TRIPLIXAM

Given the respective effects of each of the three substances present in the combination on pregnancy and breastfeeding, the use of TRIPLIXAM is not recommended during the first trimester of pregnancy. TRIPLIXAM is contraindicated during the second and third trimester of pregnancy.

TRIPLIXAM is not recommended during breastfeeding, which is why it will be necessary to interrupt breastfeeding, or to interrupt treatment with TRIPLIXAM 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 1 trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the 2 and 3 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 1 trimester of pregnancy do not allow for a conclusion. However, a slight increase in the risk of congenital malformation 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 detected, 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 human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).

Should exposure to ACE inhibitor have occurred from the 2 trimester of pregnancy, ultrasound check of fetal renal function and skull is recommended.

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

RELATED TO INDAPAMIDE:

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of indapamide in pregnant women. Prolonged maternal exposure to thiazide diuretics during the third trimester of pregnancy can reduce maternal plasma volume as well as uteroplacental blood flow, which may cause foetoplacental ischaemia and growth retardation. In addition, rare cases of hypoglycaemia and thrombocytopenia in neonates have been reported following exposure near term.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

Related to amlodipine:

In humans, the safety of amlodipine in pregnancy has not been established.

In animal studies, reproductive toxicity was observed at high doses (see section 5.3).

Breastfeeding

TRIPLIXAM is not recommended during breastfeeding.

RELATED TO PERINDOPRIL:

Due to the lack of information available on the use of perindopril during breastfeeding, perindopril is not recommended. It is preferable to use other treatments with a well-established safety profile during breastfeeding, especially in newborns or preterm infants.

RELATED TO INDAPAMIDE:

There is no sufficient data on the excretion of indapamide/metabolites in human milk.

Hypersensitivity to sulfonamide derivatives and hypokalemia may occur. A risk to newborns/infants cannot be excluded.

Indapamide is closely related to thiazide diuretics which are involved in the reduction or even suppression of milk during breastfeeding.

RELATED TO AMLODIPINE:

Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3 to 7 %, with a maximum of 15 %. The effect of amlodipine on infants is unknown.

Fertility

Related to perindopril and indapamide:

Reproductive toxicity studies have shown no effect on fertility in female and male rats. No effect on human fertility is expected.

RELATED TO AMLODIPINE:

Reversible biochemical changes in the head of the spermatozoon have been reported in some patients treated by calcium channel blockers. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In a study conducted in rats, adverse effects were detected on male fertility (see section 5.3).

No study has been conducted on the effects of TRIPLIXAM on the ability to drive vehicles and use machines.

Perindopril and indapamide do not affect the ability to drive vehicles and use machines, but individual reactions related to a decrease in blood pressure may occur in some patients.

Amlodipine may have a minor or moderate influence on the ability to drive vehicles and use machines. If patients treated with amlodipine experience dizziness, headache, fatigue, lassitude or nausea, their ability to react may be impaired.

Consequently, the ability to drive vehicles or use machines may be decreased. Precautions are recommended, particularly at the start of treatment.

Summary of the safety profile

The most frequently reported adverse reactions with perindopril, indapamide and amlodipine administered separately are: hypokalaemia, dizziness, headache, paraesthesia, somnolence, dysgeusia, visual disturbances, diplopia, tinnitus, vertigo, palpitations, flushing, hypotension (and effects related to hypotension), cough, dyspnoea, gastrointestinal disorders (abdominal pain, constipation, diarrhoea, dyspepsia, nausea, vomiting, change of bowel habit), pruritus, rash, maculopapular rash, muscle cramps, ankle swelling, asthenia, oedema and fatigue.

List of adverse reactions

The following adverse reactions have been observed during treatment with perindopril, indapamide or amlodipine and ranked under the following frequency: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data).

* Frequency estimated from clinical trial data for adverse reactions reported post-marketing (spontaneous reporting).

Description of selected adverse reactions:

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

· Indapamide 1.5 mg: Blood potassium < 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 mean decrease in blood potassium was 0.23 mmol/l.

· Indapamide 2.5 mg: Blood potassium < 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 mean decrease in blood potassium was 0.41 mmol/l.

Reporting of suspected adverse reactions

Reporting 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 report any suspected adverse reaction via the national reporting system: French National Agency for Medicines and Health Products Safety (ANSM) and network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr