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.

SUMMARY CMI

OVIDREL®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using OVIDREL?

OVIDREL contains the active ingredient choriogonadotropin alfa (rch). OVIDREL is used in women undergoing assisted reproductive techniques such as in vitro fertilisation (IVF) and in women who do not produce eggs (anovulation) or who produce too few eggs (oligo-ovulation) to trigger the release of eggs (ovulation) after other medicines have been used to develop follicles.

For more information, see Section 1. Why am I using OVIDREL? in the full CMI.

2. What should I know before I use OVIDREL?

Do not use if you have ever had an allergic reaction to OVIDREL or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, are pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use OVIDREL? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with OVIDREL and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use OVIDREL?

  • The dose of OVIDREL is one pre-filled pen (250 microgram in 0.5 mL) given as a single injection under the skin (subcutaneously) after stimulation of follicular growth with other medicines. Your doctor will explain how much and when to give the injection. Each pre-filled pen is for single use in one patient only.
  • Follow all directions given to you by your doctor or pharmacist carefully, including the Instructions for Use provided in the pack.

More instructions can be found in Section 4. How do I use OVIDREL? in the full CMI.

5. What should I know while using OVIDREL?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using OVIDREL.
Things you should not do
  • Do not stop using this medicine suddenly or change the dose without checking with your doctor.
  • Do not give this medicine to anyone else, even if they have the same condition as you.
Driving or using machines
  • Be careful driving or operating machinery until you know how OVIDREL affects you.
Looking after your medicine
  • Store OVIDREL at 2°C to 8°C (Refrigerate. Do not freeze) in its original container. Protect from light.
  • Prior to use and within its shelf life, OVIDREL pre-filled pen can also be stored below 25°C for up to 28 days in its original container and protected from light. It must be discarded if not used after these 28 days.

For more information, see Section 5. What should I know while using OVIDREL? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. Sometimes they are serious, most of the time they are not. Tell your doctor if you experience any side effects.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

OVIDREL®

Active ingredient(s): choriogonadotropin alfa (rch)

Consumer Medicine Information (CMI)

This leaflet provides important information about using OVIDREL. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using OVIDREL.

Where to find information in this leaflet:

1. Why am I using OVIDREL?
2. What should I know before I use OVIDREL?
3. What if I am taking other medicines?
4. How do I use OVIDREL?
5. What should I know while using OVIDREL?
6. Are there any side effects?
7. Product details

1. Why am I using OVIDREL?

OVIDREL contains the active ingredient choriogonadotropin alfa (rch). OVIDREL belongs to a family of hormones known as gonadotrophins, which are involved in the normal control of reproduction.

OVIDREL is used in women undergoing assisted reproductive technique such as in vitro fertilisation (IVF) and in women who do not produce eggs (anovulation) or who produce too few eggs (oligo-ovulation) to trigger the release of eggs (ovulation) after other medicines have been used to develop follicles.

2. What should I know before I use OVIDREL?

Warnings

Do not use OVIDREL if:

  • you are allergic to choriogonadotropin alfa, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • your ovaries are unable to be stimulated to produce eggs (primary ovarian failure).
  • you have uncontrolled thyroid or adrenal gland disease.
  • you have a tumour of the hypothalamus or pituitary gland.
  • you have ovarian enlargement or one or more large ovarian cysts.
  • you have cancer of your ovaries, uterus (womb) or breasts.
  • you have fibroid tumours in your uterus which would make pregnancy impossible.
  • you have been through menopause.
  • you have active blood clots disorders.
  • you have unexplained vaginal or uterine bleeding.

Check with your doctor if you:

  • have any other medical conditions
  • take any medicines for any other condition
  • or your family have had increased risk of developing blood clots, e.g. stroke, heart attacks.

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.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

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.

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.

3. What if I am taking other medicines?

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect OVIDREL.

4. How do I use OVIDREL?

How much to inject

  • The dose of OVIDREL is one pre-filled pen (250 microgram in 0.5 mL) given as a single injection under the skin after stimulation of follicular growth with other medicines.
  • Your doctor will explain how much and when to give the injection.
  • Each pre-filled pen is for single use in one patient only. Discard any residue.
  • Follow the instructions provided by your doctor, nurse or pharmacists.

When to inject OVIDREL

  • OVIDREL is given as a single injection under the skin (subcutaneously), usually near your stomach. Your doctor will tell you when to inject OVIDREL.
  • It is important that OVIDREL is injected on the correct day and at the correct time as instructed by your doctor.

How to inject OVIDREL

  • Your doctor or nurse will instruct and assist you in learning the procedure and technique of self-injection.
  • Your doctor or nurse can also give the injection to you.
  • Follow the Instructions for Use provided in the pack.
  • Do not attempt self-injection until you are sure of how to do it.
  • Do not inject in which you feel lumps, firm knots, depression, pain or discolouration.
  • Talk to your doctor if you find anything unusual when injecting.

If you forget to use OVIDREL

If you forget an injection, contact your doctor or nurse immediately for advice.

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 the medicine.

If you use too much OVIDREL

If you think that you have used too much OVIDREL, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using OVIDREL?

Things you should do

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

Remind any doctor, dentist or pharmacist you visit that you are using OVIDREL.

Things you should not do

  • Do not stop using this medicine suddenly without telling your doctor.
  • Do not change the dose unless your doctor tells you to.
  • Give this medicine to anyone else even if they have the same condition as you.

Ovarian Hyperstimulation Syndrome (OHSS)

Treatment with OVIDREL may increase your risk of developing a condition called ovarian hyperstimulation syndrome (OHSS). This is when the ovaries overreact 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.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how OVIDREL affects you.

Looking after your medicine

  • OVIDREL must be stored at 2°C to 8°C (Refrigerate. Do not freeze) in its original container. Protect from light.
  • Prior to use and within its shelf life, OVIDREL pre-filled pen can also be stored below 25°C for up to 28 days in its original container and protected from light. It must be discarded if not used after these 28 days.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

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

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Side effects

Side effectsWhat to do
  • Local reactions at the injection site, such as pain, redness or swelling
  • Headache
  • Nausea, vomiting, diarrhoea, abdominal pain or discomfort
Speak to your doctor if you have any of these side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Allergic reactions:
  • Swelling of the face, lips, tongue or other parts of the body, shortness of breath, wheezing or difficulty breathing, severe skin rash, itching or hives
Signs of severe OHSS:
  • Severe lower abdominal pain, severe pelvic pain, nausea, vomiting, diarrhoea followed by rapid weight gain, low urine output and shortness of breath
Signs of blood clots:
  • Pain, warmth, redness, numbness or tingling in arm or leg and strokes
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What OVIDREL contains

Active ingredient
(main ingredient)		choriogonadotropin alfa (rch)
Other ingredients
(inactive ingredients)		mannitol
monobasic sodium phosphate monohydrate
dibasic sodium phosphate dihydrate
phosphoric acid
sodium hydroxide
poloxamer
methionine
water for injections

Do not take this medicine if you are allergic to any of these ingredients.

What OVIDREL looks like

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

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

Who distributes OVIDREL

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

This leaflet was prepared in March 2023.

Published by MIMS June 2023

BRAND INFORMATION

Brand name

Ovidrel Pen

Active ingredient

Choriogonadotropin alfa

Schedule

S4

 

1 Name of Medicine

Choriogonadotropin alfa (rch).

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.

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.

4.2 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 technologies (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.

4.3 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 healthcare professionals and requires the availability of appropriate monitoring facilities (see Section 4.4 Special Warnings and Precautions for Use, Effects on laboratory tests).
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.
Mild manifestations of OHSS include abdominal pain, abdominal discomfort and distension, and enlarged ovaries. Moderate OHSS may additionally present with nausea, vomiting, diarrhoea, ultrasound evidence of ascites and marked ovarian enlargement. Severe OHSS further includes symptoms such as 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). Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events, such as pulmonary embolism, ischaemic stroke or myocardial infarction. 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.
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.
Independent risk factors for developing OHSS include young age, lean body mass, polycystic ovarian syndrome, higher doses of exogenous gonadotrophins, high absolute or rapidly increasing serum oestradiol levels and previous episodes of OHSS, large number of developing ovarian follicles and large number of oocytes retrieved in ART cycles.
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.
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 early identify risk factors.
OHSS may be more severe and more protracted if pregnancy occurs. Therefore, if signs of ovarian hyperstimulation occur, it is recommended that hCG is withheld and the patient is advised to refrain from coitus or use barrier contraceptive methods for at least 4 days.
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. 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.
Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, treatment with gonadotrophins must be stopped, the patient should be hospitalised and appropriate therapy should be started.

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.
To minimise the risk of higher order multiple pregnancy, careful monitoring of ovarian response and adherence to commended Ovidrel dosage and regimen of administration are recommended. 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.

4.7 Effects on Ability to Drive and Use Machines

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

4.8 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.

List of adverse reactions.

The following definitions apply to the frequency terminology used hereafter: 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; very rare < 1/10,000.

Immune system disorders.

Very rare: Mild to severe hypersensitivity reactions including rash, anaphylactic reactions and shock.

Nervous system disorders.

Common: Headache.

Vascular disorders.

Very rare: Thromboembolism.

Gastrointestinal disorders.

Common: Abdominal pain, abdominal distension, nausea, vomiting.
Uncommon: Abdominal discomfort, diarrhoea.

Reproductive system and breast disorders.

Common: Mild or moderate OHSS (including associated symptomatology) (see Section 4.4 Special Warnings and Precautions for Use).
Uncommon: Severe OHSS (including associated symptomatology) (see Section 4.4 Special Warnings and Precautions for Use).

General disorders and administration site conditions.

Common: Injection site reactions (e.g. pain, erythema, haematoma, swelling and/or irritation at the site of injection).

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.

4.9 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.

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.

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.
Prior to use and within its shelf life, Ovidrel pre-filled pen can also be stored below 25°C for up to 28 days in its original container and protected from light. It must be discarded if not used after these 28 days.

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.

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).

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes