Blopress tablets

  • Name:

    Blopress tablets

  • Company:
    info
  • Active Ingredients:

    Candesartan Cilexetil

  • Legal Category:

    Product subject to medical prescription which may be renewed (B)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 26/04/19

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Summary of Product Characteristics last updated on medicines.ie: 10/1/2019

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Takeda Products Ireland Ltd

Takeda Products Ireland Ltd

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1 - 0 of 26 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 26 April 2019 PIL

Reasons for updating

  • Change to section 2 - what you need to know - contraindications
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision
  • Change to other sources of information section
  • Change to improve clarity and readability

Updated on 15 March 2019 PIL

Reasons for updating

  • Correction of spelling/typing errors

Updated on 10 January 2019 PIL

Reasons for updating

  • Change to section 6 - what the product looks like and pack contents

Updated on 10 January 2019 SmPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

An update to pack sizes has been made.

Updated on 9 November 2018 PIL

Reasons for updating

  • Change to section 6 - what the product looks like and pack contents
  • Change to section 6 - date of revision

Updated on 9 November 2018 SmPC

Reasons for updating

  • Change to section 6.5 - Nature and contents of container
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

In section 6.5, a 28 day tablet pack size has been added.

The date of revision has been updated to 28th October 2018.

Updated on 6 July 2018 SmPC

Reasons for updating

  • Change to section 3 - Pharmaceutical form
  • Change to section 6.1 - List of excipients

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Correcton made regarding the ability to split the tablets in to equal doses and the additional excipients for the higher strengths of Blopress was omitted from the combined Blopress SPC following the PRAC update, in section 3 and section 6.1.

Updated on 29 May 2018 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

Diarrhoea as a side effect with unknown frequency has been added to section 4.8..

Updated on 24 May 2018 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 8 - Marketing authorisation number(s)
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 4 May 2018 PIL

Reasons for updating

  • Change to section 6 - marketing authorisation holder
  • Change to section 6 - date of revision

Updated on 3 November 2016 PIL

Reasons for updating

  • New PIL for new product

Updated on 3 November 2016 PIL

Reasons for updating

  • Change to section 6 - manufacturer

Updated on 12 December 2014 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may be renewed (B)

Updated on 12 December 2014 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company



Section

Change

4.1 Therapeutic indications

The wording in bold has been added/amended:

 

Treatment of adult patients with heart failure and impaired left ventricular systolic function (left ventricular ejection fraction ≤ 40%) when Angiotensin Converting Enzyme (ACE)  inhibitors are not tolerated or as add-on therapy to ACE inhibitors in patients with symptomatic heart failure, despite optimal therapy, when mineralocorticoid receptor antagonists are not tolerated (see sections 4.2, 4.4, 4.5, and 5.1).

  

4.2

The wording in bold has been updated:

 

Older people

No initial dose adjustment is necessary in elderly patients.

 

Blopress may also be administered with other antihypertensive agents (see sections 4.3, 4.4, 4.5 and 5.1).

 

Posology in Heart Failure
The following information has been added:

 

Blopress may be co-administered with an ACE-inhibitor in patients with symptomatic heart failure despite optimal standard heart failure therapy when mineralocorticoid receptor antagonists are not tolerated.

 

4.3 Contraindications

The following information has been added/amended:

 

The concomitant use of Blopress with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR< 60ml/min/1.73m2) (see sections 4.5 and 5.1).

 

4.4 Special warnings and precautions for use

The following information has been added:

 

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 (see Section 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.

 

The following information in bold has been added/amended:

 

Concomitant therapy with an ACE inhibitor in heart failure

The risk of adverse reactions, especially hypotension, hyperkalaemia and decreased renal function (including acute renal failure), may increase when Blopress 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.

 

4.5 Interaction with other medicinal products and other forms of interaction

The following information has been added:

 

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, 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).

 

5.1 Pharmacodynamic properties

The following information has been added:

 

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

 

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in 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 injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers. ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

 

ALTITUDE (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 an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

 

10. Date of revision of the text

This has been updated to 28 November 2014

Updated on 5 December 2014 PIL

Reasons for updating

  • Change to, or new use for medicine
  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to dosage and administration

Updated on 17 October 2014 SmPC

Reasons for updating

  • Change to section 10 - Date of revision of the text
  • Change to section 7 - Marketing authorisation holder

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

In section 7 Marketing Authorisation Holder the address has been updated to:

 

Takeda UK Limited

Building 3

Glory Park

Glory Park Avenue

Wooburn Green

BUCKS

HP10 0DF

United Kingdom

Updated on 10 October 2014 PIL

Reasons for updating

  • Change to date of revision
  • Change to MA holder contact details

Updated on 10 March 2014 PIL

Reasons for updating

  • Change to, or new use for medicine
  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to instructions about overdose
  • Change to side-effects
  • Change to information about pregnancy or lactation
  • Change to date of revision
  • Change to dosage and administration
  • Addition of joint PIL covering all presentations
  • Addition of information on reporting a side effect.

Updated on 10 February 2014 SmPC

Reasons for updating

  • Change to paediatric information
  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to joint SPC covering all presentations

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company



 

4.1  Therapeutic indications
Added:
  Treatment of hypertension in children and adolescents aged 6 to <18 years.4.2
   Posology and method of administration


4.2   Posology and method of administration

Added:

 

 

 

 

 

Paediatric Population

 

Children and adolescents aged 6 to <18 years:

The recommended starting dose is 4 mg once daily.

 

·        For patients weighing < 50 kg: In patients whose blood pressure is not adequately controlled, the dose can be increased to a maximum of 8 mg once daily.

 

·        For patients weighing ≥ 50 kg: In patients whose blood pressure is not adequately controlled, the dose can be increased to 8 mg once daily and then to 16 mg once daily if needed (see section 5.1).

 

Doses above 32 mg have not been studied in paediatric patients.

 

Most of the antihypertensive effect is attained within 4 weeks.

 

For children with possible intravascular volume depletion (e.g., patients treated with diuretics, particularly those with impaired renal function), Blopress treatment should be initiated under close medical supervision and a lower starting dose than the general starting dose above should be considered (see section 4.4).

 

Blopress has not been studied in children with glomerular filtration rate less than 30 ml/min/1.73m2 (see section 4.4).

 

Black paediatric patients

The antihypertensive effect of candesartan is less pronounced in black patients than in non-black patients (see section 5.1).

 

Children aged below 1 year to <6 years

The safety and efficacy in children aged 1 to <6 years of age has not been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made.

 

Blopress is contraindicated in children aged below 1 year (see section 4.3).

 

Removed: “hypertension and” from:

Paediatric Population

 

The safety and efficacy of Blopress in children aged between birth and 18 years have not been established in the treatment of heart failure. No data are available.

4.3 Contraindications

Added:  “listed in section 6.1.” to “Hypersensitivity to candesartan cilexetil or to any of the excipients listed in section 6.1.”

 

Added: Children aged below 1 year (see section 5.3).

4.4
   Special warnings and precautions for use

Added:

Use in paediatric patients including patients with renal impairment

Blopress has not been studied in children with a glomerular filtration rate less than 30 ml/min/1.73m2 (see section 4.2).

 

Added in the section on “hypotension”:

For children with possible intravascular volume depletion (e.g. patients treated with diuretics, particularly those with impaired renal function), candesartan treatment should be initiated under close medical supervision and a lower starting dose should be considered (see section 4.2).

 

Added in the section on “pregnancy”:

In post-menarche patients the possibility of pregnancy should be evaluated on a regular basis. Appropriate information should be given and/or action taken to prevent the risk of exposure during pregnancy (see sections 4.3 and 4.6).

4.5 Interaction with other medicinal products and other forms of interaction

 

Added:

Paediatric population

Interaction studies have only been performed in adults

4.6 Fertility, pregnancy and lactation

Added: “Fertility” to the section heading “Fertility, pregnancy and lactation”

 

Changed: “Lactation” heading to “Breastfeeding”

4.8 Undesirable effects

 

Added:

Paediatric population

The safety of candesartan cilexetil was monitored in 255 hypertensive children and adolescents, aged 6 to <18 years old, during a 4 week clinical efficacy study and a 1 year open label study (see section 5.1). In nearly all different system organ classes, the frequency of adverse events in children are within common/uncommon range. Whilst the nature and severity of the adverse events are similar to those in adults (see the table above), the frequency of all adverse events are higher in children and adolescent, particularly in:

 ·                                                      Headache, dizziness and upper respiratory tract infection, are “very common” (ie, ≥1/10) in children and common (≥ 1/100 to < 1/10) in adults.
·                                                      Cough is “very common” (ie, > 1/10) in children and very rare (<1/10,000) in adults.
·                                                      Rash is “common” (ie, ≥1/100 to <1/10) in children and “very rare” (<1/10,000) in adults.
·                                                      Hyperkalemia, hyponatraemia and abnormal liver function are uncommon (≥ 1/1,000 to < 1/100) in children and very rare (< 1/10,000) in adults.
·                                                      Sinus arrhythmia, Nasopharyngitis, pyrexia are “common” (ie, ≥1/100 to <1/10) and oropharyngeal pain is “very common” (ie, ≥1/10) in children; but none are reported in adults. However these are temporary and widespread childhood illnesses.

The overall safety profile for candesartan cilexetil in paediatric patients does not differ significantly from the safety profile in adults.

Added: “adult” to
The adverse experience profile of Blopress in adult heart failure patients was consistent with the pharmacology of the drug and the health status of the patients.
Added:
Reporting of suspected adverse reactionsReporting 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 to Pharmacovigilance Section, Irish Medicines Board, Kevin O’Malley House, Earlsfort Centre, Earlsfort Terrace, IRL – Dublin 2 Tel: +353 1 6764971, Fax: +353 1 6767836, Website: www.imb.ie e-mail: imbpharmacovigilance@imb.ie  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

4.9 Overdose

Added: “in an adult” to

Based on pharmacological considerations, the main manifestation of an overdose is likely to be symptomatic hypotension and dizziness. In individual case reports of overdose (of up to 672 mg candesartan cilexetil) in an adult, patient recovery was uneventful.

5.1 Pharmacodynamic properties

Added the following headings:

“Mechanism of Action”

“Pharmacodynamic effects”

“Clinical efficacy and safety”

 

Added:

Paediatric population - hypertension

The antihypertensive effects of candesartan were evaluated in hypertensive children aged 1 to <6 years and 6 to <17 years in two randomised, double-blind multicentre, 4 week dose ranging studies.

 

In children aged 1 to <6 years, 93 patients, 74% of whom had renal disease, were randomised to receive an oral dose of candesartan cilexetil suspension 0.05, 0.20 or 0.40 mg/kg once daily. The primary method of analysis was slope of the change in systolic blood pressure (SBP) as a function of dose. SBP and diastolic blood pressure (DBP) decreased 6.0/5.2 to 12.0/11.1 mmHg from baseline across the three doses of candesartan cilexetil. However, since there was no placebo group, the true magnitude of blood pressure effect remains uncertain which makes a conclusive assessment of benefit-risk balance difficult in this age group.

 

In children aged 6 to <17 years, 240 patients were randomised to receive either placebo or low, medium, or high doses of candesartan cilexetil in a ratio of 1: 2: 2: 2. For children who weighed < 50 kg, the doses of candesartan cilexetil were 2, 8, or 16 mg once daily. In children who weighed > 50 kg, the candesartan cilexetil doses were 4, 16 or 32 mg once daily. Candesartan at pooled doses reduced SiSBP by 10.2 mmHg (P< 0.0001) and SiDBP (P=0.0029) by 6.6 mmHg, from the base line. In the placebo group, there was also a reduction of 3.7 mmHg in SiSBP (p=0.0074) and 1.80 mmHg for SiDBP (p=0.0992) from the baseline. Despite the large placebo effect, all individual candesartan doses (and all doses pooled) were significantly superior to placebo. Maximum response in reduction of blood pressure in children below and above 50 kg was reached at 8mg and 16 mg doses, respectively and the effect plateaued after that point. Of those enrolled, 47% were black patients and 29% were female; mean age +/- SD was 12.9 +/- 2.6 years.

 

In children aged 6 to < 17 years there was a trend for a lesser effect on blood pressure in black patients compared to non-black patients.

5.2 Pharmacokinetic properties

Added:

Paediatric population

 

The Pharmacokinetic properties of candesartan were evaluated in hypertensive children aged 1 to <6 years and 6 to <17 years in two single dose PK studies.

 

In children aged 1 to <6 years, 10 children weighing 10 to <25 kg received a single dose of 0.2 mg/kg, oral suspension. There was no correlation between Cmax and AUC with age or weight. No clearance data has been collected; therefore the possibility of a correlation between clearance and weight/age in this population is unknown.

 

In children aged 6 to <17 years, 22 children received a single dose of 16 mg tablet. There was no correlation between Cmax and AUC with age. However weight seems to significantly correlate with Cmax (p=0.012) and AUC (p=0.011). No clearance data, has been collected, therefore the possibility of a correlation between clearance and weight/age in this population is unknown.

 

Children >6 years of age had exposure similar to adults given the same dose.

 

The pharmacokinetics of candesartan cilexetil have not been investigated in paediatric patients <1 year of age.

5.3 Preclinical safety data

Added:

In preclinical studies in normotensive neonatal and juvenile rats, candesartan caused a reduction in body weight and heart weight. As in adult animals, these effects are considered to result from the pharmacological action of candesartan. At the lowest dose of 10 mg/kg exposure to candesartan was between 12 and 78 times the levels found in children aged 1 to <6 who received candesartan cilexetil at a dose of 0.2 mg/kg and 7 to 54 times those found in children aged 6 to <17 who received candesartan cilexetil at a dose of 16 mg. As a no observed effect level was not identified in these studies, the safety margin for the effects on heart weight and the clinical relevance of the finding is unknown.

 

Added:

The renin‑angiotensin‑aldosterone system plays a critical role in kidney development in utero. Renin‑angiotensin‑aldosterone system blockade has been shown to lead to abnormal kidney development in very young mice. Administering drugs that act directly on the renin‑angiotensin‑aldosterone system can alter normal renal development. Therefore, children aged less than 1 year should not receive Blopress (see section 4.3).

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Updated on 15 February 2013 PIL

Reasons for updating

  • Change to name of manufacturer

Updated on 25 May 2011 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

In section 4.8 (undesirable effects), cough has been added

Updated on 25 May 2011 PIL

Reasons for updating

  • Change to side-effects

Updated on 11 November 2010 PIL

Reasons for updating

  • Change to warnings or special precautions for use
  • Change of contraindications
  • Change to side-effects
  • Change to drug interactions
  • Change to information about pregnancy or lactation
  • Change to date of revision

Updated on 11 November 2010 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 10 - Date of revision of the text
  • Change to improve clarity and readability

Legal category: Product subject to medical prescription which may be renewed (B)

Free text change information supplied by the pharmaceutical company

The Blopress 2-32mg SmPCs have been updated following harmonisation of the candesartan monotherapy licence in Europe. There have been many changes to the SmPC, many of which are rewording, re-positioning or re-formatting of the text.

The main changes are as follows:

Section 4.1 Therapeutic indications
There has been an amendment to the wording of the indication:

  • Treatment of essential hypertension in adults.
  • Treatment of adult patients with heart failure and impaired left ventricular systolic function (left ventricular ejection fraction ≤ 40%) as add-on therapy to Angiotensin Converting Enzyme (ACE) inhibitors or when ACE inhibitors are not tolerated (see section 5.1).

Section 4.2 Posology and method of administration
Posology in Hypertension

  • Rewording & repositioning of the highlighted text:

The recommended initial dose and usual maintenance dose of Blopress is 8 mg once daily.  Most of the antihypertensive effect is attained within 4 weeks. In some patients whose blood pressure is not adequately controlled, the dose can be increased to 16 mg once daily and to a maximum of 32 mg once daily. Therapy should be adjusted according to blood pressure response.

Blopress may also be administered with other antihypertensive agents. Addition of hydrochlorothiazide has been shown to have an additive antihypertensive effect with various doses of Blopress.

  • In patients with hepatic impairment, the recommended initial dose has increased from 2 mg once daily to 4 mg once daily
  • The section on Posology in Heart Failure has been reworded and 'The combination of an ACE inhibitor, a potassium‑sparing diuretic (e.g. spironolactone) and Blopress is not recommended and should be considered only after careful evaluation of the potential benefits and risks (see sections 4.4, 4.8 and 5.1)' has been added

4.3 Contraindications
Hypersensitivity to candesartan cilexetil or to any of the excipients.
Pregnancy and laction Second and third trimesters of pregnancy (see sections 4.4 and 4.6).
Severe hepatic impairment and/or cholestasis

4.4 Special warnings and precautions for use

  • The following has been added on pregnancy:

Pregnancy
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 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 (see sections 4.3 and 4.6).

4.5 Interaction with other medicinal products and other forms of interaction
No drug interactions of clinical significance have been identified.
Compounds which have been investigated in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (i.e. ethinylestradiol/ levonorgestrel), glibenclamide, nifedipine and enalapril. No clinically significant pharmacokinetic interactions with these medicinal products have been identified.

Based on experience with the use of other medicinal products that affect the renin-angiotensin- system, 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).

Use of candesartan with lithium is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.

4.6 Pregnancy and lactation
The following wording has been added as a boxed section and the crossed out section replaced with the bolded section:

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


There are very limited data from the use of Blopress in pregnant women.  These data are insufficient to allow conclusions about potential risk for the foetus when used during the first trimester. In humans, foetal renal perfusion, which is dependent upon the development of the renin-angiotensin-aldosterone system, begins in the second trimester. Thus, risk to the foetus increases if Blopress is administered during the second or third trimesters of pregnancy. When used in pregnancy during the second and third trimesters, medicinal products that act directly on the renin-angiotensin system can cause foetal and neonatal injury (hypotension, renal dysfunction, oliguria and/or anuria, oligohydramnios, skull hypoplasia, intrauterine growth retardation) and death.  Cases of lung hypoplasia, facial abnormalities and limb contractures have also been described.
Animal studies with candesartan cilexetil have demonstrated late foetal and neonatal injury in the kidney. The mechanism is believed to be pharmacologically mediated through effects on the renin-angiotensin-aldosterone system.
Based on the above information, Blopress should not be used in pregnancy. If pregnancy is detected during treatment, Blopress should be discontinued (see section 4.3 Contraindications).

Use in lactation

It is not known whether candesartan is excreted in human milk. However, candesartan is excreted in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant Blopress should not be given during breast-feeding (see section 4.3 Contraindications).


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.

 

Exposure to 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) (see section 5.3).

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

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see sections 4.3 and 4.4).

 

Lactation

 

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


4.8 Undesirable effects

  • Section 4.8 has been re-formatted and adverse events from clinical trials and post-marketing experience have been tabulated separately for treatment of hypertension and treatment of heart failure

5.1 Pharmacodynamic properties
When candesartan cilexetil is used together with hydrochlorothiazide, the reduction in blood pressure is additive. Concomitant administration of candesartan cilexetil with hydrochlorothiazide or amlodipine is well tolerated.  An increased antihypertensive effect is also seen when candesartan is combined with amlodipine or felodipine.

In CHARM-Alternative, the composite endpoint of cardiovascular mortality or first CHF hospitalisation was significantly reduced with candesartan in comparison with placebo, hazard ratio (HR) 0.77 (95%CI: 0.67 to 0.89, p< 0.001). This corresponds to a relative risk reduction of 23%. Of candesartan patients 33.0% (95%CI: 30.1 to 36.0) and of placebo patients 40.0% (95%CI: 37.0 to 43.1) experienced this endpoint, absolute difference 7.0% (95%CI: 11.2 to 2.8). Fourteen patients needed to be treated for the duration of the study to prevent one patient from dying of a cardiovascular event or being hospitalised for treatment of heart failure. The composite endpoint of all-cause mortality or first CHF hospitalisation was also significantly reduced with candesartan, HR 0.80 (95%CI: 0.70 to 0.92, p=0.001). Of candesartan patients 36.6% (95%CI: 33.7 to 39.7) and of placebo patients 42.7% (95%CI: 39.6 to 45.8) experienced this endpoint, absolute difference 6.0% (95%CI: 10.3 to 1.8). Both the mortality and morbidity (CHF hospitalisation) components of these composite endpoints contributed to the favourable effects of candesartan. Treatment with candesartan cilexetil resulted in improved NYHA functional class (p=0.008).

In CHARM-Added, the composite endpoint of cardiovascular mortality or first CHF hospitalisation was significantly reduced with candesartan in comparison with placebo, HR 0.85 (95%CI: 0.75 to 0.96, p=0.011). This corresponds to a relative risk reduction of 15%. Of candesartan patients 37.9% (95%CI: 35.2 to 40.6) and of placebo patients 42.3% (95%CI: 39.6 to 45.1) experienced this endpoint, absolute difference 4.4% (95%CI: 8.2 to 0.6). Twenty-three patients needed to be treated for the duration of the study to prevent one patient from dying of a cardiovascular event or being hospitalised for treatment of heart failure. The composite endpoint of all-cause mortality or first CHF hospitalisation was also significantly reduced with candesartan, HR 0.87 (95%CI: 0.78 to 0.98, p=0.021). Of candesartan patients 42.2% (95%CI: 39.5 to 45.0) and of placebo patients 46.1% (95%CI: 43.4 to 48.9) experienced this endpoint, absolute difference 3.9% (95%CI: 7.8 to 0.1). Both the mortality and morbidity components of these composite endpoints contributed to the favourable effects of candesartan. Treatment with candesartan cilexetil resulted in improved NYHA functional class (p=0.020).


5.2 Pharmacodynamic properties
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 drugs whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The terminal half-life of candesartan is approximately 9 hours. There is no accumulation following multiple doses.


In patients with mild to moderate hepatic impairment, there was a 23% increase in the AUC of candesartan (see section 4.2 Posology and method of administration).

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 (see section 4.2). There is no experience in patients with severe hepatic impairment.

10. DATE OF REVISION OF THE TEXT
16th January 2009
July 2010

Updated on 23 November 2009 PIL

Reasons for updating

  • New PIL for new product

Updated on 5 November 2009 SmPC

Reasons for updating

  • New SPC for new product

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