Atacand/Atacand Plus

Atacand: Candesartan cilexetil.
Atacand Plus: Candesartan cilexetil, hydrochlorothiazide.

Atacand: Each tablet contains 4 mg, 8 mg, 16 mg candesartan cilexetil.
Atacand Plus: One Atacand Plus tablet contains 16 mg candesartan cilexetil and 12.5 mg hydrochlorothiazide.
Excipients/Inactive Ingredients: Atacand: Carmellose calcium, hydroxypropyl cellulose, iron oxide reddish-brown E 172 (only 8 mg, 16 mg tablets), lactose monohydrate, magnesium stearate, maize starch, macrogol.
Atacand Plus: Carmellose calcium, hydroxypropyl cellulose, iron oxide red E172, iron oxide yellow E172, lactose monohydrate, magnesium stearate, maize starch and macrogol.

Pharmacotherapeutic Group: Atacand: Angiotensin II antagonists (candesartan). Atacand Plus: Angiotensin II antagonists + diuretics. ATC code: C09DA06.
Pharmacology: Pharmacodynamics: Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a role in the pathophysiology of hypertension, heart failure and other cardiovascular disorders. It also has a role in the pathogenesis of end organ hypertrophy and damage. The major physiological effects of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of salt and water homeostasis and stimulation of cell growth, are mediated via the type 1 (AT₁) receptor.
Candesartan cilexetil is a prodrug suitable for oral use. It is rapidly converted to the active drug candesartan by ester hydrolysis during absorption from the GIT. Candesartan is an angiotensin II receptor antagonist, selective for AT₁ receptors, with tight binding to and slow dissociation from the receptor. It has no agonist activity.
Atacand: Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and degrades bradykinin. There is no effect on ACE and no potentiation of bradykinin or substance P. In controlled clinical trials comparing candesartan 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 angiotensin II (AT₁) receptors results in dose-related increases in plasma renin levels, angiotensin I and II levels, and a decrease in plasma aldosterone concentration.
Hypertension: In hypertension, candesartan causes a dose-dependent, long-lasting reduction in arterial blood pressure. The antihypertensive action is due to decreased systemic peripheral resistance, 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 cilexetil, onset of antihypertensive effect generally occurs within 2 hours. With continuous treatment, most of the reduction in blood pressure with any dose is generally attained within four weeks and is sustained during long-term treatment. According to a meta-analysis, the average additional effect of a dose increase from 16 mg to 32 mg once daily was small. Taking into account the inter-individual variability, a more than average effect can be expected in some patients. Candesartan cilexetil once daily provides effective and smooth blood pressure reduction over 24 hours, with little difference between maximum and trough effects during the dosing interval. The antihypertensive effect and tolerability of candesartan and losartan were compared in two randomised, double-blind studies in a total of 1,268 patients with mild to moderate hypertension. The trough blood pressure reduction (systolic/diastolic) was 13.1/10.5 mmHg with candesartan cilexetil 32 mg once daily and 10.0/8.7 mmHg with losartan potassium 100 mg once daily (difference in blood pressure reduction 3.1/1.8 mmHg, p<0.0001/p<0.0001). The most common adverse events were respiratory infection (candesartan 6.6%, losartan 8.9%), headache (candesartan 5.8%, losartan 5.6%) and dizziness (candesartan 4.4%, losartan 1.9%).
When candesartan cilexetil is used together with hydrochlorothiazide, the reduction in blood pressure is additive. Concomitant administration of candesartan cilexetil with hydrochlorothiazide or amlodipine is well tolerated.
Candesartan is similarly effective in patients irrespective of age and gender.
Medicinal products that block the renin-angiotensin-aldosterone system have less pronounced antihypertensive effect in black patients (usually a low-renin population) than in non-black patients. This is also the case for candesartan. In an open label clinical experience trial in 5,156 patients with diastolic hypertension, the blood pressure reduction during candesartan treatment was significantly less in black than non-black patients (14.4/10.3 mmHg vs 19.0/12.7 mmHg, p<0.0001/p<0.0001).
Candesartan increases renal blood flow and either has no effect on or increases glomerular filtration rate while renal vascular resistance and filtration fraction are reduced. In a 3-month clinical study in hypertensive patients with type 2 diabetes mellitus and microalbuminuria, antihypertensive treatment with candesartan cilexetil reduced urinary albumin excretion (albumin/creatinine ratio, mean 30%, 95% confidence interval 15-42%). There is currently no data on the effect of candesartan on the progression to diabetic nephropathy.
In hypertensive patients with type II diabetes mellitus, 12 weeks treatment with candesartan cilexetil 8 mg to 16 mg had no adverse effects on blood glucose or lipid profile.
The effects of candesartan cilexetil 8-16 mg (mean dose 12 mg), once daily, on cardiovascular morbidity and mortality were evaluated in a randomised clinical trial with 4,937 elderly patients (aged 70-89 years; 21% aged 80 or above) with mild to moderate hypertension followed for a mean of 3.7 years (Study on Cognition and Prognosis in the Elderly). Patients received candesartan cilexetil or placebo with other antihypertensive treatment added as needed. The blood pressure was reduced from 166/90 to 145/80 mmHg in the candesartan group, and from 167/90 to 149/82 mmHg in the control group. There was no statistically significant difference in the primary endpoint, major cardiovascular events (cardiovascular mortality, non-fatal stroke and non-fatal myocardial infarction). There were 26.7 events per 1000 patient-years in the candesartan group versus 30.0 events per 1000 patient-years in the control group (relative risk 0.89, 95% CI 0.75 to 1.06, p=0.19).
Heart Failure: Treatment with candesartan cilexetil reduces mortality, reduces hospitalisation due to heart failure, and improves symptoms in patients with left ventricular systolic dysfunction as shown in the Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity (CHARM) programme.
This multinational, placebo controlled, double-blind study programme in chronic heart failure (CHF) patients with NYHA functional class II to IV consisted of three separate studies: CHARM-Alternative (n=2,028) in patients with LVEF ≤40% not treated with an ACE inhibitor because of intolerance (mainly due to cough, 72%), CHARM-Added (n=2,548) in patients with LVEF ≤40% and treated with an ACE inhibitor, and CHARM-Preserved (n=3,023) in patients with LVEF >40%. Patients on optimal CHF therapy at baseline were randomised to placebo or candesartan cilexetil (titrated from 4 mg or 8 mg once daily to 32 mg once daily or the highest tolerated dose, mean dose 24 mg) and followed for a median of 37.7 months. After 6 months of treatment 63% of the patients still taking candesartan cilexetil (89%) were at the target dose of 32 mg.
In CHARM-Alternative, the composite endpoint of cardiovascular mortality or first CHF hospitalisation was significantly reduced with candesartan in comparison with placebo (hazard ratio (HR) 0.77, 95% CI 0.67-0.89, p<0.001). This corresponds to a relative risk reduction of 23%. Fourteen patients needed to be treated for the duration of the study to prevent one patient from dying of a cardiovascular event or being hospitalised for treatment of heart failure. The composite endpoint of all-cause mortality or first CHF hospitalisation was also significantly reduced with candesartan (HR 0.80, 95% CI 0.70-0.92, p=0.001). Both the mortality and morbidity (CHF hospitalisation) components of these composite endpoints contributed to the favourable effects of candesartan. Treatment with candesartan cilexetil resulted in improved NYHA functional class (p=0.008).
In CHARM-Added, the composite endpoint of cardiovascular mortality or first CHF hospitalisation was significantly reduced with candesartan in comparison with placebo (HR 0.85, 95% CI 0.75-0.96, p=0.011). This corresponds to a relative risk reduction of 15%. Twenty-three patients needed to be treated for the duration of the study to prevent one patient from dying of a cardiovascular event or being hospitalised for treatment of heart failure. The composite endpoint of all-cause mortality or first CHF hospitalisation was also significantly reduced with candesartan (HR 0.87, 95% CI 0.78-0.98, p=0.021). Both the mortality and morbidity components of these composite endpoints contributed to the favourable effects of candesartan. Treatment with candesartan cilexetil resulted in improved NYHA functional class (p=0.020).
In CHARM-Preserved, no statistically significant reduction was achieved in the composite endpoint of cardiovascular mortality or first CHF hospitalisation (HR 0.89, 95% CI 0.77-1.03, p=0.118). The numerical reduction was attributable to reduced CHF hospitalisation. There was no evidence of effect on mortality in this study.
All-cause mortality was not statistically significant when examined separately in each of the three CHARM studies. However, all-cause mortality was also assessed in pooled populations, CHARM-Alternative and CHARM-Added (HR 0.88, 95% CI 0.79-0.98, p=0.018) and all three studies (HR 0.91, 95% CI 0.83-1.00, p=0.055).
The beneficial effects of candesartan on cardiovascular mortality and CHF hospitalisation were consistent irrespective of age, gender and concomitant medication. Candesartan was effective also in patients taking both beta-blockers and ACE inhibitors at the same time, and the benefit was obtained whether or not patients were taking ACE inhibitors at the target dose recommended by treatment guidelines.
In patients with CHF and depressed left ventricular systolic function (left ventricular ejection fraction, LVEF ≤40%), candesartan decreases systemic vascular resistance and pulmonary capillary wedge pressure, increases plasma renin activity and angiotensin II concentration, and decreases aldosterone levels.
Atacand Plus: 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, such as 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 results in dose related increases in plasma renin levels, angiotensin I and angiotensin II levels, and a decrease in plasma aldosterone concentration.
The effects of candesartan cilexetil 8-16 mg (mean dose 12 mg) once daily on cardiovascular morbidity and mortality were evaluated in a randomised clinical trial with 4,937 elderly patients (aged 70-89 years, 21% aged 80 or above) with mild to moderate hypertension followed for a mean of 3.7 years (Study on Cognition and Prognosis in the Elderly). Patients received candesartan or placebo with other antihypertensive treatment added as needed. The blood pressure was reduced from 166/90 to 145/80 mmHg in the candesartan group, and from 167/90 to 149/82 mmHg in the control group. There was no statistically significant difference in the primary endpoint, major cardiovascular events (cardiovascular mortality, non-fatal stroke and non-fatal myocardial infarction). There were 26.7 events per 1000 patient-years in the candesartan group versus 30.0 events per 1000 patient-years in the control group (relative risk 0.89, 95% CI 0.75 to 1.06, p=0.19).
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 hydrochloro-thiazide reduces the risk for cardiovascular morbidity and mortality.
Candesartan and hydrochlorothiazide have additive antihypertensive effects.
In hypertensive patients, Atacand 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 Atacand Plus, onset of the antihypertensive effect generally occurs within 2 hours. With continuous treatment, most of the reduction in blood pressure is attained within four weeks and is sustained during long-term treatment.
Atacand Plus once daily provides effective and smooth blood pressure reduction over 24 hours, with little difference between maximum and trough effects during the dosing interval. In a double-blind randomised study, Atacand Plus 16 mg/12.5 mg 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.
In two clinical studies (randomised, double-blind, placebo controlled, parallel group) including 275 and 1524 randomised patients respectively, the candesartan cilexetil/hydrochlorothiazide combinations 32 mg/12.5 mg and 32 mg/25 mg resulted in blood pressure reductions of 21/14 mmHg for the highest dose, and were significantly more effective than the respective monocomponents.
In a randomised, double-blind, parallel group clinical study including 1975 randomised patients not adequately controlled on 32 mg candesartan cilexetil once daily, the addition of 12.5 mg or 25 mg hydrochlorothiazide resulted in additional blood pressure reductions. The candesartan cilexetil/hydrochlorothiazide combination 32 mg/25 mg was significantly more effective than the 32 mg/12.5 mg combination, and the overall mean blood pressure reductions were 16/10 mmHg and 13/9 mmHg, respectively.
Candesartan cilexetil/hydrochlorothiazide is similarly effective in patients irrespective of age and gender.
Currently there are no data on the use of candesartan cilexetil/hydrochloro-thiazide in patients with renal disease/nephropathy, reduced left ventricular function/congestive heart failure and post myocardial infarction.
Pharmacokinetics: Concomitant administration of candesartan cilexetil and hydrochlorothiazide has no clinically significant effect on the pharmacokinetics of either medicinal product.
Absorption and distribution: Candesartan cilexetil: Following oral administration, candesartan cilexetil is converted to the active substance candesartan. The absolute bioavailability of candesartan is approximately 40% after an oral solution of candesartan cilexetil. The relative bioavailability of the tablet formulation compared with the same oral solution is approximately 34% with very little variability. The estimated absolute bioavailability of the tablet is therefore 14%. The mean peak serum concentration (C_max) is reached 3-4 hours 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 (AUC) of candesartan is not significantly affected by food.
Candesartan is highly bound to plasma protein (more than 99%). The apparent volume of distribution of candesartan is 0.1 l/kg.
Atacand Plus: 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: 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-labelled 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.
Atacand: Candesartan is mainly eliminated unchanged via urine and bile and only to a minor extent eliminated by hepatic metabolism. The terminal half-life of candesartan is approximately 9 hours. There is no accumulation following multiple doses.
Atacand Plus: Candesartan cilexetil: Candesartan is mainly eliminated unchanged via urine and bile and only to a minor extent eliminated by hepatic metabolism (CYP2C9). Available interaction studies indicate no effect on CYP2C9 and CYP3A4. Based on in vitro data, no interaction would be expected to occur in vivo with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The terminal half-life (t_½) of candesartan is approximately 9 hours. There is no accumulation following multiple doses. The half-life of candesartan remains unchanged (approximately 9 h) after administration of candesartan cilexetil in combination with hydrochlorothiazide. There is an increase in AUC (15-18%) and C_max (23-24%) of candesartan when given together with hydrochlorothiazide. This is of no clinical importance. Furthermore titration of the individual components is recommended before switching to Atacand Plus. No additional accumulation of candesartan occurs after repeated doses of the combination compared to monotherapy.
Hydrochlorothiazide: Hydrochlorothiazide is not metabolized and is excreted almost entirely as unchanged drug by glomerular filtration and active tubular secretion. The terminal t_½ of hydrochlorothiazide is approximately 8 hours. Approximately 70% of an oral dose is eliminated in the urine within 48 hours. The half-life of hydrochlorothiazide remains unchanged (approximately 8 h) after administration of hydrochlorothiazide in combination with candesartan cilexetil. No additional accumulation of hydrochlorothiazide occurs after repeated doses of the combination compared to monotherapy.
Pharmacokinetics in special populations: Candesartan cilexetil: In elderly subjects (over 65 years), C_max 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 Atacand Plus in young and elderly patients (see Dosage & Administration). In patients with mild to moderate renal impairment, C_max and AUC of candesartan increased during repeated dosing by approximately 50% and 70%, respectively, but the terminal t_½ 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 t½ of candesartan was approximately doubled in patients with severe renal impairment. The pharmacokinetics in patients undergoing haemodialysis were similar to those in patients with severe renal impairment.
In patients with mild to moderate hepatic impairment, there was a 23% increase in the AUC of candesartan.
Atacand Plus: Hydrochlorothiazide: The terminal t_½ of hydrochlorothiazide is prolonged in patients with renal impairment.
Toxicology: Preclinical safety data: There wa no evidence of abnormal systemic or target organ toxicity at clinically relevant doses. In preclinical safety studies candesartan had effects on the kidneys and on red cell parameters at high doses in mice, rats, dogs and monkeys. Candesartan caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). Effects on the kidneys (such as interstitial nephritis, tubular distension, basophilic tubules; increased plasma concentrations of urea and creatinine) were induced by candesartan which could be secondary to the hypotensive effect leading to alterations of renal perfusion. Furthermore, candesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells. These changes were considered to be caused by the pharmacological action of candesartan. For therapeutic doses of candesartan in humans, the hyperplasia/hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.
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.
Data from in vitro and in vivo mutagenicity testing indicates that candesartan will not exert mutagenic or clastogenic activities under conditions of clinical use.
There was no evidence of carcinogenicity.
Atacand Plus: There were no qualitative new toxic findings with the combination compared to that observed for each component. In preclinical safety studies candesartan itself had effects on the kidneys and on red cell parameters at high doses in mice, rats, dogs and monkeys. Candesartan caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit). Effects on the kidneys (such as regeneration, dilatation and basophilia in tubules; increased plasma concentrations of urea and creatinine) were induced by candesartan which could be secondary to the hypotensive effect leading to alterations of renal perfusion. Addition of hydrochlorothiazide potentiates the nephrotoxicity of candesartan. 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.
Furthermore, candesartan induced hyperplasia/hypertrophy of the juxtaglomerular cells. These changes were considered to be caused by the pharmacological action of candesartan and to be of little clinical relevance.
Foetotoxicity has been observed in late pregnancy with candesartan. The addition of hydrochlorothiazide did not significantly affect the outcome of foetal development studies in rats, mice or rabbits (see Use in Pregnancy and Lactation).
Candesartan and hydrochlorothiazide both show genotoxic activity at very high concentrations/doses. Data from in vitro and in vivo genotoxicity testing indicate that candesartan and hydrochlorothiazide are unlikely to exert any mutagenic or clastogenic activity under conditions of clinical use.
There was no evidence that either compound is carcinogenic.

Atacand: Hypertension.
Treatment of patients with heart failure and impaired left ventricle systolic function (left ventricular ejection fraction ≤40%) as add-on therapy to ACE inhibitors or when ACE inhibitors are not tolerated (see Pharmacology: Pharmacodynamics under Actions).
Atacand Plus: Hypertension, when monotherapy with candesartan cilexetil or hydrochlorothiazide is not sufficient.

Atacand: Dosage in Hypertension: The recommended initial dose and usual maintenance dose is 8 mg once daily. The dose may be increased to 16 mg once daily. If blood pressure is not sufficiently controlled after 4 weeks of treatment with 16 mg once daily, the dose may be further increased to a maximum of 32 mg once daily (see Pharmacology: Pharmacodynamics: Pharmacodynamics under Actions). If blood pressure control is not achieved with this dose, alternative strategies should be considered.
Therapy should be adjusted according to blood pressure response. Most of the antihypertensive effect is 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: An initial dose of 4 mg may be considered in patients at risk for hypotension, such as patients with possible volume depletion (see Precautions).
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 (Cl_creatinine <15 mL/min). (See Precautions).
Patients with hepatic impairment: Dose titration is recommended in patients with mild to moderate chronic liver disease, and a lower initial dose of 4 mg should be considered. Atacand should not be used in patients with severe hepatic impairment and/or cholestasis (see Contraindications).
Concomitant therapy: Addition of a thiazide-type diuretic such as hydrochlorothiazide has been shown to have an additive antihypertensive effect with Atacand.
Use in black patients: The antihypertensive effect of candesartan is less in black than non-black patients. Consequently, uptitration of Atacand and concomitant therapy may be more frequently needed for blood pressure control in black than non-black patients (see Pharmacology: Pharmacodynamics under Actions).
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 (see Precautions).
Special patient populations: No initial dose adjustment is necessary for elderly patients or in patients with intravascular volume depletion, renal impairment or mild to moderate 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 (see Pharmacology: Pharmacodynamics under Actions and Precautions).
Use in children and adolescents: The safety and efficacy of Atacand have not been established in children and adolescents (under 18 years).
Atacand Plus: Dosage in Hypertension: The recommended dose of Atacand Plus is 1 tablet once daily.
The dose of candesartan cilexetil should be titrated before switching to Atacand Plus.
Most of the antihypertensive effect is usually attained within 4 weeks of initiation of treatment.
When clinically appropriate a direct change from monotherapy to Atacand Plus may be considered. Dose titration of candesartan cilexetil is recommended when switching from hydrochlorothiazide monotherapy.
Use in the elderly: No 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: In patients with mild to moderate renal impairment (ie, creatinine clearance between 30-80 ml/min/1.73 m² BSA), a dose titration is recommended.
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: Patients with hepatic impairment: Dose titration is recommended in patients with mild to moderate chronic liver disease.
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.
Administration: Atacand Plus should be taken once daily with or without food.

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) patient recovery was uneventful.
Atacand Plus: 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: 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, isotonic saline solution. Sympathomimetic drugs may be administered if the previously mentioned measures are not sufficient.
Candesartan cannot be removed by haemodialysis.
Atacand: Candesartan cannot be removed by haemodialysis.
Atacand Plus: No specific information is available on the treatment of overdosage with Atacand 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 above-mentioned measures are not sufficient.
Candesartan cannot be removed by haemodialysis. It is not known to what extent hydrochlorothiazide is removed by haemodialysis.

Pregnancy and lactation (see Use in Pregnancy & Lactation). Severe hepatic impairment and/or cholestasis.
The concomitant use of Atacand/Atacand Plus with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m²) (see Interactions).
Atacand: Hypersensitivity to candesartan cilexetil or to any of the excipients.
Atacand Plus: Hypersensitivity to the active substances or to any of the excipients or to sulfonamide derived drugs (hydrochlorothiazide is a sulfonamide derived drug) or to any of the excipients.
Severe renal impairment (creatinine clearance < 30 ml/min/1.73 m² BSA).
Refractory hypokalaemia and hypercalcaemia.
Gout.

Renal impairment: As with other agents inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible patients treated with Atacand/Atacand Plus (see Contraindications).
Kidney transplantation: There is limited clinical evidence regarding Atacand/Atacand Plus use in patients who have undergone renal transplant.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of Atacand/Atacand Plus with an ACE-inhibitor or aliskiren is therefore not recommended (see Interactions).
If dual blockade therapy is considered necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Concomitant use of aliskiren with angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme (ACE) inhibitors is contraindicated in patients with diabetes mellitus (type I or II) or moderate to severe renal impairment (GFR <60 ml/min/1.73 m²) (see Contraindications and Interactions).
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.
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 medicinal products 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.
Effects on ability to drive and use machines: The effect of Atacand Plus on the ability to drive and use machines has not been studied, but based on its pharmacodynamic properties Atacand 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.
Atacand: Renal impairment: When Atacand is used in hypertensive patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended. There is limited experience in patients with very severe or end-stage renal impairment (Cl_creatinine <15 ml/min). In these patients Atacand should be carefully titrated with thorough monitoring of blood pressure.
Evaluation of patients with heart failure should include periodic assessments of renal function, especially in elderly patients 75 years or older, and patients with impaired renal function. During dose titration of Atacand, monitoring of serum creatinine and potassium is recommended. Clinical trials in heart failure did not include patients with serum creatinine >265 μmol/L (>3 mg/dL).
Renal artery stenosis: Other medicinal products 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.
Concomitant therapy with an ACE inhibitor in heart failure: The risk of adverse events, especially renal function impairment and hyperkalaemia, may increase when candesartan is used in combination with an ACE inhibitor (see Adverse Reactions). Patients with such treatment should be monitored regularly and carefully.
Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs and thiazide diuretics: The use of an ACE inhibiting drug (ACE-inhibitor or angiotensin receptor antagonist), an anti-inflammatory drug (NSAID or COX-2 inhibitor) and a thiazide diuretic at the same time increases the risk of renal impairment. This includes use in fixed-combination products containing more than one class of drug. Combined use of these medications should be accompanied by increased monitoring of serum creatinine, particularly at the institution of the combination. The combination of drugs from these three classes should be used with caution particularly in elderly patients or those with pre-existing renal impairment.
Haemodialysis: During dialysis the blood pressure may be particularly sensitive to AT₁-receptor blockade as a result of reduced plasma volume and activation of the renin-angiotensin-aldosterone system. Therefore, Atacand should be carefully titrated with thorough monitoring of blood pressure in patients on haemodialysis.
Hypotension: Hypotension may occur during treatment with Atacand in heart failure patients. As described for other agents acting on the renin-angiotensin-aldosterone system, it may also occur in hypertensive patients with intravascular volume depletion such as those receiving high dose diuretics. Caution should be observed when initiating therapy and correction of hypovolemia should be attempted.
Use in heart failure: Triple combination of Atacand with an ACE-inhibitor and a mineralocorticoid receptor antagonist used in heart failure is also not recommended. Use of these combinations should be under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
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.
Hyperkalaemia: Based on experience with the use of other medicinal products that affect the renin-angiotensin-aldosterone system, concomitant use of Atacand with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (e.g. heparin, co-trimoxazole) may lead to increases in serum potassium in hypertensive patients.
In heart failure patients treated with Atacand, hyperkalaemia may occur. During treatment with Atacand in patients with heart failure, periodic monitoring of serum potassium is recommended, especially when taken concomitantly with ACE inhibitors and potassium-sparing diuretics such as spironolactone.
General: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Atacand Plus: 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 Atacand Plus is not recommended until this condition has been corrected.
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.
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-angiotensin-aldosterone system, concomitant use of Atacand Plus and ACE inhibitors, aliskiren, potassium-sparing diuretics, potassium supplements or salt substitutes or other drugs that may increase serum potassium levels (e.g. heparin, co-trimoxazole) 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: 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.

Use in Pregnancy: The use of Atacand/Atacand Plus is contraindicated during pregnancy (see Contraindications). Patients receiving Atacand/Atacand Plus 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/Atacand Plus 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) (see Pharmacology: Toxicology: Preclinical safety data under Actions).
Atacand Plus: There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during pregnancy may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
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, Atacand/Atacand Plus should not be given during breast-feeding (see Contraindications).
Atacand Plus: Hydrochlorothiazide passes into mother's milk.

Atacand: 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.
Infections and infestations: Respiratory infection.
Laboratory findings: In general, there were no clinically important influences of Atacand on routine laboratory variables. As for other inhibitors of the renin-angiotensin-aldosterone system, small decreases in haemoglobin have been seen. Increases in creatinine, urea or potassium and decrease in sodium have been observed. Increases in S-ALAT (S-GPT) were reported as adverse events slightly more often with Atacand than with placebo (1.3% vs 0.5%). No routine monitoring of laboratory variables is usually necessary for patients receiving Atacand. However, in patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended.
Treatment of Heart Failure: The adverse experience profile of Atacand in heart failure patients was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM clinical programme, comparing Atacand in doses up to 32 mg (n=3,803) to placebo (n=3,796), 21.0% of the candesartan cilexetil group and 16.1% of the placebo group discontinued treatment because of adverse events. Adverse reactions commonly (≥1/100, <1/10) seen were: Vascular disorders: Hypotension.
Metabolism and nutrition disorders: Hyperkalaemia.
Renal and urinary disorders: Renal impairment.
Laboratory findings: Increases in creatinine, urea and potassium. Periodic monitoring of serum creatinine and potassium is recommended (see Precautions).
Post Marketing: The following adverse reactions have been reported very rarely (<1/10,000) in post marketing experience: Blood and lymphatic system disorders: Leukopenia, neutropenia and agranulocytosis.
Metabolism and nutrition disorders: Hyperkalaemia, hyponatraemia.
Nervous system disorders: Dizziness, headache.
Gastrointestinal disorders: Nausea.
Hepato-biliary disorders: Increased liver enzymes, abnormal hepatic function or hepatitis.
Skin and subcutaneous tissue disorders: Angioedema, rash, urticaria, pruritus.
Musculoskeletal, connective tissue and bone disorders: Back pain, arthralgia, myalgia.
Renal and urinary disorders: Renal impairment, including renal failure in susceptible patients (see Precautions).
Respiratory, thoracic and mediastinal disorders: Cough.
Atacand Plus: In controlled clinical studies with candesartan cilexetil/hydrochlorothiazide adverse events were mild and transient. Withdrawals from treatment due to adverse events were similar with candesartan cilexetil/hydrochlorothiazide (2.3-3.3%) and placebo (2.7-4.3%).
In a pooled analysis of clinical trial data, the following common (>1/100) adverse reactions with candesartan cilexetil/hydrochlorothiazide were reported based on an incidence of adverse events with candesartan cilexetil/hydrochlorothiazide at least 1% higher than the incidence seen with placebo: Nervous system disorders: Dizziness/vertigo.
Candesartan cilexetil: The following adverse reactions have been reported very rarely (<1/10,000) with candesartan cilexetil in post marketing experience: Blood and lymphatic system disorders: Leukopenia, neutropenia and agranulocytosis.
Metabolism and nutrition disorders: Hyperkalaemia, hyponatraemia.
Respiratory, thoracic and mediastinal disorders: Cough.
Nervous system disorders: Dizziness, headache.
Gastrointestinal disorders: Nausea.
Hepato-biliary disorders: Increased liver enzymes, abnormal hepatic function or hepatitis.
Skin and subcutaneous tissue disorders: Angioedema, rash, urticaria, pruritus.
Musculoskeletal, connective tissue and bone disorders: Back pain, arthralgia, myalgia.
Renal and urinary disorders: Renal impairment, including renal failure in susceptible patients (see Precautions).
Hydrochlorothiazide: The following adverse reactions have been reported with hydrochlorothiazide, usually with doses of 25 mg or greater. The frequencies used are: Common (>1/100), uncommon (>1/1000 and <1/100), rare (<1/1000) and not known (cannot be estimated from the available data).
Blood and lymphatic system disorders: Rare: Leucopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anaemia, bone marrow depression, haemolytic anaemia.
Immune system disorders: Rare: Anaphylactic reactions.
Eye disorders: Not known: Acute myopia, acute angle-closure glaucoma.
Metabolism and nutrition disorders: Common: Hyperglycaemia, hyperuricaemia, electrolyte imbalance (including hyponatraemia and hypokalaemia).
Psychiatric disorders: Rare: Sleep disturbances, depression, restlessness.
Nervous system disorders: Common: Light-headedness, vertigo.
Rare: Paraesthesia.
Eye disorders: Rare: Transient blurred vision.
Cardiac disorders: Rare: Cardiac arrhythmias.
Vascular disorders: Uncommon: Postural hypotension.
Rare: Necrotising angitis (vasculitis, cutaneous vasculitis).
Respiratory, thoracic and mediastinal disorders: Rare: Respiratory distress (including pneumonitis and pulmonary oedema).
Gastrointestinal disorders: Uncommon: Anorexia, loss of appetite, gastric irritation, diarrhoea, constipation.
Rare: Pancreatitis.
Hepatobiliary disorders: Rare: Jaundice (intrahepatic cholestatic jaundice).
Skin and subcutaneous tissue disorders: Uncommon: Rash, urticaria, photosensitivity reactions.
Rare: Toxic epidermal necrolysis.
Frequency not known: Systemic lupus erythematosus, cutaneous lupus erythematosus.
Musculoskeletal and connective tissue disorders: Rare: Muscle spasm.
Renal and urinary disorders: Common: Glycosuria; Rare: Renal dysfunction and interstitial nephritis.
General disorders and administration site conditions: Common: Weakness.
Rare: Fever.
Investigations: Common: Increases in cholesterol and triglycerides.
Rare: Increases in BUN and serum creatinine.
Laboratory findings: Increases in serum uric acid, blood glucose and serum ALAT (SGPT) were reported as adverse events slightly more often with candesartan cilexetil/hydrochlorothiazide (crude rates 1.1%, 1.0% and 0.9%, respectively) than with placebo (0.4%, 0.2% and 0%, respectively). Minor decreases in haemoglobin and increases in serum ASAT (SGOT) have been observed in single patients receiving candesartan cilexetil/hydrochlorothiazide. Increases in creatinine, urea or potassium and decease in sodium have been observed.

Clinical trial data has shown that dual blockade of the RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see Contraindications and Precautions).
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.
Based on experience with the use of other medicinal products that affect the renin-angiotensin-aldosterone system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (e.g. heparin Na) may lead to increases in serum potassium.
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors or hydrochlorothiazide (Atacand Plus). 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/Atacand Plus 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 bioavailability of candesartan is not affected by food.
Atacand: 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.
The antihypertensive effect of candesartan may be enhanced by other medicinal products with blood pressure lowering properties, whether prescribed as an antihypertensive or prescribed for other indications.
As with other antihypertensive agents, the antihypertensive effect of candesartan may be attenuated by NSAIDs such as indomethacin.
Atacand Plus: The bioavailability of candesartan is not affected by food.
The antihypertensive effect of Atacand 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 (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid derivatives).
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.
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.
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.
Thiazides may increase the responsiveness to nondepolarizing skeletal muscle relaxants (e.g. tubucurarine).
Treatment with a thiazide diuretic may impair glucose tolerance. Other antidiabetic drugs including insulin requirements in diabetic patients may be increased, decreased, or unchanged.
Thiazides may decrease arterial responsiveness to noradrenaline, but not enough to preclude effectiveness of the pressor agent for therapeutic use.
Hypokalemia may develop during concomitant use of steroids or adrenocorticotropic hormone (ACTH).
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 the dose adjusted accordingly.
The hyperglycaemic effect of diazoxide may be enhanced by thiazides.
Thiazides may increase the risk of adverse effects caused by amantadine.
Thiazides may reduce the renal excretion of cytotoxic medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.
Postural hypotension may become aggravated by simultaneous intake of alcohol, barbiturates or anaesthetics.
Concomitant treatment with cyclosporine may increase the risk of hyperuricaemia and gout-type complications.

Do not store above 30°C.

Angiotensin II Antagonists / Diuretics

C09CA06 - candesartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.
C09DA06 - candesartan and diuretics ; Belongs to the class of angiotensin II receptor blockers (ARBs) in combination with diuretics. Used in the treatment of cardiovascular disease.

POM

Atacand tab 4 mg (round (diameter 7 mm), white with a score and marked A/CF on one side and marked 004 on the other side) x 28's. 8 mg (round (diameter 7 mm), light pink with a score and marked A/CG on one side and marked 008 on the other side) x 28's. 16 mg (round (diameter 7 mm), pink with a score and marked A/CH on one side and marked 016 on the other side) x 28's. Atacand Plus 16 mg/12.5 mg tab (peach, oval, biconvex with a score on both sides and engraved A/CS on one side) 28's.