(1) 妊婦に関する海外情報（米国FDA、オーストラリア分類）
本剤は、海外では販売されていないが、本剤の各主成分の米FDA、オース トラリア分類は以下のとおりである。
また、本剤の使用上の注意「妊婦、産婦、授乳婦等への投与」の記載は以 下のとおりである。
【使用上の注意】「妊婦、産婦、授乳婦等への投与」
(1) 妊婦又は妊娠している可能性のある婦人には投与しないこと。ま た、投与中に妊娠が判明した場合には、直ちに投与を中止すること。
［妊娠中期及び末期にテルミサルタンを含むアンジオテンシンⅡ 受容体拮抗剤を投与された高血圧症の患者で羊水過少症、胎児・
新生児の死亡、新生児の低血圧、腎不全、高カリウム血症、頭蓋 の形成不全及び羊水過少症によると推測される四肢の拘縮、頭蓋 顔面の奇形、肺の発育不全等があらわれたとの報告がある。アム ロジピンでは、動物実験で妊娠末期に投与すると妊娠期間及び分 娩時間が延長することが報告されている。チアジド系薬剤では新 生児又は乳児に高ビリルビン血症、血小板減少症等を起こすこと がある。また、利尿効果に基づく血漿量減少、血液濃縮、子宮・
胎盤血流量減少があらわれることがある。］
(2) 授乳中の婦人には投与することを避け、やむを得ず投与する場合に は授乳を中止させること。
［テルミサルタンの動物実験（ラット）で、乳汁中へ移行すること が報告されている。また、テルミサルタンでは動物実験（ラット 出生前、出生後の発生及び母動物の機能に関する試験）の15mg/kg/
日以上の投与群で出生児の4日生存率の低下、50mg/kg/日投与群で 出生児の低体重及び身体発達の遅延が報告されている。アムロジ ピンはヒト母乳中へ移行することが報告されている 43)。ヒドロク ロロチアジドでは、母乳中に薬剤が移行することが報告されてい る。］
ⅩⅡ．参考資料
2．海外における臨床 支援情報
（つづき）
出典 記載内容
米 国 の 添 付 文書
telmisartan：（2018年2月）
Pregnancy Risk Summary
MICARDIS can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death (see Clinical Considerations). Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Studies in rats and rabbits with telmisartan showed fetotoxicity only at maternally toxic doses (see Data). When pregnancy is detected, discontinue MICARDIS as soon as possible.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.
Fetal/Neonatal adverse reactions
Use of drugs that act on the RAS in the second and third trimesters of pregnancy can result in the following: oligohydramnios, reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.
In patients taking MICARDIS during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment.
Fetal testing may be appropriate, based on the week of gestation. If oligohydramnios is observed, discontinue MICARDIS, unless it is considered lifesaving for the mother. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Closely observe infants with histories of in utero exposure to MICARDIS for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs, support blood pressure and renal perfusion.
Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
Data Animal Data
No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day [about 12 times the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis]. In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/m2 basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/m2 basis, the maximum recommended human dose of telmisartan (80 mg/day).
ⅩⅡ．参考資料
2．海外における臨床 支援情報
（つづき）
出典 記載内容
米 国 の 添 付 文書
Lactation Risk Summary
There is no information regarding the presence of telmisartan in human milk, the effects on the breastfed infant, or the effects on milk production. Telmisartan is present in the milk of lactating rats (see Data). Because of the potential for serious adverse reactions in the breastfed infant including hypotension, hyperkalemia and renal impairment, advise a nursing woman not to breastfeed during treatment with MICARDIS.
Data
Telmisartan was present in the milk of lactating rats at concentrations 1.5 to 2 times those found in plasma from 4 to 8 hours after administration.
ⅩⅡ．参考資料
2．海外における臨床 支援情報
（つづき）
出典 記載内容
米 国 の 添 付 文書
amlodipine：（2017年10月）
Pregnancy Risk Summary
The limited available data based on post-marketing reports with NORVASC use in pregnant women are not sufficient to inform a drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy [see Clinical Considerations]. In animal reproduction studies, there was no evidence of adverse developmental effects when pregnant rats and rabbits were treated orally with amlodipine maleate during organogenesis at doses approximately 10 and 20-times the maximum recommended human dose (MRHD), respectively. However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold). Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose [see Data].
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4%
and 15%-20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.
Data Animal Data
No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day (approximately 10 and 20 times the MRHD based on body surface area, respectively) during their respective periods of major organogenesis. However for rats, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold)in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.
Lactation Risk Summary
Limited available data from a published clinical lactation study reports that amlodipine is present in human milk at an estimated median relative infant dose of 4.2%. No adverse effects of amlodipine on the breastfed infant have been observed. There is no available information on the effects of amlodipine on milk production.
ⅩⅡ．参考資料
2．海外における臨床 支援情報
（つづき）
出典 記載内容
米 国 の 添 付 文書
hydrochlorothiazide：（2017年7月）
Pregnancy：
Teratogenic Effects. Pregnancy Category B*：Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg hydrochlorothiazide/kg, respectively, provided no evidence of harm to the fetus.
There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Nonteratogenic Effects：Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.
Nursing Mothers: Thiazides are excreted in breast milk.
Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue hydrochlorothiazide, taking into account the importance of the drug to the mother.
* B：Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.
オ ー ス ト ラ リアの分類：
An Australian categorisation of risk of drug use in
pregnancy
（2018年3月）
telmisartan：D
Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
amlodipine：C
hydrochlorothiazide：C
Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.
(2) 小児等に関する記載 該当資料なし
ⅩⅢ．備 考
その他の関連資料 該当資料なし