Candesartan cilexetil/Hydrochlorothiazide

Description

Candesartan cilexetil and hydrochlorothiazide tablets, USP, are a combination of an angiotensin II receptor (type AT1) antagonist and a diuretic, hydrochlorothiazide. Candesartan cilexetil is a nonpeptide compound with the chemical designation (±)2-Ethoxy-1-[[2’-(1H-tetrazol-5-yl)1,1’-biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid-1-[(cyclohexyloxy)carbonyloxy]ethyl ester, exhibiting a molecular formula of C33H34N6O6 and a molecular weight of 610.66. This compound appears as a white to off-white powder, is practically insoluble in water, and sparingly soluble in methanol. Candesartan cilexetil is a racemic mixture with one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group. Upon oral administration, it undergoes hydrolysis at the ester link to yield the active drug, candesartan, which is achiral.

Hydrochlorothiazide is chemically identified as 2H-1,2,4-Benzothiadiazine-7-sulfonamide, 6-chloro-3,4-dihydro-,1,1-dioxide, with a molecular formula of C7H8ClN3O4S2 and a molecular weight of 297.7. It is presented as a white or practically white, practically odorless crystalline powder that is 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 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 include carboxymethylcellulose calcium, corn starch, glyceryl stearate, hydroxypropyl cellulose, lactose monohydrate, magnesium stearate, and yellow iron oxide. The 16 mg/12.5 mg and 32 mg/25 mg tablets also contain red iron oxide as a colorant.

Uses and Indications

Candesartan cilexetil 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, 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 a combination of antihypertensive medications to achieve their blood pressure goals.

Numerous antihypertensive agents have demonstrated efficacy in randomized controlled trials, showing a reduction in cardiovascular morbidity and mortality, with blood pressure reduction being a significant contributor to these benefits. The most substantial cardiovascular outcome benefit observed is a decrease in the risk of stroke, alongside reductions in myocardial infarction and cardiovascular mortality.

Elevated systolic or diastolic blood pressure is associated with increased cardiovascular risk, and even modest reductions in severe hypertension can yield considerable benefits. The relative risk reduction from blood pressure lowering is consistent across various populations with differing absolute risks, with patients at higher risk—such as those with diabetes or hyperlipidemia—experiencing greater absolute benefits, regardless of their hypertension status.

It is also noted that some antihypertensive medications may exhibit smaller blood pressure-lowering effects as monotherapy in black patients, and many of these agents 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 administered once daily for patients who are not volume depleted and are receiving the medication as monotherapy. Candesartan cilexetil tablets may be taken once or twice daily, with 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 lowering.

Hydrochlorothiazide is effective at doses between 12.5 mg and 50 mg once daily. Candesartan cilexetil and hydrochlorothiazide tablets can be taken with or without food, allowing for flexibility in administration.

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 poses 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. Adverse neonatal effects may include skull hypoplasia, anuria, hypotension, renal failure, and death. Upon detection of pregnancy, it is imperative to discontinue candesartan cilexetil and hydrochlorothiazide tablets immediately.

In cases where there is no suitable alternative to therapy with renin-angiotensin system-affecting drugs, 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, discontinuation of candesartan cilexetil and hydrochlorothiazide is recommended unless the treatment 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 these medications should be closely monitored for hypotension, oliguria, and hyperkalemia.

Candesartan cilexetil and hydrochlorothiazide tablets can induce symptomatic hypotension, particularly in patients who are 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. It is essential to correct any volume and/or salt depletion prior to initiating therapy with these tablets.

In patients with heart failure, the use of candesartan cilexetil and hydrochlorothiazide tablets may lead to excessive hypotension, potentially resulting in oliguria, azotemia, and, in rare cases, acute renal failure and death. Therapy in these patients should commence under close medical supervision, with careful monitoring during the first two weeks of treatment and following any dose adjustments of candesartan or diuretics.

Regular monitoring of renal function is advised 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. Patients whose renal function may be influenced by the renin-angiotensin system are particularly at risk for developing oliguria, progressive azotemia, or acute renal failure. Consideration should be given to withholding or discontinuing therapy in patients who exhibit a clinically significant decline in renal function.

The potential for hyperkalemia exists with drugs that inhibit the renin-angiotensin system, while hydrochlorothiazide may induce hypokalemia and hyponatremia. Hypomagnesemia can also lead to difficult-to-treat hypokalemia despite potassium repletion. Therefore, periodic monitoring of serum electrolytes is essential.

Hydrochlorothiazide, classified as a sulfonamide, may cause idiosyncratic reactions, including acute transient myopia and acute angle-closure glaucoma. Symptoms such as a sudden decrease in visual acuity or ocular pain can occur within hours to weeks of initiating treatment. If left untreated, acute angle-closure glaucoma can result in permanent vision loss. The primary course of action is to discontinue hydrochlorothiazide promptly, and if intraocular pressure remains uncontrolled, immediate medical or surgical intervention may be necessary. Patients with a history of sulfonamide or penicillin allergy may be at increased risk for developing acute angle-closure glaucoma.

Hypersensitivity reactions to hydrochlorothiazide can occur in patients with or without prior allergy or bronchial asthma history, although they are more prevalent in those with such a history.

Healthcare professionals are advised to monitor renal function and serum electrolytes periodically in patients treated with candesartan cilexetil and hydrochlorothiazide tablets to ensure safe and effective use of the medication.

Side Effects

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

Common adverse reactions observed in clinical trials include respiratory system disorders such as upper respiratory tract infections (3.6% vs 3.0%) and central/peripheral nervous system effects like dizziness (2.9% vs 1.2%). Additionally, body as a whole reactions such as back pain (3.3% vs 2.4%) and influenza-like symptoms (2.5% vs 1.9%) were reported.

Serious adverse reactions reported in post-marketing experience include hematologic disorders such as neutropenia, leukopenia, and agranulocytosis. Patients may also experience immunologic reactions, including angioedema. Metabolic and nutritional disorders such as hyperkalemia and hyponatremia have been noted, alongside respiratory system disorders like cough. Skin and appendage disorders, including pruritus, rash, and urticaria, have also been reported. Rare cases of rhabdomyolysis have been documented in patients receiving angiotensin II receptor blockers.

Hydrochlorothiazide has been associated with gastrointestinal adverse reactions, including pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, constipation, gastric irritation, and anorexia. Hematologic adverse reactions may include aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Hypersensitivity reactions can manifest as anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress (including pneumonitis and pulmonary edema), photosensitivity, urticaria, and purpura.

Musculoskeletal effects such as muscle spasms and skin reactions including erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia have been reported. Special senses may be affected, leading to transient blurred vision and xanthopsia. Urogenital effects, such as impotence, have also been noted.

It is important to note that candesartan cilexetil and hydrochlorothiazide tablets can cause symptomatic hypotension, particularly in patients who are volume and/or salt depleted. Renal function should be monitored periodically in patients treated with these medications. Additionally, drugs that inhibit the renin-angiotensin system can lead to hyperkalemia, while hydrochlorothiazide may cause hypokalemia and hyponatremia. Hydrochlorothiazide can also induce an idiosyncratic reaction resulting in acute transient myopia and acute angle-closure glaucoma. Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma.

A boxed warning regarding fetal toxicity is included, indicating that when pregnancy is detected, candesartan cilexetil and hydrochlorothiazide tablets should be discontinued as soon as possible, as these drugs can cause injury and death to the developing fetus.

Drug Interactions

Co-administration of candesartan with other medications may lead to significant interactions that require careful monitoring and management.

Pharmacokinetic Interactions

Candesartan is not significantly metabolized by the cytochrome P450 system, and at therapeutic concentrations, it does not affect P450 enzymes. Therefore, interactions with drugs that inhibit or are metabolized by these enzymes are not expected.

Pharmacodynamic Interactions

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): In elderly patients, those who are volume-depleted, or individuals with compromised renal function, the use of NSAIDs, including selective COX-2 inhibitors, alongside angiotensin II receptor antagonists like 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 NSAIDs. Additionally, the antihypertensive effect of candesartan may be diminished by NSAIDs.

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

• Renin-Angiotensin System (RAS) Blockade: The dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren may increase the risk of hypotension, hyperkalemia, and renal function changes, including acute renal failure. Close monitoring of blood pressure, renal function, and electrolytes is recommended for patients on candesartan cilexetil and hydrochlorothiazide tablets in conjunction with other RAS-affecting agents.

• Potassium Levels: Co-administration 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).

• Alcohol and CNS Depressants: The potential for orthostatic hypotension may be enhanced with the use of alcohol, barbiturates, or narcotics.

Other Interactions

• Antidiabetic Medications: Dosage adjustments of antidiabetic drugs may be necessary when used concurrently.

• Thiazides and Diazoxide: The hyperglycemic effect of diazoxide may be potentiated by thiazides.

• 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 and these resins, ensuring hydrochlorothiazide is taken at least 4 hours before or 4-6 hours after the resins.

• Muscle Relaxants: There may be an increased responsiveness to muscle relaxants, such as curare derivatives, when used concurrently.

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

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

• Steroids and ACTH: Hypokalemia may develop during concurrent use of steroids or adrenocorticotropic hormone (ACTH).

• Cytotoxic Drugs: Thiazides may reduce the renal excretion of cytotoxic medications (e.g., cyclophosphamide, methotrexate) and enhance their myelosuppressive effects.

• Cyclosporine: Concurrent treatment with cyclosporine may elevate the risk of hyperuricemia and gout-type complications.

Monitoring and appropriate dosage adjustments are essential when managing patients on these combinations to mitigate potential adverse effects.

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

Safety and effectiveness in pediatric patients have not been established. Therefore, the use of this medication in children, infants, and adolescents should be approached with caution until further data is available.

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 C_max approximately 50% greater and an AUC approximately 80% higher compared to younger subjects receiving the same dosage.

Despite these elevated 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 necessary 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 fertility in mice and rats of either sex, as evidenced by 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 of these agents 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 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 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 clinical data are available regarding human overdosage with candesartan cilexetil. The most likely symptoms associated with an overdose include hypotension, dizziness, and tachycardia. In some cases, bradycardia may occur due to parasympathetic (vagal) stimulation. Should symptomatic hypotension arise, it is imperative to initiate supportive treatment promptly.

For hydrochlorothiazide, the predominant signs and symptoms of overdosage are typically related to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. If the patient has also been administered digitalis, hypokalemia may exacerbate the risk of cardiac arrhythmias.

It is important to note that candesartan is not amenable to removal by hemodialysis, and the extent to which hydrochlorothiazide can be removed by this method has not been established.

For the most current information regarding the management of overdose, healthcare professionals are advised to consult their Regional Poison Control Center. Contact numbers for certified poison control centers can be found in the Physicians’ Desk Reference (PDR). In managing overdose cases, it is crucial to consider the potential for multiple-drug overdoses, drug-drug interactions, and altered pharmacokinetics in the patient.

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 based on body surface area, demonstrated no adverse effects on fertility and reproductive performance. Similarly, hydrochlorothiazide did not adversely affect fertility in 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 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, with no evidence of carcinogenicity observed. Additionally, two-year feeding studies conducted by 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 report equivocal evidence for hepatocarcinogenicity in male mice.

In terms of mutagenicity, candesartan cilexetil or its active metabolite, candesartan, tested positive in vitro in the Chinese hamster lung (CHL) chromosomal aberration assay and the mouse lymphoma mutagenicity assay. The combination of candesartan cilexetil and hydrochlorothiazide tested negative for mutagenicity in the 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 was positive in the Ames microbial mutagenesis assay or the in vitro mouse lymphoma cell assay. Candesartan was also evaluated in vivo in the mouse micronucleus test and in vitro in the CHO gene mutation assay, yielding negative results in both cases. Candesartan cilexetil was 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 with negative outcomes.

When hydrochlorothiazide was tested alone, it yielded 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 involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene.

Postmarketing Experience

Very rarely, the following adverse events have been reported in the postmarketing experience with candesartan cilexetil, based on voluntary reports and surveillance programs:

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 include instances of hyperkalemia and hyponatremia. Respiratory system disorders have been characterized by reports of cough. Additionally, skin and appendages disorders have included pruritus, rash, and urticaria.

Furthermore, rare cases of rhabdomyolysis have been documented in patients receiving angiotensin II receptor blockers.

Patient Counseling

Healthcare providers should advise patients to discontinue candesartan cilexetil and hydrochlorothiazide tablets as soon as pregnancy is detected. It is important to inform patients that medications acting directly on the renin-angiotensin system can potentially cause injury or death to a developing fetus.

Patients should be made aware that lightheadedness may occur, particularly during the initial days of therapy, and they should report this symptom to their prescribing physician. In the event of syncope, patients are instructed to discontinue the medication and consult their physician before resuming treatment.

Healthcare providers should emphasize 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. Female patients of childbearing age should be informed about the risks associated with exposure to candesartan cilexetil and hydrochlorothiazide tablets during pregnancy. Providers should discuss treatment options with women who are planning to become pregnant and encourage patients to report any pregnancies to their physicians as soon as possible.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with USP standards and features a child-resistant closure. It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines. To maintain the integrity of the product, the container must be kept tightly closed at all times.

Additional Clinical Information

Candesartan cilexetil and hydrochlorothiazide tablets are indicated for oral administration. Clinicians should counsel female patients of childbearing age regarding the 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 Mylan Pharmaceuticals Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)