ALISKIREN (Page 5 of 7)

13.2 Animal Toxicology and/or Pharmacology

Reproductive Toxicology Studies: Reproductive toxicity studies of aliskiren hemifumarate did not reveal any evidence of teratogenicity at oral doses up to 600 mg aliskiren/kg/day (20 times the MRHD of 300 mg/day on a mg/m2 basis) in pregnant rats or up to 100 mg aliskiren/kg/day (7 times the MRHD on a mg/m2 basis) in pregnant rabbits. Fetal birth weight was adversely affected in rabbits at 50 mg/kg/day (3.2 times the MRHD on a mg/m2 basis). Aliskiren was present in placenta, amniotic fluid and fetuses of pregnant rabbits.

Juvenile Animal Studies: Juvenile toxicity studies indicated increased systemic exposure to aliskiren 85- to 385-fold in 14-day and 8-day old rats respectively, compared with adult rats. The mdr1 gene expression in juvenile rats was also significantly lower when compared to adult rats. The increased aliskiren exposure in juvenile rats appears to be mainly attributed to lack of maturation of P-gp. The overexposure in juvenile rats was associated with high mortality. [see Use in Specific Populations (8.4)].

14 CLINICAL STUDIES

14.1 Aliskiren Monotherapy

The antihypertensive effects of aliskiren tablets have been demonstrated in 6 randomized, double-blind, placebo-controlled 8-week clinical trials in patients with mild-to-moderate hypertension. The placebo response and placebo-subtracted changes from baseline in seated trough cuff blood pressure are shown in Table 2.

Table 2: Reductions in Seated Trough Cuff Blood Pressure (mmHg systolic/diastolic) in the Placebo-Controlled Studies

Aliskiren daily dose, mg

Study

Placebo mean change

75

150

300

600

Placebo-subtracted

Placebo-subtracted

Placebo-subtracted

Placebo-subtracted

1

2.9/3.3

5.7/4*

5.9/4.5*

11.2/7.5*

2

5.3/6.3

6.1/2.9*

10.5/5.4*

10.4/5.2*

3

10/8.6

2.2/1.7

2.1/1.7

5.1/3.7*

4

7.5/6.9

1.9/1.8

4.8/2*

8.3/3.3*

5

3.8/4.9

9.3/5.4*

10.9/6.2*

12.1/7.6*

6

4.6/4.1

8.4/4.9

* p value less than 0.05 versus placebo by ANCOVA with Dunnett’s procedure for multiple comparisons

p value less than 0.05 versus placebo by ANCOVA for the pairwise comparison.

The studies included approximately 2,730 patients given doses of 75 to 600 mg of aliskiren and 1,231 patients given placebo. As shown, there is some increase in response with administered dose in all studies, with reasonable effects seen at 150 mg to 300 mg, and no clear further increases at 600 mg. A substantial proportion (85% to 90%) of the blood pressure-lowering effect was observed within 2 weeks of treatment. Studies with ambulatory blood pressure monitoring showed reasonable control throughout the interdosing interval; the ratios of mean daytime to mean nighttime ambulatory BP range from 0.6 to 0.9.

Patients in the placebo-controlled trials continued open-label aliskiren for up to 1 year. A persistent blood pressure-lowering effect was demonstrated by a randomized withdrawal study (patients randomized to continue drug or placebo), which showed a statistically significant difference between patients kept on aliskiren and those randomized to placebo. With cessation of treatment, blood pressure gradually returned toward baseline levels over a period of several weeks. There was no evidence of rebound hypertension after abrupt cessation of therapy.

Aliskiren lowered blood pressure in all demographic subgroups, although black patients tended to have smaller reduction than Caucasians and Asians, as has been seen with ACEIs and ARBs.

There are no studies of aliskiren tablets or members of the direct renin inhibitors demonstrating reductions in cardiovascular risk in patients with hypertension.

14.2 Aliskiren in Combination with Other Antihypertensives

Hydrochlorothiazide (HCTZ)

Aliskiren 75, 150, and 300 mg and HCTZ 6.25, 12.5, and 25 mg were studied alone and in combination in an 8-week, 2,776-patient, randomized, double-blind, placebo-controlled, parallel-group, 15-arm factorial study. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies as shown in Table 3.

Table 3: Placebo-Subtracted Reductions in Seated Trough Cuff Blood Pressure (mmHg systolic/diastolic) in Combination with Hydrochlorothiazide

Hydrochlorothiazide, mg

Aliskiren, mg

Placebo mean change

0

6.25

12.5

25

Placebo-subtracted

Placebo-subtracted

Placebo-subtracted

Placebo-subtracted

0

7.5/6.9

3.5/2.1

6.4/3.2

6.8/2.4

75

1.9/1.8

6.8/3.8

8.2/4.2

9.8/4.5

150

4.8/2

7.8/3.4

10.1/5

12/5.7

300

8.3/3.3

12.3/7

13.7/7.3

Valsartan

Aliskiren 150 mg and 300 mg and valsartan 160 mg and 320 mg were studied alone and in combination in an 8-week, 1,797-patient, randomized, double-blind, placebo-controlled, parallel-group, 4-arm, dose-escalation study. The dosages of aliskiren and valsartan were started at 150 mg and 160 mg, respectively, and increased at 4 weeks to 300 mg and 320 mg, respectively. Seated trough cuff blood pressure was measured at baseline, 4, and 8 weeks. Blood pressure reductions with the combinations were greater than the reductions with the monotherapies as shown in Table 4. In general, the combination of aliskiren and angiotensin receptor blocker should be avoided [see Contraindications (4), Warnings and Precautions (5), and Drug Interactions (7)].

Table 4: Placebo-Subtracted Reductions in Seated Trough Cuff Blood Pressure (mmHg systolic/diastolic) in Combination with Valsartan

Aliskiren, mg

Placebo mean change

Valsartan, mg

0

160

320

0

4.6/4.1*

5.6/3.9

8.2/5.6

150

5.4/2.7

10.0/5.7

300

8.4/4.9

12.6/8.1

* The placebo change is 5.2/4.8 for week 4 endpoint which was used for the dose groups containing aliskiren 150 mg or valsartan 160 mg.

Amlodipine

Aliskiren 150 mg and 300 mg and amlodipine besylate 5 mg and 10 mg were studied alone and in combination in an 8-week, 1,685-patient, randomized, double-blind, placebo-controlled, multifactorial study. Treatment with aliskiren and amlodipine resulted overall in significantly greater reductions in diastolic and systolic blood pressure compared to the respective monotherapy components as shown in Table 5.

Table 5: Placebo-Subtracted Reductions in Seated Trough Cuff Blood Pressure (mmHg systolic/diastolic) in Combination with Amlodipine

Aliskiren, mg

Placebo mean change

Amlodipine, mg

0

5

10

0

6.8/5.4

9.0/5.6

14.3/8.5

150

3.9/2.6

13.9/8.6

17.1/10.8

300

8.6/4.9

15.0/9.6

16.4/11.1

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