Summary Basis of Decision for Striverdi Respimat
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:
Summary Basis of Decision (SBD) documents provide information related to the original authorization of a product. The SBD for Striverdi Respimat is located below.
Recent Activity for Striverdi Respimat
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 Striverdi Respimat
Updated: 2023-06-29
The following table describes post-authorization activity for Striverdi Respimat, a product which contains the medicinal ingredient olodaterol (supplied as olodaterol hydrochloride). 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 Guidance.
Drug Identification Number (DIN):
- DIN 02407868 - 2.5 µg olodaterol/actuation, solution for inhalation
Post-Authorization Activity Table (PAAT)
| Activity/submission type, control number | Date submitted | Decision and date | Summary of activities |
|---|---|---|---|
| DIN 02407868 cancelled (pre market) | Not applicable | Discontinuation date: 2021-11-10 | he manufacturer notified Health Canada that sale of the drug has been discontinued pre market. Health Canada cancelled the DIN pursuant to section C.01.014.6(1)(a) of the Food and Drug Regulations. |
| NC # 224290 | 2019-01-31 | Issued NOL 2019-05-13 | Submission filed as a Level II (90 day) Notifiable Change to update the PM with new safety information. As a result of the NC, modifications were made to the Warnings and Precautions, and Adverse Reactions sections of the PM, and corresponding changes were made to Part III: Consumer Information. The submission was reviewed and considered acceptable, and an NOL was issued. |
| NC # 191601 | 2016-01-22 | Issued No Objection Letter 2016-07-05 |
Submission filed as a Level II (120 day) Notifiable Change to update the Product Monograph (PM) to reflect revisions in the company core data sheet. Changes were made to the PM Part III: Consumer Information. The submission was reviewed and considered acceptable, and a No Objection Letter was issued. |
| SNDS # 172610 | 2014-02-27 | Issued NOC 2014-05-09 |
Submission filed as a 'labelling only' Level I - Supplement to update the Product Monograph (PM) to ensure consistency between various Respimat products, with particular reference to the sponsor's recently approved submission for Combivent Respimat. As a result of the submission, changes were made to the PM Part III: Consumer Information. There was no change to the benefit-risk assessment for Striverdi Respimat. |
| NDS # 155649 | 2012-06-28 | Issued NOC 2013-06-11 |
Notice of Compliance issued for New Drug Submission. |
Summary Basis of Decision (SBD) for Striverdi Respimat
Date SBD issued: 2013-08-09
The following information relates to the New Drug Submission for Striverdi Respimat.
Olodaterol Hydrochloride, 2.5 µg, olodaterol/actuation, solution for inhalation
Drug Identification Number (DIN):
- 02407868
Boehringer Ingelheim Canada Ltd.
New Drug Submission Control Number: 155649
On June 11, 2013, Health Canada issued a Notice of Compliance to Boehringer Ingelheim (Canada) Ltd. for the drug product, Striverdi Respimat.
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 of Striverdi Respimat is favourable for the long term, once daily maintenance bronchodilator treatment of airflow obstruction in patients with Chronic Obstructive Pulmonary Disease or COPD (including chronic bronchitis and emphysema).
1 What was approved?
Striverdi Respimat, a long-acting beta2-agonist, was authorized for the long term, once daily maintenance bronchodilator treatment of airflow obstruction in patients with Chronic Obstructive Pulmonary Disease or COPD (including chronic bronchitis and emphysema).
Striverdi Respimat is not indicated for the relief of acute deterioration of COPD. Striverdi Respimat is also not indicated for the treatment of asthma. The safety and effectiveness of Striverdi Respimat in asthma have not been established.
Striverdi Respimat is contraindicated in patients with hypersensitivity to olodaterol or to any of the excipients. All long-acting beta2-agonists are contraindicated in patients with asthma without use of a long-term control medication. Striverdi Respimat was approved for use under the conditions stated in the Striverdi Respimat Product Monograph taking into consideration the potential risks associated with the administration of this drug product.
Striverdi Respimat (2.5 µg olodaterol/actuation, as olodaterol hydrochloride) is presented as solution for inhalation. In addition to the medicinal ingredient, the solution for inhalation also contains benzalkonium chloride, citric acid, edetate disodium, and purified water.
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 Striverdi Respimat Product Monograph, approved by Health Canada and available through the Drug Product Database.
2 Why was Striverdi Respimat approved?
Health Canada considers that the benefit/risk profile of Striverdi Respimat is favourable for the long term, once daily maintenance bronchodilator treatment of airflow obstruction in patients with Chronic Obstructive Pulmonary Disease or COPD (including chronic bronchitis and emphysema).
Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality in Canada. Chronic obstructive pulmonary disease is characterized by air flow limitation that is not fully reversible, is usually progressive, and is associated with pathological changes in the lung; a combination, varying between individual patients of obstructive bronchiolitis and parenchymal destructive (emphysema). Dyspnea, a major reason for seeking medical care, develops over many years and eventually limits daily activities, resulting in significant disability and handicap and reductions in health-related quality of life.
Inhaled β2-agonists have a bronchodilator effect and are widely used in the treatment of COPD. The development of β2-agonists that provide 24-hour bronchodilatory activity with once-daily dosing may be a valuable addition to the treatment management of COPD.
Striverdi Respimat, a long acting β2-agonist, has been shown to be efficacious for patients with COPD. The market authorization was based primarily on two pairs of confirmatory replicate, 48-week Phase III studies (studies 1222.11 and 1222.12; studies 1222.13 and 1222.14). All four pivotal studies were randomized, double-blind, placebo-controlled studies with similar inclusion and exclusion criteria and concomitant medications. A total of 3,104 COPD patients were included in these studies (876 received Striverdi Respimat 5 µg, 883 received Striverdi Respimat 10 µg, and 885 received a placebo).
In each of these four studies, results showed that Striverdi Respimat 5 µg administered once daily provided significant improvement (p<0.0001 to <0.0116) in lung function as measured by FEV1 AUC0-3h [forced expiratory volume in one-second (FEV1) area under the curve from 0 to 3 hours (AUC0-3hr)] at week 12 (range from 151-172 mL in studies 1222.11 and 1222.12), and at Week 24 (range from 129 - 151 mL in studies 1222.13 and 1222.14); and trough FEV1 at Week 12 (range from 47 - 91 mL in studies 1222.11 and 1222.12), and at Week 24 (range from 53 -78 mL in studies 1222.13 and 1222.14). In addition, the bronchodilator effects of Striverdi Respimat 5 µg were maintained throughout the 48-week treatment period. There was however, no additional incremental benefit for Striverdi Respimat 10 µg once daily when compared with Striverdi Respimat 5 µg once daily. Therefore, only the 5 µg strength was approved for use by Health Canada.
In addition to the pivotal studies, the bronchodilatory profile of Striverdi Respimat 5 µg was also evaluated in two replicate, randomized, double-blind, placebo-controlled, 6-week cross-over studies (exercise tolerance studies: 1222.37 and 1222.38) and also in two pairs of replicate, placebo- and active-controlled, 6-week cross-over studies (24 Hour lung function profile studies: 1222.24 and 1222.25; 1222.39 and 1222.40). Results from these six supportive studies further support the results observed from the four pivotal studies.
Adverse events most frequently associated with Striverdi Respimat were nasopharyngitis, upper respiratory tract infection, bronchitis, urinary tract infection, dizziness, cough, diarrhea, rash, back pain, and arthralgia. Less common adverse events associated with Striverdi Respimat included ventricular extrasystoles, electrocardiogram QT prolonged, oropharyngeal pain, lower respiratory tract infection, dry mouth, myalgia, muscle spasms, asthenia, fatigue, and peripheral edema.
Long-acting beta2-adrenergic agonists, such as that of Striverdi Respimat, can increase the risk of asthma-related death. Therefore, Striverdi Respimat is not indicated for the treatment of asthma. A Black Box Warning describing this serious warning and precaution has been included in the Striverdi Respimat Product Monograph.
A Risk Management Plan (RMP) for Striverdi Respimat was submitted by Boehringer Ingelheim 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.
Overall, the therapeutic benefits primarily seen in the four pivotal studies, in addition to the six supportive studies, are positive and the benefits of Striverdi Respimat therapy seem to outweigh the risks. Striverdi Respimat 5 µg once daily has an acceptable safety profile based on the non-clinical data and clinical studies. Risk management is achieved through appropriate labelling informing the prescriber of the potential safety issues observed with Striverdi Respimat treatment in the indicated patient population, in addition to an acceptable RMP. Appropriate warnings and precautions are in place in the Striverdi Respimat 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 Striverdi Respimat?
Submission Milestones: Striverdi Respimat
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2012-06-28 |
| Screening | |
| Screening Acceptance Letter issued: | 2012-08-14 |
| Review | |
| Quality Evaluation complete: | 2013-06-11 |
| Clinical Evaluation complete: | 2013-06-11 |
| Labelling Review complete: | 2013-06-11 |
| Notice of Compliance issued by Director General, Therapeutic Products Directorate: | 2013-06-11 |
The Canadian regulatory decision on the non-clinical and clinical review of Striverdi Respimat was based on a critical assessment of the Canadian data package. In addition, the United States Food and Drug Administration (FDA) briefing document and minutes from the Pulmonary-allergy Drugs Advisory Committee (PADAC) meeting conducted on January 29, 2013 were used as added references.
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?
6 What other information is available about drugs?
Up to date information on drug products can be found at the following links:
- See MedEffect Canada for the latest advisories, warnings and recalls for marketed products.
- See the Notice of Compliance (NOC) Database for a listing of the authorization dates for all drugs that have been issued an NOC since 1994.
- See the Drug Product Database (DPD) for the most recent Product Monograph. The DPD contains product-specific information on drugs that have been approved for use in Canada and have been market notified (that is, the company has told Health Canada the product is being marketed).
- See the Notice of Compliance with Conditions (NOC/c)-related documents for the latest fact sheets and notices for products which were issued an NOC under the Notice of Compliance with Conditions (NOC/c) Guidance, if applicable. Clicking on a product name links to (as applicable) the Fact Sheet, Qualifying Notice, and Dear Health Care Professional Letter.
- See the Patent Register for patents associated with medicinal ingredients, if applicable.
- See the Register of Innovative Drugs for a list of drugs that are eligible for data protection under C.08.004.1 of the Food and Drug Regulations, if applicable.
7 What was the scientific rationale for Health Canada's decision?
7.1 Clinical Basis for Decision
Clinical Pharmacology
The clinical pharmacology program for Striverdi Respimat consisted of twelve studies conducted in healthy volunteers, Chronic Obstructive Pulmonary Disease (COPD) patients, and also in hepatic and renal impaired patients.
Olodaterol, the active ingredient in Striverdi Respimat, exerts its pharmacological effects by binding and activating β2-adrenoreceptors following topical administration by inhalation. Activation of these receptors in the airways results in a stimulation of intracellular adenyl cyclase, an enzyme that mediates the synthesis of cyclic-3', 5' adenosine monophosphate (cAMP). Elevated levels of cAMP induce the bronchodilation by relaxing smooth muscle cells in the airway. Olodaterol has the pre-clinical profile of a long-acting selective β2-adrenoreceptor agonist with a fast onset of action and a duration of action of at least 24 hours.
The effect of olodaterol on electrocardiogram (ECG) parameters was also investigated. At the 20 to 50 µg doses, increases in the QT interval, corrected according to the factor estimated from the study population (QTcN) were observed that were maximal at 40 minutes post-dosing.
In a drug interaction study using the cytochrome P450 (CYP) and P-glycoprotein (P-gp) inhibitor ketoconazole, a 1.7-fold increase of systemic exposure to olodaterol was observed. Studies revealed a trend for higher systemic exposure in Japanese (approximately 1.7-fold) and other Asians (1.2-fold) than in Caucasians.
In patients with mild and moderate hepatic impairment, systemic exposure to olodaterol was not affected. In patients with severe renal impairment (creatinine clearance <30 mL/min) systemic exposure to olodaterol was on average 1.4-fold higher, up to a maximum 2-fold higher compared to healthy volunteers.
For further details, please refer to the Striverdi Respimat Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Efficacy
Pivotal Trials
The efficacy and safety of Striverdi Respimat 5 µg once daily was evaluated in two pairs of confirmatory replicate, 48-week Phase III studies [that is (i.e.) studies 1222.11 and 1222.12; studies 1222.13 and 1222.14]. All four studies were randomized, double-blind, placebo-controlled studies with similar inclusion and exclusion criteria and concomitant medications.
In studies 1222.11 and 1222.12, the primary efficacy endpoints were change from pre-treatment baseline in FEV1 AUC0-3 [forced expiratory volume in one-second (FEV1) area under the curve from 0 to 3 hours (AUC0-3hr)] and change from pre-treatment baseline in trough (pre-dose) FEV1 after 12 weeks of treatment. In studies 1222.13 and 1222.14, the primary efficacy endpoints were change from pre treatment baseline in FEV1 AUC0-3, change from pre-treatment baseline in trough (pre-dose) FEV1, and Mahler Transition Dyspnea Index (TDI) focal score after 24 weeks of treatment; the St. George's Respiratory Questionnaire (SGRQ) total score after 24 weeks was also included as a key secondary endpoint.
Patients enrolled into these studies were 40 years of age or older with a clinical diagnosis of COPD, had a smoking history of at least 10 pack years, and had moderate to very severe pulmonary impairment (post-bronchodilator FEV1) less than 80% predicted normal [Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage II-IV]; post-bronchodilator FEV1 to forced vital capacity (FVC) ratio of less than 70%.
A total of 3,104 COPD patients were included in the four Phase III studies (876 received Striverdi Respimat 5 µg, 883 received Striverdi Respimat 10 µg, and 885 received a placebo). The majority of the 3,104 patients recruited in the 48 week Phase III studies were male (77%), white (66%) or Asian (32%), with average age of 64 years. The mean post-bronchodilator FEV1 was 1.38 L [GOLD II (50%), GOLD III (40%), and GOLD IV (10%)] at baseline. The mean β2-agonist responsiveness was 15% of baseline (0.160 L). With the exception of other long acting β2-agonists, all pulmonary medications were allowed as concomitant therapy [for example (e.g.) tiotropium (24%), ipratropium (25%), inhaled steroids (45%), xanthines (16%)]; patient enrolment was stratified by tiotropium use.
Results from each of the four studies demonstrated that Striverdi Respimat 5 µg, administered once daily, provided significant improvement (p<0.0001 to <0.0116) in lung function measured by FEV1 AUC0-3 at Week 12 (range from 151-172 mL in studies 1222.11 and 1222.12), and at Week 24 (range from 129 - 151 mL in studies 1222.13 and 1222.14); and trough FEV1 at Week 12 (range from 47 - 91 mL in studies 1222.11 and 1222.12), and at Week 24 (range from 53 -78 mL in studies 1222.13 and 1222.14).
There was however, no incremental benefit with use of the higher dose (olodaterol 10 µg once daily) when compared to the Striverdi Respimat 5 µg dose.
The bronchodilator effects of Striverdi Respimat 5 µg were maintained throughout the 48-week treatment period. The improvement in lung function was shown five minutes after the first dose.
After 24 weeks of treatment (studies 1222.13 and 1222.14 combined dataset), there were no statistically significant differences between Striverdi Respimat 5 µg once daily, and a placebo in the Mahler Transition Dyspnea Index (TDI) focal score (the mean difference to placebo was 0.318 unit, p = 0.1704).
After 24 weeks of treatment (studies 1222.13 and 1222.14 combined dataset), the mean difference between Striverdi Respimat 5 µg and a placebo regarding SGRQ total score was -2.85 units [95% Confidence Interval (CI) -0.94 to -4.75]. The improvements in SGRQ were seen in all three SGRQ domains (symptoms, activities, and impact). More patients treated with Striverdi Respimat 5 µg had an improvement of SGRQ total score greater than the minimum clinically important difference [(MCID), 4 units] compared to placebo (50.2% versus 36.4%).
In addition, patients treated with Striverdi Respimat 5 µg once daily used less daytime and nighttime rescue medication compared to patients treated with placebo.
Supportive Studies
In addition to the two sets of replicate studies to evaluate long-term efficacy and safety, Striverdi Respimat 5 µg once daily was also evaluated in six randomized, double-blind, placebo-controlled, 6 week cross over studies.
The effect of Striverdi Respimat 5 µg administered on symptom-limited exercise tolerance in COPD patients was investigated in studies 1222.37 and 1222.38. The primary endpoint in both these studies was exercise endurance time (ET) during constant rate cycle ergometry to symptom limitation at 75% maximal work capacity after 6 weeks of treatment.
Results from the studies 1222.37 and 1222.38 showed that Striverdi Respimat 5 µg once daily improved exercise endurance time by 14.0% (p = 0.0002) and 11.8% (p = 0.0018) respectively, compared to placebo. Striverdi Respimat 5 µg also reduced lung hyperinflation (reduced functional residual capacity), resulting in increased inspiratory capacity at rest and during exercise compared to a placebo.
The bronchodilatory profile of Striverdi Respimat 5 µg over the 24-hour dosing interval was evaluated in two pairs of replicate, placebo- and active-controlled, 6-week cross-over studies in 199 patients (Studies 1222.24 and 1222.25) and 230 patients (Studies 1222.39 and 1222.40) with moderate to very severe COPD. Mean β2-agonist responsiveness ranged from 14% -21% of baseline (0.18 to 0.22 L). All pulmonary medications were allowed as concomitant therapy with the exception of other long-acting ß-agonists (all studies) and anti-cholinergics (studies 1222.39 and 1222.40).
In all four studies, the primary endpoints were change from pre-treatment baseline in FEV1 AUC0-12hr and FEV1 AUC12-24hr after 6 weeks. The results of these studies suggested that following 6 weeks of treatment, the bronchodilatory effect of Striverdi Respimat 5 µg once daily was maintained during the 24-hour dosing interval when compared to placebo.
For this New Drug Submission, the sponsor initially sought approval for Striverdi Respimat (olodaterol hydrochloride) at a dose of 5 µg once daily with the following indication: Striverdi Respimat (olodaterol hydrochloride) is indicated for the long term, once-daily maintenance treatment in patients with Chronic Obstructive Pulmonary Disease or COPD (including chronic bronchitis and emphysema) to reduce airflow obstruction, to improve quality of life and to improve exercise tolerance.
Health Canada revised the indications to remove claims of improvement of quality of life and exercise tolerance because there was no adequate efficacy data to support these claims; in addition Health Canada also inserted clear warnings for Striverdi Respimat unauthorized uses. The final indication approved by Health Canada is as follows:
- Striverdi Respimat (olodaterol hydrochloride solution for inhalation) is a long-acting beta2-adrenergic agonist (LABA) indicated for the long term, once daily maintenance bronchodilator treatment of airflow obstruction in patients with Chronic Obstructive Pulmonary Disease or COPD (including chronic bronchitis and emphysema).
- Striverdi Respimat is not indicated for the relief of acute deterioration of COPD. Striverdi Respimat is not indicated for asthma use. The safety and effectiveness of Striverdi Respimat in asthma have not been established.
For more information, refer to the Striverdi Respimat Product Monograph, approved by Health Canada and available through the Drug Product Database.
Clinical Safety
The primary safety data for Striverdi Respimat were drawn mainly from the four Phase III pivotal studies previously described in the Clinical Efficacy section. In these pivotal studies, a total of 3,104 adult patients were enrolled with 876 patients receiving Striverdi Respimat 5 µg, 883 patients receiving Striverdi Respimat 10 µg, and 885 patients receiving placebo. Most patients [Number (n) = 2,544; 81.96%] completed the studies while 560 (18.04%) prematurely discontinued. A total of 240 (7.73%) discontinued due to lack of efficacy, and 61 (1.97%) due to other reasons.
A total of 53 deaths were reported during treatment. All causes of deaths were reviewed by the mortality adjudication committee (MAC). The number of deaths reported were balanced between Striverdi Respimat 5 µg (n = 13; 1.5%) and placebo (n = 13; 1.5%). The most common causes of death, based on MAC analysis, were COPD exacerbation (4 in placebo, 9 in Striverdi Respimat 5 µg), sudden cardiac death (2 in placebo, 2 in Striverdi Respimat 5 µg), unknown/sudden death (5 in placebo, 0 in Striverdi Respimat 5 µg), and lung cancer (0 in placebo, 1 in Striverdi Respimat 5 µg).
Serious adverse events (SAEs) were reported in a total of 499 patients during treatment. The distribution of SAEs reported was balanced across all treatment groups. The most common SAEs reported in patients taking Striverdi Respimat 5 µg were COPD exacerbation (4.7%) and pneumonia (1.6%).
Adverse events which occurred more frequently in Striverdi Respimat 5 µg group compared to the placebo group at a rate of ≥2% included: nasopharyngitis, upper respiratory tract infection, bronchitis, urinary tract infection, dizziness, cough, diarrhoea, rash, back pain, and arthralgia. Adverse events which occurred at a rate of <2% included: ventricular extrasystoles, electrocardiogram QT prolonged, oropharyngeal pain, lower respiratory tract infection, dry mouth, myalgia, muscle spasms, asthenia, fatigue, and peripheral edema.
Striverdi Respimat 5 µg is only indicated for the management of COPD. Striverdi Respimat 5 µg is not indicated for the treatment of asthma. Long-acting β2-adrenergic agonists may increase the risk of asthma-related death. Data from a large, placebo-controlled study conducted in the United States of America compared the safety of another long-acting β2-adrenergic agonist (salmeterol) to placebo added to usual asthma therapy, showed an increase in asthma-related deaths in patients receiving salmeterol. This finding with salmeterol is considered a class effect of long-acting β2-adrenergic agonists, including olodaterol, the active ingredient in Striverdi Respimat. As a result, a Black Box Warning describing serious warnings and precautions has been included in the Product Monograph for Striverdi Respimat.
Striverdi Respimat, as other β2-adrenergic agonists, should be administered with caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QT interval, as any effect of these on the QT interval may be potentiated. Drugs known to prolong the QT-interval may increase the risk of ventricular arrhythmia.
Beta2-adrenoceptor agonists have been associated with reductions in serum potassium levels. Concomitant treatment with xanthine derivatives, steroids, or non-potassium sparing diuretics may potentiate any hypokalemic effect of adrenergic agonists.
Beta-adrenergic blockers may weaken or antagonise the effect of Striverdi Respimat. Therefore, Striverdi Respimat should not be given together with beta-adrenergic blockers (including eye-drops) unless there are compelling reasons for their use. In this setting, cardioselective β-blockers could be considered, although they should be administered with caution.
Concomitant administration of other sympathomimetic agents (alone or as part of combination therapy) may potentiate the undesirable effects of Striverdi Respimat.
For more information, refer to the Striverdi Respimat Product Monograph, approved by Health Canada and available through the Drug Product Database.
7.2 Non-Clinical Basis for Decision
In non-clinical pharmacology studies, olodaterol was shown to be a potent agonist of the human β2 (hβ2) adrenergic receptor in vitro and is highly selective for the hβ2-adrenoceptor compared to the hβ1-adrenoceptor and the hβ3-adrenoceptor.
Inhaled olodaterol was shown to have a fast onset of action (within 10 min.) for bronchoprotection with a duration of action up to 24 hours in guinea pigs and dogs.
The target organs of toxicity in rats were skeletal muscle, heart, female reproductive tract, and the larynx and trachea. The identified target organs in dogs were heart, liver, prostate, and the trachea. The majority of the findings in rats and dogs are known pharmacological effects of β-adrenergic agonist drugs. The effects in the larynx in rodents and trachea in dogs are known species-specific effects of certain excipients in the formulation. In addition, toxicological findings were observed at systemic levels sufficiently in excess of the maximum human exposure.
Embryo-fetal development studies in rats and rabbits revealed teratogenic effects at the high dose only in rabbits. These effects have been observed for other β-adrenergic agonist drugs. Carcinogenicity studies were performed in rats and mice administered olodaterol via inhalation for 2 years. Olodaterol induced increased incidences of uterine leiomyomas and leiomyosarcomas in mice and leiomyomas of the mesovarium in rats. These types of tumours have been observed with other β2-adrenergic agonist drugs. The relevance of these findings to humans is unknown.
For more information, refer to the Striverdi Respimat 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 Striverdi Respimat 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.
The site involved in the production of Striverdi Respimat is compliant with Good Manufacturing Practices.
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 the medicinal ingredient with the excipients is supported by the stability data provided.
Based on the stability data submitted, the proposed shelf-life and storage conditions for the drug substance and drug product were adequately supported and are considered to be satisfactory. The proposed 36 month shelf-life at 15-30°C for Striverdi Respimat is considered acceptable.
The excipients used in the drug product formulation are not of animal or human origin.