Consumer medicine information

Ovidrel

Choriogonadotropin alfa

BRAND INFORMATION

Brand name

Ovidrel Pen

Active ingredient

Choriogonadotropin alfa

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ovidrel.

What is in this leaflet

This leaflet answers some common questions about OVIDREL.

It does not contain all of the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you using OVIDREL against the benefits it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this information with your medicine. You may want to read it again later.

What OVIDREL is used for

OVIDREL belongs to a family of hormones known as gonadotrophins, which are involved in the normal control of reproduction.

The active substance of OVIDREL is choriogonadotropin alfa that is produced in mammalian cells modified by recombinant DNA technology.

OVIDREL is used in women undergoing assisted reproductive techniques such as in vitro fertilisation (IVF). Other medicines are given first to bring about the growth and development of several follicles to produce eggs. Follicles are the structures in your ovaries that contain the egg. OVIDREL is then used to ripen (mature) these follicles.

OVIDREL is also used in women who do not produce eggs (anovulation), or who produce too few eggs (oligo-ovulation). It is used to trigger the release of eggs (ovulation), after other medicines have been used to develop the follicles.

Your doctor may prescribe OVIDREL for another reason.

Ask your doctor if you have any questions about why OVIDREL has been prescribed for you.

OVIDREL is not addictive.

This medicine is available only with a doctor's prescription.

Before you use OVIDREL

When you must not use it

Do not use OVIDREL if:

  • you have a history of allergy to choriogonadotropin alfa, or a similar medicine, or any other inactive ingredients (listed at the end of this leaflet).
    Symptoms of an allergic reaction to OVIDREL may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

Do not take OVIDREL if you have, or have had, any of the following medical conditions:

  • your ovaries are unable to be stimulated to produce eggs (primary ovarian failure or premature menopause)
  • uncontrolled thyroid or adrenal gland disease
  • a tumour of the hypothalamus or pituitary gland
  • ovarian enlargement or one or more large ovarian cysts
  • cancer of your ovaries, uterus (womb) or breasts
  • fibroid tumours in your uterus which would make pregnancy impossible
  • if you have been through menopause

OVIDREL should not be used in the elderly or in children.

Do not take OVIDREL after the expiry date printed on the pack. Do not take OVIDREL if the packaging is torn or shows signs of tampering. If your medicine has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start using OVIDREL, contact your doctor.

Before you start to use it

Your doctor will assess you and your partner's infertility. This may include tests for other medical conditions, which may interfere with your ability to become pregnant. If necessary, other medical conditions may be treated before starting infertility treatments and OVIDREL.

Tell your doctor if you have or have had any other pre-existing medical conditions. Treatment with OVIDREL may increase your risk of developing a condition called ovarian hyperstimulation syndrome (OHSS). This is when the ovaries over react to the hormonal treatment and develop too many follicles. The most common symptom is stomach pain. During stimulation your doctor will monitor your treatment by use of ultrasound and blood tests to measure oestrogen levels. This will help to indicate if you are likely to develop OHSS. If necessary, your doctor will delay or cancel your OVIDREL injection.

Compared to natural conception, the frequency of multiple pregnancies and births is increased in patients receiving this treatment. The majority of these are twins. In assisted reproduction techniques, the number of babies is related to the number of embryos replaced. Please discuss with your doctor.

There may be a slightly increased risk of birth defects in women using assisted reproductive technologies. This may be due to maternal age, genetic factors, multiple pregnancies or the assisted reproductive technologies.

Talk to your doctor about any concerns you may have before undergoing treatment.

Tell your doctor if you or your family have or have had increased risk of developing blood clots e.g. stroke, heart attacks.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without prescription from your pharmacy, supermarket or health food shop.

OVIDREL may interfere with the results of a blood or urinary hCG (pregnancy) test for up to 10 days. This may lead to a false positive pregnancy test.

How OVIDREL is given

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

Treatment with OVIDREL should be started under the supervision of a specialist doctor experienced in fertility treatment.

How much to inject

The dose of OVIDREL is one pre-filled pen (250 microgram in 0.5 mL) given as a single injection after stimulation of follicle growth by other medicines.

Dosage may need to be varied on the instruction of your doctor and you should be confident in your ability to adjust the dose.

Please consult your doctor or pharmacist if you are in any doubt. Your doctor will explain exactly when to give the injection.

Each pre-filled pen is for single use in one patient only. Discard any residue.

How to inject

OVIDREL is given as an injection under the skin (subcutaneously), usually near your stomach.

OVIDREL is intended to be injected by yourself or by your partner.

Your doctor or nurse will instruct and assist you in learning the procedure and technique of self-injection.

Do not attempt self-injection until you are sure of how to do it. Your partner may be trained to give the injection at home.

Your doctor or nurse can also give the injection to you.

Where to inject

OVIDREL is usually given in the stomach area (except around navel and waistline) or the front of your thigh.

Do not inject into any areas in which you feel lumps, firm knots, depressions, pain or discolouration.

Talk to your doctor if you find anything unusual when injecting.

If you forget to inject OVIDREL

You should contact your doctor immediately.

It is important that OVIDREL is injected on the correct day and at the correct time as instructed by your doctor.

You must inform your doctor if your injection was not given when directed.

Ask your doctor if you are not sure what to do or have trouble remembering to inject your medicine.

If you inject too much

Immediately contact your doctor or the Poisons Information Centre (In Australia telephone 131 126. In New Zealand telephone 0800 764 766) if you are concerned that you have given yourself too much OVIDREL.

While you are using OVIDREL

Things you must do

Tell your doctor if you start taking any new medication while using OVIDREL.

Things you must not do

Do not give this medicine to anyone else, even if their symptoms seem similar to yours or if they have the same condition as you.

Do not use OVIDREL to treat any other complaints unless your doctor says to.

Do not stop OVIDREL or change the dose without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how OVIDREL affects you.

Side effects

Tell your doctor as soon as possible if you do not feel well while you are taking OVIDREL.

Tell your doctor immediately if you experience any of the following: Early signs of ovarian hyperstimulation syndrome (OHSS) which includes severe stomach pain, nausea, vomiting, diarrhoea, shortness of breath and low urine production.

Tell your doctor if you notice any of the following and they worry you:

Common side effects:

  • injection site soreness/redness
  • headache
  • tiredness
  • nausea/vomiting, abdominal pain
  • rash

Uncommon side effects:

  • diarrhoea
  • depression
  • irritability
  • restlessness
  • breast pain
  • severe OHSS
  • mild allergic reaction
  • warning signs of blood clots (such as pain, warmth, redness, numbness or tingling in arm or leg)
  • warning signs of stroke or heart attack

Other side effects not listed above may also occur in some patients.

Tell your doctor if you notice anything else that is making you feel unwell. Do not be alarmed by this list of possible side effects. You may not experience any of them.

After using OVIDREL

Storage

Keep this medicine where young children cannot reach it. OVIDREL must be stored at 2°C to 8°C (Refrigerate. Do not freeze) in its original container. Protect from light.

Disposal

After injecting, you should discard the pen even if you have not injected all its contents. Pen and needle should be discarded in an appropriate disposal unit.

Product description

What it looks like

OVIDREL is supplied as solution for injection in a pre-filled pen. It contains no antimicrobial preservative.

Ingredients

Active ingredient:

  • choriogonadotropin alfa

Inactive Ingredients:

  • mannitol
  • monobasic sodium phosphate monohydrate
  • dibasic sodium phosphate dihydrate
  • phosphoric acid
  • sodium hydroxide
  • poloxamer
  • methionine
  • water for injections

Manufacturer/Supplier

OVIDREL is supplied in Australia by:

Merck Healthcare Pty Ltd
Suite 1, Level 1, Building B
11 Talavera Road
Macquarie Park NSW 2113
E-mail: [email protected]
Phone: 1800 633 463

OVIDREL is supplied in New Zealand by:

Healthcare Logistics
58 Richard Pearse Drive
Airport Oaks, Auckland
E-mail: [email protected]
Phone: 0800 426 252

The Australian registration number for:

OVIDREL choriogonadotropin alfa (rch) 250 microgram/0.5mL solution for injection pre-filled pen is AUST R 170446.

This leaflet was amended in March 2020.

A006-0320

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Ovidrel Pen

Active ingredient

Choriogonadotropin alfa

Schedule

S4

 

1 Name of Medicine

Choriogonadotropin alfa (rch).

6.7 Physicochemical Properties

Chemical structure.

Choriogonadotropin alfa is a water soluble glycoprotein consisting of two non-covalently linked subunits - designated alfa (α) and beta (β) consisting of 92 and 145 amino acids residues, respectively, with carbohydrate moieties linked to ASN-52 and ASN-78 (on alfa subunits) and ASN-13, ASN-30, SER-121, SER- 127, SER-132 and SER-138 (on beta subunit). The chemical formula of the proteins are C437H682N122O134S13 [alfa subunit] and C668H1090N196O203S13 [beta subunit]. Molecular weight is 70 kDa.
The primary structure of the α-subunit of the recombinant human chorionic gonadotrophin (r hCG) is identical to that of the α-subunit of the human chorionic gonadotrophin (hCG), follicle stimulating hormone (FSH) and luteinising hormone (LH). The glycoform pattern of the α subunit of r-hCG is closely comparable to the urinary derived hCG (u-hCG), the differences mainly being due to the branching and sialylation extent of oligosaccharides.
The β-subunit has both O- and N-glycosylation sites and its structure and glycosylation pattern are also very similar to that of u-hCG.

CAS number.

CAS number 177073-44-8.
Alfa subunit-(CAS-56832-30-5).
Beta subunit-(CAS-56832-34-9).

2 Qualitative and Quantitative Composition

Ovidrel is a preparation of chorionic gonadotrophin hormone produced by genetically engineered Chinese hamster ovary (CHO) cells. Each pre-filled pen contains choriogonadotropin alfa (rch) (recombinant human chorionic gonadotrophin hormone) 250 microgram in 0.5 mL.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection in pre-filled pen.
Ovidrel is presented as a sterile liquid, single dose pre-filled pen. Contains no antimicrobial preservative.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The physicochemical, immunological and biological activities of recombinant hCG are comparable to those of placental and human pregnancy urine derived hCG. Choriogonadotropin alfa stimulates late follicular maturation and resumption of oocytes meiosis and initiates rupture of the pre-ovulatory ovarian follicle.
Choriogonadotropin alfa, the active component of Ovidrel, is an analogue of LH and binds to the LH/hCG receptor of the granulosa and the 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 corpus luteum after LH secretion decreases and supports continued secretion of oestrogen 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 FSH treatment for ovulation induction.

Clinical trials.

The safety and efficacy of Ovidrel have been evaluated in four well controlled clinical studies in women; three studies for assisted reproductive technologies (ART) and one study for ovulation induction (OI).

(a) Assisted reproductive technologies (ART).

Study 9073.

The safety and efficacy of Ovidrel 250 microgram administered subcutaneously and 5000 IU of an approved urinary derived hCG product administered intramuscularly were assessed in a randomised, controlled, double blind, double dummy, phase III study in infertile women undergoing in vitro fertilisation and embryo transfer. Randomisation occurred at the time of hCG administration.
The primary efficacy parameter in this study was the number of oocytes retrieved per patient. 90 patients entered the study, of whom 44 were randomised to receive Ovidrel 250 microgram. The number of oocytes retrieved was similar in all treatment groups. The efficacy of Ovidrel 250 microgram was found to be clinically and statistically equivalent to the urinary derived hCG product for the primary endpoint of the study. The efficacy results (both primary and secondary) for the patients who received Ovidrel 250 microgram are summarised in Table 6.
The outcomes of the pregnancies are presented in Table 7.
12 of the 44 patients who received hCG reported 13 adverse events after hCG administration. Of the 84 patients, 44 had received 250 microgram of r-hCG and 40 received u-hCG. There was no report of OHSS in this study. Overall, the pattern of adverse events was similar between treatment groups and was consistent with the profile of events reported in this indication. Local tolerance to study drug was also similar and no patient developed antibodies to hCG.

Study 7927.

The safety and efficacy of Ovidrel 250 microgram and Ovidrel 500 microgram administered subcutaneously and 10,000 USP Units of an approved urinary derived hCG product administered intramuscularly were assessed in a randomised, open label, multicentre study in infertile women undergoing in vitro fertilisation and embryo transfer. Randomisation occurred at the time of hCG administration.
The primary efficacy parameter in this single cycle study was the number of oocytes retrieved per patient. 297 patients entered the study, of whom 94 were randomised to receive Ovidrel 250 microgram. The number of oocytes retrieved was similar in all treatment groups. The efficacy of Ovidrel 250 microgram and 500 microgram were both found to be clinically and statistically equivalent to the urinary derived hCG product and to each other for the primary endpoint of the study. The efficacy results (both primary and secondary) for the patients who received Ovidrel 250 microgram are summarised in Table 8.
The outcomes of the pregnancies are presented in Table 9.
132 of the 280 patients who received hCG reported 266 adverse events after hCG administration, including 27 serious adverse events. Of the 132 patients, 44 had received 250 microgram of r-hCG, 51 received 500 microgram of r-hCG and 37 had received u-hCG. 12 of the serious events occurring after hCG occurred before study completion and 12 occurred during pregnancy resulting from treatment. Overall, the pattern of adverse events was similar between treatment groups and was consistent with the profile of events reported in this indication. Local tolerance to study drug was also similar and no patient developed antibodies to hCG.

Study 7648.

The safety and efficacy of Ovidrel 250 microgram administered subcutaneously versus 5000 IU of an approved urinary derived hCG product administered subcutaneously were assessed in a second, double blind, randomised, multicentre study in infertile women undergoing in vitro fertilisation and embryo transfer.
The primary efficacy parameter in this single cycle study was the number of oocytes retrieved per patient. 205 patients entered the study, of whom 97 received Ovidrel 250 microgram. The efficacy of Ovidrel was found to be clinically and statistically equivalent to that of the approved urinary derived hCG. The efficacy results (both primary and secondary) for the 97 patients who received Ovidrel 250 microgram are summarised in Table 10.
The outcomes of the pregnancies are presented in Table 11.
64 of the 190 patients who received hCG reported 97 adverse events after hCG administration, 32 (33%) in the r-hCG group and 65 (67%) in the u-hCG group. There were 11 serious adverse events reported following hCG administration, 5 up to study completion and 6 during pregnancy resulting from treatment. Overall, the pattern of adverse events was similar between treatment groups and was consistent with the profile of events reported in this indication. Local tolerance to study drug was statistically different between treatment groups (p = 0.0001) in favour of the r-hCG treatment group and no patient developed antibodies to hCG.

(b) Ovulation induction (OI).

Study 8209.

The safety and efficacy of Ovidrel 250 microgram administered subcutaneously versus 5000 IU of an approved urinary derived hCG administered subcutaneously were assessed in a double blind, randomised, multicentre study in anovulatory infertile women.
The primary efficacy endpoint in this single cycle study was the patient ovulation rate. 242 patients entered the study, of whom 99 received Ovidrel 250 microgram. The efficacy of Ovidrel 250 microgram was found to be clinically and statistically equivalent to the approved urinary derived hCG. The efficacy results (both primary and secondary) of those patients who received Ovidrel are summarised in Table 12.
The outcomes of the pregnancies are presented in Table 13.
65 of the 198 patients who received hCG reported 100 adverse events after hCG administration. Of the 100 events, 34 (34%) occurred in 26 patients who had received 250 microgram of r-hCG and 66 (66%) occurred in 39 patients who had received u-hCG. 9 serious adverse events occurred in 7 patients after study completion during pregnancy resulting from treatment. Overall, the pattern of adverse events was similar between treatment groups and was consistent with the profile of events reported in this indication. Local tolerance to study drug was statistically different between treatment groups (p = 0.0015) in favour of the r-hCG treatment group.

Primary outcomes.

Primary efficacy endpoints of ART studies are shown in Table 14.
The studies clearly demonstrate equivalence between 250 microgram r-hCG and 5000 IU u-hCG (studies GF 7648 and GF 9073), and between 250 microgram r-hCG, 500 microgram r-hCG, and 10,000 IU u-hCG (study GF 7927) with respect to this endpoint.
Primary efficacy endpoint of ovulation induction study (GF 8209) are shown in Tables 15 and 16.

5.2 Pharmacokinetic Properties

Following intravenous administration, choriogonadotropin alfa is distributed to the extracellular fluid space within a few hours of its injection. There are no indications that choriogonadotropin alfa is metabolised and excreted differently than endogenous hCG. The terminal half-life is slightly longer after subcutaneous injection as compared to intravenous results.

Absorption.

Following subcutaneous administration of Ovidrel 250 microgram, maximum serum concentration (121 ± 44 IU/L) is reached after approximately 12 to 24 hours. The mean absolute bioavailability of Ovidrel after subcutaneous injection to healthy female volunteers is about 40%.

Distribution.

Following intravenous administration of Ovidrel 250 microgram to healthy down-regulated female volunteers, the serum profile of hCG is described by a two compartment model with an initial half-life of 4.5 ± 0.5 hours. The volume of the central compartment is 3.0 ± 0.5 L and the steady state volume of distribution is 5.9 ± 1.0 L.

Metabolism/ excretion.

After intravenous administration of Ovidrel 250 microgram to healthy down-regulated females, the mean terminal half-life is 26.5 ± 2.5 hours and the total body clearance is 0.29 ± 0.04 L/h. One tenth of the dose is excreted in the urine.
Following subcutaneous administration of Ovidrel, hCG is eliminated from the body with a mean terminal half-life of about 38 hours (37.9 ± 3.6 hours for the freeze-dried preparation and 38.2 ± 5.0 for the liquid formulation).

Bioequivalence of formulations.

Ovidrel liquid has been determined to be bioequivalent to Ovidrel freeze-dried formulation based on the statistical evaluation of AUC and Cmax. A summary of the Ovidrel freeze-dried and liquid pharmacokinetic parameters is presented in Table 17, and a summary of treatment ratios (test/reference) and 90% confidence intervals calculated from the ANOVA is presented in Table 18.

5.3 Preclinical Safety Data

Genotoxicity.

Gene mutation assays (bacteria and mammalian cells in vitro) and chromosomal aberration studies (human lymphocytes in vitro and mouse bone marrow erythrocytes in vivo) showed no evidence of genotoxic effects.

Carcinogenicity.

Long term studies in animals have not been performed to evaluate the carcinogenic potential of Ovidrel.

4 Clinical Particulars

4.1 Therapeutic Indications

Ovidrel is indicated in the treatment of:

(i) Women undergoing superovulation prior to assisted reproductive techniques such as in vitro fertilisation (IVF).

Ovidrel is administered to trigger final follicular maturation and luteinisation after stimulation of follicular growth.

(ii) Anovulatory or oligo-ovulatory women.

Ovidrel is administered to trigger ovulation and luteinisation in anovulatory or oligo-ovulatory patients after stimulation of follicular growth.

4.3 Contraindications

Ovidrel is contraindicated in women who exhibit:
prior hypersensitivity to hCG preparations or one of their excipients;
primary ovarian failure;
uncontrolled thyroid or adrenal dysfunction;
uncontrolled tumours of the hypothalamus and pituitary gland;
ovarian enlargement or cyst due to reasons other than polycystic ovarian disease;
sex hormone dependent tumours of the reproductive tract and accessory organs;
fibroid tumours of the uterus incompatible with pregnancy;
postmenopausal women;
ovarian, uterine or mammary carcinoma;
extrauterine pregnancy in the previous 3 months;
active thromboembolic disorders;
gynaecological haemorrhages of unknown aetiology.

4.4 Special Warnings and Precautions for Use

To date, there is no clinical experience with Ovidrel in other indications commonly treated with urine derived human chorionic gonadotrophin.
Gonadotrophins, including Ovidrel, should only be used by physicians who are thoroughly familiar with infertility problems and their management.
Before starting treatment, the couple's infertility should be assessed as appropriate and putative contraindications for pregnancy evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical deficiency, hyperprolactinaemia and pituitary or hypothalamic tumours and appropriate specific treatment given.
Special precautions should be taken before administering Ovidrel to patients with clinically significant systemic disease where pregnancy could lead to a worsening of the condition.
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 Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests).
To minimise the risk of OHSS and of multiple pregnancy, ultrasound scans, as well as oestradiol measurements, are recommended prior to and during stimulation therapy for all patients. In anovulation, the risk of OHSS is increased by a serum oestradiol level > 1500 picogram/mL (5400 picomol/L) and more than 3 follicles of 14 mm or more in diameter. In ART, there is an increased risk of OHSS with a serum oestradiol > 3000 picogram/mL (11,000 picomol/L) and 20 or more follicles of 12 mm or more in diameter. When the oestradiol level is > 5500 picogram/mL (20,000 picomol/L), and when there are 40 or more follicles in total, it may be necessary to withhold hCG administration.
Ovidrel has not been tested in women considered to be at risk of OHSS, who were withdrawn from the clinical studies prior to hCG administration. Because of this and because 250 microgram Ovidrel may correspond to a dose greater than 5000 IU urinary hCG, Ovidrel should be used with particular caution in women with higher order follicle numbers.
Adherence to recommended Ovidrel dosage, regimen of administration and careful monitoring of therapy will minimise the incidence of OHSS and multiple pregnancies.
Careful attention should be given to the diagnosis of infertility in candidates for hCG therapy. Prior to therapy with hCG, patients should be informed of the duration of treatment and monitoring of their condition that will be required. The risks of OHSS and multiple births in women and other possible adverse reactions (see Section 4.8 Adverse Effects (Undesirable Effects)) should also be discussed.

Overstimulation of the ovary following hCG therapy.

Ovarian enlargement.

Mild to moderate uncomplicated ovarian enlargement which may be accompanied by abdominal distension and/or abdominal pain may occur in patients treated with FSH and hCG, and generally regresses without treatment within two or three weeks. Careful monitoring of the ovarian response can minimise the risk of overstimulation.
If the ovaries are abnormally enlarged on the last day of FSH therapy, choriogonadotropin alfa should not be administered in this course of therapy. This will reduce the risk of development of OHSS.

Ovarian hyperstimulation syndrome (OHSS).

OHSS is a medical event distinct from an uncomplicated ovarian enlargement. Severe OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event. It is characterised by an apparent dramatic increase in vascular permeability, which can result in a rapid accumulation of fluid in the peritoneal cavity, thorax and potentially, the pericardium. The early warning signs of development of OHSS are severe pelvic pain, nausea, vomiting and weight gain. The following symptomatology has been seen with cases of OHSS: abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting, diarrhoea, severe ovarian enlargement, weight gain, dyspnoea and oliguria. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress and thromboembolic events (see Section 4.4 Special Warnings and Precautions for Use, Pulmonary and vascular complications). Transient liver function test abnormalities suggestive of hepatic dysfunction, which may be accompanied by morphologic changes on liver biopsy, have been reported in association with OHSS.
OHSS occurred in 4 of 236 (1.7%) patients treated with Ovidrel 250 microgram during clinical trials of ART and 3 of 99 (3.0%) patients in the OI trial. OHSS occurred in 8 of 89 (9.0%) patients who received Ovidrel 500 microgram. Two patients treated with Ovidrel 500 microgram developed severe OHSS.
OHSS may be more severe and more protracted if pregnancy occurs. OHSS develops rapidly; therefore, patients should be followed up for at least two weeks after hCG administration. Most often, OHSS occurs after treatment has been discontinued and reaches its maximum at about 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 (see Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests), the hCG must be withheld.
Embryo transfer should be deferred and embryos cryopreserved for later transfer if possible, if OHSS is developing.
If severe OHSS occurs, treatment with gonadotrophins must be stopped and the patient should be hospitalised.

Multiple births.

As with other hCG products, reports of multiple births have been associated with Ovidrel treatment. In assisted reproductive technologies (ART), the risk of multiple births is related to the number of embryos transferred. In patients undergoing ovulation induction (OI), the incidence of multiple pregnancies and births (mostly twins) is increased compared with natural conception. The patient should be advised of the potential risk of multiple births before starting treatment.
If the size and number of follicles suggest a substantial risk of multiple pregnancy with triplets or more, hCG should be withheld and contraception advised.

Miscarriage.

The rate of miscarriage, in both anovulatory patients and women undergoing ART, is higher than that found in the normal population but comparable with the rates observed in women with other fertility problems.

Congenital malformation.

The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This could be due to parental factors (e.g. maternal age, genetics), ART procedures and multiple pregnancies.

Pulmonary and vascular complications.

As with other hCG products, a potential for the occurrence of arterial thromboembolism exists.

Thromboembolic events.

In women with generally recognised 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.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

In most instances, treatment of women with FSH 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 oestradiol levels. The combination of both ultrasound and serum oestradiol measurement are useful for monitoring the development of follicles, for timing of the ovulatory trigger, as well as for detecting ovarian enlargement and minimising the risk of the OHSS and multiple gestation. It is recommended that the number of growing follicles be confirmed using ultrasonography because serum estrogens do not give an indication of the size or number of follicles.
Human chorionic gonadotrophins can cross react in the radioimmunoassay of gonadotrophins, especially luteinising 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:
1. A rise in basal body temperature.
2. Increase in serum progesterone.
3. Menstruation following a shift in basal body temperature.
When used in conjunction with the indices of progesterone production, sonographic visualisation of the ovaries will assist in determining if ovulation has occurred. Sonographic evidence of ovulation may include the following:
1. Fluid in the cul-de-sac.
2. Ovarian stigmata.
3. Collapsed follicle.
4. Secretory endometrium.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No clinically significant drug interactions have been reported during hCG therapy. Following administration, Ovidrel may interfere with the immunological determination of serum/ urinary hCG for up to ten days, leading to a false positive pregnancy test.
During Ovidrel therapy, minor thyroid stimulation is possible, of which the clinical relevance is unknown.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

See Section 4.1 Therapeutic Indications.
(Category B3)
No reproduction studies with recombinant human choriogonadotropin alfa in animals have been performed. No clinical data on exposed pregnancies are available. The potential risk for humans is unknown. Ovidrel should not be used during pregnancy.
The potential effects of choriogonadotropin alfa in lactating animals have not been studied. There are no data on the excretion of choriogonadotropin alfa in breast milk. Because many drugs are excreted in human milk, Ovidrel should not be administered to breastfeeding women.

4.8 Adverse Effects (Undesirable Effects)

Ovidrel is used to trigger final follicular maturation and early luteinisation after use of ovulation induction drugs. In this context, it is difficult to attribute undesirable effects to any one of the medications used.
In comparative trials with different doses of Ovidrel, the most common side effect was application site disorder, occurring in 14.6% of patients receiving Ovidrel 250 microgram subcutaneously, compared to 28% of patients receiving u-hCG subcutaneously.
All adverse events reported with an incidence of 2% or greater are included for studies 9073, 7927, 7648 and 8209 and all adverse events for study 23286 in Tables 1, 2, 3, 4 and 5.
The following complications have been reported after treatment with FSH/choriogonadotropin alfa: ectopic pregnancy, spontaneous abortion, missed abortion, placenta previa, premature birth, ovarian torsion and congenital anomalies including Down's syndrome with atrial septal defect, chromosomal abnormality (47, XXX) and cranial malformation. These complications have previously been reported in patients undergoing infertility treatment with gonadotrophins. Ovarian hyperstimulation syndrome (OHSS) was observed in approximately 4% of patients treated with Ovidrel. Severe OHSS was reported in less than 0.5% of patients. Severe OHSS could be complicated in rare cases by haemoperitoneum, acute pulmonary distress, ovarian torsion and thromboembolism.
The following complications have also been reported to occur after treatment with menotropins/hCG: pulmonary and vascular complications (e.g. thromboembolism), adnexal torsion as a complication of ovarian enlargement, mild to moderate ovarian enlargement and haematoperitoneum. Although these adverse events were not observed, there is the possibility that they may also occur with menotropins/r-hCG.

Postmarketing data.

Isolated cases of mild systemic allergic reactions have been reported as postmarketing data.

Skin and subcutaneous disorders.

Mild reversible skin reactions manifesting as rash.

Vascular disorders.

Very rare (1/10,000) thromboembolism (both in association with and separate from OHSS).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems in Australia, or at https://nzphvc.otago.ac.nz/reporting/ in New Zealand.

4.2 Dose and Method of Administration

Ovidrel is intended for subcutaneous administration.
Treatment with Ovidrel should be performed under the supervision of a physician experienced in the treatment of fertility problems.
In comparative clinical trials, administration of a dose of 250 microgram of Ovidrel was as effective as 5000 IU or 10,000 IU of urinary derived hCG for the assisted reproductive technique (ART) endpoint of number of oocytes retrieved per patient treated. In an ovulation induction (OI) study, 250 microgram of Ovidrel was as effective as 5000 IU of urinary hCG in inducing final follicular maturation and ovulation. Consequently, the following dosing regimen should be applied.

(i) Women undergoing superovulation prior to assisted reproductive techniques such as in vitro fertilisation (IVF).

Initially one prefilled pen of Ovidrel (250 microgram in 0.5 mL) should be administered 24 to 48 hours after the last administration of an FSH or hMG preparation, i.e. optimal stimulation of follicular growth is achieved.

(ii) Anovulatory or oligo-ovulatory women.

Initially one prefilled pen of Ovidrel (250 microgram in 0.5 mL) should be administered 24 to 48 hours after optimal stimulation of follicular growth is achieved. The patient is recommended to have intercourse on the day of and the day after, Ovidrel injection.
Ovidrel 250 microgram is equivalent to approximately 6500 IU of Profasi and adjustment to dosage should be in accord with clinical and biochemical monitoring.
Ovidrel is given as an injection under the skin (subcutaneously), usually near your stomach. Ovidrel is intended to be injected by the patient or their partner.
The patient should be instructed and assisted in learning the procedure and technique of self-injection. Prescribers and dispensors should ensure the patient or their partner have a good understanding of the principles of sterile techniques and have been assessed in their adequacy of injection technique prior to use.
Ovidrel is for single use in one patient only. Discard any residue.
Prescribers and dispensors should take the patient and their partner through the directions on 'How do I use Ovidrel' found in the consumer medicine information.

4.7 Effects on Ability to Drive and Use Machines

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

4.9 Overdose

No case of overdosage has been reported. Nevertheless, there is a possibility that ovarian hyperstimulation syndrome (OHSS) may result from an overdosage of Ovidrel (see Section 4.4 Special Warnings and Precautions for Use).
Advise your patients to immediately contact their doctor or the Poisons Information Centre (in Australia telephone 131 126, in New Zealand telephone 0800 764 766) if they are concerned that they have given themselves too much Ovidrel.

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, methionine, poloxamer, monobasic sodium phosphate monohydrate, dibasic sodium phosphate dihydrate, sodium hydroxide and phosphoric acid (for pH adjustment) and water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

Information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG) in Australia or on Medsafe Product Detail in New Zealand. The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Ovidrel should be stored at 2°C to 8°C (Refrigerate. Do not freeze) in its original container. Protect from light.

6.5 Nature and Contents of Container

Ovidrel is supplied in boxes of 1 pre-filled pen.

6.6 Special Precautions for Disposal

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

Summary Table of Changes