The MAH (Takeda Products Ireland Limited) address has been changed to:

6th Floor, South Bank House, Barrow Street, Dublin 4, Ireland.

This is the new legally registered office.

The date of revision of the SmPC is 7th July 2020.

An update to pack sizes has been made.

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

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

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.

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

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

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

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

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).

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:

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
16^th January 2009
July 2010