Acloran^® Plus is indicated for the:

Treatment of essential hypertension as substitution therapy in adult patients whose blood pressure is adequately controlled on the combination of Candesartan, Amlodipine, and Hydrochlorothiazide, taken either as three single-component formulations or as a dual-component and a single-component formulation.

Acloran^® Plus should not be used as initial therapy.

The recommended dose of Acloran^® Plus is one capsule once daily.

Dose titration with the individual components (candesartan cilexetil and hydrochlorothiazide) is recommended. When clinically appropriate, a direct change from monotherapy to Acloran^® Plus may be considered. Dose titration of candesartan

cilexetil is recommended when switching from hydrochlorothiazide monotherapy. Acloran^® Plus may be administered in patients whose blood pressure is not optimally

controlled with candesartan cilexetil or hydrochlorothiazide or amlodipine monotherapy or candesartan cilexetil & hydrochlorothiazide combination drug at lower doses.

Most of the antihypertensive effect is usually attained within 4 weeks of initiation of treatment.

Elderly

No dose adjustment is necessary in elderly patients.

Hepatic impairment

Dose titration of this medicine is recommended in patients with mild to moderate hepatic impairment.

This medicine is contraindicated in patients with severe hepatic impairment and/or cholestasis due to candesartan cilexetil component.

Renal impairment

Dose titration is recommended in patients with mild to moderate renal impairment (creatinine clearance 30-80 ml/min/1.73 m Body Surface Area (BSA)). Amlodipine is not dialysable.

This medicine is contraindicated in patients with severe renal impairment (creatinine clearance < 30 ml/min/1.73 m BSA).

Paediatric population

The safety and efficacy of this combination medicine in children from birth to

adolescents under the age of 18 years have not been established. No data are available.

Patients with reduced blood volume

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).

 

Method of administration

Hard capsule for oral administration.

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 or to other calcium antagonists, to other sulfonamides. Hydrochlorothiazide is a sulfonamide. • Second and third trimesters of pregnancy. • Severe renal impairment (creatinine clearance < 30 ml/min/1.73 m2 BSA). • Severe hepatic impairment and/or cholestasis. • Refractory hypokalaemia and hypercalcaemia. • Gout. • The concomitant use of this medicine with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR< 60 ml/min/1.73m2). • Shock (including cardiogenic shock). • Obstruction of the outflow tract of the left ventricle (e.g., high grade aortic stenosis). • Hemodynamically unstable heart failure after acute myocardial infarction.

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 ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and the patient should be subject to regular 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.

Renal impairment

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

Amlodipine may be used in such patients at normal doses. Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialysable.

Kidney transplantation

There is limited clinical evidence regarding candesartan cilexetil & hydrochlorothiazide combination drug use in patients who have undergone renal transplantation.

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 renal artery stenosis in patients with a solitary kidney.

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 this medicine is not recommended until this condition has been corrected.

Anaesthesia and surgery

Hypotension may occur during anaesthesia and surgery in patients treated with AIIRAs 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.

Non-melanoma skin cancer

A potential association of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been reported in two epidemiological case control studies based on Danish National cancer registry.

Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC although a causal relationship has not been established.

Patients taking HCTZ should be informed of the association of NMSC with HCTZ use and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and adequate protection, when exposed to sunlight should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should

be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC.

Hepatic impairment

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since even minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dosage recommendations have not been established. Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.

There is no clinical experience with this medicine in patients with hepatic impairment.

Aortic and mitral valve stenosis (obstructive hypertrophic cardiomyopathy)

As with other vasodilators, special caution is indicated in the treatment of patients suffering from haemodynamically relevant aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally will not respond to antihypertensive agents acting through inhibition of the renin-angiotensin-aldosterone system. Therefore, the use of this medicine is not recommended in this population.

Electrolyte imbalance

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 recurrent 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).

Treatment with candesartan cilexetil may cause hyperkalaemia, especially in the presence of heart failure and/or renal impairment. Concomitant use of this medicine and ACE inhibitors, aliskiren, potassium-sparing diuretics, potassium supplements, salt substitutes or other medicinal products that increase serum potassium levels (e.g. heparin sodium) may lead to increases in serum potassium. Monitoring of potassium should be undertaken as appropriate.

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. Dose adjustment of antidiabetic medicinal products, 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. At the doses contained in this medicine, only minimal effects were observed. Thiazide diuretics

increase serum uric acid concentration and may precipitate gout in susceptible patients.

Photosensitivity

Cases of photosensitivity reactions have been reported during use of thiazide diuretics. If a photosensitivity reaction occurs, it is recommended to stop treatment. If re-administration of treatment is essential, it is recommended to protect areas exposed to the sun or to artificial UVA radiation.

Choroidal effusion, Acute Myopia and Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma.

Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue

drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

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 heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system including AIIRAs, has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or atherosclerotic cerebrovascular disease could result in a myocardial infarction or stroke.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

The antihypertensive effect of this medicine may be enhanced by other antihypertensives.

This medicinal product contains lactose, as an excipient, and patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Pregnancy

Treatment with AIIRAs should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have a well-documented

safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy

should be started.

Patients with cardiac failure

Patients with heart failure should be treated with caution. In a long-term, placebo-controlled study in patients with severe heart failure (NYHA class III and IV) the reported incidence of pulmonary oedema was higher in the amlodipine treated group than in the placebo group.

Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Substances which have been investigated in clinical pharmacokinetic studies include warfarin, digoxin, oral contraceptives (i.e. ethinyl estradiol/levonorgestrel), glibenclamide and nifedipine. No pharmacokinetic interactions of clinical significance were identified in these studies.

The potassium depleting effect of hydrochlorothiazide could be expected to be potentiated by other medicinal products associated with potassium loss and hypokalaemia (e.g. other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone,

penicillin G sodium, salicylic acid derivates, steroids, ACTH).

Concomitant use of candesartan cilexetil & hydrochlorothiazide combination drug and potassium-sparing diuretics, potassium supplements or salt substitutes or other medicinal products that may increase serum potassium levels (e.g. heparin sodium) may lead to increases in serum potassium. Monitoring of potassium levels should be undertaken as appropriate .

Diuretic-induced hypokalaemia and hypomagnesaemia predisposes to the potential cardiotoxic effects of digitalis glycosides and antiarrhythmics. Periodic monitoring of serum potassium is recommended when this medicine is administered with such medicinal products, and with the following medicinal products that could induce torsades de pointes:

Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide)

Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)

Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperiodol)

Others (e.g. bepridil, cisapride, diphemanil, erythromycin iv, halofantrin, ketanserin, mizolastin, pentamidine, sparfloxacine, terfenadine, vincamine iv)

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with Angiotensin Converting Enzyme (ACE) inhibitors or hydrochlorothiazide. A similar effect has also been reported with AIIRAs. Use of candesartan and hydrochlorothiazide with lithium is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.

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

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 the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.

The diuretic, natriuretic and antihypertensive effect of hydrochlorothiazide is blunted by NSAIDs.

The absorption of hydrochlorothiazide is reduced by colestipol or cholestyramine.

The effect of non depolarising 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 the dose 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 medicinal products (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

Postural hypotension may become aggravated by simultaneous intake of alcohol, barbiturates or anaesthetics.

Treatment with a thiazide diuretic may impair glucose tolerance. Dose adjustment of antidiabetic medicinal products, including insulin, may be required. Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.

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.

Concomitant treatment with cyclosporine may increase the risk of hyperuricaemia and gout-type complications.

Concomitant treatment with baclofen, amifostin, tricyclic anti-depressants or neuroleptics may lead to enhancement of the antihypertensive effect and may induce hypotension.

Clinical trial data have shown that the incidence of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) is higher with dual blockade of the renin-angiotensin-aldosterone system (RAAS)through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren compared to the use of a single RAAS-acting agent.

Effects of other medicinal products on amlodipine

CYP3A4 inhibitors: Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.

CYP3A4 inducers: There is no data available regarding the effect of CYP3A4 inducers on amlodipine.

The concomitant use of CYP3A4 inducers (e.g., rifampicin, hypericum perforatum) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.

Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.

Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalemia, it is recommended that the co-administration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.

Effects of amlodipine on other medicinal products

The blood pressure lowering effects of amlodipine adds to the blood pressure-lowering effects of other medicinal products with antihypertensive properties.

In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, warfarin or cyclosporin.

Angiotensin II Receptor Antagonists (AIIRAs):

 

 

Angiotensin II receptor antagonists should not be used during the first trimester of pregnancy. The use of AIIRs is contraindicated during the second and third trimesters of pregnancy.

Epidemiological data regarding the risk of foetal harm following the use of ACE inhibitors during the first trimester of pregnancy have not been conclusive; however, a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data for AIIRAs, similar risks may exist for thisclass of drugs.

Unless continued AIIRA therapy is considered essential, patients planning pregnancy should receive alternative treatments which have a well-documented safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately and, if appropriate, alternative therapy should be started.

AIIRA therapy 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).

Should exposure to AIIRAs have occurred during the second trimester of pregnancy, an ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension.

Hydrochlorothiazide:

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 the second and third trimesters may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational edema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease. Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Amlodipine

The safety of amlodipine in human pregnancy has not been established.

In animal studies, reproductive toxicity was observed at high doses.

Use in pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.

Lactation

Angiotensin II Receptor Antagonists (AIIRAs):

Because no information is available regarding the use of this medicine during breastfeeding, it is not recommended and alternative treatments with better documented safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Hydrochlorothiazide:

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit milk production. The use of this medicine during breast-feeding is not recommended.

Amlodipine

It is not known whether amlodipine is excreted in breast milk. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with amlodipine should be made taking into account the benefit of breast-feeding to the child and the benefit of amlodipine therapy to the mother.

No studies on the effects on the ability to drive and use machines have been performed. When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or tiredness may occur during treatment with candesartan cilexetil & hydrochlorothiazide combination drug.

Amlodipine can have minor or moderate influence on the ability to drive and use machines. If patients taking amlodipine suffer from dizziness, headache, fatigue or nausea the ability to react may be impaired. Caution is recommended especially at the start of treatment.

The frequencies used in the tables throughout section 4.8 are:very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000)and not known (cannot be estimated from the available data).

The below adverse reactions are for candesartan cilexetil:

Infections and infestations

Common: Respiratory infection

Blood and lymphatic system disorders

Very rare: Leukopenia, neutropenia and agranulocytosis

Metabolism and nutrition disorders

Very rare: Hyperkalaemia, hyponatraemia

Nervous system disorders

Common: Dizziness/vertigo, headache

Respiratory, thoracic and mediastinal disorders

Very rare: Cough

Gastrointestinal disorders

Very rare: Nausea

Gastrointestinal disorders

Very rare: Nausea

Hepatobiliary disorders

Very rare: Increased liver enzymes, abnormal hepatic function or hepatitis

Skin and subcutaneous tissue disorders

Very rare: Angioedema, rash, urticaria, pruritus

Musculo skeletal and connective tissue disorders

Very rare: Back pain, arthralgia, myalgia

Renal and urinary disorders

Very rare: Renal impairment, including renal failure insusceptible patients

The below presents adverse reactions for hydrochlorothiazide monotherapy usually with doses of 25 mg or higher.

Blood and lymphatic system disorders

Rare: Leukopenia, neutropenia/agranulocytosis thrombocytopenia, aplastic anaemia, bone marrow depression, haemolytic anaemia

Immune system disorders

Rare: Anaphylactic reactions

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

Not known: Choroidal effusion, Acute myopia, acute angle-closure

glaucoma

Cardiac disorders

Rare: Cardiac arrhythmias

Vascular disorders

Uncommon: Postural hypotension

Rare: Necrotising angiitis (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

Not known: Systemic lupus erythematosus, cutaneous lupus erythematosus

Musculo skeletal 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

Investigations

Rare: Fever

Common: Increases in cholesterol and triglycerides

 

The most commonly reported adverse reactions during treatment with amlodipine monotherapy are somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, oedema and fatigue.

Blood and lymphatic system disorders

Very rare: Leukocytopenia, thrombocytopenia

Immune system disorders

Very rare: Allergic reactions

Metabolism and nutrition disorders

Very rare Hyperglycaemia

Uncommon Insomnia, mood changes (including anxiety), depression

Psychiatric disorders

Rare: Confusion

Common Somnolence, dizziness, headache (especially at the beginning of the treatment)

Uncommon: Tremor, dysgeusia, syncope, hypoesthesia, paresthesia

Nervous system disorders

Very rare: Hypertonia, peripheral neuropathy

Eye disorders

Uncommon: Visual disturbance (including diplopia)

Ear and labyrinth disorders

Uncommon: Tinnitus

Cardiac disorders

Common: Palpitations

Very rare: Myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation)

Common: Flushing

Uncommon: Hypotension

Vascular disorders

Very rare: Vasculitis

Respiratory, thoracic and mediastinal disorders

Uncommon: Dyspnoea, rhinitis

Very rare: Cough

Gastrointestinal disorders

Common: Abdominal pain, nausea

Uncommon: Vomiting, dyspepsia, altered bowel habits (including diarrohea and constipation), dry mouth

Very rare: Pancreatitis, gastritis, gingival hyperplasia

Hepatobiliary disorders

Very rare: Hepatitis, jaundice, hepatic enzymes increased*

Uncommon: Alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, rash, exanthema

Skin and subcutaneous tissue disorders

Very rare: Angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity

Musculoskeletal and connective tissue disorders

Common: Ankle swelling

Uncommon: Arthralgia, myalgia, muscle cramps, back pain

Renal and urinary disorders

Uncommon: Micturition disorder, nocturia, increased urinary frequency

Reproductive system and breast disorders

Uncommon: Impotence, gynecomastia

General disorders and administration site conditions

Common: Oedema, fatigue

Uncommon: Chest pain, asthenia, pain, malaise

Investigations

Uncommon: Weight increase, weight decrease.

Exceptional cases of extrapyramidal syndrome have been reported.

 

For any information about this medicinal product, please contact the Marketing Authorization Holder:

Tel: +962 6 5823618

Email: pharmacovigilance@mspharma.com

 

To report any side effect(s):

·       Saudi Arabia:

-        National Pharmacovigilance & Drug Safety Centre (NPC): ·       Fax: +966-11-205-7662 ·       Call NPC at +966-11-2038222, Ext.: 2317-2356-2353-2354-2334-2340. ·       Toll free phone : 8002490000 ·       E-mail: npc.drug@sfda.gov.sa ·       Website: www.sfda.gov.sa/npc

-   Other GCC States:

Please contact the relevant competent authority.

 

Symptoms

With regard to the pharmacological properties, overdose of candesartan cilexetil is likely to mainly cause symptomatic hypotension and dizziness. In individual case reports of overdose (of up to 672 mg candesartan cilexetil) patient recovery was uneventful.

The main effect 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 occur.

In humans experience with intentional overdose is limited.

Available data suggest that gross overdosage for amlodipine could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.

Management

No specific information is available on the treatment of overdose with candesartan and hydrochlorothiazide combination therapy. The following measures are, however, suggested in case of overdose.

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 their legs elevated. If this is not sufficient, plasma volume should be increased by infusion of isotonic saline solution. Serum electrolytes and acid-base balance should be checked and corrected, if needed. Sympathomimetic medicinal products may be administered if the above-mentioned measures are not sufficient.

Candesartan can not be removed by haemodialysis. It is not known to what extent hydrochlorothiazide is removed by haemodialysis.

Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating fluid volume and urine output.

A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine.

Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit.

Pharmaco-therapeutic group: Angiotensin II antagonists, calcium channel blockers and diuretics. ATC code: C09DX06.

 

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a role in the pathophysiology of hypertension and other cardiovascular disorders. It also has a role in the pathogenesis of organ hypertrophy and end organ 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 which is rapidly converted to the active drug, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an AIIRA and binds selectively to AT1 receptors, with tight binding to and slow dissociation from the receptor. It has no agonist activity.

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 quinines, or on the metabolism of other substances, such as substance P, AIIRAs 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 166/90to 145/80 mmHg in the candesartan group, and from 167/90 to149/82 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 26.7events per 1000 patient-years in the candesartan group versus30.0 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 hydrochlorothiazide reduces the risk for cardiovascular morbidity and mortality.

Candesartan and hydrochlorothiazide have additive antihypertensive effects.

 

Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.

The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces total ischaemic burden by the following two actions:

1) Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.

2) The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischaemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (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 a feature of amlodipine administration.

In patients with angina, once daily administration of amlodipine increases total exercise time, time to angina onset, and time to 1mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablet consumption.

Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes, and gout.

Absorption, distribution, plasma protein binding: After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%.

The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

The bioavailability of amlodipine is not affected by food intake.

Biotransformation/elimination

The terminal plasma elimination half life is about 35-50 hours and is consistent with once daily dosing.

Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.

Use in hepatic impairment

Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine resulting in a longer half-life and an increase in AUC of approximately 40-60%.

Use in the elderly

The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects.

Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients. Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group studied.

Use in children

A population PK study has been conducted in 74 hypertensive children aged from 1 to 17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving amlodipine between 1.25 and 20 mg given either once or twice daily. In children 6 to 12 years and in adolescents.

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 a tablet formulation of candesartan cilexetil compared with the same oral solution is approximately 34% with very little variability. The mean peak serum concentration (Cmax) 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.

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. Biotransformation and elimination 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 medicinal products whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The terminal half-life (t½) 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. No additional accumulation of candesartan occurs after repeated doses of the combination compared to monotherapy. 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. Hydrochlorothiazide

Hydrochlorothiazide is not metabolised 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 (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), Cmax 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 combination drug in young and elderly patients. In patients with mild to moderate renal impairment, Cmax and AUC of candesartan increased during repeated dosing by approximately 50% and 70%, respectively, but the terminal t½ 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 two studies, both including 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 study. There is no experience in patients with severe hepatic impairment. Hydrochlorothiazide The terminal t½ of hydrochlorothiazide is prolonged in patients with renal impairment.

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 The other ingredients are:

Capsule filling: Lactose Monohydrate, Maize starch, Hydroxypropyl cellulose, Carmellose Calcium, Macrogol type 8000, Starch Pregelatinized, Magnesium Stearate.

Capsule shell (16 mg/5 mg/12.5 mg): Sunset yellow (E110), Titanium dioxide (E171), Gelatin.

Capsule shell (16 mg/10 mg/12.5 mg): Azorubine – Carmoisine (E122), Sunset yellow (E110), Titanium dioxide (E171), Gelatin.

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24 Months

-         Do not store above 30°C.

Acloran^® Plus Capsules are packed in blisters, consisting of Polyamide-Aluminium-PVC (laminate) and aluminium lidding foil in a carton box with folded leaflet. In pack size of 30 hard capsules per pack.

 Not applicable