Summary Basis of Decision for Sutent
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
Sutent
Sunitinib malate, 12.5 mg, 25 mg, 50 mg, Capsules, Oral
Pfizer Canada Inc.
Submission control no: 101319
Date issued: 2007-01-17
Health Products and Food Branch
Our mission is to help the people of Canada maintain and improve their health.
Health Canada
HPFB's Mandate is to take an integrated approach to the management of the risks and benefits to health related to health products and food by:
- Minimizing health risk factors to Canadians while maximizing the safety provided by the regulatory system for health products and food; and,
- Promoting conditions that enable Canadians to make healthy choices and providing information so that they can make informed decisions about their health.
Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrSUTENT*, Malate de sunitinab, 12,5 mg, 25 mg, 50 mg gélules, Pfizer Canada Inc., N° de contrôle de la présentation 101309.
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02280795 - 12.5 mg
- 02280809 - 25 mg
- 02280817 - 50 mg
Therapeutic Classification:
Non-medicinal ingredients:
The orange capsule shells contain gelatin, red iron oxide and titanium dioxide. The caramel capsule shells also contain black iron oxide and yellow iron oxide. The imprinting ink contains povidone, propylene glycol, shellac, sodium hydroxide and titanium dioxide.
Submission type and control no:
Date of Submission:
Date of authorization:
*TM C. P. Pharmaceuticals International C.V.
Pfizer Canada Inc., Licensee
2 Notice of decision
On May 26, 2006 , Health Canada issued a Notice of Compliance to Pfizer Canada Inc. for the drug product Sutent.
Sutent contains the medicinal ingredient sunitinib malate which is a tyrosine kinase inhibitor.
Sutent is indicated for the treatment of gastrointestinal stromal tumour (GIST) after failure of imatinib mesylate treatment due to resistance or intolerance. Sutent inhibits multiple receptor tyrosine kinases, some of which are implicated in tumour growth, pathologic angiogenesis, and metastatic progression of cancer.
Priority Review status was granted for the evaluation of Sutent. Sutent has shown a significant increase in efficacy such that the overall benefit/risk profile of Sutent represents an improvement over existing therapies. Currently, there is no effective treatment for GIST patients who are resistant or become intolerant to imatinib mesylate, the only effective non-surgical treatment for GIST authorized in Canada. GIST, a serious life-threatening disease, has a high recurrence rate after surgery.
The market authorization of Sutent was based on submitted data from quality control studies, preclinical, and clinical studies. Clinical safety and efficacy were studied in a Phase III pivotal trial (n=312) and a Phase I/II supportive trial (n=55). Sutent has demonstrated a statistically significant and clinically meaningful improvement over placebo in time-to-tumour progression. Sutent is generally well tolerated by the advanced GIST population, although there are some potentially serious side effects associated with its use. Warnings have been included in the Product Monograph to address the safety issues.
Sutent (12.5 mg, 25 mg, 50 mg sunitinib, as malate salt) is presented in capsule form. The recommended dose is one 50-mg oral dose taken once daily, on a schedule of 4 weeks on treatment followed by 2 weeks off. Dosing guidelines are available in the Product Monograph.
Sutent is contraindicated in patients with hypersensitivity to sunitinib malate or to any other component of Sutent. Sutent is also contraindicated in pregnant women. Sutent should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Sutent are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and effectiveness, Health Canada considers that the benefit/risk profile of Sutent is favourable for the treatment of GIST after failure of imatinib mesylate treatment due to resistance or intolerance.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
Manufacturing Process and Process Controls
Detailed manufacturing documents were provided. The drug substance, sunitinib malate, is synthetically derived from starting materials which have well characterized structures and well defined impurity profiles. The materials are considered suitable and meet standards appropriate for their intended use. The drug substance specifications are considered satisfactory.
The manufacturing process is considered to be adequately controlled within justified limits.
Characterisation
The structure is considered to be adequately elucidated. The drug substance is highly soluble over the physiological pH range and has two known polymorphic forms. The desired polymorph is more stable and is consistently produced by the commercial synthesis.
The drug substance exhibits geometric isomerism. The undesired isomer is controlled in the drug substance specifications as an impurity with a limit qualified by Health Canada's clinical division based on the clinical/toxicology studies listed in the submission.
Other impurities and degradation products arising from manufacturing and/or storage were also reported and characterized. The proposed limits are considered satisfactorily qualified; i.e., within the ICH guidelines and/or qualified from toxicological studies, and are therefore considered acceptable.
Control of Drug Substance
Copies of the analytical methods and where appropriate, validation reports were considered satisfactory for all analytical procedures used for release and stability testing of the drug substance.
Test results of the sunitinib malate batches were provided. Data from the batch analyses were reviewed and are within the proposed acceptance criteria.
The proposed packaging components are considered acceptable. The container/closure system for the drug substance is industry standard.
Stability
Based on the real-time and accelerated stability data submitted, the proposed re-test, storage, and shipping conditions for the drug substance were supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Sutent capsules are supplied as printed hard gelatin capsules containing sunitinib malate equivalent to 12.5 mg, 25 mg, or 50 mg of sunitinib together with mannitol, croscarmellose sodium, povidone (K-25) and magnesium stearate as inactive ingredients.
The three dosage forms are described below:
- 12.5 mg capsule: Hard gelatin capsule with an orange cap and orange body, printed with white ink "Pfizer" on the cap, "STN 12.5 mg" on the body.
- 25 mg capsule: Hard gelatin capsule with a caramel cap and orange body, printed with white ink "Pfizer" on the cap, "STN 25 mg" on the body.
- 50 mg capsule: Hard gelatin capsule with a caramel cap and caramel body, printed with white ink "Pfizer" on the cap, "STN 50 mg" on the body.
The orange capsule shells contain gelatin, titanium dioxide, and red iron oxide. The caramel capsule shells also contain yellow iron oxide and black iron oxide . The imprinting ink contains shellac, propylene glycol, sodium hydroxide, povidone and titanium dioxide.
All excipients found in Sutent are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of sunitinib malate with the excipients was demonstrated by the stability data presented with the proposed commercial formulation.
The capsules are packaged in high-density polyethylene (HDPE) bottles with polypropylene closures and heat induction seal liners. Each bottle contains 28 or 30 capsules.
Pharmaceutical Development
The discussion of the manufacturing process development is considered to be complete and acceptable. The proposed commercial synthetic route was used to make drug product lots for the clinical studies, including the pivotal clinical batch.
Manufacturing Process and Process Controls
The manufacturing process for Sutent uses standard pharmaceutical equipment and unit operations. A wet granulation process is used for the capsule granules which are milled to size and encapsulated.
All equipment, operating parameters, in-process tests and detailed instructions were adequately defined in the documentation. The manufacturing process is considered to be adequately controlled within justified limits, and capable of consistently producing capsules which meet the specification acceptance criteria.
Control of Drug Product
Sutent is tested to verify that its identity, appearance, assay, content uniformity, dissolution, and the levels of moisture, degradation products and impurities are within acceptable criteria. The test specifications and analytical methods are considered acceptable. The levels of related substances proposed by the sponsor are considered to be acceptable based on ICH recommendations and the clinical/toxicology data.
Where appropriate, validation reports for analytical procedures were provided. Validation data for analytical procedures are considered satisfactory for release and stability testing of the drug product.
Data from batch analyses were reviewed and are considered to be acceptable according to the specification of the drug product. Certificates of analysis were provided for all pivotal/clinical batches and for batches made at the proposed commercial site. The information provided is considered to be sufficient and acceptable.
Stability
Based upon the real-time and accelerated stability data submitted, the proposed shelf life of 24 months is considered acceptable when Sutent capsules are packaged in HDPE bottles with heat induction seals and stored at 25°C with excursions permitted between 15°C and 30°C.
3.1.3 Facilities and Equipment
The design, operations and controls of the facilities and equipment that are involved in the production are considered suitable for the products manufactured. The manufacturing sites were listed as being Good Manufacturing Practice compliant for their related activities.
3.1.4 Adventitious Agents Safety Evaluation
All excipients used in the sunitinib malate blend are of vegetable, mineral or synthetic origin and do not contain any material of bovine, ovine or caprine derivation.
The gelatin used in the capsules is derived from bovine bone. A Certificate of Suitability from the European Directorate for the Quality of Medicines was provided which certifies that the gelatin meets European Pharmacopoeiacriteria for products at risk for transmitting agents of animal spongiform encephalopathy.
3.1.5 Summary and Conclusion
The Chemistry and Manufacturing information submitted for Sutent demonstrated that the drug substance and drug product can be consistently manufactured to meet the specifications agreed upon. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Several in vitro and in vivo studies investigated the pharmacodynamic properties and safety profile of sunitinib. Primary pharmacology experiments were performed in both biochemical enzyme assays and cell assays to characterize sunitinib for 1) potency against receptor tyrosine kinases (RTKs) that are important in the regulation of tumour angiogenesis, platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor receptor (VEGFR), 2) selectivity against a series of other RTKs, tyrosine kinases and serine-threonine kinases, and 3) effects on cellular functions that are altered during cancer progression. Inhibition of the sunitinib RTK targets was also investigated in vivo using xenograft and vascular permeability models. Anti-tumour efficacy, as well as the mechanisms involved, was evaluated in various rodent models.
The pharmacology studies conducted demonstrated that sunitinib and its primary metabolite functionally inhibited VEGFR2, and PDGFRβ. Although low nanomolar kinase inhibition activity of VEGFR1 and VEGFR3 was also demonstrated, no assays were performed to evaluate the functional significance of inhibition of these RTKs in tumour models. Also, the inhibition of PDGFRα was only demonstrated via the low nanomolar IC 50 values, and supporting inhibition coefficients were not determined.
Comprehensive selectivity data analysis indicated that sunitinib was at least 50 to 100-fold selective for its target RTKs versus the majority of kinases evaluated. Biochemical kinase inhibition assays demonstrated that the inhibition of phosphorylase kinase (an enzyme involved in the glycogenolytic enzyme cascade for energy production in liver and muscle) by sunitinib had an affinity similar to its inhibition of the kinase activity of the target RTKs. Given the incidence of decreased left ventricular ejection fraction observed in clinical trials, the effect of sunitinib on this kinase may be relevant in cardiac muscle. However, the sponsor provided experiments that demonstrated that sunitinib did not inhibit phosphorylase kinase-dependent glycogenolysis in human liver cells over a 0.03-10 μM test range.
The ability of sunitinib to inhibit target RTK phosphorylation in tumour models, as well as the extent of vascular permeability in mouse xenografts was demonstrated, from which a minimum effective plasma concentration of sunitinib was estimated to be between 50-100 ng/mL.
Target RTK inhibition was linked to dose-dependent anti-tumour activity using several in vivo models, including human xenograft models, transgenic models of cancer and carcinogen-induced models. Several models of mouse metastasis were used to demonstrate that sunitinib may also inhibit the growth of established tumour metastases in bone, the formation of metastatic colonies in lung, and tumour-induced osteolysis (as determined by measuring collagen breakdown products).
A fully efficacious dose of 40 mg/kg/day was determined in dose-response studies using tumour xenograft models. Administration of 80 mg/kg/day of sunitinib provided little additional efficacy, whereas 20 mg/kg/day was not as effective in the inhibition of VEGFR2 and PDGFRβ or tumour growth as a dose of 40 mg/kg/day.
The anti-tumour efficacy of sunitinib is thought to be achieved primarily through the inhibition of angiogenesis via the binding of the critical VEGF and PDGF receptors involved in this process. The ability of sunitinib to inhibit tumour vascularization was evaluated histochemically by examining the extent of CD-31 positive microvessels in a variety of tumour xenograft models, as well as from human newborn foreskin grafted into collagen plugs and implanted into mice with severe combined immunodeficiency.
Sunitinib inhibited angiogenesis in these models, except for one cell line expressing PDGFRβ in which tumour growth was suppressed. Inhibition of tumour cell proliferation and the induction of apoptosis by sunitinib were also demonstrated in xenograft models, however these effects may have been a secondary to the inhibition of angiogenesis. Furthermore, demonstrated tumour growth and metastasis inhibition by sunitinib were not necessarily dependent on expression of target RTKs; direct binding of tumour RTKs by sunitinib therefore does not adequately account for these affects.
Secondary pharmacodynamic effects of sunitinib were evaluated to determine biochemical and/or cellular effects of binding to 69 standard receptors, enzymes or ion channels. Sunitinib inhibited several secondary targets, the most significant of which was the human serotonin 5-HT 2A and the α 1B-adrenergic receptors. Although the inhibition of off-target receptors was deemed unlikely to be clinically relevant, this possibility cannot be ruled out due to the higher drug concentrations in tissues than in blood.
Safety studies were conducted to evaluate the effects of sunitinib on the cardiovascular, respiratory and central nervous system in animals. No formal safety studies were performed to evaluate the functional effects of sunitinib on renal/urinary, autonomic, gastrointestinal or other organ systems. Sunitinib produced a concentration-dependent inhibition of hERG potassium currents with an IC 50 value of 144 nM. The combination of the predicted total bound plasma concentration of sunitinib (Cmax) in humans (approximately 400 nM), along with the effects of sunitinib on hERG channel inhibition, action potential duration and QTc prolongation, makes the use of sunitinib a potential high risk for cardiac arrythmias in clinical studies. This risk is increased by the fact that test-compound concentrations were higher in nearly every rat tissue than in blood plasma (cardiac tissue was not examined in the monkey tissue distribution study). Studies in monkey to evaluate the effects of sunitinib on the central nervous system showed no effect on general behavior or body temperature up to a dose of 500 mg/kg. No effect on respiratory function was evident upon administration of sunitinib up to 500 mg/kg.
3.2.2 Pharmacokinetics
Absorption
Sunitinib demonstrated moderate to high systemic clearance upon intravenous administration in mice, rats, dogs and monkeys. The moderate clearance of sunitinib in monkeys was lower than the other species examined. Sunitinib was slowly absorbed in monkeys. Food, formulation and drug forms did not influence drug exposure parameters (Cmax and AUC) of monkeys. The half-life was 1 hour in mice, 2-5 hours in rats, 6 hours in dogs, and 14.9 hours in monkeys. Only rats demonstrated non-linear kinetics, and female rats had a higher systemic exposure to sunitinib compared to male rats. In repeat-dose studies, steady state systemic exposure of sunitinib was attained by day 28 or by the end of the first 28-day cycle. The AUC levels at steady state were generally less than 4 times higher than that on day 1.
Distribution
The fraction of sunitinib bound to plasma proteins was high, and independent of drug concentrations used. Approximate values of protein binding were 98% in rats, 95% in humans, and 91% in mice. Sunitinib was widely distributed into the tissues of the rat and the monkey, including a rapid uptake and clearance into/from the central nervous system. In rats, most tissues had drug levels 1.3-70 times higher than that in the blood, with the exception of brain, spinal cord and white fat. After 168 hours, only the adrenal gland, kidney, pituitary, skin and testis had measurable concentrations of the administered compound. Consistent with melanin-associated binding, the concentration of radio-labelled drug in pigmented tissues (eye, uveal tract, and skin) increased over the course of the study (50-896 fold higher than blood concentrations at 24 hours). In monkeys, studies showed a 13-308 fold higher concentration of radiolabelled compound in the adrenal glands, bone marrow, pancreas, kidney, liver, and brown fat compared to that in blood.
The concentration in white fat and the brain were 2-14 and 1-3 fold higher than that in blood plasma. The data suggest that steady state concentrations of sunitinib and its major metabolite (SU012662) were reached within the first 4 weeks of dosing, were widely distributed into tissues, and had steady state tissue concentrations generally much higher than that in the plasma.
Metabolism
Sunitinib was extensively metabolized by the liver in mice, rats, monkeys and humans. The primary metabolite in human was the N-deethylated form, SU012662. Minor metabolites were seen but were not identified. CYP3A4 was the primary cytochrome P450 enzyme responsible for the deethylation of sunitinib.
Excretion
Sunitinib and its metabolites were mainly excreted in the faeces.
Drug Interactions
Studies indicate that sunitinib has low potential to cause clinically relevant drug-drug interactions with other co-administered drugs that are metabolized by CYP450 enzymes. Sunitinib and SU012662 incubated with human liver microsomes did not inhibit CYP450 enzymes (with the exception of CYP1A2) to a degree that was clinically relevant. The clinical risk for drug interactions due to the inhibition of CYP1A2 activity is considered low due to the fact that CYP1A2 plays a relatively minor role in metabolism and other overlapping enzyme systems may compensate for any loss in CYP1A2 activity.
3.2.3 Toxicology
Acute Toxicity
Acute single-dose oral toxicity studies in rats, mice, and dogs resulted in a Maximum Tolerated Dose level (MTD) at doses greater than the tested maximum dose in all species (500 mg/kg), and greater than 1200 mg/kg in monkey (emesis in monkey was observed at doses ≥50mg/kg).
Long-Term Toxicity
Toxicologic findings were evaluated from pivotal chronic studies of repeat sunitinib administration in rats and monkeys, with dosing from 2 weeks to 6 months in rats and 9 months in monkeys. Yellow staining of the fur, skin, and urine was observed in rats administered repeat high-doses of the compound and can be attributed to the yellow colour of sunitinib and its metabolite(s). At high doses, yellow discoloration of the skin and gums, as well as skin pallor were observed in monkeys. Animals receiving high doses appeared hypoactive and displayed various symptoms of gastrointestinal toxicity (diarrhea/watery stool, emesis, dehydration). Degranulation of pancreatic acini was observed in monkeys treated with higher doses of sunitinib for 6-9 months, and at doses ≥2 mg/kg/day during the 13-week study. Acinar hypertrophy of the salivary glands was noted in rats and monkeys.
Adrenal cortical haemorrhage and enlarged/discoloured adrenal glands of increased weight were observed in monkeys and rats. Decreases in thymus, spleen, ovary and uterine weights were also observed. The clearance time for the radiolabelled compound administered to monkeys and rats was also much longer in the adrenal gland compared to that of other tissues. Marked increases in alanine aminotransferase/aspartate aminotransferase , creatine kinase , and occasionally gamma glutamyl transferase and total bilirubin were observed in both monkey and rat administered the high dose compound for 9 or 6 months respectively. An alkaline phosphatase decrease in monkeys and lipase increase in rats were also observed in these studies.
Hypocellularity of bone marrow, erythroid, and myeloid cells in both rats and monkeys was observed. Investigative studies in rats suggest that sunitinib decreases bone marrow cell counts predominantly in erythroid lineage. Slight decreases in red blood cell count, hemoglobin , hematocrit, and reticulocyte indices were observed in high dose monkeys treated for 9 months.
Growth plate thickening (physeal dysplasia) was observed in both rats and monkeys treated with sunitinib. Sunitinib may contribute to the observed physeal dysplasia by inhibiting the osteolytic process in bone marrow, thereby shifting the normal balance between osteoclast and osteoblast activity resulting in abnormal bone growth.
Reproductive Toxicity
The reproductive toxicity of sunitinib treatment was evaluated based on two definitive rat studies, where embryo-fetal lethality, increased post-implantation loss, live fetal body weight decrease and incidence of fetal skeletal malformations were identified. Male reproductive effects, as assessed by copulation, fertility and conception indices were not observed at any dose level. Sperm morphology, concentration, and motility were unaffected by treatment. Decreases in ovarian and uterine weights in monkeys and some rats, as well as vaginal atrophy in monkeys did not reverse by the conclusion of the recovery periods. No reproductive effects were seen in males.
A limited reproductive and developmental program was conducted as the proposed indication for Sutent is targeted for a patient population with life-threatening disease and relatively short life expectancy. Further reproductive studies may be required for future alternative indications.
Mutagenicity
Sunitinib was not genotoxic, as assessed by the bacterial reverse mutation test (Ames test), and was shown to be negative for inducing chromosomal aberrations in cultured human peripheral lymphocytes. Sunitinib is not considered to be clastogenic in vivo, as micronuclei in bone marrow polychromatic erythrocytes were not induced in rats treated with sunitinib up to 1500 mg/kg.
Carcinogenicity
Carcinogenicity studies were not conducted with sunitinib.
3.2.4 Summary and Conclusion
Sunitinib has been shown to target and block the signalling pathways of multiple selected receptor tyrosine kineases (RTKs), as well as to inhibit the kinase activity of phosphorylase kinase (an enzyme involved in glycogen breakdown) with an affinity similar to its inhibition of target RTKs. Although the effect of Sutent on phosphorylase kinase in cardiac muscle was not determined, it may be of particular relevance given that a potential for QT interval prolongation was detected in vitro and in vivo in non-clinical studies . However , considering the proposed indication and the context of the disease, this issue is acceptable with appropriate warnings in the labelling and Product Monograph.
Adrenal toxicity, growth plate thickening (physeal dysplasia), haematopoietic toxicity, reproductive toxicity (embryo/fetal lethality, abortion, skeletal malformations) and skin/hair discoloration were noted in the pre-clinical testing, and could pose a risk in the human use of Sutent. These adverse effects are all addressed in the Warnings and Precautions section of the Product Monograph.
Taking into consideration the available data from the non-clinical studies, and with the requested revisions to the Product Monograph, in general, there are no issues within this submission that should prevent the approval of Sutent for the proposed indication.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
The only study provided to assess the pharmacodynamic behaviour of sunitinib in patients was a population pharmacokinetics-pharmacodynamics meta-analysis of 443 evaluable patients from 6 studies, including those with solid tumours, gastrointestinal stromal tumour ( GIST) and metastatic renal cell carcinoma (MRCC). The study was unable to correlate efficacy and tolerability measures with exposure, as there was limited placebo data and the range of sunitinib doses investigated was also minimal.
The tolerability assessments were predefined, and included fatigue, nausea, vomiting, hypertension, left ventricular ejection fraction (LVEF) dysfunction, neutropenia, thrombocytopenia, anemia, pancreatic function, and performance status. Although these predefined tolerability assessments are characteristic of the known safety profile of sunitinib, they are not exhaustive, and as such, may not sufficiently describe the tolerability profile of the compound. Despite these limitations, relationships with exposure were suggested for time-to-progression, fatigue, diastolic blood pressure and absolute neutrophil count.
The results from the QT/QTc Interval Study were submitted during the review of this New Drug Submission as requested however, the clinical QTc liability assessment (as mandated by ICH Guideline E14) will require a separate review after the issuance of the Notice of Compliance (NOC). In the interim, the Product Monograph describes the non-clinical cardiovascular effects of Sutent while the clinical pharmacodynamics section notes the lack of conclusive clinical QTc data available at time of issuance of NOC.
3.3.2 Pharmacokinetics
The pharmacokinetics of sunitinib and its primary metabolite, SU012662, were evaluated in 135 healthy volunteers, in 29 patients with acute myeloid leukemia who participated in single-dose studies, and in 266 patients with solid malignant tumours who participated in multiple-dose studies. The findings from these studies provided the evidence and supported the rationale for the acceptability of a 50 mg flat dose of Sutent on a schedule of 4 weeks on and 2 weeks off, for clinical trial development. Health Canada will render a decision regarding changing the maximum recommended dose in the Product Monograph upon receipt of data regarding the safety of the 75 mg dose in patients.
Absorption
The time to reach the maximum serum concentration (Tmax) of sunitinib was between 6-12 hours post-administration for both single and multiple dosing. The absorption of the metabolite SU012662 appeared more variable and not as well characterized as the parent compound. Despite the variability in the Tmax of the metabolite, no significant effect on the extent of SU012662 exposure was detected.
A high-fat meal had no effect on the bioavailability of sunitinib. Even though a decrease in the rate of formation and absorption of SU012662 (the active metabolite) was observed, the meal did not affect the extent of SU012662 exposure.
Comparative bioavailability data were submitted for the 12.5 mg and 50 mg strengths of Sutent, but not the 25 mg strength, for the reason that the 25 mg and 50 mg strengths are proportionally formulated. A review of the data demonstrated bioequivalence of the proposed commercial capsule formulation. The three strengths of Sutent are considered to meet the requirements of the Food and Drug Act and Regulations insofar as the comparative bioavailability information is concerned.
Distribution and Protein Binding
The absolute bioavailability and volume of distribute (Vd/F) of sunitinib or its metabolite could not be determined. It is estimated that the Vd/F for sunitinib is 2230 L based on results from a population pharmacokinetic analysis in healthy subjects and cancer patients. This estimate is consistent with the large Vd/F measured in animal models (rats and monkeys), and is consistent with protein binding of the drug that was observed in the non-clinical evaluations. Protein binding in the clinical studies was not directly assessed.
Metabolism and Excretion
Sunitinib is primarily biotransformed by the cytochrome P450 enzyme in the liver to the active metabolite, SU012662. Sunitinib and SU012662 are the only drug-related compounds measurable in the systemic circulation. Other minor metabolites were found at very low levels in the urine and/or faeces.
A mass-balance study in healthy subjects using [ 14C] sunitinib evaluated the metabolism and excretion of sunitinib. Total recovery of radioactivity was 77%, with 61% recovered in the faeces and 16% in the urine, with sunitinib being the primary species identified in the plasma, faeces, and urine, followed by SU012662. The majority of radioactivity was excreted within the first 7 days. These findings indicate that faecal elimination is the primary route of elimination of sunitinib. The results are also consistent with the pre-clinical assessments. The oral clearance (CL/F) of sunitinib ranged between 34-62 L/h based on results from single and multiple dosing assessments in healthy volunteers and oncology patients.
Drug - Drug Interactions
Pre-clinical assessments identified CYP3A4 as the main enzyme responsible for the metabolism of both sunitinib and SU012662. The effect of administration of either ketoconazole, a potent CYP3A4 inhibitor, or rifampin, a potent CYP3A4 inducer, on the metabolism of sunitinib and SU012662 was investigated in healthy volunteers.
CYP3A4 Inhibitors
Administration of ketoconazole (a potent CYP3A4 inhibitor) resulted in a significant increase in the following sunitinib drug exposure parameters: mean sunitinib Cmax, AUC0-last, and AUC0-∞. The levels of Tmax and half-life were not affected suggesting that ketoconazole affects the pre-systemic clearance. Ketoconazole administration resulted in significant decreases in SU012662 Cmax, AUC0-last, and AUC0-∞, and an increase in Tmax. The magnitude of effect on the metabolite was smaller than that on the parent compound. In this study, the Cmax, AUC0-last, and AUC0-∞ appeared higher in Asian than Caucasian subjects. This may have been attributed to lower body weight in the Asian subjects.
CYP3A4 Inducers
Administration of rifampin (a potent CYP3A4 inducer) resulted in a significant decrease in sunitinib Cmax, AUC0-last, and AUC0-∞. There was no effect on Tmax, and a slight decrease in half-life, which is consistent with induction of CYP3A4. Rifampin administration resulted in an increase in SU012662 Cmax, AUC0-last, and AUC0-∞. There was a decrease in half-life, which is consistent with increased metabolism through induction of CYP3A4. The effect of rifampin on the metabolism of the metabolite was not as large as with the parent compound because the formation and metabolism of SU012662 would be expected to increase with CYP3A4 induction. In this study, there appeared to be higher exposure of SU012662 in Japanese subjects.
Special Populations
Clinical studies were not conducted in patients with hepatic or renal impairment. Population pharmacokinetic analyses of demographic data suggest that there are no clinically relevant effects of age, body weight, creatinine clearance, race, gender or ECOG score on the pharmacokinetics of sunitinib or the active metabolite.
There are no pharmacokinetic data available in pediatric patients.
3.3.3 Clinical Efficacy
Clinical efficacy was studied in a Phase III, two-arm, randomized, double-blind, multicentre, placebo-controlled pivotal trial Study A6181004 (n=312) and a Phase I/II supportive trial (n=55). Study A6181004 evaluated Sutent versus placebo in 312 patients with GIST who had experienced disease progression during prior imatinib mesylate (imatinib) therapy or who were intolerant of imatinib. Patients on both treatment arms received best supportive care in addition to study treatment. Treatment was given in 6-week cycles, with 4 weeks of daily Sutent or placebo administration followed by a 2-week off-period. Two patients were randomized to Sutent for each 1 patient randomized to receive the placebo.
The primary objective of Study A6181004 was to compare the Time to Tumour Progression (TTP) between patients receiving Sutent and patients receiving placebo. At a planned interim analysis (when slightly over half the events required for final analysis had been reported), there was a statistically significant benefit of Sutent over the placebo (median TTP 27.3 weeks vs. 6.4 weeks, HR 0.329, 95% CI 0.233 to 0.466, p< 0.001). Based on these study results, the Data Safety Monitoring Board (DSMB) recommended the study be unblinded and that crossover be allowed to active (Sutent) treatment. This submission and approval are therefore based on interim data that are both statistically and clinically compelling. Survival data are immature. The Product Monograph clearly indicates that the efficacy in GIST patients was based on interim data and that the long-term benefit has not been demonstrated at this time. The labelling and the Product Monograph clearly provide warnings about the potential toxicities of Sutent. The final clinical report should be submitted to Health Canada when available.
Secondary efficacy endpoints were: Overall Survival (OS); Progression-Free Survival (PFS); Objective Response Rate (ORR); response duration; and Quality Of Life assessment (QoL). Median OS had not been reached for either treatment arm. Two of the secondary endpoints were supportive of the primary endpoint. Median PFS showed consistency with the primary efficacy endpoint (24.6 weeks, 95% CI 12.1 to 28.3, vs. 6.0 weeks, 95% CI 4.4 to 10.0 weeks). The objective response rate was 6.8% in the Sutent arm (14 partial responses) vs. 0% in the placebo arm. Response duration and quality of life data were inconclusive.
3.3.4 Clinical Safety
Clinical safety was studied in the Phase III pivotal trial Study A6181004 (n=312) and a Phase I/II supportive trial (n=55). See Section 3.3.3 Clinical Efficacy for a description of the pivotal trial.
In Study A6181004, common adverse events ( 10%) from use of Sutent included hypertension, gastrointestinal disturbances, skin and hair abnormalities, altered sense of taste, fatigue, anorexia, anemia, and laboratory abnormalities. Common laboratory abnormalities (≥10%) included elevated liver function tests and pancreatic enzymes, electrolyte disturbances, neutropenia, and thrombocytopenia. Given the clinical benefit in this indication, however, these adverse events are considered acceptable.
The following safety issues are included in the Warnings and Precautions section of the Product Monograph. The statistics were taken from the pivotal trial, Study A6181004.
Skin and Tissues
Approximately 26% of the patients experienced Grade 1 to 2 skin discoloration which may have been due to the active substance colour (yellow). In addition, depigmentation of the hair or skin was observed, but the mechanism was not known. Rash on the palms of the hands and soles of the feet (palmar plantar erythrodysesthesia) and rash in general, were also reported in approximately 15% of the patients. These events were not cumulative, were typically reversible, and generally did not result in treatment discontinuation.
Gastrointestinal Events
The most commonly reported treatment-related gastrointestinal events in patients treated with Sutent were: nausea (33%), diarrhea (41%), stomatitis (16%), dyspepsia (15%), and vomiting (25%). Supportive care for gastrointestinal adverse events includes anti-emetic and anti-diarrheal medication.
Hemorrhagic Events
Treatment-related tumour hemorrhage occurred in 4 patients treated with Sutent (2%), whereas none of the placebo patients experienced tumour hemorrhage. Given the anti-angiogenesis action of Sutent, this adverse event is not unexpected. Tumour hemorrhage was more evident in patients with pulmonary tumours (2 metastatic renal cell carcinoma patients experienced hemoptysis, while fatal pulmonary hemorrhage occurred in two patients with squamous cell lung cancer [Sutent is not approved for use in Non Small Cell Lung Cancer]). In addition, fatal gastrointestinal perforation (likely linked to tumour necrosis) has occurred rarely in patients with intra-abdominal malignancies treated with Sutent. Prescribing physicians are advised to monitor for hemorrhagic events and to perform routine serial complete blood counts and physical examinations.
Hematological Events
Although Sutent is not as myelosuppressive as traditional chemotherapy, it must be noted that the drug does have some myelosuppressive capability. The decreased absolute neutrophil count was Grade 3 in 13.1% of patients and Grade 4 in approximately 0.9% of patients. Grade 3 and 4 thrombocytopenia was seen in 4% and 0.5% of patients, respectively. One patient developed febrile neutropenia. These events were not cumulative, were typically reversible, and generally did not result in treatment discontinuation. It is recommended that complete blood counts be performed at the beginning of each treatment cycle for patients receiving Sutent.
Cardiovascular Events
Twenty-two patients (11%) on Sutent and 3 patients (3%) on placebo had treatment-emergent LVEF values below the lower limit of normal. Patients with previous cardiac events within 12 months prior to sunitinib administration were excluded from the study. It is therefore unknown whether patients with pre-existing cardiac abnormalities have a higher risk of developing drug-related left ventricular dysfunction. Physicians are advised to weigh this risk against the potential benefits of the drug.
Hypertension Events
Hypertension (all grades) was reported in 51 of 257 patients (19%) on Sutent and 7 of 102 patients (7%) on placebo. Severe hypertension (>200 mm Hg systolic or >110 mm Hg diastolic) occurred in 9 of 237 patients (4%) on Sutent and in none of the patients on placebo. No Grade 4 hypertension was reported. No patients discontinued use of Sutent due to hypertension.
Adrenal Toxicity
Adrenal toxicity was noted in rats and monkeys at plasma exposures as low as 1.1 times the drug exposure observed in humans. In humans, Study A6181004 revealed blunting of cortisol level response to adrenocorticotropic hormone (ACTH) stimulation testing in 13 patients receiving Sutent, although no adrenal gland structural changes were noted on CT/MRI studies. It is possible that patients on Sutent who undergo a physiologic stress, such as infection, surgery, or trauma, may not be able to produce an appropriate adrenal response secondary to sub-clinical adrenal toxicity. Physicians prescribing Sutent are therefore advised to monitor for adrenal insufficiency in patients who experience a physiologic stress (such as severe infection, surgery, or trauma).
In summary, the data submitted in support of the use of Sutent for the treatment of the GIST indication are considered adequate. The Product Monograph includes the safety issues mentioned above.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The evaluation of Sutent was given Priority Review Status. Sutent has shown a significant increase in efficacy such that the overall benefit/risk profile is improved over existing therapies. Currently, there is no effective treatment for GIST patients who are resistant or who become intolerant to imatinib mesylate, the only effective non-surgical treatment for GIST approved in Canada. The pivotal trial has shown Sutent to be efficacious in each of these populations, with an overall independent core-laboratory-assessed median TTP of 27.3 weeks compared to 6.4 weeks for placebo. The capacity for Sutent to provide a GIST patient with a potential four-fold time to tumour progression is considered a benefit to that patient. These results are considered clinically meaningful given the side effects of Sutent and the small risk of serious toxicities. With clear labelling, the risk can be mitigated, such that a new treatment option can be made available to these patients. The Product Monograph clearly indicates that the efficacy in GIST patients was based on interim data, and that the long term benefit is not demonstrated at this time.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of Sutent is favourable in the treatment of GIST after failure of imatinib mesylate treatment due to resistance or intolerance. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: Sutent
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2005-04-08 |
| Request for priority status | |
| Filed: | 2005-08-15 |
| Approval issued by Bureau of Metabolism, Oncology, and Reproductive Sciences: | 2005-09-19 |
| Submission filed: | 2005-09-20 |
| Screening | |
| Screening Deficiency Notice issued: | 2005-10-31 |
| Response filed: | 2005-11-08 |
| Screening Acceptance Letter issued: | 2005-11-29 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2006-03-21 |
| Quality Evaluation complete: | 2006-04-28 |
| Clinical Evaluation complete: | 2006-05-25 |
| Biostatistics Evaluation complete: | 2006-04-26 |
| Labelling Review complete: | 2006-05-26 |
| NOC issued by Director General: | 2006-05-26 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| SUTENT | 02280817 | PFIZER CANADA ULC | SUNITINIB (SUNITINIB MALATE) 50 MG |
| SUTENT | 02280809 | PFIZER CANADA ULC | SUNITINIB (SUNITINIB MALATE) 25 MG |
| SUTENT | 02280795 | PFIZER CANADA ULC | SUNITINIB (SUNITINIB MALATE) 12.5 MG |