y 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 and other agents that affect the ras. coadministration of candesartan cilexetil and hydrochlorothiazide 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 coadminister aliskiren with candesartan cilexetil and hydrochlorothiazide in patients with diabetes. avoid use of aliskiren with candesartan cilexetil and hydrochlorothiazide 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 to 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.

blood pressure education program's joint national committee on prevention, detection, evaluation, and treatment of high blood pressure (jnc). numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmhg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy. this fixed dose combination is not indicated for initial therapy (see dosage and administration ).

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 1,000 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 1,000 and 3,000 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 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 or volume repletion. volume and/or salt depletion should be corrected before initiating therapy with candesartan cilexetil and hydrochlorothiazide. in patients with heart failure, candesartan cilexetil and hydrochlorothiazide 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 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. 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. consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on candesartan cilexetil and hydrochlorothiazide. 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% for placebo. no patient receiving candesartan cilexetil and hydrochlorothiazide 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.

nt therapy the combination may be substituted for the titrated components. dose titration by clinical effect a patient whose blood pressure is not controlled on 25 mg of hydrochlorothiazide once daily can expect an incremental effect from candesartan cilexetil and hydrochlorothiazide 16 mg/12.5 mg. a patient whose blood pressure is controlled on 25 mg of hydrochlorothiazide but is experiencing decreases in serum potassium can expect the same or incremental blood pressure effects from candesartan cilexetil and hydrochlorothiazide 16 mg/12.5 mg and serum potassium may improve. a patient whose blood pressure is not controlled on 32 mg of candesartan cilexetil can expect incremental blood pressure effects from candesartan cilexetil and hydrochlorothiazide 32 mg/12.5 mg and then 32 mg/25 mg. the maximal antihypertensive effect of any dose of candesartan cilexetil and hydrochlorothiazide can be expected within 4 weeks of initiating that dose. candesartan cilexetil and hydrochlorothiazide may be administered with other antihypertensive agents. candesartan cilexetil and hydrochlorothiazide may be administered with or without food.

eated with candesartan cilexetil and hydrochlorothiazide and that were more frequent for candesartan cilexetil and hydrochlorothiazide than placebo were: respiratory system disorder upper respiratory tract infection (3.6% vs 3%); body as a whole back pain (3.3% vs 2.4%); influenza-like symptoms (2.5% vs 1.9%); central/peripheral nervous system dizziness (2.9% vs 1.2%). postmarketing experience the following have been very rarely reported in postmarketing experience with candesartan cilexetil: digestive abnormal hepatic function and hepatitis. hematologic neutropenia, leukopenia, and agranulocytosis. immunologic angioedema metabolic and nutritional disorders hyperkalemia, hyponatremia. respiratory system disorders cough skin and appendages disorders pruritus, rash and urticaria. rare reports of rhabdomyolysis have been reported in patients receiving angiotensin ii receptor blockers. hydrochlorothiazide other adverse experiences that have been reported with hydrochlorothiazide, without regard to causality, are listed below: gastrointestinal pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, constipation, gastric irritation, anorexia hematologic aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia hypersensitivity anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, urticaria, purpura musculoskeletal muscle spasm non-melanoma skin cancer hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. in a study conducted in the sentinel system, increased risk was predominantly for squamous cell carcinoma (scc) and in white patients taking large cumulative doses. the increased risk for scc in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000 mg the risk increase was approximately 1 additional scc case for every 6,700 patients per year. skin erythema multiforme including stevens-johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia special senses transient blurred vision, xanthopsia urogenital impotence

y 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 and other agents that affect the ras. coadministration of candesartan cilexetil and hydrochlorothiazide 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 coadminister aliskiren with candesartan cilexetil and hydrochlorothiazide in patients with diabetes. avoid use of aliskiren with candesartan cilexetil and hydrochlorothiazide 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 to 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.

itors, which inhibit the biosynthesis of angiotensin ii from angiotensin i, is widely used in the treatment of hypertension. ace inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ace. because candesartan does not inhibit ace (kininase ii), it does not affect the response to bradykinin. whether this difference has clinical relevance is not yet known. candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. blockade of the angiotensin ii receptor inhibits the negative regulatory feedback of angiotensin ii on renin secretion, but the resulting increased plasma renin activity and angiotensin ii circulating levels do not overcome the effect of candesartan on blood pressure. hydrochlorothiazide is a thiazide diuretic. thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. the renin-aldosterone link is mediated by angiotensin ii, so coadministration of an angiotensin ii receptor antagonist tends to reverse the potassium loss associated with these diuretics. the mechanism of the antihypertensive effect of thiazides is unknown. pharmacokinetics general candesartan cilexetil candesartan cilexetil is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan, a selective at 1 subtype angiotensin ii receptor antagonist. candesartan is mainly excreted unchanged in urine and feces (via bile). it undergoes minor hepatic metabolism by o-deethylation to an inactive metabolite. the elimination half-life of candesartan is approximately 9 hours. after single and repeated administration, the pharmacokinetics of candesartan are linear for oral doses up to 32 mg of candesartan cilexetil. candesartan and its inactive metabolite do not accumulate in serum upon repeated once-daily dosing. following administration of candesartan cilexetil, the absolute bioavailability of candesartan was estimated to be 15%. after tablet ingestion, the peak serum concentration (c max ) is reached after 3 to 4 hours. food with a high fat content does not affect the bioavailability of candesartan after candesartan cilexetil administration. hydrochlorothiazide when plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. metabolism and excretion candesartan cilexetil total plasma clearance of candesartan is 0.37 ml/min/kg, with a renal clearance of 0.19 ml/min/kg. when candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. following an oral dose of 14 c-labeled candesartan cilexetil, approximately 33% of radioactivity is recovered in urine and approximately 67% in feces. following an intravenous dose of 14 c-labeled candesartan, approximately 59% of radioactivity is recovered in urine and approximately 36% in feces. biliary excretion contributes to the elimination of candesartan. hydrochlorothiazide hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. at least 61% of the oral dose is eliminated unchanged within 24 hours. distribution candesartan cilexetil the volume of distribution of candesartan is 0.13 l/kg. candesartan is highly bound to plasma proteins (> 99%) and does not penetrate red blood cells. the protein binding is constant at candesartan plasma concentrations well above the range achieved with recommended doses. in rats, it has been demonstrated that candesartan crosses the blood-brain barrier poorly, if at all. it has also been demonstrated in rats that candesartan passes across the placental barrier and is distributed in the fetus. hydrochlorothiazide hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. special populations pediatric the pharmacokinetics of candesartan cilexetil have not been investigated in patients < 18 years of age. geriatric the pharmacokinetics of candesartan have been studied in the elderly (≥ 65 years). the plasma concentration of candesartan was higher in the elderly (c max was approximately 50% higher, and auc was approximately 80% higher) compared to younger subjects administered the same dose. the pharmacokinetics of candesartan were linear in the elderly, and candesartan and its inactive metabolite did not accumulate in the serum of these subjects upon repeated, once-daily administration. no initial dosage adjustment is necessary (see dosage and administration ). gender there is no difference in the pharmacokinetics of candesartan between male and female subjects. renal insufficiency in hypertensive patients with renal insufficiency, serum concentrations of candesartan were elevated. after repeated dosing, the auc and c max were approximately doubled in patients with severe renal impairment (creatinine clearance < 30 ml/min/1.73m 2 ) compared to patients with normal kidney function. the pharmacokinetics of candesartan in hypertensive patients undergoing hemodialysis are similar to those in hypertensive patients with severe renal impairment. candesartan cannot be removed by hemodialysis. thiazide diuretics are eliminated by the kidney, with a terminal half-life of 5 to 15 hours. in a study of patients with impaired renal function (mean creatinine clearance of 19 ml/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours (see dosage and administration ). safety and effectiveness of candesartan cilexetil and hydrochlorothiazide in patients with severe renal impairment (crcl ≤ 30 ml/min) have not been established. no dose adjustment is required in patients with mild crcl 60 to 90 ml/min) or moderate (crcl 30 to 60 ml/min) renal impairment. hepatic insufficiency the pharmacokinetics of candesartan were compared in patients with mild (child-pugh a) or moderate (child-pugh b) hepatic impairment to matched healthy volunteers following a single dose of 16 mg candesartan cilexetil. the auc for candesartan in patients with mild and moderate hepatic impairment was increased 30% and 145% respectively. the c max for candesartan was increased 56% and 73% respectively. the pharmacokinetics of candesartan in severe hepatic impairment have not been studied. no dose adjustment is recommended for patients with mild hepatic impairment. in patients with moderate hepatic impairment, candesartan cilexetil and hydrochlorothiazide is not recommended for initiation because the appropriate starting dose, 8 mg, cannot be given. (see dosage and administration ). monitor patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. pharmacodynamics candesartan cilexetil candesartan inhibits the pressor effects of angiotensin ii infusion in a dose-dependent manner. after 1 week of once-daily dosing with 8 mg of candesartan cilexetil, the pressor effect was inhibited by approximately 90% at peak with approximately 50% inhibition persisting for 24 hours. plasma concentrations of angiotensin i and angiotensin ii, and plasma renin activity (pra), increased in a dose-dependent manner after single and repeated administration of candesartan cilexetil to healthy subjects and hypertensive patients. ace activity was not altered in healthy subjects after repeated candesartan cilexetil administration. the once-daily administration of up to 16 mg of candesartan cilexetil to healthy subjects did not influence plasma aldosterone concentrations, but a decrease in the plasma concentration of aldosterone was observed when 32 mg of candesartan cilexetil was administered to hypertensive patients. in spite of the effect of candesartan cilexetil on aldosterone secretion, very little effect on serum potassium was observed. in multiple-dose studies with hypertensive patients, there were no clinically significant changes in metabolic function including serum levels of total cholesterol, triglycerides, glucose, or uric acid. in a 12 week study of 161 patients with non-insulin-dependent (type 2) diabetes mellitus and hypertension, there was no change in the level of hba 1c . hydrochlorothiazide after oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours. clinical trials candesartan cilexetil–hydrochlorothiazide of 12 controlled clinical trials involving 4,588 patients, 5 were double-blind, placebo controlled and evaluated the antihypertensive effects of single entities vs the combination. these 5 trials, of 8 to 12 weeks duration, randomized 3,037 hypertensive patients. doses ranged from 2 to 32 mg candesartan cilexetil and from 6.25 to 25 mg hydrochlorothiazide administered once daily in various combinations. the combination of candesartan cilexetil-hydrochlorothiazide resulted in placebo-adjusted decreases in sitting systolic and diastolic blood pressures of 14 to18/8 to 11 mm hg at doses of 16 mg/12.5 mg and 32 mg/12.5 mg. the combination of candesartan cilexetil and hydrochlorothiazide 32 mg/25 mg resulted in placebo-adjusted decreases in sitting systolic and diastolic blood pressures of 16 to 19/9 to 11 mm hg. the placebo corrected trough to peak ratio was evaluated in a study of candesartan cilexetil-hydrochlorothiazide 32 mg/12.5 mg and was 88%. most of the antihypertensive effect of the combination of candesartan cilexetil and hydrochlorothiazide was seen in 1 to 2 weeks with the full effect observed within 4 weeks. in long-term studies of up to 1 year, the blood pressure lowering effect of the combination was maintained. the antihypertensive effect was similar regardless of age or gender, and overall response to the combination was similar in black and non-black patients. no appreciable changes in heart rate were observed with combination therapy in controlled trials.

candesartan after candesartan cilexetil administration. hydrochlorothiazide when plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours.

ilexetil and hydrochlorothiazide tablets usp, 32 mg/25 mg are white to off-white, oval, biconvex, uncoated tablets with breakline on both sides and engraved on one side with '41' & '6' on either side of breakline and are supplied as follows: ndc 68382-416-06 in bottle of 30 tablets ndc 68382-416-16 in bottle of 90 tablets ndc 68382-416-01 in bottle of 100 tablets ndc 68382-416-10 in bottle of 1,000 tablets ndc 68382-416-77 in carton of 100 tablets (10 x 10 unit-dose) storage: store at 20° to 25°c (68° to 77°f) [see usp controlled room temperature]. dispense in a tight, light-resistant container as defined in the usp. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088.

ide not to use potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels without consulting the prescribing physician. non-melanoma skin cancer instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening.