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Indications/Uses
For the treatment of essential hypertension where monotherapy is not sufficient.
Dosage/Direction for Use
Individualized dosage. 1 tab once daily. Candesartan cilexetil monotherapy Renal impairment Mild: 4 mg once daily. Moderate: 2 mg once daily. Hepatic impairment Mild to moderate: 2 mg once daily. Elderly 4 mg once daily.
General Dosing Recommendations: Individualize dose based on patient's requirements.
For mild hypertension: If the desired effect is not achieved with monotherapy, the patient may start with the combination therapy.
For moderate to severe hypertension: the combination therapy may be used for initial therapy.
May be taken with or without food.
Usual Recommended Dose: 1 tablet once daily, or, as prescribed by a physician.
Antihypertensive effect is evident within 4 weeks after initiation of treatment.
Dosage in Special Population: Dose titration with candesartan cilexetil monotherapy is recommended before treatment with the combination therapy.
For mild hypertension: If the desired effect is not achieved with monotherapy, the patient may start with the combination therapy.
For moderate to severe hypertension: the combination therapy may be used for initial therapy.
May be taken with or without food.
Usual Recommended Dose: 1 tablet once daily, or, as prescribed by a physician.
Antihypertensive effect is evident within 4 weeks after initiation of treatment.
Dosage in Special Population: Dose titration with candesartan cilexetil monotherapy is recommended before treatment with the combination therapy.
Overdosage
There is limited data on overdosage with candesartan in humans. Candesartan overdose will most likely manifest as hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation.
Signs and symptoms of HCTZ overdose include hypokalemia, hypochloremia, hyponatremia, dehydration resulting from excessive diuresis, dizziness, hypotension, thirst, tachycardia, ventricular arrhythmias, sedation, and muscle cramps.
Institute symptomatic treatment and monitor vital signs if symptomatic hypotension occurs. In the event of hypotension, place the patient in supine position. For severe hypotension, administer 0.9% sodium chloride injection as IV infusion to expand fluid volume.
Monitor and correct serum electrolyte and acid imbalance.
Candesartan is not removed by hemodialysis. The degree to which HCTZ is removed by hemodialysis has not been established.
Signs and symptoms of HCTZ overdose include hypokalemia, hypochloremia, hyponatremia, dehydration resulting from excessive diuresis, dizziness, hypotension, thirst, tachycardia, ventricular arrhythmias, sedation, and muscle cramps.
Institute symptomatic treatment and monitor vital signs if symptomatic hypotension occurs. In the event of hypotension, place the patient in supine position. For severe hypotension, administer 0.9% sodium chloride injection as IV infusion to expand fluid volume.
Monitor and correct serum electrolyte and acid imbalance.
Candesartan is not removed by hemodialysis. The degree to which HCTZ is removed by hemodialysis has not been established.
Administration
May be taken with or without food.
Contraindications
Hypersensitivity to candesartan, hydrochlorothiazide or to other sulfonamide-derivatives. Anuria, gout, refractory hypokalemia & hypercalcemia, severe hepatic impairment &/or cholestasis. Concomitant use w/ aliskiren in patients w/ DM or renal impairment (GFR <60 mL/min/1.73 m2). Pregnancy (2nd & 3rd trimesters) or women desiring to be pregnant. Lactation.
Hypersensitivity to any component of the product or to other sulfonamide-derivatives; Anuria; Gout; Refractory hypokalemia and hypercalcemia; Pregnant women or women desiring to be pregnant; Breastfeeding; Severe hepatic impairment and/or cholestasis.
Warnings
Angiotensin II receptor blockers can cause injury and even death to the developing fetus when used in pregnancy during the second and third trimesters. Discontinue candesartan as soon as possible upon detection of pregnancy.
Special Precautions
Symptomatic hypotension in patients w/ intravascular vol- & salt-depletion (eg, patients on dialysis or treated vigorously w/ diuretics). Childn. Candesartan: Fetal/neonatal morbidity & mortality. Correct hypovolemia. Bilateral renal artery stenosis or stenosis of the artery of a solitary kidney; hemodynamically relevant aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy, primary hyperaldosteronism. Closely monitor BP, renal function & electrolytes in patients receiving candesartan & other agents that affect the renin-angiotensin-aldosterone system. Periodically monitor serum K & creatinine levels in hypertensive patients w/ severe renal impairment. Hepatic impairment. Anesth & surgery. Patients on hemodialysis. Hyperkalemia. Concomitant use w/ K-sparing diuretics, K supplements, salt substitutes containing K or other drugs that may increase K levels (eg, heparin). Hydrochlorothiazide: Fluid/electrolyte imbalance. Renal disease resulting in severe renal impairment; hepatic disease or progressive liver disease. Patients w/ or w/o a history of allergy or bronchial asthma. SLE. May impair glucose tolerance, decrease urinary Ca excretion & cause intermittent & slight elevation of serum Ca, increase cholesterol & triglyceride levels. Hypomagnesemia. Photosensitizing actions could act as possible mechanism for non-melanoma skin cancer. Discontinue before taking parathyroid function test. Hyperuricemia may occur or acute gout may be precipitated. Idiosyncratic reaction resulting in transient myopia & acute angle-closure glaucoma. May affect ability to drive & use machines.
Use In Pregnancy & Lactation
Pregnancy: Pregnancy Categories C (first trimester) and D (second and third trimesters) (see Fetal/Neonatal Morbidity and Mortality under Precautions).
Lactation: It is not known whether candesartan is distributed in human milk. Discontinue breastfeeding or drug due to potential risk to breastfeeding infants, taking into consideration the importance of the drug to the mother.
Lactation: It is not known whether candesartan is distributed in human milk. Discontinue breastfeeding or drug due to potential risk to breastfeeding infants, taking into consideration the importance of the drug to the mother.
Adverse Reactions
Candesartan: The following undesirable effects have been reported: Body as a Whole: Asthenia, back pain, chest pain, fatigue, fever, malaise, peripheral edema.
Cardiovascular: Hypotension, tachycardia, palpitation, angina pectoris, myocardial infarction.
Gastrointestinal: Nausea, abdominal pain, diarrhea, dyspepsia, vomiting, anorexia, gastroenteritis, stomach discomfort, epigastric pain, stomatitis.
Hematologic: Epistaxis, neutropenia, leukopenia, agranulocytosis, leukocytosis, eosinophilia, anemia.
Liver/Biliary: Abnormal hepatic function, hepatitis, jaundice.
Metabolic and Nutritional/Laboratory Values: Hyperkalemia, hyponatremia, hypertriglyceridemia, hypokalemia, proteinuria; Elevations of the following: total cholesterol, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactic dehydrogenase (LDH), gamma-glutamyl transpeptidase (γ-GTP), blood urea nitrogen (BUN), creatinine phosphokinase (CPK), liver enzymes and/or bilurubin; Reductions of the following: serum total protein, hemoglobin and hematocrit.
Musculoskeletal: Arthralgia, myalgia, rhabdomyolysis (rare).
Nervous System: Dizziness, headache, vertigo, paresthesia, depression, anxiety, somnolence, syncope, lightheadedness, sleepiness.
Respiratory: Upper respiratory tract infections, bronchitis, coughing, dyspnea, pharyngitis, rhinitis, sinusitis.
Skin: Eczema, increased sweating, pruritus, rash, angioedema, urticaria.
Urinary: Renal impairment, renal failure, albuminuria, hematuria, pollakiuria.
Hydrochlorothiazide: The following undesirable effects have been reported: Body as a Whole: Weakness.
Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics, antihypertensive drugs).
Gastrointestinal: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, constipation, gastric irritation, anorexia.
Hematologic: Aplastic anemia, agranulocytosis, leucopenia, hemolytic anemia, thrombocytopenia.
Hypersensitivity reactions: Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, purpura, urticaria.
Metabolic and Nutritional: Electrolyte imbalance, glycosuria.
Musculoskeletal: Muscle spasm.
Nervous System: Restlessness.
Urinary: Renal impairment, renal failure, interstitial nephritis.
Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidernal necrolysis, alopecia.
Urogenital: Impotence.
Others: Transient blurred vision, xanthopsia.
Candesartan-HCTZ: The following undesirable effects have been reported: Body as a Whole: Inflicted injury, pain, influenza-like symptoms.
Cardiovascular: Extrasystoles, bradycardia, ECG abnormal.
Gastrointestinal: Gastritis.
Metabolic and Nutritional: Hyperuricemia, hyperglycemia, hypokalemia.
Musculoskeletal: Arthrosis, arthritis, leg cramps, sciatica.
Nervous System: Hypesthesia, insomnia.
Skin: Dermatitis.
Urinary: Urinary tract infection, cystitis.
Others: Infection, viral infection, conjunctivitis, tinnitus.
Cardiovascular: Hypotension, tachycardia, palpitation, angina pectoris, myocardial infarction.
Gastrointestinal: Nausea, abdominal pain, diarrhea, dyspepsia, vomiting, anorexia, gastroenteritis, stomach discomfort, epigastric pain, stomatitis.
Hematologic: Epistaxis, neutropenia, leukopenia, agranulocytosis, leukocytosis, eosinophilia, anemia.
Liver/Biliary: Abnormal hepatic function, hepatitis, jaundice.
Metabolic and Nutritional/Laboratory Values: Hyperkalemia, hyponatremia, hypertriglyceridemia, hypokalemia, proteinuria; Elevations of the following: total cholesterol, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactic dehydrogenase (LDH), gamma-glutamyl transpeptidase (γ-GTP), blood urea nitrogen (BUN), creatinine phosphokinase (CPK), liver enzymes and/or bilurubin; Reductions of the following: serum total protein, hemoglobin and hematocrit.
Musculoskeletal: Arthralgia, myalgia, rhabdomyolysis (rare).
Nervous System: Dizziness, headache, vertigo, paresthesia, depression, anxiety, somnolence, syncope, lightheadedness, sleepiness.
Respiratory: Upper respiratory tract infections, bronchitis, coughing, dyspnea, pharyngitis, rhinitis, sinusitis.
Skin: Eczema, increased sweating, pruritus, rash, angioedema, urticaria.
Urinary: Renal impairment, renal failure, albuminuria, hematuria, pollakiuria.
Hydrochlorothiazide: The following undesirable effects have been reported: Body as a Whole: Weakness.
Cardiovascular: Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics, antihypertensive drugs).
Gastrointestinal: Pancreatitis, jaundice (intrahepatic cholestatic jaundice), sialadenitis, cramping, constipation, gastric irritation, anorexia.
Hematologic: Aplastic anemia, agranulocytosis, leucopenia, hemolytic anemia, thrombocytopenia.
Hypersensitivity reactions: Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, purpura, urticaria.
Metabolic and Nutritional: Electrolyte imbalance, glycosuria.
Musculoskeletal: Muscle spasm.
Nervous System: Restlessness.
Urinary: Renal impairment, renal failure, interstitial nephritis.
Skin: Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidernal necrolysis, alopecia.
Urogenital: Impotence.
Others: Transient blurred vision, xanthopsia.
Candesartan-HCTZ: The following undesirable effects have been reported: Body as a Whole: Inflicted injury, pain, influenza-like symptoms.
Cardiovascular: Extrasystoles, bradycardia, ECG abnormal.
Gastrointestinal: Gastritis.
Metabolic and Nutritional: Hyperuricemia, hyperglycemia, hypokalemia.
Musculoskeletal: Arthrosis, arthritis, leg cramps, sciatica.
Nervous System: Hypesthesia, insomnia.
Skin: Dermatitis.
Urinary: Urinary tract infection, cystitis.
Others: Infection, viral infection, conjunctivitis, tinnitus.
Drug Interactions
Candesartan: Concomitant use of candesartan with lithium may cause an increase in serum lithium concentrations. Monitor serum lithium levels during concomitant use.
Candesartan administration to patients under diuretic therapy may enhance antihypertensive effect. Start candesartan at a lower dose.
Candesartan's antihypertensive effect may be enhanced by other antihypertensives.
The antihypertensive effect of angiotensin II receptor antagonists may be reduced when coadministered with non-steroidal anti-inflammatory drugs (NSAIDs) such as selective COX-2 inhibitors, aspirin (>3g/day), and nonselective NSAIDs.
Concurrent administration of angiotensin II receptor antagonists and NSAIDs may result in an increased risk of worsening of renal function (including possible acute renal failure) and an increase in serum potassium, particularly in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Regularly monitor renal function after initiation of concomitant therapy and adequately hydrate patients.
In studies, coadministration of candesartan with other drugs such as glibenclamide, nifedipine, digoxin, warfarin, HCTZ, and oral contraceptives showed no significant drug interactions. Since candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effects on P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected.
Hydrochlorothiazide: Administration of the following drugs may interact with thiazide diuretics: Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may be observed.
Amantadine: Increased risk of adverse effects.
Anticholinergic agents (e.g., atropine, biperidine): May increase availability of thiazide diuretics by decreasing gastrointestinal motility and stomach emptying rate.
Antidiabetic medicines (oral agents and insulin): Dosage adjustment of the antidiabetic drug may be necessary.
Other antihypertensive drugs: Additive effect.
Cholestyramine and colestipol resins: HCTZ absorption is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind HCTZ and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.
Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia.
Cytotoxic agents: Decreased renal excretion; increased myelosuppresive effects.
Pressor amines (e.g. adrenaline): Possible decreased response to pressor amines but not sufficient to prevent their use.
Skeletal muscle relaxants, nondepolarising (e.g. tubocurarine): Possible increased responsiveness to the muscle relaxant.
Lithium: Volume depletion increases lithium absorption and may cause lithium toxicity, unless levels are closely monitored and dosage reduced accordingly. Conversely, sudden stopping of diuretic treatment may result in a sub-therapeutic level of circulating lithium.
Non-steroidal anti-inflammatory drugs (NSAIDs) including COX-2 Inhibitors: The administration of NSAIDs including selective COX-2 inhibitors can reduce the diuretic, natriuretic and antihypertensive effects of diuretics in some patients.
Candesartan administration to patients under diuretic therapy may enhance antihypertensive effect. Start candesartan at a lower dose.
Candesartan's antihypertensive effect may be enhanced by other antihypertensives.
The antihypertensive effect of angiotensin II receptor antagonists may be reduced when coadministered with non-steroidal anti-inflammatory drugs (NSAIDs) such as selective COX-2 inhibitors, aspirin (>3g/day), and nonselective NSAIDs.
Concurrent administration of angiotensin II receptor antagonists and NSAIDs may result in an increased risk of worsening of renal function (including possible acute renal failure) and an increase in serum potassium, particularly in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Regularly monitor renal function after initiation of concomitant therapy and adequately hydrate patients.
In studies, coadministration of candesartan with other drugs such as glibenclamide, nifedipine, digoxin, warfarin, HCTZ, and oral contraceptives showed no significant drug interactions. Since candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effects on P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected.
Hydrochlorothiazide: Administration of the following drugs may interact with thiazide diuretics: Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may be observed.
Amantadine: Increased risk of adverse effects.
Anticholinergic agents (e.g., atropine, biperidine): May increase availability of thiazide diuretics by decreasing gastrointestinal motility and stomach emptying rate.
Antidiabetic medicines (oral agents and insulin): Dosage adjustment of the antidiabetic drug may be necessary.
Other antihypertensive drugs: Additive effect.
Cholestyramine and colestipol resins: HCTZ absorption is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind HCTZ and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.
Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia.
Cytotoxic agents: Decreased renal excretion; increased myelosuppresive effects.
Pressor amines (e.g. adrenaline): Possible decreased response to pressor amines but not sufficient to prevent their use.
Skeletal muscle relaxants, nondepolarising (e.g. tubocurarine): Possible increased responsiveness to the muscle relaxant.
Lithium: Volume depletion increases lithium absorption and may cause lithium toxicity, unless levels are closely monitored and dosage reduced accordingly. Conversely, sudden stopping of diuretic treatment may result in a sub-therapeutic level of circulating lithium.
Non-steroidal anti-inflammatory drugs (NSAIDs) including COX-2 Inhibitors: The administration of NSAIDs including selective COX-2 inhibitors can reduce the diuretic, natriuretic and antihypertensive effects of diuretics in some patients.
Storage
Store at temperatures not exceeding 30°C.
Action
Pharmacology: Pharmacodynamics: Candesartan: Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). It is the main pressor agent of the renin-angiotensin-aldosterone system and is important in the pathophysiology of hypertension, heart failure and other cardiovascular disorders. Major physiological effects of angiotensin II include vasoconstriction, stimulation of synthesis and release of aldosterone, regulation of salt and water homeostasis, stimulation of cell growth.
Candesartan is a nonpeptide angiotensin II receptor antagonist that selectively blocks the binding of angiotensin II to the angiotensin II subtype 1 (AT1) receptor in many tissues such as vascular smooth muscles and the adrenal gland.
Candesartan's action is independent of the pathways for angiotensin II synthesis. It does not inhibit ACE (kininase II), which converts angiotensin I to angiotensin II and degrades bradykinin. Since there is no effect on the degradation of bradykinin, angiotensin II receptor antagonists are unlikely to be associated with cough. The incidence of cough was lower in patients taking candesartan in studies comparing candesartan with ACE inhibitors.
Candesartan does not bind to or block other hormone receptors or ion channels significant in cardiovascular regulation. Angiotensin II receptor antagonism results in dose-related increases in plasma renin levels, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentration.
In hypertension, candesartan produces a dose-dependent, long-lasting reduction in arterial blood pressure. This is due to decreased systemic peripheral resistance, without reflex increase in heart rate. After discontinuation of treatment, there is no indication of rebound hypertension.
In multiple-dose studies in hypertensive patients, there were no clinically significant changes in metabolic function, including serum levels of total cholesterol, triglycerides, glucose, or uric acid. In a 12-week study, no change in the level of HbA1c was observed in patients with non-insulin-dependent (type 2) diabetes mellitus and hypertension.
Candesartan decreases systemic vascular resistance and pulmonary capillary wedge pressure, increases plasma renin activity and angiotensin II concentration, and decreases aldosterone levels in patients with chronic heart failure (CHF) and depressed left ventricular systolic function. In patients with CHF not receiving ACE inhibitors, orally administered candesartan cilexetil 8 to 16 mg once daily for up to 43 weeks significantly increased angiotensin II levels, had varying effects on the levels of atrial natriuretic factor and pro-atrial natriuretic peptide and, in combination with enalapril, transiently decreased aldosterone levels.
Candesartan is a nonpeptide angiotensin II receptor antagonist that selectively blocks the binding of angiotensin II to the angiotensin II subtype 1 (AT1) receptor in many tissues such as vascular smooth muscles and the adrenal gland.
Candesartan's action is independent of the pathways for angiotensin II synthesis. It does not inhibit ACE (kininase II), which converts angiotensin I to angiotensin II and degrades bradykinin. Since there is no effect on the degradation of bradykinin, angiotensin II receptor antagonists are unlikely to be associated with cough. The incidence of cough was lower in patients taking candesartan in studies comparing candesartan with ACE inhibitors.
Candesartan does not bind to or block other hormone receptors or ion channels significant in cardiovascular regulation. Angiotensin II receptor antagonism results in dose-related increases in plasma renin levels, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentration.
In hypertension, candesartan produces a dose-dependent, long-lasting reduction in arterial blood pressure. This is due to decreased systemic peripheral resistance, without reflex increase in heart rate. After discontinuation of treatment, there is no indication of rebound hypertension.
In multiple-dose studies in hypertensive patients, there were no clinically significant changes in metabolic function, including serum levels of total cholesterol, triglycerides, glucose, or uric acid. In a 12-week study, no change in the level of HbA1c was observed in patients with non-insulin-dependent (type 2) diabetes mellitus and hypertension.
Candesartan decreases systemic vascular resistance and pulmonary capillary wedge pressure, increases plasma renin activity and angiotensin II concentration, and decreases aldosterone levels in patients with chronic heart failure (CHF) and depressed left ventricular systolic function. In patients with CHF not receiving ACE inhibitors, orally administered candesartan cilexetil 8 to 16 mg once daily for up to 43 weeks significantly increased angiotensin II levels, had varying effects on the levels of atrial natriuretic factor and pro-atrial natriuretic peptide and, in combination with enalapril, transiently decreased aldosterone levels.
MedsGo Class
Angiotensin II Antagonists / Diuretics
Features
Dosage
16 mg / 12.5 mg
Ingredients
- Candesartan
- Hydrochlorothiazide
Packaging
Tablet 1's
Generic Name
Candesartan Cilexetil / Hydrochlorothiazide
Registration Number
DR-XY36245
Classification
Prescription Drug (RX)
Reviews
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Product Questions
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