me.
Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatinresulted in a 77% increase in exposure to simvastatin compared tosimvastatin alone [see DrugInteractions (7.2)].
Cyclosporine: A prospective study in renal transplant patients (N=11) showed on an average of40% increase in trough cyclosporine levels when concomitantly treated with amlodipine[see Drug Interactions (7.2)].
Tacrolimus: A prospective study in healthy Chinese volunteers (N=9) with CYP3A5 expressersshowed a 2.5- to 4-fold increase in tacrolimus exposure when concomitantly administered withamlodipine compared to tacrolimus alone. This finding was not observed in CYP3A5non-expressers (N=6). However, a 3-fold increase in plasma exposure to tacrolimus in a renaltransplant patient (CYP3A5 non-expresser) upon initiation of amlodipine for the treatment of
post-transplant hypertension resulting in reduction of tacrolimus dose has been reported.
Irrespective of the CYP3A5 genotype status, the possibility of an interaction cannot be excludedwith these drugs [see Drug Interactions (7.2)].
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrationscalculated to provide daily dosage levels of 0.5, 1.25, and 2.5 amlodipine mg/kg/day, showed noevidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m2basis, similar to the maximum recommended human dose of 10 mg amlodipine/day.1 For therat, the highest dose was, on a mg/m2 basis, about twice the maximum recommended humandose.1
Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects ateither the gene or chromosome level.
There was no effect on the fertility of rats treated orally with amlodipine maleate (males for64 days and females for 14 days prior to mating) at doses up to 10 mg amlodipine/kg/day(8 times the maximum recommended human dose1 of 10 mg/day on a mg/m2 basis). Based onpatient weight of 50 kg.
14 CLINICAL STUDIES
14.1 Effects in Hypertension
Adult Patients
The antihypertensive efficacy of amlodipine has been demonstrated in a total of 15 double-blind,placebo-controlled, randomized studies involving 800 patients on amlodipine and 538 onplacebo. Once daily administration produced statistically significant placebo-correctedreductions in supine and standing blood pressures at 24 hours postdose, averaging about12/6 mmHg in the standing position and 13/7 mmHg in the supine position in patients with mildto moderate hypertension. Maintenance of the blood pressure effect over the 24-hour dosinginterval was observed, with little difference in peak and trough effect. Tolerance was notdemonstrated in patients studied for up to 1 year. The 3 parallel, fixed dose, dose responsestudies showed that the reduction in supine and standing blood pressures was dose-related within
the recommended dosing range. Effects on diastolic pressure were similar in young and olderpatients. The effect on systolic pressure was greater in older patients, perhaps because of greaterbaseline systolic pressure. Effects were similar in black patients and in white patients.
Pediatric Patients
Two hundred sixty-eight hypertensive patients aged 6 to 17 years were randomized first toamlodipine 2.5 or 5 mg once daily for 4 weeks and then randomized again to the same dose or toplacebo for another 4 weeks. Pati |
