Hydrochlorothiazide (HCTZ) and use in lactation + consolidated wording for the SmPC and PL of

Transkriptio

1 Hydrochlorothiazide (HCTZ) and use in lactation + consolidated wording for the SmPC and PL of ACE-inhibitors alone or in combination with HCTZ in pregnancy and lactation Final SmPC and PL wording Agreed by PhVWP in June 2011 Doc.Ref.: CMDh/PhVWP/031/2011 July 2011 ANNEX 1: SPC text/text in blue = new text/teksti vihreällä = teksti suomeksi Substance and source of text SPC wording in section 4.3 SPC wording in section 4.4 SPC wording in section 4.6 Lisinopril, Contraindication Pregnancy: Pregnancy fosinopril, Second and third ACE inhibitors The use of ACE inhibitors is not trandopril, trimesters of should not be recommended during the first moexipril, pregnancy (see initiated during trimester of pregnancy (see section perindopril sections 4.4 and pregnancy. Unless 4.4). The use of ACE inhibitors is 4.6). continued ACE contraindicated during the second Spirapril, inhibitor therapy is and third trimester of pregnancy (see delapril considered essential, sections 4.3 and 4.4). patients planning Epidemiological evidence regarding pregnancy should be the risk of teratogenicity following changed to exposure to ACE inhibitors during alternative the first trimester of pregnancy has antihypertensive not been conclusive; however a treatments which small increase in risk cannot be have an established excluded. Unless continued ACE safety profile for use inhibitor therapy is considered in pregnancy. When essential, patients planning pregnancy is pregnancy should be changed to diagnosed, treatment alternative antihypertensive with ACE inhibitors treatments which have an should be stopped established safety profile for use in immediately, and, if pregnancy. appropriate, When pregnancy is diagnosed, alternative therapy treatment with ACE inhibitors should be started (see should be stopped immediately, and, sections 4.3 and 4.6). 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 inhibitor 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). Lisinopril, [Comment: No Lactation: Because no information SPC wording in section 5.2

2 fosinopril, trandopril, moexipril, perindopril Spirapril, delapril Fosinopril contraindication in Section 4.3 for lactation] [Comment: No contraindication in Section 4.3 for lactation.] is available regarding the use of [Product] during breastfeeding, [Product] is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. Lactation: Because only very limited information is available regarding the use of [Product] during breastfeeding, [Product] is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. Ramipril Contraindication 2nd and 3rd trimester of pregnancy (see sections 4.4 and 4.6) Pregnancy: ACE inhibitors such as ramipril, or Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued ACE inhibitor/ AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors/ AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). Imetys: Koska vain hyvin vähän tietoa on saatavissa [kauppanimi]-valmisteen käytöstä imetyksen aikana, [kauppanimi]-valmisteen käyttöä ei suositella ja imetyksen aikana käytettäväksi on valittava hoito, jonka turvallisuus tunnetaan paremmin. Tämä koskee erityisesti vastasyntyneiden tai keskosena syntyneiden rintaruokintaa. Pregnancy: TRITACE is not recommended during the first trimester of pregnancy (see section 4.4) and contraindicated during the second and third trimesters of pregnancy (see section 4.3). 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. ACE inhibitor/ Angiotensin II Receptor Antagonist (AIIRA) therapy exposure during the second and third trimesters is known to induce human fetotoxicity

3 Ramipril Benazepril [Comment: No contraindication in Section 4.3 for lactation.] Contraindication Second and third trimesters of pregnancy (see sections 4.4 and 4.6). Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive 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). (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See also 5.3 'Preclinical safety data'). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Newborns whose mothers have taken ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalaemia (see also sections 4.3 and 4.4). Lactation: Because insufficient information is available regarding the use of ramipril during breastfeeding (see section 5.2), ramipril is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. Pregnancy: The use of ACE inhibitors is not recommended during the first 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). 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 antihypertensive 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, A single oral dose of ramipril produced an undetectable level of ramipril and its metabolite in breast milk. However the effect of multiple doses is not known.

4 Benazepril Captopril [Comment: No contraindication in Section 4.3 for lactation.] Contraindication Second and third trimesters of pregnancy (see sections 4.4 and 4.6). Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive 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). hypotension, hyperkalaemia). (See section 5.3). Should exposure to ACE inhibitor 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 section 4.3 and 4.4). Lactation: Limited pharmacokinetic data demonstrate very low concentrations in breast milk (see section 5.2). Although these concentrations seem to be clinically irrelevant, the use of [Product] in breastfeeding is not recommended for preterm infants and for the first few weeks after delivery, because of the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience. In the case of an older infant, the use of [Product] in a breast-feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect. Pregnancy: The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated 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 antihypertensive 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 Lactation: In nine women given an oral dose of 20 mg of benazepril daily for 3 days (time postpartum not stated), peak milk levels of 0.9 μg/l of benazepril at 1 hour after the dose and 2 μg/l of its active metabolite benazeprilat at 1.5 hours after the dose were detected. It is estimated that the breastfed infant would receive a daily dose less than 0.14% of the maternal weight-adjusted dose of benazepril.

5 Captopril Enalapril [Comment: No contraindication in Section 4.3 for lactation.] Contraindication Second and third trimesters of pregnancy (see sections 4.4 and 4.6). Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive 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). 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). Lactation: Limited pharmacokinetic data demonstrate very low concentrations in breast milk (see section 5.2). Although these concentrations seem to be clinically irrelevant, the use of [Product] in breastfeeding is not recommended for preterm infants and for the first few weeks after delivery, because of the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience. In the case of an older infant, the use of [Product] in a breast-feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect. Pregnancy: The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated 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 antihypertensive 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 Lactation: In the report of twelve women taking oral captopril 100 mg 3 times daily, the average peak milk level was 4.7μg/L and occurred 3.8 hours after the dose. Based on these data, the maximum daily dosage that a nursing infant would receive is less than 0.002% of the maternal daily dosage.

6 Enalapril [Comment: No contraindication in Section 4.3 for lactation.] Quinapril Contraindication Pregnancy: ACE Pregnancy: 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 inhibitor 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). Lactation: Limited pharmacokinetic data demonstrate very low concentrations in breast milk (see section 5.2). Although these concentrations seem to be clinically irrelevant, the use of [Product] in breastfeeding is not recommended for preterm infants and for the first few weeks after delivery, because of the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience. In the case of an older infant, the use of [Product] in a breast-feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect. Lactation: After a single 20 mg oral dose in five postpartum women, the average peak enalapril milk level was 1.7μg/L (range 0.54 to 5.9 μg/l) at 4 to 6 hours after the dose. The average peak enalaprilat level was 1.7μg/L (range 1.2 to 2.3μg/L); peaks occurred at various times over the 24-hour period. Using the peak milk level data, the estimated maximum intake of an exclusively breastfed infant would be about 0.16% of the maternal weight-adjusted dosage. A woman who had been taking oral enalapril 10 mg daily for 11 months had peak enalapril milk levels of 2 μg/l 4 hours after a dose and peak enalaprilat levels of 0.75 μg/l about 9 hours after the dose. The total amount of enalapril and enalaprilat measured in milk during the 24 hour period was 1.44μg/L and 0.63 μg/l of milk respectively. Enalaprilat milk levels were undetectable (<0.2μg/L) 4 hours after a single dose of enalapril 5 mg in one mother and 10mg in two mothers; enalapril levels were not determined.

7 Quinapril Second and third trimesters of pregnancy (see sections 4.4 and 4.6). [Comment: No contraindication in Section 4.3 for lactation.] inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive 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). The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the 2nd and 3rd trimester 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 antihypertensive 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 inhibitor 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). Lactation: Limited pharmacokinetic data demonstrate very low concentrations in breast milk (see section 5.2). Although these concentrations seem to be clinically irrelevant, the use of [Product] in breastfeeding is not recommended for preterm infants and for the first few weeks after delivery, because of the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience. In the case of an older infant, the use of [Product] in a breast-feeding mother may be considered if this treatment is necessary for the Lactation: After a single oral dose of 20 mg of quinapril in six breast-feeding women, the M/P (milk to plasma ratio) for quinapril was Quinapril was not detected in milk after 4 hours after the dose. Quinalaprilat milk levels were undetectable (<5 μg/l) at all time points. It is estimated that a breastfed infant would receive about 1.6% of the maternal weight-

8 mother and the child is observed for any adverse effect. Angiotensin II Contraindication Pregnancy: Pregnancy: Receptor Second and third AIIRAs should not The use of AIIRAs is not Antagonists trimesters of be initiated during recommended during the first (AIIRAs) pregnancy (see pregnancy. Unless trimester of pregnancy (see section sections 4.4 and continued AIIRA 4.4). The use of AIIRAs is 4.6). therapy is considered contraindicated during the second essential, patients and third trimesters of pregnancy planning pregnancy (see sections 4.3 and 4.4). should be changed to Epidemiological evidence regarding alternative antihypertensive the risk of teratogenicity following exposure to ACE inhibitors during treatments which the first trimester of pregnancy has have an established not been conclusive; however a safety profile for use small increase in risk cannot be in pregnancy. excluded. Whilst there is no When pregnancy is controlled epidemiological data on diagnosed, treatment the risk with Angiotensin II with AIIRAs should Receptor Inhibitors (AIIRAs), be and, if similar risks may exist for this class appropriate, of drugs. Unless continued AIIRA alternative therapy therapy is considered essential, should be started (see patients planning pregnancy should sections 4.3 and 4.6). be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately and, if appropriate, alternative therapy should be started. Exposure to AIIRA therapy 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 sections 4.3 and 4.4). Angiotensin II [Contraindication Lactation: Receptor for lactation to be Because no information is available Antagonists deleted, if regarding the use of [Product] (AIIRAs) applicable] during breastfeeding, [Product] is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. Valsartan In accordance with In accordance with In accordance with SPC wording for adjusted dosage of quinapril.

9 HCTZ HCTZ SPC wording for Angiotensin II Receptor Antagonists (AIIRAs) as published on CMD(h) website in Dec 08. [Comment: No contraindication in Section 4.3 for pregnancy.] [Comment: No contraindication in Section 4.3 for lactation.] SPC wording for Angiotensin II Receptor Antagonists (AIIRAs) as published on CMD(h) website in Dec 08. Angiotensin II Receptor Antagonists (AIIRAs) as published on CMD(h) website in Dec 08. Pregnancy: There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia. Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease. Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used. Lactation: Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of [product name] during breast feeding is not recommended. If [product name] is used during breast feeding, doses should be kept as low as possible. HCTZ in combination Contraindication Second and third Pregnancy wording is in accordance with Imetys: Hydroklooritiatsidi erittyy äidinmaitoon pieninä määrinä. Suuret tiatsidiannokset voivat aiheuttaa voimakasta virtsaneritystä ja siten estää maidon tuotantoa. [Kauppanimi]:n käyttö imetysaikana ei ole suositeltavaa. Jos [Kauppanimi]:ä käytetään imetysaikana, niin annosten tulee olla mahdollisimman pieniä. Pregnancy wording is in accordance with SPC wording for Angiotensin II

10 with valsartan trimesters of pregnancy (see sections 4.4 and 4.6). SPC wording for Angiotensin II Receptor Antagonists (AIIRAs) as published on CMD(h) website in Dec 08. Receptor Antagonists (AIIRAs) as published on CMD(h) website in Dec 08.In addition the following text is included: Hydrochlorothiazide There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia. HCTZ in combination with lisinopril, trandopril, moexipril, perindopril, spirapril, delapril Contraindication Second and third trimesters of pregnancy (see sections 4.4 and 4.6). Vasta-aiheet Toinen ja kolmas raskauskolmannes (ks. kohdat 4.4 ja 4.6). Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive 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). Lactation No information is available regarding the use of valsartan during breastfeeding. Hydrochlorothiazide is excreted in human milk. Therefore the use of Diovan Comp during breast feeding is not recommended. Alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. Pregnancy ACE-inhibitors: The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester 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 antihypertensive 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

11 Raskaus: ACE:n estäjien käyttöä ei pidä aloittaa raskauden aikana. Jos ACE:n estäjiä käyttävä nainen aikoo tulla raskaaksi, hänelle tulee vaihtaa muu, raskauden aikanakin turvallinen verenpainelääkitys, ellei ACE:n estäjien käyttöä pidetä välttämättömänä. Kun raskaus todetaan, ACE:n estäjien käyttö on lopetettava heti, ja tarvittaessa on aloitettava muu lääkitys (ks. kohdat 4.3 ja 4.6). 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 inhibitor 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). Raskaus ACE:n estäjät: ACE:n estäjien käyttöä ensimmäisen raskauskolmanneksen aikana ei suositella (ks. kohta 4.4). ACE:n estäjien käyttö toisen ja kolmannen raskauskolmanneksen aikana on vasta-aiheista (ks. kohdat 4.3 ja 4.4). Epidemiologisten tutkimusten tulokset viittaavat siihen, että altistuminen ACE:n estäjille ensimmäisen raskauskolmanneksen aikana lisää sikiön epämuodostumien riskiä. Tulokset eivät kuitenkaan ole vakuuttavia, mutta pientä riskin suurenemista ei voida sulkea pois. Jos ACE:n estäjiä käyttävä nainen aikoo tulla raskaaksi, hänelle tulee vaihtaa muu, raskauden aikanakin turvallinen verenpainelääkitys, ellei ACE:n estäjien käyttöä pidetä välttämättömänä. Kun raskaus todetaan, ACE:n estäjien käyttö tulee lopettaa heti, ja tarvittaessa on aloitettava muu lääkitys. Tiedetään, että altistus ACE:n estäjille toisen ja kolmannen raskauskolmanneksen on haitallista sikiön kehitykselle (munuaisten toiminta heikkenee, lapsiveden määrä pienenee, kallon luutuminen hidastuu) ja vastasyntyneen kehitykselle (munuaisten toiminta voi pettää ja voi ilmetä hypotensiota ja hyperkalemiaa). (Ks. kohta 5.3). Jos sikiö on raskauden toisen ja kolmannen kolmanneksen aikana altistunut ACE:n estäjille, suositellaan sikiölle tehtäväksi

12 munuaisten toiminnan ja kallon ultraäänitutkimus. Imeväisikäisiä, joiden äiti on käyttänyt ACE:n estäjiä, tulisi seurata huolellisesti hypotension varalta (ks. kohdat 4.3 ja 4.4). Hydrochlorothiazide: There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia. Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease. Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used. Hydroklooritiatsidi: On olemassa vain vähän kokemusta hydroklooritiatsidin käytöstä raskauden, etenkin sen ensimmäisen kolmanneksen aikana. Eläinkokeet eivät ole riittäviä. Hydroklooritiatsidi läpäisee istukan. Hydroklooritiatsidin farmakologisesta vaikutuksesta johtuen sen käyttö toisen ja kolmannen raskauskolmanneksen aikana voi heikentää fetoplasentaalista verenkiertoa ja aiheuttaa sikiölle ja vastasyntyneelle haittavaikutuksia, kuten ikterusta, elektrolyyttitasapainon häiriöitä tai trombosytopeniaa Hydroklooritiatsidia ei pidä käyttää raskauden aikana ilmaantuneiden turvotusten, kohonneen verenpaineen tai raskausmyrkytyksen hoitoon, sillä se voi aiheuttaa plasmatilavuuden pienenemistä ja istukan verenkierron

13 HCTZ in combination with lisinopril, trandopril, moexipril, perindopril [Comment: No contraindication in Section 4.3 for lactation.] heikkenemistä ilman että se vaikuttaisi suotuisasti hoidettavan sairauden kulkuun. Hydroklooritiatsidia ei pidä käyttää essentiaalisen verenpainetaudin hoitoon raskauden aikana paitsi niissä harvoissa tilanteissa, joissa muut hoidot eivät ole mahdollisia Lactation ACE-inhibitors: Because no information is available regarding the use of [Product] during breastfeeding, [Product] is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. Imetys ACE:n estäjät: Koska ei ole olemassa tietoa [kauppanimi]-valmisteen käytöstä imetyksen aikana, [kauppanimi]- valmisteen käyttöä ei suositella ja imetyksen aikana käytettäväksi on valittava hoito, jonka turvallisuus tunnetaan paremmin. Tämä koskee erityisesti vastasyntyneiden tai keskosena syntyneiden rintaruokintaa. Hydrochlorthiazide: Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of [product name] during breast feeding is not recommended. If [product name] is used during breast feeding, doses should be kept as low as possible. HCTZ in combination with fosinopril Contraindication Second and third trimesters of pregnancy (see sections 4.4 and 4.6). Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE Hydroklooritiatsidi: Hydroklooritiatsidi erittyy äidinmaitoon pieninä määrinä. Suuret tiatsidiannokset voivat aiheuttaa voimakasta virtsaneritystä ja siten estää maidon tuotantoa. [Kauppanimi]:n käyttö imetysaikana ei ole suositeltavaa. Jos [Kauppanimi]:ä käytetään imetysaikana, niin annosten tulee olla mahdollisimman pieniä. Pregnancy ACE-inhibitors: The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is

14 Vasta-aiheet Toinen ja kolmas raskauskolmannes (ks. kohdat 4.4 ja 4.6). inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive 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). Raskaus: ACE:n estäjien käyttöä ei pidä aloittaa raskauden aikana. Jos ACE:n estäjiä käyttävä nainen aikoo tulla raskaaksi, hänelle tulee vaihtaa muu, raskauden aikanakin turvallinen verenpainelääkitys, ellei ACE:n estäjien käyttöä pidetä välttämättömänä. Kun raskaus todetaan, ACE:n estäjien käyttö on lopetettava heti, ja tarvittaessa on aloitettava muu lääkitys (ks. kohdat 4.3 ja 4.6). contraindicated during the second and third trimester 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 antihypertensive 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 inhibitor 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). Raskaus ACE:n estäjät: ACE:n estäjien käyttöä ensimmäisen raskauskolmanneksen aikana ei suositella (ks. kohta 4.4). ACE:n estäjien käyttö toisen ja kolmannen raskauskolmanneksen aikana on vasta-aiheista (ks. kohdat 4.3 ja 4.4). Epidemiologisten tutkimusten tulokset viittaavat siihen, että altistuminen ACE:n estäjille ensimmäisen raskauskolmanneksen aikana lisää sikiön epämuodostumien riskiä. Tulokset eivät kuitenkaan ole vakuuttavia, mutta pientä riskin suurenemista ei voida sulkea pois. Jos ACE:n estäjiä käyttävä nainen aikoo tulla raskaaksi, hänelle tulee vaihtaa muu, raskauden aikanakin turvallinen

15 verenpainelääkitys, ellei ACE:n estäjien käyttöä pidetä välttämättömänä. Kun raskaus todetaan, ACE:n estäjien käyttö tulee lopettaa heti, ja tarvittaessa on aloitettava muu lääkitys. Tiedetään, että altistus ACE:n estäjille toisen ja kolmannen raskauskolmanneksen on haitallista sikiön kehitykselle (munuaisten toiminta heikkenee, lapsiveden määrä pienenee, kallon luutuminen hidastuu) ja vastasyntyneen kehitykselle (munuaisten toiminta voi pettää ja voi ilmetä hypotensiota ja hyperkalemiaa). (Ks. kohta 5.3). Jos sikiö on raskauden toisen ja kolmannen kolmanneksen aikana altistunut ACE:n estäjille, suositellaan sikiölle tehtäväksi munuaisten toiminnan ja kallon ultraäänitutkimus. Imeväisikäisiä, joiden äiti on käyttänyt ACE:n estäjiä, tulisi seurata huolellisesti hypotension varalta (ks. kohdat 4.3 ja 4.4). Hydrochlorothiazide: There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia. Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease. Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used. Hydroklooritiatsidi: On olemassa vain vähän kokemusta hydroklooritiatsidin käytöstä

16 HCTZ in combination with fosinopril [Comment: No contraindication in Section 4.3 for lactation.] raskauden, etenkin sen ensimmäisen kolmanneksen aikana. Eläinkokeet eivät ole riittäviä. Hydroklooritiatsidi läpäisee istukan. Hydroklooritiatsidin farmakologisesta vaikutuksesta johtuen sen käyttö toisen ja kolmannen raskauskolmanneksen aikana voi heikentää fetoplasentaalista verenkiertoa ja aiheuttaa sikiölle ja vastasyntyneelle haittavaikutuksia, kuten ikterusta, elektrolyyttitasapainon häiriöitä tai trombosytopeniaa Hydroklooritiatsidia ei pidä käyttää raskauden aikana ilmaantuneiden turvotusten, kohonneen verenpaineen tai raskausmyrkytyksen hoitoon, sillä se voi aiheuttaa plasmatilavuuden pienenemistä ja istukan verenkierron heikkenemistä ilman että se vaikuttaisi suotuisasti hoidettavan sairauden kulkuun. Hydroklooritiatsidia ei pidä käyttää essentiaalisen verenpainetaudin hoitoon raskauden aikana paitsi niissä harvoissa tilanteissa, joissa muut hoidot eivät ole mahdollisia Lactation Fosinopril: Because only very limited information is available regarding the use of [Product] during breastfeeding, [Product] is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. Imetys Fosinopriili: Koska vain hyvin vähän tietoa on saatavilla [kauppanimi]-valmisteen käytöstä imetyksen aikana, [kauppanimi]-valmisteen käyttöä ei suositella ja imetyksen aikana käytettäväksi on valittava hoito, jonka turvallisuus tunnetaan paremmin. Tämä koskee erityisesti vastasyntyneiden tai keskosena syntyneiden rintaruokintaa. Hydrochlorothiazide: Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of [product

17 name] during breast feeding is not recommended. If [product name] is used during breast feeding, doses should be kept as low as possible. HCTZ in combination with ramipril Contraindication 2nd and 3rd trimester of pregnancy (see sections 4.4 and 4.6) Lactation (see section 4.6) Pregnancy: ACE inhibitors such as ramipril, or Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued ACE inhibitor/ AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors/ AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). Hydroklooritiatsidi: Hydroklooritiatsidi erittyy äidinmaitoon pieninä määrinä. Suuret tiatsidiannokset voivat aiheuttaa voimakasta virtsaneritystä ja siten estää maidon tuotantoa. [Kauppanimi]:n käyttö imetysaikana ei ole suositeltavaa. Jos [Kauppanimi]:ä käytetään imetysaikana, niin annosten tulee olla mahdollisimman pieniä. Pregnancy TRITAZIDE is not recommended during the first trimester of pregnancy (see section 4.4) and contraindicated during the second and third trimesters of pregnancy (see section 4.3). 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. ACE inhibitor/ Angiotensin II Receptor Antagonist (AIIRA) 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 also 5.3 'Preclinical safety data'). Should exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Newborns whose mothers have taken ACE inhibitors should be closely observed for hypotension, oliguria and

18 HCTZ in combination with ramipril HCTZ in combination with benazepril Contraindication Lactation (see section 4.6) Contraindication Second and third trimesters of pregnancy (see sections 4.4 and 4.6). Vasta-aiheet Toinen ja kolmas raskauskolmannes (ks. kohdat 4.4 ja 4.6). Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which hyperkalaemia (see also sections 4.3 and 4.4). Hydrochlorothiazide, in cases of prolonged exposure during the third trimester of pregnancy, may cause a foeto-placental ischaemia and risk of growth retardation. Moreover, rare cases of hypoglycaemia and thrombocytopenia in neonates have been reported in case of exposure near term. Hydrochlorothiazide can reduce plasma volume as well as the uteroplacental blood flow. Lactation: TRITAZIDE is contraindicated during breast-feeding. Ramipril and hydrochlorothiazide are excreted in breast milk to such an extent that effects on the suckling child are likely if therapeutic doses of ramipril and hydrochlorothiazide are administered to breast-feeding women. Insufficient information is available regarding the use of ramipril during breast-feeding and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. Hydrochlorothiazide is excreted in human milk. Thiazides during breast-feeding by lactating mothers have been associated with a decrease or even suppression of lactation. Hypersensitivity to sulphonamide-derived active substances, hypokalaemia and nuclear icterus might occur. Because of the potential for serious reactions in nursing infants from both active substances, a decision should be made whether to discontinue nursing or to discontinue therapy taking account of the importance of this therapy to the mother. Pregnancy ACE-inhibitors: The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester 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

19 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). Raskaus: ACE:n estäjien käyttöä ei pidä aloittaa raskauden aikana. Jos ACE:n estäjiä käyttävä nainen aikoo tulla raskaaksi, hänelle tulee vaihtaa muu, raskauden aikanakin turvallinen verenpainelääkitys, ellei ACE:n estäjien käyttöä pidetä välttämättömänä. Kun raskaus todetaan, ACE:n estäjien käyttö on lopetettava heti, ja tarvittaessa on aloitettava muu lääkitys (ks. kohdat 4.3 ja 4.6). small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive 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 inhibitor 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). Raskaus ACE:n estäjät: ACE:n estäjien käyttöä ensimmäisen raskauskolmanneksen aikana ei suositella (ks. kohta 4.4). ACE:n estäjien käyttö toisen ja kolmannen raskauskolmanneksen aikana on vasta-aiheista (ks. kohdat 4.3 ja 4.4). Epidemiologisten tutkimusten tulokset viittaavat siihen, että altistuminen ACE:n estäjille ensimmäisen raskauskolmanneksen aikana lisää sikiön epämuodostumien riskiä. Tulokset eivät kuitenkaan ole vakuuttavia, mutta pientä riskin suurenemista ei voida sulkea pois. Jos ACE:n estäjiä käyttävä nainen aikoo tulla raskaaksi, hänelle tulee vaihtaa muu, raskauden aikanakin turvallinen verenpainelääkitys, ellei ACE:n estäjien käyttöä pidetä välttämättömänä. Kun raskaus todetaan, ACE:n estäjien käyttö tulee lopettaa heti, ja tarvittaessa on aloitettava muu lääkitys. Tiedetään, että altistus ACE:n

20 estäjille toisen ja kolmannen raskauskolmanneksen on haitallista sikiön kehitykselle (munuaisten toiminta heikkenee, lapsiveden määrä pienenee, kallon luutuminen hidastuu) ja vastasyntyneen kehitykselle (munuaisten toiminta voi pettää ja voi ilmetä hypotensiota ja hyperkalemiaa). (Ks. kohta 5.3). Jos sikiö on raskauden toisen ja kolmannen kolmanneksen aikana altistunut ACE:n estäjille, suositellaan sikiölle tehtäväksi munuaisten toiminnan ja kallon ultraäänitutkimus. Imeväisikäisiä, joiden äiti on käyttänyt ACE:n estäjiä, tulisi seurata huolellisesti hypotension varalta (ks. kohdat 4.3 ja 4.4). Hydrochlorothiazide: There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia. Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease. Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used. Hydroklooritiatsidi: On olemassa vain vähän kokemusta hydroklooritiatsidin käytöstä raskauden, etenkin sen ensimmäisen kolmanneksen aikana. Eläinkokeet eivät ole riittäviä. Hydroklooritiatsidi läpäisee istukan. Hydroklooritiatsidin farmakologisesta vaikutuksesta johtuen sen käyttö toisen ja kolmannen raskauskolmanneksen

21 HCTZ in combination with benazepril [Comment: No contraindication in Section 4.3 for lactation.] aikana voi heikentää fetoplasentaalista verenkiertoa ja aiheuttaa sikiölle ja vastasyntyneelle haittavaikutuksia, kuten ikterusta, elektrolyyttitasapainon häiriöitä tai trombosytopeniaa Hydroklooritiatsidia ei pidä käyttää raskauden aikana ilmaantuneiden turvotusten, kohonneen verenpaineen tai raskausmyrkytyksen hoitoon, sillä se voi aiheuttaa plasmatilavuuden pienenemistä ja istukan verenkierron heikkenemistä ilman että se vaikuttaisi suotuisasti hoidettavan sairauden kulkuun. Hydroklooritiatsidia ei pidä käyttää essentiaalisen verenpainetaudin hoitoon raskauden aikana paitsi niissä harvoissa tilanteissa, joissa muut hoidot eivät ole mahdollisia Lactation Benazepril: Limited pharmacokinetic data demonstrate very low concentrations in breast milk (see section 5.2). Although these concentrations seem to be clinically irrelevant, the use of [Product] in breastfeeding is not recommended for preterm infants and for the first few weeks after delivery, because of the hypothetical risk of cardiovascular and renal effects and because there is not enough clinical experience. In the case of an older infant, the use of [Product] in a breast-feeding mother may be considered if this treatment is necessary for the mother and the child is observed for any adverse effect. Imetys Benatsepriili: Vähäisten farmakokineettisten tutkimustulosten mukaan pitoisuudet rintamaidossa ovat olleet hyvin matalat (ks. kohta 5.2). Vaikka nämä pitoisuudet näyttävätkin kliinisesti merkityksettömiltä, [Kauppanimi]- valmisteen käyttöä ei suositella imetyksen aikana, jos lapsi on keskosena syntynyt ja ensimmäisinä viikkoina synnytyksen jälkeen, sillä on olemassa teoreettinen riski kardiovaskulaarisille ja munuaisiin kohdistuville vaikutuksille eikä ole riittävästi kliinistä käyttökokemusta. Vanhempia imeväisiä rintaruokkiville äideille voidaan Lactation: In nine women given an oral dose of 20 mg of benazepril daily for 3 days (time postpartum not stated), peak milk levels of 0.9 μg/l of benazepril at 1 hour after the dose and 2 μg/l of its active metabolite benazeprilat at 1.5 hours after the dose were detected. It is estimated that the breastfed infant would receive a daily dose less than 0.14% of the maternal weight-adjusted dose of benazepril. Imetys: Yhdeksälle naiselle annettiin 20 mg:n annos benatsepriiliä kerran vuorokaudessa 3 vuorokauden ajan (aikaa synnytyksestä ei kuvattu). Havaittiin benatsepriilin 0.9 mikrog/l huippupitoisuus 1 tunti lääkkeen oton jälkeen ja metaboliitti benatseprilaatin 2 mikrog/l huippupitoisuus 1,5 tuntia lääkkeen oton jälkeen. On arvioitu että rintaruokittu lapsi voi saada vuorokaudessa alle 0.14 %:a äidin painoon

22 harkita [Kauppanimi]-valmisteen käyttöä, jos hoito on tarpeen äidille ja jos imeväistä seurataan haittavaikutusten varalta. suhteutetusta benatsepriiliannoksesta. Hydrochlorothiazide: Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of [product name] during breast feeding is not recommended. If [product name] is used during breast feeding, doses should be kept as low as possible. HCTZ in combination with captopril Contraindication Second and third trimesters of pregnancy (see sections 4.4 and 4.6). Vasta-aiheet Toinen ja kolmas raskauskolmannes (ks. kohdat 4.4 ja 4.6). Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive 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). Raskaus: ACE:n estäjien käyttöä ei pidä aloittaa raskauden aikana. Jos ACE:n estäjiä käyttävä Hydroklooritiatsidi: Hydroklooritiatsidi erittyy äidinmaitoon pieninä määrinä. Suuret tiatsidiannokset voivat aiheuttaa voimakasta virtsaneritystä ja siten estää maidon tuotantoa. [Kauppanimi]:n käyttö imetysaikana ei ole suositeltavaa. Jos [Kauppanimi]:ä käytetään imetysaikana, niin annosten tulee olla mahdollisimman pieniä. Pregnancy ACE-inhibitors: The use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section 4.4). The use of ACE inhibitors is contraindicated during the second and third trimester 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 antihypertensive 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