| Exforge HCT individual component
|| Known interactions with the following agents
|| Effect of the interaction with other medicinal products
|| CYP3A4 inhibitors (i.e. ketoconazole, itraconazole, ritonavir)
|| Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these pharmacokinetic variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.
| CYP3A4 inducers (anticonvulsant agents [e.g. carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone], rifampicin, Hypericum perforatum [St. John's wort])
|| There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.
|| Co-administration of multiple doses of 10 mg amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. It is recommended to limit the dose of simvastatin to 20 mg daily in patients on amlodipine.
| Dantrolene (infusion)
|| In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalaemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalaemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.
| Valsartan and HCT
|| Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors), acetylsalicylic acid (>3 g/day), and non-selective NSAIDs
|| NSAIDS can attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide when administered simultaneously. Furthermore, concomitant use of Exforge HCT and NSAIDs may lead to worsening of renal function and an increase in serum potassium. Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as adequate hydration of the patient.
|| Inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir)
|| The results of an in vitro
study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and of the hepatic efflux transporter MRP2. Co-administration of inhibitors of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.
|| Alcohol, barbiturates or narcotics
|| Concomitant administration of thiazide diuretics with substances that also have a blood pressure lowering effect (e.g. by reducing sympathetic central nervous system activity or direct vasodilatation) may potentiate orthostatic hypotension.
|| Thiazides, including hydrochlorothiazide, may increase the risk of adverse reactions caused by amantadine.
agents and other medicinal products affecting gastric motility
|| The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, it is anticipated that prokinetic substances such as cisapride may decrease the bioavailability of thiazide-type diuretics.
(e.g. insulin and oral antidiabetic agents)
|| Thiazides may alter glucose tolerance.
Dose adjustment of the antidiabetic medicinal product may be necessary.
| − Metformin
|| Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.
| Beta blockers and diazoxide
|| Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta blockers may increase the risk of hyperglycaemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the hyperglycaemic effect of diazoxide.
|| Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type complications.
|| Thiazides, including hydrochlorothiazide, may reduce the renal excretion of cytotoxic agents (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.
| Digitalis glycosides
|| Thiazide-induced hypokalaemia or hypomagnesaemia may occur as undesirable effects, favouring the onset of digitalis-induced cardiac arrhythmias.
| Iodine contrasting agents
|| In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with high doses of iodine products. Patients should be re-hydrated before the administration.
| Ion exchange resins
|| Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine or colestipol. This could result in sub-therapeutic effects of thiazide diuretics. However, staggering the dosage of hydrochlorothiazide and resin such that hydrochlorothiazide is administered at least 4 hours before or 4-6 hours after the administration of resins would potentially minimise the interaction.
| Medicinal products affecting serum potassium level
|| The hypokalaemic effect of hydrochlorothiazide may be increased by concomitant administration of kaliuretic diuretics, corticosteroids, laxatives, adrenocorticotropic hormone (ACTH), amphotericin, carbenoxolone, penicillin G and salicylic acid derivatives or antiarrhythmics. If these medicinal products are to be prescribed with the amlodipine /valsartan /hydrochlorothiazide combination, monitoring of potassium plasma levels is advised.
| Medicinal products affecting serum sodium level
|| The hyponatraemic effect of diuretics may be intensified by concomitant administration of medicinal products such as antidepressants, antipsychotics, antiepileptics, etc. Caution is indicated in long-term administration of these medicinal products.
| Medicinal products that could induce torsades de pointes
|| Due to the risk of hypokalaemia, hydrochlorothiazide should be administered with caution when associated with medicinal products that could induce torsades
de pointes, in particular Class Ia and Class III antiarrhythmics and some antipsychotics.
| Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol)
|| Dose adjustment of uricosuric medicinal products may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase of dose of probenecid or sulfinpyrazone may be necessary.
Co-administration of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of hypersensitivity reactions to allopurinol.
|| There have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.
skeletal muscle relaxants (e.g. tubocurarine)
|| Thiazides, including hydrochlorothiazide, potentiate the action of curare derivatives.
| Other anti-hypertensive medicinal products
|| Thiazides potentiate the antihypertensive action of other antihypertensive drugs (e.g. guanethidine, methyldopa, beta-blockers, vasodilators, calcium channel blockers, ACE inhibitors, ARBs and Direct Renin Inhibitors [DRIs]).
(e.g. noradrenaline, adrenaline)
|| Hydrochlorothiazide may reduce the response to pressor amines such as noradrenaline. The clinical significance of this effect is uncertain and not sufficient to preclude their use.
| Vitamin D and calcium salts
|| Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may potentiate the rise in serum calcium. Concomitant use of thiazide type diuretics may lead to hypercalcaemia in patients pre-disposed for hypercalcaemia (e.g. hyperparathyroidism, malignancy or vitamin-D-mediated conditions) by increasing tubular calcium reabsorption.