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Other antihypertensive agents: the antihypertensive effect of Irbesartan and Hydrochlorothiazide tablet may be increased with the concomitant use of other antihypertensive agents. Irbesartan and hydrochlorothiazide (at doses up to 300 mg irbesartan/25 mg hydrochlorothiazide) have been safely administered with other antihypertensive agents including calcium channel blockers and beta-adrenergic blockers. Prior treatment with high dose diuretics may result in volume depletion and a risk of hypotension when initiating therapy with irbesartan with or without thiazide diuretics unless the volume depletion is corrected first.
Aliskiren-containing products or ACE-inhibitors: clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent.
Lithium: reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin-converting enzyme inhibitors. Similar effects have been very rarely reported with irbesartan so far. Furthermore, renal clearance of lithium is reduced by thiazides so the risk of lithium toxicity could be increased with Irbesartan and Hydrochlorothiazide tablet. Therefore, the combination of lithium and Irbesartan and Hydrochlorothiazide tablet is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.
Medicinal products affecting potassium: the potassium-depleting effect of hydrochlorothiazide is attenuated by the potassium-sparing effect of irbesartan. However, this effect of hydrochlorothiazide on serum potassium would be expected to be potentiated by other medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium). Conversely, based on the experience with the use of other medicinal products that blunt the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin sodium) may lead to increases in serum potassium. Adequate monitoring of serum potassium in patients at risk is recommended.
Medicinal products affected by serum potassium disturbances: periodic monitoring of serum potassium is recommended when Irbesartan and Hydrochlorothiazide tablet is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides, antiarrhythmics).
Non-steroidal anti-inflammatory drugs: when angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid >3 g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect may occur.
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
Repaglinide: irbesartan has the potential to inhibit OATP1B1. In a clinical study, it was reported that irbesartan increased the Cmax and AUC of repaglinide (substrate of OATP1B1) by 1.8-fold and 1.3-fold, respectively, when administered 1 hour before repaglinide. In another study, no relevant pharmacokinetic interaction was reported, when the two drugs were co-administered. Therefore, dose adjustment of antidiabetic treatment such as repaglinide may be required.
Additional information on irbesartan interactions: in clinical studies, the pharmacokinetics of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolised by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was co-administered with warfarin, a medicinal product metabolised by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetics of irbesartan have not been evaluated. The pharmacokinetics of digoxin was not altered by co-administration of irbesartan.
Additional information on hydrochlorothiazide interactions: when administered concurrently, the following medicinal products may interact with thiazide diuretics: Alcohol: potentiation of orthostatic hypotension may occur;
Antidiabetic medicinal products (oral agents and insulins): dosage adjustment of the antidiabetic medicinal product may be required;
Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Irbesartan and Hydrochlorothiazide tablet should be taken at least one hour before or four hours after these medications;
Corticosteroids, ACTH: electrolyte depletion, particularly hypokalaemia, may be increased;
Digitalis glycosides: thiazide induced hypokalaemia or hypomagnaesemia favour the onset of digitalis-induced cardiac arrhythmias;
Non-steroidal anti-inflammatory drugs: the administration of a non-steroidal anti-inflammatory drug may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients;
Pressor amines (e.g. noradrenaline): the effect of pressor amines may be decreased, but not sufficient to preclude their use;
Nondepolarizing skeletal muscle relaxants (e.g. tubocurarine): the effect of nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide;
Antigout medicinal products: dosage adjustments of antigout medicinal products may be necessary as hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol;
Calcium salts: thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements or calcium-sparing medicinal products (e.g. vitamin D therapy) must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly;
Carbamazepine: concomitant use of carbamazepine and hydrochlorothiazide has been associated with the risk of symptomatic hyponatraemia. Electrolytes should be monitored during concomitant use. If possible, another class of diuretics should be used.
Other interactions: the hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides. Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazides may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.
