Takeda UK Ltd

4.1 Therapeutic indications

Blopress Plus is indicated for the:

• Treatment of essential hypertension in adult patients whose blood pressure is not optimally controlled with candesartan cilexetil or hydrochlorothiazide monotherapy.

No change to indications but addition of highlighted wording.

4.2 Posology and method of administration

The recommended dose of Blopress Plus is one tablet once daily.

Dose titration with the individual components (candesartan cilexetil and hydrochlorothiazide) is recommended.  When clinically appropriate a direct change from monotherapy to Blopress Plus may be considered. Dose titration of candesartan cilexetil is recommended when switching from hydrochlorothiazide monotherapy. Blopress Plus may be administered in patients whose blood pressure is not optimally controlled with candesartan cilexetil or hydrochlorothiazide monotherapy or Blopress Plus at lower doses.

Patients with renal impairment
Loop diuretics are preferred to thiazides in this population. Dose titration of candesartan cilexetil is recommended in patients with mild to moderate renal impairment (creatinine clearance ≥ 30 ml/min/1.73 m2 Body Surface Area (BSA)) before treatment with Blopress Plus (the recommended starting dose of candesartan cilexetil is 4 mg in these patients).

Addition of wording ‘mild to moderate’

4.2 Posology and method of administration

Patients with hepatic impairment

In patients with hepatic impairment, the recommended initial dose has increased from 2 mg once daily to 4 mg once daily. This means that the Blopress 2 mg dose is no longer recommended as a starting dose in any specific patient group.

Paediatric population
The safety and efficacy of Blopress Plus in children aged between birth and 18 years have not been established. No data are available.

Method of administration Oral use.

Blopress Plus can be taken with or without food. The bioavailability of candesartan is not affected by food. There is no clinically significant interaction between hydrochlorothiazide and food.

Method of administration summary added in section 4.2

The contraindication in pregnancy has been changed to specify the second and third trimesters.

Photosensitivity
Cases of photosensitivity reactions have been reported during use of thiazide diuretics (see section 4.8). If a photosensitivity reaction occurs, it is recommended to stop treatment. If re‐administration of treatment is essential, it is recommended to protect areas exposed to the sun or to artificial UVA radiation.

Additional wording added

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).

Periodic monitoring of serum potassium is recommended when Blopress Plus is administered with such medicinal products, and with the following medicinal products that could induce torsades de pointes:

•

Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide)
• Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)
• Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperiodol)
• Others (e.g. bepridil, cisapride, diphemanil, erythromycin iv, halofantrin, ketanserin, mizolastin, pentamidine, sparfloxacine, terfenadine, vincamine iv)

The boxed information on pregnancy has been added to section 4.6

Infections and infestations‐ common – respiratory infection
Nervous system disorder‐ common – dizziness/ vertigo, headache
Respiratory, thoracic and mediastinal disorders‐ very rare – cough

Updated wording to section 4.8

5.1 Pharmacodynamic properties
In a double‐blind, randomised study, Blopress Plus 16 mg/12.5 mg once daily reduced blood pressure significantly more, and controlled significantly more patients, than the combination losartan/hydrochlorothiazide 50 mg/12.5 mg once daily. In doubleblind, randomised studies, the incidence of adverse events, especially cough, was lower during treatment with Blopress Plus than during treatment with combinations of ACE inhibitors and hydrochlorothiazide.

In two clinical studies (randomised, double‐blind, placebo controlled, parallel group) including 275 and 1524 randomised patients respectively, the candesartan cilexetil/hydrochlorothiazide combinations 32 mg/12.5 mg and 32 mg/25 mg resulted in blood pressure reductions of 22/15 mmHg and 21/14 mmHg, respectively, and were significantly more effective than the respective mono components.

In a randomised, double

‐blind, parallel group clinical study including 1975 randomised patients not optimally controlled on 32 mg candesartan cilexetil once daily, the addition of 12.5 mg or 25 mg hydrochlorothiazide resulted in additional blood pressure reductions.

The candesartan cilexetil/hydrochlorothiazide combination 32 mg/25 mg was significantly more effective than the 32 mg/12.5 mg combination, and the overall mean blood pressure reductions were 16/10 mmHg and 13/9 mmHg, respectively.

Additional study information added

5.2 Pharmacokinetic properties

Concomitant administration of candesartan cilexetil and hydrochlorothiazide has no clinically significant effect on the pharmacokinetics of either medicinal product.

Pharmacokinetics in special populations. 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.