Summary Basis of Decision for Blexten

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 Blexten is located below.

Recent Activity for Blexten

SBDs written for eligible drugs 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. PAATs will be updated regularly with post-authorization activity throughout the product's life cycle.

Post-Authorization Activity Table (PAAT) for Blexten

Updated: 2023-08-09

The following table describes post-authorization activity for Blexten, a product which contains the medicinal ingredient bilastine. 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 that are found in PAATs.

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

Drug Identification Number (DIN):

  • DIN 02454130 – 20 mg bilastine, tablet, oral administration
  • DIN 02519011 – 2.5 mg bilastine, solution, oral administration
  • DIN 02519038 – 10 mg bilastine, tablet (orally disintegrating), oral administration

Post-Authorization Activity Table (PAAT)

Activity/submission type, control number Date submitted Decision and date Summary of activities
Drug product (DINs 02519011, 02519038) market notification Not applicable Date of first sale: 2022-02-10 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
SNDS # 241318 2020-07-07 Issued NOC 2021-08-11 Submission filed as a Level I – Supplement to expand the pediatric indication, add two new dosage forms, and update the PM to the 2020 format. The indication was expanded to patients 4 years of age and older. The submission was reviewed and considered acceptable, and an NOC was issued. Two new DINs (02519038, 02519011) were issued for the new presentations. A Regulatory Decision Summary was published.
SNDS # 241781 2020-07-15 Issued NOC 2020-11-25 Submission filed as a Level I – Supplement to update the product labels to meet the Plain Language Labelling requirements. The submission was reviewed and considered acceptable. As a result of the SNDS, modifications were made to the carton label. An NOC was issued.
Drug product (DIN 02454130) market notification Not applicable Date of first sale:
2019-05-30		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 222326 2018-11-28 Issued NOC
2018-12-14		 Submission filed to transfer ownership of the product (that is [i.e.] drug sponsor name) from Aralez Pharamaceuticals Trading DAC to Aralez Pharamaceuticals Canada Inc. An NOC was issued.
NC # 214883 2018-04-03 Issued NOL
2018-07-11		 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 Adverse Reactions section of the PM and corresponding changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued.
NC # 206314 2017-06-05 Issued NOL
2017-09-11		 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 Warning and Precautions section of the PM. The submission was reviewed and considered acceptable, and an NOL was issued.
Drug product (DIN 02454130) market notification Not applicable Date of first sale:
2016-12-02		 The manufacturer notified Health Canada of the date of first sale pursuant to C.01.014.3 of the Food and Drug Regulations.
NDS # 184231 2015-05-11 Issued NOC
2016-04-21		 Notice of Compliance issued for New Drug Submission.
Summary Basis of Decision (SBD) for Blexten

Date SBD issued: 2016-06-29

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

Bilastine, 20 mg, tablets, oral

Drug Identification Number (DIN):

  • 02454130

Aralez Pharamaceuticals Trading DAC

New Drug Submission Control Number: 184231

 

On April 21, 2016, Health Canada issued a Notice of Compliance to Aralez Pharamaceuticals Trading DAC for the drug product Blexten.

The market authorization was based on quality (chemistry and manufacturing), non-clinical (pharmacology and toxicology), and clinical (clinical pharmacology, safety, and efficacy) information submitted. Based on Health Canada's review, the benefit/risk profile of Blexten is favourable for:

  • Seasonal Allergic Rhinitis
    • the symptomatic relief of nasal and non-nasal symptoms of seasonal allergic rhinitis (SAR) in patients 12 years of age and older.
  • Chronic Spontaneous Urticaria
    • the relief of the symptoms associated with chronic spontaneous urticaria (CSU) (for example, pruritus and hives), in patients 18 years of age and older.

 

1 What was approved?

 

Blexten, a histamine H1-receptor antagonist, was authorized for:

  • Seasonal Allergic Rhinitis
    • the symptomatic relief of nasal and non-nasal symptoms of seasonal allergic rhinitis (SAR) in patients 12 years of age and older.
  • Chronic Spontaneous Urticaria
    • the relief of the symptoms associated with chronic spontaneous urticaria (CSU) (for example [e.g.], pruritus and hives), in patients 18 years of age and older.

No dosage adjustments are necessary in patients over 65 years. The safety and efficacy of Blexten in children under 12 years of age have not been established.

Blexten is contraindicated in patients with:

  • hypersensitivity to bilastine or to any ingredient in the formulation or component of the container;
  • a history of QT prolongation and/or torsade de pointes, including congenital long QT syndromes.

Blexten was approved for use under the conditions stated in the Blexten Product Monograph taking into consideration the potential risks associated with the administration of this drug product.

Blexten (20 mg bilastine) is presented as tablets. In addition to the medicinal ingredient, the tablet contains colloidal anhydrous silica, magnesium stearate, microcrystalline cellulose, and sodium starch glycolate.

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 Blexten Product Monograph, approved by Health Canada and available through the Drug Product Database.

 

2 Why was Blexten approved?

 

Health Canada considers that the benefit/risk profile of Blexten is favourable for the following indications:

  • the symptomatic relief of nasal and non-nasal symptoms of seasonal allergic rhinitis (SAR) in patients 12 years of age and older;
  • the relief of the symptoms associated with chronic spontaneous urticaria (CSU) (for example [e.g.], pruritus and hives) in patients 18 years of age and older.

Seasonal Allergic Rhinitis (SAR) is caused by a reaction to seasonal air-borne allergens and is characterised by nasal congestion, rhinorrhea, sneezing and nasal itching, which are often accompanied by allergic conjunctivitis causing symptoms such as ocular itching and redness, lacrimation, as well as itching of the ears and/or palate. Histamine has been implicated in the pathophysiology of SAR. It exerts its effects by binding to H1-histamine receptors in blood vessels and tissues. Allergic rhinitis represents a global health issue affecting 10% to 25% of the world population. The prevalence of allergic rhinitis is increasing worldwide and has been found recently in some communities to be as high as 33% of the population. Allergic rhinitis affects 20% to 25% of the Canadian population and evidence suggests that the prevalence of this disorder is increasing.

Chronic spontaneous urticaria (CSU) is a chronic disease affecting as many as 23% of the population. It is characterised by transient wheal and flare type skin reactions associated with severe pruritus, lasting for more than six weeks. Although rarely life-threatening, CSU has been shown to cause significant morbidity and to have a negative impact on all aspects of a patient's life, including work, school, social activities, diet and sleep. Pathogenically, the skin mast cells are the most important cells in patients with chronic urticaria, and histamine is the predominant mediator. The lifetime prevalence for all types of urticaria is 8.8%, but chronic urticaria only develops in 30% to 45% of these individuals.

Second generation antihistamines are considered an important treatment option for the treatment of SAR and CSU. Bilastine, the medicinal ingredient of Blexten, is a second generation H1-receptor antagonist that was developed for the symptomatic treatment of SAR and CSU.

Blexten has been shown to be efficacious in the treatment of SAR in patients 12 years of age and older. The market authorization was based on three pivotal double-blind, randomized, placebo- and active-controlled parallel group clinical studies (BILA 1003/RAE, BILA 1704/RAE, and BILA 0802/RAE). Each of the studies was of 14 days duration. A total of 2,359 adolescent and adult patients (aged 12 years and older) with SAR were randomized to treatment with bilastine, placebo, or the active comparator (desloratadine 5 mg or cetirizine 10 mg). The primary efficacy variable was the change in the area under the curve (AUC) of the total symptom score (TSS) from baseline to the end of the study (Day 14). TSS was comprised of the reflective total nasal symptom score (rTNSS) and the reflective total non-nasal symptom score (rTNNSS). Study BILA 0802 was considered a "negative" study since neither bilastine, nor the active comparator, demonstrated statistically significant results versus placebo. The other two pivotal studies, however, showed a statistically significant improvement for bilastine compared to placebo in the primary endpoint, AUCTSS. Additional supportive results from secondary endpoints provided evidence that bilastine leads to both statistically significant and clinically meaningful improvements in the nasal and ocular symptoms associated with SAR.

Blexten has also been shown to be efficacious in the treatment of CSU in patients 18 years of age and older. The market authorization was based on one large, dose-ranging Phase II study (BILA 0601/UCI) and one pivotal Phase III clinical trial (BILA 2006/UCI). Both studies were randomized, placebo-controlled, double-blind parallel group studies of 4 week duration, and involved 742 patients 18 years and older, of whom, 231 were treated with Blexten (bilastine 20 mg) once-daily, and 237 with placebo. The primary efficacy variable was the change from baseline in the mean of the morning (AM) and evening (PM) Total Symptom Score (TSS), defined as the sum of the itching intensity score, the wheals number score, and the maximum size of the wheals score, over the 28 days of the treatment period. The two pivotal studies have shown statistically significant efficacy for bilastine over placebo for the primary and secondary efficacy end-points and the efficacy results are considered appropriate at this time to support the indication of Blexten for the relief of the symptoms associated with CSU (e.g., pruritus and hives), in patients 18 years of age and older.

The clinical safety of bilastine has been evaluated in 19 clinical pharmacology studies performed in healthy volunteers, and in ten Phase II and Phase III studies conducted in patients with Seasonal Allergic Rhinitis (SAR), Chronic Spontaneous Urticaria (CSU), and one long-term safety study in Perennial Allergic Rhinitis (PAR).

The percentages of patients experiencing adverse events in the clinical studies were similar for Blexten, placebo and the active comparators. The most common treatment-emergent adverse effects reported in ≥1% of the subjects in the double-blind Phase III studies involving 931 subjects treated with Blexten were related to the central nervous system (headache, dizziness and somnolence) and the gastrointestinal system (abdominal pain upper). There were no deaths in the clinical trials. Twelve serious adverse events have been reported in the clinical trials, 11 of which occurred in patients treated with Blexten; however, none of these were deemed by the sponsor to be related to the treatment with Blexten.

A thorough QT study has suggested possible QT prolongation effects of Blexten, particularly in susceptible populations. Therefore, Blexten is contraindicated in patients with a history of QT prolongation and/or torsade de pointes, including congenital long QT syndromes. In addition, a cardiovascular warning and precautions are included in the Blexten Product Monograph.

As bilastine has been shown to be a substrate for P-glycoprotein (P-gp), a statement has been added to the Blexten Product Monograph regarding potential drug-drug interactions with P-gp inhibitors that may increase bilastine plasma levels. In addition, the Warnings and Precautions Section of the Blexten Product Monograph specifically points out that co-administration of Blexten and P-gp inhibitors should be avoided in subjects with moderate or severe renal impairment. Blexten has not been studied in patients with hepatic impairment. These issues have been addressed through appropriate labelling (Warnings and Precautions) in the Blexten Product Monograph.

A Risk Management Plan (RMP) for Blexten was submitted by the sponsor to Health Canada. Upon review, the RMP was considered to be acceptable. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will be put in place to minimize risks associated with the product.

A Look-alike Sound-alike brand name assessment was performed and the proposed name Blexten was accepted.

Overall, the therapeutic benefits of Blexten therapy seen in the pivotal studies are considered to outweigh the potential risks. Blexten has an acceptable safety profile based on the non-clinical data and clinical studies. The identified safety issues can be managed through labelling, and can be adequately monitored clinically. Appropriate warnings and precautions are in place in the Blexten 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 Blexten?

 

Submission Milestones: Blexten

Submission Milestone Date
Pre-submission meeting: 2014-02-05
Submission filed: 2015-05-11
Screening  
Screening Acceptance Letter issued: 2015-06-26
Review  
Biopharmaceutics Evaluation complete: 2016-03-29
Quality Evaluation complete: 2016-04-04
Clinical Evaluation complete: 2016-04-21
Labelling Review complete: 2016-04-21
Notice of Compliance issued by Director General, Therapeutic Products Directorate: 2016-04-21

 

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.

 

5 What post-authorization activity has taken place for Blexten?

 

Summary Basis of Decision documents (SBDs) for eligible drugs authorized after September 1, 2012 will include post-authorization information in a table format. The Post-Authorization Activity Table (PAAT) will include brief summaries of activities such as submissions for new uses of the product, and whether Health Canada's decision was negative or positive. The PAAT will continue to be updated during the product's lifecycle.

The PAAT for Blexten is found above.

For the latest advisories, warnings and recalls for marketed products, see MedEffect Canada.

 

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

Bilastine, the medicinal ingredient of Blexten, is a second-generation antihistamine; its principal effects are mediated via selective inhibition of peripheral H1-receptors. It shows moderate to high affinity for histamine H1-receptors and no affinity for muscarinic, serotonergic, dopaminergic and noradrenergic receptors. Bilastine has been demonstrated to have limited distribution to the brain following oral administration.

Bilastine has been evaluated in 19 Phase I trials in which its bioavailability, pharmacokinetics, and pharmacodynamics were examined. No dosage adjustment is required in patients with liver or renal insufficiency.

Possible drug-drug interactions with P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) substrates have been identified and they are discussed in the Blexten Product Monograph. In addition, the administration of bilastine with dietary compounds, including grapefruit juice may affect the plasma concentrations of bilastine and is not recommended.

Bilastine was associated with a concentration-dependent prolongation of the QTc interval. On Day 4 of treatment with the therapeutic 20 mg/day dose, the maximum mean difference from placebo was 4.0 ms (90% confidence interval [CI] 1.20, 6.73) at 1 h. On Day 4 of treatment with the supratherapeutic bilastine 100 mg/day dose, the maximum mean difference from placebo was 6.0 ms (90% CI 2.59, 9.48) at 2 h. Therefore, bilastine is contraindicated in susceptible patients that is (i.e.), those with a history of QT prolongation and/or torsade de pointes, including congenital long QT syndromes.

Bilastine administered at doses of 20 mg/day and 100 mg/day for four days was not observed to affect the QRS duration, the PR interval, or heart rate.

The clinical pharmacological data support the use of Blexten for the recommended indications.

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

Clinical Efficacy

Seasonal Allergic Rhinitis

The efficacy of Blexten for the treatment of seasonal allergic rhinitis (SAR) was evaluated in three pivotal Phase III controlled clinical studies (BILA 1003/RAE, BILA 1704/RAE, and BILA 0802/RAE) and three Phase II studies (two dose-ranging studies and the Vienna Challenge Chamber study).

The two dose-ranging studies and the Phase III pivotal trials were double-blind, randomized, placebo- and in some cases, active-controlled parallel group studies with a 14-day duration. The Vienna Challenge Chamber study utilized a cross-over design. Overall, the two dose-ranging studies and the three pivotal studies involved 2,978 patients worldwide. Of these, 923 were treated with bilastine 20 mg, 712 were treated with an active comparators and 840 received placebo. Another 75 patients participated in the cross-over Vienna Challenge Chamber Study. The majority of the patients were Caucasian and all patients had a documented history of SAR. Cetirizine, desloratadine or fexofenadine were included as active comparators.

In the two dose-ranging studies, as well as the pivotal studies, the primary efficacy variable was the change in the area under the curve (AUC) of the total symptom score (TSS) from baseline to the end of the study (Day 14). The TSS was comprised of the reflective total nasal symptom score (rTNSS) and the reflective total non-nasal symptom score (rTNNSS). The rTNSS was based on the twice daily, in the morning (AM) and evening (PM), reflective assessment of four nasal symptoms: rhinorrhea, nasal congestion, nasal itching, and sneezing, using a four point, (0 [none] to 3 [severe]) scoring scale. The rTNNSS included four non-nasal symptoms: ocular itching, tearing, ocular redness, itching of ears and/or palate. The change from baseline in rTNSS, rTNNSS, TSS, and the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) were assessed as secondary variables.

Phase II Studies

The three Phase II studies consisted of two dose-ranging studies in which bilastine was administered once-daily in doses ranging from 2.5 mg to 40 mg, and the Vienna Challenge Chamber study.

The two dose-ranging studies identified bilastine 20 mg once-daily as the most appropriate dose for the treatment of SAR.

The Phase II Vienna Challenge Chamber (VCC) study (Study BILA 2306/ACC), which compared the efficacy of Bilastine with fexofenadine and cetirizine in patients with SAR under controlled allergen exposure conditions, provided additional evidence for the superior efficacy of bilastine 20 mg over placebo in this setting. It also showed that the efficacy of bilastine is comparable to the effects of two previously authorized antihistamines, fexofenadine 120 mg and cetirizine 10 mg.

Pivotal Phase III Studies

There were three pivotal, placebo- and active-controlled, Phase III studies: Study BILA 0802/RAE, Study BILA 1003/RAE, and Study BILA 1704/RAE conducted in patients with SAR aged 12 years and older. The results for the primary endpoint were not statistically significantly different from placebo in Study BILA 0802/RAE. However, the results for the active comparator in this trial, cetirizine 10 mg, were also not statistically significant. The other two pivotal studies, however, showed a statistically significant improvement compared to placebo for the primary endpoint, AUCTSS. Since there is no validated minimal clinically important difference for TSS, the clinical significance of the primary result was justified by the results that were similar to those exerted by the active comparators. Furthermore, since the secondary endpoint of rTNSS is a well-validated endpoint in SAR with an established minimal clinically important difference of 0.55, the rTNSS difference from placebo of 0.67 in Study BILA 1003/RAE, and 1.15 in Study BILA 1704/RAE, supports these results as both statistically significant and clinically meaningful. This was considered as sufficient evidence that bilastine leads to both statistically significant and clinically meaningful improvements in the nasal and ocular symptoms associated with SAR in support of the indication of bilastine 20 mg once-daily for the symptomatic relief of nasal and non-nasal symptoms of SAR in patients 12 years of age and older.

Chronic Spontaneous Urticaria

The efficacy of Blexten for the treatment of chronic spontaneous urticaria (CSU) was evaluated in one large Phase II study (BILA 0601/UCI) and one Phase III (BILA 2006/UCI) clinical trial. Both studies were randomized, placebo-controlled, double-blind parallel group studies of 4-week duration. The Phase III trial included levocetirizine 5 mg once-daily; however, levocetirizine is not authorized for the treatment of CSU in Canada and is not considered as an active comparator.

The two studies combined involved 742 patients, aged 18 years and older, who received the study treatments during a period of 4 weeks. Of these, 231 were treated with bilastine 20 mg once-daily, and 237 with placebo. The primary efficacy variable was the change from baseline in the mean of the morning (AM) and evening (PM) Total Symptom Score (TSS), defined as the sum of the itching intensity score; the wheals number score, and the maximum size of the wheals score. Secondary efficacy parameters included change in itching score, wheal number score, maximum size of wheals, and quality of life investigation.

The two pivotal studies have shown statistically significant efficacy for bilastine over placebo for the primary and secondary efficacy endpoints and the efficacy results are considered appropriate at this time to support the indication of bilastine, 20 mg once-daily for the relief of the symptoms associated with CSU (such as pruritus and hives), in patients 18 years of age and older.

Indication

The New Drug Submission for Blexten was filed with the following proposed indications:

  • Blexten (bilastine) is indicated for the symptomatic treatment of:
    • seasonal allergic rhinitis (SAR) and associated ocular symptoms;
    • chronic idiopathic urticaria (CIU).

Health Canada modified the proposed indication to reflect the current clinical thinking (the term Chronic Idiopathic Urticaria [CIU] was replaced with Chronic Spontaneous Urticaria [CSU]). In addition, Health Canada narrowed the indication for the CSU population to reflect the study population (i.e., patients 18 years of age and older). Therefore, Health Canada recommended the following indication:

Seasonal Allergic Rhinitis
Blexten (bilastine) is indicated for the symptomatic relief of nasal and non-nasal symptoms of seasonal allergic rhinitis (SAR) in patients 12 years of age and older.

Chronic Spontaneous Urticaria
Blexten (bilastine) is indicated for the relief of the symptoms associated with chronic spontaneous urticaria (CSU) (for example (e.g.), pruritus and hives), in patients 18 years of age and older.

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

Conclusion

The efficacy data provided in this submission supports the authorization of Blexten for the symptomatic relief of nasal and non-nasal symptoms of SAR in patients 12 years of age and older, and for the relief of the symptoms associated with CSU (e.g., pruritus and hives), in patients 18 years of age and older.

Clinical Safety

The clinical safety of Blexten in patients was evaluated in 10 Phase II and III studies performed in 2,186 subjects with allergic rhinitis, or chronic spontaneous urticaria, where bilastine was used at doses ranging from 10 to 40 mg over treatment periods of 2 to 4 weeks. The percentages of patients experiencing adverse events in these studies were similar for bilastine, placebo and the active comparators. The most common treatment-emergent adverse effects reported in ≥1% of the subjects in the double-blind Phase III studies involving 931 subjects treated with bilastine 20 mg were related to the central nervous system (headache, dizziness and somnolence) and the gastrointestinal system (abdominal pain upper). There were no deaths in the clinical trials. Twelve serious adverse events have been reported in the clinical trials, 11 of which occurred in patients treated with bilastine; however, none of these were deemed by the sponsor to be related to the treatment with Blexten.

The long-term safety of bilastine has been assessed in an open-label study in 513 patients treated with bilastine 20 mg once-daily for up to one year. Over the 12-month treatment period, 68.8% of subjects reported at least one adverse event. Headache was the most frequently reported adverse event (111 patients, or 21.6%). Overall, the safety profile of bilastine was similar to that observed in the controlled 2- to 4-week Phase II and III clinical studies.

Bilastine is an H1-receptor antagonist; therefore specific safety issues associated with this pharmacological class, such as effects on the central nervous system (CNS) and cardiac safety, have been extensively evaluated during the clinical development of Blexten. There were no clinically significant effects of bilastine on the CNS; however, a thorough QT study showed a concentration-dependent prolongation of the QTc interval (see Clinical Pharmacology section). Therefore, Blexten was contraindicated in susceptible patients i.e., those with a history of QT prolongation and/or torsade de pointes, including congenital long QT syndromes. In addition, a cardiovascular warning and precautions were included in the Blexten Product Monograph.

Since bilastine was shown to be a substrate for P-glycoprotein (P-gp), the drug-drug interactions section in the Blexten Product Monograph was updated to reflect the possible interactions with P-gp inhibitors or other substrates, as this may increase bilastine plasma levels.

No specific safety issues were identified in patients with renal insufficiency and the elderly.

Overall, Blexten was generally well-tolerated, and appears to exhibit an acceptable safety profile in the treatment of patients with SAR and CSU. Appropriate warnings and precautions are in place in the approved Blexten Product Monograph to address the identified safety concerns.

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

 

 

 

7.2 Non-Clinical Basis for Decision

 

The non-clinical pharmacology data support Blexten (bilastine) as a selective H1-receptor antagonist (or inverse agonist) with anti-histamine effects, as well as anti-allergy effects in models for type I allergies and results are consistent with bilastine having few anticholinergic effects. Safety pharmacology results and characterization of the distribution of bilastine are consistent with limited distribution of bilastine to the CNS after oral dosing. Mouse and rat models were responsive to the pharmacological effects of bilastine, with attenuation of histamine/allergen induced reactions.

The clinical development of Blexten was supported by a comprehensive program of toxicity studies. The type, design, duration, and scope of the toxicity evaluation program are generally consistent with current scientific and regulatory guidelines and considered appropriate to support the intended clinical indications for Blexten.

Similarly to humans, bilastine is minimally metabolized in animals and the species selection (mouse, rat, dog, and rabbit) is appropriate from a pharmacology/toxicology and regulatory perspective. Bilastine has a very low oral acute toxicity, and lethality after intravenous dose administration occurred at concentrations that were >190 times the clinical maximum plasma concentration (Cmax). After repeat oral dosing, bilastine was tolerated with no, or only minor and abating clinical signs. Liver and thyroid changes noted in mice and rats were considered adaptive responses to high doses. In a 52-week dog study, there was an increase in epididymal spermatozoa with abnormal morphology and reduced spermatozoa motility. There were no histopathologic changes in the testes and prostate and a clear no adverse effect dose (NOAEL) was established.

Bilastine was not genotoxic in vitro and in vivo and there were no increases in tumor incidences after administration of bilastine for 22 to 24 months in mice and rats.

Studies conducted to assess reproductive toxicity found no effects on early embryonic development and fertility in male and female rats. Bilastine had no effect on rat dams and embryo-fetal development; and in pregnant rabbits, delayed ossification in fetuses was likely related to reduced food consumption. In a perinatal and postnatal development rat study, one female had 100% postimplantation loss at the high dose. There were no effects of bilastine treatment of the dams on their pups and the offspring's reproductive capacity and their offspring. The NOAELs have been determined in all studies. The exposures at NOAELs are at least 10 times and, for most findings, several hundred times higher than the clinical Cmax and area under the curve (AUC) at the clinical dose of 20 mg.

The results of the non-clinical studies as well as the potential risks to humans have been included in the Blexten Product Monograph. In view of the intended use of Blexten, there are no pharmacological/toxicological issues within this submission which preclude authorization of the product.

For more information, refer to the Blexten 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 Blexten has demonstrated that the drug substance (bilastine) 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 of 5 years is acceptable for the drug product when stored in aluminum blisters at 15-30°C.

Proposed limits of drug-related impurities are considered adequately qualified (that is, within International Council for Harmonisation (ICH) limits and/or qualified from toxicological studies).

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

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

 

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