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ELONVA_CORIFOLLITROPIN_绒促卵泡素α注射用溶液说明书

ELONVA SOLN FOR INJ 100MCG/0.5ML(绒促卵泡素α注射用溶液)

  药店国别:

  产地国家:香港

  处 方 药:

  所属类别:150微克/0.5毫升/瓶

  包装规格:150微克/0.5毫升/瓶

  计价单位:

  生产厂家中文参考译名:默克

  生产厂家英文名:Merck

  原产地英文商品名:ELONVA SOLUTION INJECTION 150mcg 0.5ml

  原产地英文药品名:CORIFOLLITROPIN ALFA

  中文参考商品译名:ELONVA注射用溶液剂 150微克/0.5毫升/瓶

  中文参考药品译名:绒促卵泡素α

  简介:

  促排卵新药Elonva已通过欧盟批准上市

  默沙东促排卵药Elonva(corifollitropin alfa注射剂)已通过欧盟批准,该药与GnRH拮抗剂联用对患者进行控制性促排卵(COS)。它主要用于那些采用辅助生殖技术(ART)生育的妇女,促进其卵泡发育。随着Elonva在欧盟地区获准,默克将可以在所有欧盟成员国推出这种产品,并采用统一标签。

  Elonva可持续一周促进患者多个卵泡发育。默克表示,在COS治疗周期之初,若采用常规重组卵泡刺激素(rFSH)治疗,在头7天需每天注射一次药物,而仅注射1剂Elonva就可以达到7剂rFSH的效果。

  Elonva的III期临床实验当中,有一项名为Engage的实验是迄今为止规模最大的针对治疗不孕症的试管婴儿临床实验项目。实验结果显示,Elonva受试组当中,患者在每一个治疗周期的受孕几率(实验主要终点)可达到38.9%,与使用rFSH的对照组效果相当,后者每一治疗周期受孕率为38.1%。

  默克研发实验室负责人米杰姆·莫尔·艾特斯表示:“Elonva在欧盟地区获准上市后,当地的不孕症妇女将可免去频繁注射促排卵药的困扰。默克将会再接再厉,致力于研发以患者为本的不孕症治疗药。”

  Elonva 100 and 150 micrograms solution for injection.

  1. Name of the medicinal product

  Elonva 100 and 150 micrograms solution for injection.

  2. Qualitative and quantitative composition

  Elonva 100 micrograms solution for injection

  Each pre-filled syringe contains 100 micrograms of corifollitropin alfa* in 0.5 ml solution for injection.

  Elonva 150 micrograms solution for injection

  Each pre-filled syringe contains 150 micrograms of corifollitropin alfa* in 0.5 ml solution for injection.

  *corifollitropin alfa is a glycoprotein produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology.

  Excipient(s) with known effect:

  This medicinal product contains less than 1 mmol (23 mg) sodium per injection, i.e., essentially ‘sodium-free’.

  For the full list of excipients, see section 6.1.

  3. Pharmaceutical form

  Solution for injection (injection).

  Clear and colourless aqueous solution.

  4. Clinical particulars

  4.1 Therapeutic indications

  Elonva is indicated for Controlled Ovarian Stimulation (COS) in combination with a Gonadotropin Releasing Hormone (GnRH) antagonist for the development of multiple follicles in women participating in an Assisted Reproductive Technology (ART) program.

  4.2 Posology and method of administration

  Treatment with Elonva should be initiated under the supervision of a physician experienced in the treatment of fertility problems.

  Posology

  In women with a body weight ≤ 60 kilograms a single dose of 100 micrograms should be administered.

  In women with a body weight > 60 kilograms a single dose of 150 micrograms should be administered.

  Stimulation day 1:

  Elonva should be administered as a single subcutaneous injection, preferably in the abdominal wall, during the early follicular phase of the menstrual cycle.

  The recommended doses of Elonva have only been established in a treatment regimen with a GnRH antagonist (see sections 4.1 and 4.4).

  Stimulation day 5 or 6:

  Treatment with a GnRH antagonist should be started on stimulation day 5 or day 6 depending on the ovarian response, i.e. the number and size of growing follicles. The concurrent determination of serum oestradiol levels may also be useful. The GnRH antagonist is used to prevent premature Luteinising Hormone (LH) surges.

  Stimulation day 8:

  Seven days after the injection with Elonva on stimulation day 1, COS treatment may be continued with daily injections of (recombinant) Follicle Stimulating Hormone [(rec)FSH] until the criterion for triggering final oocyte maturation (3 follicles ≥ 17 mm) has been reached. The daily dose of (rec)FSH may depend on the ovarian response. In normal responders a daily dose of 150 IU (rec)FSH is advised. Administration of (rec)FSH on the day of human Chorionic Gonadotropin (hCG) administration can be omitted, depending on the ovarian response. In general, adequate follicular development is achieved on average by the ninth day of treatment (range 6 to 18 days).

  As soon as three follicles ≥ 17 mm are observed, a single injection of 5,000 up to 10,000 IU hCG is administered the same day or the day thereafter to induce final oocyte maturation. In case of an excessive ovarian response, see the recommendations given in section 4.4 in order to reduce the risk for developing ovarian hyperstimulation syndrome (OHSS).

  Special population

  Renal impairment

  No clinical studies have been performed in patients with renal insufficiency. Since the rate of elimination of corifollitropin alfa may be reduced in patients with renal insufficiency, the use of Elonva in these women is not recommended (see section 4.4 and 5.2).

  Hepatic impairment

  Although data in hepatically impaired patients are not available, hepatic impairment is unlikely to affect the elimination of corifollitropin alfa (see section 5.2).

  Paediatric population

  There is no relevant use use of Elonva within the approved indication in the paediatric population.

  Method of administration

  Subcutaneous injection of Elonva may be carried out by the woman herself or her partner, provided that proper instructions are given by the physician. Self administration of Elonva should only be performed by women who are well-motivated, adequately trained and with access to expert advice.

  4.3 Contraindications

  • Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

  • Tumours of the ovary, breast, uterus, pituitary or hypothalamus.

  • Abnormal (not menstrual) vaginal bleeding without a known/diagnosed cause.

  • Primary ovarian failure.

  • Ovarian cysts or enlarged ovaries.

  • A history of Ovarian Hyperstimulation Syndrome (OHSS).

  • A previous COS cycle that resulted in more than 30 follicles ≥ 11 mm measured by ultrasound examination.

  • A basal antral follicle count > 20.

  • Fibroid tumours of the uterus incompatible with pregnancy.

  • Malformations of the reproductive organs incompatible with pregnancy.

  • Polycystic ovarian syndrome (PCOS).

  4.4 Special warnings and precautions for use

  Infertility eva luation before starting treatment

  Before starting treatment, the couple’s infertility should be assessed as appropriate. In particular, women should be eva luated for hypothyroidism, adrenocortical insufficiency, hyperprolactinemia and pituitary or hypothalamic tumours, and appropriate specific treatment given. Medical conditions that contraindicate pregnancy should also be eva luated before starting treatment with Elonva.

  Dosing during the stimulation cycle

  Elonva is intended for single subcutaneous injection only. Additional injections of Elonva should not be given within the same treatment cycle. (See also section 4.2.)

  After administration of Elonva, no additional FSH-conataining product should be administered prior to stimulation day 8 (see also section 4.2).

  Renal insufficiency

  In patients with mild, moderate or severe renal insufficiency the rate of elimination of corifollitropin alfa may be reduced (see section 4.2 and 5.2). Therefore, the use of Elonva in these women is not recommended.

  Not recommended with a GnRH agonist protocol

  There are limited data on the use of Elonva in combination with a GnRH agonist. Results of a small uncontrolled study suggest a higher ovarian response than in combination with a GnRH antagonist. Therefore, the use of Elonva is not recommended in combination with a GnRH agonist (see also section 4.2).

  Ovarian hyperstimulation syndrome (OHSS)

  OHSS is a medical event distinct from uncomplicated ovarian enlargement. Clinical signs and symptoms of mild and moderate OHSS are abdominal pain, nausea, diarrhoea, mild to moderate enlargement of ovaries and ovarian cysts. Severe OHSS may be life-threatening. Clinical signs and symptoms of severe OHSS are large ovarian cysts, acute abdominal pain, ascites, pleural effusion, hydrothorax, dyspnoea, oliguria, haematological abnormalities and weight gain. In rare instances, venous or arterial thromboembolism may occur in association with OHSS. Transient liver function test abnormalities suggestive of hepatic dysfunction with or without morphologic changes on liver biopsy have also been reported in association with OHSS.

  OHSS may be caused by administration of hCG and by pregnancy (endogenous hCG). Early OHSS usually occurs within 10 days after hCG administration and may be associated with an excessive ovarian response to gonadotropin stimulation. Late OHSS occurs more than 10 days after hCG administration, as a consequence of the hormonal changes with pregnancy. Because of the risk of developing OHSS, patients should be monitored for at least two weeks after hCG administration.

  Women with known risk factors for a high ovarian response may be especially prone to the development of OHSS following treatment with Elonva. For women having their first cycle of ovarian stimulation, for whom risk factors are only partially known, close observation for early signs and symptoms of OHSS is recommended.

  To reduce the risk of OHSS, ultrasonographic assesments of follicular developmentshould be performed prior to treatment and at regular intervals during treatment. The concurrent determination of serum oestradiol levels may also be useful. In ART there is an increased risk of OHSS with 18 or more follicles of 11 mm or more in diameter. When there are 30 or more follicles in total it is advised to withhold hCG administration.

  Depending on the ovarian response, the following measures can be considered to reduce the risk of OHSS:

  - withhold further stimulation with a gonadotropin for a maximum of 3 days (coasting);

  - withhold hCG and cancel the treatment;

  - administer a dose lower than 10,000 IU of hCG for triggering final oocyte maturation, e.g. 5,000 IU hCG or 250 micrograms rec-hCG (which is equivalent to approximately 6,500 IU);

  - cancel the fresh embryo transfer and cryopreserve embryos;

  - Avoid administration of hCG for luteal phase support.

  Adherence to the recommended Elonva dose and treatment regimen and careful monitoring of ovarian response is important to reduce the risk of OHSS. If OHSS develops, standard and appropriate management of OHSS should be implemented and followed.

  Ovarian torsion

  Ovarian torsion has been reported after treatment with gonadotropins, including Elonva. Ovarian torsion may be related to other conditions, such as OHSS, pregnancy, previous abdominal surgery, past history of ovarian torsion, and previous or current ovarian cysts. Damage to the ovary due to reduced blood supply can be limited by early diagnosis and immediate detorsion.

  Multiple pregnancy

  Multiple pregnancies and births have been reported for all gonadotropin treatments, including Elonva. The woman and her partner should be advised of the potential risks for the mother (pregnancy and delivery complications) and the neonate (low birth weight) before starting treatment. In women undergoing ART procedures the risk of multiple pregnancy is mainly related to the number of embryos transferred.

  Ectopic pregnancy

  Infertile women undergoing ART have an increased incidence of ectopic pregnancies. It is important to have early ultrasound confirmation that a pregnancy is intrauterine, and to exclude the possibility of extrauterine pregnancy.

  Congenital malformations

  The incidence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g., maternal age, sperm characteristics) and the higher incidence of multiple pregnancies.

  Ovarian and other reproductive system neoplasms

  There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility treatment. It is not established whether or not treatment with gonadotropins increases therisk of these tumours in infertile women.

  Vascular complications

  Thromboembolic events, both in association with and separate from OHSS, have been reported following treatment with gonadotropins, including Elonva. Intravascular thrombosis, which may originate in venous or arterial vessels, can result in reduced blood flow to vital organs or the extremities. In women with generally recognized risk factors for thromboembolic events, such as a personal or family history, severe obesity or thrombophilia, treatment with gonadotropins may further increase this risk. In these women the benefits of gonadotropin administration need to be weighed against the risks. It should be noted, however, that pregnancy itself also carries an increased risk of thrombosis.

  4.5 Interaction with other medicinal products and other forms of interaction

  No interaction studies with Elonva and other medicines have been performed. Since corifollitropin alfa is not a substrate of cytochrome P450 enzymes, no metabolic interactions with other medicinal products are anticipated.

  4.6 Fertility, pregnancy and lactation

  Pregnancy

  In case of inadvertent exposure to Elonva during pregnancy occurs, clinical data are not sufficient to exclude an adverse outcome of pregnancy. In animal studies reproductive toxicity has been observed (see preclinical safety data in section 5.3). The use of Elonva during pregnancy is not indicated.

  Breast-feeding

  The use of Elonva during breast-feeding is not indicated.

  Fertility

  Elonva is indicated for use in infertility (see section 4.1).

  4.7 Effects on ability to drive and use machines

  No studies on the ability to drive and use machines have been performed.

  Elonva may cause dizziness. Women should be advised that if they feel dizzy, they should not drive or use machines.

  4.8 Undesirable effects

  Summary of the safety profile

  The most frequently reported adverse reactions during treatment with Elonva in clinical trials are OHSS (5.2%, see also section 4.4), pelvic pain (4.1%) and discomfort (5.5%), headache (3.2%), nausea (1.7%), fatigue (1.4%) and breast complaints (including tenderness) (1.2%).

  Tabulated list of adverse reactions

  The table below displays the main adverse drug reactions in women treated with Elonva in clinical trials according to system organ class and frequency; very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), and very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

  Description of selected adverse reactions

  In addition, ectopic pregnancy, miscarriage and multiple gestations have been reported. These are considered to be related to ART or subsequent pregnancy.

  In rare instances, thromboembolism has been associated with Elonva therapy as with other gonadotropins.

  Reporting of suspected adverse reactions

  Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme, website www.mhra.gov.uk/yellowcard.

  4.9 Overdose

  More than one injection of Elonva within one treatment cycle or too high a dose of Elonva and/or (rec)FSH may increase the risk of OHSS. For measures to reduce the risk of OHSS see section 4.4.

  5. Pharmacological properties

  5.1 Pharmacodynamic properties

  Pharmacotherapeutic group: sex hormones and modulators of the genital system, gonadotropins

  ATC code: G03GA09

  Mechanism of action

  Corifollitropin alfa is designed as a sustained follicle stimulant with the same pharmacodynamic profile as (rec)FSH, but with a markedly prolonged duration of FSH activity. Due to its ability to initiate and sustain multiple follicular growth for an entire week, a single subcutaneous injection of the recommended dose of Elonva may replace the first seven injections of any daily (rec)FSH preparation in a COS treatment cycle. The long duration of FSH activity was achieved by adding the carboxy-terminal peptide of the β-subunit of human chorionic gonadotropin (hCG) to the β-chain of human FSH. Corifollitropin alfa does not display any intrinsic LH/hCG activity.

  Clinical efficacy and safety

  In two randomized, double-blind, clinical trials, treatment with a single subcutaneous injection of Elonva, 100 micrograms (trial A) or 150 micrograms (trial B), for the first seven days of COS resulted in a significantly higher number of retrieved oocytes compared to treatment with a daily dose of 150 or 200 IU of recFSH, respectively. However, the difference was within the predefined equivalence margins. See Table 1 below.

  Table 1: Mean number of oocytes retrieved in Trial A and Trial B

  In the 150 micrograms trial (trial B) pregnancy was also studied as primary efficacy parameter for Elonva in direct comparison to recFSH, and similar success rates were established. (See Table 2 below).

  Table 2: Ongoing pregnancy rate in Trial B

  Except for a slightly higher incidence of OHSS (not significant), the safety profile of a single injection with Elonva was comparable to daily injections with recFSH (see also section 4.8).

  Paediatric population

  The European Medicines Agency has deferred the obligation to submit the results of studies with Elonva in one or more subsets of the paediatric population in hypogonadotrophic hypogonadism. (see section 4.2 for information on paediatric use).

  5.2 Pharmacokinetic properties

  After administration of the recommended dose, serum concentrations of corifollitropin alfa are sufficient to sustain multiple follicular growth for an entire week. This justifies replacement of the first seven injections of daily (rec)FSH with a single subcutaneous injection of Elonva in COS for the development of multiple follicles and pregnancy in an ART program (see section 4.2).

  Body weight is a determinant of exposure to corifollitropin alfa. In clinical studies, serum concentrations of corifollitropin alfa were similar after administration of 100 micrograms corifollitropin alfa to women with a body weight ≤ 60 kilograms and of 150 micrograms corifollitropin alfa to women with a body weight > 60 kilograms.

  The pharmacokinetic properties of corifollitropin alfa are independent of the administered dose over a wide range (7.5-240 micrograms).

  Absorption

  After a single subcutaneous injection of Elonva, maximum serum concentrations of corifollitropin alfa are reached after 44 hours (34-57 hours1). The absolute bioavailability is 58% (48-70%1).

  Distribution

  Distribution, metabolism and elimination of corifollitropin alfa are very similar to other gonadotropins, such as FSH, hCG and LH. After absorption into the blood, corifollitropin alfa is distributed mainly to the ovaries and the kidneys.The steady state volume of distribution is 9.2 l (6.5 -13.1 l1).

  Elimination

  Corifollitropin alfa has an elimination half-life of 69 hours (59-79 hours1) and a clearance of 0.13 l/h (0.10 -0.18 l/h1). Elimination of corifollitropin alfa predominantly occurs via the kidneys, and the rate of elimination may be reduced in patients with renal insufficiency (see section 4.2 and 4.4). Hepatic metabolism contributes to a minor extent to the elimination of corifollitropin alfa.

  Other special populations

  Hepatic impairment

  Although data in hepatically impaired patients are not available, hepatic impairment is unlikely to affect the pharmacokinetic profile of corifollitropin alfa.

  1 Predicted range for 90% of subjects.

  5.3 Preclinical safety data

  Preclinical data revealed no special hazard for humans based on conventional studies of single and repeated dose toxicity and safety pharmacology.

  Reproduction toxicology studies in rats and rabbits indicated that corifollitropin alfa does not adversely affect fertility. Administration of corifollitropin alfa to rats and rabbits, prior to and directly after mating, and during early pregnancy, resulted in embryotoxicity. In rabbits, when administered prior to mating, teratogenicity has been observed. Both embryotoxicity and teratogenicity are considered a consequence of the superovulatory state of the animal not able to support a number of embryos above a physiological ceiling. The relevance of these findings for the clinical use of Elonva is limited.

  6. Pharmaceutical particulars

  6.1 List of excipients

  Sodium citrate

  Sucrose

  Polysorbate 20

  Methionine

  Sodium hydroxide (for pH adjustment)

  Hydrochloric acid (for pH adjustment)

  Water for injections

  6.2 Incompatibilities

  In the absence of compatibility studies, the medicinal product must not be mixed with other medicinal products.

  6.3 Shelf life

  3 years

  6.4 Special precautions for storage

  Store in a refrigerator (2°C-8°C).

  Do not freeze.

  For convenience, the patient is allowed to store the product at or below 25°C for a period of not more than 1 month.

  Keep the syringe in the outer carton in order to protect from light.

  6.5 Nature and contents of container

  Elonva is supplied in pre-filled luerlock syringes of 1 ml (type I hydrolytic glass), closed with a bromobutyl elastomer plunger and a tip cap. The syringe is equiped with an automatic safety system to prevent needle stick injuries after use and is packed together with a sterile injection needle. Each pre-filled syringe contains 0.5 ml solution for injection.

  Elonva is available in pack sizes of 1 pre-filled syringe.

  6.6 Special precautions for disposal and other handling

  Do not use Elonva if the solution is not clear.

  Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

  7. Marketing authorisation holder

  Merck Sharp & Dohme Limited

  Hertford Road, Hoddesdon

  Hertfordshire EN11 9BU

  United Kingdom

  8. Marketing authorisation number(s)

  Elonva 100 micrograms solution for injection: EU/1/09/609/001

  Elonva 150 micrograms solution for injection: EU/1/09/609/002

  9. Date of first authorisation/renewal of the authorisation

  Date of first authorisation: 25 January 2010

  Date of latest renewal:

  10. Date of revision of the text

  22 August 2014

  Detailed information on this medicinal product is available on the website of the European Medicines Agency

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