Ovidrel - Product Information
|Manufacture:||EMD Serono, Inc|
|Condition:||Female Infertility, Hypogonadism, Male, Ovulation Induction, Prepubertal Cryptorchidism|
|Form:||Liquid solution, Subcutaneous (SC)|
|Ingredients:||choriogonadotropin alfa, mannitol, phosphoric acid, methionine, poloxamer 188, sodium hydroxide, water.|
Action and Clinical Pharmacology
Ovidrel (choriogonadotropin alpha) is a sterile solution in pre-filled syringe or in pre-filled pen for injection preparation of choriogonadotropin alpha (recombinant human Chorionic Gonadotrophin, r-hCG). The drug substance is produced by recombinant DNA techniques. Choriogonadotropin alpha is a water soluble glycoprotein consisting of two non-covalently linked subunits - designated α and β - consisting of 92 and 145 amino acid residues, respectively, with carbohydrate moieties linked to ASN-52 and ASN-78 (on alpha subunit) and ASN-13, ASN-30, SER-121, SER-127, SER-132 and SER-138 (on beta subunit). The primary structure of the α- chain of r-hCG is identical to that of the α−chain of hCG, FSH and LH. The glycoform pattern of the α-subunit of r-hCG is closely comparable to urinary derived hCG (u-hCG), the differences mainly being due to the branching and salicylation extent of the oligosaccharides. The β- chain has both O- and N-glycosylation sites and its structure and glycosylation pattern are also very similar to that of u-hCG.
The production process involves expansion of genetically modified Chinese Hamster Ovary (CHO) cells from an extensively characterized cell bank into large scale cell culture processing. Choriogonadotropin alpha is secreted by CHO cells directly into the cell culture medium, which is then purified using a series of chromatographic steps. This process yields a product with a high level of purity and consistent product characteristics including glycoforms and biological activity. The biological activity of choriogonadotropin alpha is determined using the seminal vesicle weight gain test in male rats described in the Chorionic Gonadotrophins monograph of the European Pharmacopoeia. The in vivo biological activity of choriogonadotropin alpha has been calibrated against the third international reference preparation IS75/587 for chorionic gonadotrophin.
The physicochemical, immunological, and biological activities of recombinant hCG are comparable to those of placental and human pregnancy urine-derived hCG. Choriogonadotropin alpha stimulates late follicular maturation and resumption of oocyte meiosis, and initiates rupture of the pre-ovulatory ovarian follicle. Choriogonadotropin alpha, the active component of Ovidrel, is an analogue of Luteinizing Hormone (LH) and binds to the LH/hCG receptor of the granulosa and theca cells of the ovary to effect these changes in the absence of an endogenous LH surge. In pregnancy, hCG, secreted by the placenta, maintains the viability of the corpus luteum to provide the continued secretion of estrogen and progesterone necessary to support the first trimester of pregnancy. Ovidrel is administered when monitoring of the patient indicates that sufficient follicular development has occurred in response to follicle stimulating agent treatment for ovulation induction.
Indications and Clinical Use
Ovidrel (choriogonadotropin alpha) is indicated for the induction of ovulation (OI) and pregnancy in patients undergoing fertility treatment in whom the cause of infertility is functional and not due to primary ovarian failure.
Selection of Patients:
- Before treatment with gonadotrophins is instituted, a thorough gynecologic and endocrinologic evaluation must be performed. This should include an assessment of pelvic anatomy. Patients with tubal obstruction should receive Ovidrel only if enrolled in an in vitro fertilization program.
- Primary ovarian failure should be excluded by the determination of gonadotrophin levels.
- Appropriate evaluation should be performed to exclude pregnancy.
- Women in later reproductive life have a greater predisposition to endometrial carcinoma as well as a higher incidence of anovulatory disorders. A thorough diagnostic evaluation should always be performed in patients who demonstrate abnormal uterine bleeding or other signs of endometrial abnormalities before starting follicle stimulating agent and Ovidrel therapy.
- Evaluation of the partner’s fertility potential should be included in the initial evaluation.
Ovidrel (choriogonadotropin alpha) is contraindicated in women who exhibit:
- Hypersensitivity to choriogonadotropin alpha or to any of the excipients
- Primary ovarian failure.
- Uncontrolled thyroid or adrenal dysfunction.
- Tumours of the hypothalamus and pituitary gland.
- Abnormal uterine bleeding of undetermined origin (see Selection of Patients).
- Ovarian enlargement or cyst of unknown aetiology (see Selection of Patients).
- Ovarian, uterine or mammary cancer.
Gonadotrophins, including Ovidrel (choriogonadotropin alpha), should only be used by physicians who are thoroughly familiar with infertility problems and their management. Like other hCG products, Ovidrel is a potent gonadotrophic substance capable of causing Ovarian Hyperstimulation Syndrome (OHSS) in women with or without pulmonary or vascular complications. Gonadotrophin therapy requires a certain time commitment by physicians and supportive health professionals, and requires the availability of appropriate monitoring facilities (see Precautions: Laboratory Tests). Safe and effective induction of ovulation and use of Ovidrel in women requires monitoring of ovarian response with serum estradiol and transvaginal ultrasound on a regular basis.
Overstimulation of the Ovary Following hCG Therapy
Mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distention and/or abdominal pain may occur in patients treated with follicle stimulating agents and hCG, and generally regresses without treatment within two or three weeks. Careful monitoring of ovarian response can further minimize the risk of overstimulation. If the ovaries are abnormally enlarged on the last day of follicle stimulating agent therapy, choriogonadotropin alpha may be withheld in this course of therapy. This will reduce the risk of development of Ovarian Hyperstimulation Syndrome.
Ovarian Hyperstimulation Syndrome (OHSS)
A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in women with polycystic ovarian syndrome and usually regresses without treatment.
OHSS is a medical event distinct from uncomplicated ovarian enlargement. Mild manifestations of OHSS may include abdominal pain, abdominal discomfort and distension, or enlarged ovaries. Moderate OHSS may additionally present with nausea, vomiting, ultrasound evidence of ascites or marked ovarian enlargement.
Severe OHSS further includes symptoms such as severe ovarian enlargement, weight gain, dyspnoea or oliguria. Severe OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event. It is characterized by an increase in vascular permeability, which can result in a rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the pericardium.
Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events, such as pulmonary embolism, ischaemic stroke or myocardial infarction. Severe OHSS is potentially life-threatening.
Independent risk factors for developing OHSS include young age (age<30 years of age), lean body mass, polycystic ovarian syndrome, higher doses of exogenous gonadotropins, high absolute or rapidly rising serum oestradiol levels and previous episodes of OHSS, large number of developing ovarian follicles and large number of oocytes retrieved in ART cycles.
Adherence to recommended Ovidrel dosage and regimen of administration can minimise the risk of ovarian hyperstimulation. Monitoring of stimulation cycles by ultrasound scans as well as oestradiol measurements are recommended to identify risk factors early.
There is evidence to suggest that hCG plays a key role in triggering OHSS and that the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarian hyperstimulation occur, it is recommended that hCG be withheld and the patient be advised to refrain from coitus or use barrier contraceptive methods for at least 4 days. OHSS develops rapidly; therefore, patients should be followed for at least two weeks after hCG administration. Most often, OHSS occurs after treatment has been discontinued and reaches its maximum severity at seven to ten 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, hCG must be withheld.
When significant risk of OHSS or multiple pregnancies is likely, treatment discontinuation is advised.
If severe OHSS occurs, treatment with gonadotropins must be stopped and the patient should be hospitalized.
A physician who is experienced in the management of fluid/electrolyte imbalances and/or OHSS should be consulted.
Pulmonary and Vascular Complications
As with other hCG products, a potential for the occurrence of arterial thromboembolism exists. In women with recent or ongoing thromboembolic disease or with generally recognized risk factors for thromboembolic events, such as personal or family history, treatment with gonadotrophins may further increase the risk. In these women, the benefits of gonadotrophin administration need to be weighed against the risks. It should be noted however, that pregnancy itself as well as OHSS also carry an increased risk of thromboembolic events.
As with other hCG products, reports of multiple births have been associated with Ovidrel treatment when used in combination with follicle stimulating agents. In patients undergoing induction of ovulation, the incidence of multiple pregnancies and births is increased compared with conception in natural, non stimulated cycles. The risk of multiple births correlates to the number of embryos transferred or mature follicles that develop for ovulation induction. In assisted reproductive technologies (ART) clinical trials, involving in vitro fertilization and embryo transfer in women receiving 250 µg Ovidrel, multiple births occurred in 17 of 55 live deliveries (30.9 %). In the ovulation induction clinical trial, 2 of 15 live deliveries (13.3%) were associated with multiple births in women receiving Ovidrel 250 µg . The patient should be advised of the potential risk of multiple births before starting treatment with follicle stimulating agents and Ovidrel.
Careful attention should be given to the diagnosis of infertility in candidates for hCG therapy (see Indications and Clinical Use/Selection of Patients). After the exclusion of pre-existing conditions, elevations in ALT were found in 10 (3%) of 335 patients receiving Ovidrel (chorigonadotrophin alpha) 250 µg, 9 (10%) of 89 patients receiving Ovidrel 500 µg and in 16 (4.8%) of 328 patients receiving urinary-derived hCG. The elevations ranged up to 1.2 times the upper limit of normal. The clinical significance of these findings is not known.
Information for Patients
Prior to therapy with hCG, patients should be informed:
- Of the duration of treatment and monitoring of their condition that will be required
- Of their personal risk of ovarian hyperstimulation syndrome
- That there is a potential risk of multiple births
- That there is a potential for a false positive pregnancy test for the 10 days following administration of hCG
In most instances, treatment of women with follicle stimulating agents results only in follicular recruitment and development. In the absence of an endogenous LH surge, hCG is given when monitoring of the patient indicates that sufficient follicular development has occurred. This may be estimated by ultrasound alone or in combination with measurement of serum estradiol levels. The combination of both ultrasound and serum estradiol measurement are useful for monitoring the development of follicles, for timing of the ovulatory trigger, as well as for detecting ovarian enlargement and minimizing the risk of the Ovarian Hyperstimulation Syndrome and multiple gestation. It is recommended that the number of growing follicles be confirmed using ultrasonography because serum estrogen levels do not give an indication of the size or number of follicles.
Human chorionic gonadotrophins can cross-react in the radioimmunoassay of gonadotrophins, especially luteinizing hormone. Each individual laboratory should establish the degree of cross-reactivity with their gonadotrophin assay. Physicians should make the laboratory aware of patients on hCG if gonadotrophin levels are requested.
The clinical confirmation of ovulation, with the exception of pregnancy, is obtained by direct and indirect indices of progesterone production. The indices most generally used are as follows:
- A rise in basal body temperature
- Increase in serum progesterone and
- Menstruation following a shift in basal body temperature
When used in conjunction with the indices of progesterone production, sonographic visualization of the ovaries will assist in determining if ovulation has occurred. Sonographic evidence of ovulation may include the following:
- Fluid in the cul-de-sac
- Ovarian stigmata suggestive of a corpus luteum
- Collapsed follicle
Accurate interpretation of the indices of ovulation requires a physician who is experienced in the interpretation of these tests.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term studies to evaluate the carcinogenic potential of Ovidrel in animals have not been performed. In-vitro genotoxicity testing of Ovidrel in bacteria and mammalian cell lines, chromosome aberration assay in human lymphocytes and in-vivo mouse micronucleus have shown no indication of genetic defects.
No clinical data on exposed pregnancies are available. No reproduction studies with choriogonadotropin alpha in animals were performed. The rate of miscarriage, in both anovulatory patients and women undergoing assisted reproductive techniques, is higher than that found in the normal population but comparable with the rates observed in women with other fertility problems.
It is not known whether this drug is excreted in human milk. Ovidrel is not indicated during breastfeeding.
Ovidrel is only intended for use in female patients of reproductive age, therefore, safety and effectiveness in pediatric patients has not been established.
Ovidrel is only intended for use in female patients of reproductive age, therefore, safety and effectiveness in geriatric patients has not been established.
No clinically significant drug interactions have been reported during hCG therapy. Following administration, Ovidrel may interfere for up to ten days with the immunological determination of serum / urinary hCG, leading to a false positive pregnancy test.
The safety of Ovidrel (choriogonadotropin alpha) was examined in four clinical studies that treated 752 patients of whom 335 received Ovidrel 250 µg following follicular recruitment with gonadotrophins. When patients enrolled in four clinical studies (1 in ovulation induction and 3 in assisted reproductive technologies) were injected subcutaneously with either Ovidrel or an approved urinary-derived hCG, 14.6 % (49 of 335 patients) in the Ovidrel 250 µg group experienced application site disorders compared to 28% (92 of 328 patients) in the approved u-hCG group. Adverse events reported for Ovidrel 250 µg occurring in at least 2% of patients (regardless of causality) are listed in Table 1 for the single OI study.
|OVIDREL 250 µg (n=99)
Incidence Rate % (n)
|At Least One Adverse Event||26.2% (26)|
|Application site disorders||16.2% (16)|
|Injection site pain||8.1% (8)|
|Injection site bruising||3.0% (3)|
|Injection site inflammation||2.0% (2)|
|Injection site reaction||3.0% (3)|
|Gastro-intestinal system disorders||4.0% (4)|
|Abdominal pain||3.0% (3)|
|Reproductive disorders, female||7.1% (7)|
|Ovarian cyst||3.0% (3)|
|Ovarian hyperstimulation||3.0% (3)|
Additional adverse events not listed in Table 1 that occurred in less than 2% of patients treated with Ovidrel 250 µg, whether or not considered causally related to Ovidrel, included: breast pain, flatulence, abdominal enlargement, pharyngitis, upper respiratory tract infection, hyperglycemia and pruritis.
In three studies involving 236 patients treated with Ovidrel 250 µg and undergoing assisted reproductive technologies (Studies 7648, 7927 and 9073 - Chang, 2001), at least one adverse event was observed in 78 patients (33.1%). Application site disorders occurred in 14.0% of patients, which included injection site pain in 7.6% and injection site bruising in 4.7% of subjects. Twenty patients (8.5%) experienced gastro-intestinal system disorders, and these events included abdominal pain (4.2%), nausea (3.4%) and vomiting (2.5%). Post-operative pain was noted by 4.7% of patients participating in the studies. Adverse events that occurred in less than 2% of patients treated with Ovidrel 250 µg, whether or not considered causally related to Ovidrel, included: injection site inflammation and reaction, flatulence, diarrhea, hiccup, ectopic pregnancy, breast pain, intermenstrual bleeding, vaginal hemorrhage, vaginal discharge, cervical lesion, ovarian hyperstimulation, uterine disorders, vaginitis, vaginal discomfort, body pain, back pain, fever, dizziness, headache, hot flashes, malaise, paraesthesia, rash, emotional lability, insomnia, upper respiratory tract infection, cough, dysuria, urinary tract infection, urinary incontinence, albuminuria, cardiac arrhythmia, genital moniliasis, genital herpes, leukocytosis, heart murmur and cervical carcinoma.
The following medical events have been reported subsequent to pregnancies resulting from hCG therapy in controlled clinical studies:
- Spontaneous Abortion
- Ectopic Pregnancy
- Premature Labor
- Postpartum Fever
- Congenital abnormalities
Of 125 clinical pregnancies reported following treatment with FSH and Ovidrel 250 µg or500 µg, three were associated with a congenital anomaly of the fetus or newborn. Among patients receiving Ovidrel 250 µg, cranial malformation was detected in the fetus of one woman and a chromosomal abnormality (47, XXX) in another. These events were judged by the investigators to be of unlikely or unknown relation to treatment. These three events represent an incidence of major congenital malformations of 2.4%, which is consistent with the reported rate for pregnancies resulting from natural or assisted conception. In a woman who received Ovidrel 500 µg, one birth in a set of triplets was associated with Down’s syndrome and atrial septal defect. This event was considered to be unrelated to the study drug.
The following adverse reactions have been previously reported during gonadotrophin or menotropin therapy:
- Pulmonary and vascular complications (see Warnings)
- Adnexal torsion (as a complication of ovarian enlargement)
- Mild to moderate ovarian enlargement
There have been infrequent reports of ovarian neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for ovulation induction; however, a causal relationship has not been established. During Ovidrel therapy, a minor thyroid stimulation is possible, of which the clinical relevance is unknown. Ectopic pregnancy, ovarian torsion and other complications have been reported in patients after hCG administration. These are considered concomitant effects related to Assisted Reproductive Technologies (ART).
Ovidrel is used to trigger final follicular maturation and luteinisation for ART, and to achieve ovulation in OI, after use of medicinal products for the stimulation of follicular growth. In this context, it is difficult to attribute undesirable effects to any one of the products used.
After best evidence assessment, the following undesirable effects may be observed after administration of Ovidrel
(i) Common (>1/100, < 1/10)
- Application site disorders: Local reaction/pain at injection site
- General disorders: Headache, tiredness
- Gastro-intestinal system disorders: Vomiting/nausea, abdominal pain
- Reproductive disorders: Mild or moderate ovarian hyperstimulation syndrome
(ii) Uncommon (>1/1000, <1/100)
- Reproductive disorders: Severe ovarian hyperstimulation syndrome, Breast pain
Adverse Reactions Identified During Post-marketing Surveillance
Immune system disorders: allergic reactions.
Skin and subcutaneous disorders: Mild reversible skin reactions manifesting as rash.
Vascular disorders: very rare (1/10,000) thromboembolism, usually associated with moderate to severe OHSS.
Symptoms and Treatment of Overdosage
No case of overdosage has been reported. Nevertheless, there is a possibility that Ovarian Hyperstimulation Syndrome (OHSS) may result from an overdosage of Ovidrel (choriogonadotropin alpha) (see Warnings).
For management of a suspected drug overdose, contact your regional Poison Control Centre.
Dosage and Administration
Ovidrel (choriogonadotropin alpha) should not be administered until adequate follicular development is indicated by serum estradiol and/or vaginal ultrasonography.
Ovidrel 250 µg should be administered subcutaneously one day following the last dose of the follicle stimulating agent. Ovidrel administration should be withheld in situations where there is an excessive ovarian response, as evidenced by multiple follicular development, clinically significant ovarian enlargement or excessive estradiol production.