Candesartan cilexetil/Hydrochlorothiazide

Description

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 it has a molecular weight of 610.67. Candesartan cilexetil appears as a white to off-white powder and is practically insoluble in water while being sparingly soluble in methanol. It is a racemic mixture containing one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group.

Hydrochlorothiazide is chemically defined 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 but freely soluble in sodium hydroxide solution.

Candesartan cilexetil and hydrochlorothiazide tablets are formulated for oral administration and are available in three strengths: 16 mg or 32 mg of candesartan cilexetil combined with 12.5 mg or 25 mg of hydrochlorothiazide, resulting in the following combinations: 16 mg/12.5 mg, 32 mg/12.5 mg, or 32 mg/25 mg. The inactive ingredients in the tablets include carboxymethylcellulose calcium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, corn starch, polyethylene glycol 8000, and ferric oxide (yellow). Additionally, ferric oxide (reddish brown) is included as a colorant in the 16 mg/12.5 mg and 32 mg/25 mg tablet formulations.

Uses and Indications

Candesartan cilexetil and hydrochlorothiazide tablets are indicated for the treatment of hypertension to lower blood pressure. Effective management of hypertension is essential as it reduces the risk of both fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions.

Control of high blood pressure 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.

While numerous antihypertensive medications have demonstrated efficacy in randomized controlled trials to reduce cardiovascular morbidity and mortality, the most significant cardiovascular outcome benefit observed has been a reduction in the risk of stroke. Additionally, reductions in myocardial infarction and cardiovascular mortality have been consistently reported. Elevated systolic or diastolic blood pressure is associated with increased cardiovascular risk, with the absolute risk increase per mmHg being more pronounced at higher blood pressures. Even modest reductions in severe hypertension can yield substantial benefits.

The relative risk reduction from blood pressure lowering is comparable across various populations, regardless of their absolute risk. However, the absolute benefit is more pronounced in patients at higher risk, such as those with diabetes or hyperlipidemia. It is also noted that some antihypertensive drugs may exhibit smaller blood pressure effects when used as monotherapy in black patients.

This fixed-dose combination of candesartan cilexetil and hydrochlorothiazide is not indicated for initial therapy.

Dosage and Administration

The usual recommended starting dose of candesartan cilexetil is 16 mg administered once daily for patients who are not volume depleted and are receiving it as monotherapy. The dosing regimen may be adjusted, with candesartan cilexetil tablets being administered once or twice daily, allowing for total daily doses ranging from 8 mg to 32 mg. For patients requiring additional blood pressure reduction, titration to 32 mg is advised, as doses exceeding 32 mg do not demonstrate a greater effect on blood pressure reduction.

Hydrochlorothiazide can be effectively administered at doses ranging from 12.5 mg to 50 mg once daily. Candesartan cilexetil and hydrochlorothiazide tablets may be taken with or without food, providing flexibility in administration. Additionally, these tablets can be used in conjunction with other antihypertensive agents as part of a comprehensive treatment plan.

Contraindications

Candesartan cilexetil and hydrochlorothiazide tablets are contraindicated in patients with a known hypersensitivity to candesartan, hydrochlorothiazide, or other sulfonamide-derived drugs.

Co-administration of aliskiren with candesartan cilexetil and hydrochlorothiazide tablets is contraindicated in patients with diabetes due to the potential for adverse effects.

Additionally, these tablets are contraindicated in patients with anuria, as the lack of urine production may lead to complications associated with the pharmacological effects of the medication.

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 deformities. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. Upon detection of pregnancy, it is imperative to discontinue candesartan cilexetil and hydrochlorothiazide tablets as soon as possible.

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 conducted to monitor the intra-amniotic environment. If oligohydramnios is detected, candesartan cilexetil and hydrochlorothiazide tablets should be discontinued unless the treatment is deemed lifesaving for the mother. It is crucial to recognize that oligohydramnios may not manifest until after the fetus has sustained irreversible injury.

Candesartan cilexetil and hydrochlorothiazide tablets may induce symptomatic hypotension, particularly in patients who are volume and/or salt depleted. Therefore, it is essential to correct any volume and/or salt depletion prior to initiating therapy. In patients with heart failure, these tablets may lead to excessive hypotension, which can result in oliguria, azotemia, and, in rare cases, acute renal failure and death.

Regular monitoring of renal function is recommended for patients receiving candesartan cilexetil and hydrochlorothiazide tablets, as changes in renal function, including acute renal failure, can occur due to the effects of renin-angiotensin system inhibitors and diuretics. Additionally, these medications can cause hyperkalemia, while hydrochlorothiazide may lead to hypokalemia and hyponatremia; therefore, periodic monitoring of serum electrolytes is advised.

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 intervention in such cases is the rapid discontinuation of hydrochlorothiazide. Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, although the risk is heightened in those with such a history.

General precautions should be observed, as hydrochlorothiazide may affect glucose tolerance and elevate serum levels of cholesterol and triglycerides. It can also increase serum uric acid levels due to decreased clearance, potentially causing or exacerbating hyperuricemia and precipitating gout in susceptible individuals. Furthermore, thiazides can decrease urinary calcium excretion, leading to elevated serum calcium levels; thus, the use of candesartan cilexetil and hydrochlorothiazide tablets is contraindicated in patients with hypercalcemia. There have also been reports of thiazide diuretics exacerbating or activating systemic lupus erythematosus.

Healthcare professionals should ensure that renal function and serum electrolytes are monitored periodically in patients treated with candesartan cilexetil and hydrochlorothiazide tablets. In the event of pregnancy detection, immediate discontinuation of the medication is warranted. If oligohydramnios is observed, the tablets should be discontinued unless the treatment is considered lifesaving for the mother.

Side Effects

Patients receiving treatment may experience a range of adverse reactions, which can be categorized by frequency and seriousness.

Common adverse reactions observed in clinical trials include respiratory system disorders such as upper respiratory tract infections, reported in 3.6% of patients compared to 3.0% in the control group. Other notable common reactions include body as a whole symptoms like back pain (3.3% vs. 2.4%) and influenza-like symptoms (2.5% vs. 1.9%). Central and peripheral nervous system effects, particularly dizziness, were reported in 2.9% of patients, compared to 1.2% in the control group.

Post-marketing experience has revealed additional adverse reactions. Digestive system disorders may include abnormal hepatic function and hepatitis. Hematologic reactions such as neutropenia, leukopenia, and agranulocytosis have also been reported. Immunologic reactions include angioedema, while metabolic and nutritional disorders may present as hyperkalemia and hyponatremia. Respiratory system disorders, including cough, have been noted, as well as skin and appendage disorders such as pruritus, rash, and urticaria. Rare cases of rhabdomyolysis have been documented in patients receiving angiotensin II receptor blockers.

Specific to hydrochlorothiazide, gastrointestinal adverse reactions may include pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, constipation, gastric irritation, and anorexia. Hematologic issues can manifest as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Hypersensitivity reactions may include anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress (including pneumonitis and pulmonary edema), photosensitivity, urticaria, and purpura. Musculoskeletal reactions such as muscle spasms have also been reported.

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

Important safety information includes potential 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. Changes in renal function, including acute renal failure, can result from drugs that inhibit the renin-angiotensin system and diuretics. Additionally, potassium abnormalities may arise, with hyperkalemia linked to renin-angiotensin inhibitors and hypokalemia and hyponatremia associated with hydrochlorothiazide. Hydrochlorothiazide may also cause acute transient myopia and acute angle-closure glaucoma as an idiosyncratic reaction. Hypersensitivity reactions to hydrochlorothiazide can occur in patients with or without a history of allergy or bronchial asthma.

Drug Interactions

Co-administration of nonsteroidal anti-inflammatory drugs (NSAIDs) with candesartan may lead to a deterioration of renal function, particularly in elderly or volume-depleted patients. It is advisable to monitor renal function periodically in these individuals. Additionally, the antihypertensive effect of candesartan may be diminished by NSAIDs, including selective COX-2 inhibitors.

When candesartan is used concurrently with lithium, there is a risk of increased serum lithium concentrations and potential toxicity. Therefore, monitoring of serum lithium levels is recommended. Furthermore, the dual blockade of the renin-angiotensin system (RAS) with candesartan and other agents may elevate the risks of hypotension, hyperkalemia, and alterations in renal function; close monitoring of blood pressure and renal function is warranted in such cases.

The combination of candesartan with potassium-sparing diuretics or potassium supplements may lead to hyperkalemia, necessitating regular monitoring of serum potassium levels. It is contraindicated to co-administer aliskiren with candesartan in patients with diabetes or renal impairment (GFR <60 mL/min).

In the context of hydrochlorothiazide, the use of alcohol, barbiturates, or narcotics may enhance the risk of orthostatic hypotension. Dosage adjustments of antidiabetic medications may be necessary when used alongside hydrochlorothiazide. Additionally, the hyperglycemic effect of diazoxide may be intensified by thiazides.

Ion exchange resins can bind hydrochlorothiazide, reducing its absorption; therefore, it is recommended to administer hydrochlorothiazide at least 4 hours before or 4-6 hours after the use of these resins. Thiazide-induced hypokalemia may increase the risk of digoxin toxicity when used in conjunction with digitalis. While thiazides may reduce arterial responsiveness to noradrenaline, they do not negate its effectiveness.

Hypokalemia may also develop during the concomitant use of thiazides with steroids or adrenocorticotropic hormone (ACTH). Furthermore, thiazides may decrease the renal excretion of cytotoxic products, potentially enhancing their myelosuppressive effects. Lastly, 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 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 candesartan cilexetil and hydrochlorothiazide tablets, 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.

The safety and effectiveness of candesartan cilexetil and hydrochlorothiazide tablets in pediatric patients have not been established. Therefore, caution is advised when considering this treatment in the pediatric population.

Geriatric Use

Elderly patients (≥ 65 years) have been the subject of pharmacokinetic studies regarding candesartan. Findings 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. Consequently, no initial dosage adjustment is necessary for elderly patients, as detailed in the DOSAGE AND ADMINISTRATION section.

Healthcare providers should remain vigilant when prescribing candesartan to geriatric patients, considering the potential for increased exposure and monitoring for any adverse effects.

Pregnancy

Candesartan cilexetil and hydrochlorothiazide have not been studied for their effects on fertility in humans. However, 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 recommended human dose based on body surface area. Additionally, hydrochlorothiazide did not demonstrate any negative effects on fertility in mice and rats exposed to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to conception and throughout gestation.

Given the lack of specific fertility studies in humans, healthcare professionals should exercise caution when prescribing this combination to women of childbearing potential. It is advisable to discuss potential risks and benefits with patients who are pregnant or planning to become pregnant.

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 being treated with candesartan cilexetil and hydrochlorothiazide tablets. The use of these medications 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. Additionally, in patients with heart failure, candesartan cilexetil and hydrochlorothiazide tablets can cause excessive hypotension, which may result in oliguria, azotemia, and, in rare instances, acute renal failure and death. Therefore, therapy should be initiated under close medical supervision in these patients, with careful monitoring during the first two weeks of treatment and following any increase in the dose of candesartan or diuretic.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to this medication. 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 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 candesartan cilexetil overdosage 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 overdosage, the predominant signs and symptoms are typically related to 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 teratogenic effects were observed in the studies conducted. Fertility studies involving the combination of candesartan cilexetil and hydrochlorothiazide have not been performed. However, studies with male and female rats receiving oral doses of up to 300 mg candesartan cilexetil per kg per day, which is 83 times the maximum daily human dose of 32 mg based on body surface area, indicated no adverse effects on fertility and reproductive performance. Additionally, hydrochlorothiazide did not adversely affect fertility in mice and rats of either sex when administered via diet at doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to conception and throughout gestation.

No carcinogenicity studies have been conducted for the combination of candesartan cilexetil and hydrochlorothiazide. However, oral administration of candesartan cilexetil to mice and rats for up to 104 weeks at doses of up to 100 mg/kg/day and 1000 mg/kg/day, respectively, revealed no evidence of carcinogenicity. Two-year feeding studies conducted by the National Toxicology Program (NTP) also found 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. The NTP did report equivocal evidence for hepatocarcinogenicity in male mice.

In terms of animal pharmacology and toxicology, candesartan cilexetil or its active metabolite, candesartan, in combination with hydrochlorothiazide, tested positive in vitro in the Chinese hamster lung chromosomal aberration assay and the mouse lymphoma mutagenicity assay. However, the combination tested negative for mutagenicity in bacteria (Ames test), unscheduled DNA synthesis in rat liver, chromosomal aberrations in rat bone marrow, and 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 was further evaluated in vivo in the mouse micronucleus test and in vitro in the Chinese hamster ovary gene mutation assay, yielding negative results in both cases. Candesartan cilexetil was also assessed 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, all resulting in negative findings.

When hydrochlorothiazide was tested alone, it produced positive results 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, it 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, the following events have been reported in the postmarketing experience with candesartan cilexetil, either voluntarily or through surveillance programs:

Abnormal hepatic function and hepatitis have been noted under digestive disorders. Hematologic events include neutropenia, leukopenia, and agranulocytosis. Immunologic reactions such as angioedema have also been documented.

In terms of metabolic and nutritional disorders, cases of hyperkalemia and hyponatremia have been reported. Respiratory system disorders include instances of cough. Skin and appendages disorders have been characterized by pruritus, rash, and urticaria.

Additionally, there have been rare reports of rhabdomyolysis in patients receiving angiotensin II receptor blockers.

Patient Counseling

Healthcare providers should inform female patients of childbearing age about the potential consequences of exposure to candesartan cilexetil and hydrochlorothiazide tablets during pregnancy. It is important to discuss treatment options with women who are planning to become pregnant. Patients should be encouraged to report any pregnancies to their physicians as soon as possible.

Patients receiving candesartan cilexetil and hydrochlorothiazide tablets should be made aware that lightheadedness may occur, particularly during the initial days of therapy. They should be advised to report any instances of lightheadedness to their prescribing physician. In the event of syncope, patients should discontinue the medication and consult their physician before resuming treatment.

All patients should be cautioned 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 also be instructed not to use 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 advise them 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 Candesartan Cilexetil and Hydrochlorothiazide as submitted by ANI Pharmaceuticals, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)