CANDESARTAN CILEXETIL Drug Interactions: What You Need to Know

Drug Interactions Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effects on P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected. Interactions common to both Candesartan Cilexetil and Hydrochlorothiazide Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including candesartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving candesartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including candesartan may be attenuated by NSAIDs including selective COX-2 inhibitors.

Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists or hydrochlorothiazide. Monitor serum lithium levels during concomitant use. Interactions with Candesartan Cilexetil Dual Blockade of the Renin-Angiotensin System (RAS) Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on candesartan cilexetil and hydrochlorothiazide tablets and other agents that affect the RAS. Co-administration of candesartan cilexetil and hydrochlorothiazide tablets with potassium sparing diuretics, potassium supplements, potassium-containing salt substitutes or other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients. Do not co-administer aliskiren with candesartan cilexetil and hydrochlorothiazide tablets in patients with diabetes. Avoid use of aliskiren with candesartan cilexetil and hydrochlorothiazide tablets in patients with renal impairment (GFR <60 mL/min) (see CONTRAINDICATIONS ). Interactions with Hydrochlorothiazide Alcohol, barbiturates, or narcotics − Potentiation of orthostatic hypotension may occur. Antidiabetic drugs (oral agents and insulin) − Dosage adjustment of the antidiabetic drug may be required. Diazoxide − the hyperglycemic effect of diazoxide may be enhanced by thiazides.

Ion

Exchange resins − Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively. Stagger the dosage of hydrochlorothiazide and ion exchange resins such that hydrochlorothiazide is administered at least 4 hours before or 4-6 hours after the administration of resins. Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine) − Possible increased responsiveness to muscle relaxants such as curare derivatives. Digitalis − Thiazide-induced hypokalemia or hypomagnesemia may predispose to digoxin toxicity. Noradrenaline − Thiazides may decrease arterial responsiveness to noradrenaline, but not enough to preclude effectiveness of the pressor agent for therapeutic use. Steroids or Adrenocorticotropic Hormone − Hypokalemia may develop during concomitant use of steroids or adrenocorticotropic hormone (ACTH). Cytotoxic products − Thiazides may reduce the renal excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects. Cyclosporine − Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-type complications.

CONTRAINDICATIONS Candesartan cilexetil and hydrochlorothiazide tablets are contraindicated in patients who are hypersensitive to candesartan, to hydrochlorothiazide or to other sulfonamide-derived drugs. Do not co-administer aliskiren with candesartan cilexetil and hydrochlorothiazide tablets in patients with diabetes (see PRECAUTIONS , Drug Interactions ). Candesartan cilexetil and hydrochlorothiazide tablets are contraindicated in patients with anuria.

WARNINGS Fetal Toxicity Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue candesartan cilexetil and hydrochlorothiazide tablets as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue candesartan cilexetil and hydrochlorothiazide, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to candesartan cilexetil and hydrochlorothiazide for hypotension, oliguria, and hyperkalemia. (See PRECAUTIONS, Pediatric Use .) There was no evidence of teratogenicity or other adverse effects on embryo-fetal development when pregnant mice, rats or rabbits were treated orally with candesartan cilexetil alone or in combination with hydrochlorothiazide. For mice, the maximum dose of candesartan cilexetil was 1000 mg/kg/day (about 150 times the maximum recommended daily human dose [MRHD] 1 ). For rats, the maximum dose of candesartan cilexetil was 100 mg/kg/day (about 31 times the MRHD 1 ). For rabbits, the maximum dose of candesartan cilexetil was 1 mg/kg/day (a maternally toxic dose that is about half the MRHD 1 ). In each of these studies, hydrochlorothiazide was tested at the same dose level (10 mg/kg/day, about 4, 8, and 15 times the MRHD 1 in mouse, rats, and rabbit, respectively). There was no evidence of harm to the rat or mouse fetus or embryo in studies in which hydrochlorothiazide was administered alone to the pregnant rat or mouse at doses of up to 1000 and 3000 mg/kg/day, respectively. Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults. ___________________ 1 Doses compared on the basis of body surface area. MRHD considered to be 32 mg for candesartan cilexetil and 12.5 mg for hydrochlorothiazide.

Hypotension

Candesartan cilexetil and hydrochlorothiazide tablets can cause symptomatic hypotension. Symptomatic hypotension is most likely to occur in patients who have been volume and/or salt depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Patients with symptomatic hypotension may require temporarily reducing the dose of candesartan cilexetil and hydrochlorothiazide tablets or volume repletion. Volume and/or salt depletion should be corrected before initiating therapy with candesartan cilexetil and hydrochlorothiazide tablets. In patients with heart failure, candesartan cilexetil and hydrochlorothiazide tablets may cause excessive hypotension, which may lead to oliguria, azotemia, and (rarely) with acute renal failure and death (see WARNINGS: Impaired Renal Function ). In such patients, candesartan cilexetil and hydrochlorothiazide tablets therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of candesartan or diuretic is increased.

Impaired Renal Function

Monitor renal function periodically in patients treated with candesartan cilexetil and hydrochlorothiazide tablets. Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe heart failure, or volume depletion) may be at particular risk of developing oliguria, progressive azotemia, or acute renal failure on candesartan cilexetil and hydrochlorothiazide tablets. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on candesartan cilexetil and hydrochlorothiazide tablets.

Potassium Abnormalities

Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Monitor serum electrolytes periodically. In clinical trials of various doses of candesartan cilexetil and hydrochlorothiazide, the incidence of hypertensive patients who developed hypokalemia (serum potassium < 3.5 mEq/L) was 2.5% versus 2.1% for placebo; the incidence of hyperkalemia (serum potassium > 5.7 mEq/L) was 0.4% versus 1.0% for placebo. No patient receiving candesartan cilexetil and hydrochlorothiazide tablets 16 mg/12.5 mg or 32 mg/12.5 mg was discontinued due to increases or decreases in serum potassium.

Acute

Myopia and Secondary Angle-Closure Glaucoma Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Hypersensitivity Reaction

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.