bones was <
_ 2 mg/kg/day.
Sunitinib malate 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 Geriatric Use
cancer. Of 825 GIST and RCC patients who received Sunitinib on clinical studies, 277 (34%) were 65 and
over. In the Phase 3 pNET study, 22 (27%) patients who received Sunitinib were 65 and over. No
Pharmacodynamics/Kinetics: overall differences in safety or effectiveness were observed between younger and older patients.
Maximum plasma concentrations (Cmax) of Sunitinib are generally observed between 6 and 12
hours (Tmax) following oral administration. Food has no effect on the bioavailability of Sunitinib. Hepatic Impairment
Sunitinib may be taken with or without food. Binding of Sunitinib and its primary active No dose adjustment to the starting dose is required when administering Sunitinib to patients
metabolite to human plasma protein in vitro was 95% and 90%, respectively, with no with Child-Pugh Class A or B hepatic impairment. Sunitinib and its primary metabolite are
concentration dependence in the range of 100 - 4000 ng/mL. The apparent volume of distribution primarily metabolized by the liver. Systemic exposures after a single dose of Sunitinib were similar
(Vd/F) for Sunitinib was 2230 L. In the dosing range of 25 - 100 mg, the area under the plasma in subjects with mild or moderate (Child-Pugh Class A and B) hepatic impairment compared to
concentration-time curve (AUC) and Cmax increase proportionately with dose. Sunitinib is subjects with normal hepatic function. Sunitinib was not studied in subjects with severe
metabolized primarily by the cytochrome P450 enzyme, CYP3A4 to produce its primary active (Child-Pugh Class C) hepatic impairment. Studies in cancer patients have excluded patients with
metabolite, which is further metabolized by CYP3A4. The primary active metabolite comprises 23 ALT or AST >2.5 x ULN or, if due to liver metastases, >5.0 x ULN.
to 37% of the total exposure. Elimination is primarily via feces. In a human mass balance study of
[14C] Sunitinib, 61% of the dose was eliminated in feces with renal elimination accounting for 16% Renal Impairment
of the administered dose. Sunitinib and its primary active metabolite were the major drug-related No adjustment to the starting dose is required when administering Sunitinib to patients with
compounds identified in plasma, urine and feces, representing 91.5%, 86.4% and 73.8% of mild, moderate, and severe renal impairment. Subsequent dose modifications should be based on
radioactivity in pooled samples respectively. Minor metabolites were identified in urine and feces safety and tolerability. In patients with end-stage renal disease (ESRD) on hemodialysis, no
but generally not found in plasma. Total oral clearance (CL/F) ranged from 34 to 62 L/hr with an adjustment to the starting dose is required. However, compared to subjects with normal renal
inter-patient variability of 40%. Following administration of a single oral dose in healthy function, the Sunitinib exposure is 47% lower in subjects with ESRD on hemodialysis.
volunteers, the terminal half-lives of Sunitinib and its primary active metabolite are approximately
40 to 60 hours and 80 to 110 hours respectively. With repeated daily administration, Sunitinib OVERDOSAGE
accumulates 3- to 4-fold while the primary metabolite accumulates 7- to 10-fold. Steady-state Treatment of overdose with Sunitinib should consist of general supportive measures. There is no
concentrations of Sunitinib and its primary active metabolite are achieved within 10 to 14 days. specific antidote for overdosage with Sunitinib. If indicated, elimination of unabsorbed drug
By Day 14, combined plasma concentrations of Sunitinib and its active metabolite ranged from should be achieved by emesis or gastric lavage. A few cases of accidental overdose have been
62.9 - 101 ng/mL. No significant changes in the pharmacokinetics of Sunitinib or the primary reported; these cases were associated with adverse reactions consistent with the known safety
active metabolite were observed with repeated daily administration or with repeated cycles in profile of Sunitinib or without adverse reactions. A case of intentional overdose involving the
the dosing regimens tested. ingestion of 1,500 mg of Sunitinib in an attempted suicide was reported without adverse
reaction. In non-clinical studies mortality was observed following as few as 5 daily doses of 500
Pharmacokinetics in Special Populations mg/kg (3000 mg/m2) in rats. At this dose, signs of toxicity included impaired muscle coordination,
Population pharmacokinetic analyses of demographic data indicate that there are no clinically head shakes, hypoactivity, ocular discharge, piloerection and gastrointestinal distress. Mortality
relevant effects of age, body weight, creatinine clearance, race, gender or ECOG score on the and similar signs of toxicity were observed at lower doses when administered for longer
pharmacokinetics of Sunitinib or the primary active metabolite. durations.
Pediatric Use: The pharmacokinetics of Sunitinib have not been evaluated in pediatric patients.
Renal Insufficiency: Sunitinib systemic exposure after a single dose of Sunitinib was similar in CONTRAINDICATIONS
subjects with severe renal impairment (CLcr<30 mL/min) compared to subjects with normal renal None
function (CLcr>80 mL/min). Although Sunitinib was not eliminated through hemodialysis, the
Sunitinib systemic exposure was 47% lower in subjects with ESRD on hemodialysis compared to PRECAUTIONS
subjects with normal renal function. Hepatotoxicity, including liver failure has been observed. Monitor liver function tests before
Hepatic Insufficiency: Systemic exposures after a single dose of Sunitinib were similar in subjects initiation of treatment during each cycle of treatment, and as clinically indicated. Sunitinib should
with mild exocrine (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment be interrupted for Grade 3 or 4 drug-related hepatic adverse events and discontinued if there is
compared to subjects with normal hepatic function. no resolution. Do not restart Sunitinib if patients subsequently experience severe changes in liver
function tests or have other signs and symptoms of liver failure. Women of childbearing potential
MECHANISM OF ACTION should be advised of the potential hazard to the fetus and to avoid becoming pregnant.
Sunitinib works by blocking multiple molecular targets implicated in the growth, proliferation Cardiac toxicity including left ventricular ejection fraction declines to below the lower limit of
and spread of cancer. Two important sunitinib targets, vascular endothelial growth factor receptor normal and cardiac failure including death have occurred. Monitor patients for signs and
(VEGFR) and platelet-derived growth factor receptor (PDGFR) are expressed by many types of symptoms of congestive heart failure.
solid tumors and are thought to play a crucial role in angiogenesis, the process by which tumors Prolonged QT intervals and Torsade de Pointes have been observed.
acquire blood vessels, oxygen and nutrients needed for growth. Sunitinib also inhibits other Use with caution in patients at higher risk for developing QT interval prolongation. When using
targets important to tumor growth including KIT, FLT3 and RET. Sunitinib, monitoring with on-treatment electrocardiograms and electrolytes should be
considered.
INDICATIONS Hypertension may occur. Monitor blood pressure and treat as needed.
Sunitix is a kinase inhibitor indicated for the treatment of: Hemorrhagic events including tumor-related hemorrhage have occurred.
 Gastrointestinal stromal tumor (GIST) after disease progression on orintolerance to Perform serial complete blood counts and physical examinations.
imatinib mesylate. Osteonecrosis of the jaw has been reported. Consider preventive
 Advanced renal cell carcinoma (RCC). dentistry prior to treatment with Sunitinib. If possible, avoid invasive
 Progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in patients dental procedures, particularly in patients receiving intravenous
with unresectable locally advanced or metastatic disease. bisphosphonate therapy.
Cases of Tumor Lysis Syndrome (TLS) have been reported primarily in patients with RCC and GIST
DOSAGE AND ADMINISTRATION with high tumor burden. Monitor these patients closely and treat as clinically indicated.
GIST and RCC: 50 mg orally once daily, with or without food, 4 weeks on treatment followed by 2 Thyroid dysfunction may occur. Patients with signs and/or symptoms suggestive of
weeks off. hypothyroidism or hyperthyroidism should have laboratory monitoring of thyroid function
pNET: 37.5 mg orally once daily, with or without food, continuously without a scheduled performed and be treated as per standard medical practice.
off-treatment period. Temporary interruption of therapy with Sunitinib is recommended in patients undergoing major
Dose Modification: Dose interruptions and/or dose adjustments of 12.5 mg recommended surgical procedures.
based on individual safety and tolerability. Adrenal hemorrhage was observed in animal studies. Monitor adrenal function in case of stress
such as surgery, trauma or severe infection.
USE IN SPECIFIC POPULATIONS
Pregnancy ADVERSE EFFECTS
Pregnancy Category D The most common adverse reactions (> _20%) are fatigue, asthenia, fever, diarrhea, nausea,
Sunitinib can cause fetal harm when administered to a pregnant woman. As angiogenesis is a mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral
critical component of embryonic and fetal development, inhibition of angiogenesis following edema, rash, hand-foot syndrome, skin discoloration, dry skin, hair color changes, altered taste,
administration of Sunitinib should be expected to result in adverse effects on pregnancy. In headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia and bleeding.
animal reproductive studies in rats and rabbits, Sunitinib was teratogenic, embryotoxic and
fetotoxic. There are no adequate and well-controlled studies of Sunitinib in pregnant women. If DRUG INTERACTIONS
this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the CYP3A4 Inhibitors: Consider dose reduction of Sunitinib when administered with strong CYP3A4
patient should be apprised of the potential hazard to a fetus. Women of childbearing potential inhibitors.
should be advised to avoid becoming pregnant while receiving treatment with sunitinib. CYP3A4 Inducers: Consider dose increase of Sunitinib when administered with CYP3A4 inducers.
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 PHARMACEUTICAL INFORMATION
and structural abnormalities were observed in rats at the dose of 5 mg/kg/day (approximately 5.5 Storage condition
times the systemic exposure [combined AUC of Sunitinib + primary active metabolite] in patients Store in a cool and dry place, away from light. Keep out of the reach of children.
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 Presentation & Packing
(approximately 0.3 times the AUC in patients administered the RDD of 50mg/day). Developmental Sunitix Capsule: Each commercial box contains 28 Capsules in a bottle.
effects consisted of fetal skeletal malformations of the ribs and vertebrae in rats. In rabbits, cleft Sunitix 12.5 Capsule: Each commercial box contains 28 Capsules in a bottle.
lip was observed at 1 mg/kg/day and cleft lip and cleft palate were observed at 5 mg/kg/day Sunitix 25 Capsule: Each commercial box contains 28 Capsules in a bottle.
(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). Sunitinib (0.3, 1.0, 3.0 mg/kg/day) was evaluated in a pre- and
postnatal development study in pregnant rats. Maternal body weight gains were reduced during
gestation and lactation at doses > _1 mg/kg/day but no maternal reproductive toxicity was
observed at doses up to > _3 mg/kg/day (approximately 2.3 times the AUC in patients administered For more info:
the RDD). At the high dose of 3 mg/kg/day, reduced body weights were observed at birth and
persisted for offspring of both sexes during the pre-weaning period and in males during
post-weaning period. No other developmental toxicity was observed at doses up to 3 mg/kg/day
(approximately 2.3 times the AUC in patients administered the RDD).
®
LF22001

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
Bhaluka, Mymensingh, Bangladesh
concentrations up to 12-fold higher than in plasma. It is not known whether this drug or its
primary active metabolite are excreted in human milk. Because many drugs are excreted in Only for Export