Prescription Drug Information: Amlodipine and Valsartan (Page 5 of 7)

13.3 Animal Toxicology and/or Pharmacology

Amlodipine

No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively, about 10 and 20 times the MRHD of 10 mg amlodipine on a mg/m2 basis) during their respective periods of major organogenesis. (Calculations based on a patient weight of 60 kg.) However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) for rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Valsartan

No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses of up to 600 mg/kg/day and to pregnant rabbits at oral doses of up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. The no observed adverse effect doses of 600, 200, and 2 mg/kg/day in mice, rats and rabbits, respectively, are about 9, 6, and 0.1 times the MRHD of 320 mg/day on a mg/m2 basis. (Calculations based on a patient weight of 60 kg.)

Amlodipine Besylate and Valsartan

In the oral embryofetal development study in rats using amlodipine besylate plus valsartan at doses equivalent to 5 mg/kg/day amlodipine plus 80 mg/kg/day valsartan, 10 mg/kg/day amlodipine plus 160 mg/kg/day valsartan, and 20 mg/kg/day amlodipine plus 320 mg/kg/day valsartan, treatment-related maternal and fetal effects (developmental delays and alterations noted in the presence of significant maternal toxicity) were noted with the high dose combination. The no-observed-adverse-effect level (NOAEL) for embryofetal effects was 10 mg/kg/day amlodipine plus 160 mg/kg/day valsartan. On a systemic exposure [AUC(0-∞ )] basis, these doses are, respectively, 4.3, and 2.7 times the systemic exposure [AUC(0-∞ )] in humans receiving the MRHD (10/320 mg/60 kg).

14 CLINICAL STUDIES

Amlodipine and valsartan tablets 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 (5/80, 5/160, 5/320 mg) or amlodipine alone (5 mg), valsartan alone (80, 160, or 320 mg) or placebo. All doses with the exception of the 5/320 mg dose were initiated at the randomized dose. The high dose was titrated to that dose after a week at a dose of 5/160 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 Tablets on Sitting Diastolic Blood Pressure

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

*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.

Table 2: Effect of Amlodipine and Valsartan Tablets on Sitting Systolic Blood Pressure

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 -16.2 -10.1
5 mg -14.8 -8.6 -20.9 -14.5 -19.3 -13.2 -22.4 -16.2

*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.

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 (10/160, 10/320 mg), or amlodipine alone (10 mg), valsartan alone (160 or 320 mg) or placebo. With the exception of the 10/320 mg dose, treatment was initiated at the randomized dose. The high dose was initiated at a dose of 5/160 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 Tablets on Sitting Diastolic Blood Pressure

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

*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.

Table 4: Effect of Amlodipine and Valsartan Tablets on Sitting Systolic Blood Pressure

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

*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.

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 (10/160, 5/160 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 Tablets on Sitting Diastolic/Systolic Blood Pressure

Treatment Group Diastolic BP Systolic BP
Mean change* Treatment Difference** Mean change* Treatment Difference**
Amlodipine and valsartan tablets10/160 mg -11.4 -4.8 -13.9 -5.7
Amlodipine and valsartan tablets5/160 mg -9.6 -3.1 -12 -3.9
Valsartan 160 mg -6.6 -8.2

*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 tablets and the control group (Valsartan 160 mg).

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 (10/160 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 Tablets on Sitting Diastolic/Systolic Blood Pressure

Treatment Group Diastolic BP Systolic BP
Mean change* Treatment Difference** Mean change* Treatment Difference**
Amlodipine and valsartan tablets10/160 mg -11.8 -1.8 -12.7 -1.9
Amlodipine 10 mg -10 -10.8

*Mean Change from Baseline at Week 8 in Sitting Diastolic/Systolic Blood Pressure. Mean baseline BP was 147.0/95.1 (systolic/diastolic) mmHg.

**Treatment Difference = difference in mean BP reduction between amlodipine and valsartan tablets and the control group (Amlodipine 10 mg).

Amlodipine and valsartan tablets 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 tablets.

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 tablets group, 87.6% were Caucasian. Black and Asian patients each represented approximately 4% of the population in the studied amlodipine and valsartan tablets group.

Two additional double-blind, active-controlled studies were conducted in which amlodipine and valsartan tablets 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 5/160 mg for 2 weeks with forced titration to 10/160 mg for 2 weeks, followed by optional titration to 10/320 mg for 4 weeks and optional addition of HCTZ 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 HCTZ 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 5/160 mg for 2 weeks with forced titration to 10/160 mg for 2 weeks, followed by the optional addition of HCTZ 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 HCTZ 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 tablets 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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