Summary Basis of Decision for Daxas ™
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:
DaxasTM
Roflumilast, 500 mcg, Tablet, Oral
Nycomed Canada Inc.
Submission control no: 127683
Date issued: 2011-03-08
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02359456
Therapeutic Classification:
Non-medicinal ingredients:
Lactose monohydrate, maize starch, povidone, and magnesium stearate.
Film-coat:
Hypromellose, macrogol 4000, titanium dioxide, and yellow iron oxide.
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On November 23, 2010, Health Canada issued a Notice of Compliance (NOC) to Nycomed Canada Inc. for the drug product Daxas™.
Daxas™ contains the medicinal ingredient roflumilast which is a selective phosphodieterase 4 (PDE4) inhibitor.
Daxas™ administered once daily (500 mcg tablet per day) is indicated, as add-on therapy to bronchodilator treatment, for the maintenance treatment of severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis, that is (i.e.) patients with a history of chronic cough and sputum] in adult patients with a history of frequent exacerbations. Daxas™ should not be used as a rescue medication.
Daxas™ is a non-steroidal, anti-inflammatory agent that targets both systemic and pulmonary inflammation associated with COPD. It exerts its action by inhibiting PDE4, a major cyclic adenosine monophosphate (cAMP) metabolizing enzyme found in structural and inflammatory cells important to the pathogenesis of COPD.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Daxas™ were evaluated in two confirmatory replicate 12-month pivotal studies and four supportive studies (two 12-month and two 6-month studies). In these studies combined, 7,453 patients were randomized and treated with 3,701 patients receiving Daxas™. Patients who received Daxas™ were administered one 500 mcg tablet once daily. The inclusion and exclusion criteria and permitted concomitant medications varied with each study.
Both pivotal studies (Studies m2-124 and m2-125) were 52-week multinational, multicentre, double-blind, parallel-group, placebo-controlled, Phase III studies identical in design. Eligible patients had prior history of COPD associated with chronic bronchitis for ≥12 months, post-bronchodilator forced expiratory volume in one second (FEV1) ≤50% of predicted, and at least one documented COPD exacerbation in the previous year. Patients were permitted to continue taking either long-acting ß2-agonists (LABAs) or short-acting anticholinergics (SAMAs), as well as glucocorticosteroids for the treatment of exacerbations. Rescue medication (salbutamol or albuterol) could be used on an "as-needed" basis. Inhaled corticosteroids and tiotropium were not permitted during the pivotal studies. Lung function (pre-bronchodilator FEV1) and the rate of moderate exacerbations (requiring intervention with systemic glucocorticosteroids) or severe exacerbations (resulting in hospitalization or death) were the co-primary endpoints. The administration of Daxas™ 500 mcg once daily significantly improved lung function (pre-bronchodilator FEV1) compared to placebo by 39 mL and 58 mL, in studies m2-124 and m2-125, respectively. In addition, moderate and severe exacerbations were reduced by 15% and 19% within each study, respectively.
Two 12-month supportive studies (Studies m2-111 and m2-112) evaluated a broad population of patients with severe COPD where histories of chronic bronchitis and COPD exacerbations were not required as patient-inclusion criteria. Use of inhaled corticosteroids was allowed (61% of roflumilast-treated patients used inhaled corticosteroids). Pooled analysis data demonstrated that Daxas™ statistically significantly improved lung function compared to placebo on average by 51 mL (pre-bronchodilator FEV1) and by 53 mL (post-bronchodilator FEV1); however, the reduction in the rate of moderate to severe exacerbations in patients treated with Daxas™ did not reach statistical significance when compared with placebo.
The two six-month supportive studies (Studies m2-127 and m2-128) were similar in design to the pivotal studies, requiring patients to have a prior history of COPD associated with chronic bronchitis for at least 12 months. During the 4-week run-in, all patients received a long-acting bronchodilator (salmeterol or tiotropium) in combination with a placebo. During the treatment period, patients received either a placebo or Daxas™ 500 mcg once daily on top of either salmeterol (Study m2-127) or tiotropium (Study m2-128). Patients were permitted the use of glucocorticosteroids for the treatment of exacerbations. Rescue medication (salbutomol/albuterol) could be used on an "as-needed" basis. Results from both studies demonstrated that Daxas™ 500 mcg once daily significantly improved pre-bronchodilator FEV1 beyond concomitant salmeterol or tiotropium treatment effects. Pre-bronchodilator FEV1 improved by 49 mL and 80 mL, in Study M-127 and M-128, respectively. Although patients treated with Daxas™ had lower exacerbation rates than those treated with placebo, the difference was not statistically significant.
Daxas™ (500 mcg, roflumilast) is presented in tablet form. The recommended dose of Daxas™ is one 500 mcg tablet per day, with or without food. Further dosing guidelines are available in the Product Monograph.
Daxas™ is contraindicated for patients who are hypersensitive to roflumilast or to any ingredient in the formulation, or to any component of the container. Daxas™ is also contraindicated for use in patients with moderate or severe hepatic impairment. Daxas™ should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Daxas™ are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Daxas™ is favourable for the indication stated above.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Roflumilast, the medicinal ingredient of Daxas™ is a selective PDE4 inhibitor. It is a non-steroidal, anti-inflammatory agent that targets both systemic and pulmonary inflammation associated with COPD by inhibiting PDE4. Phosphodiesterase 4 is a major cAMP metabolizing enzyme found in structural and inflammatory cells important to the pathogenesis of COPD. The inhibition of PDE4 causes levels of intracellular cAMP to increase, thereby alleviating COPD-related malfunctions of leukocytes, airway and pulmonary vascular smooth muscle cells, endothelial and airway epithelial cells, and fibroblasts.
Manufacturing Process and Process Controls
The drug substance is synthetically derived.
Roflumilast is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance;
- The drug substance specifications are found to be satisfactory. Impurity limits meet International Conference on Harmonisation (ICH) requirements; and
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of roflumilast has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH-established limits and/or were qualified from toxicological studies and therefore, are considered to be acceptable.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of roflumilast are considered acceptable. Validation reports are considered satisfactory for all analytical procedures used for in-process, release, and stability testing of the drug substance.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term, real-time, accelerated, and stress stability data submitted, the proposed retest period and storage conditions for the drug substance are supported and are considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Daxas™ is a "first in class" PDE4 inhibitor.
Daxas™ is supplied as an immediate-release film-coated tablet. Each tablet contains 500 mcg of roflumilast. The tablets are yellow, D-shaped, and are embossed with "D" on one side. Each tablet contains the following non-medicinal ingredients: lactose monohydrate; maize starch; povidone; and magnesium stearate. In addition, the film-coat contains: hypromellose; macrogol 4000; titanium dioxide; and yellow iron oxide.
Roflumilast film-coated tablets are packaged in blisters consisting of a transparent polyvinyl chloride (PVC)/polyvinylidene chloride (PVDC) forming film, which is bonded through a heat seal to aluminum foil. The secondary packaging material for the blisters is a cardboard carton.
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 roflumilast with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review. Parameters relevant to the performance of the drug product were not affected by the changes described.
Pharmaceutical development data, including development of the container closure system, are considered acceptable. Data provided in this section include composition of Daxas™, rationale for choice of formulation, manufacturing process including packaging, information on batches used in in vitro studies for characterization and discussion on the effect of formulation change on the safety and/or efficacy of Daxas™. Studies which justified the type and proposed concentration of excipients to be used in the drug product were also reviewed and are considered acceptable.
Manufacturing Process and Process Controls
The manufacturing process uses conventional manufacturing techniques, namely: mixing; wet granulation; drying; sieving; blending; tableting; and film-coating.
All manufacturing equipment, in-process manufacturing steps and detailed operating parameters were adequately described in the submitted documentation and are found to be acceptable. The manufacturing process is considered to be adequately controlled within justified limits. The validated process is capable of consistently generating product that meets release specifications.
Control of Drug Product
Daxas™ is tested to verify that its identity, appearance, content uniformity, dissolution, moisture content, colour, levels of degradation products and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits, for individual and total degradation products, are within acceptable limits.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the long-term and accelerated stability data submitted, the proposed shelf-life at 15 to 30°C for Daxas™ is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated through compendial testing and stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations and controls of the facilities and equipment that are involved in the production of Daxas™ are considered suitable for the activities and products manufactured. All sites are compliant with Good Manufacturing Practices.
3.1.4 Adventitious Agents Safety Evaluation
The excipient, lactose monohydrate, is produced from milk. The milk source is not an issue because it is used for human consumption and according to current knowledge the lactose used does not bear a transmissible spongiform encephalopathy/bovine spongiform encephalopathy (TSE/BSE) risk, and is therefore regarded as safe for human use.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Daxas™ has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Primary Pharmacodynamics
Several in vitro and in vivo studies have studied the primary and secondary pharmacodynamics, as well as the safety pharmacology of roflumilast and its active metabolite, roflumilast N-oxide.
Results from in vitro studies demonstrated that both roflumilast and roflumilast N-oxide are potent and selective PDE4 inhibitors. Inhibition of PDE4 activity leads to the accumulation of intracellular cAMP, which is known to inhibit the production of multiple pro-inflammatory factors that may be important to the pathogenesis of COPD.
Specifically, in vitro studies with human neutrophils, monocytes/macrophages, lymphocytes, airway smooth muscle cells, lung fibroblasts, endothelial, and airway epithelial cells show that roflumilast and roflumilast N-oxide inhibit different cellular functions that contribute to lung inflammation, pulmonary remodelling, and mucociliary malfunction.
In vivo studies were conducted using mouse and guinea pig models of COPD. Roflumilast blocked the infiltration of neutrophils and other leukocytes and reduced smoke-induced destruction of the lung parenchyma, bleomycin-induced lung fibrosis, and monocrotaline and hypoxia-induced vascular remodelling.
Secondary Pharmacodynamics
Several studies were conducted using isolated tissue preparations to assess the affinity of roflumilast and roflumilast N-oxide to different receptors. Neither roflumilast, nor its active metabolite interacted with muscarinic, histaminergic, purinergic, dopaminergic, or adrenergic receptors.
Safety Pharmacology
The core battery of safety pharmacology tests did not reveal any significant effects of roflumilast on the central nervous system (CNS) or respiratory function. Both roflumilast and roflumilast N-oxide had effects on the cardiovascular system in dogs, which presented as increased ejection fraction, systolic and diastolic blood pressure, heart rate, and cardiac output. Renal function was not significantly affected. Roflumilast increased gastric acid secretion in rats and increased stomach weight in mice, mainly due to elevated acid secretion and/or inhibition of stomach emptying. Emesis was induced in dogs.
3.2.2 Pharmacokinetics
The absorption and disposition of [14C]-roflumilast were studied in mice, rats, hamsters, rabbits, dogs, and monkeys following oral and intravenous (IV) administration, as well as in guinea-pigs and minipigs following oral administration.
Absorption
Absorption following oral dosing was high in monkeys (98%), low in dogs (15%), and moderate in rabbits (46%), hamsters (48%), mice (46%), and rats (32%). The oral bioavailability of roflumilast was greatest in monkeys (48%) and mice (25%), and was lowest in rabbits (8%), rats (11%) and hamsters. In dogs, absolute bioavailability increased from 48 to 61% when a tablet formulation was used in the dose range of 0.05 to 0.75 mg /kg.
Following IV administration, plasma concentrations of roflumilast declined in a multiexponential fashion in mice, rats, hamsters, dogs and monkeys with terminal half-life values of: 0.7; 0.9; 4.1; 3.8; and 4.4 h, respectively. Plasma/serum clearance ranged from 3.9 L/h/kg in rats to 2.99 L/h/kg in rabbits, while clearance in dogs and monkeys was significantly lower (0.38 L/h/kg and 0.32 L/h/kg, respectively).
Distribution
Volumes of distribution were high in rats (5.1 L/kg) and hamsters (17 L/kg), suggesting an extensive distribution of drug-related radioactivity into the tissues. Roflumilast is highly bound to plasma/serum proteins, with an unbound fraction being lowest in the plasma of humans and minipigs (1.1%) and slightly higher in the various animal species (1.6 to 4.8%). The free fraction of the metabolite roflumilast N-oxide was 3.4% in human plasma and clearly higher in the various animal species (6.4 to 12.9%). [14C]-roflumilast-derived radioactivity was widely distributed following IV and oral dosing in rats with the liver, gastrointestinal (GI)-tract, adrenals, kidneys, fat, and nasal mucosa showing levels greater than plasma. Little radioactivity was detected in the brain and testes. Whole body autoradiographic studies and quantitative tissue distribution studies in pregnant rats showed that radioactivity was also distributed to mammary glands and the foetus at levels which slightly exceeded those in plasma on Day 18 of gestation. In addition, radioactivity was secreted into milk of breeding dams. Accumulation of radioactivity in the nasal mucosa of rodents was evident with the rat showing the greatest uptake and retention of radioactivity. The formation of the metabolite 4-amino-3,5-dichloro-pyridine (ADCP) N-oxide and its subsequent further metabolism to a reactive oxo intermediate were responsible for the retention of radioactivity in the nasal mucosa.
Metabolism
In all species investigated, roflumilast was extensively metabolized to several metabolites, including the active metabolite roflumilast N-oxide, ADCP, and ADCP N-oxide. All metabolic routes appeared to be accompanied by glucuronidation or sulphation. The metabolite profile observed in monkeys was very similar to that found in humans.
Excretion
Following IV administration of [14C]-roflumilast and its metabolites, faecal excretion was shown to be the major route of elimination in mice and dogs, while urinary excretion predominated in rats, hamsters, and rabbits.
3.2.3 Toxicology
Single-Dose Toxicity
The single-dose toxicity of roflumilast and roflumilast N-oxide was studied in mice, rats, and dogs. The non-lethal doses were ≥100 mg/kg in rodents (15,000-times the 500 mcg dose in a 75-kg human) after oral drug administration and ≥20 mg/kg after IV administration. Target organs at necropsy were the forestomach (hyperplasia), glandular stomach (ulcer, haemorrhage), small intestine (thickening, submucosal cell infiltration, serositis), testes (atrophy), and olfactory epithelium (inflammation). In dogs, the highest dose of 18 mg/kg roflumilast or roflumilast N-oxide induced vomiting and tremors but caused no mortality.
Repeat-Dose Toxicity
Repeat-dose toxicity studies were conducted in mice (6 months), rats (6 months), hamsters (3 months), dogs (12 months), and monkeys (42 weeks). Drug-related toxicities were noted in the olfactory mucosa of rats, mice, and hamsters; in the male reproductive organs (testis and epididymis) of rats; in the GI tract of rats and monkeys; and in the heart of dogs, mice, and monkeys.
Dose-related changes in rodent olfactory mucosa consisted of disorganization and degeneration/necrosis accompanied by basal cell hyperplasia and inflammatory changes of Bowman's gland and submucosa. No equivalent changes in the olfactory mucosa of dogs and monkeys were seen despite high systemic exposures to roflumilast and roflumilast N-oxide. Nasal mucosa lesions in the olfactory region are attributed to a rodent-specific metabolite. Humans do not have the corresponding olfactory-specific enzyme. The relevance of this finding to humans is unknown.
Treatment of rats with roflumilast or roflumilast N-oxide induced epididymal sperm granulomas and secondary testicular changes (seminiferous tubular dilation and degeneration/atrophy). No equivalent treatment-related changes were observed in the other animal species tested. The safety margins for potential male reproductive effects in relation to a clinical dose of 500 mcg/day roflumilast in humans are 1.7-fold for roflumilast and 6-fold for roflumilast N-oxide based on the drug exposure [plasma/serum area under the concentration time curve (AUC) of unbound drug] in repeat-dose toxicity studies in rats. No adverse treatment effects related to male reproductive parameters were noted in a 3-month clinical study in healthy male volunteers.
Roflumilast-related changes in the GI tract were seen in rats, dogs, and cynomolgus monkeys. The effects in rats (erosion, ulceration, and/or inflammation) were seen primarily in the 4-week study at a dose of 8 mg/kg/day roflumilast that resulted in overt toxicity (severe decreases in body weights and mortality). The GI effects (inflammation in the pyloric region) seen in monkeys after 4 weeks were minimal and transient as they were absent after 42 weeks of dosing. In dogs, vomiting was induced by roflumilast and roflumilast N-oxide in a dose-dependent manner.
Roflumilast affected the cardiovascular system in dogs, mice, and monkeys. The cardiac effects in dogs have been seen with other PDE inhibitors and are due to the species-specific distribution of coronary blood flow.
Genotoxicity
Roflumilast did not reveal a genotoxic potential in a standard battery of genotoxic assays in vitro and in vivo (Ames test, Escherichia coli bacterial gene mutation test, gene mutation test in V79 Chinese hamster cells, unscheduled deoxyribonucleic acid (DNA)-synthesis test, and a cytogenetic study with human lymphocytes micronucleus test) assessing different genetic endpoints.
Carcinogenicity
The carcinogenic potential of roflumilast was assessed in two-year carcinogenicity studies in mice and hamsters. In mice, there was no evidence of roflumilast-related neoplasia nor were there any statistical differences in the incidence of tumours in either gender tested. In hamsters, roflumilast treatment was associated with epithelial cell tumors localized in the olfactory mucosa of the nasal cavity. The relevance of this finding to humans is unknown.
Reproductive and Developmental Toxicity
The effects of orally administered roflumilast on reproductive parameters were studied in mice (male fertility, pre- and post-natal development), rats (fertility and embryo-foetal development), and rabbits (embryo-foetal development). In addition, the effects of roflumilast and roflumilast N-oxide on male fertility were evaluated in mice at the end of the 6-month toxicity studies. A mild retardation of embryo-foetal development (such as incomplete skull bone ossification) was observed in one of two rat studies. Increased post-implantive losses were seen which were attributed to male reproductive toxicity in rats. No effects were seen in the embryo-foetal development study in rabbits. Roflumilast was not teratogenic in rats and rabbits, even though foetuses were exposed to roflumilast. The permeability of the placental barrier for drug-related material increased with the progression of pregnancy. Signs of tocolytic activity resulting in delivery retardation and decreased postnatal survival were observed in mice. These effects occurred at systemic exposures similar to those in humans. The relevance of these findings to humans is unknown.
Local Tolerance
Local toxicity of roflumilast was tested by intramuscular administration in rats and by IV, paravenous, and intra-arterial injection in rabbits. Inflammatory reactions were seen with roflumilast injections similar to those produced by the placebo solution. No significant local intolerance towards roflumilast was apparent. When taken orally, roflumilast caused stomach erosions and intestine inflammation in rats, and stomach inflammation in monkeys. The significance of these findings to humans is unknown.
3.2.4 Summary and Conclusion
Overall, the pharmacodynamic, pharmacokinetic, and toxicologic data support the clinical dose recommended, the indication, and the targeted population, and provide an adequate identification of the risks of the drug. The non-clinical risk/benefit assessment is considered acceptable and all risks are reflected in the appropriate sections of the Product Monograph.
3.3 Clinical basis for decision
3.3.1 Human Pharmacology
In humans, roflumilast is extensively metabolized, with the formation of a major, pharmacodynamically active metabolite, roflumilast N-oxide. Since its plasma AUC is ~10-fold greater than the plasma AUC of roflumilast, the N-oxide metabolite is considered to be the main contributor to the total PDE4 inhibitory activity in vivo in humans. As a result, pharmacokinetic data were evaluated for both the parent compound and its N-oxide metabolite. The 'total PDE4 inhibitory activity', which accounts for differences in intrinsic PDE4 inhibitory activity, free concentration in plasma, and in-vivo exposures (AUC) of roflumilast and roflumilast N-oxide; therefore, pharmacokinetic considerations are based on the total PDE4 inhibitory activity.
3.3.2 Pharmacodynamics
The inhibition of PDE4 leads to elevated intracellular cAMP levels and mitigates COPD-related malfunctions of leukocytes, airway and pulmonary smooth muscle cells, endothelial and airway epithelial cells, and fibroblasts.
The anti-inflammatory effects of Daxas™ have been demonstrated in two pharmacodynamic studies conducted in humans. One study investigated the effects of Daxas™ on inflammatory cells and mediators in broncho-alveolar lavage fluid (BALF) over 28 days in 43 healthy subjects after an endotoxin [lipopolysaccharide (LPS)] challenge. In a second study, the effects on sputum cells and biochemical markers were examined in 41 COPD patients over 28 days.
Following the endotoxin challenge, Daxas™ significantly reduced the influx of neutrophils and eosinophils into the airways of healthy subjects. These findings are consistent with the anti-inflammatory properties of Daxas™ shown in non-clinical COPD models. In COPD patients, there was a decrease of tumour necrosis factor alpha (TNF-a) formation (in whole blood ex vivo after in vitro LPS stimulation) paralleled by improvement of pulmonary function as assessed by FEV1.
3.3.3 Pharmacokinetics
Absorption
Absorption following single oral dosing with 500 mcg roflumilast was rapid and the absolute bioavailability was 79%. The maximum concentration (Cmax) typically occurred within 1 hour for roflumilast, while plateau-like maximum concentrations of the N-oxide metabolite were reached after ~8 hours in the fasted state. Food intake delayed the time to maximum concentration (Tmax) of roflumilast by one hour and reduced Cmax by 40%; however, Cmax and Tmax of roflumilast N-oxide were unaffected. Steady-state plasma concentrations following repeat-dosing with 500 mcg of roflumilast were estimated to be reached after ~4 days (83 hours) for roflumilast, and after 6 days (148 hours) for roflumilast N-oxide. The exposure (AUC) of roflumilast and roflumilast N-oxide was dose-proportional over the roflumilast dose range of 250 to 1,000 mcg.
Distribution
The volume of distribution after IV infusion was high, amounting to 2.9 L/kg. Plasma protein binding of roflumilast and roflumilast N-oxide was 99% and 97%, respectively.
Metabolism
Roflumilast is extensively metabolized via Phase I [cytochrome P450 (CYP)] and Phase II (conjugation) reactions. The main metabolite found in human plasma is roflumilast N-oxide. The formation of roflumilast N-oxide is catalyzed by CYP3A4 and CYP1A2, with the former being the major contributor to the N-oxide formation. The plasma AUC of roflumilast N-oxide, on average, is ~10-fold greater than that of roflumilast.
Excretion
Following an oral dose of roflumilast, the median plasma effective half-lives of roflumilast and roflumilast N-oxide were 17 and 30 hours, respectively. Excretion in humans after oral or IV administration occurred almost exclusively in the form of roflumilast metabolites and occurred mainly via the kidneys. After IV or oral administration of radiolabelled roflumilast, ~70% of the radioactivity was recovered in the urine. Faecal elimination accounted for ~20% of the dose. The total plasma clearance of roflumilast after IV administration was slow (~0.14 L/h x kg for a 150 mcg dose, that is (i.e.) 9.6 L/h for a 70-kg person).
Bioequivalence Studies
The sponsor has developed several formulations of Daxas™, which differed in size, colour and/or shape, and strengths of roflumilast. The formulation intended to be marketed differs in size, color, and shape from the formula used in the clinical Phase II and III COPD studies. A number of studies were conducted to show bioequivalence between these formulas for both roflumilast and its active metabolite roflumilast N-oxide. On the basis of bioequivalence, the safety and efficacy of the proposed formulation was bridged to the safety and efficacy of the Phase III formulation.
3.3.4 Clinical Efficacy
The clinical efficacy of Daxas™ was evaluated in two confirmatory replicate 12-month pivotal studies and four supportive studies (two 12-month and two 6-month studies). In all these studies combined, 7,453 patients were randomized and treated, of whom 3,701 were treated with Daxas™. Patients who received Daxas™ were administered one 500 mcg tablet once daily. The inclusion and exclusion criteria as well as the permitted concomitant medications varied with each study.
Pivotal Studies
Both pivotal studies (Study m2-124 and m2-125) were 52-week, multinational, multicentre, double-blind, parallel-group, placebo-controlled, Phase III studies identical in design. After a 4-week single-blind placebo run-in period (baseline), 3,091 patients were randomized (1:1) to receive Daxas™ 500 mcg or placebo once daily for 12 months. Eligible patients had prior history of COPD associated with chronic bronchitis for ≥12 months, post-bronchodilator FEV1 ≤50% of predicted, and at least one documented COPD exacerbation in the previous year. Patients were permitted to continue taking either long-acting ß2-agonists (LABAs) or short-acting anticholinergics (SAMAs), as well as glucocorticosteroids for the treatment of exacerbations. Rescue medication (salbutamol/albuterol) could be used on an "as-needed" basis. Inhaled corticosteroids (ICS) and tiotropium were not permitted during the pivotal studies.
Lung function (pre-bronchodilator FEV1) and the rate of moderate (requiring intervention with systemic glucocorticosteroids) or severe (resulting in hospitalization or death) exacerbations were the co-primary endpoints. Secondary endpoints for both studies included further evaluation of exacerbations and lung function as well as dyspnea.
The co-primary endpoints were met in that the administration of Daxas™ 500 mcg once daily significantly improved lung function (pre-bronchodilator FEV1) compared to placebo by 39 mL and 58 mL, in studies m2-124 and m2-125, respectively. As well, moderate and severe exacerbations were reduced by 15% and 19% within each study, respectively.
With respect to the secondary endpoints, in both studies, very modest changes in dyspnea were seen after treatment with Daxas™. Although these changes were statistically significant, they may not be clinically significant. It is also important to note that patients who did not tolerate Daxas™ in these studies could terminate the study prematurely.
Supportive Studies
A history of chronic bronchitis and COPD exacerbations was not required as patient-inclusion criteria for the two 12-month supportive studies (Studies m2-111 and m2-112). In addition, different statistical methods and COPD exacerbation definitions were used. The primary endpoints were similar to the pivotal studies, however, one of the two studies used post-bronchodilator FEV1 as a means of measurement. Furthermore, use of LABAs was not allowed and use of ICS was permitted (61% of roflumilast-treated patients used ICS). Pooled analysis data demonstrated that Daxas™ statistically significantly improved lung function compared to placebo on average by 51 mL (pre-bronchodilator FEV1) and by 53 mL (post-bronchodilator FEV1); however, the rate of moderate or severe exacerbations was not statistically significantly reduced in either study.
The two 6-month supportive studies (Studies m2-127 and m2-128) were similar in design to the pivotal studies, requiring patients to have a prior history of COPD for at least 12 months. In addition, in the m2-128 study, documentation of chronic bronchitis and high reliever medication use was required. During the 4-week run-in period, all patients received a long-acting bronchodilator (salmeterol in the m2-127 study or tiotropium in the m2-128 study) in combination with a placebo. During the treatment period, patients received the respective bronchodilator and either placebo or Daxas™ 500 mcg once daily. Patients were permitted the use of glucocorticosteroids for the treatment of exacerbations. Rescue medication (salbutamol/albuterol) was permitted on an "as-needed" basis. All other COPD treatment and respective maintenance bronchodilator treatment had to be withdrawn prior to study start-up. The primary endpoint for both studies was pre-bronchodilator FEV1. Results from both studies demonstrated that Daxas™ 500 mcg once daily significantly improved pre-bronchodilator FEV1 beyond concomitant salmeterol or tiotropium treatment effects. Pre-bronchodilator FEV1 increased by 49 mL and 80 mL, in Study M-127 and Study M-128, respectively. Patients treated with Daxas™ had lower exacerbations rates than those treated with placebo; the difference was not statistically significant.
Efficacy Conclusions
Effects of Daxas™ on Lung Function
The overall assessment of the efficacy of Daxas™ suggests that the drug has a relatively weak effect as a bronchodilator. In general, the studies revealed that lung function improved by a very modest degree with Daxas™ relative to placebo. The mean between group treatment difference in the primary outcome for most of the pivotal and supportive studies, FEV1 (measure of lung function), either pre- or post-bronchodilator, was on average between 40-80 mL in favour of the Daxas™-treated patients compared to placebo-treated patients. This difference is small, and probably falls below the minimal important difference in which patients with COPD will notice an effect on their symptoms.
Effects of Daxas™ on Chronic Obstructive Pulmonary Disease (COPD) Exacerbations
Exacerbation frequency is an important outcome as there are well-established clinical and economic consequences of COPD exacerbations in this patient population. In the two pivotal studies, Daxas™ had a beneficial effect preventing acute exacerbations of COPD compared to placebo in a patient population that had a history of chronic bronchitis symptoms and frequent exacerbations within the 12 months prior to randomization. In contrast to the two pivotal studies, those studies which randomized non-selected COPD patients, rather than only COPD patients with a history of cough and sputum and previous exacerbations, did not show a significant effect of Daxas™ in reducing exacerbation rates. Therefore, it appears that Daxas™ prevents exacerbations of COPD only in those patients with persistent symptoms of chronic cough and sputum production and a previous history of exacerbations.
Effects of Daxas™ as an "add-on" medication to other bronchodilators
In studies m2-127 and m2-128 Daxas™ was added to pre-existing COPD therapy with a long-acting beta agonist or a long-acting anticholinergic bronchodilator. Both studies demonstrated relatively modest additional bronchodilatation when Daxas™ was given with tiotropium or salmeterol treatment, as well as a very modest, clinically questionable, effect on dyspnea. Neither 6-month study was powered for exacerbation endpoints, and did not show that overall rates of COPD exacerbation were decreased in the Daxas™ groups; however, the proportion of patients who experienced an exacerbation during the two 6-month studies was lower in the Daxas™-treated groups compared to the placebo-treated groups.
3.3.5 Clinical Safety
The clinical safety of Daxas™ was evaluated in the two pivotal and four supportive studies described in section 3.3.4 Clinical Efficacy by assessing adverse events (AEs), physical examinations, vital signs, clinical laboratory parameters and electrocardiograms (ECGs). The overall incidence of serious adverse events (SAEs) and AEs in general were similar between the Daxas™ and placebo groups. For the COPD safety pool, the respective SAE rates were 13.5% for the Daxas™ group and 14.2% for the placebo group. The number of deaths was similar between the Daxas™ (n = 84) and placebo (n = 86) groups.
The most common AEs related to Daxas™ (500 mcg roflumilast) were: diarrhoea (11.6%); weight decreased (6.8%); nausea (5.2%); headache (4.6%); and abdominal pain (4.2%). Diarrhoea, nausea, and headache usually began within the first 4 weeks of treatment and usually resolved within 4 weeks while still on continued treatment. Approximately 70% of the events of "weight decreased" occurred within the first 6 months of therapy. Overall, approximately 80% of the AEs with Daxas™ were mild or moderate and resolved on continued treatment.
Serious adverse events such as pneumonia, cardiac rhythm disturbances, or death did not occur more frequently with Daxas™ compared to placebo.
Roflumilast was associated with an increased risk of depression and suicide attempts (including completed suicides) compared with placebo. For patients randomized to receiving roflumilast 500 mcg/day, there were two suicide attempts and two completed suicides. There was also one completed suicide in a patient using roflumilast 250 mcg/day. In contrast, only one patient using placebo reported suicidal ideation. Two of the patients who committed suicide did so several weeks after discontinuation of roflumilast.
Further post-marketing monitoring of the risk of depression and/or suicide associated with the use of Daxas™ will be conducted.
In addition to the clinical observations, treatment with roflumilast, the medicinal ingredient of Daxas™, was associated with the production of carcinoma of the olfactory epithelium in hamsters. Carcinogenesis was related to a rodent-specific toxic metabolite.
The relevance of this finding to humans is unknown. Due to lack of relevant experience, treatment with Daxas™ should not be initiated or existing treatment with Daxas™ should be stopped in patients with cancer (except basal cell carcinoma).
The sponsor has provided a risk management plan (RMP). As part of the RMP, the sponsor has proposed a long-term post-marketing observational cohort. The objective of this study is to provide additional safety information associated with the long-term use of Daxas™. The endpoints include all-cause mortality and cause-specific mortality [for example (e.g.) suicide, lung cancer or cardiovascular-related mortality] and hospitalization due to psychiatric conditions, suicide attempts, weight loss, cancer, cardiovascular disease, etcetera.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
In the pivotal studies, Daxas™ met the defined primary end-points; however, the observed bronchodilating effect was weak. Treatment with Daxas™ led to improvement in lung function as evidenced by modest improvement in pre-bronchodilator FEV1 40 to 80 mL greater than placebo. Benefits appeared to be consistent even in patients who were already using a long-acting bronchodilator. In addition, COPD patients with a history of chronic cough and sputum and with a history of a moderate or severe exacerbation in the past year exhibited a reduction in exacerbations of approximately 17% relative to placebo and by 21% in patients with concomitant LABA treatment.
There is convincing evidence that Daxas™ is associated with non life-threatening side effects such as nausea, headache, diarrhoea, and weight loss in >15% of patients. There is a suggestion that roflumilast may be associated with a slightly greater risk of depression and possibly with a rare risk of suicidal ideation, relative to placebo.
Non-clinical studies have shown increased carcinogenicity in rodents, which is confined to the olfactory epithelium. Carcinogenesis was related to a rodent-specific toxic metabolite. The relevance of this finding to humans is unknown.
Overall, the benefits of using Daxas™ as an add-on therapy to treat COPD outweigh the risks if the drug is used in the appropriate population as specified in indication below. The risks associated with Daxas™ treatment have been clearly labelled in the Product Monograph. A Risk Management Plan (RMP) has been proposed by the sponsor to mitigate the risks of using Daxas™.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Daxas™ administered once daily (500 mcg tablet per day) is favourable as add-on therapy to bronchodilator treatment, for the maintenance treatment of severe COPD associated with chronic bronchitis (i.e. patients with a history of chronic cough and sputum) in adult patients with a history of frequent exacerbations. Daxas™ should not be used as a rescue medication. The New Drug Submission (NDS) complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the NOC pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: DaxasTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2004-01-27 - 2009-06-25 |
| Request for priority status | |
| Filed: | 2009-06-29 |
| Rejection issued by Bureau of Cardiology, Allergy and Neurological Sciences: | 2009-07-29 |
| Submission filed: | 2009-08-10 |
| Screening | |
| Screening Acceptance Letter issued: | 2009-10-01 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2010-09-30 |
| Quality Evaluation complete: | 2010-10-29 |
| Clinical Evaluation complete: | 2010-11-16 |
| Labelling Review complete: | 2010-11-16 |
| Notice of Compliance (NOC) issued by Director General: | 2010-11-23 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| DAXAS | 02359456 | ASTRAZENECA CANADA INC | ROFLUMILAST 500 MCG |