Codiceran is indicated for:

 

Treatment of primary hypertension in adult patients whose blood pressure cannot be optimally controlled with candesartan cilexetil or hydrochlorothiazide monotherapy.

Posology

The recommended dose of Codiceran is one tablet once daily.

 

Dose titration of the respective components (candesartan cilexetil and hydrochlorothiazide) is recommended. If clinically indicated, a direct switch from monotherapy to Codiceran may be considered. Dose titration of candesartan cilexetil is recommended when switching from hydrochlorothiazide monotherapy. Codiceran can be used in patients whose blood pressure cannot be optimally controlled with candesartan cilexetil or hydrochlorothiazide monotherapy or Codiceran at a lower dose.

 

Within 4 weeks of starting treatment, most of the antihypertensive effect is usually achieved.

 

Special populations

 

Elderly patients

No dose adjustment is required for elderly female patients.

 

Intravascular volume depletion

For patients at risk of hypotension, such as Patients with suspected volume depletion, dose titration of candesartan cilexetil is recommended (a starting dose of 4 mg candesartan cilexetil may be considered in these patients).

 

Impaired renal function

In patients with mild to moderate renal impairment (creatinine clearance ≥30-80 ml/min/1.73 m² body surface area (BSA)) a dose titration of [sic] is recommended. Codiceran is contraindicated in patients with severely impaired renal function (creatinine clearance <30 ml/min/1.73 m² BSA) (see Section 4.3).

 

Impaired liver function

Dose adjustment is not recommended in patients with mild to moderate chronic hepatic impairment.

Codiceran is contraindicated in patients with seriously reduced liver function and/or cholestasis (see Section 4.3).

 

Paediatric population

The safety and efficacy of Codiceran in children and adolescents between birth and 18 years has not been established. No data is available.

 

Method of administration

For oral use.

Codiceran can be taken with or without food.

The bio-availability of candesartan is not affected by the intake of food.

There is no clinically significant interaction between hydrochlorothiazide and food.

• Hypersensitivity to the active substances or to any of the excipients or to sulfonamide-derived active substances. Hydrochlorothiazide is a sulfonamide-derived active substance. • Second and third trimester of pregnancy (see Sections 4.4 and 4.6). • Severe impairment of renal function (creatinine clearance <30 ml/min/1.73 m2 BSA). • Serious impairment of liver function and/or cholestasis. • Treatment-resistant hypokalaemia or hypercalcaemia. • Gout • The concomitant use of Codiceran and medicines containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m²) (see Sections 4.5 and 5.1).

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

There is evidence to show that concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren increases the risk of hypotension, hyperkalaemia and reduced renal function (including an acute renal failure). Dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is hence not recommended (see Sections 4.5 and 5.1).

If treatment with a dual blockade is considered to be absolutely necessary, this should be administered only under the supervision of a specialist and while conducting regular tests for the renal function, electrolyte values and blood pressure.

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

 

Impaired renal function

As with other substances that inhibit the renin-angiotensin-aldosterone system, renal function changes may occur in sensitive patients treated with Codiceran (see Section 4.3).

 

Kidney transplantation

There is limited clinical data on the use of Codiceran in patients who have recently undergone a kidney transplant.

 

Renal artery stenosis

Medication that affects the renin-angiotensin-aldosterone system, including angiotensin-II receptor antagonists (AIIRAs), may increase blood urea and serum creatinine levels in patients with bilateral renal or arterial stenosis of a single kidney.

 

Intravascular volume depletion

Symptomatic hypotension may occur in patients with intravascular volume and/or sodium deficiency, as described for other substances affecting the renin-angiotensin-aldosterone system. Therefore, the use of Codiceran is not recommended unless this condition has been corrected.

 

Anaesthetics and surgery

Hypotension may occur due to a blockade of the renin-angiotensin system in patients being treated with AIIRAs, under anaesthetic and during surgical intervention. On rare occasions, this hypotension may be serious enough to warrant the intravenous administration of fluids and/or vasopressor medication.

 

Impaired liver function

Thiazides should be used with caution in patients with hepatic impairment or progressive liver disease, as even minor changes in fluid and electrolyte balance can trigger hepatic coma. There is no clinical experience with Codiceran in patients with hepatic impairment.

 

Aortal and mitral valve stenosis (obstructive, hypertrophic cardiomyopathy)

As is the case with other vasodilators, special care is indicated in patients suffering from haemodynamically relevant aortal or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

 

Primary hyperaldosteroneism

Patients with primary hyperaldosteroneism generally do not respond to medication to reduce blood pressure that acts by inhibiting the renin-angiotensin-aldosterone system. Thus, the administration of Codiceran is not recommended for this patient group.

 

Electrolyte imbalance

Regular determination of serum electrolytes should be performed at appropriate intervals. Thiazides, including hydrochlorothiazide, may cause fluid or electrolyte imbalances (hypercalcaemia, hypokalaemia, hyponatraemia, hypomagnesaemia and hypochloraemic alkalosis).

 

Thiazide diuretics may reduce renal calcium excretion and temporarily lead to slightly elevated serum calcium levels. Marked hypercalcemia may be a sign of hidden parathyroid hyperfunction. Thiazides should be discontinued before parathyroid function testing is performed.

 

Hydrochlorothiazide increases renal potassium excretion in a dose-dependent manner, which can lead to hypokalemia. This effect of hydrochlorothiazide appears to be less pronounced in combination with candesartancilexetil. A greater risk of hypokalaemia exists in patients with hepatic cirrhosis, in patients undergoing forced diuresis, in patients with insufficient oral electrolyte intake and in patients on concomitant treatment with corticosteroids or adrenocorticotropic hormone (ACTH).

 

Treatment with candesartan cilexetil may cause hyperkalemia, particularly in the presence of heart failure and/or impaired renal function. The concomitant use of Codiceran with ACE inhibitors, aliskiren, potassium-sparing diuretics, potassium preparations or potassium-containing salt substitutes or other medicinal products that can increase the serum potassium level (e.g., heparin sodium, co-trimoxazole also known as trimethoprim/sulfamethoxazole) can lead to increases in serum potassium levels. Potassium levels should be checked as required.

Thiazides have been shown to increase the renal excretion of magnesium, which can lead to hypomagnesemia.

 

Metabolic and endocrine effects

Treatment with a thiazide diuretic may negatively affect glucose tolerance. Adjustment of the dose of antidiabetic medication, including insulin, may therefore be required. Latent diabetes mellitus may manifest during treatment with thiazide. Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. Only minimal effects have been reported with the doses contained in Candesartan/HCT Sandoz. Thiazide diuretics increase serum uric acid concentration and may cause gout in predisposed patients.

 

Photosensitivity

Cases of photosensitivity during the use of thiazide diuretics have been described (see Section 4.8). If photosensitivity occurs, it is recommended to stop treatment. If resumption of treatment is required, it is recommended to protect those areas exposed to the sun or artificial UVA rays.

 

Non-melanocytic skin cancer

In two epidemiological studies based on the Danish national cancer registry, an increased risk of non-melanocytic skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] was observed with increasing cumulative doses of hydrochlorothiazide (HCTZ). Photosensitising effects of HCTZ may contribute to the development of NMSC.

 

Patients taking HCTZ should be informed about the risk of NMSC and should be advised to regularly check their skin for new lesions and report any suspicious skin changes immediately. Potential preventive measures to minimise the risk of skin cancer should be recommended to these patients, e.g., limiting exposure to sunlight and UV radiation, or, in the event of exposure, use of appropriate sun protection. Suspicious skin changes should be examined immediately, including histological examinations of biopsies if necessary. The use of HCTZ should be reviewed in patients who have already experienced NMSC (see also Section 4.8).

 

Choroidal effusion, acute myopia and secondary angle closure glaucoma

Sulphonamides and sulphonamide derivatives may trigger an idiosyncratic reaction, which may lead to choroidal effusion with visual field defects, transient myopia and acute angle closure glaucoma. The symptoms include the acute occurrence of reduced visual acuity or eye pain and typically occur within hours to weeks of the start of treatment. Untreated acute angle closure glaucoma can lead to permanent vision loss. The treatment of first choice is to stop the drug as soon as possible. Immediate surgical or medical procedures should be considered if intraocular pressure remains uncontrollable. A risk factor for the development of angle closure glaucoma could be a pre-existing sulfonamide or penicillin allergy.

 

General information

Patients whose vascular tone and renal function overwhelmingly depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with serious congestive cardiac insufficiency or underlying renal disease, including renal arterial stenosis), acute hypotension, azotemia, oliguria and – in rare cases – acute renal failure have been associated with treatment with medication influencing this system, including AIIRAs. As is the case with any medication to reduce blood pressure, an excessive drop in blood pressure in patients suffering from ischaemic heart disease or arteriosclerotic cerebrovascular disease may result in myocardial infarction or a 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 a corresponding history.

Aggravation or recurrence of systemic lupus erythematosus has been reported with thiazide diuretics.

 

The antihypertensive effect of Codiceran can be intensified by other antihypertensives.

 

Acute respiratory toxicity

Very rare severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after taking hydrochlorothiazide. Pulmonary oedema typically develops within minutes to hours after taking hydrochlorothiazide. Symptoms include dyspnoea at onset, fever, worsening of lung function, and hypotension. If ARDS is suspected, Codiceran should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be used in patients who have experienced ARDS after taking hydrochlorothiazide.

 

Pregnancy

Treatment with AIIRAs should not be initiated during pregnancy. Patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy unless the continuation of treatment with AIIRAs is absolutely necessary. When pregnancy is confirmed, treatment with AIIRAs should be discontinued immediately and, if required, alternative therapy should be initiated (see Sections 4.3 and 4.6).

 

Doping controls

The use of Codiceran can lead to positive results in doping controls due to the ingredient hydrochlorothiazide.

 

Warnings regarding excipients

This medicine contains lactose. Patients with rare hereditary galactose intolerance, complete lactase deficiency or glucose-galactose malabsorption should not take this medicine.

 

This medicine contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is virtually “sodium-free”.

The substances investigated in clinical pharmacokinetic studies include warfarin, digoxin, oral contraceptives (i.e., ethinylestradiol/levonorgestrel), glibenclamide and nifedipine. No clinically relevant pharmacokinetic interactions were determined in these studies.

 

The potassium-lowering effect of hydrochlorothiazide could be expected to be amplified by other drugs that in turn may cause potassium loss and hypokalemia (e.g., other potassium diuretics, laxatives, amphotericin, carbenoxolone, penicillin G sodium, salicylic acid derivatives, steroids, ACTH).

 

The concomitant use of Codiceran and potassium-sparing diuretics, potassium preparations or potassium-containing salt substitutes or other medicinal products that can increase the serum potassium level (e.g., heparin sodium, co-trimoxazole also known as trimethoprim/sulfamethoxazole), may lead to increases in the serum potassium levels. Where required, potassium levels should be monitored (see Section 4.4).

 

Diuretic-induced hypokalemia and hypomagnesemia predispose to the potentially cardiotoxic effects of digitalis glycosides and antiarrhythmics. Regular monitoring of serum potassium levels is recommended when Codiceran is used together with such medicinal products and with the following medicinal products that could cause torsades de pointes:

·      Class Ia anti-arrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide)

·      Class III anti-arrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide)

·      Some antipsychotics (e.g., thioridazine, chloropromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol)

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

 

Reversible increases in serum lithium concentrations and toxic effects were reported in patients using angiotensin-converting-enzyme (ACE) inhibitors or hydrochlorothiazide and lithium simultaneously. A similar effect has also been reported in AIIRAs. The use of candesartan and hydrochlorothiazide in combination with lithium is not recommended. Where this combination is essential, careful monitoring of serum lithium levels is recommended.

 

Where AIIRAs are administered simultaneously with non-steroidal, anti-inflammatory medication (NSAIDs) (i.e., selective COX-2 inhibitors, acetylsalycylic acid (>3 g/day) and with non-selective NSAIDs), this may result in a weaker blood pressure-lowering effect.

 

As is the case with ACE inhibitors, the simultaneous administration of AIIRAs and NSARs may result in an increased risk of deteriorating renal function, including potentially acute renal failure, as well as to an increase in serum potassium levels, especially in patients with pre-existing poor renal function. The combination should be administered with care, particularly in elderly patients. Patients should be sufficiently hydrated and monitoring of the renal function should be considered at regular intervals after starting concomitant treatment.

The diuretic, natriuretic and blood pressure lowering effects of hydrochlorothiazide are attenuated by NSAIDs.

 

The resorption of hydrochlorothiazide is reduced by colestipol and cholestyramine.

 

The effect of non-depolarising muscle relaxants (e.g., tubocurarine) can be increased by hydrochlorothiazide.

 

Thiazide diuretics can increase the serum calcium level due to decreased excretion. If calcium supplements or vitamin D needs to be prescribed, calcium levels should be checked and the dosage adjusted accordingly.

 

The hyperglycaemic effect of beta-blockers and diazoxide can be enhanced by thiazides.

 

Anticholinergics (e.g., atropine, biperiden) may increase the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and gastric emptying speed.

 

Thiazides may increase the risk of amantadine-mediated reactions.

 

Thiazides may reduce the renal excretion of cytotoxic medicines (e.g., cyclophosphamide, methotrexate) and enhance their myelosuppressant effect.

 

Orthostatic hypotension may be increased with concomitant use of alcohol, barbiturates, or anaesthetics.

 

Treatment with a thiazide diuretic may negatively affect glucose tolerance. Adjustment of the dose of antidiabetic medication, including insulin, may therefore be required. Metformin should be taken with caution due to the risk of possible lactic acidosis induced by possible functional renal failure in combination with hydrochlorothiazide.

 

Hydrochlorothiazide can lead to a reduced arterial reaction to blood pressure-increasing amines (e.g., adrenaline), but not to the extent that a blood pressure-increasing effect is excluded.

 

Hydrochlorothiazide may increase the risk of acute renal failure, particularly with high doses of iodinated contrast media.

 

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

 

Concomitant treatment with baclofen, amifostine, tricyclic antidepressants or neuroleptics may increase the blood pressure lowering effect and cause hypotension.

 

Data from clinical trials has shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE-inhibitors, angiotensin II receptor antagonists or aliskiren is associated with a higher rate of adverse events such as hypotension, hyperkalaemia, and impairment of renal function (including acute renal failure) as compared with the use of a single agent acting on the RAAS (see Sections 4.3, 4.4, and 5.1).

Pregnancy

 

Angiotensin-II receptor antagonists (AIIRAs):

 

The administration of AIIRAs is not recommended during the first trimester of pregnancy (see Section 4.4). The administration of AIIRAs during the second and third trimesters of pregnancy is contraindicated (see Sections 4.3 and 4.4).

 

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a slightly increased risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with Angiotensin II receptor inhibitors (AIIRAs), similar risks may exist for this class of drugs. Where the continuation of the AIIRA treatment is not regarded as essential, patients planning to become pregnant should be switched to alternative anti-hypertensive treatment with an appropriate safety profile for pregnant women. If pregnancy is confirmed, treatment with AIIRAs should be discontinued immediately and, if appropriate, alternative treatment should be initiated.

 

Exposure to AIIRA therapy during the second and third trimesters of pregnancy is known to induce foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see also Section 5.3).

In the event of exposure to AIIRAs from the second trimester of the pregnancy onwards, ultrasound examinations of the renal function and the skull are recommended.

Infants whose mothers have taken AIIRAs should be repeatedly examined for hypotension (see also Sections 4.3 and 4.4).

 

Hydrochlorothiazide:

There is limited experience in the use of hydrochlorothiazide during pregnancy, especially during the first trimester. The results of studies on animals are insufficient.

Hydrochlorothiazide crosses the placental barrier. Due to the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimesters of pregnancy may result in a disturbance of foeto-placental perfusion and in foetal and neonatal effects such as icterus, electrolyte imbalances and thrombocytopenia.

Due to the risk of decreased plasma volume and placental hypoperfusion and due to its lack of positive effect on the course of illness, hydrochlorothiazide should not be taken to treat pregnancy-related oedema, pregnancy-related hypertension or pre-eclampsia.

In the event of essential hypertension in pregnant women, hydrochlorothiazide should only be used in rare cases in which no other treatment is possible.

 

Breastfeeding

 

Angiotensin-II receptor antagonists (AIIRAs):

As no information is available regarding the use of Codiceran during breastfeeding, Codiceran is not recommended and alternative anti-hypertensive treatments with more suitable safety profiles are preferable during breastfeeding, especially while nursing a newborn or preterm infant.

 

Hydrochlorothiazide:

Hydrochlorothiazide is released into human milk in small amounts. Thiazides, at high doses that cause intense diuresis, may inhibit milk production. The use of Codiceran during breastfeeding is not recommended.

No studies on the effects on the ability to drive and use machines have been conducted. When driving or operating machines, it should be taken into account that dizziness or fatigue may occasionally occur during treatment with Candesartan/HCT Sandoz.

In controlled clinical studies with candesartan cilexetil/hydrochlorothiazide, the side effects were slight and transient. Discontinuations due to adverse events were similar for candesartan cilexetil/hydrochlorothiazide (2.3-3.3%) and placebo (2.7-4.3%).

 

In clinical studies with candesartan cilexetil/hydrochlorothiazide, side effects were limited to those previously reported with candesartan cilexetil and/or hydrochlorothiazide:

 

The table below shows the side effects of candesartan cilexetil observed during clinical studies and based on experience following marketing of the product. A summarised analysis of the data obtained during clinical studies conducted on patients with hypertension defined the side effects of candesartan cilexetil on the basis of the frequency of side effects, which was at least 1% higher than the frequency reported with placebo.

 

The frequencies given in the tables throughout Section 4.8 are as follows: very common (≥1/10), common (≥1/100 to <1/10), occasional (≥1/1,000 to <1/100), rare (≥/10,000 to <1/1,000) and very rare (<1/10,000), not known (frequency cannot be estimated from the available data).

 

System organ class	Frequency	Adverse reaction
Infections and parasitic infestations	Common	Respiratory tract infections
Blood and lymphatic system disorders	Very rare	Leukopenia, neutropenia and Agranulocytosis
Metabolism and nutrition disorders	Very rare	Hyperkalaemia, hyponatremia
Nervous system disorders	Common	Dizziness/vertigo, Headache
Respiratory, thoracic and mediastinal disorders	Very rare	Cough
Gastrointestinal disorders	Very rare	Nausea
	Not known	Diarrhoea
Hepatobiliary disorders	Very rare	Elevated liver enzyme values, liver dysfunction or hepatitis
Skin and subcutaneous tissue disorders	Very rare	Angio-oedema, skin rash, urticaria, pruritus
Musculoskeletal and connective tissue disorders	Very rare	Backache, arthralgia, Myalgia
Renal and urinary disorders	Very rare	Restriction of renal function, including renal failure in susceptible patients (see Section 4.4)

 

The following table lists side effects with hydrochlorothiazide monotherapy at a dose of usually 25 mg or higher.

 

System organ class	Frequency	Adverse reaction
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, hyperuricemia, electrolyte imbalance (including hyponatremia and hypokalemia)
Psychiatric disorders	Rare	Sleep disturbance, depressions, anxiety
Nervous system disorders	Common	Dizziness, drowsiness
	Rare	Paraesthesia
Eye disorders	Rare	Temporarily blurred vision
	Not known	Choroidal effusion, acute myopia, acute angle closure glaucoma
Cardiac disorders	Rare	Cardiac arrhythmia
Vascular disorders	Uncommon	Orthostatic hypotension
	Rare	Necrotizing angiitis (vasculitis, cutaneous vasculitis)
Respiratory, thoracic and mediastinal disorders	Rare	Respiratory distress (including pneumonitis and pulmonary oedema)
	Very rare	Acute respiratory distress syndrome (ARDS) (see Section 4.4)
Gastrointestinal disorders	Uncommon	Anorexia, loss of appetite, stomach irritation, diarrhoea, constipation
	Rare	Pancreatitis
Hepatobiliary disorders	Rare	Jaundice (intrahepatic cholestatic jaundice)
Skin and subcutaneous tissue disorders	Uncommon	Rash, urticaria, photosensitivity
	Rare	Toxic epidermal necrolysis
	Not known	Systemic lupus erythematosus, Cutaneous lupus erythematosus
Musculoskeletal and connective tissue disorders	Rare	Muscle cramps
Benign, malignant and unspecified neoplasms (including cysts and polyps)	Not known	Non-melanocytic skin cancer (basal cell carcinoma and squamous cell carcinoma)*
Renal and urinary disorders	Common	Glucosuria
	Rare	Renal dysfunction and interstitial nephritis
General disorders and administration site conditions	Common	Weakness
	Rare	Fever
Investigations	Common	Increase in cholesterol and triglycerides
	Rare	Increase in BUN and serum creatinine

 

*Non-melanocytic skin cancer: Based on the available data from epidemiological studies, a cumulative dose-dependent relationship between HCTZ and NMSC was determined (see also Sections 4.4 and 5.1).

 

To report any side effect(s):

•           Saudi Arabia:

 

 

 

 

 

•           Other GCC states:

-           Please contact the relevant competent authority.

 

Symptoms

Based on pharmacological considerations, it is probable that an overdose of candesartan cilexetil will manifest mainly as symptomatic hypotension and dizziness. Patients recovered without problems in individual overdose cases (of up to 672 mg candesartan cilexetil).

 

The main manifestation of an overdose of hydrochlorothiazide is acute fluid and electrolyte loss. Symptoms such as dizziness, hypotension, thirst, tachycardia, ventricular arrhythmias, sedation/clouding of consciousness, and muscle cramps may also be observed.

 

Measures

There is no specific information on the treatment of an overdose with Candesartan/HCT Sandoz. However, the following measures are proposed in the event of overdose.

 

If necessary, initiation of vomiting or gastric lavage should be considered. Symptomatic hypotension that may occur should be treated symptomatically and under vital signs monitoring. The patient should be placed on their back with legs raised. Where this is insufficient, the plasma volume should be increased by infusion of a physiological saline solution. Serum electrolyte and acid balance should be controlled and corrected if necessary. Where the above measures are insufficient, sympathomimetic medication may be given.

 

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

Pharmacotherapeutic group angiotensin II antagonists + diuretics

ATC code: C09DA06

 

Mechanism of action

Angiotensin II is the primary vaso-active hormone of the renin-angiotensin-aldosterone system and plays a role in the pathophysiology of high blood pressure and other cardiovascular diseases. It is also of significance in the pathogenesis of organ hypertrophy and end organ damage. The main physiological effects of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of the salt and water homeostasis and stimulation of cell growth, are conveyed via the receptor subtype 1 (AT₁).

 

Pharmacodynamic effects

Candesartan cilexetil is a prodrug that is rapidly changed into the active form of candesartan by ester hydrolysis during resorption from the gastro-intestinal tract. Candesartan is an AIIRA selective for the AT₁-receptor, which strongly binds to the receptor and gradually dissociates from it. It has no agonistic activity.

 

Candesartan does not affect ACE or other enzyme systems normally associated with the use of ACE inhibitors. Because there are no effects on the breakdown of kinins or the metabolism of other substances, such as substance P, AIIRAs are unlikely to be associated with cough. In controlled clinical comparative studies carried out with candesartan cilexetil and ACE inhibitors, the frequency of coughing among patients receiving candesartan cilexetil was lower. Candesartan neither binds with nor blocks other hormone receptors or ion channels, which are known to be significant for cardiovascular regulation. The antagonism of the AT₁ receptor results in a dose-dependent increase in the plasma renin level, angiotensin I and angiotensin II levels and to a reduction in the plasma aldosterone concentration.

 

Clinical efficacy and safety

The effect of candesartancilexetil 8-16 mg (average dose 12 mg) once daily on cardiovascular morbidity and mortality was observed in a randomised clinical study carried out on 4,937 elderly patients (70-89 years; 21% aged 80 years and older) with light to moderate hypertension over an average period of 3.7 years (Study on Cognition and Prognosis in the Elderly). The patients received candesartan or placebo in addition to other blood pressure-lowering treatment as required. In the candesartan group, blood pressure was reduced from 166/90 to 145/80 mmHg, while in the control group this reduction was from 167/90 to 149/82 mmHg. There was no statistically significant difference in the primary end point, serious cardiovascular events (cardiovascular mortality, non-fatal strokes and non-fatal myocardiac infarctions). In the candesartan group, there were 26.7 events per 1,000 patient years, compared with 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).

 

Hydrochlorothiazide inhibits active reabsorption of sodium, mainly in the distal renal tubules, and promotes the excretion of sodium, chloride, and water. The renal excretion of potassium and magnesium increases in a dose-dependent manner, while calcium is reabsorbed to a greater extent. Hydrochlorothiazide decreases plasma volume and extracellular fluid and decreases cardiac output and blood pressure. In long-term therapy, decreased peripheral resistance contributes to blood pressure reduction.

 

Large clinical studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.

 

Candesartan and hydrochlorothiazide have additive antihypertensive effects.

 

In patients with hypertension, candesartan/HCT causes a dose-dependent, long-lasting reduction in arterial blood pressure without reflective increase in heart rate. There are no indications of any serious or excessive first-dose hypotension or any rebound effect after discontinuation of treatment. Following the administration of a single dose of candesartan cilexetil/hydrochlorothiazide, the anti-hypertensive effect usually sets in within 2 hours. With continuous therapy, the antihypertensive effect is essentially achieved within 4 weeks and is maintained with long-term treatment. Candesartan/HCT once a day results in an effective and gentle reduction in blood pressure for a period of 24 hours, with little difference between the maximum and minimum effects during the dosing interval. In a double-blind, randomised study, Codiceran 16 mg/12.5 mg once daily significantly reduced blood pressure and controlled significantly more patients than a combination of losartan/hydrochlorothiazide 50 mg/12.5 mg once daily.

 

In double-blind, randomised studies, the incidence of adverse events, particularly dry cough, was lower with Codiceran than with a combination of ACE inhibitors and hydrochlorothiazide.

 

In two clinical studies (randomised, double-blind, placebo-controlled, parallel groups) with 275 and 1,524 randomised patients, the Candesartan cilexetil/hydrochlorothiazide combinations 32 mg/12.5 mg and 32 mg/25 mg led to reductions in blood pressure of 22/15 mmHg and 21/14 mmHg respectively, and were significantly more effective than the respective monocomponents.

 

In a randomised, double-blind, parallel-group clinical trial of 1,975 randomised patients who were not optimally controlled by candesartan cilexetil 32 mg once daily, the addition of 12.5 mg or 25 mg hydrochlorothiazide brought about additional reductions in blood pressure. The candesartan cilexetil/hydrochlorothiazide combination of 32 mg/25 mg was significantly more effective than the 32 mg/12.5 mg combination and the total mean blood pressure reductions were 16/10 mmHg and 13/9 mmHg, respectively.

 

Candesartan cilexetil/hydrochlorothiazide is just as effective in patients regardless of age and sex.

 

There is currently no data on the use of candesartan cilexetil/hydrochlorothiazide in patients with renal disease/nephropathy, reduced left ventricular function/congestive heart failure and after myocardial infarction.

 

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

In two large randomised, controlled studies (“ONTARGET” [ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial] and “VA NEPHRON-D” [Veterans Affairs Nephropathy in Diabetes]) the concomitant use of an ACE inhibitor with an angiotensin II receptor was investigated.

The “ONTARGET” study was conducted in patients with a history of cardiovascular or cerebrovascular disease or with type 2 diabetes mellitus accompanied by evidence of end organ damage. The “VA NEPHRON-D” study was conducted on patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney failure and/or hypotension as compared to monotherapy was observed. Based on comparable pharmacodynamic properties, these results may also be transferred to other ACE inhibitors and angiotensin II receptor antagonists. This is why ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients suffering from diabetic nephropathy.

The “ALTITUDE” study (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or angiotension II receptor antagonist in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated prematurely on account of an increased risk of adverse reactions. Cases of both cardiovascular death and strokes occurred numerically more frequently in the aliskiren group than in the placebo group, and similarly, this was also true of adverse reactions and particularly serious adverse reactions (hyperkalaemia, hypotension and renal dysfunction).

 

Non-melanocytic skin cancer: Based on the available data from epidemiological studies, a cumulative dose-dependent relationship between HCTZ and NMSC was observed. One study included a basic population of 71,533 cases of BCC and 8,629 cases of SCC with control groups of 1,430,833 or 172,462 people. A high hydrochlorothiazide dose (≥50,000 mg cumulative) was associated with an adjusted odds ratio of 1.29 (95% confidence interval: 1.23-1.35) for BCC and 3.98 (95% confidence interval: 3.68-4.31) for SCC. A clear cumulative dose-effect relationship was determined for both BCC and SCC. Another study showed a possible connection between lip cancer (SCC) and exposure to HCTZ: 633 cases of lip cancer were compared with a control group of 63,067 persons using a risk-oriented sampling procedure. A cumulative dose was found to have a relationship between the effects with an adjusted odds ratio of 2.1 (95% confidence interval: 1.7-2.6), which at high exposure (~ 25,000 mg) was reduced to an odds ratio of 3.9 (3.0‑4.9) and at the highest cumulative dose (~ 100,000 mg), also increased to an odds ratio of 7.7 (5.7-10.5) (see also Section 4.4).

The concomitant administration of candesartan cilexetil and hydrochlorothiazide has no clinically significant effects on the pharmacokinetics of the other medicinal product.

 

Absorption and distribution

 

Candesartancilexetil

Following oral administration, candesartancilexetil is converted into the active form candesartan. The absolute bio-availability of candesartan is about 40% when an oral candesartancilexetil solution has been taken. The relative bio-availability of the tablet formulation of candesartancilexetil compared to the same formulation as an oral solution amounts to approximately 34%, with very low variability. Mean maximum serum concentration (C_max) is reached 3-4 hours after tablet intake. There is a linear increase in the candesartan serum concentration with increasing doses within the treatment dosage range. Gender-specific differences in the pharmacokinetics of candesartan were not observed. The area below the serum concentration/time curve (AUC) for candesartan is not significantly influenced by food intake.

 

Candesartan is bound to plasma protein to a high degree (over 99%). The apparent distribution volume of candesartan is 0.1 l/kg.

 

Hydrochlorothiazide

Hydrochlorothiazide is rapidly resorbed from the gastrointestinal tract with an absolute bioavailability of approximately 70%. Concurrent food intake increases absorption by approximately 15%. Bioavailability may decrease in patients with heart failure and marked oedema.

 

The plasma protein binding of hydrochlorothiazide is approx. 60%. The apparent distribution volume is approx. 0.8 l/kg.

 

Biotransformation and excretion

 

Candesartancilexetil

Candesartan is mainly excreted unchanged in the urine and bile and only metabolised in the liver to a negligible extent (CYP2C9). Existing interaction studies did not show any effects on CYP2C9 and CYP3A4. Based on in vitro data, no in vivo interactions are expected with substances, the metabolism of which depends on the cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The terminal half-life (t_½) of candesartan is approximately 9 hours. There is no cumulative effect following the administration of several doses. The half-life of candesartan remains unchanged (approximately 9 hours) after administration of candesartan cilexetil in combination with hydrochlorothiazide. After repeated administration of the combination, there is no additional accumulation of candesartan compared to monotherapy.

 

The total plasma clearance of candesartan is approximately 0.37 ml/min/kg, with a renal clearance of about 0.19 ml/min/kg. Renal excretion of candesartan takes place by means of glomerular filtration and by active tubular secretion. Following an oral dose of ¹⁴C-radioactive marked candesartan cilexetil, approximately 26% of the dose is excreted in the urine in the form of candesartan and 7% as an inactive metabolite, while approximately 56% of the dose was found in the faeces in the form of candesartan and 10% as an inactive metabolite.

 

Hydrochlorothiazide

Hydrochlorothiazide is not metabolised and is almost completely excreted as unchanged active substance by glomerular filtration and active tubular secretion. The terminal t_1/2 of hydrochlorothiazide is approximately 8 hours. Approx. 70% of an oral dose is eliminated in urine within 48 hours. The half-life of hydrochlorothiazide remains unchanged (approximately 8 hours) after administration of hydrochlorothiazide in combination with candesartan cilexetil. After repeated administration of the combination, there is no additional accumulation of hydrochlorothiazide compared to monotherapy.

 

Pharmacokinetics in special populations

 

Candesartancilexetil

In older people (aged over 65 years), the C_max and AUC of candesartan are increased by approximately 50% or 80% in comparison with young test subjects. The response of the blood pressure and the frequency of side effects are similar after administration of a dose of candesartancilexetil to young and old patients, however (see Section 4.2).

 

In patients with slightly to moderately reduced renal function, the C_max and AUC values for candesartan increased by approximately 50% and 70% with repeated doses in comparison with patients with normal renal function; but the terminal t_1/2 remained unchanged. The corresponding changes in patients with a serious reduction in renal function amounted to approximately 50% and 110% respectively. The terminal t_1/2 of candesartan approximately doubled in patients with seriously reduced renal function. The pharmacokinetics in dialysis patients was similar to that of patients with a serious reduction in renal function.

 

In two studies, both of which involved patients with slightly to moderately reduced liver function, there was an increase in the average AUC of candesartan of approximately 20% in one study and 80% in the other study (see Section 4.2). No data is available on patients with severe hepatic impairment.

 

Hydrochlorothiazide

Hydrochlorothiazide terminal t_1/2 is prolonged in patients with impaired renal function.

Compared to the individual components, there were no qualitatively new toxicological findings for the combination. In preclinical safety studies, candesartan had an effect on the kidneys and the red blood cell parameters (erythrocytes, haemoglobin, haematocrit) when administered in high doses to mice, rats, dogs and monkeys. Effects on the kidneys (such as regeneration, dilation and basophilia of the tubuli; increased plasma concentrations of urea and creatinine) were caused by candesartan, which might be as a consequence of its hypotensive effect resulting in changes in kidney perfusion. The addition of hydrochlorothiazide increases the nephrotoxicity of candesartan. In addition, candesartan resulted in hyperplasia/hypertrophy of the juxtaglomerular cells. It is assumed that these changes are caused by the pharmacological activity of candesartan and are of little clinical relevance.

 

Foetotoxicity of candesartan has been observed in late pregnancy. The addition of hydrochlorothiazide did not significantly affect the outcome of foetal development studies in rats, mice and rabbits (see Section 4.6).

 

Candesartan and hydrochlorothiazide both show genotoxic activity in very high concentrations/doses. Data from in vitro and in vivo genotoxicity tests show that candesartan and hydrochlorothiazide are unlikely to have mutagenic or clastogenic effects when used clinically.

 

There was no evidence that either substance is carcinogenic.

 

Codiceran 16 mg/12.5 mg – tablets

Lactose monohydrate

Corn starch

Povidone K-30

Carrageenan (E 407)

Croscarmellose sodium

Magnesium stearate

Iron oxide, red (E172)

Iron oxide yellow (E172)

Not applicable.

24 months.

Store below 30°C

Store in the original package

Al/Al Blister with desiccant: 28 tablets.

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