Unisia is indicated as replacement therapy for essential hypertension in adults whose blood pressure is being adequately controlled with concomitant administration of amlodipine and candesartan cilexetil in the same dosage range.

Posology

Patients should take the strength that corresponds to their previous treatment.

Different strengths of this medicinal product are available for the usual dosages: The dose of 8 mg candesartan cilexetil and 2.5 mg amlodipine once daily is achieved by administering one tablet of Unisia 8 mg/2.5 mg.  

The dose of 8 mg candesartan cilexetil and 5 mg amlodipine once daily is achieved by administering one tablet of Unisia 8 mg/5 mg.

The maximum dose of candesartan cilexetil is 32 mg daily and the maximum dose of amlodipine is 10 mg daily.

Elderly (over 65 years)

The dose should be increased with caution (see sections 4.4 and 5.2).

Hepatic impairment

No dosage recommendations are available for patients with hepatic impairment. Unisia is contraindicated in patients with severe hepatic impairment and/or cholestasis (see sections 4.3, 4.4, and 5.2).

Renal impairment

No dosage adjustment is required in patients with mild to moderate renal impairment (creatinine clearance > 15 ml/min; see sections 4.4 and 5.2). Monitoring of potassium and creatinine levels is recommended in patients with moderate renal impairment.

Pediatric population

The safety and effectiveness of candesartan cilexetil/amlodipine besylate in children under 18 years of age have not yet been established. No data available.

Method of administration

The tablets can be taken with or without food.

• Hypersensitivity to the active ingredients, to dihydropyridine derivatives or to any of the excipients listed in section 6.1. • Severe hypotension. • Shock (including cardiogenic shock). • Obstruction of the left ventricular outflow tract (e.g., severe aortic stenosis). • Hemodynamically unstable heart failure following acute myocardial infarction. • Second and third trimesters of pregnancy (see sections 4.4 and 4.6). • Severe hepatic impairment and/or cholestasis. • The concomitant use of Unisia with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

Amlodipine

The safety and efficacy of amlodipine in hypertensive crisis have not yet been confirmed.

Heart failure

Caution is advised in the treatment of patients with heart failure. In a long-term placebo-controlled study, there were increased reports of pulmonary edema in patients with severe heart failure (NYHA functional class III and IV) taking amlodipine compared with the placebo group (see section 5.1). Calcium channel blockers, including amlodipine, should be used with caution in patients with chronic heart failure because these may increase the risk of future cardiovascular events as well as mortality.

Hepatic impairment

In patients with hepatic impairment, the half-life of amlodipine is prolonged and AUC values are elevated; there is no recommended dose. Amlodipine should therefore be started at the lower end of the dosing range in these patients and should be administered with caution, both when initiating therapy and when increasing the dose. In patients with severe hepatic impairment, slow dose titration and close monitoring may be necessary.

Elderly

In elderly patients, the dosage should be increased only with caution (see sections 4.2 and 5.2).

Renal impairment

Amlodipine may be used in such patients at usual doses. There is no correlation between the degree of renal impairment and changes in plasma amlodipine levels. Amlodipine is not dialyzable.

Candesartan

Renal impairment

As with other medicinal products that block the renin-angiotensin-aldosterone system, changes in renal function can be expected in susceptible patients treated with candesartan.

When candesartan 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 renal impairment or end-stage renal impairment (Cl_creatinine < 15 ml/min). In these patients, candesartan 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 in patients with impaired renal function. During dose titration of candesartan, 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).

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, hyperkalemia, and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combines use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only happen under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

Hemodialysis

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 candesartan should be carefully titrated with thorough monitoring of blood pressure in patients on hemodialysis.

Renal artery stenosis

Medicinal products that affect the renin-angiotensin-aldosterone system, including angiotensin II receptor antagonists (AIIRAs), may increase blood urea and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney.

Kidney transplantation

There is limited clinical evidence regarding candesartan use in patients who have undergone renal transplant.

Hypotension

Hypotension may occur during treatment with Candesartan Cilexetil in heart failure patients. 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.

Anesthesia and surgery

Hypotension may occur during anesthesia 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 hemodynamically 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 candesartan is not recommended in this population.

Hyperkalemia

Concomitant use of Candesartan Cilexetil with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products that may increase potassium levels (e.g. heparin, co-trimoxazole also known as trimethoprim/sulfamethoxazole) may lead to increases in serum potassium in hypertensive patients. Potassium levels should be monitored as appropriate.

Hyperkalemia may occur in heart failure patients treated with candesartan. Periodic monitoring of serum potassium is recommended. The combination of an ACE inhibitor, a potassium-sparing diuretic (e.g., spironolactone), and candesartan is not recommended and should be considered only after careful evaluation of the potential benefits and risks.

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), acute hypotension, azotemia, oliguria, or, rarely, acute renal failure have been associated with treatment with other medicinal products that affect this system. The possibility of similar effects cannot be ruled out for AIIRAs.

As with any antihypertensive agent, an excessive drop in blood pressure could lead to myocardial infarction or stroke in patients with ischemic cardiomyopathy or ischemic cerebrovascular disease.

The antihypertensive effect of candesartan may be enhanced by other medicinal products with antihypertensive properties, whether prescribed as antihypertensives or for other indications.

Pregnancy

Treatment with AIIRAs should not be initiated during pregnancy. Patients planning pregnancy should be switched to an alternative antihypertensive treatment with an established safety profile for use in pregnancy, except where continued treatment with AIIRAs is considered essential.. When pregnancy is diagnosed, treatment with AIIRAs should be discontinued immediately and, if appropriate, alternative therapy should be initiated (see sections 4.3 and 4.6).

Unisia contains sodium  

Unisia contains sodium. Each tablet conatins 0.57 mg sodium. This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.

Interactions associated with amlodipine

Effects of other medicinal products on amlodipine

CYP3A4 inhibitors

Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem) may result in a significant increase in amlodipine exposure with a resulting increased risk of hypotension. The clinical translation of these pharmacokinetic variations may be more pronounced in the elderly. Close monitoring of patients is therefore recommended and dose adjustment may be required.

CYP3A4 inducers

Co-administration of known CYP3A4 inducers may result in varying plasma concentration of amlodipine. Thus, blood pressure should be monitored and dose regulation considered, both during and after concomitant administration, particularly with potent CYP3A4 inducers (e.g., rifampicin, St. John's wort [Hypericum perforatum]).

The concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended because it may increase the bioavailability of amlodipine in some patients. This could lead to increased blood pressure lowering effects

Dantrolene (infusion)

In animals, following administration of verapamil and intravenous dantrolene, lethal ventricular fibrillation and cardiovascular collapse associated with hyperkalemia are observed. Due to risk of hyperkalemia, it is recommended that co-administration of calcium channel blockers such as amlodipine be avoided in those patients susceptible to or being treated for malignant hyperthermia.

Effects of amlodipine on other medicinal products

The antihypertensive effect of amlodipine enhances the blood pressure lowering effect of other antihypertensive medicinal products.

In clinical interaction studies, amlodipine showed no effect on the pharmacokinetics of atorvastatin, digoxin, or warfarin.  

Tacrolimus

There is a risk of increased tacrolimus blood levels from co-administration of amlodipine. To avoid tacrolimus toxicity, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.

mTOR(mechanistic target of rapamycin) inhibitors

mTOR inhibitors, such as sirolimus, temsirolimus, and everolimus, are CYP3A substrates, and amlodipine is a weak CYP3A inhibitor. Amlodipine may increase mTOR inhibitor exposure when used concomitantly with mTOR inhibitors.

Ciclosporin

No drug interaction studies have been conducted with ciclosporin and amlodipine in healthy volunteers or other populations. An exception is renal transplant patients, where variable trough concentration increases (average 0% - 40%) of ciclosporin were observed. In renal transplant patients, monitoring ciclosporin levels should be considered while using amlodipine and the dose of ciclosporin reduced if necessary.

Simvastatin

Co-administration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone. In patients on amlodipine, limit the dose of simvastatin to 20 mg daily.

Interactions associated with candesartan

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

Data from clinical trials has shown that dual blockade of the renin-angiotensin- aldosterone system (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, hyperkalemia, and decreased renal function (including acute renal failure) compared with using a single agent acting on the RAAS (see sections 4.3, 4.4, and 5.1).

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported with concomitant use of lithium and ACE inhibitors. A similar effect may occur with AIIRAs. Using candesartan with lithium is not recommended.

If the combination proves necessary, careful monitoring of serum lithium levels is recommended.

NSAIDs

When AIIRAs are administered concomitantly with nonsteroidal anti-inflammatory medicinal products (NSAIDs) (i.e., selective COX-2 inhibitors, acetylsalicylic acid [> 3 g/day], and nonselective NSAIDs), the antihypertensive effect may be attenuated.

As with ACE inhibitors, concomitant administration of AIIRAs and NSAIDs may result in an increased risk of worsening renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with pre-existing poor renal function. The combination should be administered with caution, especially in the elderly.

Patients should be adequately hydrated, and monitoring of renal function should be considered after initiation of concomitant therapy and periodically thereafter.

Potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, and other substances that can increase potassium level

Concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products (e.g., heparin) may increase potassium levels.

Potassium levels should be monitored as appropriate (see section 4.4).

Compounds that have been studied in clinical pharmacokinetics studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (ie. ethinylestradiol/levonorgestrel), glibenclamide, nifedipine, and enalapril. No clinically significant pharmacokinetic interactions with these medicinal products were observed.

Pregnancy

Candesartan cilexetil/amlodipine besylate is not recommended in the first trimester of pregnancy because no data is available and the safety profile for amlodipine and candesartan has not yet been confirmed.

Use during early pregnancy is recommended only when safer alternative therapies are not available and the disease poses a higher risk to the mother and fetus.

Unisia is contraindicated during the second and third trimesters of pregnancy due to the candesartan it contains.

Amlodipine

The safety of amlodipine during pregnancy has not yet been established. In animal studies, reproductive toxicity was observed at high doses (see section 5.3).

Candesartan

The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 4.4). The use of AIIRAs is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).

No conclusive epidemiologic data is available regarding teratogenicity risk following exposure to ACE inhibitors during the first trimester of pregnancy; however, a slightly increased risk cannot be ruled out. Although there is no controlled epidemiologic data on the risk from angiotensin II receptor antagonists (AIIRAs), similar risks may exist for this class of medicinal products. Unless continued AIIRA therapy is considered essential, patients planning to become pregnant should be switched to an alternative antihypertensive therapy with an appropriate safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be discontinued immediately and, if appropriate, alternative therapy should be initiated.

Therapy with AIIRAs during the second and third trimesters of pregnancy is known to induce human fetotoxicity (decreased renal function, oligohydramnios, delayed cranial ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia) (see also section 5.3). Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound examinations of renal function and skull are recommended.

Infants whose mothers have taken AIIRAs should be frequently reassessed for hypotension (see also sections 4.3 and 4.4).

Breast-feeding

Amlodipine is excreted in human milk. The proportion of the maternal dose that passes to the infant is estimated to be in an interquartile range of 3% to 7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.

Because no evidence is available on the use of candesartan during breast-feeding, candesartan cilexetil/amlodipine besylate tablets are not recommended; alternative antihypertensive therapy with an established safety profile during breast-feeding is preferable, especially while nursing a newborn or preterm infant.

Fertility

Amlodipine

Reversible biochemical changes in the head of spermatozoa have been reported in some patients being treated with calcium channel blockers. Clinical data regarding the potential effect of amlodipine on fertility is still insufficient. In one study on rats, male fertility was affected (see section 5.3).

Candesartan

Animal studies have shown that candesartan cilexetil had no effect on fertility in rats.

Unisia has a moderate impact on ability to drive and use machines. If patients under treatment with candesartan cilexetil/amlodipine besylate suffer from dizziness, headache, fatigue or nausea, responsiveness may be impaired. Caution is indicated here, especially when treatment first starts.

Undesirable effects previously reported with the individual compounds (amlodipine or candesartan) may potentially be an undesirable effect for candesartan cilexetil/amlodipine besylate.

Undesirable effects associated with amlodipine

Summary of the safety profile

The most commonly reported adverse reactions during treatment are drowsiness, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, edema, and fatigue.

The following adverse reactions have been observed and reported during treatment with amlodipine with the following frequencies: very common (≥ 1/10), common (≥ 1/100 to <1/10), occasional (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (frequency cannot be estimated based on available data).

In each frequency group, undesirable effects are listed in order of decreasing severity.

System organ class	Frequency	Undesirable effect
Blood and lymphatic system disorders	Very rare	Leukocytopenia, thrombocytopenia
Immune system disorders	Very rare	Allergic reactions
Metabolism and nutrition disorders	Very rare	Hyperglycemia
Psychiatric disorders	Uncommon	Depression, mood swings (including anxiety), insomnia
	Rare	Confusion
Nervous system disorders	Common	Drowsiness, dizziness, headache (especially at the beginning of treatment)
	Uncommon	Tremor, dysgeusia, syncope, hypoesthesia, paresthesia
	Very rare	Hypertonia, peripheral neuropathy
	Not known	Extrapyramidal disorder
Eye disorders	Common	Visual disturbance (including diplopia)
Ear and labyrinth disorders	Uncommon	Tinnitus
Cardiac disorders	Common	Palpitations
	Uncommon	Arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation)
	Very rare	Myocardial infarction
Vascular disorders	Common	Flushing
	Uncommon	Hypotension
	Very rare	Vasculitis
Respiratory, thoracic and mediastinal disorders	Common	Dyspnea
	Uncommon	Cough, rhinitis
Gastrointestinal disorders	Common	Abdominal pain, nausea, dyspepsia, altered bowel habits (including diarrhea and constipation)
	Uncommon	Vomiting, dry mouth
	Very rare	Pancreatitis, gastritis, gingival hyperplasia
Hepato-biliary disorders	Very rare	Hepatitis, jaundice, increase in hepatic enzymes*
Skin and subcutaneous tissue disorders	Uncommon	Alopecia, purpura, skin discoloration, hyperhidrosis, pruritus, rash, exanthema, urticaria
	Very rare	Angioedema, erythema exsudativum multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke edema, photosensitivity
	Not known	Toxic epidermal necrolysis
Musculoskeletal, connective tissue and bone disorders	Common	Ankle swelling, muscle cramps
	Uncommon	Arthralgia, myalgia, back pain
Renal and urinary disorders	Uncommon	Micturition disorder, nocturia, increased urinary frequency
Reproductive system and breast disorders	Uncommon	Impotence, gynecomastia
General disorders and	Very common	Edema
administration site conditions	Common	Fatigue, asthenia
	Uncommon	Chest pain, pain, malaise
Investigations	Uncommon	Weight gain, weight loss

*mostly consistent with cholestasis Adverse reactions

Associated with candesartan

Treatment for hypertension

In controlled clinical trials, adverse reactions were mild and transient. The overall incidence of adverse events showed no association with dose or age. Discontinuation of treatment due to adverse events were similar between candesartan cilexetil (3.1%) and placebo (3.2%).

In a pooled analysis of data from clinical trials in hypertensive patients, adverse reactions with candesartan cilexetil were defined based on the frequency of adverse events with candesartan cilexetil being at least 1% higher than the frequency observed with placebo. By this definition, the most commonly reported adverse events were dizziness/vertigo, headache, and respiratory infection.

The table below presents adverse reactions from clinical trials and post-marketing experience. The frequency shown in the tables throughout section 4.8 are: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and not known (frequency cannot be estimated from the available data).

 

System organ class	Frequency	Undesirable effect
Infections and infestations	Common	Respiratory infection
Blood and lymphatic system disorders	Very rare	Leukopenia, neutropenia and agranulocytosis
Metabolism and nutrition disorders	Very rare	Hyperkalemia, hyponatremia
Nervous system disorders	Common	Dizziness/vertigo, headache
Respiratory, thoracic and mediastinal disorders	Very rare	Cough
Gastrointestinal disorders	Very rare	Nausea
	Not known	Diarrhea
Hepato-biliary disorders	Very rare	Elevated liver enzymes, abnormal hepatic function or hepatitis
Skin and subcutaneous tissue disorders	Very rare	Angioedema, rash, urticaria, pruritus
Skeletal muscle, connective tissue and bone disorders	Very rare	Back pain, arthralgia, myalgia
Renal and urinary disorders	Very rare	Renal impairment, including renal failure in susceptible patients (see section 4.4)

Laboratory findings

In general, there were no clinically important effects of candesartan cilexetil on routine laboratory variables. As with other renin-angiotensin-aldosterone system inhibitors, there was a small decrease in hemoglobin. Patients receiving candesartan cilexetil usually do not require routine monitoring of laboratory variables. However, in patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

•    Saudi Arabia

The National Pharmacovigilance Centre (NPC)

SFDA Call Center: 19999
E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

•    Other GCC States

Please contact the relevant competent authority

Symptoms

There is no experience of overdose with candesartan cilexetil/amlodipine besylate. Candesartan overdose is likely to manifest as symptomatic hypotension with dizziness. Overdose with amlodipine may result in excessive peripheral vasodilation and possibly reflex tachycardia. Marked and possibly persistent systemic hypotension up to and including shock with fatal outcome have been reported. In individual case reports of overdoses (of up to 672 mg candesartan cilexetil), patients recovered fully.

Non-cardiogenic pulmonary oedema has rarely been reported as a consequence of amlodipine overdose that may manifest with a delayed onset (24-48 hours post-ingestion) and require ventilatory support. Early resuscitative measures (including fluid overload) to maintain perfusion and cardiac output may be precipitating factors.

Management

If ingestion was recent, induced vomiting or gastric lavage may be considered. In healthy volunteers, administration of activated charcoal up to two hours after taking 10 mg of amlodipine has been shown to reduce the amlodipine absorption rate. Clinically significant hypotension due to candesartan cilexetil/amlodipine besylate overdose requires active cardiovascular support, including close monitoring of cardiac and respiratory function, elevation of extremities, and control of fluid balance and urine output.

A vasoconstrictor may be administered to restore vascular tone and blood pressure unless contraindicated. Intravenous calcium gluconate may be useful in reversing the effects of calcium channel blockade.

For both candesartan and amlodipine, dialysis is not likely to be of benefit.

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, angiotensin II antagonists, and calcium channel blockers, ATC code: C09DB07.

Unisia combines two antihypertensive agents with complementary mechanisms of action to control blood pressure in patients with essential hypertension: Amlodipine belongs to the class of medicinal products called calcium antagonists and candesartan to the class of angiotensin II antagonists. The combination of these agents has an additive antihypertensive effect, lowering blood pressure more than either compound alone.

Amlodipine

Amlodipine is a dihydropyridine-type calcium antagonist that inhibits the influx of calcium ions into cardiac muscle cells and vascular smooth muscle cells (slow calcium channel blocker; calcium channel blocker).

The antihypertensive action of amlodipine is due to the direct relaxation of vascular smooth muscle. The precise mechanism by which amlodipine relieves angina is not yet fully known; however, it reduces ischemia through the following two actions:

1.  Peripheral arterioles are dilated. This lowers the peripheral resistance (afterload) against which the heart must work. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen demand.

2.  It is likely that amlodipine causes dilatation of coronary arteries and arterioles, both in normal and ischemic regions. This dilatation increases myocardial oxygen delivery in patients with spasm of the coronary arteries (Prinzmetal's or variant angina).

In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval.  Due to the slow onset of action, acute hypotension is not expected with amlodipine administration.

No adverse metabolic effects or changes in lipid levels occurred with amlodipine. It is suitable for use in patients with asthma, diabetes and gout.

Candesartan

Mechanism of action

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 plays 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.

Pharmacodynamic effects

Candesartan cilexetil is a prodrug suitable for oral use. During absorption from the gastrointestinal tract, it is rapidly converted to the active form candesartan by ester hydrolysis.

Candesartan is an AIIRA, selective for the AT1 receptors, that binds tightly to and dissociates slowly from the receptor. It has no agonistic activity.

Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and degrades bradykinin. It has no effect on ACE and no potentiation of bradykinin or substance P. In controlled clinical trials comparing candesartan and ACE inhibitors, the incidence of cough was lower in patients receiving candesartan cilexetil. Candesartan neither binds to nor blocks other hormone receptors or ion channels known to be important in cardiovascular regulation. Antagonism of the angiotensin II (AT1) receptors results in a dose-dependent increase in plasma renin, angiotensin I, and angiotensin II levels and a decrease in plasma aldosterone concentration.

Clinical efficacy and safety in hypertension

In hypertension, candesartan produces a dose-dependent, long-lasting reduction in arterial blood pressure. The antihypertensive effect is due to decreased systemic peripheral resistance, without reflex increase in heart rate. There is no evidence of severe or exaggerated first-dose hypotension or rebound effect after cessation of therapy.

After administration of a single dose of candesartan cilexetil, onset of antihypertensive effect generally occurs within 2 hours. With continuous therapy, antihypertensive effects are usually achieved within four weeks at any dosage and is sustained during long-term therapy. According to a meta-analysis, the average incremental effect of increasing the dose from 16 mg to 32 mg once daily was small. Taking into account inter-individual variability, an above-average effect can be expected in some patients. Candesartan cilexetil once daily produces effective and consistent blood pressure lowering over 24 hours with little difference between the maximum and trough effects during the dosing interval. The antihypertensive effect and tolerability of candesartan and losartan were compared in two randomized double-blind studies involving a total of 1,268 patients with mild to moderate hypertension. The trough reduction in blood pressure (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).

When candesartan cilexetil is used together with hydrochlorothiazide, the reduction in blood pressure is additive. An enhanced antihypertensive effect is also observed when candesartan cilexetil is combined with amlodipine or felodipine.

Medicinal products that block the renin-angiotensin-aldosterone system have a less pronounced antihypertensive effect in black patients (usually a population with low renin levels) than in non-black patients. This is also the case for candesartan. In an open-label clinical trial in 5,156 patients with diastolic hypertension, blood pressure reduction during candesartan therapy was significantly less in black than in 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 trial 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% CI: 15-42%). There is currently no data on the effect of candesartan on the progression to diabetic nephropathy.

The effects of candesartan cilexetil 8-16 mg (mean dose 12 mg) once daily on cardiovascular morbidity and mortality were analyzed in a randomized clinical trial on 4,937 elderly patients (70-89 years; 21% 80 or older) with mild to moderate hypertension over an mean of 3.7 years (Study on Cognition and Prognosis in the Elderly). Patients received candesartan cilexetil or placebo and in addition, other antihypertensive treatment as needed. 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 end point, major cardiovascular events (cardiovascular mortality, non-fatal stroke, and non-fatal myocardial infarction). There were 26.7 events per 1,000 patient-years in the candesartan group versus 30.0 events per 1,000 patient-years in the control group (relative risk 0.89; 95% CI: 0.75 to 1.06; p = 0.19).   

Two large randomized controlled trials ("ONTARGET" [ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial] and "VA NEPHRON-D" [The Veterans Affairs Nephropathy in Diabetes]) examined the concomitant use of an ACE inhibitor with an angiotensin II receptor antagonist.

The "ONTARGET" study was conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes mellitus with established end-organ damage. The "VA NEPHRON-D" study was conducted in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies showed no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while a higher risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared with monotherapy. Given their comparable pharmacodynamic properties, these results are also relevant for other ACE inhibitors and angiotensin II receptor antagonists. ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

The "ALTITUDE" study (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) investigated whether the use of aliskiren in addition to standard therapy with an ACE inhibitor or angiotensin II receptor antagonist has an added benefit in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse events. Both cardiovascular death and stroke occurred numerically more frequently in the aliskiren group than in the placebo group, as did adverse events and serious adverse events of interest (hyperkalemia, hypotension, renal dysfunction).

Absorption and distribution

Amlodipine

Following oral administration of therapeutic doses, amlodipine is well absorbed, with peak blood concentration reached after 6 to 12 hours. The absolute bioavailability in humans is about 64 to 80%. The volume of distribution is approximately 21 l/kg. In vitro, approximately 97.5% of circulating amlodipine was shown to be bound to plasma proteins. The bioavailability of amlodipine is not affected by food intake.

Candesartan

Following oral administration, candesartan cilexetil is converted to the active form candesartan. The absolute bioavailability of candesartan after an oral solution of candesartan cilexetil is approximately 40%. The relative bioavailability of the tablet formulation, compared to 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. Candesartan serum concentrations increase linearly with increasing doses within the therapeutic dosage range.

No gender related differences in the pharmacokinetics of candesartan have been observed. The area under the serum concentration/time curve (AUC) of candesartan is not significantly affected by food.

Candesartan is highly bound to plasma proteins (greater than 99%). The apparent volume of distribution of candesartan is 0.1 l/kg.

The bioavailability of candesartan is not affected by food.

Biotransformation and elimination

Amlodipine

The terminal plasma half-life is about 35 to 50 hours, suggesting once-daily dosing. Amlodipine is largely metabolized in the liver to inactive metabolites. In urine, 10% of the substance is excreted unchanged and 60% of the metabolites.

Candesartan

Candesartan is eliminated mainly unchanged via urine and bile and only to a minor extent by hepatic metabolism (CYP2C9). Available interaction studies show no effects on CYP2C9 and CYP3A4. Based on in vitro data, no interactions would be expected in vivo with substances whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. The terminal half-life of candesartan is approximately 9 hours. There is no accumulation following multiple doses.

The total plasma clearance of candesartan is approximately 0.37 ml/min/kg with a renal clearance of approximately 0.19 ml/min/kg. Renal elimination of candesartan takes place by both glomerular filtration and active tubular secretion. Following an oral dose of ¹⁴C-labeled 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 feces as candesartan and 10% as an inactive metabolite.

Pharmacokinetics in special populations

Hepatic impairment

Amlodipine

Very limited clinical data are available on the use of amlodipine in patients with hepatic impairment. Patients with liver failure exhibit decreased clearance of amlodipine, resulting in a prolonged half-life and an increase in AUC of approximately 40% to 60%.

Candesartan

In two studies, both of which included patients with mild to moderate hepatic impairment, there was an increase in the mean AUC of candesartan of approximately 20% in one study and 80% in the other (see section 4.2). There is no experience in patients with severe hepatic impairment.

Elderly

Amlodipine

The time to reach peak plasma concentrations is the same in elderly and younger patients. In elderly patients, amlodipine clearance appears to be decreased, resulting in an increase in AUC and elimination half-life. The increase in AUC and elimination half-life in patients with heart failure was in line with expectations in relation to the age group studied.

Candesartan

In the elderly (over 65 years of age), C_max and AUC of candesartan are increased by approximately 50% and 80%, respectively, compared to young subjects. However, the blood pressure response and the incidence of adverse events are similar after administration of the dose of candesartan cilexetil in young and elderly patients (see section 4.2).

Renal impairment

Amlodipine

There is no correlation between the degree of renal impairment and changes in plasma amlodipine levels. Amlodipine is not dialyzable.

Candesartan

In patients with mild to moderate renal impairment, C_max and AUC of candesartan increased by approximately 50% and 70%, respectively, during repeated dosing compared with patients with normal renal function; t_1/2 was unchanged. The corresponding changes in patients with severe renal function impairment were approximately 50% and 110%, respectively. The terminal t_1/2 of candesartan was approximately doubled in patients with severe renal impairment. The AUC of candesartan in dialysis patients was similar to that in patients with severe renal impairment.

Amlodipine

Reproductive toxicity

In reproductive toxicity studies, overdue birth, extended labor, and reduced offspring survival rates were observed in rats and mice at doses approximately 50 times higher than the maximum recommended human dose based on mg/kg.

Impairment of fertility

Doses up to 10 mg/kg/day (8 times* the maximum recommended dose of 10 mg in humans, based on mg/m²) showed no effects on fertility in rats treated with amlodipine (males: 64 days; females: 14 days before mating). In another study in rats, in which male rats were treated for 30 days with amlodipine besylate at doses comparable to those in humans, based on mg/kg, both a decrease in follicle-stimulating hormone and testosterone in plasma and a decrease in sperm density and a decrease in mature spermatids and Sertoli cells were found.

Carcinogenesis, mutagenesis

There was no evidence of carcinogenicity in rats and mice fed amlodipine at doses of 0.5, 1.25, and 2.5 mg/kg daily in the diet for two years. The highest dose (for mice, the same as, and for rats, twice* the maximum recommended human dose of 10 mg, based on mg/m²) was close to the maximum dose tolerated by mice but not by rats.

Mutagenicity studies revealed no medicinal product related effects at the gene or chromosome levels.

*Based on a 50 kg patient.

Candesartan

Fetotoxicity has been observed in late pregnancy (see section 4.6).

At clinically relevant doses, there was no evidence of abnormal systemic or target organ toxicity. In preclinical safety studies, candesartan affected kidney and red blood cell parameters at high doses in mice, rats, dogs, and monkeys. Candesartan caused a decrease in red blood cell parameters (erythrocytes, hemoglobin, hematocrit). Effects on the kidneys (such as interstitial nephritis, tubular distension, basophilic tubules; increased plasma concentrations of urea and creatinine) have been induced by candesartan, which may be a consequence of the hypotensive effect leading to changes in renal perfusion. In addition, candesartan induced hyperplasia/hypertrophy of juxtaglomerular cells. It is believed that these changes caused by the pharmacological action of candesartan. For therapeutic doses of candesartan in humans, hyperplasia/hypertrophy of renal juxtaglomerular cells appears to be of no relevance.

There was no evidence of carcinogenicity.

Data from in vitro and in vivo mutagenicity tests indicate that candesartan does not exert mutagenic or clastogenic activities under conditions of clinical use. 

-     Mannitol

-     Hydroxy propyl cellulose

-     Microcrystalline cellulose

-     Polyethylene glycol

-     Croscarmellose sodium

-     Magnesium stearate

-     Yellow iron oxide  

Not applicable.

24 months

Store below 30°C.

Store in the original package.

Orange PVC/Aclar-aluminum blisters.

Pack size: 30 Tablets (3 blisters; each blister contains 10 tablets).

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.