= Additional active ingredients
Candesartan cilexetil 16 mg, hydrochlorothiazide 12.5 mg.
PRESENTATION AND DOSSAGE
TABS: 28 X 12.5/16 mg
Essential hypertension where monotherapy with candesartan cilexetil or hydrochlorothiazide is not sufficient.
Hypersensitivity to the active substances or to any of the excipients or to sulfonamide derived drugs (hydrochlorothiazide is a sulfonamide derived drug). Pregnancy and lactation. Severe renal impairment (creatinine clearance <30 ml/min/1.73 m2 BSA). Severe hepatic impairment and/or cholestasis. Refractory hypokalaemia and hypercalcaemia. Gout.
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 & 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.
Adverse events were mild and transient, and comparable to placebo in controlled clinical studies with various doses of candesartan cilexetil/hydrochlorothiazide (candesartan cilexetil up to 16 mg and hydrochlorothiazide up to 25 mg). The overall incidence of adverse events showed no association with age or gender. Angioedema has been reported very rarely in patients treated with candesartan cilexetil. Occuring with the use of hydrochlorothiazide: Jaundice, pancreatitis, leucopenia, neturopenia/agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, photosensitivity reactions, necrotizing angitis, toxic epidermal necrolysis, anaphylactic reactions.
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 (i.e. ethinylestradiol/levonorgestrel), glibenclamide and nifedipine. The bioavailability of candesartan is not affected by food. The antihypertensive effect of Atacand Plus may be enhanced by other antihypertensives. 6 The potassium depleting effect of hydrochlorothiazide could be expected to be potentiated by other drugs associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid derivates). Based on experience with the use of other drugs that affect the renin-angiotensinaldosterone system, concomitant use of Atacand Plus and potassium-sparing diuretics, 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. Diuretic-induced hypokalaemia and hypomagnesaemia predisposes to the potential cardiotoxic effects of digitalis glycosides and antiarrhythmics. Periodic monitoring of serum potassium is recommended when Atacand 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. A similar effect may occur with angiotensin II receptor antagonists and careful monitoring of serum lithium levels is recommended during concomitant use. The antihypertensive effect of angiotensin II receptor antagonists, including Atacand Plus may be attenuated by NSAIDs, including selective COX-2 inhibitors and acetylsalicylic acid. As with ACE inhibitors, concomitant use of angiotensin II receptor antagonists 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 the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter. The diuretic, natriuretic and antihypertensive effect of hydrochlorothiazide is blunted by NSAIDs. The absorption of hydrochlorothiazide is reduced by colestipol or cholestyramine. The effect on nondepolarizing skeletal muscle relaxants (e.g. tubocurarine) may be potentiated by hydrochlorothiazide. Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements or Vitamin D must be prescribed, serum calcium levels should be monitored and dosage adjusted accordingly. The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides. 7 Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Thiazide may increase the risk of adverse effects caused by amantadine. Thiazides may reduce the renal excretion of cytotoxic drugs (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects. The risk for hypokalaemia may be increased during concomitant use of steroids or adrenocorticotropic hormone (ACTH). Postural hypotension may become aggravated by simultaneous intake of alcohol, barbiturates or anaesthetics. Treatment with a thiazide diuretic may impair glucose tolerance. Dosage adjustment of antidiabetic drugs, including insulin, may be required. Hydrochlorothiazide may cause the arterial response to pressor amines (e.g. adrenaline) to decrease but not enough to exclude a pressor effect. Hydrochlorothiazide may increase the risk of acute renal insufficiency especially with high doses of iodinated contrast media. There is no clinically significant interaction between hydrochlorothiazide and food.
The recommended dose of Atacand Plus is 1 tablet once daily. The dose of candesartan cilexetil should be titrated before switching to Atacand Plus. When clinically appropriate a direct change from monotherapy to Atacand Plus may be considered. Most of the antihypertensive effect is usually attained within 4 weeks of initiation of treatment.
Use in the elderly: No initial dosage adjustment is necessary in elderly patients.
Use in patients with intravascular volume depletion: Dose titration of candesartan cilexetil is recommended in patients at risk for hypotension, such as patients with possible volume depletion (an initial dose of candesartan cilexetil of 4 mg may be considered in these patients).
Use in impaired renal function: Loop diuretics are preferred to thiazides in this population. Dose titration of candesartan cilexetil is recommended in patients with renal impairment whose creatinine clearance is ≥ 30 ml/min/1.73 m2 BSA before treatment with Atacand Plus (the recommended starting dose of candesartan cilexetil is 4 mg in patients with mild to moderate renal impairment). Atacand Plus should not be used in patients with severe renal impairment (creatinine clearance <30 ml/min/1.73 m2 BSA).
Use in impaired hepatic function: Dose titration of candesartan cilexetil is recommended in patients with mild to moderate hepatic impairment before treatment with Atacand Plus (the recommended starting dose of candesartan cilexetil is 2 mg in these patients). Atacand Plus should not be used in patients with severe hepatic impairment and/or cholestasis.
Use in children: The safety and efficacy of Atacand Plus have not been established in children.
Symptoms: Based on pharmacological considerations, the main manifestation of an overdose of candesartan cilexetil is likely to be symptomatic hypotension and dizziness. In individual case reports of overdose (of up to 672 mg candesartan cilexetil) patient recovery was uneventful. The main manifestation of an overdose of hydrochlorothiazide is acute loss of fluid and electrolytes. Symptoms such as dizziness, hypotension, thirst, tachycardia, ventricular arrhythmias, sedation/impairment of consciousness and muscle cramps can also be observed.
Management: No specific information is available on the treatment of overdosage with Atacand Plus. The following measures are, however, suggested in case of overdosage. 11 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 above-mentioned measures are not sufficient. Candesartan can not be removed by haemodialysis. It is not known to what extent hydrochlorothiazide is removed by haemodialysis.
PREGNANCY & LACTATION
Use in pregnancy: There are very limited data from the use of Atacand Plus in pregnant women. These data are insufficient to allow conclusions about potential risk for the foetus when used during the first trimester. In humans, foetal renal perfusion, which is dependent upon the development of the renin-angiotensin-aldosterone system, begins in the second trimester. Thus risk to the foetus increases if Atacand Plus is administered during the second or third trimesters of pregnancy. When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause foetal and neonatal injury (hypotension, renal dysfunction, oliguria and/or anuria, oligohydramnios, skull hypoplasia, intrauterine growth retardation) and death. Cases of lung hypoplasia, facial abnormalities and limb contractures have also been described. 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. Hydrochlorothiazide can reduce the plasma volume as well as the uteroplacental blood flow. It may also cause neonatal thrombocytopenia. 8 Based on the above information, Atacand Plus is contra-indicated in pregnancy. If pregnancy is detected during treatment, Atacand Plus should be discontinued.
Use in lactation: 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, Atacand Plus is contra-indicated during breast-feeding.
MANUFACTURER & DISTRIBUTER:
License Holder: S.L.E., Teva Group