Sutent

Sunitinib malate.

SUTENT 12.5 mg: Each capsule contains sunitinib malate equivalent to 12.5 mg of sunitinib.
Excipients/Inactive Ingredients: Capsule content: Mannitol, Croscarmellose Sodium, Povidone, Magnesium Stearate.
Capsule shell: 12.5 mg: Gelatin, Titanium Dioxide, Red Iron Oxide.
Printing ink: Shellac, Dehydrafted Alcohol, Isopropyl Alcohol, Butyl Alcohol, Titanium Dioxide, Propylene Glycol, Sodium Hydroxide, Povidone.

Pharmacology: Pharmacodynamics: Sunitinib inhibits multiple receptor tyrosine kinases (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 (PDGFRα and PDGFRβ), VEGF 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 demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated 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 (PDGFRβ, 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 experimental models of cancer. Sunitinib demonstrated the ability to inhibit growth of tumor cells expressing dysregulated target RTKs (PDGFR, RET, or KIT) in vitro and to inhibit PDGFRβ- and VEGFR2-dependent tumor angiogenesis in vivo.
The clinical safety and efficacy of sunitinib has been studied 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 advanced renal cell carcinoma (RCC); 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-naïve and cytokine-refractory advanced RCC, respectively and on PFS for pNET.
Clinical studies: Gastrointestinal Stromal Tumor: Study 1: Study 1 (NCT#00075218) was a 2-arm, international, randomized, double-blind, placebo-controlled trial of SUTENT in patients with GIST who had disease progression during prior imatinib mesylate (imatinib) treatment or who were intolerant of imatinib. The objective was to compare time-to-tumor progression (TTP) in patients receiving SUTENT plus best supportive care versus patients receiving placebo plus best supportive care. Other objectives included progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Patients were randomized (2:1) to receive either 50 mg SUTENT or placebo orally, once daily, on Schedule 4/2 until disease progression or withdrawal from the study for another reason. Treatment was unblinded at the time of disease progression. Patients randomized to placebo were then offered crossover to open-label SUTENT and patients randomized to SUTENT were permitted to continue treatment per investigator judgment.
At the time of a prespecified interim analysis, the intent-to-treat (ITT) population included 312 patients. Two hundred seven (207) patients were randomized to the SUTENT arm and 105 patients were randomized to the placebo arm. Demographics were comparable between the SUTENT and placebo groups with regard to age (69% versus 72% <65 years for SUTENT versus placebo, respectively), gender (male: 64% versus 61%), race (White: 88% both arms, Asian: 5% both arms, Black: 4% both arms, remainder not reported), and performance status (ECOG 0: 44% versus 46%, ECOG 1: 55% versus 52%, and ECOG 2: 1 versus 2%). Prior treatment included surgery (94% versus 93%) and radiotherapy (8% versus 15%). Outcome of prior imatinib treatment was also comparable between arms with intolerance (4% versus 4%), progression within 6 months of starting treatment (17% versus 16%), or progression beyond 6 months (78% versus 80%) balanced.
The planned interim efficacy and safety analysis was performed after 149 TTP events had occurred. There was a statistically significant advantage for SUTENT over placebo in TTP, meeting the primary endpoint. Efficacy results are summarized in Table 1 and the Kaplan-Meier curve for TTP is shown in Figure 1. (See Table 1 and Figure 1.)

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Click on icon to see table/diagram/image

The final ITT population enrolled in the double-blind treatment phase of the study included 243 patients randomized to the SUTENT arm and 118 patients randomized to the placebo arm. After the primary endpoint was met at the interim analysis, the study was unblinded, and patients on the placebo arm were offered open-label SUTENT treatment. Ninety nine (99) of the patients initially randomized to placebo crossed over to receive SUTENT in the open-label treatment phase. At the protocol specified final analysis of OS, the median OS was 72.7 weeks for the SUTENT arm and 64.9 weeks for the placebo arm [hazard ratio (HR)=0.876, 95% confidence interval (CI) (0.679, 1.129)].
Study 2: Study 2 was an open-label, multi-center, single-arm, dose-escalation study conducted in patients with GIST following progression on or intolerance to imatinib. Following identification of the recommended regimen (50 mg once daily on Schedule 4/2), 55 patients in this study received the 50 mg dose of SUTENT on treatment Schedule 4/2. Partial responses (PR) were observed in 5 of 55 patients (9.1% PR rate, 95% CI 3.0%, 20.0%).
Renal Cell Carcinoma: Treatment-Naïve RCC: Study 3 (NCT#00083889) was a multi-center, international randomized study comparing single-agent SUTENT with IFN-α was conducted in patients with treatment-naïve RCC. The objective was to compare PFS in patients receiving SUTENT versus patients receiving IFN-α. Other endpoints included ORR, OS and safety. Seven hundred fifty (750) patients were randomized (1:1) to receive either 50 mg SUTENT once daily on Schedule 4/2 or to receive IFN-α administered subcutaneously at 9 million international units (MIU) 3 times a week. Patients were treated until disease progression or withdrawal from the study.
The ITT population included 750 patients, 375 randomized to SUTENT and 375 randomized to IFN-α. Demographics were comparable between the SUTENT and IFN-α groups with regard to age (59% versus 67% <65 years for SUTENT versus IFN-α, respectively), gender (Male: 71% versus 72%), race (White: 94% versus 91%, Asian: 2% versus 3%, Black: 1% versus 2%, remainder not reported), and performance status (ECOG 0: 62% versus 61%, ECOG 1: 38% each arm, ECOG 2: 0% versus 1%). Prior treatment included nephrectomy (91% versus 89%) and radiotherapy (14% each arm). The most common site of metastases present at screening was the lung (78% versus 80%, respectively), followed by the lymph nodes (58% versus 53%, respectively) and bone (30% each arm); the majority of the patients had multiple (2 or more) metastatic sites at baseline (80% versus 77%, respectively).
There was a statistically significant advantage for SUTENT over IFN-α in the endpoint of PFS (see Table 2 and Figure 2). In the prespecified stratification factors of lactate dehydrogenase (LDH) (>1.5 ULN versus ≤1.5 ULN), ECOG performance status (0 versus 1), and prior nephrectomy (yes versus no), the hazard ratio favored SUTENT over IFN-α. The ORR was higher in the SUTENT arm (see Table 2). (See Table 2 and Figure 2.)

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At the protocol-specified final analysis of OS, the median OS was 114.6 weeks for the SUTENT arm and 94.9 weeks for the IFN-α arm (HR=0.821, 95% CI: 0.673, 1.001). The median OS for the IFN-α arm includes 25 patients who discontinued IFN-α treatment because of disease progression and crossed over to treatment with SUTENT as well as 121 patients (32%) on the IFN-α arm who received post-study cancer treatment with SUTENT.
Cytokine-Refractory RCC: The use of single-agent SUTENT in the treatment of cytokine-refractory RCC was investigated in 2 single-arm, multi-center studies. All patients enrolled into these studies experienced failure of prior cytokine-based therapy. In Study 4 (NCT#00077974), failure of prior cytokine therapy was based on radiographic evidence of disease progression defined by response evaluation criteria in solid tumors (RECIST) or World Health Organization (WHO) criteria during or within 9 months of completion of 1 cytokine therapy treatment (IFN-α, interleukin-2, or IFN-α plus interleukin-2; patients who were treated with IFN-α alone must have received treatment for at least 28 days). In Study 5 (NCT#00054886), failure of prior cytokine therapy was defined as disease progression or unacceptable treatment-related toxicity. The endpoint for both studies was ORR. Duration of response (DR) was also evaluated.
One hundred and six patients (106) were enrolled into Study 4 and 63 patients were enrolled into Study 5. Patients received 50 mg SUTENT on Schedule 4/2. Therapy was continued until the patients met withdrawal criteria or had progressive disease. The baseline age, gender, race and ECOG performance statuses of the patients were comparable between Studies 4 and 5. Approximately 86%-94% of patients in the 2 studies were White. Men comprised 65% of the pooled population. The median age was 57 years and ranged from 24 to 87 years in the studies. All patients had an ECOG performance status <2 at the screening visit.
The baseline malignancy and prior treatment history of the patients were comparable between Studies 4 and 5. Across the 2 studies, 95% of the pooled population of patients had at least some component of clear-cell histology. All patients in Study 4 were required to have a histological clear-cell component. Most patients enrolled in the studies (97% of the pooled population) had undergone nephrectomy; prior nephrectomy was required for patients enrolled in Study 4. All patients had received 1 previous cytokine regimen. Metastatic disease present at the time of study entry included lung metastases in 81% of patients. Liver metastases were more common in Study 4 (27% versus 16% in Study 5) and bone metastases were more common in Study 5 (51% versus 25% in Study 4); 52% of patients in the pooled population had at least 3 metastatic sites. Patients with known brain metastases or leptomeningeal disease were excluded from both studies.
The ORR and DR data from Studies 4 and 5 are provided in Table 3. There were 36 PRs in Study 4 as assessed by a core radiology laboratory for an ORR of 34.0% (95% CI 25.0%, 43.8%). There were 23 PRs in Study 5 as assessed by the investigators for an ORR of 36.5% (95% CI 24.7%, 49.6%). The majority (>90%) of objective disease responses were observed during the first 4 cycles; the latest reported response was observed in Cycle 10. DR data from Study 4 is premature as only 9 of 36 patients (25%) responding to treatment had experienced disease progression or died at the time of the data cutoff. (See Table 3.)

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Pancreatic Neuroendocrine Tumors: Study 6 (NCT#00428597) was a multi-center, international, randomized, double-blind placebo-controlled study of single-agent SUTENT conducted in patients with unresectable pNET. Patients were required to have documented RECIST-defined disease progression within the prior 12 months and were randomized (1:1) to receive either 37.5 mg SUTENT (n=86) or placebo (n=85) once daily without a scheduled off-treatment period. The primary objective was to compare PFS in patients receiving SUTENT versus patients receiving placebo. Other endpoints included OS, ORR, and safety. Use of somatostatin analogs was allowed in the study.
Demographics were comparable between the SUTENT and placebo groups. Additionally, 49% of SUTENT patients had non-functioning tumors vs. 52% of placebo patients, and 92% patients in both arms had liver metastases. A total of 66% of SUTENT patients received prior systemic therapy compared with 72% of placebo patients and 35% of SUTENT patients had received somatostatin analogs compared with 38% of placebo patients. Patients were treated until disease progression or withdrawal from the study. Upon disease progression or study closure, patients were offered access to SUTENT in a separate extension study.
As recommended by the Independent Data Monitoring Committee, the study was terminated prematurely prior to the pre-specified interim analysis. This may have led to an overestimate of the magnitude of PFS effect. A clinically significant improvement for SUTENT over placebo in PFS was seen by both investigator and independent assessment. A hazard ratio favoring SUTENT was observed in all subgroups of baseline characteristics evaluated. OS data were not mature at the time of the analysis. There were 9 deaths in the SUTENT arm and 21 deaths in the placebo arm. A statistically significant difference in ORR favoring SUTENT over placebo was observed. Efficacy results are summarized in Table 4 and the Kaplan-Meier curve for PFS is in Figure 3. (See Table 4 and Figure 3.)

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Click on icon to see table/diagram/image

A phase 4 multinational, multi-centre, single-arm, open-label study evaluating the efficacy and safety of sunitinib was conducted in patients with progressive, advanced/metastatic, well-differentiated, unresectable pNET.
One hundred six patients (61 patients in the treatment-naïve cohort and 45 patients in the later-line cohort) received treatment with sunitinib orally at 37.5 mg once a day on a continuous daily dosing (CDD) schedule.
The investigator-assessed median PFS was 13.2 months, both in the overall population (95% CI: 10.9, 16.7) and in the treatment-naïve cohort (95% CI: 7.4, 16.8).
Pharmacokinetics: The pharmacokinetics of sunitinib and sunitinib malate were evaluated in 135 healthy volunteers and 266 subjects with solid tumors.
Absorption: Maximum plasma concentrations (C_max) are generally observed 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 - 4000 ng/mL. The apparent volume of distribution (Vd/F) for sunitinib was large (2230 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) 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.
In vitro studies indicate that sunitinib neither induces nor inhibits major CYP enzymes, including CYP3A4 (see Interactions).
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 comprises 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-oral 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 studied in subjects with severe (Child-Pugh Class C) hepatic impairment.
Renal Insufficiency: Population pharmacokinetic analyses have shown 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 investigated 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 showed a 5.6 msec maximum mean QTcF change from baseline. No subjects experienced an effect on the QTc interval greater than Grade 2 (CTCAE version 3.0). No patient presented with a cardiac arrhythmia (see Precautions).
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 observed 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: 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: Population pharmacokinetic analyses of demographic data indicate that no starting dose adjustments are necessary for weight or ECOG performance status.
Gender: Available 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 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, observed 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 genotoxic potential of sunitinib was assessed 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 observed 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 evaluated for genetic toxicity potential.
Carcinogenicity: 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 observed 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 observed 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 observed in the mouse (rasH2 transgenic) and rat carcinogenicity studies with sunitinib treatment is unclear.
Reproductive and developmental toxicity: No effects on fertility were observed in male rats dosed for 58 days prior to mating with untreated females. No reproductive effects were observed 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 performed in rats and monkeys, effects on female fertility were observed 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 conducted in rats, effects on male fertility were observed 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 observed 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 observed in clinic, and cleft lip 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 conducted as embryo-fetal effects were clearly demonstrated in the rat and reported in the preliminary study conducted in rabbits.

Gastrointestinal Stromal Tumor (GIST): SUTENT is indicated for the treatment of gastrointestinal stromal tumor after disease progression on or intolerance to imatinib mesylate.
Advanced Renal Cell Carcinoma (RCC): SUTENT is indicated for the treatment of advanced renal cell carcinoma.
Pancreatic Neuroendocrine Tumour (pNET): SUTENT is indicated for the treatment of unresectable or metastatic, well-differentiated pancreatic neuroendocrine tumours (pNET) with disease progression in adults.

Recommended Dose: For GIST and Advanced RCC, 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 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 Advanced RCC, 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 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 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 rifampin, should be avoided (see Interactions). 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 (see Interactions). 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, based on careful monitoring of tolerability.
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 established.
Use in the Elderly: Dose adjustments are not required in elderly patients. Approximately 34% of the subjects in clinical studies of sunitinib were 65 years of age or over. No significant differences in safety or efficacy were observed 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 studied in subjects with severe (Child-Pugh Class C) hepatic impairment (see Pharmacology: Pharmacodynamics: Clinical studies under Actions).
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 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 post-marketing experience, some of which were fatal, have included gastrointestinal (GI), respiratory, tumor, urinary tract and brain hemorrhages. In 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 observed in clinical trials and have been reported in post-marketing experience in patients treated with sunitinib for advanced RCC, GIST and metastatic non-small cell lung cancer (NSCLC). Sunitinib is not approved for use in patients with NSCLC.
Treatment-emergent bleeding events occurred in 18% of subjects receiving sunitinib in the double-blind treatment phase of GIST Study compared to 17% of subjects receiving placebo. In subjects receiving sunitinib for treatment-naïve advanced RCC, 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 advanced RCC, 26% experienced bleeding. Bleeding events, excluding epistaxis, occurred in 21.7% of subjects receiving sunitinib in the 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 occurred 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 clinical trials of sunitinib. Increases in serum lipase and amylase were observed 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 observed in patients treated with sunitinib. Cases of hepatic failure, some with a fatal outcome, were observed 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 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 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 ischemia and myocardial infarction, some of which were fatal, have been reported through post-marketing experience. Use sunitinib with caution in patients who are at risk for, or who have a history of, these events. In 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 advanced RCC subjects and 2% of placebo-treated subjects. These LVEF declines do not appear to have been progressive and often improved as treatment continued.
In the treatment-naïve advanced RCC 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 diagnosed with congestive heart failure (CHF).
Cardiac failure, cardiac failure congestive, or left ventricular failure were reported in 0.8% of subjects with solid tumors* and 1% of subjects treated with placebo. In the 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 ischemic attack, or pulmonary embolism within 12 months prior to sunitinib administration, were excluded from 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 shown to prolong the QTcF (Fridericia's correction) interval (see Pharmacology: Pharmacodynamics: Clinical studies under Actions). 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 observed 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 (see Dosage & Administration and Interactions).
Hypertension: Hypertension was a very common adverse reaction reported in clinical trials in subjects with solid tumors, including primarily GIST and cytokine-refractory RCC^†. 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-naïve advanced RCC compared to 3.6% of subjects receiving IFN-α. Severe hypertension occurred in 12% of treatment-naïve subjects on sunitinib and <1% of patients on IFN-α. Hypertension was reported in 26.5% of subjects receiving sunitinib in a 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.
^* From initial clinical trials including primarily patients with GIST and cytokine-refractory advanced RCC.
^† From initial clinical trials including primarily patients with GIST and cytokine-refractory advanced RCC. Aneurysms and Artery Dissections: The use of vascular endothelial growth factor (VEGF) pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating sunitinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.
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-naïve advanced RCC study and 3 subjects (<1%) in the IFN-α arm, and in 4% of subjects across the 2 cytokine-refractory advanced RCC studies. Additionally, thyroid stimulating hormone (TSH) elevations were reported in 2% of cytokine-refractory advanced RCC subjects. Overall, 7% of the cytokine-refractory advanced RCC population had either clinical or laboratory evidence of treatment-emergent hypothyroidism. In the 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 clinical studies of sunitinib, seizures have been observed 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 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 observed 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 observed 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 observed 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 continued sunitinib treatment in patients with moderate to severe proteinuria has not been systematically evaluated. Discontinue sunitinib in patients with nephrotic syndrome.
Hypoglycemia: Decreases 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 performed. Patients should be advised that they may experience dizziness during treatment with sunitinib.

Pregnancy: There are no studies in pregnant women using sunitinib.
Studies in animals have shown reproductive toxicity including fetal malformations (see Pharmacology: Pharmacokinetics under Actions). 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 childbearing 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 observed 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 observed during the pre-weaning and post-weaning periods at 3 mg/kg/day. No development toxicity was observed at 1 mg/kg/day (approximate exposure ≥0.9 times the AUC in patients administered the RDD).
Fertility: Based on non-clinical findings, male and female fertility may be compromised by treatment with sunitinib (see Pharmacology: Pharmacokinetics under Actions).
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 breastfeed while taking sunitinib.

Table 5 presents the adverse drug reactions (ADRs) by system organ class (SOC) from single-agent studies (N=7527) in advanced RCC, GIST, pNET of RCC, and from the post-marketing experience. A dataset that pooled the 12 single-agent studies in the marketed indications was used to calculate causality. ADRs are listed within each SOC by decreasing medical seriousness or clinical importance. (See Table 5.)

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ADR frequencies presented previously represent the frequencies of the events that occurred 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 (see Precautions).
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^* who experienced hemorrhagic events (see Precautions).
In clinical studies of sunitinib, seizures have been observed 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 Precautions).
Description of Selected Adverse Reactions: Infections and Infestations: Cases of serious infection (with or without neutropenia), in some cases with fatal outcome, have been reported. The infections observed 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, viral, or fungal. Rare cases of necrotizing fasciitis, including of the perineum, sometimes fatal, have been reported.
Blood and Lymphatic System Disorders: Rare 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.
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.
^*From initial clinical trials including primarily patients with GIST and cytokine-refractory advanced RCC.
Venous Thromboembolic Events (VTE): In the double-blind treatment phase of 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-naïve advanced RCC and 4 (2%) patients in the 2 cytokine-refractory advanced RCC 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 advanced RCC study experienced dose interruption. In treatment-naïve advanced RCC patients receiving IFN-α, 6 (2%) VTE occurred; 1 (<1%) patient experienced a Grade 3 DVT and 5 (1%) patients had pulmonary embolism, all Grade 4.
Pulmonary embolism was reported in approximately 2.2% of patients with solid tumors‡ 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.
^‡ From initial clinical trials including primarily patients with GIST and cytokine-refractory advanced RCC. 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.
Long-term Safety in RCC: The long-term safety of sunitinib in patients with metastatic RCC was analyzed across 9 completed clinical studies conducted in the first-line, bevacizumab-refractory and cytokine-refractory treatment settings. The analysis included 5739 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 (see Dosage & Administration).
Drugs 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 (see Dosage & Administration).

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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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