Regulatory Decision Summary for Sandoz Bisoprolol Tablets

This Supplemental New Drug Submission-Submission Relying on Third-Party Data was filed to obtain market authorization pursuant to Section C.08.004 of the Food and Drugs Regulations for Sandoz Bisoprolol Tablets (bisoprolol fumarate) for the treatment of stable chronic heart failure. In addition, two additional strength tablets (1.25 milligram [mg] and 2.5 mg) were proposed for titration when initiating heart failure treatment. A lower dose (2.5 mg) was also proposed for the treatment of mild to moderate hypertension.

The effect of the 2.5 milligram (mg) dose of Sandoz Bisoprolol Tablets in the treatment of mild to moderate hypertension was evaluated in three randomized controlled clinical trials. The findings from all three studies were consistent and demonstrated a statistically significant decrease in systolic and diastolic blood pressure from baseline. Decreases in systolic blood pressure from baseline ranged from 6.6 to 19.5 millimetre of mercury (mmHg). Diastolic blood pressure decreased from 3 to 11.7 mmHg from baseline. Two of the studies also compared the 2.5 mg dose with the 5 mg dose of bisoprolol tablets and found no significant differences in the reduction of blood pressure. The lack of safety information reported was not a major concern. The evidence provided supports the approval of 2.5 mg dose of bisoprolol for the treatment of mild to moderate hypertension.

The effect of Sandoz Bisoprolol Tablets for the treatment of heart failure was evaluated in three randomized, controlled studies, that is the Cardiac Insufficiency Bisoprolol Study (CIBIS), CIBIS II and CIBIS-ELD. CIBIS (n = 641) and CIBIS II (n = 2,647) compared bisoprolol (5 mg and 10 mg, respectively) with placebo among patients with moderate to severe heart failure (New York Heart Association [NYHA] Class III and IV). These two studies were conducted in the early 1990s. The mean age of patients in these two studies was 61 years. CIBIS-ELD (n = 876) was initiated in 2005 and examined tolerability and clinical effects of bisoprolol versus (vs.) carvedilol among elderly patients (65 years of age and older, average age 73 years). Carvedilol was approved for the treatment of heart failure in Canada. The primary outcome measure for the first two CIBIS trials was mortality. There was no significant reduction in mortality compared to the placebo group in the CIBIS trial (bisoprolol 5 milligrams per day [mg/day] 16.6% vs. placebo 20.9%; p = 0.22). In CIBIS II, with a target bisoprolol dose increased to 10 mg/day, significantly fewer deaths (all-cause mortality) were reported (bisoprolol 11.8% vs. placebo 17.3% p = 0.0001). Because of the significant mortality benefit, the trial was stopped early. Patients receiving 10 mg/day bisoprolol also reported significantly fewer sudden deaths (bisoprolol 3.6% vs. placebo 6.3%; p = 0.0011) and all-cause hospitalizations/cardiovascular deaths (bisoprolol 29% vs. placebo 35%; p = 0.0004). CIBIS-ELD found no significant difference in the percentage of patients reaching and maintaining the guideline recommended target dose for of the two beta-blockers (bisoprolol: 24% vs. carvedilol: 25%; p = 0.064). There were no significant differences between bisoprolol and carvedilol in the number of hospitalizations, or in the incidence of worsening heart failure, new atrioventricular block, hypotension, vertigo, renal dysfunction, hyperuricaemia and hyperlipidemia. CIBIS found no significant difference in premature treatment withdrawals (bisoprolol 23% vs. placebo 26%; not significant), and significantly fewer heart failure-related adverse events (for example acute pulmonary edema, heart failure without pulmonary edema and cardiogenic shock; bisoprolol 33.4% vs. placebo 47.9%; p<0.001).

The results from CIBIS and CIBIS II indicated a significant clinical benefit associated with bisoprolol use. These trials also reported that bisoprolol was well tolerated. The efficacy and safety evidence provided supports the use of bisoprolol for the treatment moderate to severe heart failure.

In order to extrapolate the safety and efficacy data from the literature references to support the approval for the treatment of stable heart failure with the Sandoz Bisoprolol Tablets, a Biopharmaceutics Classification System-based (BCS) biowaiver was requested in lieu of conducting comparative bioavailability studies between the Sandoz Bisoprolol Tablets (bisoprolol fumarate) , 1.25 mg, 2.5 mg, 5 mg and 10 mg and the Concor tablets, 1.25 mg, 2.5 mg, 5 mg and 10 mg (Merck, Germany). The BCS-based biowaiver consisted of solubility and permeability data to characterize the BCS of bisoprolol tablets, as well as comparative dissolution data between the Sandoz Bisoprolol Tablets, 2.5 mg and 10 mg and the Concor tablets, 2.5 mg and 10 mg (Merck, Germany). Based on information provided, bisoprolol is classified as a highly soluble and highly permeable drug substance. Bisoprolol is therefore classified as a BCS Class I drug substance. Further, the data provided by the sponsor confirmed that the excipients in Sandoz Bisoprolol Tablets met the applicable requirements for a BCS-based biowaiver; none of the excipients are expected to affect the bioavailability of bisoprolol. The requested waiver of the requirement to provide clinical data to support approval of the Sandoz Bisoprolol Tablets, 1.25 mg and 2.5 mg bisoprolol fumarate is granted.

In the response to the Notice of Deficiency, the Sponsor used new batches for the BCS-based biowaivers. The formulation and manufacturing process used for these new batches have been found to be representative of those proposed for the commercial lots. The Quality requirements of Health Canada’s Bioequivalence of Proportional Formulations policy have been met.

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 Sandoz Bisoprolol Tablets (1.25, 2.5, 5 and 10 mg) for the treatment of stable heart failure and the 2.5 mg dose for the treatment of mild to moderate hypertension, therefore a Notice of Compliance, pursuant to section C.08.004 of the Food and Drug Regulations was recommended.

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