Candesartan cilexetil/Hydrochlorothiazide

Description

Candesartan cilexetil and hydrochlorothiazide tablets are a combination of an angiotensin II receptor (type AT1) antagonist, candesartan cilexetil, and the diuretic hydrochlorothiazide. Candesartan cilexetil, USP is chemically defined 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. This compound appears as a white to off-white powder, is practically insoluble in water, and sparingly soluble in methanol. It is a racemic mixture with one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group. Upon oral administration, candesartan cilexetil undergoes hydrolysis at the ester link to yield the active drug, candesartan, which is achiral.

Hydrochlorothiazide, USP is 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, slightly soluble in water, and freely soluble in sodium hydroxide solution.

These tablets are formulated for oral administration and are available in three strengths: 16 mg/12.5 mg, 32 mg/12.5 mg, and 32 mg/25 mg, containing respective amounts of candesartan cilexetil USP and hydrochlorothiazide USP. The inactive ingredients include carboxymethylcellulose calcium, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, corn starch, glycerin, and ferric oxide (yellow). Additionally, ferric oxide (red) is included as a colorant in the 16 mg/12.5 mg and 32 mg/25 mg tablet formulations.

Uses and Indications

Candesartan cilexitil and hydrochlorothiazide tablets are 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, particularly 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, regular exercise, and limited sodium intake. It is important to note that many patients may require a combination of medications to achieve their blood pressure goals.

The most significant cardiovascular outcome benefit observed with this treatment is a reduction in the risk of stroke; however, reductions in myocardial infarction and cardiovascular mortality have also 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 pressure levels. Even modest reductions in severe hypertension can yield substantial health benefits.

The relative risk reduction associated with blood pressure lowering is comparable across different populations, regardless of their absolute risk levels. Consequently, the absolute benefit of treatment is greater in patients who are at higher risk, such as those with diabetes or hyperlipidemia.

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. Candesartan cilexetil can 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. Candesartan cilexetil and hydrochlorothiazide tablets may be taken with or without food. The maximal antihypertensive effect of any dose of candesartan cilexetil and hydrochlorothiazide tablets can be expected within 4 weeks of initiating that dose. These tablets may also be administered in conjunction with other antihypertensive agents.

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 is contraindicated in patients with diabetes due to the potential for adverse effects. Additionally, the use of this combination is contraindicated in patients with anuria, as it may exacerbate renal impairment.

Warnings and Precautions

Use of drugs that act on the renin-angiotensin system, such as candesartan cilexetil and hydrochlorothiazide, during the second and third trimesters of pregnancy is associated with significant fetal toxicity. These medications can impair fetal renal function, leading to increased morbidity and mortality in both the fetus and neonate. Oligohydramnios resulting from this use may contribute to fetal lung hypoplasia and skeletal deformities. Adverse neonatal outcomes may include skull hypoplasia, anuria, hypotension, renal failure, and death. Therefore, upon detection of pregnancy, it is imperative to discontinue candesartan cilexetil and hydrochlorothiazide tablets as soon as possible to mitigate these risks.

Candesartan cilexetil and hydrochlorothiazide may induce symptomatic hypotension, particularly in patients who are volume and/or salt depleted. In cases of symptomatic hypotension, it may be necessary to temporarily reduce the dosage or administer volume repletion to stabilize the patient.

Regular monitoring of renal function is essential for patients receiving candesartan cilexetil and hydrochlorothiazide. Clinicians should consider withholding or discontinuing therapy in patients who exhibit a clinically significant decline in renal function.

The use of these medications can also lead to potassium abnormalities. Specifically, drugs that inhibit the renin-angiotensin system may cause hyperkalemia, while hydrochlorothiazide is known to induce hypokalemia and hyponatremia. Therefore, periodic monitoring of serum electrolytes is recommended to ensure patient safety.

Hydrochlorothiazide has been associated with an idiosyncratic reaction that can result in acute transient myopia and secondary angle-closure glaucoma. Symptoms may include a sudden decrease in visual acuity or ocular pain. In such cases, the primary course of action is to discontinue hydrochlorothiazide as quickly as possible.

Patients may experience hypersensitivity reactions to hydrochlorothiazide, which can occur in individuals with or without a prior history of allergy or bronchial asthma. However, those with such a history are at a higher risk for these reactions.

In the event of pregnancy detection, immediate discontinuation of candesartan cilexetil and hydrochlorothiazide tablets is crucial, as these medications can cause serious injury or death to the developing fetus. Additionally, if oligohydramnios is observed, the same discontinuation should be considered unless the treatment is deemed lifesaving for the mother. Emergency medical assistance should be sought in these situations to ensure the safety of both the mother and fetus.

Side Effects

Patients may experience a range of adverse reactions while using the medication, 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 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 noted in 2.9% of participants, 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 issues such as neutropenia, leukopenia, and agranulocytosis have also been reported. Immunologic reactions, including angioedema, have been documented. Metabolic and nutritional disorders may manifest as hyperkalemia and hyponatremia. Respiratory system disorders can include cough, while skin and appendages disorders may present as pruritus, rash, and urticaria. Rare cases of rhabdomyolysis have been reported 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 reactions may involve aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Hypersensitivity reactions can include anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress (including pneumonitis and pulmonary edema), photosensitivity, urticaria, and purpura. Musculoskeletal effects may present as muscle spasms, while skin reactions can include erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia. Special senses may be affected, leading to transient blurred vision and xanthopsia, and urogenital issues such as impotence have also been reported.

Warnings associated with the use of this medication include potential fetal toxicity, particularly when used during the second and third trimesters of pregnancy, which may reduce fetal renal function and increase morbidity and mortality. Symptomatic hypotension may occur, especially in patients who are volume and/or salt depleted. Impaired renal function, including acute renal failure, can result from the use of 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 myopia and secondary 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

Candesartan, primarily excreted unchanged in urine and not significantly metabolized by the cytochrome P450 system, is not expected to interact with drugs that inhibit or are metabolized by these enzymes.

Interactions Common to Candesartan Cilexetil and Hydrochlorothiazide

Non-Steroidal Anti-Inflammatory Agents (NSAIDs) and Selective COX-2 Inhibitors: In elderly patients, those who are volume-depleted (including individuals on diuretic therapy), or those with compromised renal function, the co-administration of NSAIDs with angiotensin II receptor antagonists, including candesartan, may lead to renal function deterioration, potentially resulting in acute renal failure. These effects are generally reversible. It is advised to monitor renal function periodically in patients receiving both candesartan and NSAID therapy. Additionally, the antihypertensive effect of candesartan may be diminished by NSAIDs.

Lithium: Concomitant use of lithium with angiotensin II receptor antagonists or hydrochlorothiazide has been associated with increased serum lithium concentrations and the risk of lithium toxicity. Serum lithium levels should be monitored during concurrent administration.

Interactions Specific to Candesartan Cilexetil

Dual Blockade of the Renin-Angiotensin System (RAS): The combination of angiotensin receptor blockers, ACE inhibitors, or aliskiren with candesartan is linked to heightened risks of hypotension, hyperkalemia, and renal function changes, including acute renal failure. Blood pressure, renal function, and electrolyte levels should be closely monitored in patients receiving candesartan cilexetil alongside other RAS-affecting agents.

Potassium-Sparing Diuretics and Supplements: Coadministration of candesartan cilexetil and hydrochlorothiazide with potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes may lead to hyperkalemia. Serum potassium levels should be monitored in these patients.

Aliskiren: Aliskiren should not be co-administered with candesartan cilexetil and hydrochlorothiazide in patients with diabetes or those with renal impairment (GFR <60 ml/min).

Interactions Specific to Hydrochlorothiazide

Alcohol, Barbiturates, or Narcotics: These substances may potentiate orthostatic hypotension.

Antidiabetic Drugs: Dosage adjustments of antidiabetic medications may be necessary when used concurrently with hydrochlorothiazide.

Diazoxide: Thiazides may enhance the hyperglycemic effect of diazoxide.

Ion Exchange Resins: Single doses of cholestyramine or colestipol can significantly reduce the absorption of hydrochlorothiazide. It is recommended to stagger the administration of hydrochlorothiazide at least 4 hours before or 4-6 hours after the resins.

Skeletal Muscle Relaxants (e.g., Tubocurarine): There may be an increased responsiveness to nondepolarizing muscle relaxants.

Digitalis: Thiazide-induced hypokalemia or hypomagnesemia may increase the risk of digoxin toxicity.

Noradrenaline: Thiazides may reduce arterial responsiveness to noradrenaline, although this does not impede the therapeutic effectiveness of the pressor agent.

Steroids or Adrenocorticotropic Hormone (ACTH): Hypokalemia may occur with concurrent use of steroids or ACTH.

Cytotoxic Products: Thiazides may decrease the renal excretion of cytotoxic medications (e.g., cyclophosphamide, methotrexate), potentially enhancing their myelosuppressive effects.

Cyclosporine: Concurrent treatment with cyclosporine may elevate the risk of hyperuricemia and complications related to 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, require careful monitoring. In cases of oliguria or hypotension, it is essential to support 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 this medication in pediatric patients have not been established. Therefore, caution is advised when considering treatment in this population.

Geriatric Use

Candesartan pharmacokinetics 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 (C_max) 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 required for elderly patients.

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 human data, healthcare professionals should exercise caution when prescribing this combination to pregnant patients or women of childbearing potential. The potential risks to fetal outcomes remain undetermined, and the absence of fertility studies necessitates careful consideration of the benefits and risks in this population.

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, lactating mothers should consider whether to discontinue breastfeeding or to discontinue the medication, weighing the importance of the drug to the mother against the potential risks to the breastfed infant.

Renal Impairment

Patients with renal impairment should have their renal function monitored periodically while being treated with candesartan cilexetil and hydrochlorothiazide. It is important to note that changes in renal function, including acute renal failure, may occur due to the effects of drugs that inhibit the renin-angiotensin system and diuretics.

Particular caution is warranted for patients whose renal function may be influenced by the renin-angiotensin system, such as those with renal artery stenosis, chronic kidney disease, severe heart failure, or volume depletion. These patients may be at an increased risk of developing oliguria, progressive azotemia, or acute renal failure when receiving candesartan cilexetil and hydrochlorothiazide.

In cases where a clinically significant decrease in renal function is observed, consideration should be given to withholding or discontinuing therapy. Additionally, in patients with heart failure, the combination of candesartan cilexetil and hydrochlorothiazide may lead to excessive hypotension, which can result in oliguria, azotemia, and, in rare instances, acute renal failure and death.

Therapy should be initiated under close medical supervision, with careful monitoring during the first two weeks of treatment and following any increase in the dose of candesartan or the 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 animal models have demonstrated that no lethality was observed in mice, rats, and dogs administered single oral doses of up to 2000 mg/kg. Additionally, rats receiving a combination of candesartan cilexetil (2000 mg/kg) and hydrochlorothiazide (1000 mg/kg) also showed no lethality. However, in mice, the primary metabolite, candesartan, exhibited a minimum lethal dose greater than 1000 mg/kg but less than 2000 mg/kg.

Limited data are available regarding human overdosage with candesartan cilexetil. The most likely clinical manifestations of an overdose include hypotension, dizziness, and tachycardia. It is important to note that bradycardia may occur due to parasympathetic (vagal) stimulation.

In the event of symptomatic hypotension, supportive treatment should be initiated promptly. For hydrochlorothiazide, the common signs and symptoms associated with overdose are primarily due to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If digitalis has been co-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.

Healthcare professionals are advised to consult their Regional Poison Control Center for the most current information regarding the management of overdose. It is also crucial to consider the potential for multiple-drug overdoses, drug-drug interactions, and altered pharmacokinetics when assessing and managing a patient with suspected overdose.

Nonclinical Toxicology

Fertility studies have not been conducted with the combination of candesartan cilexetil and hydrochlorothiazide. However, 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, demonstrated no adverse effects on fertility and reproductive performance. Similarly, hydrochlorothiazide did not adversely affect the fertility of mice and rats of either sex when these species were exposed to dietary doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to conception and throughout gestation.

No carcinogenicity studies have been performed with the combination of candesartan cilexetil and hydrochlorothiazide. Candesartan cilexetil, when 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, showed no evidence of carcinogenicity. Two-year feeding studies conducted under the National Toxicology Program (NTP) also revealed no 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.

In vitro studies indicated that the combination of candesartan cilexetil or its active metabolite, candesartan, with hydrochlorothiazide tested positive in the Chinese hamster lung (CHL) chromosomal aberration assay and the mouse lymphoma mutagenicity assay. The combination tested negative for mutagenicity in the 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 found to be genotoxic 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 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 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, with negative outcomes in each instance.

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, hydrochlorothiazide was not found to be 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:

In the digestive system, cases of abnormal hepatic function and hepatitis have been noted. Hematologic events include neutropenia, leukopenia, and agranulocytosis. Immunologic reactions such as angioedema have also been reported. Metabolic and nutritional disorders observed include hyperkalemia and hyponatremia. Additionally, respiratory system disorders, specifically cough, have been documented. Skin and appendages disorders such as pruritus, rash, and urticaria have been reported as well.

Furthermore, rare cases of rhabdomyolysis have been associated with the use of 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 during pregnancy. It is important to discuss alternative 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 should be advised 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 the event of syncope, patients should discontinue the medication and consult their physician before resuming treatment.

All patients should be made aware 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 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 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

Candesartan cilexetil and hydrochlorothiazide tablets are indicated for oral administration. Clinicians should counsel female patients of childbearing age regarding the potential risks associated with exposure to these medications during pregnancy and discuss alternative treatment options for those planning to conceive. Patients should promptly report any pregnancies to their healthcare provider.

Patients may experience lightheadedness, particularly during the initial days of therapy, and should inform their physician if this occurs. In cases of syncope, discontinuation of the medication is advised until a physician is consulted. It is important to educate patients about the risks of inadequate fluid intake, excessive sweating, diarrhea, or vomiting, which can lead to significant drops in blood pressure. Additionally, patients should avoid potassium supplements, potassium-containing salt substitutes, or other medications that may elevate serum potassium levels without prior consultation with their physician. Those taking hydrochlorothiazide should be advised to protect their skin from sun exposure and to undergo regular skin cancer screenings.

Post-marketing experience has revealed very rare occurrences of adverse effects, including abnormal hepatic function, hepatitis, neutropenia, leukopenia, agranulocytosis, angioedema, hyperkalemia, hyponatremia, cough, pruritus, rash, urticaria, and rare cases of rhabdomyolysis in patients receiving angiotensin II receptor blockers.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Candesartan Cilexetil and Hydrochlorothiazide as submitted by Macleods Pharmaceuticals Limited. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)