Drug Interactions
In the presence of thiazide diuretics possible decreased response to pressor amines may be seen but not sufficient to preclude their use.
ATACAND PLUS may be taken with or without food (see Dosage and Administration).
Thiazide diuretic potentiation of orthostatic hypotension may occur.
Intensified electrolyte depletion, particularly hypokalemia, may occur when given concomitantly with thiazide diuretics.
No significant drug interactions have been reported with glyburide, nifedipine or oral contraceptives co-administered with candesartan cilexetil to healthy volunteers. Co-administration of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol, may increase the risk of adverse effects caused by amantadine, may enhance the hyperglycemic effect of diazoxide, and may reduce the renal excretion of cytotoxic drugs (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.
The bioavailability of thiazide diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate.
There have been reports in the literature of hemolytic anemia occurring with concomitant use of hydrochlorothiazide and methyldopa.
Absorption of thiazide diuretics is decreased by cholestyramine.
Administration of thiazide diuretics with vitamin D or with calcium salts may potentiate the rise in serum calcium.
Concomitant treatment with cyclosporin may increase the risk of hyperuricemia and gout type complications.
| Candesartan cilexetil | Effect | Clinical Comment |
| Diuretics | Patients on diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with candesartan cilexetil. | The possibility of symptomatic hypotension with the use of ATACAND can be minimized by discontinuing the diuretic prior to initiation of treatment and/or lowering the initial dose of candesartan cilexetil (see Warnings and Precautions, Cardiovascular, Hypotension and Dosage and Administration). No drug interaction of clinical significance has been identified with thiazide diuretics in patients treated with up to 25 mg hydrochlorothiazide with 16 mg ATACAND for 8 weeks. |
| Agents Increasing Serum Potassium | ATACAND decreases the production of aldosterone. | Potassium-sparing diuretics or potassium supplements should be given only for documented hypokalemia and with frequent monitoring of serum potassium. Potassium-containing salt substitutes should also be used with caution. |
| Lithium Salts | As with other drugs which eliminate sodium, lithium clearance may be reduced. Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. | Serum lithium levels should be monitored carefully if lithium salts are to be administered. |
| NSAIDS | In some patients, the administration of a nonsteroidal anti-inflammatory agent/drug (NSAID) can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. | When ATACAND PLUS and NSAIDs are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained. |
Insulin requirements in diabetic patients treated with diuretics may be increased, decreased or unchanged. Diabetes mellitus which has been latent may become manifest during thiazide administration.
Thiazide drugs may increase the responsiveness to tubocurarine.
When candesartan cilexetil was administered at 16 mg once daily under steady state conditions, no pharmacodynamic effect on prothrombin time was demonstrated in subjects stabilized on warfarin.
Combination treatment with candesartan cilexetil and digoxin in healthy volunteers had no effect on AUC or Cmax values for digoxin compared to digoxin alone. Similarly, combination treatment had no effect on AUC or Cmax values for candesartan compared to candesartan cilexetil alone.
Thiazide-induced electrolyte disturbances may predispose to digitalis-induced arrhythmias.
Information for the Patient
Atacand Plus
Dosage and Administration
The recommended initial dose of candesartan cilexetil is 16 mg, once daily. Total daily doses of candesartan cilexetil should range from 8 to 32 mg. Doses higher than 32 mg do not appear to have a greater effect on blood pressure reduction, and there is relatively little experience with such doses. Most of the antihypertensive effect is present within 2 weeks and the maximal blood pressure reduction is generally obtained within 4 weeks. For patients with possible depletion of intravascular volume (e.g. patients treated with diuretics, particularly those with impaired renal function) consideration should be given to administration of a lower dose. If blood pressure is not controlled by ATACAND alone, a thiazide diuretic may be added (see Drug Interactions, Drug-Drug Interaction, Table 2: Diuretics).
No dose adjustment of ATACAND PLUS is necessary for elderly patients. As greater sensitivity of some older patients cannot be ruled out, appropriate caution is recommended (see Warnings and Precautions, Geriatrics (>65 years of age)).
In patients receiving diuretics, candesartan cilexetil therapy should be initiated with caution, since these patients may be volume-depleted and thus more likely to experience hypotension following initiation of additional antihypertensive therapy.
Whenever possible, all diuretics should be discontinued two to three days prior to the administration of candesartan cilexetil, to reduce the likelihood of hypotension (see Warnings and Precautions, Cardiovascular, Hypotension). If this is not possible because of the patient's condition, candesartan cilexetil should be administered with caution and the blood pressure monitored closely. Thereafter, the dosage should be adjusted according to the individual response of the patient.
Once the patient has been stabilized on the individual components as described below, one 16 mg/12.5 mg tablet once daily may be taken if the doses on which the patient was stabilized are the same as those in the fixed combination (see Indications and Clinical Use).
Initiation of therapy requires consideration of recent antihypertensive treatment, the extent of blood pressure elevation, salt restriction, and other pertinent clinical factors.
ATACAND PLUS should be taken once daily, at approximately the same time each day, with or without food.
If a patient misses a dose of ATACAND PLUS and remembers within 12 hours, the patient should take the dose as soon as possible and then go back to the regular schedule. If it is more than 12 hours after the patient remembers, they should not take the missed dose; the next dose should be taken on time.
A double dose of ATACAND PLUS should never be taken to make up for a missed dose.
No dosage adjustment of ATACAND PLUS is necessary in patients with mild to moderate chronic liver disease.
Since dosage adjustment of candesartan cilexetil is necessary in patients with severely impaired hepatic function and/or cholestasis, and thiazide diuretics may precipitate hepatic coma, use of ATACAND PLUS is not recommended in these patients (see Warnings and Precautions, Hepatic Impairment).
The safety and efficacy of ATACAND PLUS have not been established in children.
The dosage of ATACAND PLUS (candesartan cilexetil/hydrochlorothiazide) must be individualized. The fixed combination is not for initial therapy. The dose of ATACAND PLUS should be determined by titration of the individual components.
No dosage adjustment of candesartan cilexetil is necessary in patients with mildly impaired renal function.
In patients with moderately or severely impaired renal function, or in patients undergoing dialysis, a lower initial dose of 4 mg should be considered.
The usual regimens of therapy with ATACAND PLUS may be followed as long as the patient's creatinine clearance is >30 mL/min/1.73 m2 BSA. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so ATACAND PLUS is not recommended.
Adverse Reactions
constipation, dyspepsia, dry mouth, toothache.
An increase in creatinine and urea has been observed with ATACAND PLUS.
hypertonia, hypoesthesia, paresthesia, vertigo.
Potentially serious clinical adverse events have been reported to occur with hydrochlorothiazide, such as: jaundice (intrahepatic cholestatic jaundice), pancreatitis, leukopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anemia, haemolytic anemia, photosensitivity reactions, necrotising angitis (vasculitis), toxic epidermal necrolysis, anaphylactic reactions, respiratory distress (including pneumonitis and pulmonary edema), hypokalemia, renal dysfunction and interstitial nephritis.
abnormal urine, cystitis.
At least 653 hypertensive patients have been treated with candesartan cilexetil/hydrochlorothiazide 16 mg/12.5 mg tablets.
In controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of ATACAND PLUS.
allergy, asthenia, pain, syncope.
A small decrease (mean decrease of 0.1 mmol/L) in serum potassium was observed in patients treated with ATACAND PLUS but was rarely of clinical importance. Values of serum potassium below the predefined lower critical limit were recorded in 0.6% of patients in controlled clinical trials with ATACAND PLUS. An increase in serum potassium has rarely been observed with ATACAND PLUS. A decrease in sodium has been observed with ATACAND PLUS.
depression, impotence, neurosis.
In controlled clinical trials, elevations of blood glucose occurred in 1.0% of patients treated with ATACAND PLUS compared to 0.2% of patients receiving placebo.
arthritis, arthropathy, myalgia, myopathy, skeletal pain, tendon disorder.
Angioedema, (involving swelling of the face, lips and/or tongue) has been reported rarely in patients treated with candesartan cilexetil.
In other post-marketing experience, renal impairment, including renal failure in susceptible patients, has been observed (see Warnings and Precautions, Renal, Renal Impairment for definition of susceptible patients).
Very rare cases of abnormal hepatic function or hepatitis have also been reported.
Other adverse events reported for candesartan cilexetil where a causal relationship could not be established include very rare cases of leukopenia, neutropenia and agranulocytosis.
Cases of muscle pain, muscle weakness, myositis and rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
ATACAND PLUS (candesartan cilexetil/hydrochlorothiazide) has been evaluated for safety in over 2500 patients treated for hypertension, including more than 700 treated for six months or more, and 500 for about one year or more. In placebo controlled double blind trials candesartan cilexetil/hydrochlorothiazide combination was administered to 1025 hypertensive patients. Approximately 600 patients received ATACAND PLUS 16 mg/12.5 mg. The overall exposure to the candesartan cilexetil/hydrochlorothiazide combination amounts to 977 patient-years.
In general, adverse events were mild and transient in placebo controlled clinical studies with various doses of candesartan cilexetil/hydrochlorothiazide up to 16 mg/25 mg. In controlled clinical trials, discontinuation due to adverse events occurred in 3.3% and 2.7% of patients treated with ATACAND PLUS and placebo, respectively. The incidence of serious adverse events observed with candesartan cilexetil/hydrochlorothiazide was 2.7% (71 out of 2582 patients).
eczema, pruritus, rash, skin disorder, sweating, (rarely) urticaria.
diabetes mellitus, hyperkalaemia, hyponatraemia.
Increases in serum uric acid were found in 1.1% of patients treated with ATACAND PLUS and 0.4% of patients treated with placebo.
Small decreases in hemoglobin were observed in patients treated with ATACAND PLUS but were rarely of clinical importance. Values of hemoglobin below the predefined critical limit were recorded in 0.9% of patients in controlled clinical trials with ATACAND PLUS.
In controlled clinical trials, elevations of ALT (>3 times the upper limit of normal) occurred in 0.9% of patients treated with ATACAND PLUS compared to 0% of patients receiving placebo. Minor increases in serum AST have been observed in single patients receiving candesartan cilexetil/hydrochlorothiazide.
angina pectoris, circulatory failure, flushing, hypotension, myocardial infarction, peripheral ischemia, thrombophlebitis.
Indications and Clinical Use
The safety and efficacy of ATACAND PLUS have not been established in children.
No overall differences in safety or effectiveness were observed between the younger and elderly patients but greater sensitivity of some older patients cannot be ruled out and appropriate caution is recommended.
Overdosage
Limited data are available in regard to overdosage of candesartan cilexetil in humans. The most likely manifestations of overdosage would be hypotension, dizziness and tachycardia; bradycardia could occur from reflex parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive 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 also be administered if the above-mentioned measures are not sufficient. In case reports detailing overdosage (up to 672 mg candesartan cilexetil) patient recovery was uneventful.
Candesartan cilexetil is not removed from the plasma by hemodialysis.
The most common symptoms observed from overdosage of hydrochlorothiazide are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.
Dosage Forms, Composition and Packaging
Each oval, biconvex, peach tablet, with a score and marked 
on one side, contains: candesartan cilexetil 16 mg and hydrochlorothiazide 12.5 mg. Nonmedicinal ingredients: calcium carboxymethylcellulose, hydroxypropyl cellulose, iron oxide, lactose, magnesium stearate, maize starch and polyethylene glycol. Blister packs of 30.
Warnings and Precautions
Thiazides may increase the responsiveness to tubocurarine.
Oral doses ≥10 mg candesartan cilexetil/kg/day administered to pregnant rats during late gestation and continued through lactation were associated with reduced survival and an increased incidence of hydronephrosis in the offspring. Candesartan cilexetil given to pregnant rabbits at an oral dose of 3 mg/kg/day caused maternal toxicity (decreased body weight and death) but, in surviving dams, had no adverse effects on fetal survival, fetal weight, or external, visceral, or skeletal development. No maternal toxicity or adverse effects on fetal development were observed when oral doses up to 1000 mg candesartan cilexetil/kg/day were administered to pregnant mice.
Patients receiving thiazides, including hydrochlorothiazide (HCTZ), should be carefully observed for clinical signs of fluid and electrolyte imbalance (hyponatremia, hypochloremic alkalosis and hypokalemia).
Periodic determinations of serum electrolytes, to detect possible electrolyte disturbance, should be performed at appropriate intervals. Warning signs or symptoms of fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscle fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances such as nausea and vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g. increased ventricular irritability).
Any chloride deficit during thiazide therapy is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients in hot weather. Appropriate therapy is water restriction rather than administration of salt, except in rare instances, when the hyponatremia is life threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazide therapy.
Thiazides may decrease serum PBI (protein bound iodine) levels without signs of thyroid disturbance.
Thiazides have been shown to increase excretion of magnesium; this may result in hypomagnesemia.
Thiazides may decrease urinary calcium excretion and may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Increase in cholesterol, triglycerides and glucose levels may be associated with thiazide diuretic therapy. However, at the 12.5 mg dose, present in ATACAND PLUS (candesartan cilexetil/hydrochlorothiazide), minimal or no effect was reported.
Occasionally, symptomatic hypotension has occurred after administration of candesartan cilexetil. It is more likely to occur in patients who are volume-depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting, or undergoing surgery with anaesthesia. In these patients, because of the potential fall in blood pressure, therapy should be started under close medical supervision. Similar considerations apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident.
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid or electrolyte balance may precipitate hepatic coma (see Dosage and Administration, Hepatic Impairment).
No studies were carried out with candesartan cilexetil/hydrochlorothiazide fixed combination in patients with impaired hepatic function.
Drugs that act directly on the renin-angiotensin-aldosterone-system (RAAS) can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, ATACAND PLUS should be discontinued as soon as possible.
The use of ARBs is not recommended during pregnancy. Epidemiological evidence regarding the risk of teratogenicity following exposure to angiotensin converting enzyme inhibitors (another class of therapeutic products interfering with the RAAS) during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Given the current evidence available on the risk with ARBs, similar risks may exist for this class of drugs. Patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin receptor (AT1) blockers should be stopped immediately, and, if appropriate, alternative therapy should be started.
The use of ARBs during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
Infants with a history of in utero exposure to ARBs should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit. Candesartan cilexetil is not removed from plasma by dialysis.
Thiazides cross the placental barrier and appear in cord blood. The routine use of diuretics in otherwise healthy pregnant women is not recommended and exposes mother and fetus to unnecessary hazard including fetal or neonatal jaundice, thrombocytopenia and possibly other adverse experiences which have occurred in the adult. Diuretics do not prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia.
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.
Use of candesartan cilexetil should include appropriate assessment of renal function. Thiazides should be used with caution.
Because of the hydrochlorothiazide component, ATACAND PLUS is not recommended in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m2 BSA).
There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.
No overall differences in safety or effectiveness were observed between the younger and elderly patients but greater sensitivity of some older patients cannot be ruled out and appropriate caution is recommended.
Sensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported in patients treated with hydrochlorothiazide.
Azotemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease the diuretic should be discontinued.
The safety and efficacy of ATACAND PLUS have not been established in children.
It is not known whether candesartan is excreted in human milk, but significant levels have been found in the milk of lactating rats. Thiazides appear in human milk. Because many drugs are excreted in human milk, and because of their potential for affecting the nursing infant adversely, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Storage and Stability
Store at 15-30°C.
Action and Clinical Pharmacology
In patients with mild to moderate hepatic impairment, there was an increase in the AUC of candesartan of approximately 20%. There was no drug accumulation in plasma in these patients. In patients with moderate to severe hepatic impairment, the Cmax and AUC increased up to five times in a very small group administered a single dose of 16 mg candesartan (see Dosage and Administration, Hepatic Impairment).
The plasma concentration of candesartan was higher in the elderly (≥65 years) (Cmax was approximately 50% higher, and AUC was approximately 80% higher) compared to younger subjects administered the same dose. The pharmacokinetics of candesartan were linear in the elderly, and candesartan and its inactive metabolite did not accumulate in the serum of these subjects upon repeated, once-daily administration.
The bioavailability may decrease in patients with cardiac failure and pronounced edema. The plasma protein binding of hydrochlorothiazide is approximately 60%. The apparent volume of distribution is approximately 0.8 L/kg.
hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with an absolute bioavailability of approximately 70%. Concomitant food intake increases the absorption by approximately 15%.
ATACAND PLUS (candesartan cilexetil/hydrochlorothiazide) combines the actions of candesartan cilexetil, an angiotensin II AT1 receptor blocker, and that of a thiazide diuretic, hydrochlorothiazide.
Hydrochlorothiazide is not metabolized and is excreted almost entirely as unchanged drug by glomerular filtration and active tubular secretion. The terminal t½ 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 (8 hours) after administration of hydrochlorothiazide in combination with candesartan cilexetil. No accumulation of hydrochlorothiazide occurs after repeated doses of the combination compared to monotherapy.
The terminal t½ of hydrochlorothiazide is prolonged in the elderly and in patients with renal failure or chronic heart failure.
Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
In patients with mild to moderate renal impairment (Clcreat 31-60 mL/min/1.73 m2), Cmax and AUC of candesartan increased by 40-60% and 50-90%, respectively, but t½ was not altered, compared to patients with normal renal function (Clcreat >60 mL/min/1.73 m2) during repeated dosing. There was no drug accumulation in plasma in patients with mild to moderate renal impairment. The increases in Cmax and AUC in patients with severe renal impairment (Clcreat 15-30 mL/min/1.73 m2) were 40-60% and 110%, respectively. The terminal t½ of candesartan was approximately doubled in patients with severe renal impairment, and these changes resulted in some accumulation in plasma. The pharmacokinetics of candesartan in patients undergoing hemodialysis were similar to those in patients with severe renal impairment (see Dosage and Administration, Renal Impairment).
No gender-related differences in the pharmacokinetics of candesartan have been observed.
Candesartan cilexetil is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan. It undergoes minor hepatic metabolism by O-deethylation to an inactive metabolite. In vitro studies indicate that cytochrome P450 isoenzyme CYP 2C9 is involved in the biotransformation of candesartan to its inactive metabolite. 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.
Contraindications
ATACAND PLUS (candesartan cilexetil/hydrochlorothiazide) is contraindicated in:
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Patients who are hypersensitive to any component of this product (see Dosage Forms, Composition and Packaging).
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Patients with anuria and patients who are hypersensitive to other sulfonamide-derived drugs, because of the hydrochlorothiazide component (see Warnings and Precautions, Immune and Adverse Reactions, Post-Market Adverse Drug Reactions).
