Health Canada
Symbol of the Government of Canada

Common menu bar links

Drugs and Health Products

Summary Basis of Decision (SBD) PrRAPAFLOTM

Help on accessing alternative formats, such as Portable Document Format (PDF), Microsoft Word and PowerPoint (PPT) files, can be obtained in the alternate format help section.

Contact: Bureau of Metabolism, Oncology and Reproductive Sciences

PrRAPAFLOTM

Silodosin, 8 mg and 4 mg capsules
Watson Laboratories
Submission Control Number 121740
Date Issued 2011/05/04

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. These documents are all available on the Health Canada website.

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. For information related to post-market warnings or advisories as a result of adverse events (AE), interested parties are advised to access the Health Canada website.

For further information on a particular product, readers may also access websites of other regulatory jurisdictions, available under 'Related Links' on the Health Canada website. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.

Other Drug 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'.

Table of Contents

1 Product and Submission Information

Brand Name:
PrRAPAFLOTM
Manufacturer/Sponsor:
Watson Laboratories, Inc.
Medicinal Ingredient:
Silodosin
International Non-proprietary Name:
Silodosin
Strengths:
8 mg and 4 mg
Dosage form:
Capsule
Route of Administration:
Oral
Drug Identification Numbers (DINs):
Multiple DINs:
02361671 - 8 mg
02361663 - 4 mg
Therapeutic Classification:
α1-adrenergic blocker
Non-medicinal Ingredients:
D-mannitol, magnesium stearate, pregelatinized starch, and sodium lauryl sulfate.
The size number 1 and number 3 hard gelatin capsules contain gelatin and titanium dioxide. The number 1 capsules are printed with edible ink containing FD&C Blue Number 1 Aluminum Lake and yellow iron oxide. The number 3 capsules are printed with edible ink containing yellow iron oxide.
Submission Type and Control Number:
New Drug Submission,
Control Number: 121740
Date of Submission:
2009/12/21
Date of Authorization:
2011/01/11

RAPAFLO is a trademark of Watson Laboratories, Inc.

2 Notice of Decision

On January 11, 2011, Health Canada issued a Notice of Compliance to Watson Laboratories, Inc. for the drug product Rapaflo.

Rapaflo contains the medicinal ingredient silodosin which is an α1-adrenergic blocker.

Rapaflo is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). Silodosin is highly selective for α1A-adrenoreceptors. Blockade of α1A-adrenoreceptors causes smooth muscle in the prostate to relax, resulting in an improvement in urine flow and a reduction in BPH symptoms. Silodosin has a substantially lower affinity for the α1B-adrenoreceptors.

The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Rapaflo were demonstrated in two Phase III, 12-week, randomized, double-blind, placebo-controlled, multicentre studies. A total of 923 patients were randomized and 466 patients received Rapaflo 8 mg daily. The primary efficacy assessment was the International Prostate Symptom Score (IPSS) which evaluated irritative (frequency, urgency, and nocturia), and obstructive (hesitancy, incomplete emptying, intermittency, and weak stream) symptoms. In both studies, the mean changes in the total IPSS score from baseline to week 12 were statistically significantly greater for groups treated with Rapaflo compared to those treated with placebo. The efficacy of Rapaflo was maintained for up to 1 year of treatment in patients who continued in a 40-week open-label extension study. In all clinical studies, Rapaflo was generally well-tolerated.

Rapaflo (8 mg and 4 mg, silodosin) is presented in capsule form. The recommended dosage is 8 mg once daily with a meal. In patients with moderate renal impairment, the dose should be reduced to 4 mg once daily taken with a meal. Dosing guidelines are available in the Product Monograph.

Rapaflo is contraindicated for patients with the following conditions:

  • Patients known to have hypersensitivity to silodosin or any component of the Rapaflo formulation;
  • Patients with severe hepatic impairment (Child-Pugh scores ≥10);
  • Patients with severe renal impairment (Creatinine Clearance < 30 mL/min;
  • Patients using concomitant potent cytochrome P450 (CYP) 3A4 inhibitors [for example (e.g.), ketoconazole, clarithromycin, itraconazole, or ritonavir]; and
  • Patients using concomitant alpha-blockers (e.g., prazosin, terazosin, or doxazosin).

Rapaflo 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 Rapaflo 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 Rapaflo is favourable for the treatment of the signs and symptoms of BPH.

3 Scientific and Regulatory Basis for Decision

3.1 Quality Basis for Decision

3.1.1 Drug Substance (Medicinal Ingredient)

General Information

Silodosin, the medicinal ingredient of Rapaflo, is a selective antagonist for the α1A-adrenoreceptor subtype in the prostate and bladder. Blockade of α1A-adrenoreceptors cause the smooth muscle in the prostate to relax, resulting in an improvement in urine flow and a reduction in BPH symptoms.

Manufacturing Process and Process Controls

The drug substance is synthetically derived. In-process controls performed during manufacture were reviewed and are considered acceptable.

Characterization

The structure of silodosin has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and were 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 International Conference of Harmonisation (ICH) established limits and/or qualified from toxicological studies and are considered acceptable.

Control of Drug Substance

The drug substance specifications and analytical methods used for quality control of silodosin are considered acceptable.

Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of silodosin.

Batch analysis results were reviewed and the results comply with the specifications and demonstrate consistent quality of the batches produced.

The proposed packaging components are considered acceptable.

Stability

Based on the long-term, real-time, and accelerated stability data submitted, the proposed retest period for the drug substance were supported and are considered satisfactory.

3.1.2 Drug Product

Description and Composition

Rapaflo is available in two strengths: 8 mg and 4 mg. The formulations are directly proportional and differ only in terms of the size of the capsule and fill weight to provide 8 mg and 4 mg of product.

The 8 mg strength has a size number 1, opaque, white capsule imprinted with green ink: "WATSON 152" on the cap and "8 mg" on the body. Each capsule contains 8 mg silodosin, and the following inactive ingredients: D-mannitol; magnesium stearate; regelatinized starch; and sodium lauryl sulfate. The capsule consists of gelatin and titanium dioxide, and is printed with ink containing FD&C Blue Number 1 Aluminum Lake and yellow iron oxide. The 8 mg capsules are supplied in bottles of 30 capsules and 90 capsules.

The 4 mg strength has a size number 3, opaque, white capsule imprinted with gold ink: "WATSON 151" on the cap and "4 mg" on the body. Each capsule contains 4 mg silodosin, and the following inactive ingredients: D-mannitol; magnesium stearate; pregelatinized starch; and sodium lauryl sulfate. The capsule consists of gelatin and titanium dioxide, and is printed with ink containing yellow iron oxide. The 4 mg capsules are supplied in bottles of 30 capsules and 90 capsules.

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 silodosin 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

The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.

The validated process is capable of consistently generating product that meets release specifications.

Control of Drug Product

Rapaflo is tested to verify that its identity, appearance, content uniformity, assay, dissolution, water content, degradation products, drug-related impurities, and microbiological impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable.

The validation process is considered to be complete.

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 real-time, long-term, and accelerated stability data submitted, the proposed 36-month shelf-life at 15-30°C for Rapaflo is considered acceptable, when the product is protected from light and moisture. The compatibility of the drug product with the container closure system was demonstrated through quality control testing and stability studies.

3.1.3 Facilities and Equipment

The design, operations, and controls of the facilities and equipment that are involved in the production of Rapaflo 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

The excipient, gelatin, in the capsule shell is of animal origin. A letter of attestation confirming that the material is not from a bovine spongiform encephalopathy (BSE)/ transmissible spongiform encephalopathy (TSE) affected country/area has been provided for this product indicating that it is considered to be safe for human use.

3.1.5 Conclusion

The Chemistry and Manufacturing information submitted for Rapaflo 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 treatment effects of silodosin are related to its effects on sympathetic nervous system adrenoreceptors. A number of receptor binding studies demonstrated that silodosin when compared with tamsulosin hydrochloride, prazosin hydrochloride, and terazosin hydrochloride showed a higher affinity and selectivity for the α1A-adrenoreceptor. Furthermore, silodosin also showed higher uroselectivity compared to the other available therapeutic drugs and a longer duration of inhibitory effects when compared to tamsulosin. Affinity binding assays were also conducted with silodosin metabolites, with all metabolites demonstrating lower affinities than silodosin. Also important to note is that studies have demonstrated that silodosin has low affinities for other adrenoreceptors (other than β2-adrenoreceptors), suggesting that the use of silodosin would less likely exhibit effects through receptor types other than α1A-adrenoreceptors in clinical use.

Safety pharmacology studies were conducted to assess the effects of silodosin on the cardiovascular system, central nervous system, and respiratory system. Very little if any effects were observed on the central nervous system or the respiratory system in both rats and dogs treated with silodosin. While silodosin had no effect on heart rate or electrocardiography, there was an effect seen on blood pressure in dogs; a decrease of approximately 20% of the baseline values after oral administration of silodosin at 20 mg/kg, and a decrease was also observed with the 0.20 mg/kg dose. The 20 mg/kg dose is approximately 800-times higher than the effective dosage of 0.026 mg/kg in dogs; however, these findings do raise the possibility of effects on blood pressure in humans at the clinically recommended dose. Therefore, labelling should clearly indicate the potential for decreased blood pressure following silodosin administration. Safety pharmacology studies conducted with the glucuronide of silodosin (the main plasma metabolite of silodosin) showed no significant effects on the cardiovascular system, central nervous system, and respiratory system.

3.2.2 Pharmacokinetics

Absorption

The bioavailability of silodosin in rats was 9.2-9.4% based on results using 0.3 or 1 mg/kg doses. Results showed that the drug was poorly absorbed from the stomach, but widely absorbed in the intestinal area. In the dog, the bioavailability of silodosin after oral administration of 0.5 mg/kg was 25.2% with peak levels occurring within 1.5 hours. After the administration of silodosin to mice, rats, and dogs, the maximum plasma concentration (Cmax) was usually reached by approximately 2 hours. In mice and rats after multiple dosing, plasma concentrations increased as dosage levels increased.

Distribution

After single or multiple dosing in rats, radiolabelled silodosin was rapidly and widely distributed to all tissues; however, low levels were found in the cerebrum, cerebellum, eyeball, and spinal cord. Levels were high in the gastrointestinal tract and in the urinary bladder. Limited radioactivity was detected in foetuses.

Metabolism

Silodosin was metabolized in the liver. Repeated oral administration of silodosin in male rats had modest effects on hepatic drug-metabolizing enzymes.

Excretion

The main route of excretion was through the faeces.

3.2.3 Toxicology

Single-Dose Toxicity

A single-dose oral administration study in rats revealed that the approximate lethal dose was 800 mg/kg for males and females. In dogs, the approximate lethal dose was 1,500 mg/kg for orally administered silodosin. Both of these dose levels are much higher than the human therapeutic dose (0.11 mg/kg/day) and demonstrate a significant safety margin.

Repeat-Dose Toxicity

The major clinical signs observed in the repeat-dose animal studies were consistent with the drug class-related effects. The no observed adverse effect level (NOAEL) was estimated to be at 10 mg/kg/day after repeat oral dosing in male dogs. After repeat oral dosing in male rats, the NOAEL was estimated to be at 5 mg/kg/day. It is important to note that even at the NOAEL dose, some effects were noted but were expected based on the pharmacological mechanism of action of α1-adrenoreceptor antagonists. When comparing the NOAELs obtained through the various studies with the recommended clinical dose of silodosin, it is clear that the data demonstrates a good safety margin, although the potential for reduced blood pressure should be noted.

Genotoxicity/Mutagenicity

Silodosin did not appear to be genotoxic in both the in vitro and in vivo genotoxicity assays incorporating proper controls. The glucuronide metabolite did not appear to be mutagenic, nor did it induce chromosomal aberrations under the conditions tested.

Carcinogenicity

Carcinogenicity studies were carried out in both male and female animals. In mice, silodosin was carcinogenic in females at doses of 150 mg/kg/day and higher; however, this is likely due to increased prolactin levels which do not occur at lower silodosin doses. Additionally, silodosin at doses of 100 mg/kg/day were not carcinogenic in male mice. In male rats, doses of 150 mg/kg/day increased the incidence of thyroid follicular adenomas; however, the lower dose of 50 mg/kg/day was not carcinogenic. This increase in thyroid follicular adenomas is thought to be due to the up-regulation of uridine diphosphate-glucuronosyl transferase (UDP-GT) activity in rats, which leads to increased catabolism of thyroid hormones leading to increased secretion of thyroid stimulating hormone (TSH) from the pituitary. It has been reported that thyroid tumours in humans are not induced by this mechanism. Furthermore, there is a significant safety margin (72-fold) between human clinical doses and doses that did not induce thyroid tumours in rats; therefore, it would appear that there is no carcinogenic risk with human therapeutic doses. The accumulation of lipofuscin-like substance observed in the 52-week study was also shown to not be due to silodosin inhibiting serine or cysteine proteases.

Reproductive and Developmental Toxicity

Silodosin did affect fertility and mating rates in male and female rats at doses of 20 mg/kg/day and higher. Silodosin was not teratogenic in rats at doses up to 1000 mg/kg/day and in rabbits at doses up to 60 mg/kg/day. Furthermore, the NOAEL for pre- and post-natal development in rats was much higher than the dose that elicits general maternal toxicity (30 mg/kg/day). The NOAEL for pre- and post-natal survival of the offspring and behavioral development and reproductive capacity of first filial generation (F1) offspring in rats was >300 mg/kg/day. Again, the data supports the statement that silodosin is not teratogenic at human therapeutic doses.

Other Toxicity Studies

Other toxicity studies demonstrated that silodosin does not cause haemolysis in human blood nor significant irritation after intramuscular injection in rabbits.

Studies were performed to determine the effects of silodosin on blood hormone levels. The NOAEL with respect to blood hormone levels was estimated to be 15 mg/kg in rats and 20 mg/kg in mice.

In male mice, the NOAEL for in vivo phototoxicity of silodosin was 100 mg/kg and in female mice, 150 mg/kg.

3.2.4 Summary and Conclusion

A comprehensive program of non-clinical pharmacology, pharmacokinetics, and toxicology studies has been conducted to support the submitted New Drug Submission (NDS) for Rapaflo. The required studies to support a market application have been completed and submitted. Pivotal pharmacology, pharmacokinetics, and toxicology studies supporting the NDS were all conducted in compliance with Good Laboratory Practice. The reports were well-documented and raise no concerns about their authenticity or validity.

Two issues of concern were identified during the review of the non-clinical data. The first and most important issue is the problem of orthostatic hypotension which was observed in the animal studies at therapeutic dose levels for humans, and also in human pharmacokinetic, pharmacodynamic, and clinical studies. This effect has been labelled in the Product Monograph appropriately and is a well-known and manageable class adverse event. The second issue of concern was an observation of carcinogenicity (thyroid) in some animal studies. The sponsor has provided adequate explanations to satisfy our concerns as to the mechanism. There is a 72-fold safety margin with regard to the carcinogenic dose versus human therapeutic doses. In clinical studies, there was no observation of carcinogenicity of any kind. The observation of carcinogenicity in the animal studies is labelled in the appropriate section of the Product Monograph.

Overall, the non-clinical pharmacology and toxicology data submitted support the use of Rapaflo (silodosin) for the currently approved indication.

3.3 Clinical Basis for Decision

Rapaflo contains the medicinal ingredient silodosin which is a highly selective inhibitor for α1A-adrenoreceptors in the prostate and bladder. Silodosin has been marketed in the United States and the European Union (EU) since 2008 for treating the symptoms of BPH. The post-marketing data as well as the Food and Drug Administration (FDA) and EU review reports on silodosin were consulted and used as an additional resource during the review of this NDS. Health Canada found that the FDA and EU review reports validated Health Canada's overall assessment by providing similar conclusions in regards to clinical pharmacology, efficacy, and safety.

3.3.1 Pharmacodynamics

In vitro studies have shown that silodosin is highly selective for α1A-adrenoreceptors which are primarily located in the human prostate, bladder base, bladder neck, prostatic capsule and prostatic urethra. Blockade of these α1A-adrenoreceptors causes smooth muscle in these tissues to relax, thus decreasing bladder outlet resistance and reducing the symptoms of BPH such as hesitant, interrupted, weak stream; urgency and leaking or dribbling; and/or more frequent urination. Silodosin has a substantially lower affinity for the α1B-adrenoreceptors. The α1A1B binding ratio of silodosin is extremely high (162:1).

No rigorous dose-response investigations in humans have been performed with silodosin to investigate short-term pharmacodynamic effects thought to be predictive of therapeutic response since no robust biomarker or procedure is known. However, in all clinical pharmacology studies, vital signs (systolic and diastolic blood pressure, heart rate) were closely monitored. During a dose-escalation investigation using supratherapeutic doses of silodosin (16-48 mg daily), a general dose relationship was apparent for both symptomatic postural hypotension and maximum change from baseline in blood pressure. The maximum tolerated dose appeared to be 48 mg as a result of these two effects.

3.3.2 Pharmacokinetics

Absorption

After oral administration, silodosin was quickly absorbed and reached Cmax 0.9 to 2.3 hours after administration. The Cmax values were dose proportional between single doses of 0.5 mg and 12 mg. Similar dose linearity was observed with multiple daily doses of 16 mg to 48 mg, and between single and multiple doses of 4 mg and 8 mg. The absolute bioavailability was approximately 32%. Food appears to decrease the Cmax, delay the time to reach Cmax, but had no significant effect on the exposure, area under the curve (AUC) values.

A bioequivalence study was not required as dose proportionality between the 4 and 8 mg capsules was already established.

Distribution

The volume of distribution was 49.5 L, approximately equal to body water. The binding rate of silodosin to human plasma protein was approximately 97%, and the protein binding of silodosin glucuronide (the main metabolite of silodosin) was approximately 91%. The blood cell transfer rate was 2.2-3.7%, suggesting that only a small percentage of silodosin transfers to blood cells.

Metabolism

Silodosin undergoes extensive metabolism through glucuronidation, alcohol and aldehyde dehydrogenase, and cytochrome P450 (CYP) 3A4 pathways. The main metabolite of silodosin is a glucuronide conjugate (KMD-3213G) which has been shown in vitro to be active, has an extended half-life, and reaches exposure levels (AUC) approximately 4-times greater than that of silodosin. The second major metabolite (KMD-3293) is formed via alcohol and aldehyde dehydrogenases and reaches plasma exposures similar to that of silodosin; however this metabolite is not expected to contribute significantly to the pharmacologic activity.

Excretion

Silodosin is excreted mostly in the faeces. Following oral administration of radiolabelled silodosin, the recovery of radioactivity after 10 days was approximately 33.5% in the urine and 54.9% in the faeces.

Drug Interaction Studies

CYP3A4 is the principal hepatic enzyme isoform involved in the metabolism of silodosin. Silodosin is also a substrate for P-glycoprotein. Substances that inhibit or induce these enzymes and transporters may affect the plasma concentrations of silodosin and its active metabolite.

The blood levels and exposure of silodosin were increased in a clinically significantly manner when silidosin was administered with ketoconazole, a potent CYP3A4 inhibitor. Concomitant use with potent CYP3A4 inhibitors (such as ketoconazole, itraconazole or ritonavir) is not recommended.

Steady-state digoxin plasma concentrations (a substrate of P-glycoprotein) were not significantly affected by silodosin. Rapaflo is not recommended in patients taking strong P-glycoprotein inhibitors such as cyclosporine.

Special Populations

Differences in the pharmacokinetics of silodosin between young and elderly healthy subjects were not clinically significant.

Plasma concentrations of silodosin and its main metabolites were higher in subjects with moderate renal impairment compared to subjects with normal renal function. A dosage adjustment is required for patients with moderate renal impairment, and Rapaflo is contraindicated in patients with severe renal impairment.

When silodosin was administered to subjects with moderate liver dysfunction, the pharmacokinetics of silodosin and its main metabolites were only slightly altered. The renal clearance was increased in subjects with moderate liver dysfunction. The pharmacokinetics of silodosin in subjects with severe hepatic impairment have not been studied, and therefore Rapaflo is contraindicated in patients with severe liver impairment.

3.3.3 Clinical Efficacy

The efficacy of Rapaflo (silodosin) for the relief of symptoms of benign BPH was demonstrated in two pivotal Phase III 12-week, randomized, double-blind, placebo-controlled, multicentre studies. Supporting studies included a Phase II multicentre, randomized, double-blind, dose-adjusted, placebo-controlled, parallel study with 4 mg and 8 mg Rapaflo, and a European study that evaluated the efficacy of silodosin (8 mg once daily) to a positive comparator drug and placebo. Long-term efficacy was demonstrated in open-label extension studies of up to 12-months in duration.

In the two pivotal studies (Study 1 and Study 2), 457 patients received placebo and 466 patients received Rapaflo 8 mg daily. The primary efficacy assessment was the International Prostate Symptom Score (IPSS) which evaluated irritative (frequency, urgency, and nocturia), and obstructive (hesitancy, incomplete emptying, intermittency, and weak stream) symptoms. Maximum urine flow rate (Qmax) was a secondary efficacy measure.

In both studies, Rapaflo 8 mg once daily was an effective agent for treating the signs and symptoms of BPH as measured by the IPSS and maximum urinary flow rate. Treatment effects were highly significant for the IPSS primary endpoint within 3-4 days of first dose. Highly significant effects were also observed on the irritative and obstructive subscores of the IPSS within the same time frame. Within 3-4 days of the first dose, the mean change from baseline in the IPPS score was -3.9 for the Rapaflo group compared to -2.0 for the placebo group in Study 1, and -4.4 for the Rapaflo group compared to -2.5 for the placebo group in Study 2. These positive treatment effects remained relatively constant throughout the 12-week treatment period. Additionally, patients reported significant improvements in the quality of life questions at Weeks 1, 2, and 4 in Study 1, and at all timepoints measured in Study 2. Statistically significant treatment effects on maximum urine flow rates were noted within 2 to 6 hours after the first dose and at the end of both Study 1 and 2. No clinically meaningful differences were noted in treatment effects in patients of different races, geriatric status, or renal status (normal renal function, mild or moderate renal insufficiency). Patients who received Rapaflo in Study 1 and 2 and who continued in a 40-week extension study continued to see improvements in total IPSS for up to 1-year of treatment.

The efficacy of Rapaflo over placebo was demonstrated in the other controlled clinical studies, as well. In the Phase II study, a greater improvement (reduction) of the American Urological Association (AUA) symptom index score from baseline to end of study was observed in both the Rapaflo 8 mg (-6.8▒5.8) and 4 mg (-5.7▒5.5) groups compared with the placebo group (-4.0▒5.5). These reductions were statistically significant and represented significant overall reductions in both the total irritable and total obstructive components of the score. A greater improvement was also observed in Qmax in the 8 mg (3.4▒5.7 mL/sec) and in the 4 mg (2.9▒4.0 mL/sec) groups compared to the placebo group (1.5▒4.4 mL/sec). In the European study, treatment with Rapaflo was superior to placebo with respect to the change from Baseline to Endpoint or to Week 12 in the total IPSS-1 score.

3.3.4 Clinical Safety

The clinical safety of Rapaflo was assessed in a number of Phase I, Phase II and Phase III studies, and the data provided supports the safety and tolerability of the 8 mg once a day dose. Analysis of the safety data does not indicate that there is a significant difference between the 4 mg and 8 mg dose.

In the two 12-week pivotal Phase III studies (Study 1 and Study 2) 466 patients were exposed to Rapaflo 8 mg once daily and 457 patients were administered placebo. No deaths were related to its use, although one patient had one serious event of syncope that was judged to be possibly related to the use of Rapaflo. The patient in whom this event occurred was also receiving another alpha-blocker that confounded the determination of relatedness. Of the most common treatment-emergent adverse events, retrograde ejaculation (28.1%), dizziness (3.2%), diarrhea (2.6%), orthostatic hypotension (2.6%), headache (2.4%), nasopharyngitis (2.4%), and nasal congestion (2.1%) were the most frequent drug-related events. The most common cause leading to discontinuation of Rapaflo was retrograde ejaculation (2.8%). Individual haematology, serum chemistry, urinalysis, and other clinical laboratory tests [prostate-specific antigen (PSA), haemoglobin A1c, prolactin, and thyroid function tests] were assessed but Rapaflo caused no meaningful change in any clinical laboratory analyte investigated. Rapaflo demonstrated no potential for effect on resting supine blood pressure, and the percentages of patients treated with Rapaflo with a positive orthostatic test at 1 and 3 minutes were 1.3% and 1.9%, respectively. Rapaflo demonstrated no potential to alter the results of the physical examination, breast or thyroid palpation and examinations, or electrocardiogram (ECG).

The safety profile of Rapaflo 8 mg once daily was similar in the long-term open-label 40-week extension studies. Retrograde ejaculation was the most common treatment-emergent adverse event. Others included dizziness, diarrhea, orthostatic hypotension, nasal congestion, decreased libido, and headache. Rapaflo was not associated with any significant change in laboratory parameters, and there were no clinically significant findings in vital signs, laboratory parameters or 12-lead ECG interpretations.

A QT study was provided, and Rapaflo (8 mg and 24 mg) demonstrated no meaningful effects on heart rate, PR, or QRS interval duration in 183 healthy subjects.

Retrograde ejaculation and orthostatic hypotension were the key adverse events. Retrograde ejaculation occurred in 10 to 15% of patients. This adverse event is reversible with discontinuation of the drug and is largely innocuous in nature. A single instance of syncope when silodosin was used concomitantly with another α1-antagonist underscores the need for appropriate labelling. The identified safety issues are well-labelled in the Product Monograph. Based on data provided in this submission and both FDA and EU approval reports, there are no barriers to the approval of this product based on safety.

3.4 Benefit/Risk Assessment and Recommendation

3.4.1 Benefit/Risk Assessment

The effectiveness and safety of Rapaflo have been demonstrated in the pivotal Phase III placebo-controlled clinical studies. Rapaflo had an early and sustained positive effect on the symptoms of BPH as measured by a change from baseline in the IPSS score which evaluated irritative (frequency, urgency, and nocturia), and obstructive (hesitancy, incomplete emptying, intermittency, and weak stream) symptoms. Treatment with Rapaflo also produced rapid and significant increases in maximum urinary flow rates, as well as positive effects in quality of life as measured by the IPSS Quality of Life subscale.

The most common drug-related treatment-emergent adverse events were retrograde ejaculation, dizziness, diarrhea, orthostatic hypotension, headache, nasopharyngitis, and nasal congestion. All common adverse events observed were consistent with the side-effect profile of approved α1-adrenergic antagonist drugs. No new safety issues for this drug class arose from the clinical studies. Like other alpha blockers, the most significant risk is hypotension. This adverse event is well-recognized with this class of drugs and is identified in the Warnings and Precautions section of the Product Monograph. The risks associated with Rapaflo treatment have been clearly labelled in the Product Monograph.

Overall, the data presented in this application demonstrate that Rapaflo has a favourable benefit to risk profile. Conclusions regarding the safety and efficacy of silodosin were similar in the EU and FDA review reports. Rapaflo has been available internationally for some years now, and post-marketing does not indicate that the safety profile is markedly different from that seen in the clinical studies up to this point.

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 Rapaflo is favourable in the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). 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 Milestone Date
Pre-submission meeting: 2008/10/30
Submission filed: 2009/12/21
Screening
Screening Deficiency Notice issued: 2010/02/12
Response filed: 2010/02/26
Screening Acceptance Letter issued: 2010/03/18
Review 1
Biopharmaceutics Evaluation complete: 2010/11/17
Quality Evaluation complete: 2011/01/07
Clinical Evaluation complete: 2011/01/11
Labelling Review complete: 2011/01/10
Notice of Compliance issued by Director General: 2011/01/11