最高の成熟親指

1.6 外国における使用状況等に
関する資料
目次
1.6 外国における使用状況等に関する資料..............................................................................................1
1.6.1 外国における承認状況 ................................................................................................................1
1.6.2 外国の添付文書...........................................................................................................................3
1.6.2.1 米国の添付文書（原文）......................................................................................................3
1.6.2.2 EU の添付文書（原文）......................................................................................................12
1.6.2.3 米国の添付文書（和訳の概要）.........................................................................................18
1.6.2.4 英国の添付文書（和訳の概要）.........................................................................................21
企業中核データシート（CCDS） .................................................................................................. 別添
1.6 外国における使用状況等に関する資料
1.6 外国における使用状況等に関する資料
1.6.1 外国における承認状況
本剤の外国での承認状況を表 1.6-1に示す．外国において，本剤は 0.5 mL 中 0.25 mg の Org 37462 を
含有するプレフィルドシリンジ製剤の剤型で，
「生殖補助医療のための調節卵巣刺激を受ける女性にお
ける早期の黄体形成ホルモンサージの予防」の適応で承認されている．本剤は，1999 年米国で，続いて
2000 年に EU で承認された．2006 年 4 月現在，70 カ国以上で承認されている．
表 1.6-1 外国の承認状況（2006 年 4 月現在）
国名
販売名
承認年月日
米国
Ganirelix Acetate Injection
1999 年 7 月 29 日
オーストリア
Orgalutran
2000 年 5 月 17 日
ベルギー
Orgalutran
2000 年 5 月 17 日
デンマーク
Orgalutran
2000 年 5 月 17 日
アイルランド
Orgalutran
2000 年 5 月 17 日
フィンランド
Orgalutran
2000 年 5 月 17 日
フランス
Orgalutran
2000 年 5 月 17 日
ドイツ
Orgalutran
2000 年 5 月 17 日
英国
Orgalutran
2000 年 5 月 17 日
ギリシャ
Orgalutran
2000 年 5 月 17 日
イタリア
Orgalutran
2000 年 5 月 17 日
ルクセンブルク
Orgalutran
2000 年 5 月 17 日
オランダ
Orgalutran
2000 年 5 月 17 日
ポルトガル
Orgalutran
2000 年 5 月 17 日
スペイン
Orgalutran
2000 年 5 月 17 日
スウェーデン
Orgalutran
2000 年 5 月 17 日
マルタ
Orgalutran
2000 年 5 月 17 日
スロベニア
Orgalutran
2000 年 5 月 17 日
ニュージーランド
Orgalutran
2000 年 11 月 9 日
スイス
Orgalutran
2000 年 7 月 13 日
ノルウェー
Orgalutran
2000 年 9 月 21 日
アイスランド
Orgalutran
2000 年 9 月 28 日
リトアニア
Orgalutran
2000 年 11 月 9 日
ブルガリア
Orgalutran
2000 年 12 月 12 日
チェコ
Orgalutran
2000 年 12 月 20 日
ラトビア
Orgalutran
2000 年 12 月 20 日
エストニア
Orgalutran
2000 年 12 月 21 日
アルゼンチン
Orgalutran
2001 年 1 月 12 日
クウェート
Orgalutran
2001 年 3 月 1 日
オーストラリア
Orgalutran
2001 年 3 月 19 日
ハンガリー
Orgalutran
2001 年 4 月 17 日
エクアドル
Orgalutran
2001 年 4 月 19 日
スロバキア
Orgalutran
2001 年 4 月 20 日
ブラジル
Orgalutran
2001 年 5 月 7 日
キプロス
Orgalutran
2001 年 5 月 24 日
オランダ領アンティル
Orgalutran
2001 年 5 月 30 日
ポーランド
Orgalutran
2001 年 6 月 13 日
1
1.6 外国における使用状況等に関する資料
表 1.6-1 外国の承認状況（2006 年 4 月現在）（続き）
国名
販売名
承認年月日
ルーマニア
Orgalutran
2001 年 7 月 12 日
メキシコ
Orgalutran
2001 年 8 月 9 日
コロンビア
Orgalutran
2001 年 9 月 13 日
アラブ首長国連邦
Orgalutran
2001 年 10 月 2 日
インド
Orgalutran
2001 年 10 月 8 日
シリア
Orgalutran
2001 年 11 月 25 日
セルビア・モンテネグロ
Orgalutran
2002 年 1 月 15 日
バーレイン
Orgalutran
2002 年 2 月 12 日
アルバ
Orgalutran
2002 年 2 月 20 日
ベネズエラ
Orgalutran
2002 年 2 月 21 日
イスラエル
Orgalutran
2002 年 3 月 24 日
ヨルダン
Orgalutran
2002 年 3 月 10 日
カタール
Orgalutran
2002 年 4 月 10 日
スーダン
Orgalutran
2002 年 4 月 16 日
カナダ
Orgalutran
2002 年 5 月 3 日
香港
Orgalutran
2002 年 7 月 5 日
オマーン
Orgalutran
2002 年 7 月 20 日
フィリピン
Orgalutran
2002 年 8 月 9 日
ロシア
Orgalutran
2002 年 8 月 27 日
タイ
Orgalutran
2002 年 10 月 4 日
モロッコ
Orgalutran
2002 年 10 月 29 日
ペルー
Orgalutran
2002 年 12 月 13 日
シンガポール
Orgalutran
2003 年 1 月 7 日
エジプト
Orgalutran
2003 年 4 月 8 日
ウクライナ
Orgalutran
2003 年 4 月 8 日
台湾
Orgalutran
2003 年 6 月 10 日
サウジアラビア
Orgalutran
2003 年 7 月 2 日
チリ
Orgalutran
2003 年 8 月 22 日
ベトナム
Orgalutran
2003 年 8 月 15 日
トルコ
Orgalutran
2003 年 9 月 29 日
インドネシア
Orgalutran
2003 年 10 年 20 日
マレーシア
Orgalutran
2003 年 11 月 18 日
韓国
Orgalutran
2004 年 7 月 19 日
パキスタン
Orgalutran
2004 年 7 月 27 日
バングラデシュ
Orgalutran
2004 年 8 月 19 日
2
1.6 外国における使用状況等に関する資料
1.6.2 外国の添付文書
本品の外国における添付文書の代表例として，米国及び EU の添付文書の原文及び和訳の概要を示し
た．
1.6.2.1 米国の添付文書（原文）
Ganirelix Acetate Injection
FOR SUBCUTANEOUS USE ONLY
DESCRIPTION
Ganirelix Acetate Injection is a synthetic decapeptide with high antagonistic activity against naturally occurring
gonadotropin-releasing hormone (GnRH). Ganirelix Acetate is derived from native GnRH with substitutions of
amino acids at positions 1, 2, 3, 6, 8, and 10 to form the following molecular formula of the peptide:
N-acetyl-3-(2-naphthyl)-D-alanyl-4-chloro-D-phenylalanyl-3-(3-pyridyl)-D-alanyl-L-seryl-L-tyrosyl-N9,N10-dieth
yl-D-homoarginyl-L-leucyl-N9,N10-diethyl-L-homoarginyl-L-prolyl-D-alanylamide acetate. The molecular weight
for Ganirelix Acetate is 1570.4 as an anhydrous free base. The structural formula is as follows:
Ganirelix Acetate
Ganirelix Acetate Injection is supplied as a colorless, sterile, ready-to-use, aqueous solution intended for
SUBCUTANEOUS administration only. Each sterile, prefilled syringe contains 250 µg/0.5 mL of Ganirelix
Acetate, 0.1 mg glacial acetic acid, 23.5 mg mannitol, and water for injection adjusted to pH 5.0 with acetic acid,
NF and/or sodium hydroxide, NF.
CLINICAL PHARMACOLOGY
The pulsatile release of GnRH stimulates the synthesis and secretion of luteinizing hormone (LH) and
follicle-stimulating hormone (FSH). The frequency of LH pulses in the mid and late follicular phase is
approximately 1 pulse per hour. These pulses can be detected as transient rises in serum LH. At midcycle, a large
increase in GnRH release results in an LH surge. The midcycle LH surge initiates several physiologic actions
including: ovulation, resumption of meiosis in the oocyte, and luteinization. Luteinization results in a rise in
serum progesterone with an accompanying decrease in estradiol levels.
3
1.6 外国における使用状況等に関する資料
Ganirelix Acetate acts by competitively blocking the GnRH receptors on the pituitary gonadotroph and subsequent
transduction pathway. It induces a rapid, reversible suppression of gonadotropin secretion. The suppression of
pituitary LH secretion by Ganirelix Acetate is more pronounced than that of FSH. An initial release of endogenous
gonadotropins has not been detected with Ganirelix Acetate, which is consistent with an antagonist effect. Upon
discontinuation of Ganirelix Acetate, pituitary LH and FSH levels are fully recovered within 48 hours.
Pharmacokinetics
The pharmacokinetic parameters of single and multiple injections of Ganirelix Acetate Injection in healthy adult
females are summarized in Table I. Steady-state serum concentrations are reached after 3 days of treatment. The
pharmacokinetics of Ganirelix Acetate are dose-proportional in the dose range of 125 to 500 µg.
TABLE I: Mean (SD) pharmacokinetic parameters of 250 µg of Ganirelix Acetate following a single
subcutaneous (SC) injection (n=15) and daily SC injections (n=15) for seven days.
Ganirelix Acetate
single dose
Ganirelix Acetate
multiple dose
tmax
h
t1/2
h
Cmax
ng/mL
AUC
ng•h/mL
CL/F
L/h
Vd/F
L
1.1 (0.3)
12.8 (4.3)
14.8 (3.2)
96 (12)
2.4 (0.2)†
43.7 (11.4)†
1.1 (0.2)
16.2 (1.6)
11.2 (2.4)
77.1 (9.8)
3.3 (0.4)
76.5 (10.3)
tmax
Time to maximum concentration
t1/2
Elimination half-life
Cmax
Maximum serum concentration
AUC
Area under the curve; Single dose: AUC0–∞; multiple dose: AUC0–24
Vd
Volume of distribution
†
Based on intravenous administration
CL
Clearance = Dose/AUC0–∞
F
Absolute bioavailability
Absorption
Ganirelix Acetate is rapidly absorbed following subcutaneous injection with maximum serum concentrations
reached approximately one hour after dosing. The mean absolute bioavailability of Ganirelix Acetate following a
single 250 µg subcutaneous injection to healthy female volunteers is 91.1%.
Distribution
The mean (SD) volume of distribution of Ganirelix Acetate in healthy females following intravenous
administration of a single 250 µg dose is 43.7 (11.4) liters (L). In vitro protein binding to human plasma is 81.9%.
4
1.6 外国における使用状況等に関する資料
Metabolism
Following single dose intravenous administration of radiolabeled Ganirelix Acetate to healthy female volunteers,
Ganirelix Acetate is the major compound present in the plasma (50–70% of total radioactivity in the plasma) up to
4 hours and urine (17.1–18.4% of administered dose) up to 24 hours. Ganirelix Acetate is not found in the feces.
The 1–4 peptide and 1–6 peptide of Ganirelix Acetate are the primary metabolites observed in the feces.
Excretion
On average, 97.2% of the total radiolabeled Ganirelix Acetate dose is recovered in the feces and urine (75.1% and
22.1%, respectively) over 288 h following intravenous single dose administration of 1 mg [14C]-Ganirelix Acetate.
Urinary excretion is virtually complete in 24 h, whereas fecal excretion starts to plateau 192 h after dosing.
Special Populations
The pharmacokinetics of Ganirelix Acetate Injection have not been determined in special populations such as
geriatric, pediatric, renally impaired and hepatically impaired patients (see PRECAUTIONS).
Drug-Drug Interactions
Formal in vivo or in vitro drug-drug interaction studies have not been conducted (see PRECAUTIONS). Since
Ganirelix Acetate can suppress the secretion of pituitary gonadotropins, dose adjustments of exogenous
gonadotropins may be necessary when used during controlled ovarian hyperstimulation (COH).
Clinical Studies
The efficacy of Ganirelix Acetate Injection was established in two adequate and well-controlled clinical studies
which included women with normal endocrine and pelvic ultrasound parameters. The studies intended to exclude
subjects with polycystic ovary syndrome (PCOS) and subjects with low or no ovarian reserve. One cycle of study
medication was administered to each randomized subject. For both studies, the administration of exogenous
recombinant FSH [Follistim® (follitropin beta for injection)] 150 IU daily was initiated on the morning of Day 2
or 3 of a natural menstrual cycle. Ganirelix Acetate Injection was administered on the morning of Day 7 or 8 (Day
6 of recombinant FSH administration). The dose of recombinant FSH administered was adjusted according to
individual responses starting on the day of initiation of Ganirelix Acetate. Both recombinant FSH and Ganirelix
Acetate were continued daily until at least three follicles were 17 mm or greater in diameter at which time hCG
[Pregnyl® (chorionic gonadotropin for injection, USP)] was administered. Following hCG administration,
Ganirelix Acetate and recombinant FSH administration were discontinued. Oocyte retrieval, followed by in vitro
fertilization (IVF) or intracytoplasmatic sperm injection (ICSI), was subsequently performed.
In a multicenter, double-blind, randomized, dose-finding study, the safety and efficacy of Ganirelix Acetate
Injection were evaluated for the prevention of LH surges in women undergoing COH with recombinant FSH.
Ganirelix Acetate Injection doses ranging from 62.5 µg to 2000 µg and recombinant FSH were administered to
332 patients undergoing COH for IVF (see TABLE II). Median serum LH on the day of hCG administration
decreased with increasing doses of Ganirelix Acetate. Median serum E2 (17β-estradiol) on the day of hCG
5
1.6 外国における使用状況等に関する資料
administration was 1475, 1110, and 1160 pg/mL for the 62.5, 125, and 250 µg doses, respectively. Lower peak
serum E2 levels of 823, 703, and 441 pg/mL were seen at higher doses of Ganirelix Acetate 500, 1000, and 2000
µg, respectively. The highest pregnancy and implantation rates were achieved with the 250 µg dose of Ganirelix
Acetate Injection as summarized in Table II.
TABLE II: Results from the multicenter, double-blind, randomized, dose-finding study to assess the efficacy of
Ganirelix Acetate Injection to prevent premature LH surges in women undergoing COH with recombinant FSH.
No. subjects
receiving
Ganirelix Acetate
No. subjects with
ET†
No. of subjects
with LH rise ≥ 10
mIU/mL*
Serum LH
(mIU/mL) on day
of hCG‡
5th–95th
percentiles
Serum E2
(pg/mL) on day
of hCG‡ 5th–95th
percentiles
Vital pregnancy
rate Ω
per attempt,
n (%)
per transfer,
n (%)
Implantation rate
(%)ϒ
62.5 µg
31
Daily dose (µg) of Ganirelix Acetate Injection
125 µg
250 µg
500 µg
1000 µg
66
70
69
66
2000 µg
30
27
61
62
54
61
27
4
6
1
0
0
0
3.6
2.5
1.7
1.0
0.6
0.3
0.6–19.9
0.6–11.4
< 0.25–6.4
0.4–4.7
< 0.25–2.2
< 0.25–0.8
1475
1110
1160
823
703
441
645–3720
424–3780
384–3910
279–2720
284–2360
166–1940
7 (22.6)
17 (25.8)
25 (35.7)
8 (11.6)
9 (13.6)
2 (6.7)
7 (25.9)
17 (27.9)
25 (40.3)
8 (14.8)
9 (14.8)
2 (7.4)
14.2 (26.8)
16.3 (30.5)
21.9 (30.6)
9.0 (23.7)
8.5 (21.7)
4.9 (20.1)
(Protocol 38602)
*
‡
ϒ
†
Ω
Following initiation of Ganirelix Acetate therapy. Includes subjects who have complied with daily injections
Median values
Mean (standard deviation)
ET: Embryo Transfer
As evidenced by ultrasound at 5–6 weeks following ET
Transient LH rises alone were not deleterious to achieving pregnancy with Ganirelix Acetate at doses of 125 µg
(3/6 subjects) and 250 µg (1/1 subjects). In addition, none of the subjects with LH rises ≥ 10 mIU/mL had
premature luteinization indicated by a serum progesterone above 2 ng/mL.
A multicenter, open-label, randomized study was conducted to assess the efficacy and safety of Ganirelix Acetate
Injection in women undergoing COH. Follicular phase treatment with Ganirelix Acetate 250 µg was studied using
6
1.6 外国における使用状況等に関する資料
a luteal phase GnRH agonist as a reference treatment. A total of 463 subjects were treated with Ganirelix Acetate
by subcutaneous injection once daily starting on Day 6 of recombinant FSH treatment. Recombinant FSH was
maintained at 150 IU for the first 5 days of ovarian stimulation and was then adjusted by the investigator on the
sixth day of gonadotropin use according to individual responses. The results for the Ganirelix Acetate arm are
summarized in Table III.
TABLE III: Results from the multicenter, open-label, randomized study to assess the efficacy and safety of
Ganirelix Acetate Injection in women undergoing COH.
Ganirelix Acetate 250 µg
463
5.4 (2.0)
9.6 (2.0)
1190
373–3105
1.6
0.6–6.9
13
10.7 (5.3)
440
8.7 (5.6)
62.1%
399
2.2 (0.6)
6.0 (4.5)
No. subjects treated
Duration of GnRH analog (days)§¥
Duration of recombinant FSH (days)§¥
Serum E2 (pg/mL) on day of hCG‡
5th–95th percentiles
Serum LH (mIU/mL) on day of hCG‡
5th–95th percentiles
No. of subjects with LH rise ≥ 10 mIU/mL*
No. of follicles > 11 mm§¥
No. of subjects with oocyte retrieval
No. of oocytes¥
Fertilization rate
No. subjects with ET†
No. of embryos transferred¥
No. of embryos¥
Ongoing pregnancy rate٧
per attempt, n (%)λ
per transfer, n (%)
Implantation rate (%)¥
94 (20.3)
93 (23.3)
15.7 (29)
(Protocol 38607)
*
Following initiation of Ganirelix Acetate therapy
‡
Median values
§
Restricted to subjects with hCG injection
¥
Mean (standard deviation)
†
ET: Embryo Transfer
Ω
As evidenced by ultrasound at 12–16 weeks following ET
λ
Includes one patient who achieved pregnancy with intrauterine induction
Some centers were limited to the transfer of ≤ 2 embryos based on local practice standards
The mean number of days of Ganirelix Acetate treatment was 5.4 (2–14). There was no incidence of drug-related
allergic reactions within the adequate and well-controlled clinical studies.
LH Surges
The midcycle LH surge initiates several physiologic actions including: ovulation, resumption of meiosis in the
oocyte, and luteinization. In 463 subjects administered Ganirelix Acetate Injection 250 µg, a premature LH surge
prior to hCG administration, (LH rise ≥ 10 mIU/mL with a significant rise in serum progesterone > 2 ng/mL, or a
significant decline in serum estradiol) occurred in less than 1% of subjects.
7
1.6 外国における使用状況等に関する資料
INDICATIONS AND USAGE
Ganirelix Acetate Injection is indicated for the inhibition of premature LH surges in women undergoing controlled
ovarian hyperstimulation.
CONTRAINDICATIONS
Ganirelix Acetate Injection is contraindicated under the following conditions:
•
Known hypersensitivity to Ganirelix Acetate or to any of its components.
•
Known hypersensitivity to GnRH or any other GnRH analog.
•
Known or suspected pregnancy (see PRECAUTIONS).
WARNINGS
Ganirelix Acetate Injection should be prescribed by physicians who are experienced in infertility treatment.
Before starting treatment with Ganirelix Acetate, pregnancy must be excluded. Safe use of Ganirelix Acetate
during pregnancy has not been established (see CONTRAINDICATIONS and PRECAUTIONS).
PRECAUTIONS
General
Caution is advised in patients with hypersensitivity to GnRH. These patients should be carefully monitored after
the first injection. Anaphylactic reactions or ganirelix antibody formation have not been reported in the clinical
trials for Ganirelix Acetate Injection.
The packaging of this product contains natural rubber latex which may cause allergic reactions.
Information for Patients
Prior to therapy with Ganirelix Acetate Injection, patients should be informed of the duration of treatment and
monitoring procedures that will be required. The risk of possible adverse reactions should be discussed (see
ADVERSE REACTIONS).
Ganirelix Acetate should not be prescribed if the patient is pregnant
Laboratory Tests
A neutrophil count ≥ 8.3 ( x 109/L) was noted in 11.9% (up to 16.8 x 109/L) of all subjects treated within the
adequate and well-controlled clinical trials. In addition, downward shifts within the Ganirelix Acetate Injection
group were observed for hematocrit and total bilirubin. The clinical significance of these findings was not
determined.
Drug Interactions
No formal drug-drug interaction studies have been performed.
8
1.6 外国における使用状況等に関する資料
Carcinogenesis and Mutagenesis, Impairment of Fertility
Long-term toxicity studies in animals have not been performed with Ganirelix Acetate Injection to evaluate the
carcinogenic potential of the drug. Ganirelix Acetate did not induce a mutagenic response in the Ames test (S.
typhimurium and E. coli) or produce chromosomal aberrations in in vitro assay using Chinese Hamster Ovary
cells.
Pregnancy
Pregnancy Category X
Ganirelix Acetate Injection is contraindicated in pregnant women. When administered from Day 7 to near term to
pregnant rats and rabbits at doses up to 10 and 30 µg/day (approximately 0.4 to 3.2 times the human dose based
on body surface area), Ganirelix Acetate increased the incidence of litter resorption. There was no increase in fetal
abnormalities. No treatment-related changes in fertility, physical, or behavioral characteristics were observed in
the offspring of female rats treated with Ganirelix Acetate during pregnancy and lactation.
The effects on fetal resorption are logical consequences of the alteration in hormonal levels brought about by
the antigonadotrophic properties of this drug and could result in fetal loss in humans. Therefore, this drug should
not be used in pregnant women (see CONTRAINDICATIONS).
Nursing Mothers
Ganirelix Acetate Injection should not be used by lactating women. It is not known whether this drug is excreted
in human milk.
Geriatric Use
Clinical studies with Ganirelix Acetate Injection did not include a sufficient number of subjects aged 65 and over.
ADVERSE REACTIONS
The safety of Ganirelix Acetate Injection was evaluated in two randomized, parallel-group, multicenter controlled
clinical studies. Treatment duration for Ganirelix Acetate ranged from 1 to 14 days. Table IV represents adverse
events (AEs) from first day of Ganirelix Acetate administration until confirmation of pregnancy by ultrasound at
an incidence of ≥ 1% in Ganirelix Acetate-treated subjects without regard to causality.
TABLE IV: Incidence of common adverse events (Incidence ≥ 1% in Ganirelix Acetate-treated subjects).
Completed controlled clinical studies (All-subjects-treated group).
Ganirelix Acetate N=794
% (n)
4.8 (38)
3.7 (29)
3.0 (24)
2.4 (19)
1.8 (14)
1.1 (9)
1.1 (9)
1.0 (8)
Adverse Events Occurring in ≥ 1%
Abdominal Pain (gynecological)
Death Fetal
Headache
Ovarian Hyperstimulation Syndrome
Vaginal Bleeding
Injection Site Reaction
Nausea
Abdominal Pain (gastrointestinal)
9
1.6 外国における使用状況等に関する資料
Congenital Anomalies
Ongoing clinical follow-up studies of 283 newborns of women administered Ganirelix Acetate Injection were
reviewed. There were three neonates with major congenital anomalies and 18 neonates with minor congenital
anomalies.
The
major
congenital
anomalies
were:
hydrocephalus/meningocele,
omphalocele,
and
Beckwith-Wiedemann Syndrome. The minor congenital anomalies were: nevus, skin tags, sacral sinus,
hemangioma, torticollis/asymmetric skull, talipes, supernumerary digit finger, hip subluxation, torticollis/high
palate, occiput/abnormal hand crease, hernia umbilicalis, hernia inguinalis, hydrocele, undescended testis, and
hydronephrosis. The causal relationship between these congenital anomalies and Ganirelix Acetate is unknown.
Multiple factors, genetic and others (including, but not limited to ICSI, IVF, gonadotropins, progesterone) may
confound ART (Assisted Reproductive Technology) procedures.
OVERDOSAGE
There have been no reports of overdosage with Ganirelix Acetate Injection in humans.
DOSAGE AND ADMINISTRATION
After initiating FSH therapy on Day 2 or 3 of the cycle, Ganirelix Acetate Injection 250 µg may be administered
subcutaneously once daily during the mid to late portion of the follicular phase. By taking advantage of
endogenous pituitary FSH secretion, the requirement for exogenously administered FSH may be reduced.
Treatment with Ganirelix Acetate should be continued daily until the day of hCG administration. When a
sufficient number of follicles of adequate size are present, as assessed by ultrasound, final maturation of follicles
is induced by administering hCG. The administration of hCG should be withheld in cases where the ovaries are
abnormally enlarged on the last day of FSH therapy to reduce the chance of developing OHSS (Ovarian
Hyperstimulation Syndrome).
Directions for Using Ganirelix Acetate Injection
1.
Ganirelix Acetate Injection is supplied in a sterile, prefilled syringe and is intended for
SUBCUTANEOUS administration only.
2.
Wash hands thoroughly with soap and water.
3.
The most convenient sites for SUBCUTANEOUS injection are in the abdomen around the navel or
upper thigh.
4.
The injection site should be swabbed with a disinfectant to remove any surface bacteria. Clean about
two inches around the point where the needle will be inserted and let the disinfectant dry for at least one
minute before proceeding.
5.
With syringe held upward, remove needle cover.
6.
Pinch up a large area of skin between the finger and thumb. Vary the injection site a little with each
injection.
7.
The needle should be inserted at the base of the pinched-up skin at an angle of 45–90° to the skin
surface.
10
1.6 外国における使用状況等に関する資料
8.
When the needle is correctly positioned, it will be difficult to draw back on the plunger. If any blood is
drawn into the syringe, the needle tip has penetrated a vein or artery. If this happens, withdraw the
needle slightly and reposition the needle without removing it from the skin. Alternatively, remove the
needle and use a new, sterile, prefilled syringe. Cover the injection site with a swab containing
disinfectant and apply pressure; the site should stop bleeding within one or two minutes.
9.
Once the needle is correctly placed, depress the plunger slowly and steadily, so the solution is correctly
injected and the skin is not damaged.
10.
Pull the syringe out quickly and apply pressure to the site with a swab containing disinfectant.
11.
Use the sterile, prefilled syringe only once and dispose of it properly.
HOW SUPPLIED
Ganirelix Acetate Injection is supplied in:
Disposable, sterile, prefilled 1 mL glass syringes containing 250 µg/0.5 mL of Ganirelix Acetate. Each
Ganirelix Acetate sterile, prefilled syringe is affixed with a 27 gauge x 1/2-inch needle and is
blister-packed.
Single syringe
NDC 0052-0301-51
Storage
Store at 25°C (77°F); excursions permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature].
Protect from light.
only
11
1.6 外国における使用状況等に関する資料
1.6.2.2
EU の添付文書（原文）
1. NAME OF THE MEDICINAL PRODUCT
Orgalutran 0.25 mg/0.5 ml solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Orgalutran contains the synthetic decapeptide ganirelix (INN) with high antagonistic activity to the naturally
occurring gonadotrophin releasing hormone (GnRH). The amino acids at positions 1, 2, 3, 6, 8 and 10 of the
natural GnRH decapeptide have been substituted resulting in N-Ac-D-Nal(2)1, D-pClPhe2, D-Pal(3)3,
D-hArg(Et2)6, L-hArg(Et2)8, D-Ala10]-GnRH with a molecular weight of 1570.4.
Each pre-filled syringe of Orgalutran contains the active substance ganirelix, 0.25 mg in 0.5 ml aqueous solution.
For excipients, see 6.1.
3. PHARMACEUTICAL FORM
Solution for injection.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
The prevention of premature luteinising hormone (LH) surges in women undergoing controlled ovarian
hyperstimulation (COH) for assisted reproduction techniques (ART).
In clinical trials Orgalutran was used with recombinant human follicle stimulating hormone (FSH).
4.2 Posology and method of administration
Orgalutran should only be prescribed by a specialist experienced in the treatment of infertility.
Posology
Orgalutran is used to prevent premature LH surges in patients undergoing COH. Controlled ovarian
hyperstimulation with FSH may start at day 2 or 3 of menses. Orgalutran (0.25 mg) should be injected
subcutaneously once daily, starting on day 6 of FSH administration. The start of Orgalutran may be delayed in
absence of follicular growth, although clinical experience is based on starting Orgalutran on day 6 of FSH.
Orgalutran and FSH should be administered approximately at the same time. However, the preparations should
not be mixed and different injection sites are to be used. FSH dose adjustments should be based on the number
and size of growing follicles, rather than on the amount of circulating oestradiol (see Section 5.1
Pharmacodynamic properties). Daily treatment with Orgalutran should be continued up to the day that sufficient
12
1.6 外国における使用状況等に関する資料
follicles of adequate size are present. Final maturation of follicles can be induced by administering human
chorionic gonadotrophin (hCG). Because of the half-life of ganirelix, the time between two Orgalutran injections
as well as the time between the last Orgalutran injection and the hCG injection should not exceed 30 hrs, as
otherwise a premature LH surge may occur. Therefore, when injecting Orgalutran in the morning, treatment with
Orgalutran should be continued throughout the gonadotrophin treatment period including the day of triggering
ovulation. When injecting Orgalutran in the afternoon the last Orgalutran injection should be given in the
afternoon prior to the day of triggering ovulation.
Orgalutran has shown to be safe and effective in patients undergoing multiple treatment cycles.
The need for luteal phase support in cycles using Orgalutran has not been studied. In clinical trials, luteal phase
support was given according to study centres’ practice.
Subjects with renal or hepatic impairment: There is no experience of the use of Orgalutran in subjects with renal
or hepatic impairement. Therefore, specific dose recommendations cannot be given (see Section 4.3
Contraindications).
Method of administration
Orgalutran should be administered subcutaneously, preferably in the upper leg. The injection site should be varied
to prevent lipoatrophy. The patient or her partner may perform the injections of Orgalutran themselves, provided
that they are adequately instructed and have access to expert advice.
4.3 Contraindications
‐Hypersensitivity to the active substance or to any of the excipients.
‐Hypersensitivity to gonadotrophin-releasing hormone (GnRH) or any other GnRH analogue
‐Moderate or severe impairment of renal or hepatic function
‐Pregnancy or lactation.
4.4 Special warnings and special precautions for use
Special care should be taken in women with signs and symptoms of active allergic conditions. In the absence of
clinical experience, Orgalutran treatment is not advised in women with severe allergic conditions.
Ovarian hyperstimulation syndrome (OHSS) may occur during or following ovarian stimulation. OHSS must be
considered an intrinsic risk of gonadotrophin stimulation. OHSS should be treated symptomatically, e.g. with rest,
intravenous infusion of electrolyte solutions or colloids and heparin.
The incidence of congenital malformations after Assisted Reproductive Technologies (ART) may be higher than
after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal
age, sperm characteristics) and an increased incidence of multiple gestations.
The safety and efficacy of Orgalutran have not been established in women weighing less than 50 kg or more than
13
1.6 外国における使用状況等に関する資料
90 kg (see also Section 5.1 Pharmacodynamic properties and Section 5.2 Pharmacokinetic properties).
4.5 Interaction with other medicinal products and other forms of interaction
Interactions of Orgalutran with other medicines have not been investigated.
The possibility of interactions with commonly used medicinal products, including histamine liberating
products, cannot be excluded.
4.6 Pregnancy and lactation
No clinical data on exposed pregnancies are available. See also Section 4.4, Special warnings and special
precautions for use.
In animals, exposure to ganirelix at the time of implantation resulted in litter resorption (see Section 5.3
Preclinical safety data). The relevance of these data for humans is unknown.
It is not known whether ganirelix is excreted in breast milk. The use of Orgalutran is contraindicated during
pregnancy and lactation. (see Section 4.3 Contraindications).
4.7 Effects on ability to drive and use machines
The effects of Orgalutran on ability to drive and use machines have not been studied.
4.8 Undesirable effects
Orgalutran may cause a local skin reaction at the site of injection (predominantly redness, with or without
swelling). In clinical studies, one hour after injection, the incidence of at least once a moderate or severe local skin
reaction per treatment cycle, as reported by patients, was 12% in Orgalutran treated patients and 25% in patients
treated subcutaneously with a GnRH agonist. The local reactions generally disappear within 4 hours after
administration.
Adverse reactions for Orgalutran are all uncommon (<1%). The incidences as reported in clinical trials are:
Nausea (0.5%), headache (0.5%) and malaise (0.3%).
Very rarely cases of hypersensitivity reactions including various symptoms such as rash, facial swelling and
dyspnoea have been reported among patients administered Orgalutran with FSH.
Worsening of a pre-existing eczema has been reported in one subject after the first Orgalutran dose.
Other reported undesirable effects are related to the controlled ovarian hyperstimulation treatment for ART,
notably. pelvic pain, abdominal distension,OHSS (See also section 4.4 Special warnings and precautions for use
of this SPC), ectopic pregnancy and spontaneous abortion.
14
1.6 外国における使用状況等に関する資料
4.9 Overdose
Overdose in humans may result in a prolonged duration of action. In case of overdose, Orgalutran treatment
should be (temporarily) discontinued.
No data on acute toxicity of Orgalutran in humans are available. Clinical studies with subcutaneous administration
of Orgalutran at single doses up to 12 mg did not show systemic undesirable effects. In acute toxicity studies in
rats and monkeys non-specific toxic symptoms such as hypotension and bradycardia were only observed after
intravenous administration of ganirelix over 1 and 3 mg/kg, respectively.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: anti-gonadotrophin-releasing hormones; ATC code: H01CC01.
Orgalutran is a GnRH antagonist, which modulates the hypothalamic-pituitary-gonadal axis by competitive
binding to the GnRH receptors in the pituitary gland. As a result a rapid, profound, reversible suppression of
endogenous gonadotrophins occurs, without initial stimulation as induced by GnRH agonists. Following
administration of multiple doses of 0.25 mg Orgalutran to female volunteers serum LH, FSH and E2
concentrations were maximally decreased by 74%, 32% and 25% at 4, 16 and 16 hours after injection,
respectively. Serum hormone levels returned to pre-treatment values within two days after the last injection.
In patients undergoing controlled ovarian stimulation the median duration of Orgalutran treatment was 5 days.
During Orgalutran treatment the average incidence of LH rises (>10 IU/l) with concomitant progesteron rise (>1
ng/ml) was 1.2% compared to 0.8% during GnRH agonist treatment. There was a tendency towards an increased
incidence of LH and progesterone rises in women with a higher body weight (>80 kg), but no effect on clinical
outcome was observed. However, based on the small number of patients treated so far, an effect can not be
excluded. Early LH rises, prior to the start of Orgalutran at day 6 of stimulation, did occur especially in high
responders, but did not affect the clinical outcome. In these patients LH production was rapidly suppressed after
the first Orgalutran administration.
In controlled studies of Orgalutran, using a long protocol of GnRH agonist as a reference, treatment with the
Orgalutran regimen resulted in a faster follicular growth during the first days of stimulation but the final cohort of
growing follicles was slightly smaller and produced on average less oestradiol. This different pattern of follicular
growth, requires that FSH dose adjustments are based on the number and size of growing follicles, rather than on
the amount of circulating oestradiol.
5.2 Pharmacokinetic properties
After a single subcutaneous administration of 0.25 mg, serum levels of ganirelix rise rapidly and reach peak levels
(Cmax) of approximately 15 ng/ml within 1 to 2 hours (tmax). The elimination half-life (t½ ) is approximately 13
hours and clearance is approximately 2.4 l/h. Excretion occurs via faeces (approximately 75%) and urine
(approximately 22%). The bioavailability of Orgalutran following subcutaneous administration is approximately
15
1.6 外国における使用状況等に関する資料
91%.
Pharmacokinetic parameters after multiple subcutaneous dosing of Orgalutran (once daily injection) were similar
to those after a single subcutaneous dose. After repeated dosing 0.25 mg/day steady-state levels of approximately
0.6 ng/ml were reached within 2 to 3 days.
Pharmacokinetic analysis indicates an inverse relationship between bodyweight and serum concentrations of
Orgalutran.
Metabolite profile:
The major circulating component in plasma is ganirelix. Ganirelix is also the main compound found in urine.
Faeces only contain metabolites. The metabolites are small peptide fragments formed by enzymatic hydrolysis of
ganirelix at restricted sites. The metabolite profile of Orgalutran in humans was similar to that found in animals.
5.3 Preclinical safety data
Preclinical data reveal no special hazard for humans based on safety pharmacology, repeated dose toxicity and
genotoxicity.
Reproduction studies carried out with ganirelix at doses of 0.1 to 10 μg/kg/day subcutaneously in the rat and 0.1 to
50 μg/kg/day subcutaneously in the rabbit showed increased litter resorption in the highest dose groups. No
teratogenic effects were observed.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Acetic acid, mannitol and water for injections. The pH may have been adjusted with sodium hydroxide and acetic
acid.
6.2 Incompatibilities
In the absence of incompatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not freeze.
Store in the original package in order to protect from light.
16
1.6 外国における使用状況等に関する資料
6.5 Nature and contents of container
Orgalutran is presented as a sterile, ready for use, aqueous solution and supplied in disposable prefilled syringes
(siliconised Type I glass), containing 0.5 ml closed with a rubber piston. Each pre-filled syringe is affixed with a
needle closed by a needle shield of natural rubber.
Supplied in cartons containing 1 or 5 pre-filled syringes.
6.6 Instructions for use and handling <and disposal>
No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
N.V. Organon, Kloosterstraat 6, Postbus 20, 5340 BH Oss, The Netherlands
8. MARKETING AUTHORISATION NUMBER(S)
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10. DATE OF REVISION OF THE TEXT
17
1.6 外国における使用状況等に関する資料
1.6.2.3 米国の添付文書（和訳の概要）
表 1.6-2に米国の添付文書の和訳の概要を示した．
表 1.6-2 米国の添付文書の和訳の概要
販
売
名
供給形態
Ganirelix Acetate Injection（ガニレリクス酢酸塩注射剤）は以下の形態で供給される：
剤型・含量
使い捨ての滅菌プレフィルドシリンジ 1 mL 容器に，ガニレリクス酢酸塩 250 μg/0.5 mL を含有。
各 Ganirelix Acetate Injection 滅菌プレフィルドシリンジには，27 gauge×0.5 inch の針が添付され，
ブリスター包装されている。
注射筒 1 本
効能又は効果
NDC 0052-0301-51
Ganirelix Acetate Injection（ガニレリクス酢酸塩注射剤）の適応：調節卵巣刺激を受ける女性におけ
る早期の LH サージの予防
用法及び用量
月経周期 2 又は 3 日目に FSH 治療を開始後，卵胞期中期から後期にかけて Ganirelix Acetate Injection
（ガニレリクス酢酸塩注射剤）250 μg を 1 日 1 回皮下投与する。内因性下垂体性 FSH の分泌を利用
すると，外因性の FSH 投与量が少なくなる可能性がある。Ganirelix Acetate Injection の連日投与は hCG
投与日まで続けること。超音波断層検査により，適切な大きさの卵胞が十分な数確認されたならば，
hCG 投与により最終的な卵胞の成熟が引き起こされる。FSH 最終投与日に卵巣が異常に腫大してい
る場合は，卵巣過剰刺激症候群を引き起こす可能性を少なくするために，hCG 投与をやめること。
Ganirelix Acetate Injection（ガニレリクス酢酸塩注射剤）使用の手引き
1. Ganirelix Acetate Injection は，滅菌したプレフィルドシリンジで提供され，皮下投与のみで使用す
ることを意図している。
2.手を石鹸及び水で十分洗浄すること。
3.皮下注射の最も都合の良い場所は，へその周囲の腹部又は大腿部上部である。
4.注射部位は，表面の細菌を除去するために消毒薬で消毒すること。針の差込み部位の周辺 2 インチ
を清浄にし，注射前少なくとも 1 分間消毒薬を乾燥すること。
5.注射筒を上に向け，針カバーを取り除くこと。
用法及び用量
6.皮膚の広い範囲を親指と人差し指でつまみあげること。注射の度に注射部位を少し変えること。
7.つまみあげられた皮膚の底部に，皮膚表面に対して 45-90 度の角度で注射針を挿入すること。
8.注射針が正しく挿入された場合，プランジャーを引き上げることは難しくなる。何がしかの血が注
射筒に混入した場合，注射針の先端が静脈又は動脈を貫通したことになる。この場合，針を少し
引き，皮膚から完全に引き抜くことなく再固定すること。又は，針を引き抜き，新しい滅菌プレ
フィルドシリンジを使うこと。注射部位を消毒綿で覆い，圧力をかけること；その部位は 1，2 分
で止血する。
9.注射針が正しく固定されたならば，プランジャーをゆっくり，確実に押し下げること。そうすれば，
液が注入され，皮膚が損傷されない。
10.注射針をすばやく抜き取り，消毒綿で注射部位を押さえること。
11.滅菌プレフィルドシリンジの使用は 1 回限りとし，適切に廃棄すること。
禁忌
Ganirelix Acetate Injection（ガニレリクス酢酸塩注射剤）は次の患者には投与しないこと：
・Ganirelix Acetate Injection 又はその賦形剤に過敏症を有する者
・GnRH 又は他の GnRH 誘導体に過敏症を有する者
・妊娠又は妊娠が疑われる者
18
1.6 外国における使用状況等に関する資料
表 1.6-2 米国の添付文書の和訳の概要（続き）
警告
Ganirelix Acetate Injection（ガニレリクス酢酸塩注射剤）は不妊治療に経験のある医師により処方さ
れること。Ganirelix Acetate Injection による治療を始めるにあたって，妊娠は排除されなければなら
ない。妊娠中の Ganirelix Acetate Injection の使用に関する安全性は確立されていない（禁忌と使用上
の注意を参照のこと）。
基本的な注意
GnRH に過敏症の者には注意を払うこと。これらの患者は初回投与後注意深く観察すること。
Ganirelix Acetate Injection（ガニレリクス酢酸塩注射剤）の臨床試験では，アナフィラキシー反応や
ganirelix の抗体産生は報告されていない。
本製品の包装には天然ゴム latex が含まれており，これがアレルギー反応を引き起こす可能性がある。
患者への情報
Ganirelix Acetate Injection（ガニレリクス酢酸塩注射剤）による治療の前に，患者は治療期間及び必
要なモニタリング手順について説明を受けなければならない。起こる可能性のある副作用の危険性
について十分話し合われなければならない（副作用を参照のこと）。
Ganirelix Acetate Injection は妊婦には処方しないこと。
臨床検査
適切な対照を置き，よく管理された臨床試験において，全ての被験者の 11.9%に好中球数の増加（≥
8.3×109/L）が見られた（最高値 16.8×109/L）。さらに，ヘマトクリット及び総ビリルビンの下方への
シフトが見られた。これらの臨床での重要性についてはわかっていない。
薬物相互作用
使用上の注意
正式な薬物間相互作用についての検討は実施していない。
発癌性及び変異原性，生殖能の減退
薬物の発癌性を評価することを目的とした，動物における Ganirelix Acetate Injection（ガニレリクス
酢酸塩注射剤）の長期毒性試験は実施していない。Ganirelix Acetate Injection は，Ames 試験（S.
typhimurium 及び E. coli）及び Chinese Hamster 卵巣細胞を用いた in vitro での染色体異常試験におい
て変異原性を発現しなかった。
妊婦
Pregnancy Category X
Ganirelix Acetate Injection（ガニレリクス酢酸塩注射剤）は，妊婦には使用してはならない。ラット
及びウサギに 10 及び 30 μg/day（体表面積に基づくとヒトの投与量の 0.4 から 3.2 倍）を妊娠 7 日目
から投与した場合，Ganirelix Acetate Injection は胎児死亡の発現数を増加させた。胎児異常の増加は
認められなかった。妊娠及び授乳中の雌ラットに Ganirelix Acetate Injection を投与した場合，その出
産児の繁殖力，身体あるいは行動特性に変化は認められなかった。
胎児死亡への影響は本薬剤の抗ゴナドトロピン作用によりもたらされたホルモン濃度の変化とい
う論理的な結果によるものであり，ヒトでも胎児死亡が起こりうる。したがって，本薬剤は妊婦に
使用してはならない（禁忌を参照のこと）。
授乳婦
Ganirelix Acetate Injection（ガニレリクス酢酸塩注射剤）は，授乳婦には使用してはならない。本剤
が乳汁中に排泄されるかどうかは不明である。
高齢者への投与
Ganirelix Acetate Injection（ガニレリクス酢酸塩注射剤）の臨床試験には，十分な数の 65 歳以上の被
験者は含まれていなかった。
19
1.6 外国における使用状況等に関する資料
表 1.6-2 米国の添付文書の和訳の概要（続き）
副作用
Ganirelix Acetate Injection（ガニレリクス酢酸塩注射剤）の安全性を，無作為化，多施設比較試験 2
試験において評価した。Ganirelix Acetate Injection の投与期間は 1～14 日間であった。Ganirelix Acetate
Injection の投与初日から超音波断層検査による妊娠確認までの Ganirelix Acetate Injection 投与群にお
いて，因果関係に関係なく 1%以上の発現率で発現した有害事象を表に示した。
Ganirelix Acetate Injection 投与群において 1%以上の発現率で発現した有害事象
腹痛（婦人科の）
Ganirelix Acetate Injection 投与群（N=794）
% (n)
4.8 (38)
胎児死亡
3.7 (29)
1%以上の発現率で発現した有害事象
使用上の注意
頭痛
3.0 (24)
卵巣過剰刺激症候群
2.4 (19)
腟出血
1.8 (14)
注射部反応
1.1 (9)
嘔気
1.1 (9)
腹痛（消化管障害）
1.0 (8)
先天異常
Ganirelix Acetate Injection（ガニレリクス酢酸塩注射剤）の投与を受けた女性から生まれた新生児 283
名のフォローアップ試験（現在進行中）をまとめた。重度の先天異常が 3 名の新生児に，また軽度
の先天異常が 18 名の新生児に認められた。重度の先天異常は，水頭症／髄膜瘤，臍帯ヘルニア及び
Beckwith-Wiedemann Syndrome であった。軽度の先天異常は，母斑，skin tags，仙骨洞，血管腫，斜
頸・不斉頭骨，彎曲足，過剰指，股不全脱臼，斜頸・high plate，occipt/abnormal hand crease，hemia
umbilicalis，鼠径ヘルニア，水瘤，停留睾丸及び水腎症であった。これらの先天異常と Ganirelix Acetate
Injection との因果関係はわかっていない。遺伝的及びその他（ICSI，IVF，ゴナドトロピン，プロゲ
ステロンなど；これらに限定はされないが）の種々の要因が，生殖補助医療（ART）を混乱させて
いる可能性がある。
過量投与
ヒトにおける Ganirelix Acetate Injection（ガニレリクス酢酸塩注射剤）の過量投与に関する報告はな
い。
20
1.6 外国における使用状況等に関する資料
1.6.2.4 英国の添付文書（和訳の概要）
表 1.6-3に英国の添付文書の和訳の概要を示した．
表 1.6-3 英国の添付文書の和訳の概要
販
売
名
剤型・含量
Orgalutran 0.25 mg/0.5 mL 注射液剤
剤型：注射液剤
効能効果
効能又は効果
生殖補助医療（ART）のための調節卵巣刺激（COS）を受ける女性における早期の黄体形成ホルモ
ン（LH）サージの予防。
臨床試験において，Orgalutran は遺伝子組換えヒト卵胞刺激ホルモン（FSH）とともに使用した。
薬用量と投与方法
Orgalutran は不妊治療の経験のある専門家によってのみ処方されこと。
薬用量
Orgalutran は COS を受ける患者における早期の LH サージの予防のために使用される。FSH を用い
た COS 治療は月経周期の 2 又は 3 日目から行われる。FSH 投与の 6 日目から Orgalutran（0.25 mg）
の 1 日 1 回皮下投与を開始する。臨床経験では FSH 投与 6 日目に Orgalutran の投与を開始すること
を基本としているが，卵胞の成長がみられない場合，Orgalutran の投与開始を遅らせてもよい。
Orgalutran と FSH はほぼ同じ時間に投与すること。しかしながら，両製剤は混合してはならず，ま
た注射部位を別とすること。
用法及び用量
FSH 投与量の調整は，血中のエストラジオール値よりも成長卵胞の数と大きさに基づくこと。
Orgalutran の投与は，適切な大きさの卵胞が十分な数確認されるまで毎日続けること。最終的な卵胞
の成熟は，ヒト絨毛性ゴナドトロピン（hCG）の投与により行う。Ganirelix の半減期に基づくと，2
回の Orgalutran の投与間隔および最後の Orgalutran 投与と hCG 投与の間隔は 30 時間を超えてはなら
ない。30 時間を超えると早期の LH サージが起こるかもしれない。そのため，午前中に Orgalutran
を投与する場合，排卵誘発日を含むゴナドトロピンによる治療期間中 Orgalutran の投与を継続する
こと。午後に Orgalutran を投与する場合，最後の Orgalutran 投与は，排卵誘発日の前日の午後とする
こと。
Orgalutran は複数治療周期で治療を行った患者においても，安全であり有効であった。
Orgalutran を用いた周期の黄体期管理の必要性は検討していない。治験における黄体期管理は医療機
関で通常行われている方法で行われた。
腎臓又は肝臓に機能障害のある患者：腎臓又は肝臓に機能障害のある患者に Orgalutran を使用した
例がない。そのため特定の推奨用量を示すことができない（薬効の項参照）。
投与方法
Orgalutran は皮下注射すること。大腿部が望ましい。投与部位は脂肪組織萎縮症を避けるため変える
こと。患者あるいは患者のパートナーが自分達で Orgalutran を投与してもよい。この場合，患者ら
に十分な説明を行い，専門家のアドバイスが受けられるようにすること。
禁忌
・活性成分あるいは賦形剤に対して過敏症を有する患者
・ゴナドトロピン放出ホルモン（GnRH）あるいはいずれかの GnRH 誘導体に過敏症を有する患者
・腎機能または肝機能に中等度あるいは高度の障害を有する患者
使用上の注意
・妊娠または授乳中の患者。
特記すべき警告と使用上の注意
アレルギーの徴候や症状を示している女性に使用する場合，特に注意を払うこと。臨床使用の経験
がないので，高度なアレルギー状態の女性での Orgalutran の使用は勧められない。
21
1.6 外国における使用状況等に関する資料
表 1.6-3 英国の添付文書の和訳の概要（続き）
卵巣過剰刺激症候群（OHSS）が，卵巣刺激中あるいは刺激後に起こる可能性がある。OHSS はゴナ
ドトロピンによる刺激で特にみられる可能性のある固有のリスクである。OHSS の徴候がみられた
場合，対症療法として例えば休息，電解質液あるいはコロイドとヘパリンの静注を行うこと。
生殖補助医療（ART）後の先天異常の発現率は，自然妊娠によるものよりも高い可能性がある。こ
れは，親の特性（例えば，母親の年齢，精子の特性など）における違い，及び多胎妊娠の増加など
によるものと考えられる。
Orgalutran は 50 kg 未満および 90 kg を超える女性での安全性と有効性は確立されていない。
他の薬剤との相互作用
Orgalutran と他の薬剤との相互作用は検討されていない。
通常用いられる医薬品，例えばヒスタミン遊離を起こすような医薬品との相互作用の可能性は除外
することはできない。
妊婦及び授乳婦
Orgalutran を妊婦に投与した臨床データはない（特記すべき警告と使用上の注意を参照のこと）。
動物において，着床時に ganirelix を暴露すると胎児が死亡した。これらのデータとヒトでの関連性
については不明である。
Ganirelix が乳汁中に排泄されるかどうかは不明である。
妊娠および授乳中は，Orgalutran の使用は禁忌である（禁忌を参照のこと）。
使用上の注意
運転および機械操作能力への影響
Orgalutran の運転および機械操作能力への影響については検討していない。
望ましくない作用
Orgalutran は注射部位に局所的な皮膚反応（腫脹を伴うあるいは伴わない優勢な発赤)がみられる可
能性がある。臨床試験では，投与後 1 時間時点で，治療周期あたり少なくとも 1 回中等度あるいは
高度の局所皮膚反応を発現した率は，Orgalutran を投与した患者で 12%，GnRH アゴニストを皮下投
与した患者で 25%であった。局所反応は通常，投与後 4 時間以内に消失する。
臨床試験において報告された有害事象は全て 1%未満であった。報告された有害事象は，嘔気（0.5%），
頭痛（0.5%）及び倦怠感（0.3%）であった。
FSH と Orgalutran が投与された患者に，ごくまれに，発疹，顔面腫脹及び呼吸困難などの過敏症反
応が報告されている。
初回 Orgalutran 投与で，湿疹が悪化した例が 1 例報告されている。
他の有害事象は，例えば，腹痛，OHSS，子宮外妊娠及び流産などであり，ART のための調節卵巣刺
激に関連していた。
過量投与
ヒトにおける過量投与は，作用の持続時間を延長する可能性がある。過量投与の場合，Orgalutran の
投与を（一時的に）中止すること。
ヒトにおける急性毒性に関するデータはない。Orgalutran の 12 mg までの単回皮下投与試験では，全
身的な好ましくない効果はみられなかった。ラット及びサルを用いた急性毒性試験において，降圧
作用や徐脈などの非特異的な毒性症状が，それぞれ 1 及び 3 mg/kg を超える ganirelix を静脈内投与
した場合のみに観察された。
22
abcd
CONFIDENTIAL
No.:
Organon
Prepared by:
No. of pages:
Date:
8
20
COMPANY CORE DATA SHEET OF ORGALUTRAN
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COMPANY CORE DATA SHEET
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ORGALUTRAN