Highly purified menotrophin.
Each vial of IVF-M HP Inj. 75 IU is accompanied by a solvent containing isotonic sodium chloride for injection.
1 vial of IVF-M HP Inj. 75 IU contains Highly purified menotrophin 75 IU (FSH 75 IU + LH 75 IU).
Excipient/Inactive Ingredients: Lactose monohydrate, Polysorbate 20, Sodium hydroxide and Hydrochloric acid.
PHARMACOLOGY: Pharmacodynamics: Menotrophin (Human Menopausal Gonadotrophin, HMG) is a gonadotrophin extracted from the urine of postmenopausal women. It has both luteinising hormone and follicle stimulating hormone activity in a 1:1 ratio. Human Chorionic Gonadotrophin (hCG), a naturally occurring hormone in postmenopausal urine, is present in IVF-M HP and is the main contributor of the LH activity.
In the ovaries, the FSH-component in HMG induces an increase in the number of growing follicles and stimulates their development. FSH increases the production of oestradiol in the granulosa cells by aromatising androgens that originate in the Theca cells under the influence of the LH-component. Follicular growth can be stimulated by FSH in the total absence of LH, but the resulting follicles develop abnormally and are associated with low oestradiol levels and inability to luteinize to a normal ovulatory stimulus.
In line with the action of LH activity in enhancing steroidogenesis, oestradiol levels associated with treatment with HMG are higher than with recombinant FSH preparations in downregulated IVF/ICSI cycles. This issue should be considered when monitoring patient's response based on oestradiol levels.
Pharmacokinetics: 8 female rats were given a single subcutaneous injection of IVF-M HP at a dose level of 50 IU/kg body weight, and blood was serially taken up to 48 hours. The serum FSH concentration Cmax (mean ± SD) was 60.94 ± 14.12 mIU/mL and the area under the curve (AUCt) of FSH concentration was (mean ± SD) 1327.6 ± 271.6 mIU∙hr/mL. Median Tmax of FSH concentrations was 8 hours. FSH was eliminated with a half-life (T½) (mean ± SD) of 9.9 ± 0.6 hours.
Treatment of female infertility in the following groups of patients: 1. Anovulation (including WHO Group Ⅱ) in women who have been unresponsive to treatment with clomiphene citrate.
2. Women undergoing controlled ovarian hyperstimulation for multiple follicular development for assisted reproductive technologies (ART).
RECOMMENDED DOSE: 1. Anovulation (including WHO Group Ⅱ) in women who have been unresponsive to treatment with clomiphene citrate: The treatment should be started within the initial 7 days of the menstrual cycle. IVF-M HP may be given daily by subcutaneous injection to provide a dose of 75 IU for 7 days to maximum 12 days until an adequate response is achieved based on estradiol level (Serum estradiol level 1.1~2.9 nMol/L = 300~800 pg/mL) and maturation of follicles (Diameter ≤ 18 mm). If serum estradiol levels rise too rapidly (more than twice in 2~3 days) or FSH is given concomitantly, the dose should be decreased. If the ovaries do not respond, discontinue the treatment or the dosage can be increased to 150 IU per day. Treatment with the previous dosage may be repeated at least twice, before increase the dosage to 150 IU per day. When an optimal response is obtained, administration of IVF-M HP is stopped. A single injection of 5,000 IU to 10,000 IU of human chorionic gonadotrophin (hCG) should be given 1 day after the last IVF-M HP injection. If the ovaries are abnormally enlarged on the last day of the treatment, hCG injection should be withheld. It will minimize the incidence of Ovarian Hyperstimulation Syndrome (OHSS).
2. Women undergoing controlled ovarian hyperstimulation for multiple follicular development for assisted reproductive technologies (ART): In a protocol using down-regulation with a Gonadotrophin-releasing hormone (GnRH) agonist or antagonist, the recommended initial dose of IVF-M HP is 225 IU daily. Based on clinical monitoring (including serum estradiol levels and ovarian ultrasound) subsequent dosing should be adjusted according to individual patient response.
Usually IVF-M HP therapy starts on day 2 or 3 of the menstrual cycle with 150~300 IU daily until an adequate maturation of follicles is obtained. Generally adequate development of follicle is achieved around 10th day of treatment (Treatment period is approximately 5~20 days). Dose adjustment should not be made more frequently than once every two days and should not exceed more than 150 IU per adjustment. The maximum daily dose given should not be higher than 450 IU and dosing beyond 20 days in a treatment cycle is not recommended. If FSH is given concomitantly, the dose should be decreased.
When adequate response is obtained, 24~48 hours after the last IVF-M HP injection, 5,000~10,000 IU hCG should be administered to induce final follicular maturation. Ovulation occurs after 32~48 hours. The patient is recommended to have coitus every day from the day of hCG administration until the day of expecting ovulation. If there is evidence of ovulation but not pregnant, repeat the previous treatment cycle for at least twice before increasing the dosage.
MODE OF ADMINISTRATION: The powder must be reconstituted with the solvent provided prior to use and injected subcutaneously. Use immediately after reconstitution and discard the unused material.
Preparation process: 1) Withdraw 1.0 mL of the solvent from the vial.
2) Inject into the vial containing the powder.
3) Roll the vial gently between the hands until the solution is clear. Do not shake.
4) Draw up the solution from the vial into syringe.
5) Administer the solution immediately.
OVERDOSE AND TREATMENT: The effect of overdose is unknown, nevertheless one could expect ovarian hyperstimulation syndrome to occur, which is categorized as mild, moderate or severe. Symptoms usually appear 3~6 days after treatment with hCG.
1) Mild hyperstimulation: Symptoms: Abdominal swelling and pain, ovaries enlarged to about 5cm diameter.
Therapy: Rest, careful observation and symptomatic relief. Ovarian enlargement declines rapidly.
2) Moderate hyperstimulation: Symptoms: Pronounced abdominal distension and pain, nausea, vomiting, occasional diarrhea, ovaries enlarged up to 12cm diameter.
Therapy: Pelvic examination of enlarged ovaries should be gentle in order to avoid rupture of the cysts. Rest and close observation to detect any progression. Symptoms subside spontaneously over 2~3 weeks.
3) Severe hyperstimulation: Symptoms: Pronounced abdominal distension and pain, pleural effusion, ascites, decreased blood volume, reduced urine output, electrolyte imbalance and sometimes shock, ovaries enlarge to in excess of 12cm diameter.
Therapy: Hospitalization and treatment should be conservative and concentrate on restoring blood volume and preventing shock. Acute symptoms subside over several days and ovaries return to normal over 20~40 days if conception does not occur. But symptoms may be prolonged if conception occurs.
This product is contraindicated in patients with: 1) Hypersensitive to the active substance or any of the ingredients used in this product.
2) Pregnancy and lactation.
3) Ovarian cysts or enlarged ovaries not due to polycystic ovary syndrome.
4) Gynaecological haemorrhage of unknown aetiology.
5) Ovarian, uterine or mammary carcinoma.
6) OHSS (If severe OHSS occurs, treatment should be stopped immediately).
7) Venous or arterial thromboembolism or medical history of this disease.
8) Infertile except for anovulation unless undergoing IVF (in vitro fertilization).
9) A high FSH level (indicating primary ovarian failure).
10) Hereditary problem regarding lactose, for example, galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption.
11) Tumours of the pituitary gland or hypothalamus.
1) IVF-M HP treatment should be precluded in which a satisfactory outcome cannot be expected, for example, ovarian dysgenesis, absent uterus, premature menopause or tubal occlusion.
2) Before starting treatment, patient should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinemia, or pituitary tumour, and appropriate specific treatment given first.
3) Evaluation of the partner's semen analysis should be available before IVF-M HP treatment.
4) In patients with amenorrhea and anovulation, adherence to recommended dosage, regimen of administration and careful monitoring of therapy will minimize the incidence of ovarian hyperstimulation. Excessive estrogenic responses to IVF-M HP seldom give rise to significant side effects unless hCG is administered to trigger ovulation. In case of high estrogen level and excessive follicular development, withheld administration of IVF-M HP and hCG and advise the patient to refrain from coitus or to use barrier methods for at least 4 days.
5) In patients with amenorrhea and anovulation, the incidence of multiple births following IVF-M HP and hCG treatment has been reported to be 10~40%, the majority of them being twins. In patients undergoing ART procedures the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the age of the patient.
Some patients undergoing assisted reproductive technology with a history of tubal disease are at risk of ectopic pregnancy. The relationship between IVF-M HP treatment and ectopic pregnancy has not been established.
The incidence of pregnancy wastage by miscarriage or abortion is higher than in the normal population but comparable in women with other fertility problems. The prevalence of congenital abnormalities is not increased by IVF-M HP.
6) IVF-M HP should only be used by physicians who are thoroughly familiar with infertility problems and their management. Since the product is capable of causing mild to moderate adverse reaction, patients should be appropriately monitored.
Adherence to recommended dosage and careful monitoring of therapy will minimize the incidence of ovarian hyperstimulation and multiple pregnancy.
I. Ovarian Hyperstimulation may occur: Ovarian Enlargement: Mild to moderate ovarian enlargement which may be accompanied by abdominal distension and abdominal pain occurs in approximately 20% of women treated with IVF-M HP and hCG, and generally regresses naturally within two or three weeks. The lowest effective dose in relation to the treatment objective should be used and careful monitoring of the ovarian response is required to avoid such events. If abnormal ovarian enlargement occurs on the last day of IVF-M HP treatment, hCG should not be administered in order to minimize the risk of developing Ovarian Hyperstimulation Syndrome (OHSS).
Ovarian Hyperstimulation Syndrome (OHSS): OHSS may progress rapidly to become a serious medical event. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and rarely, in the pericardial cavities. The early warning signs of development of OHSS are severe pelvic pain, nausea, vomiting, and weight gain.
The following symptoms may be observed: abdominal pain, abdominal distension, severe ovarian enlargement, weight gain, dyspnea, oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhea, hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress, and thromboembolic events.
When treated with this product, severe OHSS occurs in approximately 6% of anovulatory patients and 0.25% of patients undergoing in vitro fertilization.
As OHSS may progress rapidly, patients should be followed for at least two weeks after the hCG administration. Most often, OHSS occurs after the treatment has been discontinued and reaches its maximum severity at about 7~10 days following treatment. Usually OHSS resolves spontaneously with the onset of menses. If there is evidence that OHSS may be developing prior to hCG administration, the hCG administration should be withheld. If severe OHSS occurs, gonadotrophin treatment should be stopped and the patient hospitalised and specific therapy for OHSS such as rest, fluid and electrolyte management, and analgesics started.
In ART, aspiration of all follicles prior to ovulation may reduce the occurrence of hyperstimulation. OHSS may be more severe and more protracted if pregnancy occurs. This syndrome occurs with higher incidence in patients with polycystic ovary syndrome (PCOS).
If the phenomenon of hemoconcentration associated with fluid loss occurs, intake and output of body fluid, weight, hematocrit, serum and urinary electrolytes, urine specific gravity, BUN and creatinine, and abdominal girth should be assessed daily or often.
A risk of injury to the ovary increases with OHSS. Pelvic examination should be avoided as it can cause rupture of the ovarian cyst, resulting in a hemoperitoneum. If bleeding occurs, the surgical intervention should be considered to retain ovarian tissue. In case of significant ovarian enlargement after ovulation, intercourse is prohibited because of the risk of hemoperitoneum caused by rupture of an ovarian cyst.
The management of OHSS is divided into three phases. Because the use of diuretics can accelerate the hypovolemia, it should be avoided except in the late phase of convalescence.
1. Acute phase: Prevent hemoconcentration, thromboembolic phenomena, and kidney damage. Control reduced blood volume and normalizes electrolytes. Watch out for the development of hyperkalemia.
2. Chronic phase: After the acute phase is successfully managed as previously mentioned, excessive fluid accumulation in abdominal cavity, thoracic cavity, and pericardium should be limited by instituting high potassium, high sodium, and fluid restriction.
3. Resolution phase: As body fluid returns from abdominal cavity, thoracic cavity, and pericardium to intravenous compartment, a fall in hematocrit and increasing urinary output may be observed. Because peripheral pulmonary edema may result in case the kidneys are unable to excrete the fluid rapidly, if necessary, diuretics can be used.
II. Pulmonary and vascular complications may occur (atelectasis, acute respiratory distress syndrome, thromboembolic events both in association with and without OHSS): This can lead to venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke), arterial occlusion and loss of limb. Very rarely can lead to death.
III. Multiple birth related with this drug has been reported: In the clinical trial, single birth occurred in 79.2% and multiple birth (mainly twins) occurred in 20.8% of total pregnancies. The patient should be advised of the potential risk of multiple births before starting treatment.
IV. Hypersensitive/Anaphylaxis reaction has been reported regarding this drug: These reactions typically included urticaria, facial edema, angioneurotic edema, and dyspnea from laryngeal edema. The relationship between these symptoms and proteinuria has not been established.
General precautions: This product should be used under the medical and biological supervision.
Not for use in the treatment of amenorrhea if pregnancy is not desired.
Before starting treatment, the patients should be evaluated and precluded for anatomical abnormality of the reproductive system (primary ovarian failure) or other hormonal disorders (thyroid, adrenal, diabetes, etc.).
Response is monitored by measuring the serum estradiol levels and by ovarian ultrasound during ovulation induction with hCG following IVF-M HP treatment. Such direct monitoring will minimize the risk of OHSS and multiple pregnancy, and it is useful to monitor the follicular maturation and development, and to determine the timing of hCG administration. Also, indirect parameters as follows may be combined: Examinations of changes in the vaginal cytology, appearance and volume of the cervical mucus, spinnbarkeit, ferning of cervical mucus.
The clinical confirmation of ovulation is obtained by direct or indirect indices of progesterone production such as a rise in basal body temperature, increase in serum progesterone, and menstruation following the shift in basal body temperature. Additionally, fluid in the cul-de-sac, ovarian sign, collapsed follicle, secretory endometrium can be the evidence of ovulation by the ultrasound examination.
Before starting treatment, patients should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinemia and pituitary or hypothalamic tumours, and appropriate specific treatment given.
There is considerable inter-patient variability in response to menotrophin administration.
There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for infertility treatment. It is not yet established if treatment with gonadotrophins increases the baseline risk of these tumours in infertile women.
Women with generally recognised risk factors for thromboembolic events, such as personal or family history, severe obesity (Body Mass Index ≥ 30kg/m2) or thrombophilia may have an increased risk of venous or arterial thromboembolic events, during or following treatment with gonadotrophin. In these women, the benefits of gonadotrophin administration need to be weighed against the risks. It should be noted however, that pregnancy itself also carries an increased risk of thromboembolic events.
Use in Pregnancy: The incidence of pregnancy wastage by miscarriage or abortion caused by this product is comparable in women with other fertility problems.
Multiple pregnancy, especially high order, carries an increased risk of adverse maternal and perinatal outcomes.
1) This product should not be given during pregnancy or to lactating mothers.
2) The relationship between treatment of luteinizing hormone and the birth of congenitally defective child has not been established yet. But according to the epidemiological investigation, between the women who had delivered babies with congenital defects in heart and limbs and so on and the control group, there was a significant difference in the frequency of use of LH and/or LH∙FSH during the early stage of pregnancy.
3) The prevalence 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 multiple pregnancies.
The incidence of pregnancy wastage by miscarriage or abortion caused by this product is comparable in women with other fertility problems.
Multiple pregnancy, especially high order, carries an increased risk of adverse maternal and perinatal outcomes.
1) Skin: a local reaction at the injection site (pain, itchiness, swelling or redness), rash, anaphylaxis, shock, acne.
2) Hypersensitivity: urticaria, facial edema, angioneurotic edema, and dyspnea from laryngeal edema may occur.
3) Genitourinary: OHSS, multiple pregnancy, ovarian enlargement, ovarian cyst, breast pain, ovarian torsion.
4) Cardiovascular: Cerebral thrombosis, thromboembolism, hypotension, hemoconcentration, tachycardia.
5) Respiratory: Hydrothorax, dyspnea, tachypnea.
6) Gastrointestinal: Nausea, vomiting, diarrhea, abdominal cramps, abdominal distension, abdominal pain, abdominal discomfort.
7) Nervous system: Dizziness, headache, malaise.
8) Others: Abortion, pyrexia, pelvic pain, arthralgia, lower abdominal pain, ascites, oliguria, occasional pain after treatment, long-term use of menotrophin can lead to the formation of antibodies in very rare cases, excessive increase of serum estradiol levels (If there is any steep rise in values, treatment should be immediately discontinued and hCG withheld), hemoperitoneum, fatigue, musculoskeletal pain, facial blush (hot flush), visual disorders.
In case this product is given to induce ovulation concomitantly with or subsequently to the ovarian stimulating hormone, excessive ovarian reaction such as Meigs syndrome accompanied by ovarian enlargement, rupture of the enlarged ovary, ascites, and hydrothorax may occur. Furthermore, thrombosis and cerebral infarction may occur due to hemoconcentration and hypercoagulation.
Do not store above 30℃. Protect from light.
SHELF-LIFE: 24 months.
G03GA02 - human menopausal gonadotrophin ; Belongs to the class of gonadotropins. Used as ovulation stimulants.
Sign Out
