Sanofi Pharma Bristol-Myers Squibb SNC

It is unknown whether irbesartan or its metabolites are excreted in human milk.  Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its metabolites in milk (for details see 5.3).

New sub heading added:
Fertility:

Irbesartan had no effect upon fertility of treated rats and their offspring up to dose levels inducing the first signs of parental toxicity (see section 5.3).

Section 5.3, following text added:

Fertility and reproductive performance were not affected in studies of male and female rats even at oral doses of irbesartan causing some parental toxicity (from 50 to 650 mg/kg/day), including mortality at the highest dose.  No significant effects on the number of corpora lutea, implants, or live foetuses were observed.  Irbesartan did not affect survival, development, or reproduction of offspring.  Studies in animals indicate that the radiolabeled irbesartan is detected in rat and rabbit fetuses.  Irbesartan is excreted in the milk of lactating rats.

Section 6.5: updated to reflect marketed pack size in UK
Section 8: updated to reflect marketed products in UK
Section 10: date of revision amended with latest approval
Legal Cateogory added; POM

Additional information to 4.8

Updated section

SmPC section 4.5 Interaction with other medicinal products and other forms of interaction

Colestyramine and Colestipol resins: absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. CoAprovel should be taken at least one hour before or four hours after these medications;

Implement the CHMP recommendation on a harmonised labelling relating to the use of Angiotensin II Receptor Antagonists during pregnancy and lactation. Furthermore, minor typographical changes have been introduced in the SPC.

_{4.2 Posology and method of administration
(...) Intravascular volume depletion: volume and/or sodium depletion should be corrected prior to administration of CoAprovel.}

_{Paediatric patients: CoAprovel is no experiencenot recommended for use in children and adolescents due to a lack of data on safety and efficacy.}

4.6         Pregnancy and lactation

Pregnancy:   

Thiazides cross the placental barrier and appear in cord blood.   They may cause a decrease in placental perfusion, foetal electrolyte disturbances and possibly other reactions that have occurred in the adults.   Cases of neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported with maternal thiazide therapy.   Since CoAprovel contains hydrochlorothiazide, it is not recommended during the first trimester of pregnancy.   A switch to a suitable alternative treatment should be carried out in advance of a planned pregnancy.

CoAprovel is contraindicated in the second and third trimesters of pregnancy (see section 4.3). In the second and third trimesters, substances that act directly on the renin-angiotensin-system can cause foetal or neonatal renal failure, foetal skull hypoplasia and even foetal death. If pregnancy is diagnosed, CoAprovel should be discontinued as soon as possible, skull and renal function should be checked with echography if, inadvertently, the treatment was taken for a long period.

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 Angiotensin II Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIR

As should be stopped immediately, and, if appropriate, alternative therapy should be started.

AIIRAs therapy exposure 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 also sections 4.3 and 4.4).

Thiazides cross the placental barrier and appear in cord blood. They may cause a decrease in placental perfusion, foetal electrolyte disturbances and possibly other reactions that have occurred in the adults. Cases of neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported with maternal thiazide therapy. Since CoAprovel contains hydrochlorothiazide, it is not recommended during the first trimester of pregnancy. A switch to a suitable alternative treatment should be carried out in advance of a planned pregnancy.

Lactation: CoAprovel is contraindicated during breast-feeding.

Section 4.4:

Addition of:

  Lactose:   This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Section 5.1:

Addition of:

Efficacy and safety of CoAprovel as initial therapy for severe hypertension (defined as SeDBP ¡Ý 110 mmHg) was evaluated in a multicentre, randomised, double-blind, active-controlled, 8‑week, parallel-arm study. A total of 697 patients were randomised in a 2:1 ratio to either irbesartan/hydrochlorothiazide 150 mg/12.5 mg or to irbesartan 150 mg and systematically force-titrated (before assessing the response to the lower dose) after one week to irbesartan/hydrochlorothiazide 300 mg/25 mg or irbesartan 300 mg, respectively.

The study recruited 58% males. The mean age of patients was 52.5 years, 13% were ¡Ý 65 years of age, and just 2% were ¡Ý 75 years of age. Twelve percent (12%) of patients were diabetic, 34% were hyperlipidaemic and the most frequent cardiovascular condition was stable angina pectoris in 3.5% of the participants.

The primary objective of this study was to compare the proportion of patients whose SeDBP was controlled (SeDBP < 90 mmHg) at week 5 of treatment. Forty-seven percent (47.2%) of patients on the combination achieved trough SeDBP < 90 mmHg compared to 33.2% of patients on irbesartan (p = 0.0005). The mean baseline blood pressure was approximately 172/113 mmHg in each treatment group and decreases of SeSBP/SeDBP at five weeks were 30.8/24.0 mmHg and 21.1/19.3 mmHg for irbesartan/hydrochlorothiazide and irbesartan, respectively (p < 0.0001).

The types and incidences of adverse events reported for patients treated with the combination were similar to the adverse event profile for patients on monotherapy. During the 8‑week treatment period, there were no reported cases of syncope in either treatment group. There were 0.6% and 0% of patients with hypotension and 2.8% and 3.1% of patients with dizziness as adverse reactions reported in the combination and monotherapy groups, respectively.

Section 10

Changed from '28 August 2006' to 'January 2007'