Aprovasc Drug Interactions

For the irbesartan and amlodipine combination: Based on a pharmacokinetic study where irbesartan and amlodipine were administered alone or in combination, there is no pharmacokinetic interaction between irbesartan and amlodipine.
No drug interaction studies have been performed with Aprovasc and other medicinal products.
Irbesartan: Based on in vitro data, no interactions would be expected to occur with drugs for which metabolism depends on cytochrome P450 isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 or CYP3A4.
Irbesartan is primarily metabolized by CYP2C9, however, during clinical interaction studies no significant interactions were observed when irbesartan was co-administered with warfarin (metabolized by CYP2C9).
Co-administration with nifedipine or hydrochlorothiazide has no effect on the pharmacokinetic profile of irbesartan.
Irbesartan has no effect on the pharmacokinetics of simvastatin (metabolized by CYP3A4) or digoxin (substrate of P-glycoprotein efflux transporter).
Based on experience with the use of other drugs with an effect on the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium may increase serum potassium levels.
Use of Aprovasc concomitantly with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or moderate to severe renal insufficiency (glomerular filtration rate [GFR] <60 mL/min/1.73 m²), and is not recommended in other patients.
Angiotensin-converting enzyme (ACE) inhibitors: The use of Aprovasc in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.
In elderly patients, volume-depleted patients (including those treated with diuretics), or in patients with impaired renal function, co-administration of irbesartan with NSAIDs, including selective COX-2 inhibitors, or with angiotenisin II receptor antagonists, including irbesartan, can cause deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Renal function should be monitored periodically in patients receiving occasional treatment with irbesartan and NSAIDs. The antihypertensive effect of angiotenisin II receptor antagonists, including irbesartan, may be attenuated by NSAIDs including selective COX-2 inhibitors.
Amlodipine: Amlodipine has been safely co-administered with thiazide diuretics, beta blockers, alpha blockers, ACE inhibitors, long-acting nitrates, sublingual glyceryl trinitrate, NSAIDs, antibiotics, and oral hypoglycemic drugs.
Data from in vitro studies with human plasma indicate that amlodipine has no effect on the protein binding of the medicinal products studied (digoxin, phenytoin, warfarin or indomethacin).
Cimetidine: Co-administration of amlodipine with cimetidine had no effect on the pharmacokinetic profile of amlodipine.
Grapefruit juice: Co-administration of 240 mL of grapefruit juice with a single 10 mg oral dose of amlodipine in 20 healthy subjects had no significant effect on the pharmacokinetics of amlodipine.
Aluminum/magnesium (antacids): Concomitant administration of an antacid containing aluminum/magnesium with a single dose of amlodipine had no significant effect on the pharmacokinetic profile of amlodipine.
Sildenafil: When amlodipine and sildenafil were used in combination, each agent independently exerted a blood pressure lowering effect.
Atorvastatin: Co-administration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.
Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in healthy subjects.
Warfarin: Co-administration of amlodipine did not significantly change the effect of warfarin on prothrombin time.
Cyclosporine: Pharmacokinetic studies with cyclosporine have demonstrated that amlodipine has no significant effect on cyclosporine pharmacokinetics.
Lithium: Increased serum lithium concentrations and lithium toxicity have been reported with concomitant use of irbesartan requiring monitoring of lithium levels during co-administration.
Laboratory test abnormalities: No clinically significant changes in laboratory test parameters were observed in controlled clinical studies with irbesartan in hypertensive patients. No special monitoring of laboratory parameters is required in patients with essential hypertension receiving treatment with irbesartan.
Special precautions related to the carcinogenic, mutagenic and teratogenic effects, and effects on fertility: Irbesartan: No carcinogenic evidence was observed with administration of irbesartan at doses of up to 500/1000 mg/kg/day in rats (male/female, respectively) and 1000 mg/kg/day in mice for 2 years. These doses provided a systemic exposure 4-25 times (rats) and 4-6 times (mice) the exposure in humans receiving 300 mg/day.
Irbesartan was not mutagenic in a battery of in vitro tests (Ames microbial test, rat hepatocyte DNA repair test, V79 mammalian-cell forward gene-mutation assay). Irbesartan was negative in several tests for induction of chromosomal aberrations (in vitro human lymphocyte assay; in vivo mouse micronucleus study).
Fertility and reproductive performance were not affected in studies of male and female rats, even at doses causing some parental toxicity (up to 650 mg/kg/day). No significant effects on the number of corpora luteal implants, or live fetuses were observed. Irbesartan had no effect on survival, development, or reproduction of offspring.
Transient toxic effects (increased renal pelvic cavitation, hydroureter or subcutaneous edema) were observed in rat fetuses at doses of 50 mg/kg/day or higher, which resolved after birth. In rabbits, maternal mortality, abortion and early resorption were observed at doses of 30 mg/kg/day. No other teratogenic effects were observed in rats or rabbits.
Amlodipine: Carcinogenesis: Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25 and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (similar to the maximum recommended human dose of 10 mg on a mg/m² basis for mice, and about twice^* this maximum dose for rats) was close to the maximum tolerated dose for mice but not for rats.
Mutagenesis: Mutagenesis studies revealed no amlodipine-related effects at either the gene or chromosome levels.
Infertility: There was no effect on fertility in rats treated with amlodipine (males for 64 days and females for 14 days prior to mating) at doses up to 10 mg/kg/day (8 times^* the maximum recommended human dose of 10 mg on a mg/m² basis).
^* Based on a 50 kg patient.