Candesartan + Hydrochlorothiazide

(kan de sar' tan + hye droe klor oh thye' a zide) 

Molecule Info

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Important Safety Information

FETAL TOXICITY 
When pregnancy is detected, discontinue Candesartan and Candesartan HCT as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

  • Candesartan is contraindicated in patients who are hypersensitive to any component of this product
  • Candesartan HCT is contraindicated in patients who are hypersensitive to any component of this product. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs
  • Do not co-administer aliskiren with Candesartan or Candesartan HCT in patients with diabetes
  • Advise patients as to the risks of using Candesartan or Candesartan HCT during pregnancy. When pregnancy is detected, Candesartan and Candesartan HCT should be discontinued as soon as possible. Neonates with a history of in utero exposure to Candesartan or Candesartan HCT should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion
  • Children <1 year of age must not receive Candesartan for hypertension
  • Patients with symptomatic hypotension may require temporarily reducing the dose of Candesartan and Candesartan HCT and volume repletion. Volume and/or salt depletion should be corrected before initiating therapy with Candesartan or Candesartan HCT
  • Hypotension may occur during major surgery and anesthesia in patients treated with angiotensin II receptor antagonists including Candesartan and Candesartan HCT
  • Candesartan and Candesartan HCT should be used with caution in patients with severe renal impairment. Monitor renal function periodically in patients treated with Candesartan and Candesartan HCT. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Candesartan and Candesartan HCT. Candesartan and Candesartan HCT should be used with caution in patients with moderate hepatic impairment.
  • Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically
  • In heart failure patients receiving Candesartan, hypotension, increases in serum creatinine, and hyperkalemia have occurred. Caution should be observed when initiating therapy. Evaluation of patients with heart failure should always include assessment of renal function and volume status. Monitoring of blood pressure, serum creatinine, and serum potassium is recommended during drug dose escalation and periodically thereafter
  • During concomitant use of Candesartan or Candesartan HCT with NSAIDs in patients who are elderly, volume depleted, or with compromised renal function, periodic monitoring of renal function is recommended
  • Thiazide diuretics have been reported to cause acute myopia and secondary angle-closure glaucoma
  • Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma
  • The most common adverse reactions reported with Candesartan (incidence ≥2% and greater than placebo) were back pain, dizziness, upper respiratory tract infection, pharyngitis, and rhinitis
  • The most common adverse reactions reported with Candesartan HCT (incidence ≥2% and greater than placebo) were upper respiratory tract infection, back pain, flu-like symptoms, and dizziness

Content(s)

Candesartan cilexetil, hydrochlorothiazide.

Indication(s)

For the treatment of essential hypertension in adults when monotherapy is not sufficiently effective. This fixed-dose combination is not indicated for initial therapy.

Dosage

Recommended Dose: 1 tab once daily with or without food.  Most of the antihypertensive effect is usually attained within 4 weeks of initiation of treatment. Impaired Renal Function: Dose titration of candesartan cilexetil is recommended before treatment with Candesartan Plus in patients with renal impairment whose creatinine clearance is ≥30 mL/min/1. 73 m2 BSA. Candesartan Plus should not be used in patients with severe renal impairment. Loop diuretics are preferred to thiazides in this population. Impaired Hepatic Function: Dose titration of candesartan cilexetil is recommended before treatment with Candesartan Plus in patients with mild to moderate hepatic impairment. Candesartan Plus should not be used in patients with severe hepatic impairmentand/or cholestasis. Elderly: No special dosage recommendations.

Administration

May be taken with or without food.

Overdose

Symptoms: Based on pharmacological considerations, the main manifestation of an overdose of candesartan cilexetil is likely to be symptomatic hypotension and dizziness.  In 2 case reports of overdose, patient recovery was uneventful. The main manifestation of an overdose of hydrochlorothiazide is acute loss of fluid and electrolytes.  Symptoms eg, dizziness, hypotension, thirst, tachycardia, ventricular arrhythmias, sedation/impairment of consciousness and muscle cramps can also be observed. Treatment: No specific information is available on the treatment of Overdosage with Candesartan Plus.  The following measures are, however, suggested in case of Overdosage. When indicated, induction of vomiting or gastric lavage should be considered.  If symptomatic hypotension should occur, symptomatic treatment should be instituted and vital signs monitored.  The patient should be placed supine with the legs elevated.  If this is not sufficient, plasma volume should be increased by infusion of isotonic saline solution.  Serum electrolyte and acid balance should be checked and corrected, if needed.  Sympathomimetic drugs may be administered if the previously mentioned measures are not sufficient. Candesartan cannot be removed by haemodialysis.  It is not known to what extent hydrochlorothiazide is removed by haemodialysis.

Contraindications

Hypersensitivity to any component of Candesartan Plus or to sulfonamide-derived drugs. Severe renal impairment. Severe hepatic impairment and/or cholestasis.  Gout. Use in pregnancy & lactation: Candesartan is contraindicated during pregnancy and lactation. There is no experience with the use of Candesartan Plus in pregnant women, but animal studies with candesartan cilexetil have demonstrated late foetal and neonatal injury in the kidney.  The mechanism is believed to be pharmacologically mediated through effects on the renin-angiotensin-aldosterone system. In humans, foetal renal perfusion, which is dependent upon the development of the renin-angiotensin-aldosterone system, begins in the 2nd trimester.  Thus, risk to the foetus increases if Candesartan Plus is administered during the 2nd or 3rd trimesters of pregnancy. Hydrochlorothiazide can reduce the plasma volume as well as the uteroplacental blood flow.  It may also cause neonatal thrombocytopenia. Based on the previously mentioned information, Candesartan Plus should not be used in pregnancy.  If pregnancy is detected during treatment, Candesartan Plus should be discontinued. It is not known whether candesartan is excreted in human milk.  However, candesartan is excreted in the milk of lactating rats.  Hydrochlorothiazide passes into mother's milk.  Because of the potential for adverse effects on the nursing infant, breastfeeding should be discontinued if the use of Candesartan Plus is considered essential.

Special Precautions

General: In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system, treatment with other drugs that affect this system has been associated with acute hypotension, azotaemia, oliguria or rarely, acute renal failure.  The possibility of similar effects cannot be excluded with angiotensin II receptor antagonists.  As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or atherosclerotic cerebrovascular disease could result in a myocardial infarction or stroke. Renal Artery Stenosis: Other drugs that affect the renin-angiotensin-aldosterone system ie, angiotensin-converting enzyme inhibitors, may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.  While this is not reported with Candesartan Plus, a similar effect may be anticipated with angiotensin II receptor antagonists. Intravascular Volume Depletion: In patients with intravascular volume and/or sodium depletion, symptomatic hypotension may occur, as described for other agents acting on the renin-angiotensin-aldosterone system.  Therefore, the use of Candesartan Plus is not recommended until this condition has been corrected. Renal Impairment/Kidney Transplantation: When Candesartan Plus is used in patients with impaired renal function, a periodic monitoring of potassium, creatinine and uric acid levels is recommended.  Loop diuretics are preferred to thiazides in this population. There is no experience regarding the administration of Candesartan Plus in patients with a recent kidney transplantation. Aortic and Mitral Valve Stenosis or Obstructive Hypertrophic Cardiomyopathy: As with other vasodilators, special caution is indicated in patients suffering from haemodynamically relevant aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy. Electrolyte Imbalance: As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.  Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance. Hydrochlorothiazide dose-dependently increases urinary potassium excretion which may result in hypokalaemia.  This effect of hydrochlorothiazide seems to be less evident when combined with candesartan cilexetil. Based on experience with the use of other drugs that affect the renin-angiotensin-aldosterone system, concomitant use of Candesartan Plus and potassium-sparing diuretics, potassium supplements or salt substitutes, or other drugs that may increase serum potassium levels may lead to increases in serum potassium. Metabolic and Endocrine Effects: Treatment with a thiazide diuretic may impair glucose tolerance.  Dosage adjustment of antidiabetic drugs, including insulin, may be required.  Latent diabetes mellitus may become manifest during thiazide therapy.  Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy.  However, at the 12. 5-mg dose contained in Candesartan Plus, minimal or no effects were reported.  Thiazide diuretics increase serum uric acid concentration and may precipitate gout in susceptible patients. Effects on the Ability to Drive or Operate Machinery: The effect of Candesartan Plus on the ability to drive or operate machines has not been studied, but based on its pharmacodynamic properties, Candesartan Plus is unlikely to affect this ability.  When driving vehicles or operating machines, it should be taken into account that occasionally, dizziness or weariness may occur during treatment of hypertension. Use in children: The safety and efficacy of Candesartan Plus have not been established in children.

Adverse Drug Reaction(s)

Adverse events were mild and transient and comparable to placebo in controlled clinical studies with various doses of candesartan cilexetil /hydrochlorothiazide.  The overall incidence of adverse events showed no association with age or gender.  Withdrawals from treatment due to adverse events were similar with candesartan cilexetil/hydrochlorothiazide and placebo. Candesartan Cilexetil: The following adverse reactions have been reported very rarely with candesartan cilexetil in post-marketing experience. Blood and Lymphatic System Disorders: Leukopenia, neutropenia and agranulocytosis. Metabolism and Nutrition Disorders: Hyperkalemia, hyponatraemia. Hepatobiliary Disorders: Increased liver enzymes, abnormal hepatic function or hepatitis. Skin and Subcutaneous Tissue Disorders: Angioedema, rash, urticaria, pruritus. Renal and Urinary Disorders: Renal impairment, including renal failure in susceptible patients. Hydrochlorothiazide: The following adverse reactions have been reported with hydrochlorothiazide monotherapy, usually with doses of ≥25 mg.  The frequencies used are: Uncommon and rare. Blood and Lymphatic System Disorders: Rare: Leukopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia. Immune System Disorders: Rare: Anaphylactic reactions. Vascular Disorders: Rare: Necrotising angiitis. Respiratory, Thoracic and Mediastinal Disorders: Rare: Respiratory distress. Gastrointestinal Disorders: Rare: Pancreatitis. Hepatobiliary Disorders: Rare: Jaundice. Skin and Subcutaneous Tissue Disorders: Uncommon: Photosensitivity reactions.  Rare: Toxic epidermal necrolysis. Renal and Urinary Disorders: Rare: Renal dysfunction and interstitial nephritis. Laboratory Findings: In general, there were no clinically important influences of candesartan cilexetil/hydrochlorothiazide on routine laboratory variables.  Increases in serum uric acid, blood glucose and serum ALAT were reported as adverse events slightly more often with candesartan cilexetil/hydrochlorothiazide than with placebo.  Minor decreases in haemoglobin and increases in serum ASAT have been observed in single patients receiving candesartan cilexetil/hydrochlorothiazide.  Increases in creatinine, urea or potassium and decrease in sodium have been observed. Click to view ADR Monitoring Website

Drug Interactions

No drug interactions of clinical significance have been identified for candesartan cilexetil. Compounds which have been investigated in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, Oral   contraceptives, glibenclamide and nifedipine. The bioavailability of candesartan is not affected by food. The antihypertensive effect of Candesartan Plus may be enhanced by other antihypertensives.  The potassium-depleting effect of hydrochlorothiazide could be expected to be potentiated by other drugs associated with potassium loss and hypokalaemia. Diuretic-induced hypokalaemia and hypomagnesaemia predisposes to the potential cardiotoxic effects of digitalis glycosides and antiarrhythmics.  Periodic monitoring of serum potassium is recommended when Candesartan Plus is administered with such drugs. Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors or hydrochlorothiazide.  While not reported with Candesartan Plus, the possibility of a similar effect cannot be excluded and careful monitoring of serum lithium levels is recommended during concomitant use. The diuretic, natriuretic and antihypertensive effects of hydrochlorothiazide are blunted by NSAIDs. The absorption of hydrochlorothiazide is reduced by colestipol orcholestyramine. There is no clinically significant interaction between hydrochlorothiazide and food.

Pregnancy Category (FDA) 

Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk.

Storage

Store below 30°C.

Description

Each tablet may contain candesartan cilexetil 16 mg and hydrochlorothiazide 12. 5 mg.  It also contains the following excipients: Calcium carboxymethylcellulose, hydroxypropyl cellulose, iron oxide E172, lactose, magnesium stearate, maize starch and polyethylene glycol.

Pharmacology

Angiotensin II antagonist and diuretic.

Pharmacodynamic Properties: Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension and other cardiovascular disorders.  It also has an important role in the pathogenesis of organ hypertrophy and end organ damage.  The major physiological effects of angiotensin II eg, vasoconstriction, aldosterone stimulation, regulation of salt and water homeostasis, and stimulation of cell growth are mediated via the type 1 receptor. Candesartan cilexetil is a prodrug which is rapidly converted to the active drug, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract.  Candesartan is an angiotensin II receptor antagonist, selective for AT1receptors, with tight binding to and slow dissociation from the receptor.  It has no agonist activity. Candesartan does not influence ACE or other enzyme systems usually associated with the use of ACE inhibitors.  Since there is no effect on the degradation of kinins, or on the metabolism of other substances eg, substance P, angiotensin II receptor antagonists are unlikely to be associated with cough.  In controlled clinical trials comparing candesartan cilexetil with ACE inhibitors, the incidence of cough was lower in patients receiving candesartan cilexetil.  Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.  The antagonism of the AT1 receptors result in dose-related increases in plasma renin levels, angiotensin I and angiotensin II levels and a decrease in plasma aldosterone concentration. In the Study on Cognition and Prognosis in the Elderly trial, the effects of cardesartan cilexetil-based antihypertensive treatment on cardiovascular morbidity and mortality, cognitive function and quality of life were assessed in 4937 elderly patients with hypertension.  Table shows the study results for the primary endpoint and its components.  Both treatment regimens lowered systolic and diastolic blood pressure effectively and were generally well tolerated.  Cognitive function and quality of life were well maintained in both treatment arms.  Hydrochlorothiazide inhibits the active reabsorption of sodium, mainly in the distal kidney tubules, and promotes the excretion of sodium, chloride and water.  The renal excretion of potassium and magnesium increases dose dependently, while calcium is reabsorbed to a greater extent.  Hydrochlorothiazide decreases plasma volume and extracellular fluid and reduces cardiac output and blood pressure.  During long-term therapy, reduced peripheral resistance contributes to the blood pressure reduction. Large clinical studies have shown that long-term treatment with hydrochlorothiazide reduces the risk for cardiovascular morbidity and mortality. Candesartan and hydrochlorothiazide have additive antihypertensive effects. In hypertensive patients, Candesartan Plus causes an effective and long-lasting reduction in arterial blood pressure without reflex increase in heart rate.  There is no indication of serious or exaggerated first dose hypotension or rebound effect after cessation of treatment.  After administration of a single dose of Candesartan Plus, onset of the antihypertensive effect generally occurs within 2 hrs.  With continuous treatment, most of the reduction in blood pressure is attained within 4 weeks and is sustained during long-term treatment.  Candesartan Plus once daily provides effective and smooth blood pressure reduction >24 hrs, with little difference between maximum and trough effects during the dosing interval.  In double-blind, randomised study, Candesartan Plus once daily reduced blood pressure significantly more and controlled significantly more patients than an approved similar fixed combination product containing losartan 50 mg and hydrochlorothiazide 12. 5 mg.  In double-blind, randomised studies, the incidence of adverse events, especially cough, was lower during treatment with candesartan cilexetil/hydrochlorothiazide than during treatment with combinations of ACE inhibitors and hydrochlorothiazide. Candesartan Plus is similarly effective in patients irrespective of age and gender.

Pharmacokinetics: 

Absorption and Distribution: Candesartan Cilexetil: Following Oral   administration, candesartan cilexetil is converted to the active drug candesartan.  The absolute bioavailability of candesartan is approximately 40% after an Oral   solution of candesartan cilexetil.  The relative bioavailability of a tablet formulation of candesartan cilexetil compared with the same Oral   solution is approximately 34% with very little variability.  The mean peak serum concentration is reached 3-4 hrs following tablet intake.  The candesartan serum concentrations increase linearly with increasing doses in the therapeutic dose range.  No gender-related differences in the pharmacokinetics of candesartan have been observed.  The area under the serum concentration versus time curve of candesartan is not significantly affected by food. Candesartan is highly bound to plasma protein.  The apparent volume of distribution of candesartan is 0. 1 L/kg. Hydrochlorothiazide: Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with an absolute bioavailability of approximately 70%.  Concomitant intake of food increases the absorption by approximately 15%.  The bioavailability may decrease in patients with cardiac failure and pronounced oedema. The plasma protein-binding of hydrochlorothiazide is approximately 60%.  The apparent volume of distribution is approximately 0. 8 L/kg. Metabolism and Elimination: Candesartan Cilexetil: Candesartan is mainly eliminated unchanged via the urine and bile, and only to a minor extent eliminated by hepatic metabolism.  The terminal half-life of candesartan is approximately 9 hrs.  There is no accumulation following multiple doses.  The half-life of candesartan remains unchanged after administration of candesartan cilexetil in combination with hydrochlorothiazide.  There is a slight clinically nonsignificant increase in AUC and Cmax of candesartan when given together with hydrochlorothiazide.  No accumulation of candesartan occurs after repeated doses of the combination compared to monotherapy. Total plasma clearance of candesartan is about 0. 37 mL/min/kg, with a renal clearance of about 0. 19 mL/min/kg.  The renal elimination of candesartan is both by glomerular filtration and active tubular secretion.  Following an Oral   dose of 14C-labeled candesartan cilexetil, approximately 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite while approximately 56% of the dose is recovered in the faeces as candesartan and 10% as the inactive metabolite. Hydrochlorothiazide: Hydrochlorothiazide is not metabolized and is excreted almost entirely as unchanged drug by glomerular filtration and active tubular secretion.  The terminal t1/2 of hydrochlorothiazide is approximately 8 hrs.  Approximately 70% of an Oral   dose is eliminated in the urine within 48 hrs.  The half-life of hydrochlorothiazide remains unchanged after administration of hydrochlorothiazide in combination with candesartan cilexetil.  No accumulation of hydrochlorothiazide occurs after repeated doses of the combination compared to monotherapy. Special Populations: Candesartan Cilexetil: In elderly subjects, Cmax and AUC of candesartan are increased by approximately 50% and 80%, respectively in comparison to young subjects.  However, the blood pressure response and the incidence of adverse events are similar after a given dose of Candesartan Plus in young and elderly patients. In patients with mild to moderate renal impairment, Cmax and AUC of candesartan increased during repeated dosing by approximately 50% and 70%, respectively, but the terminal t1/2 was not altered compared to patients with normal renal function.  The corresponding changes in patients with severe renal impairment were approximately 50% and 110%, respectively.  The terminal t1/2 of candesartan was approximately doubled in patients with severe renal impairment.  The pharmacokinetics in patients undergoing haemodialysis were similar to those patients with severe renal impairment. In patients with mild to moderate hepatic impairment, there was an increase in the AUC of candesartan of approximately 20%.  In patients with moderate to severe hepatic impairment, the increase in the AUC of cardesartan was approximately 80%. Hydrochlorothiazide: The terminal t1/2 of hydrochlorothiazide is prolonged in patients with renal impairment.

ATC Classification

C09DA06 - candesartan and diuretics; Belongs to the class of angiotensin II antagonists in combination with diuretics.  Used in the treatment of cardiovascular disease.

 

Brand/Product Info


Total Products : 1 
Brand Name Manufacturer/Marketer Composition Dosage Form Pack Size & Price
GIRAN-H Aristopharma Ltd. Candesartan cilexetil INN 8mg+ Hydrochlorothiazide BP 12.5mg Tablet 30's: 180.00 MRP

Gen. MedInfo

Combination product

This product contains two medications, CANDESARTAN  and HYDROCHLOROTHIAZIDE. Please see the individual monographs for information about each of the medications contained in this product.

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