Angiotensin II antagonists (angiotensin II receptor antagonists)

Candesartan cilexetil

Amias 2 mg Tablets. Amias 4 mg Tablets. Amias 8 mg Tablets. Amias 16 mg Tablets. Amias 32 mg Tablets.

Tablet. Amias 2 mg Tablets are round white tablets. Amias 4 mg Tablets are round white tablets with a single score line on both sides. Amias 8 mg Tablets are round pale pink tablets with a single score line on both sides. Amias 16 mg Tablets are round light pink tablets with one convex side and one scored flat side, embossing 16 on convex side. Amias 32 mg Tablets are round light pink tablets with convex faces, debossed 32 on one face and scored on the other face.

Essential hypertension. Treatment of patients with heart failure and impaired left ventricle systolic function (left ventricular ejection fraction 40%) as add-on therapy to ACEinhibitors or when ACE-inhibitors are not tolerated.

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. 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 patients with intravascular volume depletion

An initial dose of 4 mg may be considered in patients at risk for hypotension, such as patients with possible volume depletion.

 Use in impaired renal function

The starting dose is 4 mg in patients with renal impairment, including patients on haemodialysis. The dose should be titrated according to response. There is limited experience in patients with very severe or end-stage renal impairment (Cl_creatinine <15 ml/min). 

 Use in impaired hepatic function

An initial dose of 2 mg once daily is recommended in patients with mild to moderate hepatic impairment. The dose may be adjusted according to response. There is no experience in patients with severe hepatic impairment.

Concomitant therapy

Addition of a thiazide-type diuretic such as hydrochlorothiazide has been shown to have an additive antihypertensive effect with Amias.

Dosage in heart failure

The usual recommended initial dose of Amias is 4 mg once daily. Up-titration to the target dose of 32 mg once daily or the highest tolerated dose is done by doubling the dose at intervals of at least 2 weeks.

Special patient populations

No initial dose adjustment is necessary for elderly patients or in patients with intravascular volume depletion, renal impairment or mild to moderate hepatic impairment.

Concomitant therapy

Amias can be administered with other heart failure treatment, including ACE inhibitors, betablockers, diuretics and digitalis or a combination of these medicinal products.

Administration

Amias should be taken once daily with or without food.

Use in black patients

The antihypertensive effect of candesartan is less in black than non-black patients. Consequently, uptitration of Amias and concomitant therapy may be more frequently needed for blood pressure control in black than non-black patients.

The safety and efficacy of Amias have not been established in children and adolescents (under 18 years).

No initial dosage adjustment is necessary in elderly patients.

Hypersensitivity to candesartan cilexetil or to any of the excipients.

Pregnancy and lactation.

Severe hepatic impairment and/or cholestasis.

Renal impairment

As with other agents inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible patients treated with Amias.

When Amias 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 Amias 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 Amias, 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).

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. Patients with such treatment should be monitored regularly and carefully.

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 Amias should be carefully titrated with thorough monitoring of blood pressure in patients on haemodialysis.

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.

Kidney transplantation

There is no experience regarding the administration of Amias in patients with a recent kidney transplantation.

Hypotension

Hypotension may occur during treatment with Amias 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.

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.

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 will not generally respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin-aldosterone system. Therefore, the use of Amias is not recommended.

Hyperkalaemia

Based on experience with the use of other medicinal products that affect the renin-angiotensin-aldosterone system, concomitant use of Amias with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (e.g. heparin) may lead to increases in serum potassium in hypertensive patients.

In heart failure patients treated with Amias, hyperkalaemia may occur. During treatment with Amias 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

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 cardiopathy or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

No drug interactions of clinical significance have been identified.

Compounds which have been investigated in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinylestradiol/ levonorgestrel), glibenclamide, nifedipine and enalapril.

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.

Based on experience with the use of other medicinal products that affect the reninangiotensinaldosterone 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) 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. A similar effect may occur with angiotensin II receptor antagonists and careful monitoring of serum lithium levels is recommended during concomitant use.

When Angiotensin II receptor antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (>3g/day) and non-selective NSAIDs), attenuation of the antihypertensive effect may occur.

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 bioavailability of candesartan is not affected by food.

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 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:

The frequencies used in the tables throughout this section are: very common ( 1/10) common (1/100 <1/10), uncommon (1/1000, <1/100 ), rare (1/10 000, <1/1000) and very rare (<1/10 000)

Laboratory findings

In general, there were no clinically important influences of Amias 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 (SGPT) were reported as adverse events slightly more often with Amias than with placebo (1.3% vs 0.5%). No routine monitoring of laboratory variables is usually necessary for patients receiving Amias. 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 Amias 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 Amias 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 seen were:

Laboratory findings

Increases in creatinine, urea and potassium. Periodic monitoring of serum creatinine and potassium is recommended.

Post marketing

The following adverse reactions have been reported in post marketing experience:

Takeda UK Ltd

(POM)

30 June 2009