Source: Medicines Authority (MT) Revision Year: 2023 Publisher: Aspen Healthcare Malta Limited, 89, Level 0, Triq is-Siggiewi, Siggiewi, SGW2021, Malta
Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see section 4.3 and 4.6).
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 ACEinhibitors, 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 occur under specialist supervision and subject to frequent 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.
As with other agents inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated 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 or end-stage renal disease (Clcr < 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 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).
The risk of adverse reactions, especially hypotension, hyperkalaemia and decreased renal function (including acute renal failure), may increase when Clodipan is used in combination with an ACE-inhibitor (see section 4.8). Triple combination of an ACE-inhibitor, a mineralocorticoid receptor antagonist and candesartan is also not recommended. Use of these combinations should be under specialist supervision and subject to frequent 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.
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 haemodialysis.
There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney when treated with medicinal products that affect the renin-angiotensin-aldosterone system.
There is no experience regarding the administration of candesartan in patients with a recent kidney transplantation.
Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by e.g. vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of candesartan. If hypotension occurs with Clodipan, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of sodium chloride 9 mg/ml (0.9%) solution for infusion. Treatment can be continued once blood pressure has been stabilised.
Hypotension may occur during anaesthesia and surgery in patients treated with angiotensin II antagonists due to blockade of the renin-angiotensin system. Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors.
As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.
Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of candesartan is not recommended.
The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause hyperkalaemia. Hyperkalaemia may be fatal in the elderly, in patients with renal insufficiency, in diabetic patients, in patients concomitantly treated with other medicinal products that may increase potassium levels, and/or in patients with intercurrent events.
Before considering the concomitant use of medicinal products that affect the renin-angiotensin aldosterone system, the benefit risk ratio should be evaluated. The main risk factors for hyperkalaemia to be considered are:
In patients whose vascular tone and renal function depend predominantly on the activity of the renin angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system has been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure (see section 4.8). As with any antihypertensive medicinal product, excessive reduction of blood pressure in patients with ischaemic cardiomyopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.
The antihypertensive effect of candesartan may be enhanced by other medicinal products with blood pressure lowering properties, whether prescribed as an antihypertensive or prescribed for other indications.
The safety and efficacy of amlodipine in hypertensive crisis has not been established.
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 (see section 5.1).
Amlodipine half-life is prolonged and AUC values are higher in patients with impaired liver function; dose recommendations have not been established. Clodipan should therefore be used with caution in patients with mild to moderate hepatic impairment. For severe hepatic impairment, see section 4.3.
In the elderly increase of the dosage should take place with care (see sections 4.2 and 5.2).
Amlodipine may be used in such patients at usual doses. Changes in amlodipine plasma concentrations are not correlated with degree of renal impairment. Amlodipine is not dialysable.
This medicinal product contains lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
No interactions between the two components of this fixed dose combinations have been observed in clinical studies.
The blood pressure lowering effect of Clodipan can be increased by concomitant use of other antihypertensive medicinal products.
Based on their pharmacological properties it can be expected that the following medicinal products may potentiate the hypotensive effects of all antihypertensives including Clodipan, e.g. baclofen, amifostine, neuroleptics or antidepressants. Furthermore, orthostatic hypotension may be aggravated by alcohol.
Reduction of the antihypertensive effect.
Compounds which have been investigated in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinylestradiol/levonorgestrel), glibenclamide, nifedipine and enalapril. No clinically significant pharmacokinetic interactions with these medicinal products have been identified.
Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other medicinal products (e.g. heparin) may increase potassium levels. Monitoring of potassium should be undertaken as appropriate (see section 4.4).
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. A similar effect may occur with AIIRAs. Use of candesartan 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.
Clinical trial data has shown that dual blockade of the 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, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
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 pharmacokinetic (PK) variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.
Clarithromycin is an inhibitor of CYP3A4. There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Close observation of patients is recommended when amlodipine is co-administered with clarithromycin.
Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant use particularly with strong CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum).
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.
In animals, lethal ventricular fibrillation and cardiovascular collapse were 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.
The blood pressure lowering effect of amlodipine adds to the blood pressure-lowering effects of other medicinal products with antihypertensive properties.
There is a risk of increased tacrolimus blood levels when co-administered with amlodipine. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.
No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0% - 40%) of cyclosporine were observed. Consideration should be given for monitoring cyclosporine levels in renal transplant patients on amlodipine, and cyclosporine dose reductions should be made as necessary.
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. The dose of simvastatin to be limited to 20 mg daily in patients on amlodipine.
In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.
Clodipan is not recommended during the first trimester of pregnancy as no data are available and safety profile has not been established for both amlodipine and candesartan. Use in early pregnancy is only recommended when there is no safer alternative and when the disease itself carries greater risk for the mother and foetus.
Clodipan is contraindicated during the second and third trimesters of pregnancy due to candesartan content.
The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4). Exposure to AIIRA therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of foetal renal function and skull is recommended.
The use of AIIRAs is not recommended during the first trimester of pregnancy (see section 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 small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with AIIRAs, similar risks may exist for this class of drugs.
Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established 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.
Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3 and 4.4).
The safety of amlodipine in human pregnancy has not been established.
In animal studies, reproductive toxicity was observed at high doses (see section 5.3).
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.
Because no information is available regarding the use of candesartan and amlodipine during breast-feeding, it is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3-7%, with a maximum of 15%. The effect of amlodipine on infants is unknown. 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 information is available regarding potential effect of candesartan and amlodipine on fertility.
Animal studies have shown that candesartan cilexetil had no adverse effect on fertility in rats (see section 5.3).
Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility (see section 5.3).
No studies on the effects of candesartan on the ability to drive and use machines have been performed. However, it should be taken into account that occasionally dizziness or weariness may occur during treatment with candesartan.
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.
No clinical studies have been performed. Undesirable effects observed for particular active ingredients are described below.
Adverse reactions previously reported with one of the individual components (candesartan or amlodipine) may be potential adverse reactions with Clodipan as well, even if not observed in clinical trials or during the post-marketing period.
In controlled clinical studies with candesartan for treatment of hypertension adverse reactions were mild and transient. The overall incidence of adverse events showed no association with dose or age. Withdrawals from treatment due to adverse events were similar with candesartan cilexetil (3.1%) and placebo (3.2%).
In a pooled analysis of clinical trial data of hypertensive patients, adverse reactions with candesartan cilexetil were defined based on an incidence of adverse events with candesartan cilexetil at least 1% higher than the incidence seen with placebo. By this definition, the most commonly reported adverse reactions were dizziness/vertigo, headache and respiratory infection.
The most commonly reported adverse reactions during treatment were oedema (very common) somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle swelling, and fatigue (common).
The frequencies used 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), not known (cannot be estimated from the available data).
The Table 1 below presents adverse reactions from clinical trials and post-marketing experience.
Table 1:
| MedDRA System Organ Class | Frequency | Undesirable Effect |
|---|---|---|
| Infections and infestations | Common | Respiratory infection |
| Blood and lymphatic system disorders | Very rare | Leukopenia, neutropenia, 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 |
| Not known | Diarrhoea | |
| Hepatobiliary disorders | Very rare | Increased liver enzymes, abnormal hepatic function, hepatitis |
| Skin and subcutaneous tissue disorders | Very rare | Angioedema, rash, urticaria, pruritus |
| Musculoskeletal and connective tissue disorders | Very rare | Back pain, arthralgia, myalgia |
| Renal and urinary disorders | Very rare | Renal impairment, including renal failure in susceptible patients |
As for other inhibitors of the renin-angiotensin-aldosterone system, small decreases in haemoglobin have been seen. No routine monitoring of laboratory variables is usually necessary for patients receiving candesartan. However, in patients with renal impairment, periodic monitoring of serum potassium and creatinine levels is recommended.
Within each frequency grouping, adverse reactions in Table 2 are presented in order of decreasing seriousness.
Table 2:
| MedDRA System organ class | Frequency | Adverse reactions |
|---|---|---|
| Blood and lymphatic system disorders | Very rare | Leukocytopenia, thrombocytopenia |
| Immune system disorders | Very rare | Allergic reactions |
| Metabolism and nutrition disorders | Very rare | Hyperglycaemia |
| Psychiatric disorders | Uncommon | Insomnia, mood changes (including anxiety), depression |
| Rare | Confusion | |
| Nervous system disorders | Common | Somnolence, dizziness, headache (especially at the beginning of the 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 | Dyspnoea |
| Uncommon | Cough, rhinitis | |
| Gastrointestinal disorders | Common | Abdominal pain, nausea, dyspepsia, altered bowel habits (including diarrhoea and constipation) |
| Uncommon | Vomiting, dry mouth | |
| Very rare | Pancreatitis, gastritis, gingival hyperplasia | |
| Hepatobiliary disorders | Very rare | Hepatitis, jaundice, hepatic enzymes increased* |
| Skin and subcutaneous tissue disorders | Uncommon | Alopecia, purpura, skin discolouration, hyperhidrosis, pruritus, rash, exanthema, urticaria |
| Very rare | Angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, photosensitivity | |
| Not known | Toxic epidermal necrolysis | |
| 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, gynaecomastia |
| General disorders and administration site conditions | Very common | Oedema |
| Common | Fatigue, asthenia | |
| Uncommon | Chest pain, pain, malaise | |
| Investigations | Uncommon | Weight increase, weight decrease |
* mostly consistent with cholestasis
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 the ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal.
Not applicable.
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