Candesartan cilexetil/Hydrochlorothiazide

Uses and Indications

Candesartan cilexetil and hydrochlorothiazide tablets are indicated for the treatment of hypertension, aimed at lowering blood pressure. Lowering blood pressure is associated with a reduction in 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. Many patients may require more than one antihypertensive medication to achieve their blood pressure goals.

Numerous antihypertensive drugs have demonstrated efficacy in randomized controlled trials, showing a reduction in cardiovascular morbidity and mortality. The most significant and consistent cardiovascular outcome benefit observed is a reduction in the risk of stroke, with additional reductions in myocardial infarction and cardiovascular mortality also noted. Elevated systolic or diastolic blood pressure increases 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 from blood pressure lowering is similar across various populations with differing absolute risks, with greater absolute benefits seen in patients at higher risk independent of their hypertension, such as those with diabetes or hyperlipidemia. It is important to note that this fixed-dose combination is not indicated for initial therapy.

Some antihypertensive drugs may exhibit smaller blood pressure effects when used as monotherapy in black patients, and many have additional approved indications and effects, including those related to angina, heart failure, or diabetic kidney disease.

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, as doses larger than 32 mg do not appear to provide a greater blood pressure lowering effect.

Hydrochlorothiazide is effective in doses of 12.5 to 50 mg once daily. Candesartan cilexetil and hydrochlorothiazide tablets may be administered with or without food and can be used in conjunction with other antihypertensive agents. The maximal antihypertensive effect of any dose can be expected within 4 weeks of initiating that dose.

Contraindications

Candesartan cilexetil and hydrochlorothiazide tablets are contraindicated in patients who are hypersensitive to candesartan, hydrochlorothiazide, or other sulfonamide-derived drugs. The co-administration of aliskiren with candesartan cilexetil and hydrochlorothiazide is not recommended in patients with diabetes. Additionally, these tablets are contraindicated in patients with anuria.

Warnings and Precautions

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, candesartan cilexetil and hydrochlorothiazide tablets should be discontinued as soon as possible. In cases where there is no appropriate alternative therapy, the mother should be informed of the potential risks to the fetus, and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, the medication should be discontinued unless it is considered lifesaving for the mother. It is important to note that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure should be closely monitored for hypotension, oliguria, and hyperkalemia.

Candesartan cilexetil and hydrochlorothiazide can cause symptomatic hypotension, particularly in patients who have been volume and/or salt depleted due to prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Patients experiencing symptomatic hypotension may require a temporary reduction in dosage or volume repletion. Volume and/or salt depletion should be corrected before initiating therapy.

In patients with heart failure, the combination may lead to excessive hypotension, which can result in oliguria, azotemia, and, in rare cases, acute renal failure and death. Therapy should be initiated under close medical supervision, with careful monitoring during the first two weeks of treatment and whenever the dose is increased.

Renal function should be monitored periodically in patients treated with candesartan cilexetil and hydrochlorothiazide, as changes in renal function, including acute renal failure, can occur. Patients whose renal function may depend on the renin-angiotensin system are at particular risk for developing oliguria, progressive azotemia, or acute renal failure. Therapy should be withheld or discontinued in patients who experience a clinically significant decrease in renal function.

Drugs that inhibit the renin-angiotensin system can cause hyperkalemia, while hydrochlorothiazide can lead to hypokalemia and hyponatremia. Serum electrolytes should be monitored periodically, as hypomagnesemia can complicate hypokalemia treatment.

Hydrochlorothiazide, a sulfonamide, may cause an idiosyncratic reaction resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include a sudden decrease in visual acuity or ocular pain, typically occurring within hours to weeks of initiation. The primary treatment is to discontinue hydrochlorothiazide as quickly as possible, and prompt medical or surgical intervention may be necessary if intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Hypersensitivity reactions to hydrochlorothiazide can occur in patients with or without a history of allergy or bronchial asthma, but are more likely in those with such a history.

General precautions include monitoring renal function and serum electrolytes periodically. Hydrochlorothiazide may also alter glucose tolerance and increase serum cholesterol and triglyceride levels. It can raise serum uric acid levels, potentially exacerbating hyperuricemia and precipitating gout in susceptible patients. Thiazides decrease urinary calcium excretion and may elevate serum calcium levels; therefore, the use of candesartan cilexetil and hydrochlorothiazide should be avoided in patients with hypercalcemia. Additionally, thiazide diuretics have been reported to exacerbate or activate systemic lupus erythematosus.

Emergency medical help should be sought when pregnancy is detected, necessitating the discontinuation of candesartan cilexetil and hydrochlorothiazide tablets. If oligohydramnios is observed, the medication should be discontinued unless it is deemed lifesaving for the mother.

Side Effects

Common adverse reactions observed in clinical trials include:

• Respiratory System Disorder:

  • Upper respiratory tract infection (3.6% vs 3.0%)

• Body as a Whole:

  • Back pain (3.3% vs 2.4%)

  • Influenza-like symptoms (2.5% vs 1.9%)

• Central/Peripheral Nervous System:

  • Dizziness (2.9% vs 1.2%)

Post-marketing experience has identified additional adverse reactions, which include:

• Digestive:

  • Abnormal hepatic function and hepatitis.

• Hematologic:

  • Neutropenia, leukopenia, and agranulocytosis.

• Immunologic:

  • Angioedema.

• Metabolic and Nutritional Disorders:

  • Hyperkalemia, hyponatremia.

• Respiratory System Disorders:

  • Cough.

• Skin and Appendages Disorders:

  • Pruritus, rash, and urticaria.

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

Adverse reactions specifically associated with hydrochlorothiazide include:

• Gastrointestinal:

  • Pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, constipation, gastric irritation, anorexia.

• Hematologic:

  • Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia.

• Hypersensitivity:

  • Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, urticaria, purpura.

• Musculoskeletal:

  • Muscle spasm.

• Non-melanoma Skin Cancer:

  • Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, predominantly for squamous cell carcinoma (SCC).

• Skin:

  • Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia.

• Special Senses:

  • Transient blurred vision, xanthopsia.

• Urogenital:

  • Impotence.

Warnings associated with the use of candesartan cilexetil and hydrochlorothiazide include:

• Fetal Toxicity:

  • Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy can cause injury and death to the developing fetus. When pregnancy is detected, discontinuation of therapy is recommended as soon as possible.

• Hypotension:

  • Candesartan cilexetil and hydrochlorothiazide can cause symptomatic hypotension, especially in patients who have been volume and/or salt depleted.

• Impaired Renal Function:

  • Changes in renal function, including acute renal failure, can occur.

• Potassium Abnormalities:

  • Hyperkalemia can occur; hydrochlorothiazide can cause hypokalemia and hyponatremia.

• Acute Myopia and Secondary Angle-Closure Glaucoma:

  • Hydrochlorothiazide can cause an idiosyncratic reaction resulting in acute transient myopia and acute angle-closure glaucoma.

• Hypersensitivity Reaction:

  • Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma.

Drug Interactions

Co-administration of candesartan cilexetil and hydrochlorothiazide with non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, may lead to deterioration of renal function, particularly in elderly patients, those who are volume-depleted, or individuals with compromised renal function. These effects can include acute renal failure, although they are typically reversible. Therefore, renal function should be monitored periodically in patients receiving this combination therapy. Additionally, the antihypertensive effect of candesartan may be diminished by NSAIDs.

Increased serum lithium concentrations and potential lithium toxicity have been observed when lithium is used concurrently with candesartan or hydrochlorothiazide. Monitoring of serum lithium levels is recommended during such concomitant use.

The dual blockade of the renin-angiotensin system (RAS) with candesartan and other agents, such as angiotensin-converting enzyme (ACE) inhibitors or aliskiren, is associated with heightened risks of hypotension, hyperkalemia, and alterations in renal function, including acute renal failure. Close monitoring of blood pressure, renal function, and electrolytes is advised for patients on this combination.

Coadministration of candesartan cilexetil and hydrochlorothiazide with potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes may result in hyperkalemia; serum potassium levels should be monitored in these patients. Furthermore, the use of aliskiren with this combination is contraindicated in patients with diabetes or renal impairment (GFR <60 mL/min).

Hydrochlorothiazide may potentiate orthostatic hypotension when used with alcohol, barbiturates, or narcotics. Adjustments in the dosage of antidiabetic medications may be necessary when these drugs are used together. The hyperglycemic effect of diazoxide may be enhanced by thiazides.

Ion exchange resins, such as cholestyramine or colestipol, can significantly reduce the absorption of hydrochlorothiazide; therefore, it is recommended to administer hydrochlorothiazide at least 4 hours before or 4-6 hours after these resins.

Thiazide-induced hypokalemia or hypomagnesemia may increase the risk of digoxin toxicity. Additionally, thiazides may reduce arterial responsiveness to noradrenaline, although this does not negate the effectiveness of noradrenaline for therapeutic use. Hypokalemia may also develop when thiazides are used concurrently with steroids or adrenocorticotropic hormone (ACTH).

Finally, thiazides may decrease the renal excretion of cytotoxic products, such as cyclophosphamide and methotrexate, potentially enhancing their myelosuppressive effects. Concomitant treatment with cyclosporine may increase the risk of hyperuricemia and gout-type complications.

Pediatric Use

Neonates with a history of in utero exposure to candesartan cilexetil and hydrochlorothiazide may experience complications such as oliguria or hypotension. In such cases, it is crucial to provide support for blood pressure and renal perfusion, which may include interventions like exchange transfusions or dialysis to address hypotension and/or substitute for impaired renal function.

Safety and effectiveness of candesartan cilexetil and hydrochlorothiazide in pediatric patients have not been established.

Geriatric Use

The pharmacokinetics of candesartan have been evaluated in elderly patients (≥ 65 years). Studies indicate that plasma concentrations of candesartan are significantly higher in this population, with Cmax approximately 50% greater and AUC approximately 80% greater compared to younger subjects receiving the same dosage. Despite these increased levels, the pharmacokinetics remain linear in elderly patients, and neither candesartan nor its inactive metabolite accumulates in the serum with repeated once-daily administration. Therefore, no initial dosage adjustment is necessary for elderly patients. Healthcare professionals should continue to monitor these patients for any potential adverse effects, given the altered pharmacokinetics.

Pregnancy

Candesartan cilexetil and hydrochlorothiazide have not been specifically studied for safety during pregnancy, and no information regarding dosage modifications or special precautions for pregnant patients is provided.

Fertility studies have not been conducted with the combination of these two agents. However, studies in male and female rats have shown that reproductive performance was not adversely affected when given oral doses of up to 300 mg of candesartan cilexetil per kg per day, which is approximately 83 times the maximum daily human dose based on body surface area. Additionally, hydrochlorothiazide did not demonstrate any adverse effects on fertility in mice and rats of either sex when 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 data on the use of candesartan cilexetil and hydrochlorothiazide during pregnancy, healthcare professionals should exercise caution and consider the potential risks versus benefits when prescribing these medications to pregnant patients.

Lactation

It is not known whether candesartan is excreted in human milk; however, studies have shown that candesartan is present in rat milk. Thiazides, which are components of this medication, are known to appear in human milk. Due to the potential for adverse effects on breastfed infants, healthcare providers should carefully consider whether to discontinue breastfeeding or to discontinue the medication, weighing the importance of the drug to the lactating mother against the potential risks to the nursing infant.

Renal Impairment

Patients with renal impairment should be closely monitored when treated with candesartan cilexetil and hydrochlorothiazide tablets or ATACAND HCT. Periodic assessment of renal function is essential, as these medications can lead to changes in renal function, including acute renal failure, particularly in patients whose renal function may rely 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 patients experience a clinically significant decrease in renal function, it is advisable to consider withholding or discontinuing therapy. Additionally, patients with heart failure may be particularly susceptible to excessive hypotension, which can result in oliguria, azotemia, and, in rare instances, acute renal failure and death.

To mitigate these risks, therapy should be initiated under close medical supervision, especially in patients with heart failure. It is recommended that these patients be monitored closely for the first two weeks of treatment and whenever there is an increase in the dose of candesartan or the diuretic component. Furthermore, any volume and/or salt depletion should be corrected prior to starting treatment with these medications, and patients experiencing symptomatic hypotension may require a temporary reduction in dosage or volume repletion.

Hepatic Impairment

Patients with hepatic impairment have no specific dosage adjustments, special monitoring requirements, or precautions outlined in the drug inserts for Candesartan Cilexetil and Hydrochlorothiazide or Atacand Hct. Therefore, healthcare providers should exercise caution and consider individual patient factors when prescribing these medications to patients with liver problems, as the lack of specific guidance may necessitate closer monitoring of therapeutic effects and potential side effects.

Overdosage

In cases of overdosage with candesartan cilexetil and hydrochlorothiazide, no lethality was observed in acute toxicity studies involving mice, rats, and dogs administered single oral doses of up to 2000 mg/kg of candesartan cilexetil. However, limited data are available regarding human overdosage. The most likely manifestations of overdosage with candesartan cilexetil include hypotension, dizziness, and tachycardia, with the potential for bradycardia resulting from parasympathetic (vagal) stimulation.

If symptomatic hypotension occurs, supportive treatment should be initiated promptly. For hydrochlorothiazide, the predominant signs and symptoms associated with overdosage are typically due to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. It is important to note that if digitalis has been administered concurrently, hypokalemia may exacerbate cardiac arrhythmias.

Candesartan is not removable by hemodialysis, and the extent to which hydrochlorothiazide is removed by hemodialysis has not been established. For the most current information regarding the management of overdose, it is recommended to consult the Regional Poison Control Center. In managing overdose situations, healthcare providers should also consider the potential for multiple-drug overdoses, drug-drug interactions, and altered pharmacokinetics in the patient.

Nonclinical Toxicology

Teratogenic Effects

No fertility studies have been conducted with the combination of candesartan cilexetil and hydrochlorothiazide. However, 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, which is 83 times the maximum daily human dose of 32 mg on a body surface area basis. Hydrochlorothiazide also demonstrated no adverse 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.

Carcinogenesis

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 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) 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). However, the NTP did find equivocal evidence for hepatocarcinogenicity in male mice.

Mutagenesis

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 tested 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 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. 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.

Impairment of Fertility

As previously noted, no fertility studies have been conducted with the combination of candesartan cilexetil and hydrochlorothiazide. However, 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. Hydrochlorothiazide also showed no adverse effects on fertility in mice and rats exposed to relevant doses prior to conception and throughout gestation.

Storage and Handling

Candesartan Cilexetil and Hydrochlorothiazide is supplied in tablet form.

Tablets 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) as defined by USP Controlled Room Temperature. It is essential to keep the container tightly closed to maintain the integrity of the product.

When dispensing, the tablets should be placed in a tight, light-resistant container that complies with USP standards and includes a child-resistant closure.