Summary Basis of Decision for Civanex MC
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:
CivanexMC
Zucapsaicin, 0.075% w/w, Cream, Topical
Winston Laboratories, Inc.
Submission control no: 121952
Date issued: 2010-11-17
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):
- 02354772
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On July 15, 2010, Health Canada issued a Notice of Compliance to Winston Laboratories, Inc. for the drug product CivanexTM.
CivanexTM contains the medicinal ingredient zucapsaicin which is a topical analgesic.
CivanexTM is indicated to be used in conjunction with oral cyclooxygenase-2 (COX-2) inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs) for the relief of severe pain in adults with osteoarthritis of the knee, not controlled with oral COX-2 inhibitors or NSAIDs alone, for a duration of no more than three months. Osteoarthritis of the knee, the most common joint disorder, is an active dynamic process involving all joint tissues: bone, cartilage, ligaments, muscle, and synovium. Although the exact mechanism of action of zucapsaicin is not fully understood, current evidence suggests that it achieves its analgesic effect via the TRPV-1 (Transient Receptor Potential Vanilloid-1) receptor. The intended targets for zucapsaicin are the neurons involved in the transmission of pain from the affected joint. Topical application of zucapsaicin over painful joints leads to desensitization of these neurons.
The market authorization was based on quality, non-clinical, and clinical information submitted. Evidence of safety and efficacy to support the proposed indication was based primarily on a single 12-week, Phase III, randomized, double-blind, controlled, parallel-group, multicentre study in subjects with osteoarthritis of the knee taking concomitant oral NSAIDs or COX-2 inhibitors. Patients were randomized to receive CivanexTM (zucapsaicin cream 0.075%) or the inactive control, zucapsaicin cream 0.01%, applied three times daily. The three co-primary endpoints were osteoarthritis of the knee pain, physical function (both assessed using the Western Ontario and McMaster Universities Arthritis Index [WOMAC]), and subject global evaluation. The results of the study indicated that the efficacy of CivanexTM was similar to zucapsaicin cream 0.01% for patients experiencing mild to moderate pain while using oral NSAIDs or COX-2 inhibitors; however, the efficacy of CivanexTM was greater than zucapsaicin cream 0.01% in patients still experiencing severe pain while using oral NSAIDs or COX-2 inhibitors. After further analysis of baseline by treatment interaction, the results indicated that based on all three co-primary endpoints, patients who exhibited the best response to CivanexTM were those who were in the worst condition as determined by baseline scores.
CivanexTM (zucapsaicin cream, 0.075% w/w) is presented as a cream for topical application. A small amount (pea size) of CivanexTM cream is applied to unbroken skin in three locations around the affected knee and gently rubbed in three times daily. The applications should be evenly spaced throughout the waking hours and should be at least 4 hours apart. Further dosing guidelines are available in the Product Monograph.
CivanexTM is contraindicated for patients with a known history of sensitivity to zucapsaicin or to any ingredient in the formulation or component of the container. The application of CivanexTM to broken or irritated skin or areas with a compromised skin barrier is also contraindicated. CivanexTM 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 CivanexTM 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 CivanexTM is favourable for the indication stated above.
3 Scientific and Regulatory Basis for Decision
A New Drug Submission (NDS) for CivanexTM (zucapsaicin) was filed with Health Canada on October 30, 2008. Upon review, Health Canada concluded that there was a lack of efficacy in the pivotal study for the target population of the intended indication, which led to a negative benefit/risk analysis. Therefore, the drug submission received a Notice of Non-compliance (NON). The sponsor responded to the NON, limited the indication to a subpopulation of patients that displayed a benefit with CivanexTM, shortened the exposure time, and added the concomitant use with NSAIDs or COX-2 inhibitors to the indication. As a result, a Notice of Compliance (NOC) was issued for CivanexTM on July 15, 2010.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Zucapsaicin, the medicinal ingredient of CivanexTM is a topical analgesic. Current evidence suggests that the topical application of zucapsaicin over painful joints leads to desensitization of neurons involved in the transmission of pain from the affected joint in adult patients with osteoarthritis of the knee.
Manufacturing Process and Process Controls
The drug substance is synthetically derived. The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of zucapsaicin has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Appropriate tests are adequately controlling the levels of product- and process-related impurities.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of zucapsaicin are considered acceptable. Data from batch analyses were reviewed and are within the proposed acceptance criteria.
The proposed packaging components are considered acceptable.
Stability
Based on the long-term, accelerated, and stress stability data submitted, the proposed retest period, shelf-life, and storage conditions for the drug substance are supported and are considered satisfactory.
3.1.2 Drug Product
Description and Composition
CivanexTM is a white, slightly translucent cream available in 30 g and 60 g epoxy-lined aluminum tubes with polypropylene caps.
Each gram of CivanexTM cream contains 0.75 mg of zucapsaicin in a benzyl alcohol, cetyl alcohol, glyceryl stearate, isopropyl myristate, polyethylene glycol 100 stearate, purified water, sorbitol solution, and white petrolatum base.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of zucapsaicin 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
CivanexTM is tested to verify that its identity, appearance, assay, pH, viscosity, fill volume, package integrity, and levels of degradation products and microbiological impurities 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.
The validation process is considered to be complete. Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to be within International Conference on Harmonisation (ICH)-established limits and/or were qualified from batch analysis and therefore, are considered to be acceptable.
Stability
Based on the real-time, long-term, accelerated, and stress stability data submitted, the proposed 36-month shelf-life is considered acceptable for the product, packaged in 7.5 g, 30 g, and 60 g epoxy-lined aluminum tubes with white polypropylene caps stored between 15-30°C with an in-use shelf-life of 6 weeks stored at 15-30°C.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of CivanexTM are considered suitable for the activities and products manufactured.
All of the proposed manufacturing sites comply with the requirements of Division 2 of the Food and Drug Regulations.
3.1.4 Adventitious Agents Safety Evaluation
Glyceryl stearate and polyethylene glycol 100 stearate are the only excipients of animal origin included in the formulation of CivanexTM. There is extensive clinical experience with these excipients in topical creams as they are used in formulations of currently marketed topical capsaicin products in Europe, the United States, and Canada, and there have not been any bovine spongiform encephalitis (BSE) issues associated with the use of these products.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for CivanexTM 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
Zucapsaicin, the medicinal ingredient of CivanexTM, is the synthetically produced Z-isomer of naturally occurring capsaicin. The pharmacologic activity of capsaicin in the relief of pain associated with osteoarthritis is well established and topical capsaicin creams have been marketed worldwide for the last 20 years.
The drug submission referencedanimal studies that have demonstrated the antinociceptive properties of zucapsaicin, as well as the efficacy of zucapsaicin compared to that of capsaicin. Analysis of spinal cord sections revealed that zucapsaicin reduced calcitonin gene related peptide (CGRP) in the dorsal root ganglia and sciatic nerves. The decreases in dorsal root ganglia, sciatic CGRP, and substance-P (SP) levels indicate that civamide affects the peptidergic afferent neurons via a desensitization mechanism. When zucapsaicin was compared to capsaicin, zucapsaicin exhibited antinociceptive effects at the same or lower doses than capsaicin via a similar mechanism as capsaicin.
The cardiovascular effects of zucapsaicin were studied in minipigs following 9 months of chronic dermal exposure (three times per day) and in dogs following 28 days of oral dosing. In both studies, all electrocardiograms (ECGs) were normal at all collection points.
3.2.2 Pharmacokinetics
Absorption
The pharmacokinetic (PK) studies conducted in rats and minipigs established that there was minimal absorption of 0.075% zucapsaicin cream into the systemic circulation, following topical application. Dose-dependent increases in exposure were observed in creams containing >0.075% zucapsaicin in a 6-month rat study; however in the 9-month minipig study, circulation levels of zucapsaicin were generally below the limit of detection, 2.5 ng/mL. Overall, the PK studies established that there was minimal absorption of zucapsaicin into the systemic circulation after topical application.
Distribution
Following a single intravenous (IV) dose of zucapsaicin, the highest concentrations (from greatest to least) of zucapsaicin were found in the gastrointestinal contents, bone marrow, liver, whole blood, spleen, heart, and kidney.
The distribution studies indicated that the majority of zucapsaicin and its metabolites are eliminated within 72 hours, and that elimination probably continues beyond 72 hours. The tissue distribution profiles were similar after dermal and IV administration, but different after oral administration, possibly reflecting first-pass metabolism.
Metabolism
In vivo studies established that zucapsaicin is extensively metabolized in rats, and that the metabolite profile may depend on gender and route of administration, but does not depend on dose after oral administration.
In vitro studies with microsomes, hepatocytes, and known substrates for specific cytochrome P450 (CYP) isozymes established that zucapsaicin can be extensively metabolized in humans.
Excretion
The excretion studies in rats showed that zucapsaicin and its metabolites are primarily excreted in the urine and faeces with a negligible amount in the expired air. Approximately one-half to two-thirds of the excreted radioactivity was present in the faeces indicating biliary excretion.
3.2.3 Toxicology
Single-Dose Toxicity
The acute single-dose studies were performed in rats and mice using the oral and IV routes of administration of zucapsaicin. With oral administration, the dose of drug that is lethal to one-half of the experimental animals (LD50) was >87.5 mg/kg and <60 mg/kg in male and female mice, respectively; and >90 mg/kg and >60 mg/kg in male and female rats, respectively. The IV LD50 was >0.175 mg/kg and >0.25 mg/kg in female and male mice, respectively; and >0.25 mg/kg in both male and female rats.
Repeat-Dose Toxicity
Repeat dermal dosing produced local effects at the site of application. The only evidence of systemic effect was a decrease in mean body weight in male rats treated with zucapsaicin cream 3.0%. Overall, there was no systemic toxicity following topical treatment with zucapsaicin cream.
Zucapsaicin cream 0.075% produced very slight erythema in minipigs and very slight to moderate erythema in rats. When higher concentrations were applied, no change in response was noted in the minipigs, but rats exhibited an increased incidence of moderate and severe erythema. All effects were minor and were not considered to be toxicologically significant.
Genotoxicity
In vitro and in vivo genetic toxicity studies were conducted using zucapsaicin. Genetic toxicity studies revealed negative findings in the Ames test, the mouse micronucleus assay, the induction of chromosome aberrations in bone marrow cells, and the chromosomal aberration assay in Chinese hamster ovary cells.
Carcinogenicity
Dermal exposure to zucapsaicin cream in transgenic mice, at concentrations of up to 40-times the intended clinical concentration and approximately 600-times the clinical dose of zucapsaicin per cm2 of treated skin revealed that zucapsaicin is non-oncogenic and produces minimal dermal and systemic toxicity in the transgenic mouse model. The study provided conclusive evidence of the non-oncogenic potential of zucapsaicin.
Reproductive and Developmental Toxicity
No significant findings were reported in the rat fertility and reproductive studies. The no-observed-adverse-effect-level (NOAEL) for male fertility and reproductive performance was approximately 621-times the exposure at the maximum human dose, and the NOAEL for female fertility and reproductive performance was approximately 856-times the exposure of the maximum human dose. Zucapsaicin did not exhibit teratogenic potential in rats and rabbits, and no significant effects with respect to pre- and post-natal development were reported.
Local Tolerance
The topical effects of CivanexTM (including histopathology of the treatment site) were comprehensively evaluated in the toxicology studies and there was no significant evidence of toxicity.
3.2.4 Conclusion
The non-clinical studies for this drug submission are considered acceptable. Based on the non-clinical pharmacology and toxicology studies, there are no major safety concerns that would suggest unexpected adverse effects in patients treated with CivanexTM at the recommended therapeutic dose.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Clinical pharmacodynamic studies on the drug substance, zucapsaicin, were not considered necessary due to the lack of systemic absorption of zucapsaicin after the topical application of the drug product, CivanexTM.
3.3.2 Pharmacokinetics
Zucapsaicin serum concentrations were below the level of quantitation (LOQ) of 0.5 ng/mL at all time-points for all of the subjects that received topical administration of 0.65 grams of zucapsaicin cream 0.075% which would deliver 0.488 mg of zucapsaicin in each application for a total daily dose of 2.928 mg of zucapsaicin each day for six days and a total daily dose of 0.976 mg of zucapsaicin on the seventh day. The application rate of zucapsaicin was 1.2 times the proposed maximum daily dose. A maximum systemic absorption of less than the LOQ (that is [i.e.], <0.5 ng/mL) would appear to offer little if any risk of systemic toxicity. Despite the limits imposed by population size and methodology, no systemic absorption of zucapsaicin was observed.
Given the lack of systemic exposure to zucapsaicin, further exploration of the PK profile via a standard battery of clinical studies was not conducted and was not considered necessary. Owing to the lack of systemic absorption, zucapsaicin has no potential for hepatic metabolism and the potential for plasma protein binding is non-existent. Systemic absorption and distribution of zucapsaicin with topical application has not been observed clinically.
Site of Application
Zucapsaicin cream has been tested in humans for its phototoxic, photoallergic, and contact sensitization potential. Zucapsaicin concentrations of 0.025%, 0.075%, 0.25%, 1.0%, and vehicle alone were not found to be significant irritants or contact sensitizers. These concentrations and the vehicle alone have also been determined to lack photoallergic or phototoxic potential.
Zucapsaicin cream 0.075% produced local reactions of burning and stinging which were, tolerable (mild to moderate) and reversible. No serious adverse events (AEs) were reported.
Drug Interactions
In a clinical study, 0.65 g of CivanexTM was applied to both knees three times a day for seven days (approximate dose of 3.9 g/day). At the end of the treatment period, no measurable levels of zucapsaicin were detected in serum. The LOQ for the assay was 0.5 ng/mL. In an in vitro study to evaluate the potential for zucapsaicin to inhibit six CYP isozymes (CYP 1A2, 2C9, 2C19, 2D6, 2E1, and 3A4) following topical application, the systemic levels of zucapsaicin were below the 50% inhibitory concentration (IC50) values for any of the isozymes tested, and it is unlikely that zucapsaicin would affect other drugs metabolized by these isozymes.
3.3.3 Clinical Efficacy
The clinical efficacy of CivanexTM was primarily based on a single 12-week, Phase III, randomized, double-blind, controlled, parallel-group, multicentre study in 695 patients with osteoarthritis of the knee. All patients received a stable dose of oral COX-2 inhibitors (42%) or NSAIDs (58%) and were randomized to receive applications of either CivanexTM (zucapsaicin cream 0.075%) (number [n] =344) or the inactive control zucapsaicin cream 0.01% (n=351) three times daily. The primary endpoint was the Time Weighted Average (TWA) change from baseline of three co-primary endpoints: osteoarthritis pain of the knee and physical function, both assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC), and the Subject's Global Evaluation (SGE). The results of this study failed to demonstrate a clinically significant benefit of CivanexTM over zucapsaicin cream 0.01% for the treatment of osteoarthritis of the knee in this patient population, and therefore the drug submission for CivanexTM received a NON.
Upon further analysis, it was found that the efficacy of CivanexTM was similar to zucapsaicin cream 0.01% for patients experiencing mild to moderate pain while using oral NSAIDs or COX-2 inhibitors; and the efficacy of CivanexTM was greater than zucapsaicin cream 0.01% in patients still experiencing severe pain while using oral NSAIDs or COX-2 inhibitors. With the use of piece-wise linear regression to assess the significant treatment by baseline interaction, it was revealed that CivanexTM was significantly more effective than zucapsaicin cream 0.01% in patients with a baseline pain score >10. Similarly, the results of the WOMAC Function and SGE scores were significantly better than zucapsaicin cream 0.01% in patients with baseline function scores >39, and baseline SGE scores <1. For all three co-primary endpoints in the 12-week controlled study, the patients who exhibited the best response to CivanexTM were those in the worst condition as determined by baseline scores. The response to the NON addressed the previous issue of the poor risk/benefit analysis by limiting the indication to those patients with high levels of pain despite the use of concomitant oral NSAIDs or COX-2 inhibitors. The indication was further restricted by limiting the treatment duration to 3 months and adding the need for concomitant NSAIDs.
A statistical consult from Health Canada's Office of Science supported the use of piece-wise linear regression to identify the subgroup of patients with the largest benefit from treatment.
3.3.4 Clinical Safety
In the Phase II and Phase III studies, 689 subjects were exposed to CivanexTM with 475 exposed for 3 months, 320 for 6 months, and 285 for 12 months.
In the 12-week Phase III study (described in section 3.3.3. Clinical Efficacy), there were no serious AEs or systemic AEs that were determined by the investigator to be directly attributed to the study drug. This was expected as CivanexTM is not absorbed systemically. At least one AE was reported in 229 (67%) of the patients treated with CivanexTM and in 181 (52%) of the patients treated with zucapsaicin cream 0.01%. The majority of AEs were mild to moderate in nature, and aside from application site reactions, the majority were determined by the investigator to be not related to the study drug.
Application site burning sensations were the most frequently reported AEs by both treatment groups, and were predominantly mild to moderate in severity. The other common AE was application site warmth.
Burning sensations were initially reported on Day 1 by 18% and 4% of the CivanexTM and zucapsaicin cream 0.01% groups, respectively. By Day 14, the corresponding numbers were 10% and 3%, and by Day 84, the numbers were reduced to 3% and 1%. The burning sensations were transient with approximately 50% of the events lasting 0-30 minutes, approximately 23% of the events lasting 31-60 minutes, and the remaining 27% lasting more than 1 hour. While most of the AEs were mild or moderate, 10% of the patients treated with CivanexTM experienced severe application site burning compared to 1% in the zucapsaicin cream 0.01% group.
Application site warmth, was reported in 19 (6%) of the patients treated with CivanexTM compared to 10 (3%) in the zucapsaicin cream 0.01% group
The number of withdrawals due to AEs were significantly more in the CivanexTM group (25 [7%]) compared to the zucapsaicin cream 0.01% group (6 [2%]). Half of the withdrawals in the CivanexTM group were due to burning sensations at the application sites.
A total of 351 patients were enrolled in a long-term open-label study for patients who completed the controlled 12-week Phase III clinical study. The safety profile was similar in this study with the most commonly reported AEs being application site burning sensation (22%) and application site warmth (4%). The percentage of patients completing the year-long study was 81%.
Overall, CivanexTM was generally well-tolerated. The severe burning sensations were transient and self-limiting and do not preclude the use of CivanexTM.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
CivanexTM in conjunction with oral COX-2 inhibitors or NSAIDs has been shown to relieve severe pain not controlled with oral COX-2 inhibitors or NSAIDs alone, in adults with osteoarthritis of the knee. Data from the pivotal Phase III study indicated that there was an increased effect on relief of the signs and symptoms of osteoarthritis in patients with increased baseline scores of the WOMAC Pain Subscale and the WOMAC Function Subscale. The indication for CivanexTM focuses on this population.
CivanexTM is not absorbed systemically, and the majority of the adverse events were mild to moderate and dissipated over time. Therefore, the benefit/risk assessment is favourable in this restricted population of patients when used in conjunction with oral NSAIDs or COX-2 inhibitors. All concerns regarding the safety of CivanexTM have been adequately addressed in the Product Monograph.
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 CivanexTM in conjunction with COX-2 inhibitors or NSAIDs is favourable for the relief of severe pain in adults with osteoarthritis of the knee, not controlled with oral COX-2 inhibitors or NSAIDs alone, for the duration of no more than three months. The NDS complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the NOC pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: CivanexMC
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2008-01-17 |
| Submission filed: | 2008-10-30 |
| Screening 1 | |
| Screening Acceptance Letter issued: | 2008-12-19 |
| Review 1 | |
| Quality Evaluation complete: | 2009-10-13 |
| Biostatistics Evaluation complete: | 2009-07-02 |
| Notice of Non Compliance issued by Director General (efficacy issues): | 2009-10-15 |
| Response filed: | 2010-02-01 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2010-02-19 |
| Review 2 | |
| Clinical Evaluation complete: | 2010-07-08 |
| Labelling Review complete: | 2010-07-12 |
| Notice of Compliance issued by Director General: | 2010-07-15 |