ORION SUNITINIB

Sunitinib is a small-molecule multi-targeted receptor tyrosine kinase (RTK) inhibitor.

On January 26, 2006, the agent was formally approved by the US FDA for the indications of treating renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST).

For these purposes, sunitinib is generally available as an Oral administered formulation.

Sunitinib inhibits cellular signaling by targeting multiple RTKs.

These include all platelet-derived growth factor receptors (PDGF-R) and vascular endothelial growth factor receptors (VEGF-R).

Sunitinib also inhibits

KIT (CD117), the RTK that drives the majority of GISTs.

In addition, sunitinib inhibits other RTKs including RET, CSF-1R, and flt3.

Sunitinib is indicated for the following conditions: 3 Treatment of adult patients with gastrointestinal stromal tumor (GIST) following disease progression on (or intolerance to) imatinib mesylate Treatment of adult patients with advanced renal cell carcinoma (RCC) Adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy Treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic disease

Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA on January 26, 2006.

Platelet-derived growth factor receptor beta Inhibitor

Vascular endothelial growth factor receptor 1 Inhibitor Mast/stem cell growth factor receptor Kit Inhibitor + 5 more targets.

Maximum plasma concentrations (Cmax) of sunitinib are generally observed between and 12 hours (Tmax) following oral administration.

Food has no effect on the bioavailability of sunitinib.

Sunitinib may be taken with or without food.

The pharmacokinetics were similar in healthy volunteers and in the solid tumor patient populations tested, including patients with GIST and RCC.

L (apparent volume of distribution, Vd/F).

Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4.

Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4.

Elimination is primarily via feces.

In a human mass balance study of sunitinib, 61% of the dose was eliminated in feces, with renal elimination accounting for 16% of the administered dose.

Following administration of a single oral dose in healthy volunteers, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40-60 hours and 80-110 hours, respectively.

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The maximally tolerated dose for rat, mouse, and dog when given Oral is greater than 500 mg/kg. The maximally tolerated dose of a non-human primate is greater 1200 mg/kg.

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).

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. pNET: The recommended dosage is 37.5 mg orally once daily. 2.1 Recommended 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. 2.2 Recommended 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. 2.3 Recommended 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. 2.4 Dosage 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 Table 2.

Recommended Dosage Modifications for Sunitinib Malate Capsules for Adverse Reactions Adverse Reaction Severity Dosage Modifications for Sunitinib Malate Capsules Hepatotoxicity Grade 3 Withhold until resolution to Grade to 1 or baseline.

Resume at a reduced dose.

For recurring

Grade 3 permanently discontinue.

Grade 4 Permanently discontinue.

Cardiovascular events

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) Withhold until resolution to Grade to 1 or baseline.

Resume at reduced dose.

Clinically manifested congestive heart failure (CHF) Permanently discontinue.

Grade 3 Withhold until resolution to Grade to 1 or baseline.

Hemorrhagic events

Grade 3 or 4 Withhold until resolution to Grade to 1 or baseline.

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

Thrombotic microangiopathy Any Grade

Permanently discontinue.

Proteinuria or

Nephrotic syndrome 3 or more grams proteinuria in 24 hours in the absence of nephrotic syndrome Withhold until resolution to Grade to 1 or baseline.

Nephrotic syndrome or recurrent proteinuria of 3 or more grams per 24 hours despite dose reductions Permanently discontinue.

Dermatological toxicities

Erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), Necrotizing fasciitis Any Grade Permanently discontinue.

Reversible posterior leukoencephalopathy syndrome Any Grade Permanently discontinue.

Osteonecrosis of the jaw Any Grade 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.

Impaired wound healing Any Grade

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. 2.5 Dosage Modification for Drug Interactions Strong CYP3A4 Inhibitors 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: 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 Strong CYP3A4 Inducers 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. 2.6 Dosage 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.

Sunitinib malate capsules, 12.5 mg are supplied as yellow to orange-yellow granules filled in hard gelatin capsule with orange opaque cap and orange opaque body, imprinted with “STN” on the cap and “12.5 mg” on the body with white ink.

Bottles of 28 capsules: NDC 82293-014-10 Sunitinib malate capsules, 25 mg are supplied as yellow to orange-yellow granules filled in hard gelatin capsule with caramel opaque cap and orange opaque body, imprinted with “STN” on the cap and “25 mg” on the body with white ink.

Bottles of 28 capsules: NDC 82293-015-10 Sunitinib malate capsules, 37.5 mg are supplied as yellow to orange-yellow granules filled in hard gelatin capsule with yellow opaque cap and yellow opaque body, imprinted with “STN” on the cap and “37.5 mg” on the body with black ink.

Bottles of 28 capsules: NDC 82293-016-10 Sunitinib malate capsules, 50 mg are supplied as yellow to orange-yellow granules filled in hard gelatin capsule with caramel opaque cap and caramel opaque body, imprinted with “STN” on the cap and “50 mg” on the body with white ink.

Bottles of 28 capsules: NDC 82293-017-10 Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) .

Dispense in tight containers (USP).

Based on animal reproduction studies and its mechanism of action, sunitinib malate can cause fetal harm when administered to a pregnant woman.

There are no available data in pregnant women to inform a drug-associated risk.

In animal developmental and reproductive toxicology studies, oral administration of sunitinib to pregnant rats and rabbits throughout organogenesis resulted in teratogenicity (embryolethality, craniofacial and skeletal malformations) at 5.5 times and 0.3 times the combined AUC (the combined systemic exposure of sunitinib plus its active metabolite) in patients administered the recommended daily doses (RDD) of 50 mg, respectively.

Advise females of reproductive potential of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown.

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

In a female fertility and early embryonic development study, female rats were administered oral sunitinib (0.5 mg/kg/day, 1.5 mg/kg/day, 5 mg/kg/day) for 21 days prior to mating and for 7 days after mating.

Embryolethality was observed at 5 mg/kg/day (approximately 5 times the combined AUC in patients administered the RDD of 50 mg).

In embryo-fetal developmental toxicity studies, oral sunitinib was administered to pregnant rats (0.3 mg/kg/day, 1.5 mg/kg/day, 3 mg/kg/day, 5 mg/kg/day) and rabbits (0.5 mg/kg/day, 1 mg/kg/day, 5 mg/kg/day, 20 mg/kg/day) during the period of organogenesis.

In rats, embryolethality and skeletal malformations of the ribs and vertebrae were observed at the dose of 5 mg/kg/day (approximately 5.5 times the combined AUC in patients administered the RDD of 50 mg).

No adverse fetal effects were observed in rats at doses ≤3 mg/kg/day (approximately 2 times the combined AUC in patients administered the RDD of 50 mg).

In rabbits, embryolethality was observed at 5 mg/kg/day (approximately 3 times the combined AUC in patients administered the RDD of 50 mg), and craniofacial malformations (cleft lip and cleft palate) were observed at ≥1 mg/kg/day (approximately 0.3 times the combined AUC in patients administered the RDD of 50 mg).

Sunitinib (0.3 mg/kg/day, 1 mg/kg/day, 3 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 (approximately 0.5 times the combined AUC in patients administered the RDD of 50 mg).

At 3 mg/kg/day (approximately 2 times the combined AUC in patients administered the RDD of 50 mg), reduced neonate body weights were observed at birth and persisted in the offspring of both sexes during the preweaning period and in males during postweaning period.

No adverse developmental effects were observed at doses ≤1 mg/kg/day.

The safety and effectiveness of sunitinib malate in pediatric patients have not been established.

Safety and pharmacokinetics of sunitinib were assessed in an open-label study (NCT00387920) in pediatric patients 2 years to <17 years of age (n = 29) with refractory solid tumors.

In addition, efficacy, safety and pharmacokinetics of sunitinib was assessed in another open-label study (NCT01462695) in pediatric patients 2 years to <17 years of age (n = 27) with high-grade glioma or ependymoma.

The maximum tolerated dose (MTD) normalized for body surface area (BSA) was lower in pediatric patients compared to adults.

Sunitinib was poorly tolerated in pediatric patients.

The occurrence of dose-limiting cardiotoxicity prompted an amendment of the NCT00387920 study to exclude patients with previous exposure to anthracyclines or cardiac radiation.

No responses were reported in patients in either of the trials.

Apparent clearance and volume of distribution normalized for BSA for sunitinib and its active major metabolite were lower in pediatrics as compared to adults.

The effect on open tibial growth plates in pediatric patients who received sunitinib malate has not been adequately studied.

Data below.

Physeal dysplasia was present in cynomolgus monkeys with open growth plates treated with sunitinib for ≥3 months (3-month dosing 2 mg/kg/day, 6 mg/kg/day, 12 mg/kg/day; 8 cycles of dosing 0.3 mg/kg/day, 1.5 mg/kg/day, 6.0 mg/kg/day) at doses that were >0.4 times the combined AUC (the combined systemic exposure of sunitinib plus its active metabolite) in patients administered the RDD of 50 mg. The no-effect level (NOEL) was 1.5 mg/kg/day in monkeys treated intermittently for 8 cycles, but was not identified in monkeys treated continuously for 3 months.

In developing rats treated continuously for 3 months (1.5 mg/kg, 5.0 mg/kg, and 15.0 mg/kg) or 5 cycles (0.3 mg/kg/day, 1.5 mg/kg/day, 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 combined AUC in patients administered the RDD of 50 mg).

Additionally, tooth caries were present in rats at >5 mg/kg. The incidence and severity of physeal dysplasia were dose related and reversible upon cessation of treatment; however, findings in the teeth were not.

In rats, the NOEL in bones was ≤2 mg/kg/day.

Of the 7527 patients with GIST, RCC (advanced and adjuvant), or pNET who received sunitinib malate, 32% were 65 years and older, and 7% were 75 years and older.

Patients aged 65 years of age and older had a higher incidence of Grade 3 or 4 adverse reactions (67%) than younger patients (60%).

In the

GIST study, 73 (30%) of the patients who received sunitinib malate were 65 years and older.

In the mRCC study, 152 (41%) of patients who received sunitinib malate were 65 years and older.

No overall differences in safety or effectiveness were observed between these patients and younger patients.

In the pNET study, 22 (27%) of the patients who received sunitinib malate were 65 years and older.

Clinical studies of sunitinib malate did not include sufficient numbers of patients with pNET to determine if patients 65 years of age and older respond differently than younger patients.