Aprovasc Drug Interactions

For 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 conducted with Irbesartan/Amlodipine (Aprovasc) and other medicinal products.
For Irbesartan: Based on in vitro information, no interactions are expected with drugs whose metabolism is dependent on CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 or CYP3A4 cytochrome isoenzymes.
Irbesartan is metabolized mainly by CYP2C9; however, no significant interactions were observed during clinical interaction studies when irbesartan was administered concomitantly with warfarin (a drug metabolized by CYP2C9).
Irbesartan does not affect the pharmacokinetics of simvastatin (metabolized by CYP3A4) or digoxin (substrate of P-glycoprotein efflux transporter).
The pharmacokinetics of irbesartan is not affected by concomitant administration of nifedipine or hydrochlorothiazide.
The combination of lrbesartan/Amlodipine (Aprovasc) with medications containing aliskiren is contraindicated in patients with diabetes mellitus or with moderate to severe renal failure (glomerular filtration rate (GFR) <60 ml/min/1.73 m²) and is not recommended in other patients.
Angiotensin-converting enzyme inhibitors (ACE inhibitors): Use of lrbesartan/Amlodipine (Aprovasc) in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.
Repaglinide: Irbesartan has the potential to inhibit OATP1B1. In a clinical study, it was reported that irbesartan increased the C_max and the AUC of repaglinide (OATP1B1 substrate) 1.8-fold and 1.3-fold, respectively, when administered 1 hour before repaglinide. In another study, no relevant pharmacokinetic interaction was reported when two drugs were administered together. Therefore, it may be necessary to adjust the dose in antidiabetic treatment such as repaglinide (see General under Precautions).
Based on the experience with the use of other medications that affect the renin-angiotensin system, the concomitant use of Irbesartan with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medications that may increase kalaemia with irbesartan can cause an increase in serum potassium, sometimes severe, and requires close monitoring of serum potassium.
In elderly patients with volume depletion (including those on treatment with diuretics), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including irbesartan, can cause impaired renal function, including possible acute renal failure. These effects are usually reversible. Renal function should be monitored periodically in patients receiving periodic treatment with irbesartan and NSAIDs. The antihypertensive effect of angiotensin II receptor antagonists, including irbesartan, may be attenuated by NSAIDs including selective COX-2 inhibitors.
Lithium: Increases in serum lithium concentrations and lithium toxicity has been reported with the concomitant use of Irbesartan. Monitor levels in patients receiving Irbesartan and lithium.
For Amlodipine: Amlodipine has been safely administered concomitantly with thiazide diuretics, alpha-blockers, beta blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual glyceryl trinitrate, non-steroidal anti-inflammatory drugs, and oral hypoglycemic drugs.
Data obtained from in vitro studies with human plasma show that amlodipine has no effect on protein binding with the medications studied (digoxin, phenytoin, warfarin or indomethacin).
Cimetidine: Co-administration of amlodipine with cimetidine did not alter amlodipine pharmacokinetics.
Grapefruit juice: The administration of amlodipine with grapefruit or grapefruit juice is not recommended as, in some patients, its bioavailability may increase, resulting in an increase in the blood pressure lowering effects.
Sildenafil: When using amlodipine and sildenafil in combination, each agent independently exerted its own blood pressure reductive effect.
Atorvastatin: Simultaneous administration of multiple doses of 10 mg of amlodipine with 80 mg of atorvastatin showed no significant change in the steady-state of atorvastatin pharmacokinetic parameters.
Digoxin: Simultaneous administration of amlodipine with digoxin did not modify serum concentrations of digoxin or its renal clearance in healthy volunteers.
Warfarin: Simultaneous administration of amlodipine did not significantly modify the effect of warfarin on prothrombin time.
Effects of other medicinal products on amlodipine: CYP3A4 inhibitors: Concomitant use of amlodipine with strong or moderate inhibitors of CYP3A4 (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may give rise to a significant increase in amlodipine exposure. The clinical translation of these PK variations may be more pronounced in elderly subjects. Clinical monitoring and dose adjustment may be necessary.
Inducers of CYP3A4: Concomitant administration of inducers known as CYP3A4 may cause variations in plasma concentrations of amlodipine; therefore, blood pressure should be monitored and the dose considered should be adjusted during and after concomitant medication, particularly with potent CYP3A4 inducers (for example, rifampicin, hypericum perforatum).
Dantrolene (infusion): In animals, fatal ventricular fibrillation and cardiovascular collapse have been observed in association with hyperkalemia after intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, it is recommended that concomitant administration of calcium channel blockers such as amlodipine should be avoided in patients susceptible to malignant hyperthermia and in the treatment of malignant hyperthermia.
Effects of amlodipine on other medicinal products: The blood pressure reducing effects of amlodipine are added to the blood pressure reducing effects of other medicinal products with antihypertensive properties.
Tacrolimus: There is a risk of an increase in blood tacrolimus levels when it is administered together with amlodipine, but the pharmacokinetic mechanism of this interaction is not fully understood. In order to avoid tacrolimus toxicity, administration of amlodipine in a patient treated with tacrolimus requires monitoring of the levels of tacrolimus in the blood and adjustment of the dose of tacrolimus where appropriate.
Molecular target of rapamycin (mTOR) inhibitors: mTOR inhibitors such as sirolimus, temsirolimus and everolimus are CYP3A substrates.
Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase the exposure of mTOR inhibitors.
Cyclosporine: No studies have been conducted on the pharmacological interaction between cyclosporine and amlodipine in healthy volunteers or other populations, except kidney transplant patients, where they vary. Increases have been seen in the minimum concentration (average 0% - 40%) of cyclosporine. Monitoring should be considered to control cyclosporine levels in kidney transplant patients being treated with amlodipine, and cyclosporine doses should be reduced where necessary.
Simvastatin: Concomitant administration of multiple doses of 10 mg of amlodipine with 80 mg of simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. Limit the dose of simvastatin in patients taking amlodipine to 20 mg per day.
Aluminum/magnesium (antacid): The simultaneous administration of an antacid with aluminum/magnesium with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
Drug/Laboratory Test Interactions: There were no clinically significant changes in laboratory parameters in clinical studies controlled with Irbesartan in hypertensive patients. No special control of laboratory parameters is required in patients with essential hypertension receiving the treatment.