BIPRETERAX ARGININE /

Given the respective effects of each of the two substances in this combination on pregnancy and breastfeeding, the use of BIPRETERAX 10 mg/2,5 mg is not recommended during the first trimester of pregnancy. BIPRETERAX 10 mg/2,5 mg is contraindicated during the second and third trimesters of pregnancy.

BIPRETERAX 10 mg/2,5 mg is not recommended during breastfeeding, therefore an alternative solution should be considered, either stopping breastfeeding or stopping treatment, taking into account the importance of this treatment for the mother.

Pregnancy

Related to perindopril

The use of ACE inhibitors is not recommended during the 1st trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the 2nd and 3rd trimesters of pregnancy (see sections 4.3 and 4.4).

The available epidemiological data regarding the risk of malformation after exposure to ACE inhibitors in the 1st trimester of pregnancy do not allow for a conclusion. However, a small increase in the risk of congenital malformations cannot be excluded. Unless continued ACE inhibitor 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 ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to ACE inhibitors during the 2nd and 3rd trimesters of pregnancy is known to induce foetotoxicity (decreased renal function, oligohydramnios, cranial ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3). In case of exposure from the 2nd trimester of pregnancy, it is recommended to perform a foetal ultrasound to check renal function and the bones of the skull vault. Newborns whose mothers have been treated with ACE inhibitors must be monitored for blood pressure (see sections 4.3 and 4.4).

Related to indapamide

There are no or limited data (less than 300 pregnancies) on the use of indapamide in pregnant women.

Prolonged exposure to thiazide diuretics during the third trimester of pregnancy can reduce maternal plasma volume and uteroplacental blood flow, which may lead to foetoplacental ischaemia and growth retardation.

Animal studies have not shown direct or indirect harmful effects on reproduction (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of indapamide during pregnancy.

Breastfeeding

BIPRETERAX 10 mg/2,5 mg is not recommended during breastfeeding.

Related to perindopril

Due to the lack of information available on the use of périndopril during breastfeeding, périndopril is not advised. It is preferable to use other treatments with a well-established safety profile during breastfeeding, particularly in the newborn or preterm infant.

Related to indapamide

There are no sufficient data on the excretion of indapamide/metabolites in human milk. Hypersensitivity to sulfonamide-derived drugs and hypokalaemia may occur. A risk to the newborns/infants cannot be excluded.

Indapamide is closely related to thiazide diuretics which have been associated with a decrease or even suppression of lactation during breastfeeding.

Indapamide is not recommended during breastfeeding.

Fertility

Related to perindopril and indapamide

Reproductive toxicity studies showed no effect on fertility in female and male rats (see section 5.3). No effect on fertility is expected in humans.

Related to périndopril, indapamide and BIPRETERAX 10 mg/2,5 mg

Neither of the two active ingredients, nor BIPRETERAX 10 mg/2,5 mg affect alertness but individual reactions related to low blood pressure may occur in some patients, particularly at the start of treatment or when combined with another antihypertensive drug.

Consequently, the ability to drive vehicles or use machines may be decreased.

Summary of the safety profile

Administration of perindopril inhibits the renin-angiotensin-aldosterone axis and tends to reduce the potassium loss caused by indapamide. Six per cent of patients treated with BIPRETERAX presented with hypokalaemia (potassium level < 3.4 mmol/l).

The most frequently observed adverse effects are:

· with perindopril: dizzy sensations, headache, paresthesia, dysgeusia, visual disturbances, vertigo, tinnitus, hypotension, cough, dyspnoea, abdominal pain, constipation, dyspepsia, diarrhoea, nausea, vomiting, pruritus, rash, muscle cramps and asthenia,

· with indapamide: hypokalaemia, hypersensitivity reactions, mainly dermatological, in patients with a predisposition to allergic and asthmatic reactions and maculopapular eruptions.

Tabulated summary of adverse effects

The following adverse effects were observed during clinical trials and/or post-MA use and were classified according to the following frequencies:

Very common (≥ 1/10) ; common (≥ 1/100, < 1/10) ; uncommon (≥ 1/1 000, < 1/100), rare (≥ 1/10 000, < 1/1 000), very rare (< 1/10 000), frequency indeterminate (cannot be estimated on the basis of available data).

* Frequency estimated from clinical trial data for adverse effects reported after marketing (spontaneous notifications).

Description of certain adverse effects:

During phase II and III studies comparing indapamide 1,5 mg and 2,5 mg, the analysis of kaliemia showed a dose-dependent effect of indapamide:

· Indapamide 1,5 mg: A kaliemia < 3,4 mmol/l was observed in 10% of patients and < 3,2 mmol/l in 4 % of patients after 4 to 6 weeks of treatment. After 12 weeks of treatment, the average decrease in kaliemia was 0,23 mmol/l.

· Indapamide 2,5 mg: A kaliemia < 3,4 mmol/l was observed in 25% of patients and < 3,2 mmol/l in 10 % of patients after 4 to 6 weeks of treatment. After 12 weeks of treatment, the average decrease in kaliemia was 0,41 mmol/l.

Reporting of suspected adverse effects

Reporting suspected adverse effects after medicinal product authorization is important. It allows for continuous monitoring of the benefit/risk ratio of the medicinal product. Healthcare professionals report any suspected adverse effect via the national reporting system: French National Agency for Medicines and Health Products Safety (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr .