Atacand Hct Information
Atacand hct (Candesartan cilexetil,hydrochlorothiazide) Use In Pregnancy
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.
WARNINGS, Fetal/Neonatal Morbidity and Mortality
Atacand hct (Candesartan cilexetil,hydrochlorothiazide) Description
Atacand hct (Candesartan cilexetil,hydrochlorothiazide) (candesartan cilexetil-hydrochlorothiazide) combines an angiotensin II receptor (type AT) antagonist and a diuretic, hydrochlorothiazide.
Candesartan cilexetil, a nonpeptide, is chemically described as (±)-1-Hydroxyethyl 2-ethoxy-1-[-(-1-tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester).
Its empirical formula is CHNO, 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-2-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is CHClNOS 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 (Candesartan cilexetil,hydrochlorothiazide) is available for oral administration in three tablet strengths of candesartan cilexetil and hydrochlorothiazide.
Atacand hct (Candesartan cilexetil,hydrochlorothiazide) 16-12.5 contains 16 mg of candesartan cilexetil and 12.5 mg of hydrochlorothiazide. Atacand hct (Candesartan cilexetil,hydrochlorothiazide) 32-12.5 contains 32 mg of candesartan cilexetil and 12.5 mg of hydrochlorothiazide. Atacand hct (Candesartan cilexetil,hydrochlorothiazide) 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, corn starch, 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.
Atacand hct (Candesartan cilexetil,hydrochlorothiazide) Clinical Pharmacology
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 AT 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 AT receptor found in many tissues, but AT is not known to be associated with cardiovascular homeostasis. Candesartan has much greater affinity (>10,000-fold) for the AT receptor than for the AT 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 (Candesartan cilexetil,hydrochlorothiazide) Indications And Usage
Atacand hct (Candesartan cilexetil,hydrochlorothiazide) is indicated for the treatment of hypertension. This fixed dose combination is not indicated for initial therapy (see ).
Atacand hct (Candesartan cilexetil,hydrochlorothiazide) Contraindications
Atacand hct (Candesartan cilexetil,hydrochlorothiazide) 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.
Atacand hct (Candesartan cilexetil,hydrochlorothiazide) Warnings
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 (Candesartan cilexetil,hydrochlorothiazide) , when pregnancy is detected, Atacand hct (Candesartan cilexetil,hydrochlorothiazide) 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 (Candesartan cilexetil,hydrochlorothiazide) 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 (Candesartan cilexetil,hydrochlorothiazide) 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 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 (Candesartan cilexetil,hydrochlorothiazide) , 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 (Candesartan cilexetil,hydrochlorothiazide) , or the treatment should start under close medical supervision (see ).
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.
Atacand hct (Candesartan cilexetil,hydrochlorothiazide) Precautions
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 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 CHL chromosomal aberration assay. Neither compound tested positive in the Ames microbial mutagenesis assay or in the mouse lymphoma cell assay. Candesartan (but not its O-deethyl metabolite) was also evaluated in the mouse micronucleus test and in the Chinese hamster ovary (CHO) gene mutation assay, in both cases with negative results. Candesartan cilexetil was evaluated in the Ames test, the mouse lymphoma cell assay, the rat hepatocyte unscheduled DNA synthesis assay and the 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 the CHO sister chromatid exchange (clastogenicity) and mouse lymphoma cell (mutagenicity) assays and in the non-disjunciton assay. Hydrochorothiazide was not genotoxic in the Ames test for point mutations and the CHO test for chromosomal aberrations, or 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
and D
WARNINGS, Fetal/Neonatal Morbidity and Mortality
Of the total number of subjects in all clinical studies of Atacand hct (Candesartan cilexetil,hydrochlorothiazide) (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 (Candesartan cilexetil,hydrochlorothiazide) Adverse Reactions
Atacand hct (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 Atacand hct (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 Atacand hct (Candesartan cilexetil,hydrochlorothiazide) and that were more frequent for Atacand hct (Candesartan cilexetil,hydrochlorothiazide) than placebo were: upper respiratory tract infection (3.6% vs 3.0%); back pain (3.3% vs 2.4%); influenza-like symptoms (2.5% vs 1.9%); dizziness (2.9% vs 1.2%).
The frequency of headache was greater than 2% (2.9%) in patients treated with Atacand hct (Candesartan cilexetil,hydrochlorothiazide) 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 (Candesartan cilexetil,hydrochlorothiazide) included: inflicted injury, fatigue, pain, chest pain, peripheral edema, asthenia; vertigo, paresthesia, hypesthesia; bronchitis, sinusitis, pharyngitis, coughing, rhinitis, dyspnea; arthralgia, myalgia, arthrosis, arthritis, leg cramps, sciatica; nausea, abdominal pain, diarrhea, dyspepsia, gastritis, gastroenteritis, vomiting; hyperuricemia, hyperglycemia, hypokalemia, increased BUN, creatine phosphokinase increased; urinary tract infection, hematuria, cystitis; hepatic function abnormal, increased transaminase levels; tachycardia, palpitation, extrasystoles, bradycardia; depression, insomnia, anxiety; ECG abnormal; eczema, sweating increased, pruritus, dermatitis, rash; epistaxis; infection, viral infection; conjunctivitis; 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:
Hematologic:
Metabolic and Nutritional Disorders:
Renal:
Skin and Appendages Disorders:
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 (Candesartan cilexetil,hydrochlorothiazide) .
Creatinine, Blood Urea Nitrogen
Hemoglobin and Hematocrit
Potassium
Liver Function Tests
Atacand hct (Candesartan cilexetil,hydrochlorothiazide) Dosage & 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.
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 ) 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.
A patient whose blood pressure is not controlled on 32 mg of ATACAND can expect incremental blood pressure effects from Atacand hct (Candesartan cilexetil,hydrochlorothiazide) 32-12.5 mg and then 32-25 mg. The maximal antihypertensive effect of any dose of Atacand hct (Candesartan cilexetil,hydrochlorothiazide) can be expected within 4 weeks of initiating that dose.
Thiazide diuretics should be used with caution in patients with hepatic impairment; therefore, care should be exercised with dosing of Atacand hct (Candesartan cilexetil,hydrochlorothiazide) .
Atacand hct (Candesartan cilexetil,hydrochlorothiazide) may be administered with other antihypertensive agents.
Atacand hct (Candesartan cilexetil,hydrochlorothiazide) may be administered with or without food.
Atacand hct (Candesartan cilexetil,hydrochlorothiazide) How Supplied
No. 3825 — Tablets Atacand hct (Candesartan cilexetil,hydrochlorothiazide) 16-12.5, are peach, oval, biconvex, non-film-coated tablets, scored on both sides and coded with ACS on one side. They are supplied as follows:
No. 3826 — Tablets Atacand hct (Candesartan cilexetil,hydrochlorothiazide) 32-12.5, are yellow, oval, biconvex, non-film-coated tablets, scored on both sides and coded with ACJ on one side. They are supplied as follows:
No. 3899 — Tablets Atacand hct (Candesartan cilexetil,hydrochlorothiazide) 32–25, are pink, oval, biconvex, non-film-coated tablets, scored on both sides and coded with ACD on one side. They are supplied as follows:
