Nibinase

NIBINASE 12.5: Hard gelatin capsule, size 4, with opaque reddish brown cap and opaque reddish brown body, self lock capsule, imprinted with 'RM53' on cap and 'RM53' on body in white ink, containing yellow to orange colored powder.
Each capsule contains Sunitinib Malate 16.706 mg equivalent to Sunitinib 12.5 mg.
NIBINASE 50: Hard gelatin capsule, size 1, with opaque caramel cap and opaque caramel body, self lock capsule, imprinted with 'RM56' on cap and 'RM56' on body in white ink, containing yellow to orange colored powder.
Each capsule contains Sunitinib Malate 66.825 mg equivalent to Sunitinib 50 mg.
Excipients/Inactive Ingredients: Mannitol, Croscarmellose sodium, Povidone (K 30), Magnesium stearate, Purified water, Hard gelatin capsule.

Pharmacology: Pharmacodynamics: Sunitinib inhibits multiple receptor tyrosine kinase (RTKs) that are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was identified as an inhibitor of platelet-derived growth factor receptors (PDGFR_α and PDGFR_β), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity of these RTKs has been reported in biochemical and cellular assays. And inhibition of function has been reported in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays.
Sunitinib inhibited the phosphorylation of multiple RTKs (PDGFR_β, VEGFR2, KIT) in tumor xenografts expressing RTK targets in vivo and demonstrated inhibition of tumor growth or tumor regression, and/or inhibited in metastases in some reported experimental models of cancer. Sunitinib reported to demonstrate the ability to inhibit growth of tumor cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFR_β, and VEGFR2-dependent tumor angiogenesis in vivo.
Reported clinical studies: The clinical safety and efficacy of sunitinib has been reported in subjects with malignant GIST who were resistant to imatinib (i.e., those who experienced disease progression during or following treatment with imatinib); or intolerant to imatinib (i.e., those who experienced significant toxicity during treatment with imatinib that precluded further treatment); in subjects with metastatic renal cell carcinoma (MRCC); the adjuvant treatment of patients at high risk of the recurrence of RCC following nephrectomy; and in subjects with unresectable pNET.
Efficacy is based on time to tumor progression and an increase in survival in GIST.
Efficacy is based on progression-free survival (PFS) and objective response rates (ORR) for treatment-naive and cytokine-refractory MRCC, respectively, and on PFS for pNET.
Pharmacokinetics: The pharmacokinetics of sunitinib and sunitinib malate were reported in 135 healthy volunteers and 266 subjects with solld tumors.
Absorption: Maximum plasma concentration (C_max) are generally reported between 6-12 hours (T_max) following oral administration. Food has no effect on the bioavailability of sunitinib.
Distribution: Binding of sunitinib and its primary active metabolite to human plasma protein in vitro was 95% and 90%, respectively, with no apparent concentration dependence in the range of 100-4,000 ng/mL. The apparent volume of distribution (Vd/F) for sunitinib was large (2,230 L), indicating distribution into the tissues. In the dosing range of 25-100 mg, the area under the plasma concentration-time curve (AUC) and C_max increased proportionately with dose.
Metabolism: The calculated in vitro Ki values for all CYP isoforms tested (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11) reported 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.
Reported in-vitro studies indicate that sunitinib neither induces nor inhibits major CYP enzymes, including CYP3A4.
Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4. The primary active metabolite comprise 23% to 37% of the total exposure.
Elimination: Excretion is primarily via feces (61%) with renal elimination of drug and metabolites accounting for 16% of the administered dose. Sunitinib and its primary active metabolite were the major drug-related compounds identified in plasma, urine and feces, representing 91.5%, 86.4%, and 73.8% of radioactivity in pooled samples, respectively. Minor metabolites were identified in urine and feces, but generally were not found in plasma. Total oral clearance (CL/F) ranged from 34-62 L/hr with an inter-patient variability of 40%. Following administration of a single dose in healthy volunteers, the terminal half-lives of sunitinib and its primary active desethyl metabolite were approximately 40-60 hours and 80-110 hours, respectively.
Pharmacokinetics in special patient groups: Hepatic Insufficiency: Sunitinib and its primary metabolite are mainly metabolized by the liver. Systemic exposures after a single dose of sunitinib were similar in subjects with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment compared to subjects with normal hepatic function. Sunitinib was not reported in subjects with severe (Child-Pugh Class C) hepatic impairment.
Renal Insufficiency: Population pharmacokinetic analyses have reported that sunitinib pharmacokinetics were unaltered in subjects with calculated creatinine clearances in the range of 42-347 mL/min. Systemic exposures after a single dose of sunitinib were similar in subjects with severe renal impairment (CL_cr <30 mL/min) compared to subjects with normal renal function (CL_cr >80 mL/min). Although sunitinib and its primary metabolite were not eliminated through hemodialysis in subjects with ESRD, the total systemic exposures were lower by 47% for sunitinib and 31% for its primary metabolite compared to subjects with normal renal function.
Cardiac Electrophysiology: QT interval prolongation was reported in a Phase 1 trial with 24 evaluable subjects, aged 20-87 years, with advanced malignancies. At therapeutic plasma concentrations, the maximum QTcF mean change from baseline was 9.6 msec (90% CI upper limit of 15.1 msec). At approximately twice the therapeutic concentrations, the maximum QTcF mean change from baseline was 15.4 msec (90% CI upper limit of 22.4 msec). Moxifloxacin (400 mg) used as a positive control reported a 5.6 msec maximum mean QTcF change from baseline. No subjects reported an effect on the QTc interval greater than Grade 2 (CTCAE version 3.0). No patient reported with a cardiac arrhythmia.
Plasma Pharmacokinetics: Following administration of a single oral dose in healthy volunteers, the elimination half-lives of sunitinib and its primary active metabolite are approximately 40-60 hours, and 80-110 hours, respectively. With repeated daily administration, sunitinib accumulates 3- to 4-fold while the primary active metabolite accumulates 7- to 10-fold. Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 to 14 days. By Day 14, combined plasma concentrations of sunitinib and its active metabolite are 62.9-101 ng/mL which are target concentrations predicted from preclinical data to inhibit receptor phosphorylation in vitro and result in tumor stasis/growth reduction in vivo. No significant changes in the pharmacokinetics of sunitinib or the primary, active metabolite were reported with repeated daily administration or with repeated cycles in the dosing regimens tested.
The pharmacokinetics were similar in all solid tumor populations tested and in healthy volunteers.
Population Pharmacokinetics: Reported population pharmacokinetic analyses of demographic data indicate that there are no clinically relevant effects of age, body weight, creatinine clearance, gender, race or ECOG score on the pharmacokinetics of sunitinib or the primary active metabolite.
Weight, performance status: Reported population pharmacokinetic analyses of demographic data indicate that no starting dose adjustments are necessary for weight or ECOG performance status.
Gender: Available reported data indicate that females could have about 30% lower apparent clearance (CL/F) of sunitinib than males: this difference, however, does not necessitate starting dose adjustments.
Toxicology: Preclinical safety data: In reported rat and monkey repeated dose toxicity studies up to 9-months duration, the primary target organ effects were identified in the gastrointestinal tract (emesis and diarrhea in monkeys); adrenal gland (cortical congestion and/or hemorrhage in rats and monkeys, with necrosis followed by fibrosis in rats); hemolymphopoietic system (bone marrow hypocellularity, and lymphoid depletion of thymus, spleen, and lymph node); exocrine pancreas (acinar cell degranulation with single-cell necrosis); salivary gland (acinar hypertrophy); bone joint (growth plate thickening); uterus (atrophy); and ovaries (decreased follicular development). All findings occurred at clinically relevant sunitinib plasma exposure levels. Additional effects, reported in other studies included: QTc interval prolongation, LVEF reduction, and testicular tubular atrophy, increased mesangial matrix in kidney, hemorrhage in GI tract and oral mucosa, and hypertrophy of anterior pituitary cells. Changes in the uterus (endometrial atrophy) and bone growth plate (physeal thickening or dysplasia of cartilage) are thought to be related to the pharmacological action of sunitinib. Most of these findings were reversible after 2 to 6 weeks without treatment.
Genotoxicity: The genotoxicity potential of sunitinib was reported in vitro and in vivo. Sunitinib was not mutagenic in bacteria using metabolic activation provided by rat liver. Sunitinib did not induce structural chromosome aberrations in human peripheral blood lymphocyte cells in vitro. Polyploidy (numerical chromosome aberrations) was reported in human peripheral blood lymphocytes in vitro, both in the presence and absence of metabolic activation. Sunitinib was not clastogenic in rat bone marrow in vivo. The major active metabolite was not reported for genetic toxicity potential.
Carcinogenicity: Although definitive carcinogenicity studies with sunitinib have not been reported, in a 1-month, oral gavage dose-range finding study (0, 10, 25, 75, or 200 mg/kg/day) with continuous daily dosing in rasH2 transgenic mice, carcinoma and hyperplasia of Brunner's glands of the duodenum were reported at the highest dose (200 mg/kg/day) tested.
A 6-month, oral gavage carcinogenicity study (0, 8, 25, or 75 [reduced to 50] mg/kg/day), with daily dosing was conducted in rasH2 transgenic mice. Gastroduodenal carcinomas, an increased incidence of background hemangiosarcomas, and/or gastric mucosal hyperplasia were reported at doses of ≥25 mg/kg/day following 1- or 6-months duration (≥7.3 times the AUC in subjects administered the RDD).
In a 2-year rat carcinogenicity study (0, 0.33, 1, or 3 mg/kg/day), administration of sunitinib in 28-day cycles followed by 7-day dose-free periods resulted in increases in the incidence of pheochromocytomas and hyperplasia in the adrenal medulla of male rats given 3 mg/kg/day following >1 year of dosing (≥7.8 times the AUC in subjects administered the RDD). Brunner's glands carcinoma occurred in the duodenum at ≥1 mg/kg/day in females and at 3 mg/kg/day in males, and mucous cell hyperplasia was evident in the glandular stomach at 3 mg/kg/day in males, which occurred at ≥0.9, 7.8 and 7.8 times the AUC in subjects administered the RDD, respectively. The relevance to humans of the neoplastic findings reported in the mouse (rasH2 transgenic) and rat carcinogenicity studies with sunitinib treatment is unclear.
Reproductive and developmental toxicity: No effects on fertility were reported in male rats doses for 58 days prior to mating with untreated females. No reproductive effects were reported in female rats treated for 14 days prior to mating with untreated males, at doses resulting in systemic exposures approximately 5 times the systemic exposure in humans. However, in repeated-dose toxicity studies reported in rats and monkeys, effects on female fertility were reported in the form of follicular atresia, degeneration of corpora lutea, endometrial changes in the uterus and decreased uterine and ovarian weights at clinically relevant systemic exposure levels. Moreover, in repeat-dose toxicity studies reported in rats, effects on male fertility were reported in the form of tubular atrophy in the testes, reduction of spermatozoa in epididymides and colloid depletion in prostate and seminal vesicles at plasma exposure levels 25 times the systemic exposure in humans. Not all the effects reported in male rats were reversible at the end of the recovery period (6 weeks).
In rats, treatment-related embryo-fetal mortality was evident as significant reductions in the number of live fetuses, increased numbers of resorptions (early and total), corresponding increased post-implantation loss, and total litter loss in 8 of 28 pregnant females at plasma exposure levels 5.5 times the systemic exposure in humans. In rabbits, reductions in gravid uterine weights and number of live fetuses were due to increases in the number of resorptions (early and total), increases in post-implantation loss, and complete litter loss in 4 of 6 pregnant females at plasma exposure levels 3 times the systemic exposure in humans.
Sunitinib treatment in rats during organogenesis resulted in developmental effects at ≥5 mg/kg/day consisting of increased incidence of fetal skeletal malformations, predominantly characterized as retarded ossification of thoracic/lumbar vertebrae. Developmental effects in rats occurred at plasma exposure levels 6 times the systemic exposure in humans. In rabbits, developmental effects consisted of increased incidence of cleft lip at plasma exposure levels approximately equal to that reported in clinic, and cleft palate at plasma exposure levels 2.7 times the systemic exposure in humans.
A definitive rabbit embryo-fetal development toxicity study was not reported as embryo-fetal effects were clearly demonstrated in the rat and reported in the preliminary study reported in rabbits.

Sunitinib is indicated for the treatment of gastrointestinal stromal tumor (GIST) after failure of imatinib mesylate treatment due to resistance or intolerance.
Sunitinib is indicated for the treatment of advanced and/or metastatic renal cell carcinoma (MRCC).
Sunitinib is indicated for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumors (pNET) with disease progression.
Sunitinib is indicated for the adjuvant treatment of adult patients at high risk of recurrent renal cell carcinoma (RCC) following nephrectomy.

For GIST and MRCC, the recommended dose of sunitinib is 50 mg taken orally once daily for 4 consecutive weeks, followed by a 2-week off period (Schedule 4/2) to comprise a complete cycle of 6 weeks.
For adjuvant treatment of RCC, the recommended dose of sunitinib is 50 mg taken orally once daily on Schedule 4/2 for nine 6-week cycles (approximately 1 year).
For pNET, the recommended dose of sunitinib is 37.5 mg taken orally once daily without a scheduled rest period.
Sunitinib may be taken with or without food.
If a dose is missed, the patient should not be given an additional dose. The patient should take the usual prescribed dose on the following day.
Dose modifications: Safety and Tolerability: For GIST and MRCC, dose modifications in 12.5 mg increments or decrements may be applied based on individual safety and tolerability up to 75 mg or down to 25 mg.
For adjuvant treatment of RCC, dose modification in 12.5 mg decrements may be applied, based on individual safety and tolerability, down to 37.5 mg. The maximum dose administered in the reported Phase 3 adjuvant RCC study was 50 mg daily.
For pNET, dose modification in 12.5 mg increments or decrements may be applied based on individual safety and tolerability. The maximum dose administered in the reported Phase 3 pNET study was 50 mg daily.
Dose interruptions may be required based on individual safety and tolerability.
CYP3A4 Inhibition/Induction: Co-administration of sunitinib with strong CYP3A4 inducers such as rifampicin, should be avoided. If this is not possible, the dose of sunitinib may need to be increased in 12.5 mg increments to a maximum of 87.5 mg (GIST and RCC) or 62.5 mg (pNET) daily, based on careful monitoring of tolerability.
Co-administration of sunitinib with strong CYP3A4 inhibitors, such as ketoconazole, should be avoided. If this is not possible, the dose of sunitinib may need to be reduced in 12.5 mg decrements to a minimum of 37.5 mg (GIST and RCC) or 25 mg (pNET) daily.
Selection of an alternate concomitant medication with no or minimal potential to induce or inhibit CYP3A4 is recommended.
Use in Pediatrics: The safety and efficacy of sunitinib in pediatric patients have not been reported.
Use in the Elderly: Dose adjustments are not required in elderly patients. Approximately 34% of the subjects in the reported clinical studies of sunitinib were 65 years of age or over. No significant differences in safety or efficacy were reported between younger and older patients.
Hepatic Insufficiency: No dose adjustment is necessary when administering sunitinib to patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. Sunitinib was not reported to study in subjects with severe (Child-Pugh Class C) hepatic impairment.
Renal Insufficiency: No starting dose adjustment is required when administering sunitinib to patients with renal impairment (mild-severe) or with end-stage renal disease (ESRD) on hemodialysis. Subsequent dose adjustments should be based on individual safety and tolerability.

There is no specific antidote for overdose with sunitinib and treatment of overdose should consist of general supportive measures. If indicated, elimination of unabsorbed drug may be achieved by emesis or gastric lavage. Cases of overdose have been reported; some cases were associated with adverse reactions consistent with the known safety profile of sunitinib.

Use of sunitinib is contraindicated in patients with hypersensitivity to sunitinib or to any of the excipients.

Skin and tissues: Skin discoloration, possibly due to the active substance color (yellow) was a very common adverse reaction reported in reported clinical trials. Patients should be advised that depigmentation of the hair or skin may also occur during treatment with sunitinib. Other possible dermatologic effects may include dryness, thickness or cracking of the skin, blisters or occasional rash on the palms of the hands and soles of the feet.
The previously mentioned events were not cumulative, were typically reversible and generally did not result in treatment discontinuation.
Severe cutaneous reactions have been reported, including cases of erythema multiforme (EM) and cases suggestive of Stevens-Johnson syndrome (SJS), some of which were fatal. If signs or symptoms of SJS or EM (e.g., progressive skin rash often with blisters or mucosal lesions) are present, sunitinib treatment should be discontinued. If the diagnosis of SJS is confirmed, treatment must not be re-started. In some cases of suspected EM, patients tolerated the reintroduction of sunitinib therapy at a lower dose after resolution of the reaction; some of these patients also received concomitant treatment with corticosteroids or antihistamines.
Hemorrhagic events: Hemorrhagic events reported through reported post-marketing experience, some of which were fatal, have included gastrointestinal (GI), respiratory, tumor, urinary tract and brain hemorrhages. In reported clinical trials, tumor hemorrhage occurred in approximately 2% of subjects with GIST. These events may occur suddenly, and in the case of pulmonary tumors, may present as severe and life-threatening hemoptysis or pulmonary hemorrhage. Cases of pulmonary hemorrhage, some with a fatal outcome, have been reported in clinical trials and have been reported in reported post-marketing experience in patients treated with sunitinib for MRCC, GIST and metastatic non-small cell lung cancer (NSCLC). Sunitinib is not approved for use in patients with NSCLC.
In the reported studies, treatment-emergent bleeding events occurred in 18% of subjects (37 out of 202 subjects) receiving sunitinib in the double-blind treatment phase of GIST study compared to 17% of subjects (17 out of 102 subjects) receiving placebo. In subjects receiving sunitinib for treatment-naive MRCC, 39% of patients had bleeding events compared with 11% of subjects receiving interferon-α (IFN-α). Seventeen (4.5%) subjects on sunitinib versus 5 (1.7%) of subjects on IFN-α experienced Grade 3 or greater bleeding events. Of subjects receiving sunitinib for cytokine-refractory MRCC, 26% experienced bleeding. In patients receiving sunitinib for adjuvant treatment of RCC, 30.7% of patients had bleeding events compared with 8.2% of patients receiving placebo. Bleeding events, excluding epistaxis, occurred in 21.7% of subjects receiving sunitinib in the reported phase 3 pNET study compared to 9.85% of subjects receiving placebo. Routine assessment of these events should include complete blood counts and physical examination.
Gastrointestinal tract: Serious, sometimes fatal GI complications including GI perforation, have reported in subjects with intra-abdominal malignancies treated with sunitinib.
Gastrointestinal events: Nausea, diarrhea, stomatitis, dyspepsia, and vomiting were the most commonly reported treatment-related GI events. Supportive care for GI adverse events requiring treatment may include anti-emetic or anti-diarrheal medication.
Pancreatitis: Pancreatitis has been reported in reported clinical trials of sunitinib. Increases in serum lipase and amylase were reported in subjects with various solid tumors who received sunitinib. Increases in lipase levels were transient and were generally not accompanied by signs or symptoms of pancreatitis in subjects with various solid tumors. If symptoms of pancreatitis are present, patients should have sunitinib discontinued and be provided with appropriate supportive care.
Hepatotoxicity: Hepatotoxicity has been reported in patients treated with sunitinib. Cases of hepatic failure, some with a fatal outcome, were reported in <1% of solid tumor patients treated with sunitinib. Monitor liver function tests (alanine transaminase [ALT], aspartate transaminase [AST], bilirubin levels) before initiation of treatment, during each cycle of treatment, and as clinically indicated. Sunitinib should be interrupted for Grade 3 or 4 hepatic-related adverse events and discontinued if there is no resolution.
Hematological: Decreased absolute neutrophil counts and decreased platelet counts were reported in reported clinical trials. Such events were not cumulative, were typically reversible and generally did not result in treatment discontinuation. In addition, some cases of fatal hemorrhage associated with thrombocytopenia were reported through reported post-marketing experience.
Complete blood counts should be performed at the beginning of each treatment cycle for patients receiving treatment with sunitinib.
Cardiovascular: Cardiovascular events, including heart failure, cardiomyopathy, myocardial ischaemia and myocardial infarction, some of which were fatal, have been reported through reported post-marketing experience. Use sunitinib with caution in patients who are at risk for, or who have a history of, these events. In reported clinical trials, decreases in left ventricular ejection fraction (LVEF) of ≥20% and below the lower limit of normal (LLN) occurred in approximately 2% of sunitinib-treated GIST subjects, 4% of cytokine-refractory MRCC subjects (7 out of 169 patients) and 2% of placebo-treated subjects (2 out of 102 patients). These LVEF declines do not appear to have been progressive and often improved as treatment continued.
In the reported treatment-naive MRCC study, 27% and 15% of subjects on sunitinib and IFN-α, respectively, had an LVEF value below the LLN. Two (<1%) subjects who received sunitinib were diagnoses with congestive heart failure (CHF).
In the reported adjuvant treatment of RCC study, all-causality ejection fraction decreased was reported for 1.3% of patients in the sunitinib arm and for 2.0% of patients in the placebo arm. No patients who received sunitinib were diagnosed with CHF.
Cardiac failure, cardiac failure congestive, or left ventricular failure were reported in 0.8% of subjects with solid tumors (reported from initial clinical trials including primarily patients with GIST and cytokine-refractory MRCC) and 1% of subjects treated with placebo. In the reported phase 3 pNET study, 1 (1.2%) subject who received sunitinib had treatment-related fatal cardiac failure.
Subjects who presented with cardiac events, such as myocardial infarction (including severe/unstable angina), coronary/peripheral artery bypass graft, symptomatic CHF cerebrovascular accident or transient ischaemic attack, or pulmonary embolism within 12 months prior to sunitinib administration, were excluded from reported sunitinib 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 sunitinib. Baseline and periodic evaluations of LVEF should also be considered while the patient is receiving sunitinib. In patients without cardiac risk factors, a baseline evaluation of ejection fraction should be considered.
In the presence of clinical manifestations of CHF, discontinuation of sunitinib is recommended. The dose of sunitinib should be interrupted and/or reduced in patients without clinical evidence of CHF but with an ejection fraction <50% and >20% below baseline.
QT interval prolongation: At approximately twice the therapeutic concentrations, sunitinib has been reported to prolong the QTF (Fridericia's correction) interval. There were no patients with greater than Grade 2 Common Terminology Criteria for Adverse Events version 3.0 (CTCAE) QT/QTc interval prolongation. QT interval prolongation may lead to an increased risk for ventricular arrhythmias including torsade de pointes. Torsade de pointes has been reported in <0.1% of sunitinib-exposed patients. Sunitinib should be used with caution in patients with a known history of QT interval prolongation, patients who are taking antiarrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances. Concomitant treatment with strong CYP3A4 inhibitors, which may increase sunitinib plasma concentrations, should be used with caution and the dose of sunitinib reduced.
Hypertension: Hypertension was a very common adverse reaction reported in clinical trials in subjects with solid tumors, including primarily GIST and cytokine-refractory RCC (reported from initial clinical trials including primarily patients with GIST and cytokine-refractory MRCC). Sunitinib dosing was reduced or temporarily delayed in approximately 2.7% of this patient population. None of these subjects were discontinued from treatment with sunitinib. Severe hypertension (>200 mmHg systolic or 110 mmHg diastolic) occurred in 4.7% of this patient population. Hypertension was reported in approximately 33.9% of subjects receiving sunitinib for treatment-naive MRCC compared to 3.6% of subjects receiving IFN-α. Severe hypertension occurred in 12% of treatment-naive subjects on sunitinib and <1% of patients on IFN-α. Hypertension was reported in 36.9% of patients receiving sunitinib and in 11.8% of patients on placebo in the reported adjuvant treatment of RCC study. Hypertension was reported in 26.5% of subjects receiving sunitinib in a reported phase 3 pNET study, compared to 4.9% of subjects receiving placebo. Severe hypertension occurred in 10% of pNET subjects on sunitinib and 3% of subjects on placebo. Patients should be screened for hypertension and controlled as appropriate. Temporary suspension is recommended in patients with severe hypertension that is not controlled with medical management. Treatment may be resumed once hypertension is appropriately controlled.
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 sunitinib treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction on sunitinib 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.
Acquired hypothyroidism was noted in 6.2% of GIST subjects on sunitinib versus 1% on placebo. Hypothyroidism was reported as an adverse event in 16% of subjects on sunitinib in the treatment-naive MRCC study and 3 subjects (<1%) in the IFN-α arm, and in 4% of subjects across the reported 2 cytokine-refractory MRCC studies. Additionally, thyroid stimulating hormone (TSH) elevations were reported in 2% of cytokine-refractory MRCC subjects. Overall, 7% of the cytokine-refractory MRCC population had either clinical or laboratory evidence of treatment-emergent hypothyroidism. In the adjuvant treatment of reported RCC study, hypothyroidism was reported as an adverse event in 18.0% of patients receiving sunitinib and in 1.3% of patients on placebo. In the reported phase 3 pNET study, hypothyroidism was reported in 6 (7.2%) subjects receiving sunitinib and in 1 (1.2%) subject on placebo.
Cases of hyperthyroidism, some followed by hypothyroidism, have been reported in clinical trials and through post-marketing experience.
Seizures: In reported clinical studies of sunitinib, seizures have been reported in subjects with radiological evidence of brain metastases. In addition, there have been rare (<1%) reports, some fatal, of subjects presenting with seizures and radiological evidence of reversible posterior leukoencephalopathy syndrome (RPLS). 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 sunitinib is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.
Surgical procedures: Cases of impaired wound healing have been reported during sunitinib therapy. Temporary interruption of sunitinib therapy is recommended for precautionary reasons in patients undergoing major surgical procedures. There is limited reported clinical experience regarding the timing of reinitiation of therapy following major surgical intervention. Therefore, the decision to resume sunitinib therapy following a major surgical intervention should be based upon clinical judgment of recovery from surgery.
Osteonecrosis of the Jaw (ONJ): ONJ has been uncommonly reported in clinical trials and has been reported in post-marketing experience in patients treated with sunitinib. The majority of cases occurred in patients who had received prior or concomitant treatment with intravenous (IV) bisphosphonates, for which ONJ is an identified risk. Caution should therefore be exercised when sunitinib and IV bisphosphonates are used either simultaneously or sequentially.
Invasive dental procedures are also an identified risk factor for ONJ. Prior to treatment with sunitinib, a dental examination and appropriate preventive dentistry should be considered. In patients being treated with sunitinib, who have previously received or are receiving IV bisphosphonates, invasive dental procedures should be avoided, if possible.
Tumor Lysis Syndrome (TLS): Cases of TLS, some fatal, have been rarely reported in clinical trials and have been reported in post-marketing experience in patients treated with sunitinib. Patients generally at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and treated as clinically indicated.
Necrotizing fasciitis: Rare cases of necrotizing fasciitis, including of the perineum, sometimes fatal, have been reported. Sunitinib therapy should be discontinued in patients who develop necrotizing fasciitis, and appropriate treatment should be promptly initiated.
Thrombotic microangiopathy: Thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS), sometimes leading to renal failure or a fatal outcome, has been reported in clinical trials and in post-marketing experience of sunitinib as monotherapy and in combination with bevacizumab. Discontinue sunitinib in patients developing TMA. Reversal of the effects of TMA has been reported after treatment discontinuation.
Proteinuria: Cases of proteinuria and nephrotic syndrome have been reported. Baseline urinalysis is recommended, and patients should be monitored for the development or worsening of proteinuria. The safety of continues sunitinib treatment in patients with moderate to severe proteinuria has not been systematically reported. Discontinue sunitinib in patients with nephrotic syndrome.
Hypoglycemia: Decreased in blood glucose, in some cases clinically symptomatic, have been reported during sunitinib treatment. Blood glucose levels in diabetic patients should be checked regularly in order to assess if anti-diabetic drug dosage needs to be adjusted to minimize the risk of hypoglycemia.
Effects on ability to drive and use machines: No studies on the effects on the ability to drive or operate machinery have been reported. Patients should be advised that they may experience dizziness during treatment with sunitinib.

Pregnancy: There are no reported studies in pregnant women using sunitinib.
Studies in animals have reported reproductive toxicity including fetal malformations. Sunitinib should not be used during pregnancy or in any woman not employing adequate contraception unless the potential benefit justifies the potential risk to the fetus. If sunitinib is used during pregnancy, or if the patient becomes pregnant while receiving sunitinib, the patient should be apprised of the potential hazard to the fetus. Women of child-bearing potential should be advised to avoid becoming pregnant while receiving treatment with sunitinib.
Sunitinib (0.3, 1.0, 3.0 mg/kg/day) was evaluated in a pre- and post-natal development study in pregnant rats. Maternal body weight gains were reduced during gestation and lactation at ≥1 mg/kg/day but no maternal reproductive toxicity was reported up to 3 mg/kg/day (estimate exposure ≥2.3 times the AUC in patients administered the recommended daily dose [RDD]). Reduced offspring body weights were reported during the pre-weaning and post-weaning periods at 3 mg/kg/day. No development toxicity was reported at 1 mg/kg/day (approximate exposure ≥0.9 times the AUC in patients administered the RDD).
Sunitinib did not cause genetic damage when tested in reported in vitro assays (bacterial mutation [AMES Assay], human lymphocyte chromosome aberration) and in vivo rat bone marrow micronucleus test.
Fertility: Based on reported non-clinical findings, male and female fertility may be compromised by treatment with sunitinib.
Lactation: Sunitinib and/or its metabolites are excreted in rat milk. 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, women should not breast-feed while taking sunitinib.

Adverse drug reaction (ADR) frequencies presented in this section represent the frequencies of the events that reported in sunitinib-treated subjects regardless of causality assessment.
The most important serious adverse reactions associated with sunitinib treatment of patients with solid tumors were pulmonary embolism, thrombocytopenia, tumor hemorrhage, febrile neutropenia, and hypertension.
The most common ADRs of any grade included: fatigue; gastrointestinal disorders, such as diarrhea, nausea, stomatitis, dyspepsia and vomiting skin discoloration; rash; palmar plantar erythrodysesthesia; dry skin; hair color changes; mucosal inflammation; asthenia; dysgeusia; anorexia and hypertension. Fatigue, hypertension and neutropenia were the most common ADRs of Grade 3 maximum severity and increased lipase was the most frequently occurring ADRs of Grade 4 maximum severity in subjects with solid tumors.
Epistaxis was the most frequent hemorrhagic ADR, having been reported for approximately half of the subjects with solid tumors (reported from initial clinical trials including primarily patients with GIST and cytokine-refractory MRCC) who experienced hemorrhagic events.
In reported clinical studies of sunitinib, seizures have been reported in subjects with radiological evidence of brain metastases. In addition, there have been reports (<1%), some fatal, of subjects presenting with seizures and radiological evidence of RPLS. (See Tables 1, 2, 3, 4, 5a and 5b.)

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Reported post-marketing experience: The ADRs that have been reported during post-marketing use of sunitinib from any source (clinical trials, spontaneous reports and other sources) are listed as follows. 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.
Infections and infestations: Cases of serious infection (with or without neutropenia), in some cases with fatal outcome, have been reported. The infections reported most commonly with sunitinib treatment are infections typically seen in cancer patients, e.g., respiratory infections (e.g., pneumonia, bronchitis), urinary tract infections, skin infections (e.g., cellulitis), sepsis/septic shock, and abscess (e.g., oral, genital, anorectal, skin, limb, visceral). Infections may be bacterial, or fungal. Rare cases of necrotizing fasciitis, including of the perineum, sometimes fatal, have been reported.
Investigations: TSH, and blood uric acid increase have been reported.
Blood and lymphatic system disorders: Cases of thrombotic microangiopathy, in some cases with fatal outcome, have been reported. Temporary suspension of sunitinib is recommended following resolution, treatment may be resumed at the discretion of the treating physician.
Immune system disorders: Hypersensitivity reactions, including angioedema, have been reported.
Endocrine disorders: Cases of hyperthyroidism, some followed by hypothyroidism, have been reported in reported clinical trials and through reported post-marketing experience. Cases of thyroiditis have been reported.
Metabolism and nutrition disorders: Cases of TLS, some fatal, have been reported in patients treated with sunitinib.
Decreases in blood glucose, in some cases clinically symptomatic, have been reported during sunitinib treatment.
Nervous system disorders: Taste disturbance, including ageusia, has been reported.
Cardiac disorders: Cardiac failure, cardiac failure congestive, prolonged QT interval, and Torsade de pointes. Cardiomyopathy, myocardial ischaemia, left ventricular, and myocardial infarction, in some cases with fatal outcome, have been reported.
Vascular disorders: Arterial thromboembolic events (ATE): Cases of arterial thromboembolic events (ATE), sometimes fatal, have been reported in patients treated with sunitinib. The most frequent events included cerebrovascular accident, transient ischaemic attack and cerebral infarction. Risk factors associated with ATE, in addition to the underlying malignant disease and age ≥65 years, included hypertension, diabetes mellitus, and prior thromboembolic disease.
Venous thromboembolic events (VTE): In the double-blind treatment phase of reported GIST study, 7 patients (3%) on sunitinib and none on placebo experienced VTE; 5 of the 7 were Grade 3 deep vein thrombosis (DVT), and 2 were Grade 1 or 2. Four of these 7 GIST patients discontinued treatment following first observation of DVT. Thirteen patients (3%) receiving sunitinib for treatment-naive MRCC and 4 (2%) patients in the 2 cytokine-refractory MRCC reported studies had VTE reported. Nine of these patients had pulmonary embolism: 1 was Grade 2 and 8 were Grade 4. Eight patients had DVT: 1 with Grade 1, 2 with Grade 2, 4 with Grade 3, and 1 with Grade 4. One patient with pulmonary embolism in the cytokine-refractory MRCC reported study experienced dose interruption. In treatment-naive MRCC subjects receiving IFN-α, 6 (2%) VTE reported; 1 (<1%) patient experienced a Grade 3 DVT and 5 (1%) patients had pulmonary embolism, all Grade 4. In the adjuvant treatment of reported RCC study, pulmonary embolism was reported in 2.0% of patients receiving sunitinib and 0.7% of patients receiving placebo. DVT was reported in 0.3% of patients receiving sunitinib and placebo.
Pulmonary embolism was reported in approximately 2.2% of patients with solid tumors (reported from initial clinical trials including primarily patients with GIST and cytokine-refractory MRCC) who received sunitinib. None of these events resulted in a patient discontinuing treatment with sunitinib; however, a dose reduction or temporary delay in treatment occurred in a few cases. There were no further occurrences of pulmonary embolism in these patients after treatment was resumed.
Hemorrhagic events: Cases of pulmonary, gastrointestinal, tumor, urinary tract, and brain hemorrhage, some fatal, have been reported in patients treated with sunitinib.
Hepatobiliary disorders: Hepatic failure and cholecystitis, particularly acalculous cholecystitis.
Respiratory, thoracic and mediastinal disorders: Pulmonary embolism, in some cases with fatal outcome, has been reported. Cases of pleural effusion have been reported.
Gastrointestinal disorders: Pancreatitis, gastrointestinal perforation, and esophagitis.
Skin and subcutaneous tissue disorders: Cases of pyoderma gangrenosum, erythema multiforme and Stevens-Johnson syndrome have been reported.
Musculoskeletal and connective tissue disorders: Rare cases of myopathy and/or rhabdomyolysis with or without acute renal failure, in some cases with fatal outcome, have been reported. Most of these patients had pre-existing risk factors and/or were receiving concomitant medications known to be associated with these adverse reactions. Patients with signs or symptoms of muscle toxicity should be managed as per standard medical practice.
Cases of fistula formation, sometimes associated with tumor necrosis and/or regression, in some cases with fatal outcome, have been reported.
Cases of ONJ have been reported in patients treated with sunitinib, most of which occurred in patients who had identified risk factors for ONJ, in particular exposure to IV bisphosphonates and/or a history of dental disease requiring invasive dental procedures.
Renal and urinary disorders: Cases of renal impairment and/or failure, in some cases with fatal outcome, have been reported. Cases of proteinuria and nephrotic syndrome have been reported.
Long-term safety in RCC: The long-term safety of sunitinib in patients with metastatic RCC was analyzed across 9 completed reported clinical studies conducted in the first-line, bevacizumab-refractory and cytokine-refractory treatment settings. The analysis included 5,739 patients, of whom 807 (14%) were treated for ≥2 years up to 6 years. Prolonged treatment with sunitinib was not associated with new types or increased severity of treatment-related adverse events and except for hypothyroidism, toxicity was not cumulative.

Drugs that may increase sunitinib plasma concentrations: Concomitant administration of sunitinib with the strong CYP3A4 inhibitor ketoconazole resulted in a 49% and 51% increase of the complex [sunitinib + primary active metabolite] C_max and AUC_0-∞ values, respectively, after a single dose of sunitinib in healthy volunteers.
Administration of sunitinib with strong inhibitors of the CYP3A4 family (e.g., ritonavir, itraconazole, erythromycin, clarithromycin, grapefruit juice) may increase sunitinib concentrations. Concomitant administration with inhibitors should therefore be avoided, or the selection of an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 should be considered, If this is not possible, the dosage of sunitinib may need to be reduced.
Drug that may decrease sunitinib plasma concentrations: Concomitant use of sunitinib with the CYP3A4 inducer rifampin resulted in a 23% and 46% reduction of the complex [sunitinib + primary active metabolite] C_max and AUC_0-∞ values, respectively, after a single dose of sunitinib in healthy volunteers.
Administration of sunitinib with strong inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, phenobarbital or Hypericum perforatum also known as St. John's wort) may decrease sunitinib concentrations. Concomitant administration with inducers should therefore be avoided, or selection of an alternate concomitant medication with no or minimal potential to induce CYP3A4 should be considered. If this is not possible, the dosage of sunitinib may need to be increased.

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Targeted Cancer Therapy

L01EX01 - sunitinib ; Belongs to the class of other protein kinase inhibitors. Used in the treatment of cancer.

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