- 4.4    Special warnings and precautions for use

- 4.5    Interaction with other medicinal products and other forms of interaction

- 4.8    Undesirable effects

1) In sections 4.5 Type II C.I.4: to implement the changes submitted in February 2014 for indapamide. (Interaction with allopurinol and updating potassium-sparing diuretics [section 4.5],

2) In section 4.6 April 2013 CMDh QRD template implemented

3) In section 4.8 Addition of SOC eye disorders  

4) In sections 4.3, 4.4, 4.5, 4.6, 4.8 Type II C.I.4: to implement changes approved last August 2013 for perindopril (Coversyl*).

The following has been added to section 4.4:

Pregnancy and lactation:

ACE inhibitors should not be initiated during pregnancy. 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 (see sections 4.3 and 4.6).

Use of perindopril is not recommended during breast feeding.

The following has been added to section 4.6:

Pregnancy :

Linked to perindopril :

The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contra-indicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).

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. 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 inhibitor therapy during the second and third trimesters 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 inhibitors have occurred from the second trimester of pregnancy, ultrasound check of 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).

Linked to indapamide:

Previous wording:
COVERSYL ARGININE PLUS 5mg/1.25mg should not be used during the first trimester of pregnancy. When a pregnancy is planned or confirmed the switch to an alternative treatment should be initiated as soon as possible. Controlled studies with ACE inhibitors have not been done in humans, but in a limited number of cases with first trimester exposure there do not appear to have been any malformations consistent with human fetotoxicity as described below.

COVERSYL ARGININE PLUS 5mg/1.25mg is contraindicated during the second and third trimesters of pregnancy (see section 4.3).

Prolonged ACE inhibitors exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, retardation of skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia) (see section 5.3).

Should exposure to COVERSYL ARGININE PLUS 5mg/1.25mg have occurred from the second trimester of pregnancy, an ultrasound check of renal function and the skull is recommended
 In section 4.6 regarding lactation

"Use of perindopril is not recommended during breast feeding"
 replaces the previous wording which was: The excretion of perindopril into breast milk is unknown.