Foetotoxicity of angiotensin II antagonists - Congrès ESH

Afssaps

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Drugs
23/06/2004

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• DRUGS

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• Publié par: ansm-drugs
• Publié le: 23 juin 2004
• Nombre de lectures: 11
• Licence : En savoir +
  Paternité, pas d'utilisation commerciale, pas de modification
• Langue: English

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FOETOTOXICITY OF ANGIOTENSIN II ANTAGONISTS Schéhérazade Ouaret1, Patrick Carlier2, Sophie Choulika1, Catherine Tchinou1, Carmen Kreft-Jaïs1 1 : Unité de Pharmacovigilance. Agence française de sécurité sanitaire des produits de santé (Afssaps) Saint-Denis, France - www.afssaps.sante.fr 2 : Centre Régional de Pharmacovigilance de Fernand Widal Paris, France

Introduction  Angiotensin II antagonists (AIIA) are indicated for essential hypertension.  are marketed in France starting 1995:Six Products  National Marketing Authorisation: candesartan, eprosartan, losartan, valsartan  European Centralised Marketing Authorisation : irbesartan, telmisartan The use of AIIA is contra-indicated during the 2 nd and 3 rd trimester of pregnancy since first approval and launch in 1995. This contra-indication was established“by analogy” to angiotensin converting enzyme (ACE) inhibitors whose renal foetotoxicity is well documented, as well as data on reproductive toxicity of AIIA in animals.

Methods  All reports of pregnancies between 1995-2003, exposed to AIIA were searched in the National Pharmacovigilance Database.  Review of the literature Design of the French Pharmacovigilance System The French pharmacovigilance system consists of a network of 31 regional pharmacovigilance centres (RPVC) based in pharmacology or clinical toxicology departments from university hospitals, coordinated by the Pharmacovigilance U the French Health Products Safety Agency (Afssaps). Regional pharmacovigilance centres and Afssaps are connected via a national da which contains all adverse drug reactions (ADRs) reported by healthcare profess to the RPVC. 31 RPVC connected to Afssaps Lille via the national database

Brest

Amiens Caen Rouen  Paris  (6 RPVC) yc tSarbs Nna ourg Rennes

Angers

Nantes

Poitiers

Bordeaux

Toulouse

Tour

Dijon Besançon

Lyon LimogesCl F e e r r m ra on d t- Saint-Etienne n Grenoble

Montpellier

Marseille

Nice

Results Fifteen serious foetal and neonatal cases following an exposure beyond the 1st trimester of pregnancy were reported between 2001-2003: (10 cases from national database and 6 from literature), 1 case is a duplicate literature / data base.

Patients characteristics  Age: 24-42 years  AIIA prescribed for essential HTA  Exposure: before conception to beyond 1 st trimester  Mean exposure: 30 weeks of amenorrhea (20-39 week amenorrhea: WA )  Only 1 case exposed: 17-31 WA Symptoms and clinical signs  Oligoamnios, face and limb abnormalities  Foetal and neonatal renal failure  Neonatal hypotension  Hypoplasia of the skull bones in 1case Pregnancy outcome  3 therapeutic abortions (exposure: 23, 25 and 28 WA)  (exposure: 24 and 31 WA in 2 cases)3 intra-uterine deaths  9 live newborns: - 4 died prematurely between day 2 to day 4 due to multivisceral failure ( exposure: 28 WA in 1 case and until delivery in the other 3). - 1 developed a chronic renal failure (exposure: 28 WA) - 3 had acute renal failure with a favourable outcome (exposure: 31 WA in 1case, and until delivery in the 2 others) - 1 normal newborn (exposed during the first 20 weeks of amenorrhea) Histology A renal biopsy was practised in 7 cases: 2 intra-uterine deaths, 3 therapeutic abortions and 2 newborns who died  was normal in four cases, and unknown forMacroscopy: the three others. An hydronephroisis was observed in two cases.   wasMicroscopy: renal tubular dysplasia observed in one case, complete renal dysgenesis in one case, tubular abnormality in one case and in two cases there was no histological abnormality. In one case, histological assessment could not be done because of severe maceration, and in one case data was not available.

Summary Product Characteristics (SPC) Angiotensin converting enzyme (ACE) Angiotensin II antagonists (AIIA) inhibitors  1995First Marketing Authorisation in First Marketing Authorisation in 1981 4.3- Contraindication: None 4.3- Contraindication: 1985 > Contraindication of ACE inhibitors AIIA are contraindicated during during the 2 nd & 3 rd trimester of pregnancy, the 2 nd & 3 rd trimester of pregnancy based on: “b p y p   r a o nal l o . gy”to ACE inhibitors, since first a va  Animal foetotoxicity in different species  Foetotoxicity and neonatal renal toxicity in human  Dome of the skull abnormality

National database:contains all ADRs reported by healthcare professionals to Regional Pharmaco-Vigilance Centres since 1985 (245000).

All Database adverse events (1995-2003)

151691

AEs database

AEs Alla

1

Pregnancy AEs

200000

150000

100000

50000

0

All AEs collected from 1995 to 2003: 151691 cases AEs reported with AIIA use: 1941 cases AEs reported with AIIA use during pregnancy: 10 cases

Conclusion Considering the experience gained with ACE inhibitors and the contraindication of AIIA during the 2nd and 3rd trimester since first approval, no case was expected with the use of angiotensin II antagonists. However, fifteen cases were reported. It should be noted that the first cases were reported six years after AIIA marketing authorisation. This highlights the necessity to remind prescribers that Summary of Product Characteristic recommendations should be regularly read.

Actions taken by Afssaps:

The Afssaps strengthened the information relative to the contraindication of AIIA in the Summary of Product Characteristics and in the Patient Information Leaflet.

Four points were highlighted:

1The use of AIIA is contra-indicated duringthe 2 nd and 3 rd trimester of pregnancy.

2The discovery of pregnancy in a patient treated with AIIA should lead to the immediate interruption of treatment. 3case of exposure during the 1In st trimester,there is no argument to worry a patient exposed during this period, animal studies have not highlighted any teratogenic effects. 4All women of childbearing age should be informed about the foetotoxicity of AIIA and the need of pregnancy planning.

A Dear Doctor Letter was sent to more than 120 000 practitioners (General practitioners, Cardiologists, Internists, Nephrologists, Paediatricians, Gynaecologists and Obstetricians )

A Press release available on Afssaps web site:fre.ntsa.www.spassfa