Summary Basis of Decision for Otezla

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
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Otezla is located below.
Recent Activity for Otezla

The SBDs written for eligible drugs (as outlined in Frequently Asked Questions: Summary Basis of Decision [SBD] Project: Phase II) approved after September 1, 2012 will be updated to include post-authorization information. This information will be compiled in a Post-Authorization Activity Table (PAAT). The PAAT will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decisions were negative or positive. The PAATs will be updated regularly with post-authorization activity throughout the product life cycle.

Post-Authorization Activity Table (PAAT) for Otezla

Updated:  2024-12-09

The following table describes post-authorization activity for Otezla, a product which contains the medicinal ingredient apremilast. For more information on the type of information found in PAATs, please refer to the Frequently Asked Questions: Summary Basis of Decision (SBD) Project: Phase II and to the List of abbreviations found in Post-Authorization Activity Tables (PAATs)

For additional information about the drug submission process, refer to the Guidance Document: The Management of Drug Submissions and Applications.

 

Drug Identification Number (DIN):

  • DIN 02434318 - 10 mg, 20 mg and 30 mg apremilast tablet kit, oral administration
  • DIN 02434334 - 30 mg apremilast tablet, oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DIN 02434318) market notification Not applicable Date of first sale 2022-01-10 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
Drug product (DIN 02434334) market notification Not applicable

Date of first sale 2021-01-18

The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations
SNDS # 233030 2019-11-05 Issued NOC 2020-08-10 Submission filed as a Level I – Supplement for a new indication. The indication authorized was: the treatment of adult patients with oral ulcers associated with Behçet’s disease who are candidates for systemic therapy. The submission was reviewed and considered acceptable, and an NOC was issued
NDS # 234568 2019-12-19 Issued NOC 2020-01-29 Submission filed to transfer ownership of the drug product from Celgene Inc. to Amgen Canada Inc. An NOC was issued.
NC # 208674 2017-08-23 Issued NOL
2017-11-03
Submission filed as a Level II (90 day) Notifiable Change (Risk Management Change) to update the PM with safety-related changes. As a result of the NC, modifications were made to the Warnings and Precautions section of the PM, and to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
NDS # 164228 2013-04-19 Issued NOC
2015-06-10
Regulatory Decision Summary published.
Drug product (DIN 02434334) market notification Not applicable Date of first sale:
2014-12-01
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
Drug product (DIN 02434318) market notification Not applicable Date of first sale:
2014-11-27
The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS #169862 2013-11-08 Issued NOC
2014-11-12
Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Otezla

Date SBD issued: 2015-01-20

The following information relates to the New Drug Submission for Otezla.

Apremilast, 10 mg, 20 mg, and 30 mg, tablets, oral

Drug Identification Number (DIN):

  • DIN 02434318 - 10 mg, 20 mg and 30 mg tablet kit
  • DIN 02434334 - 30 mg tablet

Celgene Inc.

New Drug Submission Control Number: 169862

 

On November 12, 2014, Health Canada issued a Notice of Compliance to Celgene Inc. for the drug product, Otezla.

The market authorization was based on quality (chemistry and manufacturing), non‑clinical (pharmacology and toxicology), and clinical (pharmacology, safety, and efficacy) information submitted. Based on Health Canada’s review, the benefit/risk profile of Otezla is favourable for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

 

1 What was approved?

 

Otezla, an inhibitor of phosphodiesterase 4 (PDE4) enzyme activity, was authorized for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Otezla has not been studied and is therefore not indicated in combination with other systemic (conventional or biologic) therapies or phototherapy for psoriasis.

No overall differences were observed in the safety or efficacy profile of elderly patients ≥65 years of age and younger adult patients <65 years of age in the clinical studies. Due to limited data available in very elderly patients (≥75 years of age), Otezla should be used with caution in this patient population.

The safety and effectiveness of Otezla in pediatric patients have not been established. Otezla should not be used in this patient population.

Otezla is contraindicated for patients who are pregnant, or who are breastfeeding. Otezla is also contraindicated for patients with a known hypersensitivity to the active substance or to any of the excipients in the drug product. Otezla was approved for use under the conditions stated in the Otezla Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Otezla (10 mg, 20 mg, and 30 mg apremilast) is presented as a tablet. In addition to the medicinal ingredient, apremilast, the tablet also contains croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, iron oxide red, iron oxide yellow (20 and 30 mg only) and iron oxide black (30 mg only).

For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

Additional information may be found in the Otezla Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Otezla approved?

 

Health Canada considers that the benefit/risk profile of Otezla is favourable for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Psoriasis is a chronic inflammatory skin condition which can range from mild to severe. Approximately 1.7% of the Canadian population has psoriasis. Plaque psoriasis, characterized by scaly, erythematous patches, papules, and plaques that are often pruritic, is the most common form, affecting 80% to 90% of psoriasis patients. Systemic therapies, which include phototherapy; conventional agents such as methotrexate, cyclosporine and acitretin; and biological therapies, are the treatment of choice for moderate to severe plaque psoriasis. Except for calcipotriol with betamethasone ointment, topical agents are only considered useful as adjuncts to systemic or phototherapies, and impractical as monotherapies for moderate to severe forms of psoriasis. Apremilast is a phosphodiesterase type 4 (PDE4) inhibitor and the first drug in its class to treat plaque psoriasis.

The safety and efficacy of Otezla 30 mg twice a day for treating moderate to severe plaque psoriasis were supported by two similar Phase III pivotal studies. The primary endpoint, a 75% improvement on the Psoriasis Area and Severity Index (PASI-75), is a clinically meaningful endpoint for evaluating the efficacy of therapeutics for plaque psoriasis. The proportions of psoriasis patients who achieved this endpoint were 28% and 23% more than placebo in the clinical studies, which represents a reasonable patient population who would benefit from this drug. The major secondary endpoint, a score of clear or almost clear with at least a 2 point reduction from baseline on the static Physician Global Assessment (sPGA), showed a more modest, but still statistically significant, level of efficacy as those observed with PASI-75. Other secondary endpoints were also generally supportive of the primary endpoint. Based on PASI-75, the efficacy of Otezla was observed across patient subgroups and remained stable up to Week 32. The study design prohibited estimates of efficacy beyond Week 32, but suggested that some responders at Week 32 could continue to benefit for up to a year.

The most commonly occurring adverse events associated with Otezla were gastrointestinal (diarrhea, nausea, vomiting), headache, and upper respiratory tract infections. Large imbalances relative to placebo were observed for gastrointestinal and headache events. These events were also more common in women than in men. However, the majority of these were mild in intensity and short-lived (2-4 weeks) with continued drug use. Treatment with Otezla was also associated with weight loss, with nearly 20% of patients experiencing a weight loss of 5% from baseline following one year of treatment. Women were more susceptible to weight loss than men. Preliminary safety signals were also observed for depression- and tachyarrhythmia- related events. Otezla modestly elevated heart rate, but showed no evidence of QT prolongation.

Strategies for mitigating the risks include: approval of a risk mitigation plan; indicating against the use of Otezla in combination with other systemic agents to treat psoriasis (due to lack of evidence); contraindicating use in patients with a hypersensitivity to Otezla, as well as to pregnant and nursing women; creating a registry to monitor pregnancy outcomes; and including warnings related to events of weight loss, tachyarrhythmia (especially atrial fibrillation), and depression (including depressed mood and suicidal ideation). Largely due to theoretical concerns, additional precautions were added for women attempting to conceive, patients susceptible to immunosuppression, very elderly (≥75 years old) patients, and patients with renal impairment. A dosage adjustment is required in patients with severe renal impairment.

There are several therapies available to treat moderate to severe plaque psoriasis with varying degrees of efficacy and risks. Otezla, while having generally modest efficacy, carries a low likelihood of serious risks and may offer greater convenience of use compared to certain other therapies. Unlike several other agents used to treat psoriasis, there was no evidence of risk for hepatotoxicity, nephrotoxicity, or serious infections.

Overall, the therapeutic benefits seen in the pivotal studies are considered positive and the benefits of Otezla therapy are considered to outweigh the potential risks. Otezla has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling and adequate monitoring. Appropriate warnings and precautions are in place in the Otezla Product Monograph to address the identified safety concerns.

This New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations. For more information, refer to the Clinical, Non-Clinical, and Quality (Chemistry and Manufacturing) Basis for Decision sections.

 

3 What steps led to the approval of Otezla?

 

Submission Milestones: Otezla

Submission Milestone Date
Pre-submission meeting: 2013-06-04
Submission filed: 2013-11-08
Screening  
Screening Acceptance Letter issued: 2014-01-16
Review  
Biopharmaceutics Evaluation complete: 2014-06-30
Quality Evaluation complete: 2014-10-20
Clinical Evaluation complete: 2014-11-12
Labelling Review complete: 2014-10-30
Notice of Compliance issued by Director General: 2014-11-12

 

For additional information about the drug submission process, refer to the Management of Drug Submissions Guidance.

 

4 What follow-up measures will the company take?

 

Requirements for post-market commitments are outlined in the Food and Drugs Act and Regulations.

 

6 What other information is available about drugs?

 

Up to date information on drug products can be found at the following links:

 

7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical basis for decision

 

Clinical Pharmacology

Apremilast, the medicinal ingredient of Otezla, is a small-molecule inhibitor of phosphodiesterase 4 (PDE4), and works intracellularly to modulate a network of pro-inflammatory and anti-inflammatory mediators. In clinical studies in patients with psoriasis, apremilast decreased lesional skin epidermal thickness, inflammatory cell infiltration, and expression of pro-inflammatory genes.

Apremilast pharmacokinetics were significantly altered in patients with severe renal impairment and dosage reductions to a maximum of 30 mg once a day (QD) is indicated in these patients. No dosage adjustment is necessary for patients with hepatic impairment.

Exposure and maximal concentrations of apremilast decreased to 72% and 42%, respectively, and may result in loss of efficacy, when co-administered with rifampin a cytochrome P450 (CYP) 3A4 inducer. Co-administration with CYP3A4 inducers (phenobarbital, rifampin, carbamazepine, and phenytoin) is therefore not recommended. Apremilast has not been evaluated and is not indicated in combination with potent immunosuppressive drugs (e.g.: cyclosporine, tacrolimus) or biological therapeutics for psoriasis such as TNF antagonistsm and anti-IL-12/23 p40 antibodies.

In a double-blind, placebo- and positive-controlled, randomized, multiple-dose, four period crossover study performed to investigate the effects of apremilast on electrocardiogram (ECG) interval parameters in healthy volunteers [number (n) = 60], a modest elevation in heart rate was observed. Apremilast was tested at a therapeutic dose of 30 mg twice a day (BID) on Days 1-4 and 30 mg QD on Day 5, and at a supratherapeutic dose of 50 mg BID on Days 1-4 and 50 mg QD on Day 5. On Day 5 of treatment, the maximum mean difference from placebo in heart rate was 3.4 beats per minute (bpm) [90% confidence interval (CI) 1.1, 5.6] for the 30 mg dose and 4.9 bpm (90% CI 3.3, 6.6) for the 50 mg dose. Apremilast did not have noteworthy effects on the QTc, QRS, or PR intervals on Day 5 of treatment at the doses tested.

Overall, the clinical pharmacological data support the use of Otezla for the specified indication.

For further details, please refer to the Otezla Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Otezla was based on two pivotal, multicentre, randomized, double-blind, placebo-controlled Phase III studies (Studies ESTEEM 1 and ESTEEM 2) which enrolled a total of 1,257 patients 18 years of age and older, with a diagnosis of plaque psoriasis for at least 12 months, moderate to severe plaque psoriasis at screening [that is (i.e.) had a body surface area (BSA) involvement of ≥10%, static Physician Global Assessment (sPGA) of ≥3 (moderate or severe disease), and a Psoriasis Area and Severity Index (PASI) score ≥12], and who were candidates for phototherapy or systemic therapy. Concomitant anti-psoriatic medications were prohibited during the study up to Week 32, with the exception of low potency topical corticosteroids on the face, axillae and groin, coal tar shampoo and/or salicylic acid scalp preparations. Efficacy on a background of other medications or phototherapy has not been adequately studied with Otezla.

Study ESTEEM 1 and Study ESTEEM 2 had a similar design through Week 32. In both studies, patients were randomized 2:1 to Otezla 30 mg BID or placebo for 16 weeks (Placebo-Controlled Phase). All patients were initiated on study drug with dose-titration over 5 days. From Weeks 16-32, all patients received Otezla 30 mg BID (Maintenance Phase). From Weeks 32-52, a selected subgroup of patients underwent a Randomized Treatment Withdrawal Phase.

Baseline demographics were generally similar across the treatment groups in each study and comparable between the studies. Across both studies, patients ranged in age from 18 to 83 years, with an overall median age of 46 years. A total of 108 patients (8.6%) were aged ≥65 years old, including 9 patients (0.7%) aged ≥75 years old. Most of the patients (68%) were male. Race was predominantly White (90%).

Baseline disease characteristics were generally similar across the treatment groups in each study and comparable between the studies. The mean baseline BSA involvement was 25.2% (median 21.0%), the mean baseline PASI score was 19.1 (median 16.8), and the proportions of patients with sPGA scores of 3 (moderate) and 4 (severe) at baseline were 70.0% and 29.8%, respectively. The mean duration since diagnosis of plaque psoriasis was 19.0 (median 16.6) years. A total of 18% of patients had a history of psoriatic arthritis.

Approximately 35% of patients had not received prior phototherapy, conventional systemic or biologic therapy for the treatment of psoriasis. Approximately 30% of all patients had received prior phototherapy, 38% had received prior conventional systemic therapy, and 30% had received prior biologic therapy for the treatment of psoriasis.

In both studies, the primary efficacy endpoint was the difference in the proportions of patients in the Otezla 30 mg BID and placebo treatment groups who achieved at least a 75% improvement on the Psoriasis Area and Severity Index (PASI-75) at Week 16 in reference to the baseline visit. The primary analysis was based on the Full Analysis Set (FAS), using a last observation carried forward (LOCF) approach to impute missing values at Week 16. In Study ESTEEM 1, the placebo-adjusted response rate (95% CI) in the proportion of patients achieving PASI-75 at Week 16, was 27.8% (23.1, 32.5; p<0.0001) for Otezla 30 BID patients. The percentage of responders was 5.3% (15/282) in the placebo group, and 33.1% (186/562) in the Otezla group. In Study ESTEEM 2, the placebo-adjusted response rate (95% CI) in the proportion of patients achieving PASI-75 at Week 16, was 23.0% (16.3, 29.6; p<0.0001) for Otezla. The percentage of responders was 5.8% (8/137) in the placebo arm, and 28.8% (79/274) in the Otezla group.

The major secondary endpoint was the difference in proportions of patients in the Otezla 30 mg BID and placebo groups who achieved a static sPGA score of clear (0) or almost clear (1) with at least a 2-point reduction from baseline at Week 16. In Study ESTEEM 1, the placebo-adjusted response rate (95% CI) in the proportion of Otezla-treated patients achieving a sPGA score of 0 or 1 at Week 16, was 17.8% (13.7, 21.9; p<0.0001). In Study ESTEEM 2, the placebo-adjusted response rate (95% CI) in the proportion of Otezla-treated patients achieving a sPGA score of 0 or 1 at Week 16, was 16.1% (10.2, 21.9; p<0.0001). These data, as well as certain other secondary endpoints, including the proportion of patients who achieved PASI-50 (50% improvement, regarded as a minimally meaningful difference), supported the primary endpoint.

Despite trends in the data to suggest that some early (Week 32) responders could continue to benefit from Otezla for up to 52 weeks, any meaningful conclusion on the durability of efficacy beyond Week 32 cannot be supported due to the study design. In patients exposed to Otezla for up to one year, the most common reason for discontinuation was lack of efficacy, reported by 21% of patients.

Overall, Otezla was demonstrated to have clinically meaningful efficacy on a modest, but reasonable, proportion of patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

For more information, refer to the Otezla Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The primary safety data pool (PSOR Phase III Data Pool) consisted of data from the two pivotal, Phase III, multicentre, randomized, double-blind, placebo-controlled studies (Studies ESTEEM 1 and ESTEEM 2) described in the Clinical Efficacy section. In this data pool, a total of 1,184 patients with moderate to severe plaque psoriasis were exposed to Otezla (apremilast), 968 patients were treated for at least 24 weeks and 564 patients were treated for at least 52 weeks. The more comprehensive Apremilast Data Pool included data from 2,357 Phase II/III patients exposed to Otezla 30 mg BID, 1,308 of which were from the psoriasis clinical program, and the remainder from the psoriatic arthritis or rheumatoid arthritis clinical programs. While this data pool included patients with different disease profiles, it was considered useful for detecting uncommon adverse event signals.

During the 16-week placebo-controlled period of the two pivotal studies, the primary reason for discontinuation of Otezla was due to adverse events (4.3%) whereas in the full Otezla Exposure Period, which included patients treated for more than 52 weeks, 644/1184 (54.4%) of patients discontinued, primarily due to of lack of efficacy (25.4%), voluntary withdrawal (10.8%) and adverse events (8.4%).

In the PSOR Phase III Data Pool, 57.2% of patients randomized to the placebo group experienced an adverse event during the placebo-controlled period (Weeks 0-16) compared to 68.9% of patients randomized to Otezla. The most common adverse events in the Otezla group which were greater than in the placebo group were diarrhea (17.8%), nausea (16.6%), upper respiratory tract infection (8.4%), nasopharyngitis (7.3%), tension headache (7.3%), and headache (5.8%). The incidences of these events were higher in females than males. In particular, nausea was experienced by 29.7% of women (9.9% of males), diarrhea by 24.0% of women (14.6% of men), vomiting by 7.9% of women (1.6% of men), and tension headache by 11.5% of women (5.2% of men). The majority of the adverse events of diarrhea, nausea, headache, and tension headache occurred at the highest incidence during the first 2 weeks of dosing with Otezla. These events were generally mild in intensity, with the incidence of severe episodes being uncommon.

In general, the safety profile of Otezla did not change between the earlier and later exposure periods within the pivotal studies.

In the full period of exposure to Otezla (including patients with >52 week total exposure), the most common severe events reported by treated patients were psoriasis (0.5%), headache (0.4%), migraine (0.4%), diarrhea (0.3%), nausea (0.3%) and vomiting (0.3%). The most common adverse events leading to discontinuation were nausea (1.4%), diarrhea (0.9%), psoriasis (0.9%), headache (0.4%) and vomiting (0.4%); and the most common serious adverse events were nephrolithiasis (0.3%), osteoarthritis (0.3%), and coronary heart disease (0.3%). In the psoriasis clinical program, a total of 6 deaths were reported; 2 in patients with no previous exposure to Otezla. A death of acute cardiac failure in a 30-year old female was reported with no plausible etiology or significant risk factors. No death in these studies could be causally associated with Otezla.

In the more comprehensive Apremilast Data Pool, exposure to Otezla was associated with an increased incidence of tachyarrhythmias, including atrial fibrillation. During the placebo-controlled period, the incidence of adverse events subsumed by the preferred term, tachyarrhythmia, was 0.2% for placebo and 0.6% for Otezla. The most frequent tachyarrhythmic adverse event was atrial fibrillation with an incidence of 0.1% (0.2 events per 100 subject years) for placebo-treated patients and 0.3% (0.8 events per 100 subject years) for patients treated with Otezla.

In the PSOR Phase III Data Pool, during the placebo-controlled period, the incidence of depression (excluding suicide and self-injury) was 1.2% for patients treated with Otezla (0.5% for placebo). In the broader Apremilast Data Pool, the incidence of depression as a serious adverse event was 0.85% for Otezla (0% for placebo), with the incidence of adverse events of suicidal ideation and behavior of 0.12% for Otezla (0.07% for placebo).

Weight loss of >5% of baseline body weight was reported during the placebo-controlled period in 13.3% of patients treated with Otezla (5.0% of patients on placebo), and in 19.6% of patients following 52 weeks of treatment, with 5.7% of patients with weight decreases of ≥10% of baseline body weight.

Despite a lack of clinical evidence, there are potential safety concerns for the use of Otezla in pregnant and breastfeeding women. Although not substantiated by mechanistic or non-clinical evidence for teratogenicity, Otezla does share a portion of its molecule with a class of teratogens (thalidomide, lenalidomide and pomalidomide). However, the key pharmacophore believed to be responsible for the teratogenicity of thalidomide, lenalidomide and pomalidomide (the amino-glutarimide ring, which binds to the cereblon protein) is different in Otezla. In studies with mice, developmental malformations were not observed up to the highest dosage of 80 mg/kg/day (4.0-fold the clinical exposure), and no treatment-related fetal developmental effects or malformations were observed in monkeys up to the highest dosage of 1000 mg/kg/day (3.5-fold the clinical exposure). In mice and monkeys, Otezla was not teratogenic.

Non-clinical data demonstrated that treatment with apremilast is associated with embryofetal risk (increased resorptions in mice and increased abortions in monkeys) and nursing mouse pup mortality at dose levels that are equivalent to 2-4 times human exposure. In humans, significant weight loss observed with Otezla, particularly in women, can pose a theoretical risk for use in pregnancy. Given its potential for exposure in women of child-bearing potential and intended use for a non-life-threatening condition, Otezla is contraindicated in women who are pregnant, or who are breastfeeding.

An increased risk of serious infection was not observed, but based on its mechanism of action, there is a theoretical increased risk of infection in susceptible populations, which were limited in the studies. Based on a signals observed in the non-clinical studies, events of vasculitis were examined across all the clinical studies conducted with Otezla, including nonpsoriasis studies. In total, the sponsor confirmed 3 cases of vasculitis in patients exposed to Otezla, one which was serious and led to discontinuation, the others resolved while on the study drug.

Overall, the safety profile of Otezla is acceptable and manageable for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. Appropriate warnings and precautions are in place in the approved Otezla Product Monograph to address the identified safety concerns.

For more information, refer to the Otezla Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical profile (pharmacology and toxicology) of apremilast, the medicinal ingredient in Otezla, has been adequately characterized. Apremilast is a small molecule inhibitor of phosphodiesterase 4 (PDE4) enzyme activity that mediates anti-inflammatory effects in vitro and in vivo.

In mice and rats, apremilast-related mortality was primarily attributed to vascular and/or perivascular inflammation. Dose-related inflammatory responses associated with arteritis and perivascular inflammation were also noted in various tissues and organs. These findings were not observed in monkeys.

In a monkey embryo-fetal developmental toxicity study, oral dosages of 20, 50, 200, and 1000 mg/kg/day resulted in a dose-related increase in prenatal loss (abortions) from 50 mg/kg/day (2-fold clinical exposure). Prenatal loss was not observed at 20 mg/kg/day (1.4-fold clinical exposure). No treatment-related fetal developmental effects or malformations were observed in the monkey up to the highest dosage of 1000 mg/kg/day in the study (3.5-fold the clinical exposure). Apremilast was not teratogenic in monkeys.

In a mouse post‑natal development study, increased peri‑ and post‑natal pup mortality and reduced pup body weights were observed during the first week of lactation in apremilast‑treated animals. These effects were likely due to apremilast‑related pup toxicity and/or lack of maternal care.

The results of the non‑clinical studies as well as the potential risks to humans have been included in the Otezla Product Monograph.

For more information, refer to the Otezla Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

 

7.3 Quality Basis for Decision

 

The Chemistry and Manufacturing information submitted for Otezla 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. Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Based on the stability data submitted, the proposed shelf‑life is considered acceptable.

Proposed limits of drug-related impurities are considered adequately qualified [that is (i.e.) within International Conference on Harmonisation (ICH) limits and/or qualified from toxicological studies].

All sites involved in production are compliant with Good Manufacturing Practices.

All non-medicinal ingredients found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations.

There are no reagents used in the apremilast drug substance manufacturing process that are at risk of transmitting Bovine Spongiform Encephalopathy (BSE)/Transmissible Spongiform Encephalopathy (TSE). The lactose used in manufacture of the drug product is free of BSE/TSE risk as the lactose was manufactured from milk used to manufacture cheese for human use. The magnesium stearate used in manufacture of drug product is of vegetable origin and therefore pose no risk of BSE/TSE. Certification letters attesting to these claims were provided by the sponsor.