Regulatory Decision Summary for Noyada

The purpose of this New Drug Submission (NDS) under the pathway of Submissions Relying on Third-Party Data was to seek approval for Noyada (captopril oral solution) for the treatment of essential or renovascular hypertension, congestive heart failure, and diabetic nephropathy in adults. In addition, the Sponsor was seeking approval for the treatment of hypertension and short-term treatment of heart failure in pediatric patients older than one month of age.

Three published studies (2 randomized controlled, one randomized open label) were submitted to support the use of Noyada in adults for the treatment of essential or renovascular hypertension. The first study (Veterans trial) was a randomized, double blind, placebo controlled trial (n = 722) comparing the effect of different doses of captopril (12.5, 25, 37.5 or 50 milligrams [mg]) to placebo. The primary endpoint was blood pressure (BP) reduction. After 7 weeks of treatment, the reduction of BP in captopril group (pooled of all dose strengths) was 12.2 ± 0.8/9.4 ± 0.4 millimetres of mercury (mmHg) (systolic BP [SBP]/diastolic BP [DBP]) compared to 2.0 ± 1.7/3.4 ± 0.8 mmHg in the placebo group. The second study (UKPDS 39) was a randomized control trial (n = 1,148) in the hypertensive patients with type 2 diabetes (SBP/DBP 160/94 mmHg). It compared captopril (25-50 mg twice daily) with atenolol (50-100 mg once daily) to achieve the target blood pressure (less than 150/85 mmHg). The primary endpoint was any diabetes related endpoint, including deaths related to diabetes and all-cause mortality. There was no difference between the treatment groups with respect to any diabetes related endpoint, relative risk (RR) = 1.10 (0.86-1.41), p = 0.43, deaths related to diabetes RR = 1.27 (0.82-1.97), p = 0.28 and all-cause mortality RR = 1.14 (0.81-1.61), p = 0.44. The last study (CAPPP) was an open label, randomized trial (n = 10,985) comparing captopril (50-100 mg/day) to conventional therapy (beta-blocker plus diuretic) on cardiovascular morbidity and mortality in patients with hypertension. The primary endpoint was a composite of fatal and non-fatal myocardial infarction, stroke and other cardiovascular deaths. There was no difference in the primary endpoint between the captopril and conventional therapy, relative risk, RR = 1.05 (0.90-1.22), p = 0.52.

Limited safety information was provided in these published studies. The reported adverse events (AEs) included urticarial, maculopapular rash, loss of taste, nausea and vomiting, proteinuria, hypotension, cough and headache. Overall, the efficacy and safety evidence provided supports approval of Noyada for the treatment of essential and renovascular hypertension.

Two pivotal trials were submitted to support the heart failure indication. SAVE trial was a multicenter, randomized double blind trial (n = 2,231) comparing captopril (titrated to 50 mg three times daily) to placebo in patients who survived the acute phase of myocardial infarction (MI) (between 3-16 days post MI) and did not have active ischemia, with left ventricular ejection fraction of less than or equal to 40%. All-cause mortality was significantly reduced in the captopril group compared to placebo, with the risk reduction, RR = 19% (3-32%), p = 0.019. The mortality benefit was clear after one year of follow up, and persisted over the 4 years of follow up. ISIS-4 trial was a large scale (n = 58,050), randomized, double blind, placebo control trial, conducted with factorial design 2 x 2 x 2 that compared placebo with captopril, mononitrate and magnesium given within 24 hours of the onset of symptoms of MI. Captopril statistically significantly reduced mortality within 5 weeks of the onset of MI (captopril, 7.19%) versus (placebo, 7.69%), p = 0.02. Both trials included a high percentage of elderly patients that was appropriate and representative of the age of the patient population suffering from heart failure. Subgroup analysis demonstrated that effect of captopril on mortality risk reduction was independent of age.

Withdrawal due to AEs was higher in the captopril (6%) than placebo group (3%) in the SAVE trial. In the ISIS-4 trial, profound hypotension requiring treatment discontinuation, cardiogenic shock, dizziness and renal dysfunction were significantly more reported with captopril than placebo.

Consistent results in both, ISIS-4 and SAVE trials with respect to decrease in all-cause mortality, and known safety profile of captopril, despite the limitations of the safety data from pivotal trials support the approval of Noyada for the treatment of heart failure post MI.

Two published studies were submitted to support the use of Noyada for the treatment of diabetic nephropathy in adults. The Collaborative Study was a randomized, double blind trial, comparing captopril (25 mg, three times daily) to placebo in patients (n = 409) with insulin-dependent diabetes mellitus (IDDM). The primary endpoint was a doubling of the baseline serum creatinine to at least 117 micromoles per litre (mcmol/L). There was significant reduction in doubling of serum creatinine in the captopril group, i.e., risk reduction was RR = 48% (16-69%), p = 0.007. Patients in the captopril group had 50% reduction in the combined endpoint of death, dialysis and transplantation. The Microalbuminuria Captopril Study was combined analysis of two randomized, double blind trials (n = 235) comparing captopril (50 mg, twice daily) to placebo. The primary endpoint was progression to clinical albuminuria, defined as an albumin excretion rate (AER), and rate of change in AER. The risk of progression to arterial albuminuria in the captopril group was statistically significantly reduced, with risk reduction of RR = 69.2% (31.7-86.1%), p = 0.004.

AEs leading to discontinuation were reversible neutropenia, hemolytic anemia, postural hypotension, worsening of seizure control, and skin rash in the captopril group.

The efficacy and safety evidence provided supports approval of Noyada for the treatment of diabetic nephropathy in adults.

In the first review cycle, the Sponsor was requested to provide evidence that the product administered in the referenced third-party safety and efficacy studies included in the submission was the same as the reference product administered in the comparative bioavailability study (Study No. 3780). The Sponsor did not provide direct head-to-head comparison to establish the critical formulation bridge. Without direct head-to-head comparison between the product referenced in third-party safety and efficacy studies and the reference product administered in the comparative bioavailability study (Study No. 3780), it was not possible to establish that the products are the same. Therefore, a Notice of Non-Compliance (NON) was issued.

In the response to NON, the Sponsor requested a waiver of the requirement to provide comparative bioavailability data for Noyada oral solution based on Biopharmaceutics Classification System (BCS) principles. Based on the data and information provided, captopril meets the BCS criteria for designation as a Class III (high solubility, low permeability) drug substance. Therefore, a waiver of the requirement to provide comparative bioavailability data is acceptable and approval of Noyada is adequately justified.

In the first review cycle, based on the information provided, it was concluded that the benefit-harm-uncertainty profile for Noyada in pediatrics (greater than 1 month of age) was not favorable. Therefore, a NON was issued regarding the pediatric indication.

In the response to the NON, the additional information provided by the sponsor and the totality of evidence available was still considered insufficient, due to the lack of robust data to support the safety and efficacy of Noyada in the proposed pediatric population. As a result, the Product Monograph (PM) was revised to state that the “safety and efficacy have not been fully established in the pediatric population”, and all pediatric dosing recommendations were removed.

A Risk Management Plan was submitted and reviewed by the Marketed Health Products Directorate and was considered acceptable.

Overall, the benefit-harm-uncertainty profile is favourable for Noyada for the recommended indications in adults. Therefore a Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations was recommended.

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