Candesartan Cilexetil And Hydrochlorothiazide
FDA Drug Information • Also known as: Atacand Hct, Candesartan Cilexetil And Hydrochlorothiazide
- Brand Names
- Atacand Hct, Candesartan Cilexetil And Hydrochlorothiazide
- Drug Class
- Thiazide Diuretic [EPC]
- Route
- ORAL
- Dosage Form
- TABLET
- Product Type
- HUMAN PRESCRIPTION DRUG
⚠ Boxed Warning (Black Box)
WARNING: FETAL TOXICITY
Description
DESCRIPTION ATACAND HCT (candesartan cilexetil-hydrochlorothiazide) combines an angiotensin II receptor (type AT 1 ) antagonist and a diuretic, hydrochlorothiazide. Candesartan cilexetil, a nonpeptide, is chemically described as (±)-1-Hydroxyethyl 2-ethoxy-1-[ p -( o -1 H -tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester). Its empirical formula is C 33 H 34 N 6 O 6 and its structural formula is: Candesartan cilexetil is a white to off-white powder with a molecular weight of 610.67. It is practically insoluble in water and sparingly soluble in methanol. Candesartan cilexetil is a racemic mixture containing one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group. Following oral administration, candesartan cilexetil undergoes hydrolysis at the ester link to form the active drug, candesartan, which is achiral. Hydrochlorothiazide is 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C 7 H 8 ClN 3 O 4 S 2 and its structural formula is: Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.72, which is slightly soluble in water, but freely soluble in sodium hydroxide solution. ATACAND HCT is available for oral administration in three tablet strengths of candesartan cilexetil and hydrochlorothiazide. ATACAND HCT 16-12.5 contains 16 mg of candesartan cilexetil and 12.5 mg of hydrochlorothiazide. ATACAND HCT 32-12.5 contains 32 mg of candesartan cilexetil and 12.5 mg of hydrochlorothiazide. ATACAND HCT 32-25 contains 32 mg of candesartan cilexetil and 25 mg of hydrochlorothiazide. The inactive ingredients of the tablets are carboxymethylcellulose calcium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, cornstarch, polyethylene glycol 8000, and ferric oxide (yellow). Ferric oxide (reddish brown) is also added to the 16-12.5 mg and 32-25 mg tablets as colorant. Chemical Structure for Candesartan cilexetil Chemical...
What Is Candesartan Cilexetil And Hydrochlorothiazide Used For?
INDICATIONS AND USAGE ATACAND HCT 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 ATACAND HCT. 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 ).
Dosage 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. ATACAND 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 ATACAND HCT in patients with creatinine clearance < 30 mg/min cannot be provided (see SPECIAL POPULATIONS, Renal Insufficiency ). Use in moderate to severe Hepatic Impairment: ATACAND HCT 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 ATACAND HCT 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 ATACAND HCT 16-12.5 mg and serum potassium may improve. A patient whose blood pressure is not controlled on 32 mg of ATACAND can expect incremental blood pressure effects from ATACAND HCT 32-12.5 mg and then 32-25 mg. The maximal antihypertensive effect of any dose of ATACAND HCT can be expected within 4 weeks of initiating that dose. ATACAND HCT may be administered with other antihypertensive agents. ATACAND HCT may be administered with or without food.
Side Effects (Adverse Reactions)
ADVERSE REACTIONS Candesartan Cilexetil-Hydrochlorothiazide ATACAND HCT 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 ATACAND HCT 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 ATACAND HCT and that were more frequent for ATACAND HCT 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 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 To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Warnings and Precautions
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 ATACAND HCT 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 ATACAND HCT, 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 ATACAND HCT 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] Doses compared on the basis of body surface area. MRHD considered to be 32 mg for candesartan cilexetil and 12.5 mg for hydrochlorothiazide. ). 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...
Drug 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 ATACAND HCT and other agents that affect the RAS. Co-administration of ATACAND HCT 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 ATACAND HCT in patients with diabetes. Avoid use of aliskiren with ATACAND HCT 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...
Contraindications
CONTRAINDICATIONS ATACAND HCT is contraindicated in patients who are hypersensitive to candesartan, to hydrochlorothiazide or to other sulfonamide-derived drugs. Do not co-administer aliskiren with ATACAND HCT in patients with diabetes (see PRECAUTIONS, Drug Interactions ). ATACAND HCT is contraindicated in patients with anuria.
Overdosage
OVERDOSAGE Candesartan Cilexetil-Hydrochlorothiazide No lethality was observed in acute toxicity studies in mice, rats and dogs given single oral doses of up to 2000 mg/kg of candesartan cilexetil or in rats given single oral doses of up to 2000 mg/kg of candesartan cilexetil in combination with 1000 mg/kg of hydrochlorothiazide. In mice given single oral doses of the primary metabolite, candesartan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg. Limited data are available in regard to overdosage with candesartan cilexetil in humans. The most likely manifestations of overdosage with candesartan cilexetil would be hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be initiated. For hydrochlorothiazide, the most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. Candesartan cannot be removed by hemodialysis. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. Treatment To obtain up-to-date information about the treatment of overdose, consult your Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR) . In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and altered pharmacokinetics in your patient.
How Supplied
HOW SUPPLIED ATACAND HCT 16-12.5 mg Tablets are peach, oval, biconvex, non-film-coated tablets, scored on both sides and coded with ACS on one side. They are supplied in bottles of 90 tablets (NDC 62559-650-90). ATACAND HCT 32-12.5 mg Tablets are yellow, oval, biconvex, non-film-coated tablets, scored on both sides and coded with ACJ on one side. They are supplied in bottles of 90 tablets (NDC 62559-651-90). ATACAND HCT 32-25 mg Tablets are pink, oval, biconvex, non-film-coated tablets, scored on both sides and coded with ACD on one side. They are supplied in bottles of 90 tablets (NDC 62559-652-90). Storage: Store at 20° to 25°C (68° to 77°F); excursions permitted at 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. Manufactured under the license from Takeda Pharmaceutical Company, Ltd. Manufactured by: AstraZeneca AB, SE-151 85 Södertälje, Sweden Distributed by: ANI Pharmaceuticals, Inc. Baudette, MN 56623 ATACAND HCT is a registered trademark of the AstraZeneca group of companies and is licensed to ANI Pharmaceuticals. 10114 Rev 07/25 logo
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.