ATACAND HCT® 16-12.5
(candesartan cilexetil?hydrochlorothiazide)
TABLETS
ATACAND HCT® 32-12.5
(candesartan cilexetil?hydrochlorothiazide)
TABLETS

When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, ATACAND HCT should be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

ATACAND HCT (candesartan cilexetil-hydrochlorothiazide) combines an angiotensin II receptor (type AT₁) antagonist and a diuretic, hydrochlorothiazide.

Candesartan cilexetil, a nonpeptide, is chemically described as (±)-1-Hydroxyethyl 2-ethoxy-1-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester).

Its empirical formula is C₃₃H₃₄N₆O₆, 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-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C₇H₈ClN₃O₄S₂ 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 two 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. The inactive ingredients of the tablets are calcium carboxymethylcellulose, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, corn starch, polyethylene glycol 8000, and ferric oxide (yellow). Ferric oxide (reddish brown) is also added to the 16-12.5 mg tablet as colorant.

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT₁ receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathways for angiotensin II synthesis.

There is also an AT₂ receptor found in many tissues, but AT₂ is not known to be associated with cardiovascular homeostasis. Candesartan has much greater affinity (>10,000-fold) for the AT₁ receptor than for the AT₂ receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, 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.

ATACAND HCT is indicated for the treatment of hypertension. This fixed dose combination is not indicated for initial therapy (see DOSAGE AND ADMINISTRATION).

ATACAND HCT is contraindicated in patients who are hypersensitive to any component of this product.

Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin- converting enzyme inhibitors. Post-marketing experience has identified reports of fetal and neonatal toxicity in babies born to women treated with candesartan cilexetil during pregnancy. Because candesartan cilexetil is a component of ATACAND HCT, when pregnancy is detected, ATACAND HCT should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.

These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of ATACAND HCT as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, ATACAND HCT should be discontinued unless it is considered life saving for the mother. Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.

Based on adverse events reported from all clinical trials of ATACAND HCT, excessive reduction of blood pressure was rarely seen in patients with uncomplicated hypertension treated with candesartan cilexetil and hydrochlorothiazide (0.4%). Initiation of antihypertensive therapy may cause symptomatic hypotension in patients with intravascular volume- or sodium- depletion, eg, in patients treated vigorously with diuretics or in patients on dialysis. These conditions should be corrected prior to administration of ATACAND HCT, or the treatment should start under close medical supervision (see DOSAGE AND ADMINISTRATION).

If hypotension occurs, the patients should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment which usually can be continued without difficulty once the blood pressure has stabilized.

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-disjunciton assay. Hydrochorothiazide 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.

Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS, Fetal/Neonatal Morbidity and Mortality.

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.

Safety and effectiveness in pediatric patients have not been established.

Of the total number of subjects in all clinical studies of ATACAND HCT (2831), 611 (22%) were 65 and over, while 94 (3%) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Hydrochlorothiazide is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

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%).

The frequency of headache was greater than 2% (2.9%) in patients treated with ATACAND HCT but was less frequent than the rate in patients treated with placebo (5.2%).

Other adverse events that have been reported, whether or not attributed to treatment, with an incidence of 0.5% or greater from the more than 2800 patients worldwide treated with ATACAND HCT included:Body as a Whole: inflicted injury, fatigue, pain, chest pain, peripheral edema, asthenia; Central and Peripheral Nervous System: vertigo, paresthesia, hypesthesia; Respiratory System Disorders: bronchitis, sinusitis, pharyngitis, coughing, rhinitis, dyspnea; Musculoskeletal System Disorders: arthralgia, myalgia, arthrosis, arthritis, leg cramps, sciatica; Gastrointestinal System Disorders: nausea, abdominal pain, diarrhea, dyspepsia, gastritis, gastroenteritis, vomiting; Metabolic and Nutritional Disorders: hyperuricemia, hyperglycemia, hypokalemia, increased BUN, creatine phosphokinase increased; Urinary System Disorders: urinary tract infection, hematuria, cystitis; Liver/Biliary System Disorders: hepatic function abnormal, increased transaminase levels; Heart Rate and Rhythm Disorders: tachycardia, palpitation, extrasystoles, bradycardia; Psychiatric Disorders: depression, insomnia, anxiety; Cardiovascular Disorders: ECG abnormal; Skin and Appendages Disorders: eczema, sweating increased, pruritus, dermatitis, rash; Platelet/Bleeding-Clotting Disorders: epistaxis; Resistance Mechanism Disorders: infection, viral infection; Vision Disorders: conjunctivitis; Hearing and Vestibular Disorders: tinnitus.

Reported events seen less frequently than 0.5% included angina pectoris, myocardial infarction and angioedema.

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.

Metabolic and Nutritional Disorders: hyperkalemia, hyponatremia.

Renal: renal impairment, renal failure.

Skin and Appendages Disorders: Pruritus and urticaria.

Rare reports of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with the administration of ATACAND HCT.

Creatinine, Blood Urea Nitrogen— Minor increases in blood urea nitrogen (BUN) and serum creatinine were observed infrequently. One patient was discontinued from ATACAND HCT due to increased BUN. No patient was discontinued due to an increase in serum creatinine.

Hemoglobin and Hematocrit—Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.2 g/dL and 0.4 volume percent, respectively) were observed in patients treated with ATACAND HCT, but were rarely of clinical importance.

Potassium— A small decrease (mean decrease of 0.1 mEq/L) was observed in patients treated with ATACAND HCT. In placebo-controlled trials, hypokalemia was reported in 0.4% of patients treated with ATACAND HCT as compared to 1.0% of patients treated with hydrochlorothiazide or 0.2% of patients treated with placebo.

Liver Function Tests—Occasional elevations of liver enzymes and/or serum bilirubin have occurred.

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.

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.

To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.

The side effects (See WARNINGS) of candesartan cilexetil are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (eg, pancreatitis), the former much more common than the latter.

Therapy with any combination of candesartan cilexetil and hydrochlorothiazide will be associated with both sets of dose-independent side effects.

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.

Patients with Renal Impairment: The usual regimens of therapy with ATACAND HCT may be followed as long as the patient’s creatinine clearance is > 30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so ATACAND HCT is not recommended.

Patients with Hepatic Impairment: The usual regimens of therapy with ATACAND HCT may be followed in patients with mild hepatic impairment. In patients with moderate hepatic impairment, consideration should be given to initiation of ATACAND at a lower dose, such as 8 mg. If a lower starting dose is selected for candesartan cilexetil, ATACAND HCT is not recommended for initial titration because the appropriate initial starting dose of candesartan cilexetil cannot be given. (See CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency).

Thiazide diuretics should be used with caution in patients with hepatic impairment; therefore, care should be exercised with dosing of ATACAND HCT.

ATACAND HCT may be administered with other antihypertensive agents.

ATACAND HCT may be administered with or without food.

No. 3825 — Tablets ATACAND HCT 16-12.5, are peach, oval, biconvex, non-film-coated tablets, coded ACS on one side and 162 on the other. They are supplied as follows:

NDC 0186-0162-28 unit dose packages of 100.

NDC 0186-0162-54 unit of use bottles of 90.

No. 3826 — Tablets ATACAND HCT 32-12.5, are yellow, oval, biconvex, non-film-coated tablets, coded ACJ on one side and 322 on the other. They are supplied as follows:

NDC 0186-0322-28 unit dose packages of 100.

NDC 0186-0322-54 unit of use bottles of 90.

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed.

ATACAND HCT is a trademark of the AstraZeneca group of companies

©AstraZeneca 2005

Manufactured under the license from Takeda Pharmaceutical Company, Ltd.

by: AstraZeneca AB, S-151 85 Södertälje, Sweden

for: AstraZeneca LP, Wilmington, DE 19850

Made in Sweden