Summary Basis of Decision for Volibris ™
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:
VolibrisTM
Ambrisentan, 5 mg and 10 mg, Tablet, Oral
GlaxoSmithKline Inc.
Submission control no: 113287
Date issued: 2008-07-31
Health Products and Food Branch
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Health Products and Food Branch
Également disponible en français sous le titre : Sommaire des motifs de décision (SMD), PrVOLIBRISMD, ambrisentan, 5 mg et 10 mg, comprimés, GlaxoSmithKline Inc., N° de contrôle de la présentation 113287
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):
- 02307065 - 5 mg
- 02307073 - 10 mg
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
™ VOLIBRIS used under license by GlaxoSmithKline Inc.
2 Notice of decision
On March 20, 2008, Health Canada issued a Notice of Compliance to GlaxoSmithKline Inc. for the drug product Volibris™.
Volibris™ contains the medicinal ingredient ambrisentan which is a selective endothelin receptor antagonist.
Volibris™ is indicated for treatment of idiopathic ('primary') pulmonary arterial hypertension (PAH) and PAH associated with connective tissue disease in patients with WHO functional class II or III symptoms who have not responded to conventional therapy.
PAH is a rare, progressive disease characterized by elevation of mean pulmonary artery pressure and pulmonary vascular resistance. Ambrisentan selectively inhibits the endothelin type A (ETA) receptor (receptors found in the smooth muscle tissue of blood vessels) and blocks the action of endothelin, a naturally occurring vasoconstrictor. Ambrisentan lowers the blood pressure in the blood vessels between the heart and lungs by relaxing these blood vessels.
The market authorization was based on quality, non-clinical, and clinical information submitted. The safety and efficacy of Volibris™ were demonstrated in two randomized, double-blind, multicentre, placebo-controlled 12-week studies including 393 PAH patients and long term (more than 12 months) open-label studies. Overall, Volibris™ was well tolerated. The efficacy was assessed by change from baseline in a 6-minute walk distance (6MWD) test at 12 weeks. In both studies, treatment with Volibris™ resulted in a significant improvement in 6MWD for each dose (5mg and 10mg). The improvement in exercise capacity was evident after 4 weeks of treatment and was maintained at week 12 of the double-blind treatments.
Volibris™ (5 mg and 10 mg, ambrisentan) is presented as tablets. Volibris™ should be initiated at a dose of 5 mg once daily. Additional benefit may be obtained by increasing the dose to 10 mg once daily. Patients with PAH associated with connective tissue disease may require 10 mg Volibris™ for optimal efficacy. Dosing guidelines are available in the Product Monograph.
Volibris™ is contraindicated for patients who are pregnant or patients with a known or suspected hypersensitivity to Volibris™ or any of its components. Volibris™ 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 Volibris™ are described in the Product Monograph.
Health Canada considers that the benefit/risk profile of Volibris™ is favourable for the treatment of idiopathic ('primary') PAH and PAH associated with connective tissue disease in patients with
WHO functional class II or III symptoms who have not responded to conventional therapy.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Pulmonary arterial hypertension (PAH) is a rare, progressive disease characterized by elevation of mean pulmonary artery pressure and pulmonary vascular resistance. Ambrisentan, the medicinal ingredient of Volibris™ is a selective antagonist of the endothelin type A (ETA) receptors (receptors found in the smooth muscle tissue of blood vessels) and blocks the action of endothelin, a naturally occurring vasoconstrictor. Ambrisentan lowers the blood pressure in the blood vessels between the heart and lungs by relaxing these blood vessels.
Manufacturing Process and Process Controls
Ambrisentan is synthetically derived.
The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
Detailed characterization studies were performed to provide assurance that ambrisentan consistently exhibits the desired characteristic structure.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH recommended guidelines and therefore, are considered to be acceptable.
Control of Drug Substance
The drug substance specifications used for quality control of ambrisentan are considered acceptable. Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of ambrisentan. Data from batch analyses were reviewed and are within the proposed acceptance criteria.
Stability
Based on the long-term and accelerated stability data submitted, the proposed re-test period, storage conditions, and shipping conditions for the drug substance are supported and considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Volibris™ (ambrisentan) is formulated for oral administration as immediate-release film-coated tablets in 5 mg and 10 mg strengths. Each tablet strength is differentiated by colour, shape, and markings.
- 5 mg film-coated tablets are square, pale pink tablets engraved with 'GS' on one side and 'K2C' on the other.
- 10 mg film-coated tablets are oval, deep pink tablets engraved with 'GS' on one side and 'KE3' on the other.
Volibris™ tablets are packaged in opaque polyvinyl chloride/polyvinylidene chloride (PVC/PVdC) and aluminum foil blisters, in packs of 30 tablets.
Each film-coated tablet contains the following non-medicinal ingredients: microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, magnesium stearate, polyvinyl alcohol, talc, titanium dioxide and macrogol/polyethylene glycol 3350, lecithin, and FD&C Red #40 Aluminium Lake.
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 ambrisentan with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
Volibris™ tablets are manufactured into tablet cores using a standard direct compression process followed by aqueous film-coating.
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
Control of Drug Product
Volibris™ tablets are tested to verify that the identity, appearance, content uniformity, dissolution, levels of degradation products, and microbiological impurities are within acceptance criteria. The test specifications are considered acceptable to control the drug product, and the impurity limits were set according to ICH recommendations.
Copies of the analytical methods and, where appropriate, validation reports are considered satisfactory for all analytical procedures used for release and stability testing of Volibris™.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to be within ICH established limits and/or were qualified from batch analysis and therefore, are considered to be acceptable.
Stability
Based on the long-term and accelerated stability data submitted, the proposed 24-month shelf-life for Volibris™ is considered acceptable when the drug product is packaged in PVC/PVdC and aluminum foil blisters and stored at 15-30°C.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production are considered suitable for the activities and products manufactured. All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
No materials of animal origin are used in the manufacture of the drug substance. Moreover, there are no excipients of human or animal origin used in the manufacture of Volibris™ tablets with the exception of lactose monohydrate, which is manufactured from bovine milk.
The supplier of the lactose confirms that the milk used in the manufacture of the lactose is sourced from healthy animals in the same condition as milk collected for human consumption. The milk source is unlikely to present any risk of Bovine Spongiform Encephalopathy (BSE)/Transmissible Spongiform Encephalopathy (TSE) contamination and the manufacture of lactose monohydrate complies with CPMP Guideline "Note for Guidance on Minimizing the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products".
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Volibris™ 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
The non-clinical studies demonstrated that ambrisentan is an endothelin antagonist with a dissociation constant (Ki) of 16 pM against human myocardial native ETA receptors, with selectivity for the ETA receptor approximately 4000-fold higher relative to the ETB receptor. The clinical impact of high selectivity for the ETA receptor is not known. Oral doses of ambrisentan were demonstrated to block the pressor effects of exogenous endothelin in the intact rat, to decrease arterial blood pressure in intact rats and dogs, and to inhibit neointimal proliferation after arterial damage in the pig. Unfortunately, no studies were performed on the pharmacodynamics of ambrisentan in animal models of pulmonary hypertension. Hypoxia is a well-recognized stimulus for pulmonary blood vessel remodelling and pulmonary hypertension development. This model has been used previously in several ETA receptors antagonists. Safety pharmacology studies showed that ambrisentan had no relevant effects on the central nervous system; did not affect body weight, body temperature and gastro-intestinal motility; did not induce relevant changes in cardiovascular and respiration parameters; and did not affect coagulation time.
However, in rats, ambrisentan (single IV or oral doses) reduced renal sodium, chloride, and calcium excretion rates in a dose-dependent manner. Therefore, it may cause sodium retention and it might be the cause of edema in humans; the adverse event most frequently observed with the administration of endothelin receptor antagonists (ERAs) in humans.
3.2.2 Pharmacokinetics
Absorption
Ambrisentan was well absorbed following oral administration as indicated by the high oral bioavailability both in rats (85%) and dogs (72%). Drug exposure was increased dose-proportionally with an increase in oral dose.
Distribution
In radioactive studies with rats, ambrisentan was widely distributed into the tissues with the highest concentrations observed at 1 hour post-dose in most tissues. The highest concentrations were observed in the gastrointestinal (GI) tract, liver, plasma, lungs, blood, kidney and mesenteric lymph nodes, in decreasing order. Plasma protein binding was high in all animals tested: mice (91.8%), rats (97.2%), rabbits (96.8%) and dogs (96.4%).
Metabolism
The metabolic pathways of ambrisentan were qualitatively similar in mice, rats, rabbits, dogs, and humans. With the exception of the mouse, the parent drug was the most prominent drug-related component in the plasma. Phase I metabolism in liver microsomes of rat, dog, and human was low. Incubation of ambrisentan with rat, dog, and human hepatocytes resulted in a turnover of 15-21% after 24 hours. In the preclinical species tested, up to six metabolites were formed. Cytochrome P450 enzymes: CYP450, CYP3A4, CYP3A5 and CYP2C19 were involved in the metabolism of ambrisentan.
Excretion
The feces were the primary route of excretion of ambrisentan-related material in all species except for rabbit suggesting that hepatic clearance by metabolism and biliary excretion can be assumed as the major pathways of excretion. In mice, rats, and dogs, the fecal recovery of radioactivity was 66-76% of the dose and urinary excretion was 7% of the dose. In rabbits, the recovery in the feces and urine was 24% and 44%, respectively.
Drug Interactions
Based on the in vitro drug-drug interactions data, ambrisentan would potentially interact with strong inhibitors of P-glycoprotein (P-gp), and CYP3A4, and substrates of the Organic Anion Transport Protein (OATP), CYP2A6, CYP2C8, and uridine 5' diphosphate glucoronosyltransferase (UGTs).
3.2.3 Toxicology
Single-Dose Acute Toxicity
Ambrisentan had a relatively low order of acute toxicity based on mortality. Clinical signs of acute toxicity included forced respiration, ataxia, and clonic convulsions. These signs suggested potential effects on respiratory and central nervous systems at high dose levels (administered orally or intravenously). Reports identified acute cardiovascular failure as potentially associated with fatality in the single-dose studies, although this interpretation was based only on gross pathology findings.
Repeat-dose Toxicity
Repeat-dose oral administration of ambrisentan resulted in increased treatment-related mortality, clinical, and pathologic effects in animals. Treatment-related mortality occurred in mice and rats at drug exposure values that were relatively small multiples of the expected human drug exposure at the maximum anticipated dose of 10mg.
Treatment-related mortality in dogs occurred at drug exposure levels that were large multiples of the anticipated human drug exposure. The mechanisms leading to the increased mortality in animals were not defined.
Clinical signs attributed to ambrisentan administration in rodents and/or dogs were mainly associated with the respiratory and GI systems, or reflected general malaise at high-dose levels. A range of treatment-related microscopic findings were present particularly in the liver, heart, nasal cavity, testes and epididymides, kidneys, adrenal glands, stomach, and GI tract.
The effects to the liver in rodents and dogs were generally minimal to moderate and can be considered reflective of adaptive events rather than indicative of overt toxicity.
Heart lesions (myocardial hypertrophy) occurred at the 10 mg/kg dose in the 104-week rat study. This dose level resulted in drug exposure values of approximately 0.6-fold to 2.5-fold the drug exposure anticipated in humans at the maximum intended dose of 10mg.
A spectrum of treatment-related inflammatory and/or degenerative epithelial changes occurred in the nasal cavity in rodents accompanied by osseous metaplasia of the nasal turbinates in studies of progressively longer duration. The relevance of the osseous hyperplasia of the ethmoid turbinates which occurred in rats at doses of ≥16 mg/kg remains unknown.
Atrophic and inflammatory or occlusive treatment-related changes were present in the testes and epididymides/efferent ducts of rodents and dogs.
The kidney lesions and atrophy of the stomach fundic glands generally occurred in dogs at fairly high dose levels (≥300 mg/kg). Adrenal changes generally consisted of cortical hypertrophy or hemagiectasia at ≥100 mg/kg in rodents.
Pathology findings at doses that achieved drug exposure values comparable or lower than that anticipated in humans administered 10 mg ambrisentan consisted of: testicular and olfactory epithelial lesions in mice (60 mg/kg), and testicular lesions in rats and dogs (5 mg/kg and 30 mg/kg, respectively). The olfactory epithelial lesions observed mainly in rodents may have relevance for humans, based on reports of increased incidence of upper respiratory tract conditions (including nasal congestion, rhinitis, and sinusitis) in the clinical trials. The testicular lesions in animals have not been proven to be completely reversible.
Genotoxicity
Ambrisentan was clastogenic in human lymphocytes in vitro, but negative in an in vitro bacterial reverse mutation assay and in two in vivo studies after single oral doses up to 2000 mg/kg.
Carcinogenicity
Ambrisentan administration resulted in a decreased survival rate but was not carcinogenic in the 2-year carcinogenicity studies in rats and mice.
Reproductive and Developmental Toxicity
Consistent with the treatment-related effects noted in the male reproductive tract in the repeat-dose general toxicity studies, ambrisentan administration was associated with reduced fertility and effects on sperm in the reproductive study in rats. Ambrisentan was severely teratogenic when administered to rats or rabbits during the period of organogenesis.
3.2.4 Conclusion
The pharmacological activity of ambrisentan as a specific, competitive, endothelin receptor antagonist has been demonstrated in the non-clinical studies. The pharmacology and toxicology studies for this drug submission are considered acceptable. Doses used in the toxicity studies provided adequate systemic exposure, and margins of safety were determined for each of the toxicities identified. Appropriate warnings and precautionary measures are in place in the Product Monograph to address the identified safety concerns. Overall, the non-clinical pharmacology and toxicology studies support the use of Volibris™ (ambrisentan) for the proposed indication.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
In a Phase II study, the effects of ambrisentan on cardiopulmonary hemodynamics, at baseline and after 12 weeks, were assessed in a selected subset of subjects (n=29) with moderate to severe pulmonary arterial hypertension (PAH). Treatment with ambrisentan resulted in a significant increase in the mean cardiac index, and a decrease in mean pulmonary artery pressure, and mean pulmonary vascular resistance for the combined ambrisentan group.
Analysis of combined results from two Phase III studies showed decreased levels of B-type natriuretic peptide (BNP) in PAH patients treated with ambrisentan for 12 weeks. A positive association was observed between change in BNP and improvement in WHO functional class at Week 12.
3.3.2 Pharmacokinetics
Pharmacokinetics of ambrisentan were evaluated for single doses up to 100 mg and multiple doses up to 10 mg once daily in healthy volunteers, and single doses up to 5 mg and multiple doses up to 10 mg per day in PAH patients.
Absorption
Ambrisentan was rapidly absorbed with the time to maximum concentration occurring 1-2 hours in healthy volunteers and 2-3 hours in PAH patients. The maximum plasma concentration (Cmax) levels and drug exposure (AUC) levels were higher in PAH patients compared to healthy volunteers. The absolute bioavailability of ambrisentan in humans is not known.
Pharmacokinetic data from healthy volunteers did not seem to indicate any degree of accumulation of ambrisentan with multiple dosing, whereas, in PAH patients there was an indication of moderate accumulation; AUC levels showed an accumulation up to 1.9 fold with multiple dosing. Based on a half-life range of 9-15 hours, the estimated degree of accumulation would be 1.2-1.5 fold.
Co-administration with food does not appear to have a significant effect on absorption. AUC levels increased 9% with food, but this increase was neither statistically nor clinically significant.
Distribution
In the in vitro studies,ambrisentan binding to plasma proteins was high (98.8%). Binding was primarily to albumin (96.5%) and to a lesser extent to "1-acid glycoprotein (14.2%). The distribution of ambrisentan into red blood cells was low; approximately 94% of the drug was mainly in the plasma.
Metabolism
Three metabolites of ambrisentan were identified: 4-hydroxymethyl ambrisentan glucuronide (Metabolite 1), ambrisentan glucuronide (Metabolite 2), and 4-hydroxymethyl ambrisentan (Metabolite 3). All three metabolites were presumably formed hepatically and were found as circulating metabolites. Based on relative exposure, Metabolite 1 and Metabolite 2 were considered as minor with Metabolite 3 representing 21.3% of the total radioactivity AUC exposure.
Excretion
Renal elimination was a minor route of elimination with approximately 2-3% of the dose excreted unchanged in the urine. Approximately 88% of the administered dose of radioactivity was recovered in the urine (22.1%) and feces (65.4%), collectively, indicating that ambrisentan and/or its metabolites were preferentially eliminated via the feces. Approximately 40% of the total administered dose of radioactivity was excreted as unchanged ambrisentan; 3.3% was recovered in the urine and 36% was recovered in the feces. With regard to the unchanged ambrisentan recovered in the feces, it has not been determined what fraction of this was unabsorbed or absorbed and then excreted in the feces via the bile.
The half-life after multiple dosing was approximately 15 hours in healthy volunteers and 9-15 hours in PAH patients. The mean oral clearance in healthy volunteers was approximately 2 L/h or 33 mL/minute and appeared to be consistent across single doses up to 100 mg and multiple doses up to 10 mg/day. Population pharmacokinetics indicate that the clearance of ambrisentan was lower in PAH patients. This observation is supported by the higher AUC and Cmax values reported in PAH patients.
3.3.3 Clinical Efficacy
The efficacy and safety of Volibris™ (ambrisentan) in patients with PAH were evaluated in two randomized, double-blind, multicentre, placebo-controlled, Phase III pivotal studies (ARIES-1 and ARIES-2). In both studies, Volibris™ was an additive to the supportive/background medication, which may have included a combination of digoxin, anticoagulants, diuretics, oxygen and vasodilators (calcium channel blockers, ACE inhibitors). ARIES-1 (n=201) compared Volibris™ 5 mg and 10 mg with placebo. ARIES-2 (n=192) compared Volibris™ 2.5 mg and 5 mg with placebo. The primary endpoint was the change from baseline in the 6-minute walk distance (6MWD) after 12 weeks of treatment compared to placebo. Secondary endpoints included assessments of clinical worsening, WHO functional class, the Borg Dyspnea Index (BDI), and SF-36® Health Survey.
In both studies, a statistically significant increase in physical capacity was observed with patients treated with 2.5 mg, 5 mg, and 10 mg of Volibris™, as compared to placebo. In ARIES-1, the increase in the 6MWD was larger in the 10 mg dose group (51.4 m) than in the 5 mg dose group (30.6 m). In ARIES-2, the increase in the 6MWD was larger in the 5 mg dose group (59.4 m) than in the 2.5 mg dose group (32.3 m).
Efficacy results in the different treatment groups were analyzed according to the severity of the disease (WHO functional class). In class II patients, treatment with doses 5 and 10 mg showed statistically significant increases in the 6MWD. In class III patients, only the 5 mg dose in ARIES-2 and the 10 mg dose in ARIES-1 induced a statistically significant increase in the 6MWD. A further analysis of the 6MWD results based on the etiology of the PAH (idiopathic vs. non-idiopathic) showed that the increase in 6MWD for each dose in idiopathic PAH patients was statistically significant, whereas only the highest dose led to a statistically significant increase of 6MWD in the non-idiopathic PAH patients when compared to placebo.
ARIES-1 and ARIES-2 had extension phases. After the initial 12 weeks, the patients were allowed to continue the study for another 24 weeks while still blinded, and the placebo patients were randomized to a treatment group (i.e. 2.5, 5, or 10 mg dose group). Longer term data were collected, and the 6MWD was increased in all groups. No apparent dose relationship was observed on the long-term data.
The physical functional evaluation of 6MWD was complemented by the secondary endpoint measurements pertaining to symptoms and quality of life:
- A significant delay in time to clinical worsening of PAH was demonstrated under treatment with Volibris™ and the probability of not having a clinical worsening event was superior.
- Patients were principally in functional class II (34.8%) or III (55.0%) at baseline. After 12 weeks, more than 2/3 of the patients remained in the same WHO functional class. When a change occurred, it corresponded mainly to an improvement.
- A statistically significant decrease in the BDI (equivalent to an improvement of breathlessness after the 6MWD) was observed for all doses.
- A few aspects of the quality of life outlined in the SF-36® survey were improved in patients treated with Volibris™ (e.g., physical function score).
3.3.4 Clinical Safety
The clinical safety of Volibris™ was evaluated in the Phase III studies (described in section 3.3.3 Clinical Efficacy) as well as in the Phase II studies. Patients in the Phase III studies were able to continue treatment in an extension study where the focus was mainly on the safety of the drug. At the time of data cut-off for the safety update period, the majority of patients (87.2%) had received Volibris™ for at least 24 weeks, 295 (77.0%) patients for at least 48 weeks, more than half of the patients (52.5%) for at least 72 weeks, and over a quarter (27.4%) of the patients had received Volibris™ for more than 96 weeks.
The common adverse events reported with long-term treatment were similar to those reported during the 12-week treatment period. During the long-term studies, the commonly reported events were peripheral edema, headache, upper respiratory tract infection, dizziness, cough, arthralgia, right ventricular failure, pulmonary hypertension, dyspnea exacerbated, palpitations, diarrhea, nausea, nasopharyngitis, nasal congestion, and anemia.
A total of 35% of the patients in the combined Volibris™ group had at least one treatment-emergent non-fatal serious adverse event (SAE) during long term therapy (mean exposure of 71.4 weeks and a maximum exposure of 148 weeks). SAEs were reported according to the highest dose received. This limits the ability to examine dose relationship. However, under these circumstances, a dose relationship seemed to exist for the following SAEs: worsening of PAH, right ventricular failure, hemorrhage (pulmonary/gastrointestinal/intracranial), pneumonia, and peripheral edema.
Peripheral edema was the most common and dose-related AE reported during the first 24 weeks as well as throughout the duration of the studies. Few AEs were reported with a frequency independent of the study dose. Only one AE (dyspnea) showed a reverse relationship with the treatment dose. Peripheral edema as a body response to PAH symptoms was not unexpected. However, the frequency of occurrence of the peripheral edema was very high, and dose-dependent. During long-term therapy, the 10 mg dose, 55% of the patients reported at least one event compared to the 5 mg dose where 37.5% of the patients reported at least one event. The high frequency of this AE is noted in the Product Monograph.
A total of 9 patients had abnormal readings of liver transaminases with a concentration >3x the upper limit of normal (ULN). Only one patient had levels of alanine transaminase and aspartate aminotrasferase >8x ULN. A number a patients (19%) showed an increase of γ-glutamyl transferase (>3x ULN). The clinical significance of this is not known. Liver toxicity has been observed with endothelin receptor antagonist drugs.
Mean hemoglobin levels, hematocrit, and red blood cell counts decreased by about Week 4 in patients taking Volibris™ and then remained stable. The cause of the decrease is not fully understood.
Several patients died during the course of the studies; the cause of death was mostly related to the disease affecting this patient population. However, one death was possibly linked to drug-induced hepatotoxicity. Two other causes of death (decrease of platelet count, and dehydration) were also considered as possibly related to Volibris™. Similarly, most of the SAEs were related to the conditions of the patient population.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk assessment
Volibris™ has been shown to significantly improve exercise capability in patients with PAH in the WHO functional class II or III. Efficacy with the highest doses (5 mg and 10 mg) was evident after 4 weeks of treatment and was maintained at week 12 of the double-blind treatments.
One of the major safety concerns identified during the clinical development of Volibris™ was the potential for hepatic injury. While there were few patients that showed abnormal serum aminotransferases levels, it cannot be assumed that the aminotransferases levels will resolve upon discontinuation of Volibris™. Furthermore, there was one death possibly linked to drug-induced hepatotoxicity. In order to limit the potential for hepatic injury, liver function tests should be evaluated prior to the initiation of Volibris™, and monthly evaluations should continue thereafter. Detailed recommendations are presented in the Product Monograph.
Marked decreases in hemoglobin and hematocrit levels were observed with the use of Volibris™, therefore Volibris™ is not recommended for patients with clinically significant anemia.
An additional safety issue is the potential harmful effects of Volibris™ on the unborn fetus. There are no human data regarding the use of Volibris™ during pregnancy; therefore, the potential effects in humans are unknown. From animal data, ambrisentan did cause teratogenicity in rats. Therefore, the use of Volibris™ during pregnancy is contraindicated; women of child-bearing age should use two forms of reliable contraception; and prior to initiating treatment, a pregnancy test should be performed.
Overall, the studies demonstrated thatVolibris™ was well-tolerated and associated with a manageable safety profile. Based on the safety and efficacy profile, the benefits of Volibris™ therapy seem to outweigh the risks. Restrictions to manage risks associated with the identified safety concerns have been incorporated into the Product Monograph to manage the use of Volibris™.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and effectiveness, Health Canada considers that the benefit/risk profile of Volibris™ is favourable in the treatment of idiopathic PAH and PAH associated with connective tissue disease in patients with WHO functional class II or III symptoms who have not responded to conventional therapy.
The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: VolibrisTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting | 2007-02-01 |
| Submission filed | 2007-04-03 |
| Screening | |
| Screening Acceptance Letter issued | 2007-05-25 |
| Review | |
| Biopharmaceutics Evaluation complete | 2008-01-22 |
| Quality Evaluation complete | 2008-03-12 |
| Clinical Evaluation complete | 2008-02-22 |
| Labelling Review complete | 2008-02-01 |
| NOC issued by Director General | 2008-03-20 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| VOLIBRIS | 02307073 | GLAXOSMITHKLINE INC | AMBRISENTAN 10 MG |
| VOLIBRIS | 02307065 | GLAXOSMITHKLINE INC | AMBRISENTAN 5 MG |