Summary Basis of Decision for Zolinza ™
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:
ZolinzaTM
Vorinostat, 100 mg, Capsule, Oral
Merck Frosst Canada Ltd.
Submission control no: 104562
Date issued: 2010-01-18
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):
- 02327619
Therapeutic Classification:
Non-medicinal ingredients:
Capsule shell: gelatin, titanium dioxide, and may contain sodium lauryl sulfate
Submission type and control no:
Date of Submission:
Date of authorization:
ZOLINZA™ is a Trademark of Merck & Co., Inc. Used under license
2 Notice of decision
On June 11, 2009, Health Canada issued a Notice of Compliance to Merck Frosst Canada Ltd. for the drug product Zolinza™.
Zolinza™ contains the medicinal ingredient vorinostat which is a histone deacetylase (HDAC) inhibitor, anti-neoplastic agent.
Zolinza™ is indicated for the treatment of cutaneous manifestations in patients with advanced cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease subsequent to prior systemic therapies. The anti-neoplastic effect of vorinostat is attributed to the inhibition of HDAC activity and subsequent accumulation of acetylated proteins, including histones. Histone acetylation results in transcriptional activation of genes, including tumour suppressor genes, whose expression leads to induction of differentiation, apoptosis, and/or inhibition of tumour growth.
The market authorization was based on quality, non-clinical, and clinical information submitted. The pivotal study was an open-label, single-arm, multicentre, Phase IIb study in which 74 patients with CTCL of all stages were treated with 400 mg Zolinza™ once daily. Dose modification (300 mg once daily for 7 days/week, 300 mg for 5 consecutive days/week) was allowed by the protocol after recovery from dose-related toxicities. The pivotal study demonstrated a 29.7% (22/74) response rate in cutaneous manifestations of the disease in all patients treated with Zolinza™. In patients with Stage IIB and higher CTCL, the response rate in cutaneous manifestations was 29.5% (18/61). Overall, the median time to response was less than two months; however, in rare cases it took up to 6 months for patients to achieve an objective response to Zolinza™. Clinically important adverse events associated with Zolinza™ included thromboembolism including fatal cases, and thrombocytopenia and anemia.
Zolinza™ (100 mg, vorinostat) is presented in capsule form. The recommended dose is 400 mg orally once daily with food. Dosing guidelines are available in the Product Monograph.
Zolinza™ is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation, as well as patients who have severe hepatic impairment (total bilirubin ≥× the upper limit of normal). Zolinza™ 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 Zolinza™ are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Zolinza™ is favourable for the treatment of cutaneous manifestations in patients with advanced CTCL who have progressive, persistent, or recurrent disease subsequent to prior systemic therapies.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Vorinostat, the medicinal ingredient of Zolinza™, is an HDAC inhibitor, anti-neoplastic agent. HDACs catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors. The anti-neoplastic effect of vorinostat is attributed to the inhibition of HDAC activity and subsequent accumulation of acetylated proteins, including histones. Histone acetylation results in transcriptional activation of genes, including tumour suppressor genes, whose expression leads to induction of differentiation, apoptosis, and/or inhibition of tumour growth.
Manufacturing Process and Process Controls
Vorinostat is synthetically derived.
In-process controls performed during manufacture were reviewed and are considered acceptable. The specifications for the raw materials used in manufacturing the drug substance are also considered satisfactory.
Characterization
The structure of vorinostat has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are considered satisfactory.
Impurities arising from manufacturing and/or storage were reported and characterized. The proposed limits for these impurities were within International Conference on Harmonisation (ICH) established limits or were qualified through toxicology studies and are therefore considered to be acceptable.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of vorinostat.
The specifications are considered acceptable for the drug substance. Data from the batch analyses were reviewed and are within the proposed acceptance criteria.
Stability
Based on the long-term, accelerated, and stress stability data submitted, the proposed shelf-life for the drug substance is supported and is considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Zolinza™, 100 mg capsule, is a white, opaque, hard gelatin capsule with "568" over "100 mg" printed within the radial bar in black ink on the capsule body. The drug product is presented in high density polyethylene bottles of 120 capsules.
Each 100 mg Zolinza™ capsule contains 100 mg vorinostat. The non-medicinal ingredients (excipients) in the capsule fill are magnesium stearate, microcrystalline cellulose, and sodium croscarmellose. The capsule shell excipients are gelatin and titanium dioxide, and the capsule shell may contain sodium lauryl sulfate.
All excipients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of vorinostat with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process, and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Zolinza™ is tested to verify that its identity, appearance, content uniformity, assay, dissolution, particle size, and levels of degradation products are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits for individual and total degradation products are within acceptable limits.
Validation reports submitted for all analytical procedures used for in-process and release testing of the drug product are considered satisfactory.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the long-term and accelerated stability data submitted, the proposed 24-month shelf-life at 15-30°Celsius for Zolinza™ is considered acceptable.
The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
All sites are compliant with Good Manufacturing Practices.
3.1.4 Adventitious Agents Safety Evaluation
The gelatin used in the capsule shell is of animal origin. A letter of attestation confirming that the material is not from a Bovine Spongiform Encephalopathy (BSE)/Transmissible Spongiform Encephalopathy (TSE) affected country/area has been provided for this product indicating that it is considered safe for human use.
The magnesium stearate used in the manufacture of the capsule fill is of non-bovine origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Zolinza™ has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. 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
Non-clinical pharmacology studies were conducted in vitro and in vivo. In vitro, vorinostat induced apoptosis and inhibited cell growth in a wide variety of transformed cells in culture. In human colon carcinoma cells, inhibition of cell proliferation was observed at concentrations of vorinostat that caused the accumulation of acetylated histones. In vivo, vorinostat demonstrated anti-neoplastic activity in rodent tumour models including xenograft models of human breast, and colon carcinoma. Overall, tumour regression was not observed; however, vorinostat did mediate a decrease in tumour growth rate.
3.2.2 Pharmacokinetics
Absorption
Absorption of vorinostat is rapid as indicated by the time to maximum concentration (Tmax) values in both rats [18 minutes (min)] and dogs (42 min). Serum concentration of vorinostat declined rapidly in rats and dogs, and the half-life of vorinostat was short in both animal species (12 min).
Distribution
Vorinostat exhibited a volume of distribution that was greater than total body water in rats and approximately equal to total body water in dogs at steady state (Vss). Vorinostat was moderately bound to plasma proteins: 31% in mice, 32% in rats, 44% in dogs, 63% in rabbits, and 71% in humans. Vorinostat preferentially binds to human serum albumin followed by α1-acid glycoprotein.
Vorinostat and the two major metabolites, O-glucuronide vorinostat and 4-anilino-4-oxobutanoic acid, exhibit the potential to cross the placenta in rats and rabbits.
Metabolism
Vorinostat is extensively metabolized in the liver to O-glucuronide vorinostat and 4-anilino-4-oxobutanoic acid. Although both metabolites were major components in the serum of rats and dogs, only 4-anilino-4-oxobutanoic acid was a major metabolite in the urine of rats and dogs. The cytochrome P450 (CYP) enzymes do not play a significant role in the metabolism of vorinostat.
Excretion
In rats and dogs, vorinostat was primarily excreted in the urine within the first 24 hours.
Drug Interactions
At concentrations ≥10 µM, vorinostat exhibited some potential to suppress the activity of CYP enzymes, CYP2C9 and CYP3A4 in gene expression studies. The maximum plasma concentration (Cmax) in humans is approximately 1.2 µM, indicating that the observed changes in CYP enzyme activities are likely not pharmacologically relevant.
In clinical trials, prolongation of prothrombin time (PT) and International Normalized Ratio (INR) were observed infrequently in patients receiving Zolinza™ concomitantly with coumarin-derivative anticoagulants. Increased PT was noted in the rat repeat-dose toxicology studies of up to 26 weeks duration. Thus, prolongation of PT and INR in the clinical setting may be the consequence of a pharmacodynamic drug interaction between Zolinza™ and coumarin-derivative anticoagulants.
3.2.3 Toxicology
The standard battery of non-clinical experiments was performed with no significant deviations. Where appropriate, all studies were Good Laboratory Practice (GLP) compliant and conducted in accordance with international regulatory guidelines.
Single-Dose Toxicity
Vorinostat exhibited low acute toxicity in mice, rats, and dogs. Lympho-haematopoietic tissues (bone marrow, thymus and spleen) were identified as the likely target organs of toxicity in the single-dose studies.
Repeat-Dose Toxicity
Repeat-dose toxicity studies of up to 26 weeks duration were conducted in rats and dogs. Rats received doses of 20, 50, and 150 mg/kg/day and dogs received doses of 20, 60, and 160 mg/kg/day.
In rats, a no-effect level was not established. Decreased levels of platelets, white blood cells, and lymphocytes were observed. Immunophenotyping indicated that total T lymphocytes, TH cells, Tc cells, and total B cells were decreased. At the microscopic level erythroid hyperplasia and myeloid hypoplasia were observed in femur and sternum bone marrow. At doses of 50 mg/kg/day and 150 mg/kg/day, dose-dependent reductions in food consumption, body weight gain, decreased serum globulin, and increased pro-thrombin time were observed. At 150 mg/kg/day, extravascular hemolysis, increased absolute reticulocyte counts and lymphoid depletion (spleen, thymus) were noted.
In a 4-week dog study, a dose of 100 mg/kg/day produced severe adverse clinical signs, decreased body weight and food consumption, hematological toxicity, and gastrointestinal (GI) lesions. The no-effect level was 40 mg/kg/day. In a 26-week dog study, GI lesions were also noted along the length of the GI tract at 160 mg/kg/day. The no-effect level was 60 mg/kg/day.
Reversibility of toxic effects was assessed in the high-dose rats and dogs. Most findings were reversible. Partial recovery was observed with respect to body weight (male rats) and select erythroid and myeloid blood cell parameters (male rats). In dogs, recovery was observed for all GI findings in the 26-week but not the 4-week study.
Genotoxicity
Vorinostat was weakly positive in the mutagenicity and clastogenicity assays, and in the in vivo mouse micronucleus assay. Vorinostat was clastogenic in transformed cells but was negative in non-transformed cells. Chromosomal aberrations were associated with suppression of cell growth, suggesting that aberration induction may be an indirect effect due to perturbation of DNA synthesis.
Carcinogenicity
Carcinogenicity studies were not performed for vorinostat. Oncolytic agents intended for treatment of advanced systemic disease do not generally require carcinogenicity studies.
Reproductive and Developmental Toxicity
Female rats received oral doses of 15, 50, and 150 mg/kg/day vorinostat. Female toxicity was observed at 150 mg/kg/day [<1 times the human exposure based on the area under the concentration-time curve for 0-24 hours (AUC0-24)]. There were no vorinostat-related effects on mating, fertility or fecundity indices at doses up to 150 mg/kg/day. An increased number of corpora lutea was observed from 15 mg/kg/day. An increased number of resorptions and increased percent peri-implantation loss was observed from 50 mg/kg/day. An increase in percent post-implantation loss and a decreased number of live fetuses per litter were observed at 150 mg/kg/day. The no observed adverse effect level (NOAEL) for reproductive performance was <15 mg/kg/day, based on the number of corpora lutea.
Rats and rabbits received oral doses of 5, 15 and 50 mg/kg/day vorinostat; and 20, 50 and 150 mg/kg/day vorinostat; respectively. Treatment-related developmental effects including decreased mean live fetal weights, low incidences of incomplete ossifications and low incidences of skeletal variations were observed at the highest doses of vorinostat tested. The NOAEL was 15 and 20 mg/kg/day in rats and rabbits, respectively (<1 times the human exposure based on AUC0-24). An increased incidence of gallbladder malformations was observed in rabbits.
3.2.4 Conclusion
The pharmacology and toxicology studies for this drug submission are considered acceptable. The non-clinical data provided in the submission are considered complete; the standard battery of experiments was performed with no significant deviations. Primary adverse effects in chronic toxicity studies included anorexia, decreased food consumption, body-weight loss, decreased activity, haematologic and GI effects (all findings were noted at <1 times the human exposure based on AUC0-24). Overall, the pharmacology and toxicology studies support the use of Zolinza™ for the proposed indication.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Vorinostat is an HDAC inhibitor that induces the accumulation of acetylated proteins. A pharmacodynamic study to demonstrate the link between vorinostat HDAC inhibitory effect and measurement of a CTCL disease marker has not been submitted.
3.3.2 Pharmacokinetics
Absorption
Following oral administration of a single 400 mg dose of vorinostat under fasted state in patients with cancer [number (n) = 23], the Cmax was reached in 1.5 hours with an AUC0-24h of 3.87 µM hour and a short half-life (1.7 hours). The drug exposure (mean AUC0-24h) increased by 38% and a delay of absorption (Tmax of 4 hours) were reported with a high-fat meal compared to the fasted state. Oral administration of multiple 400 mg doses of vorinostat with food resulted in a further 21% increase in mean AUC0-24h with similar Cmax and Tmax values comparable to the single dose.
Distribution
Vorinostat was approximately 71% bound to human plasma proteins in vitro over the concentration range of 0.5 to 50 µg/mL.
Metabolism
The major metabolic pathways of vorinostat involve glucuronidation to produce O-glucuronide vorinostat, and hydrolysis followed by β-oxidation to produce 4-anilino-4-oxobutanoic acid. Both metabolites did not inhibit HDAC1 at concentrations ≥10 µM in vitro. The effect of the two metabolites on other HDACs and enzyme/receptor molecules is unknown. There was negligible biotransformation of vorinostat by the CYP system.
Excretion
Vorinostat is primarily eliminated in the urine via the two metabolites, O-glucuronide vorinostat and 4-anilino-4-oxobutanoic acid, which accounted for ~52% of the vorinostat dose. Vorinostat accounted for <1% of the dose recovered as unchanged drug in urine. The mean terminal half-life (t½) was ~2 hours for both vorinostat and the O-glucuronide metabolite, while that of the 4-anilino-4-oxobutanoic acid metabolite was 11 hours.
Drug Interactions
Prolongation of PT and INR levels was observed in patients receiving Zolinza™ in combination with coumarin-derived anticoagulants. Severe thrombocytopenia accompanied with GI bleeding and anaemia was reported in patients that were administered Zolinza™ concomitantly with other HDAC inhibitors such as valproic acid.
Clinical studies have not been conducted to evaluate drug interactions of vorinostat with other drugs, herb products, laboratory tests, and lifestyle.
Special Population
Based upon an exploratory analysis of limited data; gender, race, and age do not appear to have meaningful pharmacokinetic (PK) effects on vorinostat. Increased systemic exposure of the two major metabolites was observed in patients ≥65 years of age and the clinical implication is unknown. Vorinostat has not been evaluated in patients <18 years of age.
Limited results from an ongoing PK study in patients with hepatic impairment revealed higher incidence and severity of commonly observed adverse experiences following the administration of 100 or 200 mg vorinostat once daily. Based on these results, vorinostat is contraindicated in patients who have severe hepatic impairment (total bilirubin ≥× the upper limit of normal). Vorinostat is not recommended in patients with moderate hepatic impairment.
Vorinostat has not been evaluated in patients with renal impairment. Since the two major metabolites were excreted via the kidney at >50% of the total vorinostat dose, and increased serum creatinine, uric acid, and urine protein were commonly reported in patients in the pivotal study, patients with pre-existing renal impairment should be treated with caution.
3.3.3 Clinical Efficacy
The pivotal study was an open-label, single-arm, multicentre, Phase IIb study conducted in patients with CTCL who were refractory to or intolerant of other prior therapy. A total of 74 patients with CTCL of all stages were treated once daily with 400 mg Zolinza™. Dose modifications, for example (e.g.) 300 mg once daily for 7 days/week, or 300 mg for 5 consecutive days/week were allowed for patients after recovery from dose-related toxicities.
The primary endpoint was the response rate of cutaneous manifestations measured by the modified Severity Weighted Assessment Tool (mSWAT) in patients with advanced CTCL (Stage IIB and higher) who had progressive, persistent, or recurrent disease on or following at least two systemic therapies. One of these therapies had to contain bexarotene unless the patient was intolerant of or not a candidate for bexarotene therapy. The results of the assessment of T cell (CD4+CD26-) cell count were not taken into consideration in the response assessment and worsening in T cell (CD4+CD26-) count did not overrule a cutaneous response measured by mSWAT.
Twenty-two patients (30%) were evaluated as responders by a reduction of ≥50% in the mSWAT scores compared to baseline, in at least two consecutive assessments. Temporary response was observed in 4 responders who had a partial response supported by only two assessments (21-28 days apart) followed by worsening mSWAT scores indicating a loss of response. Median time to response was less than 2 months and median duration of response was not reached at the time of final data cut-off date of the pivotal study. In patients with Stage IIB and higher CTCL, 18/61 patients (30%) were evaluated as responders.
Secondary endpoints were pruritus relief, duration of response, time to response, and time to progression. Other pre-specified disease measurements monitored during the study included T cell (CD4+CD26-) count in patients with Sézary syndrome, measurements of tumour cell body surface area, and lymph nodes by physical exam. There was no apparent correlation between the cutaneous response measured by mSWAT score reduction and improvement of any of those disease measurements. Among the 10 responders with Sézary syndrome, 4 patients had an improvement in T cell (CD4+CD26-) count along with mSWAT score improvement, whereas 6 had unchanged or worsening T cell (CD4+CD26-) counts.
Concomitant topical medications currently recommended for managing CTCL were widely used in the study population including the 22 responders. The concomitant medications included anti-neoplastic agents, tacrolimus, medications used to reduce skin symptoms in CTCL (e.g., corticosteroids, antihistamines, anti-inflammatory and other unspecified dermatologic products], antibiotics, and central nervous system (CNS) therapeutics.
A major concern in patients with more advanced disease (Sézary syndrome and/or stage IV disease with significant blood, nodal and/or visceral involvement) is disease progression and survival. The endpoint measured by a cutaneous response rate may not be sufficient to address the survival issue in those patient populations. In addition, there was no evidence to suggest that vorinostat could treat the disease itself because monitoring of other disease manifestations (e.g., Sézary cell count, lymph node involvement, tumour surface area and visceral measurement) was not pre-defined in the study protocol and improvement of any of the measurements was not confirmed in the pivotal study.
In a supportive study, 33 patients with CTCL were assigned to one of three dosage regimes (Cohort 1: 400 mg once daily continuously; Cohort 2: 300 mg twice daily, 3 days per week; Cohort 3: Induction 300 mg twice daily, maintenance 200 mg twice daily). The overall response rate based on the Physician?s Global Assessment was 25% in patients with Stage IIB or higher CTCL (n=28) and 36% in the 11 patients with Sézary syndrome.
3.3.4 Clinical Safety
Safety results from 86 CTCL patients treated once daily with 400 mg Zolinza™ in two single-arm clinical studies revealed that AEs occurred most commonly in the following categories: GI system, general and administration site, nervous system, metabolism and nutrition, infection and infestations, respiratory, thoracic and mediastinal. The most common AEs with frequencies of >20% were diarrhoea, fatigue, nausea, anorexia, dysgeusia, thrombocytopaenia and decreased body weight. Serious drug-related AEs included pulmonary embolism, anaemia, dehydration, thrombocytopaenia, death (of unknown cause), deep vein thrombosis, GI haemorrhage, ischaemic stroke, streptococcal bacteraemia, and syncope. Patients with Stage IV disease and a high Eastern Cooperative Oncology Group (ECOG) score at baseline had a higher risk of experiencing serious adverse events.
Thromboembolic events (venous and arterial) were a major safety concern for Zolinza™. Deep vein thrombosis and pulmonary embolism were the two events most commonly reported in patients of multiple trials. Approximately 5% of the patients (4/86) experienced pulmonary embolism during a median exposure of 4 months. Arterial thromboembolic events including single cases of cerebral ischaemia, myocardial infarction, ischaemic stroke, ischaemia, and hepatic ischaemia/infarction were also reported.
In the pivotal study, 9/74 (12%) patients discontinued study treatment and 10 (13.5%) patients had a dose modification due to adverse experiences. The supportive study revealed serious infections including sepsis, febrile neutropaenia, and lobar pneumonia, which might be associated with the higher systemic exposure of the other regimens used in the study. In the pivotal study, three patients died within 30 days following the last dose of Zolinza™ and two of these deaths were considered by the investigator to be possibly related to Zolinza™. The causes of death for the three patients were ischaemic stroke, disease progression, and death of unknown cause, respectively.
The most common laboratory AEs were increased blood creatinine, increased serum magnesium, increased serum cholesterol and triglyceride, increased serum glucose, decreased haemoglobin, and abnormal urine protein. Common laboratory Grade 3-4 AEs were decreased lymphocyte count, decreased platelet count, increased serum glucose, and abnormal INR.
In a dedicated QT study, a single 800 mg dose of vorinostat (with similar systemic exposure to the clinical recommended dose of 400 mg at steady-state) was associated with statistically significant QTc prolongation from 2 to 24 hours post-dosing. All point estimates within this time frame exceeded the threshold of regulatory concern of 5 ms. The maximum increase was 13.06 ms at 4 hours post-dosing. Drugs that cause QTc prolongation of this magnitude at therapeutically relevant concentrations can be expected to cause rare events of torsade de pointes and sudden death during clinical use, especially when administered to patients with underlying risk factors or who are receiving concomitant medications that also cause QTc prolongation. Vorinostat was also observed to increase heart rate. Heart rate was significantly increased from 2 to 12 hours post-dosing, with a maximum increase of 8.32 (90% CI 5.02, 11.63) beats per minute (bpm). Increased heart rate raises concerns about tachyarrhythmias and an increased risk of ischaemic heart disease. Warnings regarding QTc prolongation have been added to the Zolinza™ Product Monograph.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Zolinza™ is a novel compound intended to treat cutaneous manifestation in patients with CTCL who have failed at least two prior therapies. Approximately 30% patients of all-stage CTCL showed ≥50% improvement in cutaneous manifestation by mSWAT scores. Based on limited data from patients with Sézary syndrome, 4 of the 10 responders experienced decreased T cell (CD4+CD26-) counts in conjunction with their cutaneous improvement. However, a correlation between the cutaneous improvement and other disease markers including T cell (CD4+CD26-) count cannot be concluded for the responders due to discordant outcomes between the mSWAT scores and Sézary cell count, lymph node, and/or tumour surface area involvement. Visceral involvement was not monitored in patients with or without baseline Stage IVB disease in the pivotal study.
Approximately 5% of the patients experienced pulmonary embolism during a median exposure of the 4-month study period in 86 patients with all-stage CTCL in the pivotal and supportive trials. Warnings regarding thromboembolic events/pulmonary embolism have been placed in the Zolinza™ Product Monograph.
Many concerns were raised by Health Canada during the review regarding the efficacy and safety of Zolinza™ in the patient population of interest, of which some can only be addressed by a placebo-controlled study. However, given that CTCL is a rare disease for which, in the advanced and refractory disease setting, there is an unmet medical need in Canada and that it is unlikely a placebo-controlled study with Zolinza in patients with CTLC is feasible, it is Health Canada?s opinion that the benefit of Zolinza™ in alleviating cutaneous symptoms in ~30% patients with advanced stage CTCL outweighs the risk. The indication has been limited to treatment of the cutaneous manifestations of the disease as tumour response at other sites of the disease has not been demonstrated. In addition, the indication has been limited to advanced disease as the benefit-risk profile is not considered acceptable in less advanced disease.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Zolinza™ is favourable in the treatment of cutaneous manifestations in patients with advanced CTCL who have progressive, persistent or recurrent disease subsequent to prior systemic therapies. The New Drug Submission (NDS) complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance (NOC) pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: ZolinzaTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2007-10-09 |
| Submission filed: | 2008-06-27 |
| Screening | |
| Screening Acceptance Letter issued: | 2008-08-15 |
| Review | |
| Quality Evaluation complete: | 2009-06-08 |
| Clinical Evaluation complete: | 2009-06-11 |
| Labelling Review complete: | 2009-06-10 |
| Notice of Compliance issued by Director General: | 2009-06-11 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| ZOLINZA | 02327619 | MERCK CANADA INC | VORINOSTAT 100 MG |