= Additional active ingredients
PRESENTATION AND DOSSAGE
TABS: 28 x 8 mg.
TABS: 28 x 16 mg.
NO INTERACTION WITH FOOD
Hypersensitivity, pregnancy, lactation.
Renal impairment/Kidney transplantation: Loop diuretics are preferred to thiazides in this population. When Atacand Plus is used in patients with impaired renal function, a periodic monitoring of potassium, creatinine and uric acid levels is recommended. There is limited clinical evidence regarding Atacand Plus use in patients who have undergone renal transplant.
Renal artery stenosis: Other drugs that affect the renin-angiotensin-aldosterone system, i.e. angiotensin converting enzyme (ACE) inhibitors, may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. 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 3 system. Therefore, the use of Atacand Plus is not recommended until this condition has been corrected
Anaesthesia and surgery: Hypotension may occur during anaesthesia and surgery in patients treated with angiotensin II antagonists due to blockade of the renin-angiotensin system. Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors.
Hepatic impairment: Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma. There is no clinical experience with Atacand Plus in patients with hepatic impairment.
Aortic and mitral valve stenosis (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.
Primary hyperaldosteronism: Patients with primary hyperaldosteronism generally will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin-aldosterone system. Therefore the use of Atacand Plus is not recommended.
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 (hypercalcaemia, hypokalaemia, hyponatraemia, hypomagnesaemia and hypochloraemic alkalosis). Thiazide diuretics may decrease the urinary calcium excretion and may cause intermittent and slightly increased serum calcium concentrations. Marked hypercalcaemia may be a sign of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function. 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. The risk for hypokalaemia may be increased in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients with an inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or adrenocorticotropic hormone (ACTH). Based on experience with the use of other drugs that affect the renin-angiotensinaldosterone system, concomitant use of Atacand Plus and potassium-sparing diuretics, 4 potassium supplements or salt substitutes or other drugs that may increase serum potassium levels (e.g. heparin sodium) may lead to increases in serum potassium. Although not documented with Atacand Plus treatment with angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists may cause hyperkalaemia, especially in the presence of heart failure and/or renal impairment. Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.
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 Atacand Plus minimal or no effects were reported. Thiazide diuretics increase serum uric acid concentration and may precipitate gout in susceptible patients.
General: In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), 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. Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics. This medicinal product contains lactose, as an excipient, and patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption should not take this medicine.
Treatment of Hypertension: In controlled clinical studies adverse events were mild and transient and comparable to placebo. The overall incidence of adverse events showed no association with dose or age. Withdrawals from treatment due to adverse events were similar with candesartan cilexetil (3.1%) and placebo (3.2%). In a pooled analysis of clinical trial data, the following common (>1/100) adverse reactions with candesartan cilexetil were reported based on an incidence of adverse events with candesartan cilexetil at least 1% higher than the incidence seen with placebo:
Nervous system disorders: Dizziness/vertigo, headache. Musculoskeletal, connective.
tissue and bone disorders: Back pain.
Infections and infestations: Respiratory infection.
Compounds which have been investigated in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinylestradiol/levonorgestrel), glibenclamide, nifedipine and enalapril. No pharmacokinetic interactions of clinical significance were identified in these studies.Candesartan is eliminated only to a minor extent by hepatic metabolism (CYP2C9). Available interaction studies indicate no effect on CYP2C9 and CYP3A4 but the effect on other cytochrome P450 isoenzymes is presently unknown. Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. A similar effect may occur with angiotensin II receptor antagonists (AIIRAs) and careful monitoring of serum lithium levels is recommended during concomitant use. The antihypertensive effect of angiotension II receptor antagonists, including Atacand may be attenuated by NSAIDs, including selective COX-2 inhibitors and acetylsalicylic acid. As with ACE inhibitors, concomitant use of AIIRAs and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in older patients and in volume depleted patients. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy and periodically thereafter. The antihypertensive effect of Atacand may be enhanced by other antihypertensives. The bioavailability of candesartan is not affected by food.
Use in the elderly No initial dosage adjustment is necessary in elderly patients.
Use in patients with intravascular volume depletion An initial dose of 4 mg may be considered in patients at risk for hypotension, such as patients with possible volume depletion.
Use in impaired renal function: The starting dose is 4 mg in patients with renal impairment, including patients on haemodialysis. The dose should be titrated according to response. There is limited experience in patients with very severe or end-stage renal impairment (Clcreatinine < 15 ml/min).
Use in impaired hepatic function: initial dose of 2 mg once daily is recommended in patients with mild to moderate hepatic impairment. The dose may be adjusted according to response. There is no experience in patients with severe hepatic impairment. Concomitant therapy Atacand may be administered with other antihypertensive agents. Dosage in Heart Failure The usual recommended initial dose of Atacand is 4 mg once daily. Up-titration to the target dose of 32 mg once daily or the highest tolerated dose is done by doubling the dose at intervals of at least 2 weeks. Special patient populations No initial dose adjustment is necessary for elderly patients or in patients with intravascular volume depletionrenal or hepatic impairment.
Concomitant therapy Atacand can be administered with other heart failure treatment, including ACE inhibitors, beta-blockers, diuretics and digitalis or a combination of these medicinal products. Use in children and adolescents The safety and efficacy of Atacand have not been established in children and adolescents (under 18 years).
Symptoms: Based on pharmacological considerations, the main manifestation of an overdose is likely to be symptomatic hypotension and dizziness. In individual case reports of overdose (of up to 672 mg candesartan cilexetil) in an adult, patient recovery was uneventful.
Management: 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, for example, 8 isotonic saline solution. Sympathomimetic drugs may be administered if the abovementioned measures are not sufficient. Candesartan is not removed by haemodialysis.
PREGNANCY & LACTATION
Use in pregnancy: The use of Atacand is contraindicated during pregnancy. Patients receiving Atacand should be made aware of that before contemplating a possibility of becoming pregnant so that they can discuss appropriate options with their treating physician. When pregnancy is diagnosed, treatment with Atacand must be stopped immediately and if appropriate, alternative therapy should be started When used in pregnancy, drugs that act directly on the renin-angiotensin system can cause fetal and neonatal injury and death. Exposure to angiotensin II receptor antagonist therapy is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
Use in lactation: It is not known whether candesartan is excreted in human milk. However, candesartan is excreted in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, breast feeding should be discontinued if the use of Atacand is considered essential
MANUFACTURER & DISTRIBUTER:
License Holder: S.L.E., Teva Group