Aliskiren (Page 5 of 8)

Specific Populations

Renally Impaired Patients: Aliskiren was evaluated in adult patients with varying degrees of renal insufficiency. The rate and extent of exposure (AUC and Cmax ) of aliskiren in subjects with renal impairment did not show a consistent correlation with the severity of renal impairment. Adjustment of the starting dose is not required in these patients [see Warnings and Precautions (5.2)].

The pharmacokinetics of aliskiren following administration of a single oral dose of 300 mg was evaluated in adult patients with End Stage Renal Disease (ESRD) undergoing hemodialysis. When compared to matched healthy subjects, changes in the rate and extent of aliskiren exposure (Cmax and AUC) in ESRD patients undergoing hemodialysis were not clinically significant.

Timing of hemodialysis did not significantly alter the pharmacokinetics of aliskiren in ESRD patients. Therefore, no dose adjustment is warranted in ESRD patients receiving hemodialysis.

Hepatically Impaired Patients: The pharmacokinetics of aliskiren were not significantly affected in patients with mild to severe liver disease. Consequently, adjustment of the starting dose is not required in these patients.

Pediatric Patients:

The pharmacokinetics of aliskiren were evaluated in an 8-day pharmacokinetic study in 39 pediatric patients with hypertension 6 years to 17 years of age. Aliskiren was given as daily doses of 2 mg/kg (0.67 times the lowest approved recommended dosage in a 50 kg pediatric patient) or 6 mg/kg (the highest recommended approved dosage in a 50 kg pediatric patient), administered as mini-tablets (3.125 mg oral pellets). The pharmacokinetic parameters of aliskiren were similar to those in adults, and the results of this study do not suggest that age or gender have any significant effect on aliskiren systemic exposure in patients 6 to 17 years of age. Exposure decreased with increase in body weight.

In an 8-week randomized double blind study with aliskiren monotherapy in 267 pediatric patients with hypertension 6 years to 17 years of age [see Clinical Studies (14.4)] , fasting trough aliskiren concentrations at Day 28 demonstrated similar drug trough exposure levels to those observed in other trials using similar aliskiren doses in both adults and pediatric patients.

Geriatric Patients: Exposure (measured by AUC) is increased in elderly patients 65 years and older. Adjustment of the starting dose is not required in these patients.

Racial or Ethnic Groups: The pharmacokinetic differences between blacks, Caucasians, and Japanese are minimal.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenic potential was assessed in a 2-year rat study and a 6-month transgenic (rasH2) mouse study with aliskiren hemifumarate at oral doses of up to 1500 mg aliskiren/kg/day. Although there were no statistically significant increases in tumor incidence associated with exposure to aliskiren, mucosal epithelial hyperplasia (with or without erosion/ulceration) was observed in the lower gastrointestinal tract at doses of greater than or equal to 750 mg/kg/day in both species, with a colonic adenoma identified in 1 rat and a cecal adenocarcinoma identified in another, rare tumors in the strain of rat studied. On a systemic exposure (AUC0-24hr ) basis, 1500 mg/kg/day in the rat is about 4 times and in the mouse about 1.5 times the maximum recommended human dose (MRHD) (300 mg aliskiren/day). Mucosal hyperplasia in the cecum or colon of rats was also observed at doses of 250 mg/kg/day (the lowest tested dose) as well as at higher doses in 4- and 13- week studies.

Aliskiren hemifumarate was devoid of genotoxic potential in the Ames reverse mutation assay with S. typhimurium and E. coli , the in vitro Chinese hamster ovary cell chromosomal aberration assay, the in vitro Chinese hamster V79 cell gene mutation test and the in vivo mouse bone marrow micronucleus assay.

Fertility of male and female rats was unaffected at doses of up to 250 mg aliskiren/kg/day (8 times the MRHD of 300 mg Aliskiren/60 kg on a mg/m2 basis.)

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.

14 CLINICAL STUDIES

14.1 Aliskiren Monotherapy

The antihypertensive effects of Aliskiren 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 mg (0.5 times the lowest recommended dosage) to 600 mg (twice the highest recommended dosage) of aliskiren and 1,231 patients given placebo. The recommended dosage of Aliskiren is either 150 or 300 mg once daily [see Dosage and Administration (2.1) ]. As shown in Table 1, there is some increase in response with administered dose in all studies, with reasonable effects seen at 150mg to 300mg, 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.

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 or members of the direct renin inhibitors demonstrating reductions in cardiovascular risk in patients with hypertension.

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