Regulatory Decision Summary for VIACORAM

The efficacy and safety of Viacoram (perindopril arginine/amlodipine besylate), were supported by three double-blind, randomized, controlled trials in adult patients with mild to moderate essential hypertension.

The Fixed Dose Combination (FDC) of perindopril arginine 3.5 mg/amlodipine besylate 2.5 mg (Per 3.5/Aml 2.5) was studied as an initial therapy in patients with mild to moderate uncomplicated essential hypertension. Perindopril 3.5 mg/amlodipine 2.5 mg was superior to placebo in reducing systolic blood pressure (SBP)/diastolic blood pressure (DBP) (the difference in the change from baseline to last post-baseline value was -7.2/-4.1 mmHg, p<0.001 for both). The blood pressure controlled rate (SBP <140 mmHg and DBP <90 mmHg) by Per 3.5/Aml 2.5 was superior to placebo (43.5% versus [vs.] 26.6%, p<0.001). Perindopril 3.5 mg/amlodipine 2.5 mg was also superior to Per 3.5 or Aml 2.5 administered separately, as monotherapy, in reducing SBP/DBP. The  additional SBP/DBP reductions of the combination were -5.0/-3.6 and -5.2/-3.0 mmHg as compared to Per 3.5 and Aml 2.5, respectively, p<0.001 for all comparisons.
 
The highest strength of the FDC, perindopril arginine 14 mg/amlodipine 10 mg (Per 14/Aml 10), was studied in a randomised, double-blind, active controlled trial in which patients received the FDC of Per 14/Aml 10, perindopril erbumine 16 mg (PERe 16), or amlodipine 10 mg (Aml 10). Treatment with the combination (Per 14/Aml 10) resulted in statistically and clinically significant reduction in SBP (-10.1 mmHg vs. PERe 16 and -4.0 mmHg vs. Aml 10) and DBP (-6.3 mmHg vs. PERe 16 and -2.5 mmHg vs. Aml 10) (p< 0.01 and p<0.001 respectively). The proportion of patients with a controlled blood pressure  was also significantly higher (51%) in the FDC group compared to Aml 10 (37%, p = 0.001) and PERe 16 (26%, p<0.001) groups.

The safety profile of the highest dose combination (Per 14/Aml 10) was comparable to those of the lower doses except for the expected higher rate of dose-dependent amlodipine-induced peripheral oedema. However, a lower incidence of peripheral oedema with Per 14/Aml 10 (7.2%) compared to Aml 10 (12.5%) was observed in the short-term study.

The long-term tolerance of the combination was consistent with the known safety profiles of each individual product. In the long-term study, the most frequently reported emergent adverse events were: cough (2.3-2.7%), peripheral oedema (1.1-6.5%) and nasopharyngitis (1.4-2.9%) in patients on Per 3.5/Aml 2.5, Per 7/Aml 5, and Per 14/Aml 10, respectively.

Based on the studies conducted, the indication of the combination product is restricted to adult patients (between 18 and 65 years old) with mild to moderate essential hypertension. It is not indicated for switching therapy from the individual drugs currently on the market.

Overall, the combination product demonstrated better antihypertensive efficacy than either component administered alone and demonstrated decreased incidence of peripheral oedema, the most common adverse event associated with the use of amlodipine given alone.