Data from FDA - Curated by EPG Health - Last updated 22 December 2016

Indication(s)

INDICATIONS AND USAGE Candesartan cilexetil-hydrochlorothiazide is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with candesartan cilexetil-hydrochlorothiazide. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High 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).

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Advisory information

contraindications
CONTRAINDICATIONS Candesartan cilexetil-hydrochlorothiazide is contraindicated in patients who are hypersensitive to candesartan, to hydrochlorothiazide or to other sulfonamide-derived drugs. Do not co-administer aliskiren with candesartan cilexetil-hydrochlorothiazide in patients with diabetes (see PRECAUTIONS, Drug Interactions). Candesartan cilexetil-hydrochlorothiazide is contraindicated in patients with anuria.
Special warnings and precautions
PRECAUTIONS Metabolic Disturbances Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides. Hydrochlorothiazide may raise the serum uric acid level due to reduced clearance of uric acid and may cause or exacerbate hyperuricemia and precipitate gout in susceptible patients. Thiazides decrease urinary calcium excretion and may cause elevation of serum calcium. Avoid using candesartan cilexetil-hydrochlorothiazide in patients with hypercalcemia. Systemic Lupus Erythematosus Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. Information for Patients Pregnancy Female patients of childbearing age should be told about the consequences of exposure to candesartan cilexetil-hydrochlorothiazide during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible. Symptomatic Hypotension Tell patients receiving candesartan cilexetil-hydrochlorothiazide that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. Tell patients that if syncope occurs, discontinue candesartan cilexetil-hydrochlorothiazide until the physician has been consulted. Tell all patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. Hyperkalemia Tell patients receiving candesartan cilexetil-hydrochlorothiazide not to use potassium supplements, salt substitutes containing potassium, or other drugs that may increase serum potassium levels without consulting the prescribing physician. 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-hydrochlorothiazide and other agents that affect the RAS. Co-administration of candesartan cilexetil-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 co-administer aliskiren with candesartan cilexetil-hydrochlorothiazide in patients with diabetes. Avoid use of aliskiren with candesartan cilexetil-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 4-6 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. Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with the combination of candesartan cilexetil and hydrochlorothiazide. There was no evidence of carcinogenicity when candesartan cilexetil was orally administered to mice and rats for up to 104 weeks at doses up to 100 and 1000 mg/kg/day, respectively. Rats received the drug by gavage whereas mice received the drug by dietary administration. These (maximally-tolerated) doses of candesartan cilexetil provided systemic exposures to candesartan (AUCs) that were, in mice, approximately 7 times and, in rats, more than 70 times the exposure in man at the maximum recommended daily human dose (32 mg). Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice. Candesartan cilexetil or candesartan (the active metabolite), in combination with hydrochlorothiazide, tested positive in vitro in the Chinese hamster lung (CHL) chromosomal aberration assay and mouse lymphoma mutagenicity assay. The candesartan cilexetil/hydrochlorothiazide combination tested negative for mutagenicity in bacteria (Ames test), for unscheduled DNA synthesis in rat liver, for chromosomal aberrations in rat bone marrow and for micronuclei in mouse bone marrow. Both candesartan and its O-deethyl metabolite tested positive for genotoxicity in the in vitro CHL chromosomal aberration assay. Neither compound tested positive in the Ames microbial mutagenesis assay or in the in vitro mouse lymphoma cell assay. Candesartan (but not its O-deethyl metabolite) was also evaluated in vivo in the mouse micronucleus test and in vitro in the Chinese hamster ovary (CHO) gene mutation assay, in both cases with negative results. Candesartan cilexetil was evaluated in the Ames test, the in vitro mouse lymphoma cell assay, the in vivo rat hepatocyte unscheduled DNA synthesis assay and the in vivo mouse micronucleus test, in each case with negative results. Candesartan cilexetil was not evaluated in the CHL chromosomal aberration or CHO gene mutation assays. When hydrochlorothiazide was tested alone, positive results were obtained in vitro in the CHO sister chromatid exchange (clastogenicity) and mouse lymphoma cell (mutagenicity) assays and in the Aspergillus nidulans non-disjunction assay. Hydrochlorothiazide was not genotoxic in vitro in the Ames test for point mutations and the CHO test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. No fertility studies have been conducted with the combination of candesartan cilexetil and hydrochlorothiazide. Fertility and reproductive performance were not affected in studies with male and female rats given oral doses of up to 300 mg candesartan cilexetil/kg/day (83 times the maximum daily human dose of 32 mg on a body surface area basis). Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg, respectively, prior to conception and throughout gestation. Nursing Mothers It is not known whether candesartan is excreted in human milk, but candesartan has been shown to be present in rat milk. Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Neonates with a history of in utero exposure to candesartan cilexetil-hydrochlorothiazide: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Safety and effectiveness in pediatric patients have not been established.
Adverse reactions
ADVERSE REACTIONS Candesartan Cilexetil-Hydrochlorothiazide Candesartan cilexetil-hydrochlorothiazide has been evaluated for safety in more than 2800 patients treated for hypertension. More than 750 of these patients were studied for at least six months and more than 500 patients were treated for at least one year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall incidence of adverse events reported with candesartan cilexetil-hydrochlorothiazide was comparable to placebo. The overall frequency of adverse experiences was not related to dose, age, gender, or race. In placebo-controlled trials that included 1089 patients treated with various combinations of candesartan cilexetil (doses of 2-32 mg) and hydrochlorothiazide (doses of 6.25-25 mg) and 592 patients treated with placebo, adverse events, whether or not attributed to treatment, occurring in greater than 2% of patients treated with candesartan cilexetil-hydrochlorothiazide and that were more frequent for candesartan cilexetil-hydrochlorothiazide than placebo were: Respiratory System Disorder: upper respiratory tract infection (3.6% vs 3.0%); 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%). Post-Marketing Experience The following have been very rarely reported in post-marketing 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 Skin: erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia Special Senses: transient blurred vision, xanthopsia Urogenital: impotence

Usage information

Dosing and administration
DOSAGE AND ADMINISTRATION The usual recommended starting dose of candesartan cilexetil is 16 mg once daily when it is used as monotherapy in patients who are not volume depleted. Candesartan cilexetil can be administered once or twice daily with total daily doses ranging from 8 mg to 32 mg. Patients requiring further reduction in blood pressure should be titrated to 32 mg. Doses larger than 32 mg do not appear to have a greater blood pressure lowering effect. Hydrochlorothiazide is effective in doses of 12.5 to 50 mg once daily. Use in Renal Impairment: Dosing recommendations for candesartan cilexetil-hydrochlorothiazide in patients with creatinine clearance <30 mg/min cannot be provided (see SPECIAL POPULATIONS, Renal Insufficiency). Use in moderate to severe Hepatic Impairment: candesartan cilexetil-hydrochlorothiazide is not recommended for initiation because the appropriate starting dose, 8 mg, cannot be given (see SPECIAL POPULATIONS, Hepatic Insufficiency). Replacement 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-hydrochlorothiazide 16-12.5 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-hydrochlorothiazide 16-12.5 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-hydrochlorothiazide 32-12.5 mg and then 32-25 mg. The maximal antihypertensive effect of any dose of candesartan cilexetil-hydrochlorothiazide can be expected within 4 weeks of initiating that dose. Candesartan cilexetil-hydrochlorothiazide may be administered with other antihypertensive agents. Candesartan cilexetil-hydrochlorothiazide may be administered with or without food.
Pregnancy and lactation
Nursing Mothers It is not known whether candesartan is excreted in human milk, but candesartan has been shown to be present in rat milk. Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Interactions

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-hydrochlorothiazide and other agents that affect the RAS. Co-administration of candesartan cilexetil-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 co-administer aliskiren with candesartan cilexetil-hydrochlorothiazide in patients with diabetes. Avoid use of aliskiren with candesartan cilexetil-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 4-6 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.

More information

Category Value
Authorisation number NDA021093
Agency product number 0J48LPH2TH
Orphan designation No
Product NDC 49884-663,49884-662,49884-664
Date Last Revised 05-07-2016
Type HUMAN PRESCRIPTION DRUG
RXCUI 578330
Marketing authorisation holder Par Pharmaceutical Inc.
Warnings WARNING: FETAL TOXICITY • When pregnancy is detected, discontinue candesartan cilexetil-hydrochlorothiazide as soon as possible. • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See Warnings: Fetal Toxicity