Pfizer Laboratories (Pty)ltd Page 1 of 27 SUTENT CAPSULES SCHEDULING STATUS: S4 PROPRIETARY NAME (and dosage form): SUTENT 12,5 mg Capsules SUTENT 25 mg Capsules SUTENT 50 mg Capsules COMPOSITION: Each capsule contains 12,5 mg, 25 mg or 50 mg of sunitinib (as malate). PHARMACOLOGICAL CLASSIFICATION: A 26 Cytostatic Agents PHARMACOLOGICAL ACTION: Pharmacodynamic properties Sunitinib malate is a small molecule that simultaneously inhibits multiple receptor tyrosine kinases (RTKs) that are implicated in tumour growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases (>80 kinases) and was identified as a potent inhibitor of platelet-derived growth factor receptors (PDGFRα and PDGFRβ), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3),
Pfizer Laboratories (Pty)ltd Page 2 of 27 stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Inhibition of the tyrosine kinase activity of these RTKs by sunitinib 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 malate demonstrated inhibition of activity of target RTKs (PDGFR, VEGFR2, KIT) in tumours in vivo and demonstrated the ability to inhibit tumour growth, cause tumour regression, and/or inhibit metastatic progression in a variety of rodent cancer models. Consistent with its multi-targeted profile, sunitinib malate demonstrated the ability to directly inhibit growth of tumour cells expressing dysregulated RTK targets (PDGFR, RET, or KIT) and to inhibit PDGFR - and VEGFR2-dependent tumour angiogenesis. Pharmacokinetic properties Absorption Sunitinib is absorbed after oral administration with maximum concentrations (C max ) generally observed from 6 12 hours (T max ) post-dose. Food has no effect on the bioavailability of sunitinib. Distribution Binding of sunitinib and its primary active metabolite to human plasma protein in in vitro assays was 95 % and 90 %, respectively, with no apparent concentration dependence.
Pfizer Laboratories (Pty)ltd Page 3 of 27 Biotransformation Sunitinib is metabolized primarily by CYP3A4, the cytochrome P450 enzyme, which produces its primary active metabolite, which is then further metabolized by CYP3A4. Elimination Excretion is primarily via faeces (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 faeces, representing 91.5 %, 86.4 % and 73.8 % of radioactivity in pooled samples, respectively. Minor metabolites were identified in urine and faeces, but generally were not found in plasma. Total oral clearance (CL/F) was 34-62 l/hr. Plasma Pharmacokinetics Following oral administration in healthy volunteers, the elimination half-lives of sunitinib and its primary active desethyl metabolite are approximately 40-60 hours, and 80-110 hours, respectively. In the dosing ranges of 25 to 100 mg, the area under the plasma concentration-time curve (AUC) and C max increase proportionally with dose. With repeated daily administration, sunitinib accumulates 3- to 4-fold and its primary metabolite accumulates 7- to 10-fold. Steady-state concentrations of sunitinib and its primary active metabolite are achieved within 10 to 14 days.
Pfizer Laboratories (Pty)ltd Page 4 of 27 By day 14, combined plasma concentrations of sunitinib and is 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 tumour stasis/growth reduction in vivo. The primary active metabolite comprises 23 to 37 % of the total exposure. No significant changes in the pharmacokinetics of sunitinib or the primary, active metabolite are observed with repeated daily administration or with repeated cycles in the dosing regimens tested. The pharmacokinetics were similar in all solid tumour populations tested and in healthy volunteers. Population pharmacokinetic analyses of demographic data indicate that no dose adjustments are necessary for weight, creatinine clearance, gender, race or ECOG score. INDICATIONS: SUTENT is indicated for the treatment of gastrointestinal stromal tumour (GIST) after failure of imatinib mesylate treatment due to resistance or intolerance. SUTENT is indicated for the treatment of treatment-naïve advanced and/or metastatic renal cell carcinoma. SUTENT is also indicated for the treatment of metastatic renal cell carcinoma (MRCC) after failure of cytokine-based therapy (interferon, interleukin-2). Efficacy is based on time to tumour progression and an increase in survival in GIST and on objective response rates for MRCC.
Pfizer Laboratories (Pty)ltd Page 5 of 27 Efficacy and safety has not been demonstrated for more than 12 months. CONTRA-INDICATIONS: Use of SUTENT is contra-indicated in patients with hypersensitivity to sunitinib malate or to any other constituent of SUTENT capsules. WARNINGS: QT Interval prolongation Torsade de pointes has been observed in <0.1 % of sunitinib-exposed patients. SUTENT should be used with caution in patients with a known history of QT interval prolongation, patients who are taking antidysrhythmics, or patients with relevant pre-existing cardiac disease, bradycardia, or electrolyte disturbances (see Special Precautions). Thyroid dysfunction Baseline laboratory measurement of thyroid function is recommended and patients with hypothyroidism or hyperthyroidism should be treated as per standard medical treatment prior to the start of SUTENT treatment. All patients should be observed closely for signs and symptoms of thyroid dysfunction on SUTENT 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 (see Special Precautions). INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION: When SUTENT is co-administered with other medications, there is a potential for medicine interaction.
Pfizer Laboratories (Pty)ltd Page 6 of 27 Medicines that may increase SUTENT plasma concentrations: Concurrent administration of SUTENT with the CYP3A4 inhibitor, ketoconazole, resulted in 59 % and 74 % increases in sunitinib C max and AUC 0- values, respectively, after a single dose of SUTENT in healthy volunteers. Administration of SUTENT with other inhibitors of the CYP3A4 family (e.g., itraconazole, erythromycin, clarithromycin) may increase SUTENT concentrations. Medicines that may decrease SUTENT plasma concentrations: Concomitant use of SUTENT with the CYP3A4 inducer, rifampin, resulted in a more than 56 % and 78 % reduction in sunitinib C max and AUC 0- values, respectively, after a single dose of SUTENT in healthy volunteers. Administration of SUTENT with other inducers of the CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, phenobarbital or Hypericum perforatum known also as St. John s Wort) may decrease SUTENT concentrations. To maintain SUTENT target concentrations, dose adjustment of SUTENT, or selection of comedications with less enzyme induction potential, should be considered. 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 SUTENT and its primary active metabolite are unlikely to have any clinically relevant drug-drug interactions with drugs that may be metabolized by these enzymes. PREGNANCY AND LACTATION: SUTENT use in pregnancy and lactation has not been established.
Pfizer Laboratories (Pty)ltd Page 7 of 27 DOSAGE AND DIRECTIONS FOR USE: Therapy should be initiated by a physician experienced in the treatment of renal cell carcinoma or GIST. The recommended dose of SUTENT is one 50 mg dose orally, taken daily for 4 consecutive weeks, followed by a 2-week rest period (Schedule 4/2) to comprise a complete cycle of 6 weeks. In patients receiving SUTENT with a potent CYP3A4 inducer such as rifampin, the dosage of SUTENT may need to be increased in 12.5 mg increments (up to 75 mg per day). Clinical response and tolerability should be carefully monitored. In patients receiving SUTENT with a CYP3A4 inhibitor such as ketoconazole, the doses of SUTENT may need to be reduced, based on tolerability and/or clinical response. Selection of an alternate concomitant medication with no, or minimal potential to induce or inhibit CYP34 should be considered. Dose modifications in 12.5 mg increments may be applied based on individual safety and tolerability. Daily doses should not exceed 75 mg nor be decreased below 25 mg. Population pharmacokinetic analyses of demographic data indicate that no dose adjustments are necessary for age, body weight, creatinine clearance, race, gender or ECOG (Eastern Cooperative Oncology Group) score.
Pfizer Laboratories (Pty)ltd Page 8 of 27 Paediatric use: The safety and efficacy of SUTENT in paediatric patients have not been established. Elderly patients use: No significant differences in safety or effectiveness were observed between younger and older patients. Hepatic Insufficiency: No dosage adjustment is necessary when administering sunitinib to patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. SUTENT was not studied in patients with severe (Child-Pugh Class B). Renal Insufficiency: No clinical studies have been performed in patients with impaired renal function. Studies excluded patients with serum creatinine > 2.0 x ULN. Population pharmacokinetic analyses have shown that SUTENT pharmacokinetics were unaltered in the range of renal function evaluated, as measured by creatinine clearance (42-347 ml/min). SUTENT 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.
Pfizer Laboratories (Pty)ltd Page 9 of 27 SIDE-EFFECTS AND SPECIAL PRECAUTIONS: Side-Effects: The most important treatment-related serious adverse events associated with SUTENT treatment of solid tumour patients were pulmonary embolism (1 %), thrombocytopenia (1 %), tumour haemorrhage (0.9 %), febrile neutropenia (0.4 %), and hypertension (0.4 %). The most common treatment-related adverse events (experienced by at least 20 % of the patients) of any grade included: fatigue; gastrointestinal, such as diarrhoea, nausea, stomatitis, dyspepsia and vomiting; skin discolouration; dysgeusia and anorexia. Fatigue, hypertension and neutropenia were the most common treatment-related adverse events of Grade 3 maximum severity and increased lipase was the most frequently occurring treatmentrelated adverse event of Grade 4 maximum severity in patients with solid tumours. Treatment related adverse reactions that were reported in >5 % of solid tumour patients are listed below, by system organ class, frequency and grade of severity. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Pfizer Laboratories (Pty)ltd Page 10 of 27 Table 1: Treatment-related adverse events reported in 5 % of GIST Patients GIST System Organ Class Blood and lymphatic system Endocrine Frequency Event All Grades Grade 3 Grade 4 Very Common Anaemia 33 (12.8%) 13 (5.1%) 1 (0.4%) Common Neutropenia 24 (9.3%) 15 (5.8%) 1 (0.4%) Thrombocytopenia 23 (8.9%) 6 (2.3%) 1 (0.4%) Common Hypothyroidism 15(5.8%) 0(0.0%) 1(0.4%) Metabolism and Very Common Anorexia 44 (17.1%) 1 (0.4%) 0 (0.0%) nutrition Nervous system Vascular Very Common Dysgeusia 48 (18.7%) 0 (0.0%) 0 (0.0%) Headache 27 (10.5%) 2 (0.8%) 0 (0.0%) Very Common Hypertension 43 (16.7%) 18 (7.0%) 0 (0.0%) Respiratory, Common Epistaxis 17 (6.6%) 0 (0.0%) 0 (0.0%) thoracic and mediastinal Renal and urinary Common Chromaturia 13 (5.1%) 0 (0.0%) 0 (0.0%)
Pfizer Laboratories (Pty)ltd Page 11 of 27 GIST System Organ Class Gastrointestinal Frequency Event All Grades Grade 3 Grade 4 Very Common Diarrhoea 90 (35.0%) 13 (5.1%) 0 (0.0%) Nausea 69 (26.8%) 2 (0.8%) 0 (0.0%) Stomatitis 49 (19.1%) 2 (0.8%) 0 (0.0%) Dyspepsia 32 (12.5%) 2 (0.8%) 0 (0.0%) Vomiting 46 (17.9%) 1 (0.4%) 0 (0.0%) Abdominal pain 30 (11.7%) 5 (1.9%) 1 (0.4%) Common Glossodynia 17 (6.6%) 0 (0.0%) 0 (0.0%) Constipation 13 (5.1%) 1 (0.4%) 0 (0.0%) Oral pain 16 (6.2%) 0 (0.0%) 0 (0.0%) Flatulence 15 (5.8%) 0 (0.0%) 0 (0.0%) Dry mouth 15 (5.8%) 0 0.0%) 0 (0.0%) 15 (5.8%) 0 (0.0%) 0 (0.0%) Gastrooesophageal reflux disease Skin and Very common Skin discolouration 65 (25.3%) 0 (0.0%) 0 (0.0%) subcutaneous tissue Palmar-plantar erythrodysaesthesia syndrome 55 (21.4%) 14 (5.4%) 0 (0.0%) Rash 39 (15.2%) 2 (0.8%) 0 (0.0%) Common Hair colour changes 22 (8.6%) 0 (0.0%) 0 (0.0%) Dry skin 15 (5.8%) 0 (0.0%) 0 (0.0%)
Pfizer Laboratories (Pty)ltd Page 12 of 27 GIST System Organ Class Musculoskeletal, connective tissue and bone Frequency Event All Grades Grade 3 Grade 4 Common Pain in extremity 21 (8.2%) 1 (0.4%) 0 (0.0%) Arthralgia 15 (5.8%) 2 (0.8%) 0 (0.0%) Myalgia 13 (5.1%) 0 (0.0%) 0 (0.0%) General Very common Fatigue/Asthenia 135 (52.5%) 25 (9.7%) 0 (0.0%) and administration Mucosal inflammation 30 (11.7%) 0 (0.0%) 0 (0.0%) site conditions Common Oedema 21 (8.2%) 1 (0.4%) 0 (0.0%) Investigations Common Haemoglobin 16 (6.2%) 2 (0.8%) 0 (0.0%) decreased Blood creatine 14 (5.4%) 0 (0.0%) 0 (0.0%) phosphokinase increase Ejection fraction 13 (5.1%) 1 (0.4%) 0 (0.0%) decreased Lipase increase 13 (5.1%) 5 (1.9%) 4 (1.6%) Platelet count 13 (5.1%) 2 (0.8%) 1 (0.4%) decreased Any adverse event 222 (86.4%) 88 (34.2%) 24 (9.3%)
Pfizer Laboratories (Pty)ltd Page 13 of 27 Table 2: Treatment-related adverse events reported in 5 % of Cytokine-refractory MRCC Patients Cytokine-refractory MRCC System Organ Class Blood and lymphatic system Frequency Event All Grades Grade 3 Grade 4 Very Common Neutropenia 17 (10.1%) 8 (4.7%) 1 (0.6%) Common Anaemia 16 (9.5%) 6 (3.6%) 0 (0.0%) Thrombocytopenia 15 (8.9%) 5 (3.0%) 2 (1.2%) Leukopenia 14 (8.3%) 7 (4.1%) 0 (0.0%) Eye Common Lacrimation 9 (5.3%) 0 (0.0%) 0 (0.0%) increased Metabolism and nutrition Nervous system Very common Anorexia 47 (27.8%) 1 (0.6%) 0 (0.0%) Common Dehydration 12 (7.1%) 4 (2.4%) 0 (0.0%) Decreased appetite 11 (6.5%) 0 (0.0%) 0 (0.0%) Very common Dysgeusia 71 (42%) 0 (0.0%) 0 (0.0%) Headache 25 (14.8%) 1 (0.6%) 0 (0.0%) Common Dizziness 13 (7.7%) 2 (1.2%) 0 (0.0%) Paraesthesia 9 (5.3%) 0 (0.0%) 0 (0.0%) Vascular Very common Hypertension 28 (16.6%) 7 (4.1%) 0 (0.0%) Respiratory, thoracic and Common Epistaxis 16 (9.5%) 0 (0.0%) 0 (0.0%) Dyspnoea 9 (5.3%) 0 (0.0%) 0 (0.0%) mediastinal
Pfizer Laboratories (Pty)ltd Page 14 of 27 Cytokine-refractory MRCC System Organ Class Gastrointestinal Skin and subcutaneous tissue Musculoskeletal, connective tissue and bone General and administration site conditions Frequency Event All Grades Grade 3 Grade 4 Very Common Diarrhoea 83 (49.1%) 5 (3.0%) 0 (0.0%) Nausea 84 (49.7%) 2 (1.2%) 0 (0.0%) Stomatitis 70 (41.4%) 6 (3.6%) 0 (0.0%) Dyspepsia 69 (40.8%) 1 (0.6%) 0 (0.0%) Vomiting 52 (30.8%) 2 (1.2%) 0 (0.0%) Constipation 34 (20.1%) 0 (0.0%) 0 (0.0%) Glossodynia 25 (14.8%) 0 (0.0%) 0 (0.0%) Abdominal pain 17 (10.1%) 2 (1.2%) 0 (0.0%) Common Flatulence 16 (9.5%) 0 (0.0%) 0 (0.0%) Abdominal 9 (5.3%) 0 (0.0%) 0 (0.0%) distension Dry mouth 9 (5.3%) 0 (0.0%) 0 (0.0%) Very common Skin discolouration 54 (32.0%) 0 (0.0%) 0 (0.0%) Rash 46 (27.2%) 0 (0.0%) 0 (0.0%) Hair colour changes 24 (14.2%) 0 (0.0%) 0 (0.0%) Dry skin 22 (13.0%) 0 (0.0%) 0 (0.0%) Palmar-plantar 21 (12.4%) 6 (3.6%) 0 (0.0%) erythrodysaesthesia Erythema 20 (11.8%) 0 (0.0%) 0 (0.0%) Common Alopecia 13 (7.7%) 0 (0.0%) 0 (0.0%) Dermatitis 10 (5.9%) 2 (1.2%) 0 (0.0%) exfoliative Periorbital oedema 9 (5.3%) 0 (0.0%) 0 (0.0%) Very common Pain in extremity 21 (12.4%) 1 (0.6%) 0 (0.0%) Common Myalgia 15 (8.9%) 1 (0.6%) 0 (0.0%) Very common Fatigue/ Asthenia 108 (63.9%) 19 (11.2%) 0 (0.0%) Mucosal inflammation 30 (17.8%) 1 (0.6%) 0 (0.0%)
Pfizer Laboratories (Pty)ltd Page 15 of 27 Cytokine-refractory MRCC System Organ Class Frequency Event All Grades Grade 3 Grade 4 Injury, poisoning, Very common Blister 13 (7.7%) 4 (2.4%) 0 (0.0%) and procedural complications Investigations Very common Lipase increased 17 (10.1%) 12 (7.1%) 3 (1.8%) Common Ejection fraction 16 (9.5%) 1 (0.6%) 0 (0.0%) abnormal Blood amylase 9 (5.3%) 6 (3.6%) 0 (0.0%) increased Weight decreases 11 (6.5%) 0 (0.0%) 0 (0.0%) WBC decreased 10 (5.9%) 3 (1.8%) 0 (0.0%) Platelet count 9 (5.3%) 3 (1.8%) 2 (1.2%) decreased Any adverse event 166 (98.2%) 77 (45.6%) 14 (8.3%) Table 3: Treatment-related adverse events reported in 5 % of patients with Treatment-naïve MRCC who received SUTENT or IFN-α System Organ Class Infections and infestations Blood and lymphatic system Treatment-naïve MRCC Sunitinib (n=375) IFN-α (n=360) Frequency Event All Grades Grade All Grade 3/4 Grades 3/4 Common Influenza 5 (1.3%) 0 28 0 (0.0%) (7.8%) (0.0%) Very common Thrombocytopenia 57 (15.2%) 25 25 9 (6.7%) (6.9%) (2.5%) Neutropenia 51 (13.6%) 25 25 9 (6.7%) (6.9%) (2.5%) Common Leukopenia 31 (8.3%) 8 13 3 (2.1%) (3.6%) (0.8%)
Pfizer Laboratories (Pty)ltd Page 16 of 27 System Organ Class Blood and lymphatic system Metabolism and nutrition Psychiatric Nervous system Vascular Respiratory, thoracic and mediastinal Frequency Event All Grades Treatment-naïve MRCC Sunitinib (n=375) IFN-α (n=360) Grade All Grade 3/4 Grades 3/4 Common Anaemia 25 (6.7%) 5 (1.3%) 28 (7.8%) Very common Anorexia 96 (25.6%) 4 (1.1%) 94 (26.1%) Common Decreased appetite 29 (7.7%) 0 (0%) 37 (10.3%) Dehydration 19 (5.1%) 5 11 (1.3%) (3.1%) Common Insomnia 15 (4.0%) 0 (0%) 18 (5.0%) Depression 10 (2.7%) 0 (0%) 28 (7.8%) Very common Dysgeusia 158 (42.1%) 0 (0%) 49 (13.6%) Headache 41 (10.9%) 2 50 (0.5%) (13.9%) Common Paraesthesia 19 (5.1%) 0 (0%) 3 (0.8%) Dizziness 18 (4.8%) 0 (0%) 25 (6.9%) Very common Hypertension 89 (23.7%) 31 4 (8.3%) (1.1%) Very common Epistaxis 44 (11.7%) 3 4 (0.8%) (1.1%) Common Dyspnoea 21 (5.6%) 4 27 (1.1%) (7.5%) Pharyngolaryngeal 19 (5.1%) 1 1 pain (0.3%) (0.3%) 4 (1.1%) 5 (1.4%) 1 (0%) 1 (0.3%) 0 (0%) 4 (1.1%) 0 (0%) 0 (0%) 0 (0%) 1 (0.3%) 1 (0.3%) 0 (0%) 4 (1.1%) 0 (0%)
Pfizer Laboratories (Pty)ltd Page 17 of 27 Treatment-naïve MRCC System Organ Class Gastrointestinal Sunitinib (n=375) IFN-α (n=360) Frequency Event All Grades Grade All Grade 3/4 Grades 3/4 Very common Diarrhoea 199 (53.1%) 18 45 0 (4.8%) (12.5%) (0.0%) Nausea 166 (44.3%) 12 120 4 (3.2%) (33.3%) (1.1%) Dyspepsia 96 (25.6%) 2 11 0 (0%) (0.5%) (3.1%) Stomatitis 94 (25.1%) 3 6 1 (0.8%) (1.7%) (0.3%) Vomiting 90 (24.0%) 13 36 2 (3.5%) (10.0%) (0.6%) Abdominal pain 45 (12.0%) 4 14 0 (0%) (1.1%) (3.9%) Dry mouth 40 (10.7%) 0 (0%) 23 1 (6.4%) (0.3%) Common Oral pain 35 (9.3%) 0 (0%) 1 0 (0%) (0.3%) Glossodynia 34 (9.1%) 0 (0%) 1 0 (0%) (0.3%) Flatulence 29 (7.7%) 0 (0%) 6 0 (0%) (1.7%) Constipation 29 (7.7%) 0 (0%) 13 0 (0%) (3.6%) Gastrooesophageal 28 (7.5%) 0 (0%) 2 0 (0%) reflux (0.6%) disease
Pfizer Laboratories (Pty)ltd Page 18 of 27 System Organ Class Skin and subcutaneous tissue Musculoskeletal and connective tissue General and administration site conditions Treatment-naïve MRCC Sunitinib (n=375) IFN-α (n=360) Frequency Event All Grades Grade All Grade 3/4 Grades 3/4 Very common Rash 85 (22.7%) 2 26 2 (0.5%) (7.3%) (0.6%) Palmar-plantar 76 (20.3%) 19 2 0 (0%) erythrodysaesthesia (5.1%) (0.6%) syndrome Dry skin 60 (16.0%) 1 17 0 (0%) (0.3%) (4.7%) Skin discolouration 58 (15.5%) 0 (0%) 0 (0%) 0 (0%) Hair colour changes 54 (14.4%) 0 (0%) 1 0 (0%) (0.3%) Common Alopecia 29 (7.7%) 0 (0%) 27 (7.5%) 0 (0%) Erythema 26 (6.9%) 1 (0.3%) Skin exfoliation 25 (6.7%) 1 (0.3%) Pruritus 21 (5.6%) 1 (0.3%) Very common Pain in extremity 42 (11.2%) 2 (0.5%) Common Arthralgia 33 (8.8%) 1 (0.3%) Myalgia 20 (5.3%) 1 (0.3%) Very common Fatigue 191 (50.9%) 27 (7.2%) Mucosal 75 (20.0%) 6 inflammation (1.6%) Asthenia 63 (16.8%) 17 (4.5%) 3 0 (0%) (0.8%) 3 0 (0%) (0.8%) 10 0 (0%) (2.8%) 11 0 (0%) (3.1%) 45 0 (0%) (12.5%) 56 1 (15.6%) (0.3%) 184 42 (51.1%) (11.7%) 4 1 (1.1%) (0.3%) 71 13 (19.7%) (3.6%)
Pfizer Laboratories (Pty)ltd Page 19 of 27 System Organ Class General and administration site conditions Treatment-naïve MRCC Sunitinib (n=375) IFN-α (n=360) Frequency Event All Grades Grade All Grade 3/4 Grades 3/4 Common Oedema 29 (7.7%) 0 (0%) 4 0 (0%) (1.1%) Pyrexia 27 (7.2%) 3 121 0 (0%) (0.8%) (33.6%) Chills 24 (6.4%) 2 103 0 (0%) (0.5%) (28.6%) Uncommon Influenza-like illness 2 (0.5%) 0 (0%) 25 (6.9%) 1 (0.3%) Investigations Very common Ejection fraction decreased 38 (10.1%) 8 (2.1%) 10 (2.8%) 2 (0.6%) Common Weight decreased 34 (9.1%) 0 (0%) 43 0 (0%) (11.9%) Platelet count 25 (6.7%) 9 3 0 (0%) decreased (2.4%) (0.8%) Any adverse event 357 (95.2%) 206 (54.9%) 329 (91.4%) 113 (31.4%)
Pfizer Laboratories (Pty)ltd Page 20 of 27 The following adverse events have been reported in SUTENT clinical trials: System Organ Class Frequency Adverse Events Cardiac Uncommon Cardiac failure, cardiac failure congestive, left ventricular failure Rare Prolonged QT interval, torsade de pointes Gastrointestinal Uncommon Pancreatitis Rare Gastrointestinal perforation Hepatobiliary Uncommon Hepatic failure Investigations Common Elevated thyroid stimulating hormone (TSH) Post-marketing experience: The following adverse events have been identified during postapproval use of SUTENT. Infection and infestations: Cases of serious infection (with or without neutropenia) in some cases with fatal outcome have been reported. Musculoskeletal and connective tissue : Cases of myopathy and/or rhabdomyolysis, some with acute renal failure 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. Blood and lymphatic system : Cases of thrombotic microangiopathy and haemolytic uraemic syndrome have been reported. Temporary suspension of SUTENT is recommended; following resolution, treatment may be resumed at the discretion of the treating physician.
Pfizer Laboratories (Pty)ltd Page 21 of 27 Renal and urinary : Cases of proteinuria and cases of nephrotic syndrome have been reported. Baseline urinalysis is reported, and patients should be monitored for the development or worsening of proteinuria. The safety of continued SUTENT treatment in patients with moderate to severe proteinuria has not been systematically evaluated. Discontinue patients with nephrotic syndrome. Special Precautions: In-vitro studies indicate that SUTENT neither induces nor inhibits major CYP enzymes, including CYP3A4. The dose of SUTENT may need to be reduced based on tolerability when co-administered with CYP3A4 inhibitors. The dose of SUTENT may need to be increased when it is co-administered with potent CYP3A4 inducers. Skin and tissues Skin discolouration due to drug colour (yellow) is a common treatment-related adverse event occurring in approximately 30 % of patients. Patients should be advised that depigmentation of the hair or skin may also occur during treatment with SUTENT. 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. Mouth pain/irritation was reported in approximately 14 % of patients. Dysgeusia (taste disturbance) was reported in approximately 28 % of patients. The above events were not cumulative, were typically reversible and generally did not result in treatment discontinuation.
Pfizer Laboratories (Pty)ltd Page 22 of 27 Gastrointestinal Events Nausea, diarrhoea, stomatitis, dyspepsia and vomiting were the most commonly reported treatment-related gastrointestinal events. Supportive care for gastrointestinal adverse events requiring treatment may include medication with an anti-emetic or anti-diarrhoeal medication. Gastrointestinal tract Serious, sometimes fatal gastrointestinal complications including gastrointestinal perforation have occurred in patients with intra-abdominal malignancies treated with SUTENT. Haemorrhage Treatment-related tumour haemorrhage occurred in approximately 2 % of patients with GIST. Tumour haemorrhage has not been observed in patients with MRCC or other solid tumours. Routine assessment of this event should include complete blood counts and physical examination. In patients receiving SUTENT for treatment-naïve MRCC, 28 % had bleeding events. Of patients receiving SUTENT for cytokine-refractory MRCC, 26 % experienced bleeding. Routine assessment of this event should include complete blood counts and physical examination. Treatment-related epistaxis was reported in 8 % of patients with solid tumours. Epistaxis was the most common treatment-related haemorrhagic adverse event, having been reported for approximately half of the patients with solid tumours who experienced haemorrhagic events. Hypertension Treatment-related hypertension was reported in approximately 16 % of patients with solid tumours. SUTENT dosing was reduced or temporarily delayed in approximately 2.7 % of this
Pfizer Laboratories (Pty)ltd Page 23 of 27 patient population. None of these patients were discontinued from treatment with SUTENT. Severe hypertension (>200 mmhg systolic or 110 mmhg diastolic) occurred in 4.7 % of this patient population. Patients should be screened for hypertension and controlled as appropriate. Treatment-related hypertension was reported in approximately 24 % of patients receiving SUTENT for treatment-naïve MRCC. Severe hypertension occurred in 5 % of treatment-naïve patients on SUTENT. 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. Haematological Decreased absolute neutrophil counts of Grade 3 and 4 severity were reported in 13.1 % and 0.9 % patients, respectively. Decreased platelet counts of Grade 3 and 4 severity were reported in 4 % and 0.5 % patients respectively. The above events were not cumulative, were typically reversible and generally did not result in treatment discontinuation. Complete blood counts should be performed at the beginning of each treatment cycle for patients receiving treatment with SUTENT. Cardiovascular Decreases in left ventricular ejection fraction (LVEF) of 20 % and below the lower limit of normal occurred in approximately 2 % of SUTENT-treated GIST patients and of 4 % MRCC patients and 2 % of placebo-treated patients. In the treatment-naïve MRCC STUDY, 21 % patients on SUTENT had an LVEF value below the lower limit of normal. One (<1 %) patient who received SUTENT was diagnosed with congestive heart failure.
Pfizer Laboratories (Pty)ltd Page 24 of 27 These LVEF declines do not appear to have been progressive and often improved as treatment continued. Treatment-related adverse events of cardiac failure, cardiac failure congestive or left ventricular failure were reported in 0.7 % of patients with solid tumours and 1% of patients treated with placebo. All patients had GIST. The relationship, if any, between receptor tyrosinase kinase (RTK) inhibition and cardiac function remains unclear. Data from non-clinical (in vitro and in vivo) studies, at doses higher than the recommended human dose, indicate that SUTENT has the potential to inhibit the cardiac action potential repolarization process (e.g. prolongation of QT interval). Increases in the QTc interval to over 500 msec occurred in 0.5 % and changes from baseline in excess of 60 msec occurred in 1.1 % of the 450 solid tumour patients; both these parameters are recognized as potentially significant changes. These observed changes in QT interval have not been associated with any adverse clinical events such as dysrhythmia. Pulmonary Embolism Treatment-related pulmonary embolism was reported in approximately 1.1 % patients with solid tumours who received SUTENT. None of these events resulted in a patient discontinuing treatment with SUTENT; 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. Pancreatic Function Increases in serum lipase and amylase were observed in patients with various solid tumours who received SUTENT. Increases in lipase levels were transient and were generally not accompanied by signs or symptoms of pancreatitis in subjects with various solid tumours. Pancreatitis was observed in 0.4 % of patients with solid tumours. Hepatic failure was observed in <1 % of solid tumour patients treated with SUTENT. If symptoms of pancreatitis or hepatic
Pfizer Laboratories (Pty)ltd Page 25 of 27 failure are present, patients should have proper medical follow-up. QT Interval Prolongation At approximately twice the therapeutic concentrations, SUTENT has been shown to prolong the QTcF (Fredericia s correction) interval. QT interval prolongation may lead to an increased risk for ventricular dysrhythmias including torsade de pointes. Thyroid Dysfunction Treatment-emergent acquired hypothyroidism was noted in 4 % of GIST patients. Hypothyroidism was reported as an adverse event in 2 % of patients on SUTENT in the treatment-naïve MRCC study. Overall 7 % of the cytokine-refractory MRCC population had either clinical or laboratory evidence of treatment-emergent hypothyroidism. Rare cases of hyperthyroidism, have been reported in clinical trials and through post-marketing surveillance. Venous Thromboembolic Events Seven patients (3 %) on SUTENT in a GIST study experienced venous thromboembolic events; five of the seven were Grade 3 deep vein thrombosis (DVT). Seven (2 %) patients receiving SUTENT for treatment-naïve MRCC had venous thrombolic events reported such as pulmonary embolism. 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 SUTENT.
Pfizer Laboratories (Pty)ltd Page 26 of 27 KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT: There is no experience of acute overdosage with SUTENT. There is no specific antidote for overdosage with SUTENT and treatment of overdose should consist of general supportive measures. If indicated, elimination of unabsorbed drug may be achieved by emesis or gastric lavage. IDENTIFICATION: SUTENT 12,5 mg Capsules: Hard gelatin capsules with orange cap and orange body, printed with white ink Pfizer on the cap, STN 12,5 mg on the body, containing yellow to orange granules. SUTENT 25 mg Capsules: Hard gelatin capsules with caramel cap and orange body, printed with white ink Pfizer on the cap, STN 25 mg on the body, containing yellow to orange granules. SUTENT 50 mg Capsules: Hard gelatin capsules with caramel cap and caramel body, printed with white ink Pfizer on the cap, STN 50 mg on the body, containing yellow to orange granules. PRESENTATION: Opaque blue-white high density polyethylene bottles with a white child resistant polypropylene closure and a heat induction seal liner containing 28 or 30 hard gelatine capsules. SUTENT capsules are available in blister strips of 28 capsules.
Pfizer Laboratories (Pty)ltd Page 27 of 27 STORAGE INSTRUCTIONS: Store at or below 30 ºC. Keep out of reach and sight of children. REGISTRATION NUMBERS: SUTENT 12,5 mg Capsules: 41/26/0197 SUTENT 25 mg Capsules: 41/26/0195 SUTENT 50 mg Capsules: 41/26/0196 NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE: Pfizer Laboratories (Pty) Ltd 85 Bute Lane Sandton 2196 South Africa DATE OF PUBLICATION OF THIS PACKAGE INSERT: 26 November 2010