Atacand Hct

Description

ATACAND HCT (candesartan cilexetil-hydrochlorothiazide) is a combination of an angiotensin II receptor (type AT1) antagonist and the diuretic hydrochlorothiazide. Candesartan cilexetil is a nonpeptide compound chemically described as (±)-1-Hydroxyethyl 2-ethoxy-1-p-(o-1H-tetrazol-5-ylphenyl)benzyl-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester), with an empirical formula of C33H34N6O6 and a molecular weight of 610.67. It appears as a white to off-white powder that 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.

Hydrochlorothiazide is chemically identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide, with an empirical formula of C7H8ClN3O4S2 and a molecular weight of 297.72. It is a white or practically white crystalline powder that is slightly soluble in water and freely soluble in sodium hydroxide solution.

ATACAND HCT is available for oral administration in three tablet strengths: 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; and ATACAND HCT 32-25 contains 32 mg of candesartan cilexetil and 25 mg of hydrochlorothiazide. The inactive ingredients in the tablets include carboxymethylcellulose calcium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, cornstarch, polyethylene glycol 8000, and ferric oxide (yellow). Additionally, ferric oxide (reddish brown) is included as a colorant in the 16-12.5 mg and 32-25 mg tablets.

Uses and Indications

ATACAND HCT is indicated for the treatment of hypertension to lower blood pressure. Effective management of high blood pressure is essential for reducing the risk of both fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions.

Control of hypertension should be integrated into a comprehensive cardiovascular risk management strategy, which includes lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. It is important to note that many patients may require more than one antihypertensive agent to achieve their blood pressure goals.

Numerous antihypertensive medications have demonstrated efficacy in randomized controlled trials, showing a reduction in cardiovascular morbidity and mortality. The most significant cardiovascular outcome benefit observed is a reduction in the risk of stroke, along with reductions in myocardial infarction and overall cardiovascular mortality. Elevated systolic or diastolic blood pressure is associated with increased cardiovascular risk, with a greater absolute risk increase per mmHg at higher blood pressures. Even modest reductions in severe hypertension can yield substantial benefits.

The relative risk reduction associated with blood pressure lowering is consistent across various populations with differing absolute risks, with greater absolute benefits observed in patients at higher risk, such as those with diabetes or hyperlipidemia.

This fixed-dose combination is not indicated for initial therapy.

Dosage and Administration

The usual recommended starting dose of candesartan cilexetil is 16 mg once daily when used as monotherapy in patients who are not volume depleted. ATACAND may be administered once or twice daily, with total daily doses ranging from 8 mg to 32 mg. For patients requiring further reduction in blood pressure, titration to 32 mg is advised. Doses exceeding 32 mg do not demonstrate a greater effect on blood pressure reduction.

Hydrochlorothiazide is effective at doses of 12.5 to 50 mg once daily. ATACAND HCT can be administered in conjunction with other antihypertensive agents. It may be taken with or without food, providing flexibility in administration.

Contraindications

ATACAND HCT is contraindicated in patients with a known hypersensitivity to candesartan, hydrochlorothiazide, or other sulfonamide-derived drugs.

Co-administration of aliskiren with ATACAND HCT is contraindicated in patients with diabetes due to the potential for adverse effects.

Additionally, ATACAND HCT is contraindicated in patients with anuria, as the drug's mechanism of action is not applicable in this condition.

Warnings and Precautions

The use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy is associated with significant risks, including reduced fetal renal function and increased morbidity and mortality for both the fetus and neonate. Oligohydramnios resulting from such therapy can lead to fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. Therefore, ATACAND HCT should be discontinued as soon as pregnancy is detected.

In cases where there is no suitable alternative to therapy with renin-angiotensin system inhibitors, healthcare providers must inform the mother of the potential risks to the fetus. Serial ultrasound examinations should be performed to monitor the intra-amniotic environment. If oligohydramnios is detected, ATACAND HCT should be discontinued unless it is deemed lifesaving for the mother. It is crucial to note that oligohydramnios may not manifest until after the fetus has sustained irreversible injury. Infants with a history of in utero exposure to ATACAND HCT should be closely monitored for hypotension, oliguria, and hyperkalemia.

ATACAND HCT may induce symptomatic hypotension, particularly in patients who are volume and/or salt depleted. In such cases, a temporary reduction in the dose of ATACAND HCT or volume repletion may be necessary. It is recommended that volume and/or salt depletion be corrected prior to initiating therapy with ATACAND HCT.

Patients with heart failure are at risk for excessive hypotension when treated with ATACAND HCT, which may lead to oliguria, azotemia, and, in rare instances, acute renal failure and death. Initiation of therapy should occur under close medical supervision, with careful monitoring during the first two weeks of treatment and following any increase in the dose of candesartan or diuretic.

Renal function should be monitored periodically in patients receiving ATACAND HCT, as changes in renal function, including acute renal failure, can occur due to the effects of drugs that inhibit the renin-angiotensin system and diuretics. Therapy should be withheld or discontinued in patients who experience a clinically significant decrease in renal function.

The use of drugs that inhibit the renin-angiotensin system can lead to hyperkalemia, while hydrochlorothiazide may cause hypokalemia and hyponatremia. Therefore, periodic monitoring of serum electrolytes is essential.

Hydrochlorothiazide has been associated with idiosyncratic reactions, including acute transient myopia and acute angle-closure glaucoma, characterized by a sudden decrease in visual acuity or ocular pain. The primary course of action in such cases is to discontinue hydrochlorothiazide promptly. Additionally, hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, with a higher likelihood in those with such a history.

General precautions include the potential for hydrochlorothiazide to alter glucose tolerance and elevate serum levels of cholesterol and triglycerides. It may also increase serum uric acid levels due to reduced clearance, potentially causing or exacerbating hyperuricemia and precipitating gout in susceptible individuals. Thiazides can decrease urinary calcium excretion, leading to elevated serum calcium levels; therefore, ATACAND HCT should be avoided in patients with hypercalcemia. Furthermore, thiazide diuretics have been reported to exacerbate or activate systemic lupus erythematosus.

Regular laboratory tests should include monitoring renal function and serum electrolytes to ensure patient safety during treatment with ATACAND HCT. In the event of pregnancy detection, ATACAND HCT should be discontinued immediately. If oligohydramnios is observed, the medication should be stopped unless it is considered lifesaving for the mother.

Side Effects

Patients may experience a range of adverse reactions while using the medication. Common adverse reactions observed in clinical trials include respiratory system disorders such as upper respiratory tract infections (3.6% vs. 3.0%), body as a whole reactions like back pain (3.3% vs. 2.4%) and influenza-like symptoms (2.5% vs. 1.9%), as well as central and peripheral nervous system effects including dizziness (2.9% vs. 1.2%).

In addition to these common reactions, post-marketing experience has revealed several other adverse effects. Digestive system disorders may include abnormal hepatic function and hepatitis. Hematologic reactions such as neutropenia, leukopenia, and agranulocytosis have also been reported. Immunologic reactions may manifest as angioedema, while metabolic and nutritional disorders can lead to hyperkalemia and hyponatremia. Respiratory system disorders may present as cough, and skin and appendage disorders can include pruritus, rash, and urticaria. Rare cases of rhabdomyolysis have been documented in patients receiving angiotensin II receptor blockers.

Specific adverse reactions associated with hydrochlorothiazide include gastrointestinal issues such as pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, constipation, gastric irritation, and anorexia. Hematologic concerns may involve aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Hypersensitivity reactions can range from anaphylactic reactions and necrotizing angiitis to respiratory distress, including pneumonitis and pulmonary edema, as well as photosensitivity, urticaria, and purpura. Musculoskeletal effects may include muscle spasms.

Hydrochlorothiazide is also associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Skin reactions may encompass erythema multiforme, including Stevens-Johnson syndrome, exfoliative dermatitis, and alopecia. Patients may experience transient blurred vision and xanthopsia as part of special senses disorders, while urogenital effects may include impotence.

Important safety considerations include fetal toxicity, as the use of drugs acting on the renin-angiotensin system during the second and third trimesters of pregnancy can reduce fetal renal function and increase morbidity and mortality. Symptomatic hypotension may occur, particularly in patients who are volume and/or salt depleted. Potassium abnormalities, including hyperkalemia and hypokalemia, are also possible. Hydrochlorothiazide may cause an idiosyncratic reaction leading to acute transient myopia and acute angle-closure glaucoma. Hypersensitivity reactions to hydrochlorothiazide can occur in patients with or without a prior history of allergy or bronchial asthma.

Drug Interactions

Co-administration of nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, with candesartan may lead to a deterioration in renal function, potentially resulting in acute renal failure. It is advisable to monitor renal function periodically in patients receiving this combination. Additionally, the antihypertensive effect of candesartan may be diminished when used alongside NSAIDs.

When lithium is administered concurrently with candesartan, there have been reports of increased serum lithium concentrations and potential lithium toxicity. Therefore, it is essential to monitor serum lithium levels in patients receiving both medications.

The use of angiotensin receptor blockers, ACE inhibitors, or aliskiren in conjunction with each other can lead to dual blockade of the renin-angiotensin system (RAS), which is associated with heightened risks of hypotension, hyperkalemia, and alterations in renal function. Close monitoring of blood pressure and renal function is recommended in these cases.

For patients taking ATACAND HCT, co-administration with potassium-sparing diuretics or potassium supplements may result in hyperkalemia; thus, monitoring of serum potassium levels is warranted. Furthermore, it is contraindicated to co-administer aliskiren with ATACAND HCT in patients with diabetes or renal impairment (GFR <60 mL/min).

The concomitant use of alcohol, barbiturates, or narcotics with hydrochlorothiazide may enhance the risk of orthostatic hypotension. Additionally, dosage adjustments of antidiabetic medications may be necessary when used alongside hydrochlorothiazide.

Thiazides, including hydrochlorothiazide, may enhance the hyperglycemic effect of diazoxide. To avoid reduced absorption, hydrochlorothiazide should be administered at least 4 hours before or 4-6 hours after ion exchange resins.

Thiazide-induced hypokalemia or hypomagnesemia can increase the risk of digoxin toxicity. While thiazides may decrease arterial responsiveness to noradrenaline, this effect is not sufficient to negate their therapeutic efficacy. Hypokalemia may also develop during concurrent use of steroids or adrenocorticotropic hormone (ACTH) with hydrochlorothiazide.

Finally, concomitant treatment with cyclosporine may elevate the risk of hyperuricemia and complications associated with gout.

Packaging & NDC

The table below lists all NDC Code configurations of Atacand Hct (candesartan cilexetil and hydrochlorothiazide), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

Pediatric patients, particularly neonates with a history of in utero exposure to ATACAND HCT, require careful monitoring. In cases of oliguria or hypotension, it is essential to focus on supporting blood pressure and renal perfusion. Interventions such as exchange transfusions or dialysis may be necessary to address hypotension and/or to compensate for impaired renal function.

Currently, the safety and effectiveness of ATACAND HCT in pediatric patients have not been established. Therefore, caution is advised when considering its use in this population.

Geriatric Use

The pharmacokinetics of candesartan have been evaluated in elderly patients aged 65 years and older. Studies indicate that the plasma concentration of candesartan is significantly higher in this population, with a maximum concentration (Cmax) approximately 50% greater and the area under the curve (AUC) approximately 80% higher compared to younger subjects receiving the same dosage.

Despite these increased plasma levels, the pharmacokinetics of candesartan remain linear in elderly patients, and neither candesartan nor its inactive metabolite accumulates in the serum following repeated once-daily administration.

Importantly, no initial dosage adjustment is required for elderly patients. However, healthcare providers should remain vigilant in monitoring these patients for any potential adverse effects due to the increased plasma concentrations.

Pregnancy

There are no fertility studies conducted with the combination of candesartan cilexetil and hydrochlorothiazide. However, available data from animal studies indicate that fertility and reproductive performance were not adversely affected in male and female rats administered oral doses of up to 300 mg candesartan cilexetil/kg/day, which is approximately 83 times the maximum daily human dose of 32 mg when adjusted for body surface area. Additionally, hydrochlorothiazide did not demonstrate any negative effects on the fertility of mice and rats of either sex in studies where these animals were exposed to dietary doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to conception and throughout gestation.

Given the lack of specific studies on the combination in pregnant patients, healthcare professionals should exercise caution when prescribing this combination to women of childbearing potential. It is advisable to weigh the potential benefits against any unknown risks to fetal outcomes.

Lactation

It is not known whether candesartan is excreted in human milk; however, it has been demonstrated to be present in rat milk. Thiazides are known to appear in human milk.

Due to the potential for adverse effects on the nursing infant, healthcare professionals should consider the importance of the drug to the lactating mother when making a decision to either discontinue nursing or discontinue the medication.

Renal Impairment

Patients with renal impairment should be monitored for renal function periodically while receiving ATACAND HCT. The use of this medication may lead to changes in renal function, including acute renal failure, particularly in patients whose renal function is dependent on the renin-angiotensin system. This includes individuals with conditions such as renal artery stenosis, chronic kidney disease, severe heart failure, or volume depletion, who may be at an increased risk of developing oliguria, progressive azotemia, or acute renal failure.

In cases where a clinically significant decrease in renal function occurs, it may be necessary to withhold or discontinue therapy with ATACAND HCT. Additionally, patients with heart failure may experience excessive hypotension, which can result in oliguria, azotemia, and, in rare instances, acute renal failure and death. For patients presenting with symptomatic hypotension, a temporary reduction in the dose of ATACAND HCT or volume repletion may be required. It is also essential to correct any volume and/or salt depletion prior to initiating therapy with ATACAND HCT.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to this drug. Consequently, there are no dosage adjustments, special monitoring requirements, or precautions outlined for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the prescribing information.

Overdosage

In cases of overdosage with candesartan cilexetil, acute toxicity studies conducted in mice, rats, and dogs have demonstrated that no lethality was observed following the administration of single oral doses up to 2000 mg/kg. However, healthcare professionals should be vigilant for potential symptoms associated with overdosage.

The most likely manifestations of overdosage with candesartan cilexetil include hypotension, dizziness, and tachycardia. Additionally, bradycardia may occur due to parasympathetic stimulation. In instances where symptomatic hypotension is present, it is imperative to initiate supportive treatment to manage the patient's condition effectively.

For hydrochlorothiazide, the common signs and symptoms of overdosage primarily stem from electrolyte depletion, which may include hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. It is important to note that if digitalis has been administered, hypokalemia may exacerbate the risk of cardiac arrhythmias.

Candesartan is not amenable to removal by hemodialysis, and the extent to which hydrochlorothiazide can be removed by this method has not been established. Therefore, in the event of an overdose, it is crucial to consult the Regional Poison Control Center for the most current information regarding treatment protocols and management strategies.

Nonclinical Toxicology

No fertility studies have been conducted with the combination of candesartan cilexetil and hydrochlorothiazide. However, fertility and reproductive performance were not adversely affected in studies involving male and female rats administered oral doses of up to 300 mg candesartan cilexetil/kg/day, which is 83 times the maximum daily human dose of 32 mg on a body surface area basis. Additionally, hydrochlorothiazide did not demonstrate any negative effects on the fertility of mice and rats of either sex in studies where these species were exposed, via their diet, to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to conception and throughout gestation.

No carcinogenicity studies have been conducted with the combination of candesartan cilexetil and hydrochlorothiazide. Nevertheless, there was no evidence of carcinogenicity when candesartan cilexetil was administered orally to mice and rats for up to 104 weeks at doses of up to 100 mg/kg/day and 1000 mg/kg/day, respectively. Two-year feeding studies conducted under the auspices of the National Toxicology Program (NTP) revealed no evidence of carcinogenic potential for 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. However, the NTP did find equivocal evidence for hepatocarcinogenicity in male mice.

Candesartan cilexetil or its active metabolite, candesartan, in combination with hydrochlorothiazide, tested positive in vitro in the Chinese hamster lung (CHL) chromosomal aberration assay and the mouse lymphoma mutagenicity assay. The 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 were positive for genotoxicity in the in vitro CHL chromosomal aberration assay, but 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 evaluated in vivo in the mouse micronucleus test and in vitro in the Chinese hamster ovary (CHO) gene mutation assay, yielding negative results in both cases. Candesartan cilexetil was also 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, with negative results in each instance.

When hydrochlorothiazide was tested alone, positive results were obtained in vitro in the CHO sister chromatid exchange (clastogenicity) and mouse lymphoma cell (mutagenicity) assays, as well as in the Aspergillus nidulans non-disjunction assay. However, hydrochlorothiazide was not genotoxic in vitro in the Ames test for point mutations, 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.

Postmarketing Experience

Very rarely reported postmarketing experiences with candesartan cilexetil include abnormal hepatic function and hepatitis within the digestive system, as well as hematologic events such as neutropenia, leukopenia, and agranulocytosis. Immunologic reactions have included angioedema. Metabolic and nutritional disorders reported include hyperkalemia and hyponatremia. Respiratory system disorders have been noted as cough, while skin and appendages disorders include pruritus, rash, and urticaria.

Additionally, rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Hydrochlorothiazide has been associated with various adverse experiences, including gastrointestinal issues such as pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, constipation, gastric irritation, and anorexia. Hematologic events reported include aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Hypersensitivity reactions have included anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress (including pneumonitis and pulmonary edema), photosensitivity, urticaria, and purpura. Musculoskeletal events such as muscle spasm have also been reported.

Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC) in white patients taking large cumulative doses. The increased risk for SCC in the overall population is approximately 1 additional case per 16,000 patients per year, while for white patients taking a cumulative dose of ≥50,000 mg, the risk increase is approximately 1 additional SCC case for every 6,700 patients per year. Other skin-related adverse events include erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia. Special senses may be affected by transient blurred vision and xanthopsia, while urogenital issues such as impotence have also been reported.

Patient Counseling

Healthcare providers should advise patients that if pregnancy is detected, ATACAND HCT should be discontinued as soon as possible. It is important to discuss the potential consequences of exposure to ATACAND HCT during pregnancy with female patients of childbearing age. Providers should engage in conversations about alternative treatment options for women who are planning to become pregnant and encourage patients to report any pregnancies to their physicians promptly.

Patients receiving ATACAND HCT should be informed that lightheadedness may occur, particularly during the initial days of therapy. They should be instructed to report any instances of lightheadedness to their prescribing physician. In cases of syncope, patients should discontinue ATACAND HCT and consult their physician before resuming treatment.

Healthcare providers should also inform all patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to a significant drop in blood pressure, which may result in lightheadedness or syncope.

Patients should be cautioned against using potassium supplements, salt substitutes containing potassium, or any other medications that may elevate serum potassium levels without prior consultation with their prescribing physician.

For those taking hydrochlorothiazide, it is essential to instruct patients to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Storage and Handling

The product is supplied in a configuration that includes specific NDC numbers, which are essential for identification and inventory management. It should be stored at a temperature range of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) in accordance with USP Controlled Room Temperature guidelines.

To ensure the integrity of the product, it is crucial to keep the container tightly closed at all times. Proper adherence to these storage conditions will help maintain the product's efficacy and safety.

Additional Clinical Information

No further data are available.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Atacand Hct as submitted by ANI Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)