Amlodipine and Valsartan (Page 6 of 8)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Amlodipine
Rats and mice treated with amlodipine maleate in the diet for up to 2 years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on mg/m2 basis, similar to the MRHD of 10 mg amlodipine/day. For the rat, the highest dose was, on a mg/m2 basis, about 2.5 the MRHD. (Calculations based on a 60 kg patient.)
Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level.
There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m2 basis).
Valsartan
There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at concentrations calculated to provide doses of up to 160 and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.4 and 6 times, respectively, the MRHD of 320 mg/day on a mg/m2 basis. (Calculations based on a 60 kg patient.)
Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli , a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with Chinese hamster ovary cells, and a rat micronucleus test. Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses of up to 200 mg/kg/day. This dose is about 6 times the MRHD on a mg/m2 basis.

14 CLINICAL STUDIES

Amlodipine and valsartan was studied in 2 placebo-controlled and 4 active-controlled trials in hypertensive patients. In a double-blind, placebo-controlled study, a total of 1012 patients with mild-to-moderate hypertension received treatments of 3 combinations of amlodipine and valsartan (5 mg/80 mg, 5 mg/160 mg, 5 mg/320 mg) or amlodipine alone (5 mg), valsartan alone (80 mg, 160 mg, or 320 mg) or placebo. All doses with the exception of the 5 mg/320 mg dose were initiated at the randomized dose. The high dose was titrated to that dose after a week at a dose of 5 mg/160 mg. At week 8, the combination treatments were statistically significantly superior to their monotherapy components in reduction of diastolic and systolic blood pressures.

Table 1: Effect of Amlodipine and Valsartan on Sitting Diastolic Blood Pressure
* Mean Change and Placebo-Subtracted Mean Change from Baseline (mmHg) at Week 8 in Sitting Diastolic Blood Pressure. Mean baseline diastolic BP was 99.3 mmHg.
Amlodipine dosage Valsartan dosage
0 mg 80 mg 160 mg 320 mg
Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted
0 mg -6.4 -9.5 -3.1 -10.9 -4.5 -13.2 -6.7
5 mg -11.1 -4.7 -14.2 -7.8 -14 -7.6 -15.7 -9.3

Table 2: Effect of Amlodipine and Valsartan on Sitting Systolic Blood Pressure
* Mean Change and Placebo-Subtracted Mean Change from Baseline (mmHg) at Week 8 in Sitting Systolic Blood Pressure. Mean baseline systolic BP was 152.8 mmHg.
Amlodipine dosage Valsartan dosage
0 mg 80 mg 160 mg 320 mg
Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted
0 mg -6.2 -12.9 -6.8 -14.3 -8.2 -16.3 -10.1
5 mg -14.8 -8.6 -20.7 -14.5 -19.4 -13.2 -22.4 -16.2

In a double-blind, placebo-controlled study, a total of 1246 patients with mild to moderate hypertension received treatments of 2 combinations of amlodipine and valsartan (10 mg/160 mg, 10 mg/320 mg), or amlodipine alone (10 mg), valsartan alone (160 mg or 320 mg) or placebo. With the exception of the 10 mg/320 mg dose, treatment was initiated at the randomized dose. The high dose was initiated at a dose of 5 mg/160 mg and titrated to the randomized dose after 1 week. At week 8, the combination treatments were statistically significantly superior to their monotherapy components in reduction of diastolic and systolic blood pressures.

Table 3: Effect of Amlodipine and Valsartan on Sitting Diastolic Blood Pressure
* Mean Change and Placebo-Subtracted Mean Change from Baseline (mmHg) at Week 8 in Sitting Diastolic Blood Pressure. Mean baseline diastolic BP was 99.1 mmHg.
Amlodipine dosage Valsartan dosage
0 mg 160 mg 320 mg
Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted
0 mg -8.2 -12.8 - 4.5 -12.8 -4.5
10 mg -15 -6.7 - 17.2 - 9 -18.1 -9.9
Table 4: Effect of Amlodipine and Valsartan on Sitting Systolic Blood Pressure
* Mean Change and Placebo-Subtracted Mean Change from Baseline (mmHg) at Week 8 in Sitting Systolic Blood Pressure. Mean baseline systolic BP was 156.7 mmHg.
Amlodipine dosage Valsartan dosage
0 mg 160 mg 320 mg
Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted Mean Change* Placebo-subtracted
0 mg -11 -18.1 -7 -18.5 -7.5
10 mg -22.2 -11.2 -26.6 -15.5 -26.9 -15.9

In a double-blind, active-controlled study, a total of 947 patients with mild to moderate hypertension who were not adequately controlled on valsartan 160 mg received treatments of 2 combinations of amlodipine and valsartan (10 mg/160 mg, 5 mg/160 mg) or valsartan alone (160 mg). At week 8, the combination treatments were statistically significantly superior to the monotherapy component in reduction of diastolic and systolic blood pressures.

Table 5: Effect of Amlodipine and Valsartan on Sitting Diastolic/Systolic Blood Pressure
* Mean Change from Baseline at Week 8 in Sitting Diastolic/Systolic Blood Pressure. Mean baseline BP was 149.5/96.5 (systolic/diastolic) mmHg.** Treatment Difference = difference in mean BP reduction between amlodipine and valsartan and the control group (Valsartan 160 mg).
Treatment Group Diastolic BP Systolic BP
Mean change* Treatment Difference** Mean change* Treatment Difference**
Amlodipine and Valsartan 10 mg/160 mg -11.4 -4.8 -13.9 -5.7
Amlodipine and Valsartan 5 mg/160 mg -9.6 -3.1 -12 -3.9
Valsartan 160 mg -6.6 -8.2

In a double-blind, active-controlled study, a total of 944 patients with mild to moderate hypertension who were not adequately controlled on amlodipine 10 mg received a combination of amlodipine and valsartan (10 mg/160 mg) or amlodipine alone (10 mg). At week 8, the combination treatment was statistically significantly superior to the monotherapy component in reduction of diastolic and systolic blood pressures.

Table 6: Effect of Amlodipine and Valsartan on Sitting Diastolic/Systolic Blood Pressure
*Mean Change from Baseline at Week 8 in Sitting Diastolic/Systolic Blood Pressure. Mean baseline BP was 147/95.1 (systolic/diastolic) mmHg. **Treatment Difference = difference in mean BP reduction between amlodipine and valsartan and the control group (Amlodipine 10 mg).
Treatment Group Diastolic BP Systolic BP
Mean change* Treatment Difference** Mean change* Treatment Difference**
Amlodipine and Valsartan 10 mg/160 mg -11.8 -1.8 -12.7 -1.9
Amlodipine 10 mg -10 -10.8

Amlodipine and valsartan was also evaluated for safety in a 6-week, double-blind, active-controlled trial of 130 hypertensive patients with severe hypertension (mean baseline BP of 171/113 mmHg). Adverse events were similar in patients with severe hypertension and mild/moderate hypertension treated with amlodipine and valsartan.
A wide age range of the adult population, including the elderly was studied (range 19 to 92 years, mean 54.7 years). Women comprised almost half of the studied population (47.3%). Of the patients in the studied amlodipine and valsartan group, 87.6% were Caucasian. Black and Asian patients each represented approximately 4% of the population in the studied amlodipine and valsartan group.
Two additional double-blind, active-controlled studies were conducted in which amlodipine and valsartan was administered as initial therapy. In 1 study, a total of 572 black patients with moderate to severe hypertension were randomized to receive either combination amlodipine/valsartan or amlodipine monotherapy for 12 weeks. The initial dose of amlodipine/valsartan was 5 mg/160 mg for 2 weeks with forced titration to 10 mg/160 mg for 2 weeks, followed by optional titration to 10 mg/320 mg for 4 weeks and optional addition of hydrochlorothiazide 12.5 mg for 4 weeks. The initial dose of amlodipine was 5 mg for 2 weeks with forced titration to 10 mg for 2 weeks, followed by optional titration to 10 mg for 4 weeks and optional addition of hydrochlorothiazide 12.5 mg for 4 weeks. At the primary endpoint of 8 weeks, the treatment difference between amlodipine/valsartan and amlodipine was 6.7/2.8 mmHg.
In the other study of similar design, a total of 646 patients with moderate to severe hypertension (MSSBP of ≥160 mmHg and <200 mmHg) were randomized to receive either combination amlodipine/valsartan or amlodipine monotherapy for 8 weeks. The initial dose of amlodipine/valsartan was 5 mg/160 mg for 2 weeks with forced titration to 10 mg/160 mg for 2 weeks, followed by the optional addition of hydrochlorothiazide 12.5 mg for 4 weeks. The initial dose of amlodipine was 5 mg for 2 weeks with forced titration to 10 mg for 2 weeks, followed by the optional addition of hydrochlorothiazide 12.5 mg for 4 weeks. At the primary endpoint of 4 weeks, the treatment difference between amlodipine/valsartan and amlodipine was 6.6/3.9 mmHg.
There are no trials of the amlodipine and valsartan combination tablet demonstrating reductions in cardiovascular risk in patients with hypertension, but the amlodipine component and several ARBs, which are the same pharmacological class as the valsartan component, have demonstrated such benefits.

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