Summary Basis of Decision for Toctino

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:

Drug
Toctino

Alitretinoin, 10 mg and 30 mg, Capsule, Oral

Basilea Pharmaceuticals Corp.

Submission control no: 119010

Date issued: 2010-04-12

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:

Toctino

Manufacturer/sponsor:

Basilea Pharmaceuticals Corp.

Medicinal ingredient:

Alitretinoin

International non-proprietary Name:

Alitretinoin

Strength:

10 mg and 30 mg

Dosage form:

Capsule

Route of administration:

Oral

Drug identification number(DIN):

  • 02337630 - 10 mg
  • 02337649 - 30 mg

Therapeutic Classification:

Immunomodulator/anti-inflammatory agent

Non-medicinal ingredients:

Capsule content: DL-alpha-tocopherol, medium chain triglycerides, partially hydrogenated soybean oil, soybean oil, and yellow wax.

Capsule shell: Gelatin, glycerol, iron oxide, sorbitol, and purified water.

Submission type and control no:

New Drug Submission, Control Number: 119010

Date of Submission:

2007-12-19

Date of authorization:

2009-11-13
2 Notice of decision

On November 13, 2009, Health Canada issued a Notice of Compliance to Basilea Pharmaceuticals Corp. for the drug product, Toctino.

Toctino contains the medicinal ingredient alitretinoin which is an immunomodulator/anti-inflammatory agent.

Toctino is indicated for the treatment of severe chronic hand eczema refractory to high potency topical corticosteroids in adults. Alitretinoin plays an anti-inflammatory and immunomodulatory role by down-regulation of the production of chemokines in cytokine-induced dermal cells and suppression of the expansion of cytokine-induced leucocytes and antigen presenting cells.

The market authorization was based on quality, non-clinical, and clinical information submitted. The safety and efficacy of Toctino in patients with severe chronic hand eczema (CHE) refractory to high potency topical corticosteroids was established in two double-blind, placebo-controlled Phase III studies. The treatment duration was 12 to 24 weeks. A total of 1032 patients with severe CHE were enrolled. Treatment with alitretinoin led to a significantly higher proportion of patients with clear/almost clear hands, compared to placebo. The response rate was found to be dose dependent. Response rates for different CHE subtypes were also dose dependent, except for patients with pomphlyx. Toctino has a safety profile common to retinoids. Toctino is highly teratogenic and should only be prescribed by physicians knowledgeable in the use of retinoids systemically, who understand the risk of teratogenicity in females of child-bearing potential. An adequate Risk Management Plan is in place and the Product Monograph contains the appropriate information, similar to other retinoid products currently marketed in Canada.

Toctino (10 mg and 30 mg alitretinoin) is presented as capsules. The recommended dose range for Toctino is 10 mg - 30 mg once daily with a meal. The recommended starting dose is 30 mg once daily. Dose reductions to 10 mg once daily may be considered in patients with unacceptable side effects. Patients at high risk for cardiac events should start on the lowest possible dose of Toctino and be carefully monitored due to increases in lipid levels. Dosing guidelines are available in the Product Monograph.

Toctino is contraindicated for women who are pregnant or breastfeeding.

Toctino is also contraindicated in patients with:

  • hepatic insufficiency;
  • severe renal insufficiency;
  • uncontrolled hypercholesterolemia;
  • uncontrolled hypertriglyceridemia;
  • uncontrolled hypothyroidism;
  • hypervitaminosis A;
  • hypersensitivity either to alitretinoin, to other retinoids or to any of the excipients;
  • rare hereditary problems of fructose intolerance;
  • concomitant treatment with tetracyclines.

Toctino 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 Toctino 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 Toctino is favourable for the treatment of severe chronic hand eczema refractory to high potency topical corticosteroids in adults.

3 Scientific and Regulatory Basis for Decision

A New Drug submission for Toctino was filed with Health Canada on December 19, 2007. During review, there were outstanding concerns with the analytical method used in the pivotal comparative bioavailability study (BAP00300), and there were concerns that there was insufficient data to characterize the effect of food on the proposed Toctino capsules. These outstanding concerns were issued to the sponsor in a Notice of Non-Compliance (NON) dated February 11, 2009. In response to the NON, the issues of concern were resolved, and additional information was provided for the Product Monograph, resulting in the issuance of a Notice of Compliance on November 13, 2009. A timeline of these events are reported in section 4 Submission Milestones. For more information see Comparative Bioavailability Studies in section 3.3.2 Pharmacokinetics.

3.1 Quality Basis for Decision

3.1.1 Drug Substance (Medicinal Ingredient)
General Information

Alitretinoin, the medicinal ingredient of Toctino, is an immunomodulator/anti-inflammatory agent. Alitretinoin belongs to the family of retinoids and is believed to modify the immune system and have an anti-inflammatory effect on eczematous lesions of the hands by reducing the production of some substances responsible for inflammation, thereby reducing and helping to clear eczema.

Manufacturing Process and Process Controls

The drug substance, alitretinoin, is synthetically derived. Materials used in the manufacture of the drug substance are considered to be suitable and/or meet standards appropriate for their intended use. The manufacturing process is considered to be adequately controlled within justified limits.

Characterization

The structure of alitretinoin has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.

Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within International Conference of Harmonisation (ICH) established limits and/or were qualified from toxicology studies and batch analyses; and therefore considered to be acceptable.

Control of Drug Substance

The drug substance specifications and analytical methods used for quality control of alitretinoin are considered acceptable.

No deficiencies were found with respect to the validation reports.

Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.

The drug substance packaging is considered acceptable.

Stability

Based on the long-term, real-time, and accelerated stability data submitted, the proposed shelf-life and storage conditions for the drug substance were supported and are considered to be satisfactory.

3.1.2 Drug Product
Description and Composition

The drug product, Toctino, is presented as oval, soft gelatin capsules of two different strengths. The 10 mg capsule contains 10 mg of alitretinoin and the 30 mg capsule contains 30 mg of alitretinoin. Both strengths have the following non-medicinal ingredients: soybean oil, partially hydrogenated soybean oil, medium chain triglycerides, yellow wax, and DL-alpha-tocopherol. The capsule shells contain gelatin, glycerol, sorbitol, water, and iron oxide.

The capsules are available in blister packs of 10 capsules. Each box contains 3 blister packs.

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 alitretinoin 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 manufacturing process uses conventional manufacturing techniques. The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.

Control of Drug Product

Toctino is tested to verify that its identity, appearance, content uniformity, assay, dissolution, disintegration in water, levels of degradation products, and drug-related impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable.

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 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, and accelerated stability data submitted, the proposed 36-month shelf-life at 15-30°C for Toctino is considered acceptable.

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 Toctino are considered suitable for the activities and products manufactured. All sites are Good Manufacturing Practices (GMP) compliant for the manufacturing activities.

3.1.4 Adventitious Agents Safety Evaluation

Two excipients of animal origin are used in the gelatin to produce the capsule shells. None of these materials come within the scope of the European Medicines Agency (EMEA) guideline, EMEA/410/01 Rev.2, on transmissible spongiform encephalopathies, and both materials are considered safe for use in oral medicinal products.

3.1.5 Conclusion

The Chemistry and Manufacturing information submitted for Toctino 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

Alitretinoin, an endogenous retinoid, is a close analogue to the well-characterized isotretinoin and tretinoin. As a result, the scope of the non-clinical program was limited and extensive study of the pharmacodynamic (PD) profile of alitretinoin was not warranted due to the available information on the action of retinoids, both in vivo and in vitro.

The non-clinical pharmacokinetic (PK) program comprised of the standard studies required to characterize the PK properties of alitretinoin in animals.

The toxicity studies consisted of the standard studies required to characterize the toxicological profile after single and repeated administration of alitretinoin to support chronic clinical use of the drug.

3.2.1 Pharmacodynamics

On the molecular level, the activity of alitretinoin was mediated by nuclear retinoid A receptors (RARs) and retinoid X receptors (RXRs). Studies showed alitretinoin to have several potent immunomodulatory and anti-inflammatory activities which included chemokine suppression, expansion of activated leukocytes, expansion of activated antigen-presenting cells, and allogenic activation of leukocytes. Also, alitretinoin had antiproliferative effects, where it was shown to improve dermal repair and induce cellular differentiation, and inhibit clonal and tumour cell growth. Although much information on the biological activity of retinoids is available, the exact mechanism of action of alitretinoin with respect to chronic hand eczema (CHE) remains unknown.

In mice, no effects on the central nervous system (CNS) were observed with single oral doses of 20, 200, or 2000 mg/kg. In dogs, no cardiovascular or respiratory effects were reported at single oral doses of 10 or 30 mg/kg. Both species had alitretinoin plasma concentrations much higher than the expected therapeutic concentration.

3.2.2 Pharmacokinetics
Absorption

Alitretinoin had delayed absorption and intermediate oral availability which was dependent on the formulation used.

Distribution

The volume of distribution was 6 to 18 times greater than the plasma volume; a volume of distribution greater than the extracellular volume suggesting that tissue exposure will occur.

In the plasma of dogs, rats, and mice, alitretinoin was highly bound (>95%) to proteins.

Metabolism and Excretion

The pharmacokinetics of alitretinoin were roughly linear with dose and time, and there were no relevant gender differences. There was no accumulation of alitretinoin or its metabolites and excretion was rapid, predominantly via biliary excretion and metabolism. The main metabolic pathways for all endogenous retinoids are oxidation, isomerisation, and glucuronidation. Alitretinoin was found to inhibit the cytochrome P450 (CYP) enzyme CYP3A4, but only at very high concentrations.

3.2.3 Toxicology
Single-Dose Toxicity

Alitretinoin was shown to be of low acute toxicity. In mice, the lethal dose that killed 50% of the animals tested (LD50) was >4000 mg/kg at 24 hours, after a single intraperitoneal dose.

Repeat-Dose Toxicity

The toxicity profile of alitretinoin essentially reflects the well-known features of hypervitaminosis A and most side effects were reversible upon treatment discontinuation. The degree of hypervitaminosis A associated with alitretinoin was comparable to isotretinoin and tretinoin.

Dose-dependent retinoid-specific toxicity (consistent with hypervitaminosis A) was manifested in studies with repeat-dose administration (rat: up to 6 months; mice: up to 13 weeks; dog: up to 9 months). The dose-limiting toxic effects were bone fractures in rats (also evaluated by X-ray), and skin and mucus membrane effects in dogs.

In rats, findings included impaired general condition, minor changes in haematological and clinical chemistry parameters [for example (e.g.) reduced red blood parameters, increased platelet count, and increased triglycerides], hypertrophy, increased glycogen storage and fatty change of the liver, bone fractures, thickening of epiphyseal cartilage, hyperplasia and hyperkeratosis of the forestomach and esophagus, degenerative changes in the female reproductive organs and eyes, and medullary calcification of the kidneys. Transient minor behavioral changes (such as paddling and salivation) were noted in rats after prolonged administration of high doses.

In mice, the main findings at high doses of alitretinoin included increased liver weight, and degenerative changes of the male reproductive organs.

In dogs, impaired general condition, skin and mucus membrane effects, gastro-intestinal irritation, minor changes in haematological and clinical chemistry parameters (previously mentioned), liver hypertrophy, and changes in male reproductive organs were observed. In a 39-week study in dogs, alitretinoin at doses up to 6 mg/kg/day had no effect on thyroid stimulating hormone (TSH) or thyroxin (T4).

Genotoxicity

Alitretinoin showed no genotoxic activity with the Ames test, the human chromosome aberration assay, and the micronucleus test.

Carcinogenicity

Carcinogenicity studies with alitretinoin showed no increase in neoplastic lesions in mice and rats.

Reproductive and Developmental Toxicity

Alitretinoin had no effects on fertility and reproductive performance in male and female rats.

Like other oral retinoids, alitretinoin was found to be teratogenic in an in vitro limb bud cell assay and in a pilot teratology study in mice. Since alitretinoin is an acknowledged teratogen, no regulatory teratogenicity or pre- and post-natal studies were performed.

Phototoxicity

Alitretinoin was phototoxic, and its phototoxic potential was confirmed in vitro and in vivo after dermal application. Phototoxicity after oral administration was not examined.

Local Tolerance

Alitretinoin was found to cause marked dose-dependent skin irritation, which was apparent within 5 days of a >0.5% topical application of alitretinoin.

3.2.4 Conclusion

Alitretinoin has demonstrated several potent immunomodulatory and anti-inflammatory activities that may be related to the activity of alitretinoin in CHE. The non-clinical PK and toxicity studies support its safe use in humans as described in the Product Monograph. Adequate statements are in place in the Product Monograph to address the identified safety concerns. Alitretinoin, like other oral retinoids, was found to be highly teratogenic.

3.3 Clinical basis for decision

3.3.1 Pharmacodynamics

The exact mechanism of action of alitretinoin with respect to chronic hand eczema (CHE) in particular, remains unclear. However, the efficacy of alitretinoin in CHE is unquestioned, owing to the favourable results from clinical studies in patients suffering from moderate or severe CHE.

Analysis of human skin samples of patients suffering from nickel allergy demonstrated an overexpression of CXCR3 ligands and CCL20 chemokines. In vitro studies evaluated the immunomodulatory and anti-inflammatory effect of alitretinoin. The findings demonstrated that structural cells of the skin including epidermal keratinocytes and endothelial cells, as well as, leukocyte subsets are targets for alitretinoin. Within structural cells, alitretinoin markedly suppressed pathogenically relevant chemokine expression of CXCR3 ligands and CCL20 suggesting that this drug may impair the recruitment of distinct leukocyte subsets to sites of skin inflammation. It was also shown that alitretinoin markedly inhibits the expansion of pro-inflammatory cytokine activated T-lymphocytes and antigen presenting leucocytes subsets. Through these mechanisms alitretinoin may interfere with the initiation, as well as, the maintenance of contact dermatitis lesions.

Mean plasma levels of retinol/retinol ester and retinol binding protein decreased by 25% and 35%, respectively, 24 hours after administration of the first dose in subjects receiving 40 mg alitretinoin. No further decrease was observed for either parameter at later assessments. No conspicuous change was observed for either marker in subjects receiving 20 mg alitretinoin. These results are consistent with the dose-dependent decrease in plasma retinol associated with single dose administration of alitretinoin. The absence of further decrease in retinol plasma level with repeated dosing suggests that a plateau effect may have been reached before the end of the 14-day administration. All observed values remained well above the threshold levels associated with mild changes in dark adaptation. Electroretinography was conducted in subjects treated with the 40 mg dose of alitretinoin, and revealed no effect of alitretinoin on retinal function.

3.3.2 Pharmacokinetics
Absorption

Peak plasma concentrations of alitretinoin were observed within 3 to 4 hours after drug intake following oral administration of 5, 15, 40, 80, and 150 mg alitretinoin in healthy volunteers.

Chronic administration of alitretinoin for up to 24 weeks did not result in accumulation or time-dependent changes in the disposition of alitretinoin or its major metabolite, 4-oxo-alitretinoin, at a dose of 10 to 30 mg administered orally. In addition, systemic exposure to alitretinoin and 4-oxo-alitretinoin was linear over the dose range of 10 to 30 mg.

The systemic exposure was increased when alitretinoin was administered with food.

Comparative Bioavailability Studies

A pivotal comparative bioavailability study (BAP00300) was conducted under fed conditions to bridge the 10 and 20 mg Toctino (alitretinoin) capsules that were administered in the pivotal Phase III clinical studies to the proposed commercial 10 mg and 30 mg Toctino capsules. The data from Study BAP00300 met the applicable Health Canada standards for comparative bioavailability, however, due to outstanding concerns with the analytical method that was used to analyze the subject samples, the data from pivotal Study BAP00300 was not considered to be reliable. Additionally, the data from the food-effect study (BAP00007) was deficient and as a result there was insufficient data to characterize the effect of food on the rate and extent of absorption of alitretinoin from the proposed Toctino capsules. These outstanding concerns from the review were issued to the sponsor in a Notice of Non-Compliance (NON) dated February 11, 2009.

The concerns regarding the bioavailability of the Phase III capsules compared to the proposed commercial preparation for the 10 and 30 mg dosage were addressed by the sponsor in the NON-Response. The response was considered acceptable. As well, discussions regarding the food-effect study resulted in the agreement that an additional food-effect study was not required. It is well known that the absorption of this class of drugs is enhanced by food, and that the clinical trials were done in a fed-state. Therefore, providing clear information in the labelling and the Product Monograph stating that the medication must be taken with food is found to be acceptable. The presentation of this information in this manner is in line with other marketed retinoids.

Distribution

In plasma of humans, alitretinoin was highly bound (99%) to plasma proteins. The volume of distribution was not determined in humans. In the animal studies, the volume of distribution was greater than the plasma volume.

Metabolism

Alitretinoin is metabolized by oxidation in the liver by CYP3A4 into the metabolite 4-oxo-alitretinoin, and then further metabolized to give all-trans retinoic acid and 4-oxo-all-trans retinoic acid. Similar to the parent compound, maximum plasma concentrations of all metabolites occurred between 2 and 5 hours after dosing followed by a rapid decline.

Excretion

After the oral administration of radiolabelled alitretinoin, total urinary and faecal recovery of the radiolabelled material was considered as complete with individual values ranging from 90-99% within 5-7 days. Alitretinoin appeared to be completely absorbed and extensively metabolized. Metabolic clearance was the major pathway of elimination.

Drug Interactions

Co-administration with strong CYP3A4 or human P-glycoprotein (Pgp) inhibitors, such as ketoconazole, increased levels of alitretinoin. The drug exposure of alitretinoin, as measured by the area under the curve (AUC) values, was approximately 40% higher with the coadministration of ketoconazole.

Single and repeat administration of alitretinoin did not alter the pharmacokinetics of ciclosporin or ketoconazole. A slight reduction of simvastatin levels was observed when co-administrated with alitretinoin.

CYP3A4 substrates such as ciclosporin and simvastatin did not affect the pharmacokinetics of alitretinoin. Strong inhibition of CYP3A4/PgP by ketoconazole significantly increased alitretinoin levels but not that of the 4-oxo-metabolites. Exposure to alitretinoin and 4-oxo-metabolites remained constant with time, with no indication of accumulation or auto-induction, and therefore, dose proportionality can be assumed up to 30 mg.

Alitretinoin was well-tolerated alone or in combination with single doses of interaction drugs and no new safety signals were identified.

3.3.3 Clinical Efficacy

The efficacy and safety of Toctino were primarily evaluated from two pivotal randomized, double-blind, placebo-controlled, parallel group, multicentre, Phase III studies, Study BAP00089 and Study BAP00091.

Study BAP 00089 included 1032 patients in the intent-to-treat (ITT) population. Patients in this study had severe CHE refractory to high potency topical corticosteroids, and had disease duration of at least six months. Treatment was for 12 or 24 weeks, with either 10 or 30 mg of Toctino, or placebo. The primary endpoint was to demonstrate that the response rate based on Physician Global Assessment (PGA) in one or both Toctino groups is superior to the response rate in the placebo group at the end of therapy (Week 12 or Week 24), or at the latest assessment for patients withdrawn prematurely.

Secondary endpoints included: the proportion of patients achieving at least mild disease, time to achieving clear to almost clear hands, reduction in total lesion symptom score, the patient global assessment (PaGA) of disease severity, and reduction in extent of disease. Women of childbearing potential were required to use two types of contraception and received extensive instructions and counselling in order to avoid pregnancy.

At the end of therapy, 115 (27.5%) patients in the Toctino 10 mg group, 195 (47.7%) patients in the Toctino 30 mg group, and 34 (16.6%) patients in the placebo group were responders [that means (i.e.), patients for whom the PGA rating was clear or almost clear]. In the ITT analysis, the difference between placebo and Toctino yielded p-values of p=0.004 for the 10 mg dose and p <0.001 for the 30 mg dose. Therefore, both of the Toctino doses (10 mg and 30 mg) were statistically significantly superior to placebo with respect to the PGA at the end of therapy. The response was dose dependent. Response rates for different CHE subtypes were also dose dependent, except for patients with pomphlyx. The secondary efficacy endpoints were consistent with the primary efficacy endpoint (PGA at end of therapy).

Study BAP00091 comprised of 360 patients in two cohorts. Cohort A included patients who had responded to treatment in Study BAP00089 and then relapsed. Cohort B included patients who were non-responding to treatment in Study BAP00091 after 12 weeks of treatment with 30 mg of alitretinoin. Patients who remained classified as "severe" after initial treatment were not included in the study. Responding patients in Cohort A received the same dosage of Toctino as they previously received (10 or 30 mg) and the non-responding patients in Cohort B received 30 mg of Toctino. Responding patients who had received a placebo in the original study continued to receive placebo. Primary and secondary efficacy endpoints were the same as the original study (Study BAP00089). Patients were treated for 12 or 24 weeks.

Results showed that there was a response rate of 50.4% (rated clear or almost clear) for patients who did not respond to the 10 mg dose in the previous study but had taken 30 mg dose in this study. Additional treatment with the 30 mg dose in non-responders demonstrated a 39.1% response rate. In Cohort A, 79.6% of the patients treated with 30 mg responded compared to 8.3% in the corresponding placebo arm. The difference between the 10 mg group and corresponding placebo group did not reach statistical significance (47.6% versus 10%; p=0.10) but this may be explained by the low number of patients assigned to this group (10 received Toctino and 1 received placebo). Overall, the data showed that either a higher dose or a treatment prolongation can benefit patients who fail to respond to Toctino treatment initially.

3.3.4 Clinical Safety

Toctino, given at 10 mg or 30 mg once daily for up to 24 weeks, was generally well-tolerated in the treatment of patients with severe CHE in both pivotal studies; Study BAP00089 and Study BAP00091 (see 3.3.3 Clinical Efficacy).

In Study BAP00089, the most frequent adverse event (AE) in patients treated with Toctino was headache, with the percentage in the 30 mg dose group almost twice as high as that in the 10 mg dose group. Other frequent AEs were nasopharyngitis, eczema and erythema, and dry lips. Erythema and dry lips were also considerably more frequent in patients treated with 30 mg compared to those that were treated with 10 mg. Lab results showed increased levels of triglycerides with treatment. Other known retinoid effects included decreased haemoglobin, decreased TSH, decreased T4 levels, and increased creatine phosphokinase (CPK) levels. The frequency of treatment-emergent AEs leading to treatment discontinuation was higher in the 30 mg dose group compared to the 10 mg dose group. The most frequent treatment-emergent AEs (i.e., those occurring in at least 5 patients overall) leading to treatment discontinuation were headache, and various skin and subcutaneous tissue disorders. The number of AEs requiring treatment was considerably higher in the 30 mg dose group than the 10 mg dose group, mostly because of the higher incidence of headache associated with the higher dose of Toctino. One patient died in this study due to a myocardial infarction. The investigator assessed this event as being unrelated to the study medication.

In Study BAP00091, the proportion of patients experiencing moderate, severe, or life-threatening AEs was greater in the Toctino 30 mg dose groups (Cohort A and Cohort B) compared to the Toctino 10 mg group or the placebo group. Headache was the most frequently reported AE. All reports of headache occurred in the 30 mg dose groups (Cohort A 30 mg: 7 patients, 14%; Cohort B 30 mg: 29 patients, 11.9%). The frequency of dry lip, dry mouth, and cheilitis (mucocutaneous events often associated with retinoid use) was not noticeably higher in the active treatment groups compared to the placebo group. Laboratory changes included increased serum cholesterol and triglycerides, and changes in T4, CPK, TSH, and haemoglobin. During the study period, there was one patient death (acute cardiac failure) that was unrelated to the study drug.

A supportive open-label safety study (BAP00626) included 248 patients that were administered 30 mg of alitretinoin once daily for 24 weeks. The AEs were typical class effects of oral retinoids such as headache, flushing, nasopharyngitis, and skin disorders. A total of 21 patients withdrew due to AEs, mostly due to headache. The most commonly observed changes in laboratory parameters were changes in serum cholesterol, triglycerides, and TSH, consistent with the class effects of oral retinoids. There were no deaths reported in this study. One serious AE, angioneurotic oedema, was assessed as being remotely related to study treatment.

Review of a thorough QTc study in 48 healthy volunteers showed a dose-related increase in heart rate with Toctino use. In subjects receiving Toctino 30 mg for 3 days, the maximum mean increase in heart rate was 4.4 bpm at 3 hours post-dosing. In subjects receiving a single dose of Toctino 60 mg, significant increases in heart rate were observed from 3 to 12 hours post-dosing, with a maximum mean increase of 10.6 bpm at 8 hours post-dosing. The incidence of heart rate values greater than 100 bpm and =25% higher than baseline was 8.7% for the placebo treatment, 8.3% for the Toctino 30 mg treatment, and 23.9% for the Toctino 60 mg treatment. It is not possible to exclude from this limited size study a moderate effect on QTcF after the exposure of 30 mg Toctino.

3.4 Benefit/Risk Assessment and Recommendation

3.4.1 Benefit/Risk Assessment

Toctino provides patients with severe CHE another option for treatment. Because of the severity of their condition, patients have had to be satisfied with either treatment with topical corticosteroids or the off-label use of immune modulating drugs such as methotrexate, which are not without their own unwanted side effects. This is not to say the use of Toctino is without risk. In fact the risks are severe, given that this medication is a powerful teratogen, and the risks to an unborn foetus include deformity and death. It is therefore important that the risk management program for Toctino include, for all women of child-bearing potential, significant pregnancy prevention information and counselling, including using two reliable forms of contraception simultaneously and the requirement to undergo regular pregnancy testing, as seen with other retinoids on the market. Despite this, the benefit/risk assessment of Toctino remains positive due to the fact that it will enable patients who are sometimes severely disabled by untreatable chronic eczema to have a new therapeutic option.

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 Toctino is favourable for the treatment of severe chronic hand eczema refractory to high potency topical corticosteroids in adults. 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 (NOC) pursuant to section C.08.004 of the Food and Drug Regulations.

4 Submission Milestones

Submission Milestones: Toctino

Submission MilestoneDate
Pre-submission meeting:2005-12-07
Submission filed:2007-12-19
Screening 12008-01-21
Screening Deficiency Notice issued:2008-02-11
Response filed:2008-03-10
Screening Acceptance Letter issued:2008-04-17
Review 1
Quality Evaluation complete:2009-02-09
Biopharmaceutics Evaluation complete:2009-02-09
Clinical Evaulation complete:2009-02-09
Notice of Non-Compliance issued by Director General (clinical safety and efficacy issues):2009-02-11
Pre-submission meeting:2009-04-23
Response filed:2009-05-08
Screening 2
Screening Acceptance Letter issued:2009-06-17
Review 2
Biopharmaceutics Evaluation complete:2009-10-19
Clinical Evaulation complete:2009-10-27
Labelling Review complete:2009-11-12
Notice of Compliance (NOC) issued by Director General:2009-11-13