Consumer medicine information

Ovaleap

Follitropin alfa

BRAND INFORMATION

Brand name

Ovaleap

Active ingredient

Follitropin alfa

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ovaleap.

SUMMARY CMI

OVALEAP®

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 OVALEAP?

OVALEAP contains the active ingredient follitropin alfa. OVALEAP is used to stimulate development of follicles in women who do not ovulate and women undergoing assisted reproductive technologies (ART) such as in vitro fertilisation (IVF) and in men in combination with hCG to stimulate the production of sperm. For more information, see Section 1. Why am I using OVALEAP? in the full CMI.

2. What should I know before I use OVALEAP?

Do not use if you have ever had an allergic reaction to OVALEAP 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, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use OVALEAP? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with OVALEAP 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 OVALEAP?

  • Your doctor will decide the correct dose of OVALEAP for you. Your dose of OVALEAP may be adjusted depending on your individual response to treatment. Please consult your doctor if you are in any doubt.
  • OVALEAP is given as a course of daily injections. You should have your injection at the same time each day.

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

5. What should I know while using OVALEAP?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using OVALEAP.
  • See your doctor regularly. Your doctor will monitor you closely throughout your treatment.
Things you should not do
  • Do not stop using this medicine suddenly.
  • Do not use OVALEAP if you are pregnant or breastfeeding
  • Do not use OVALEAP if your ovaries are enlarged, you have an unexplained ovarian cyst, you have unexplained vaginal or uterine bleeding, you have cancer of the ovaries, uterus or breasts, your ovaries have failed or you have fibroids in your uterus which would make pregnancy impossible
  • Do not use OVALEAP if you have increased levels of gonadotrophins indicating failure of the testes or your infertility is due to disorders other than hypogonadotrophic hypogonadism (low levels of gonadotrophins)
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how OVALEAP affects you.
Drinking alcohol
  • Tell your doctor if you drink alcohol
Looking after your medicine
  • Prior to use, store OVALEAP in the original package at 2°C to 8°C (Refrigerate. Do not freeze.). Protect from light. Should refrigeration be unavailable, OVALEAP can be stored below 25°C for up to 3 months and away from light. OVALEAP must be discarded if it has not used for 3 months.

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

6. Are there any side effects?

Common side effects include injection site reactions, headache, dizziness, stomach pain, abdominal distension or abdominal discomfort, nausea, vomiting, diarrhoea, acne, weight gain and an increase in breast tissue (in men). 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

OVALEAP®

Active ingredient(s): follitropin alfa

Consumer Medicine Information (CMI)

This leaflet provides important information about using OVALEAP. 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 OVALEAP.

Where to find information in this leaflet:

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

1. Why am I using OVALEAP?

OVALEAP contains the active ingredient follitropin alfa which is similar to follicle stimulating hormone (FSH) found naturally in humans. OVALEAP belongs to a class of hormones called gonadotrophins. FSH is necessary for the growth and development of egg cells (follicles) in women, and sperm production in men.

OVALEAP is an approved biosimilar to the reference product Gonal-f®.

In women OVALEAP is used to bring about the development of follicles in women who are not ovulating and who have not responded to treatment with clomiphene citrate.

OVALEAP is also used to stimulate the development of several follicles in women undergoing assisted reproductive technologies (ART) such as in vitro fertilisation (IVF).

In men OVALEAP is used in combination with human chorionic gonadotrophin (hCG) to stimulate the production of sperm.

2. What should I know before I use OVALEAP?

Warnings

Do not use OVALEAP if:

  • you are allergic to follitropin 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.

Do not use OVALEAP if you have tumours of the hypothalamus or pituitary gland.

For women, do not use OVALEAP if:

  • you are pregnant
  • you are breastfeeding
  • your ovaries are enlarged
  • you have an unexplained ovarian cyst
  • you have unexplained vaginal or uterine bleeding
  • you have cancer of the ovaries, uterus or breasts
  • your ovaries have failed
  • you have fibroids in your uterus or malformations of the sexual organs which would make pregnancy impossible

For men, do not use OVALEAP if:

  • you have increased levels of gonadotrophins indicating failure of the testes
  • your infertility is due to disorders other than hypogonadotrophic hypogonadism (low levels of gonadotrophins)

Check with your doctor if you:

  • have any other medical conditions
  • take any medicines for any other condition

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

Do not use OVALEAP if you are pregnant.

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

Do not use OVALEAP if you are breastfeeding

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

If you are not certain whether these conditions apply to you, or you are worried about anything on this list, tell your doctor.

Use in children and the elderly

Do not give this medicine to a child or elderly person

Before you start using OVALEAP

Your doctor will assess you and your partner's fertility. 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 including OVALEAP.

Tell your doctor if you have or have had any of the following medical conditions:

  • disorders of the thyroid gland
  • disorders of the adrenal glands
  • high prolactin levels in the blood
  • porphyria or a family history of porphyria

For women

Your doctor will assess if you have any medical conditions which interfere with your ability to become pregnant.

Treatment with OVALEAP 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 become larger.

The most common symptom is lower abdominal pain. During stimulation your doctor will monitor your treatment by the use of ultrasound and/or blood tests to help determine if you are likely to develop OHSS. If necessary your doctor will delay or cancel your OVALEAP injection. You may also be advised to refrain from sexual intercourse until the end of the cycle if this occurs.

Compared to natural conception, the frequency of multiple pregnancies and births is higher in patients receiving treatments that stimulate follicle growth for ovulation induction. The majority of these are twins. Your doctor will monitor your response to treatment to minimise the chance of multiple pregnancies, because of the greater risks they carry for mothers and babies.

Compared to natural conception, the frequency of pregnancy loss is higher in patients undergoing treatments to stimulate follicle growth for ovulation induction

There may be a slightly increased risk of birth defects in women using assisted reproductive technologies. This may be due to increased maternal age, genetic factors, multiple pregnancies or the procedures. An effect of medicines used to induce ovulation has not been excluded.

Tell your doctor if you or a family member have or have had signs of blood clots (e.g. pain, warmth, redness, numbness or tingling in the arm or leg).

Treatment with OVALEAP and hCG may increase the risk of blood clots forming in your blood vessels.

Talk to your doctor about any concerns you may have before undergoing treatment or before you start using OVALEAP.

For men

Elevated FSH blood levels are indicative of testicular failure. Your doctor may ask you for a semen analysis to assess your response to treatment.

Talk to your doctor about any concerns you may have before you start using OVALEAP

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.

Tell your doctor if you have any allergies to foods, dyes, preservatives or any other medicines.

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

Your doctor has more information on medicines to be careful with or avoid while using OVALEAP.

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

4. How do I use OVALEAP?

How much to take/use

  • Your doctor will decide the correct dose of OVALEAP for you.
  • Your dose of OVALEAP may be adjusted depending on your individual response to treatment.
  • Please consult your doctor if you are in any doubt.
  • The following is a guide to the common dose.

Women who are not ovulating

  • The common dose usually starts at 75IU (5.5 microgram) daily. The dose may be adjusted as your treatment progresses. The maximal daily dose is usually not higher than 225 IU (16.5 microgram).

Women undergoing assisted reproductive technologies

  • The common dose usually starts at 150 IU (11 microgram) daily, commencing on day 2 or 3 of the cycle. The dose may be adjusted as your treatment progresses. The maximal daily dose is usually not higher than 450 IU (33 microgram).

Men with hypogonadotrophic hypogonadism

  • OVALEAP is commonly given with hCG. The common dose usually starts at 150 IU (11 microgram) three times a week.

When to take OVALEAP

  • You should have your injection at the same time each day.
  • OVALEAP is given as a course of daily injections.
  • Treatment with OVALEAP should be started under the supervision of a specialist doctor experienced in fertility treatment.
  • Do not use OVALEAP on anyone else. It is for your use only.

How to inject OVALEAP

  • OVALEAP is given as a subcutaneous (under your skin) injection in the lower abdominal area or thigh.
  • OVALEAP is intended to be injected by you or your partner. OVALEAP cartridges should only be administered using the OVALEAP Pen which is available separately.
  • Alternatively your doctor or a nurse may give you these injections.
  • If your doctor or nurse decides you can give the injections yourself, the doctor or nurse will teach you the injection technique. You can also find separate instructions for use provided with the OVALEAP Pen.
  • Do not self-inject until you are sure of how to do it.
  • Read the Instructions for Use provided in the pack carefully before commencing injections.
  • Your partner may be trained to give the injection at home.

Where to inject OVALEAP

  • OVALEAP is usually given in the lower abdominal area (except around the navel and waistline) or the front of your thigh. The injection site should be changed daily to lessen possible injection site reactions.
  • Do not inject into any areas in which you feel lumps, firm knots, depressions, pain, or see any discolouration.
  • Talk to your doctor if you find anything unusual when injecting.

How long to use OVALEAP for

For women

  • The length of treatment varies with each patient. It is possible to have more than one treatment cycle of OVALEAP.

For men

  • The combination treatment of OVALEAP and hCG could continue for at least 4 months and may continue for up to 18-24 months.

If you forget to use OVALEAP

OVALEAP should be used regularly at the same time each day. If you forget an injection or are not sure what to do, contact your doctor or nurse immediately for advice.

Do not inject a double dose on any day.

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

If you use too much OVALEAP

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

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26 or in New Zealand call 0800 764 766), 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 OVALEAP?

Things you should do

See your doctor regularly. Your doctor will monitor you closely throughout your treatment.

If you are about to be started on any new medicine, tell your doctor and pharmacist that you are using OVALEAP.

If you plan to have surgery, tell your doctor or dentist that you are using OVALEAP.

Your doctor will carefully monitor your response to OVALEAP by using ultrasound, blood tests or semen analysis.

Call your doctor straight away if you:

  • Become pregnant while using OVALEAP.

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

Things you should not do

If you are self-injecting do not:

  • Stop using this medicine suddenly.
  • Change the dose unless your doctor tells you to. Changing your dose without advising your doctor can increase your risk of unwanted side effects or can prevent the drug from working properly.
  • Give this medicine to anyone else, even if their symptoms seem similar to yours or if they have the same condition as you.

Driving or using machines

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

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

  • Prior to using, store OVALEAP in the original package at 2°C to 8°C (Refrigerate. Do not freeze.). Protect from light.
  • Should refrigeration be unavailable, OVALEAP can be stored below 25°C for up to 3 months and away from light. OVALEAP must be discarded if it has not been used after 3 months.

Do not use OVALEAP if the solution contains particles or is not clear.

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 windowsills.

Keep it where young children cannot reach it.

When to discard your medicine

After first piercing OVALEAP pen with a needle, OVALEAP may be stored below 25°C for a maximum of 28 days with the cap on, in order to protect the product from light.

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.

If you are self-injecting, you should discard all sharps into a disposal unit.

Do not use this medicine after the expiry date.

Do not use OVALEAP if you notice any visible signs of deterioration or damage to the container.

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.

Less serious side effects

Less serious side effectsWhat to do
Head related:
  • Headaches, dizziness
Stomach or bowel related:
  • stomach pain, abdominal distension or abdominal discomfort
  • nausea, vomiting
  • diarrhoea
Skin related:
  • pain, redness, itching or swelling at the site of injection during your treatment with OVALEAP
  • acne (for men)
Hormone related
  • weight gain (in men)
Reproductive system:
  • vaginal bleeding
  • some breast development (in men)
Speak to your doctor if you have any of these less serious 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.
Heart and blood related:
  • warning signs of stroke or heart attack
  • warning signs of blood clots such as pain, warmth, redness, numbness or tingling in your arm or leg
  • inflammation, swelling or pain in your legs
Reproductive system:
  • signs of severe OHSS such as severe lower abdominal pain, severe pelvic pain, nausea, vomiting, diarrhoea followed by rapid weight gain, reduced amounts of urine and shortness of breath
  • Ectopic pregnancy (embryo implanted outside the womb) may occur, especially in women with prior tubal disease.
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 OVALEAP contains

Active ingredient
(main ingredient)		Each cartridge contains the active ingredient follitropin alfa (rch) (recombinant human follicle stimulating hormone) 300 IU/0.5 mL or 450 IU/0.75 mL or 900 IU/1.5 mL.
Other ingredients
(inactive ingredients)		Mannitol
Monobasic sodium phosphate dihydrate
Sodium hydroxide
Benzyl alcohol
Polysorbate 20
Methionine
Benzalkonium chloride
Water for injections

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

What OVALEAP looks like

OVALEAP contains sterile solution for injection in a cartridge.

OVALEAP solution for injection is available in the following strengths and pack sizes:

  • 300 IU/0.5 mL (22 microgram). The pack contains 1 cartridge of solution for injection and 10 needles for administration (AUST R 328122)
  • 450 IU/0.75 mL (33 microgram). The pack contains 1 cartridge of solution for injection and 10 needles for administration (AUST R 328120)
  • 900 IU/1.5 mL (65.52 microgram). The pack contains 1 cartridge of solution for injection and 20 needles for administration (AUST R 328121)

The OVALEAP cartridge is designed for use in conjunction with the OVALEAP pen only, which is available separately.

Who distributes OVALEAP

Theramex Australia Pty Ltd
60 Margaret Street,
Sydney, NSW 2000
For enquiries call: 1800 THERAMEX or 1800 843 726

This leaflet was prepared in March 2021.

Published by MIMS July 2022

BRAND INFORMATION

Brand name

Ovaleap

Active ingredient

Follitropin alfa

Schedule

S4

 

1 Name of Medicine

Follitropin alfa (rch).
Ovaleap is a biosimilar medicine to Gonal-f solution for injection. The evidence for comparability supports the use of Ovaleap for the listed indications.

2 Qualitative and Quantitative Composition

Ovaleap is produced by a Chinese Hamster Ovary cell line transfected with the human FSH subunit genes (i.e. by recombinant DNA technology). Each cartridge contains the active ingredient follitropin alfa (rch) (recombinant human follicle stimulating hormone) 300 IU/0.5 mL, 450 IU/0.75 mL or 900 IU/1.5 mL.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection available in packs containing 1 glass cartridge and 10 or 20 injection needles. The Ovaleap cartridge is designed for use in conjunction with the Ovaleap Pen only, which is separately available.

4 Clinical Particulars

4.1 Therapeutic Indications

1. The treatment of anovulatory infertility in women who have been unresponsive to clomiphene citrate or where clomiphene citrate is contraindicated.
2. For controlled ovarian hyperstimulation in women undergoing assisted reproductive technologies.
3. Ovaleap is indicated with concomitant human chorionic gonadotrophin (hCG) therapy for the stimulation of spermatogenesis in gonadotrophin-deficient men in whom hCG alone is ineffective.

4.2 Dose and Method of Administration

Treatment with Ovaleap should be initiated under the supervision of a physician experienced in the treatment of fertility disorders.
Ovaleap should be administered subcutaneously. The injection site should be alternated daily to prevent lipoatrophy. Self-administration of Ovaleap should only be performed by patients who are well motivated, adequately trained and who have access to expert advice. Ovaleap cartridge should only be administered using the Ovaleap Pen. The instructions for use of the pen will be provided together with the Ovaleap Pen. Each Ovaleap pen is for individual patient use only.

Women with anovulatory infertility (WHO group II).

The objective of Ovaleap therapy is to develop a single mature Graafian follicle from which the ovum will be liberated after the administration of hCG.
Ovaleap may be given as a course of daily injections. In menstruating patients treatment should commence within the first 7 days of the menstrual cycle. Treatment should be tailored to the individual patient's response as assessed by measuring 1) follicle size by ultrasound and/or 2) oestrogen secretion. A commonly used regimen commences at 75 - 150 IU (5.46 to 10.92 microgram) FSH daily and is increased by 37.5 IU (2.73 microgram) up to 75 IU (5.46 microgram) at 7 or 14 day intervals if necessary, to obtain an adequate, but not excessive response. If a patient fails to respond adequately after 5 weeks of treatment, that cycle should be abandoned.
When an optimal response is obtained, a single injection of 250 microgram r-hCG or 5000 IU up to 10,000 IU urinary human chorionic gonadotropin (u-hCG) should be administered 24 - 48 hours after the last Ovaleap injection. The patient is recommended to have coitus on the day of, and the day following hCG administration.
If an excessive response is obtained, treatment should be stopped and hCG withheld (see Section 4.4 Special Warnings and Precautions for Use). Treatment should recommence in the next cycle at a dosage lower than that of the previous cycle.

Women undergoing assisted reproductive technologies.

A commonly used regimen for superovulation involves the administration of 150 IU (10.92 microgram) to 225 IU (16.5 microgram) of Ovaleap daily, commencing on days 2 or 3 of the cycle. Treatment is continued until adequate follicular development has been achieved (as assessed by monitoring of serum oestrogen concentrations and/or ultrasound examination), with the dose adjusted according to the patient's response, to usually not higher than 450 IU (32.76 microgram) daily.
A single injection of 250 microgram r-hCG or 5000 IU up to 10,000 IU u-hCG is administered 24 - 48 hours after the last Ovaleap injection to induce final follicular maturation. In clinical trials, final follicular maturation was judged to be when at least two follicles were ≥ 16 mm mean diameter and when E2 levels were within the physician's acceptable range for the number of follicles present.
Down-regulation with either a GnRH agonist or antagonist is now commonly used in order to suppress the endogenous LH surge and to control tonic levels of LH. Dosage regimens should be customised in order to achieve the desired result. In a commonly used protocol Ovaleap is started approximately 2 weeks after the start of agonist treatment, both being continued until adequate follicular development is achieved. For example, following two weeks treatment with an agonist, 225 IU (16.5 microgram) Ovaleap is administered (subcutaneously) for the first 7 days. The dose is then adjusted according to the ovarian response.

Men with hypogonadotrophic hypogonadism.

Prior to combined therapy with Ovaleap and hCG, pre-treatment should begin with hCG alone at the appropriate dosage to achieve masculinisation and serum testosterone level within the eugonadal range (> 9 - 10 nanomol/L). This starting dose should be increased to the necessary dosage in order to obtain normal testosterone values. If after an inadequate trial of hCG alone (usually 6 months) at effective doses, Ovaleap should be given concomitantly at the dosage of 150 IU (10.92 microgram) three times a week. This regimen should be continued for a minimum of 4 months. If after this period, the patient has not responded, the combination treatment (hCG plus Ovaleap 150 IU (10.92 microgram) 3 times a week) may be continued. Current clinical experience indicates that prolonged treatment for up to 18 - 24 months may be necessary to achieve spermatogenesis or fertility.

4.3 Contraindications

Ovaleap is contraindicated for safety reasons in:
cases of prior hypersensitivity to follitropin alfa, or to any excipients of Ovaleap;
tumours of the hypothalamus or pituitary gland.
FSH therapy is contraindicated for safety reasons where the following exist:

In women.

Pregnancy and lactation;
ovarian enlargement or ovarian cyst of unknown aetiology;
gynaecological haemorrhages of unknown aetiology;
ovarian, uterine or breast carcinoma.
FSH is contraindicated when an effective response cannot be obtained, such as:

In women.

Primary ovarian failure as indicated by high levels of FSH (ovarian dysgenesis, premature menopause);
malformations of sexual organs incompatible with pregnancy;
fibroid tumours of the uterus incompatible with pregnancy.

In men.

Elevated gonadotrophin levels that indicate primary testicular failure;
infertility disorders other than hypogonadotrophic hypogonadism.

Use in elderly and children.

Ovaleap should not be used in the elderly or children.

4.4 Special Warnings and Precautions for Use

Ovaleap is a potent gonadotrophic substance capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management.
Gonadotrophin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of Ovaleap calls for monitoring of ovarian response with ultrasound, alone or preferably in combination with measurement of serum oestradiol levels, on a regular basis. There may be a degree of inter-patient variability in response to FSH administration, with a poor response to FSH in some patients and exaggerated response in others. The lowest effective dose in relation to the treatment objective should be used in both men and women.
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 appropriate specific treatment given.
Ovaleap should be used with caution in patients with known hypersensitivity to gonadotrophin presentations that do not contain FSH, due to the risk of cross-sensitivity. The first injection of Ovaleap in such patients must be performed under direct medical supervision.
Self-administration of Ovaleap should only be performed by patients who are well motivated, adequately trained and with access to expert advice. During training of the patient for self-administration, special attention should be given to specific instructions for use of the Ovaleap Pen. The instructions for use of the pen will be provided together with the Ovaleap Pen.

Treatment in women.

Patients should be selected carefully according to the following guidelines: a thorough gynaecological and endocrinological evaluation must be performed; presence of early pregnancy should be ruled out; aetiology of any abnormal vaginal bleeding should be established before starting Ovaleap therapy; evaluation of semen quality of the partner should be performed; or other appropriate investigations should be performed as required.

Ovarian hyperstimulation syndrome (OHSS).

Mild to moderate uncomplicated ovarian enlargement, which may be accompanied by abdominal distension and/or abdominal pain, occurs in approximately 20% of those treated with follitropin and hCG, and generally regresses without treatment within two or three weeks. In the presence of marked ovarian enlargement, treatment should be discontinued.
Patients undergoing superovulation are at an increased risk of developing Ovarian Hyperstimulation Syndrome (OHSS) in view of the excessive oestrogen response and multiple follicular development. Distinct from uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and, rarely, in the pericardial cavities.
OHSS can become a serious complication of human gonadotrophin therapy and sometimes leads to fatal complications if not adequately treated.
Mild manifestations of OHSS include abdominal pain, abdominal discomfort and distension, and enlarged ovaries. Moderate OHSS may additionally present with nausea, vomiting, ultrasound evidence of ascites and marked ovarian enlargement. Severe OHSS further includes symptoms such as severe ovarian enlargement, weight gain, dyspnoea or oliguria. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, pleural effusions or acute pulmonary distress. Rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events, such as pulmonary embolism, ischaemic stroke or myocardial infarction.
Independent risk factors for developing OHSS have been reported to include young age, lean body mass, polycystic ovarian syndrome (PCOS), higher doses of exogenous gonadotrophin 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.
Careful monitoring of ovarian response with ultrasound alone or preferably in combination with measurement of oestradiol levels is recommended prior to and during stimulation therapy, especially in patients with PCOS.
OHSS may progress rapidly (within 24 hours) or over several days to become a serious medical event. It most often occurs after treatment with follitropin or hCG has been discontinued, reaching its maximum at about seven to ten days following treatment. Therefore, patients should be followed for at least two weeks after follitropin or hCG administration.
If there are any symptoms or signs of OHSS, the patient must be evaluated, investigated, and monitored. Adherence to recommended Ovaleap dosage and regimen of administration can minimise the risk of OHSS. Monitoring of stimulation cycles by ultrasound scans as well as oestradiol measurements are recommended to identify risk factors early.
Excessive oestrogenic response seldom gives rise to significant hyperstimulation unless hCG is administered to induce ovulation. Cases of OHSS are more common, more severe and more protracted if pregnancy occurs. Therefore, if signs of OHSS occur, it is recommended that hCG be withheld and the physician should advise the patient to refrain from intercourse for at least 4 days. Intercourse should be prohibited in those patients in whom significant ovarian enlargement occurs after ovulation because of the danger of haemoperitoneum resulting from ruptured ovarian cysts.
Mild or moderate OHSS requires careful monitoring and may resolve spontaneously. Worsening of symptoms suggests progression of OHSS and requires prompt clinical reassessment. If necessary, the physician should recommend cessation of treatment or withholding hCG injection, and closely monitor the ovarian response. Severe OHSS requires admission to hospital and commencement of appropriate therapy in addition to cessation of gonadotrophins treatment. Treatment of OHSS is primarily symptomatic, consisting of bed rest, fluid and electrolyte management, and analgesics if needed.
The phenomenon of haemoconcentration associated with fluid loss into the peritoneal cavity, pleural cavity and pericardial cavity has been seen to occur and should be thoroughly assessed in the following manner: 1) fluid intake and output, 2) weight, 3) haematocrit, 4) serum and urinary electrolytes, 5) urine specific gravity, 6) BUN and creatinine, and 7) abdominal girth. These determinations are to be performed daily or more often if the need arises. Appropriate imaging examination, especially ultrasound, should also be used for identifying, localising and quantifying fluid loss.
There is an increased risk of injury to the ovary with OHSS. The ascitic, pleural and pericardial fluids should not be removed unless absolutely necessary to relieve symptoms such as pulmonary distress or cardiac tamponade. Pelvic examination may cause rupture of an ovarian cyst, which may result in haemoperitoneum and should therefore be avoided. If this does occur, and if bleeding becomes such that surgery is required, the surgical treatment should be designed to control bleeding and to retain as much ovarian tissue as possible.

Thromboembolic events.

Thromboembolic events, including thrombophlebitis, pulmonary embolism, stroke and arterial occlusion both in association with, and separate from OHSS, have been reported following gonadotrophin therapy. In rare cases, thromboembolic events have resulted in death.
In women with recent or ongoing thromboembolic disease or women with generally recognised risk factors for thromboembolic events, such as personal or family history, treatment with gonadotrophins may further increase the risk for aggravation or occurrence of such events. 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 carries an increased risk of thromboembolic events.

Multiple pregnancies.

In patients undergoing induction of ovulation, the incidence of multiple pregnancy is increased compared with natural conception. The majority of multiple conceptions are twins. Multiple pregnancies, especially higher order, carry an increased risk of adverse maternal and perinatal outcomes. The patient should be advised of the potential risk of multiple births before starting treatment.
To minimise the risk of twins or higher order multiple pregnancy, careful monitoring of ovarian response is recommended. Appropriate management, such as cycle cancellation, should be considered in line with current clinical practice. The incidence of multiple pregnancy can be minimised by using the recommended dose and schedule of administration (see Section 4.2 Dose and Method of Administration).
In patients undergoing ART procedures, the risk of multiple pregnancy is related mainly to the number of embryos replaced, their quality and the patient's age. Single embryo transfer in good prognosis cycles substantially reduces the risk of multiple pregnancy with little effect on live birth rates.

Pregnancy loss.

The incidence of pregnancy loss by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction or ART than following natural conception, but comparable with the rates found in women with other fertility problems.

Congenital anomalies.

The prevalence of congenital anomalies after the use of ART may be slightly higher than after spontaneous conceptions. Possible contributing factors include aspects inherent in the couple's infertility, ovulation induction agents, other medicines used in treatment and the ART procedures. While there is no specific evidence from clinical trials or post-marketing data implicating gonadotrophin use in adverse effects on pregnancy, embryonal or fetal development, parturition or postnatal development, ovulation induction agents cannot be excluded as a contributing factor.

Treatment in men.

Elevated endogenous FSH levels are indicative of primary testicular failure. Such patients are unresponsive to Ovaleap/hCG therapy. Semen analysis is recommended in assessing the response to treatment.

Porphyria.

In patients with porphyria or a family history of porphyria, follitropin alfa may increase the risk of an acute attack. Deterioration or a first appearance of this condition may require cessation of treatment.

Use in the elderly.

Ovaleap should not be used in the elderly population (see Section 4.3 Contraindications).

Paediatric use.

Ovaleap should not be used in the paediatric population (see Section 4.3 Contraindications).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No clinically significant drug interactions have been reported during Ovaleap therapy. Concomitant use of Ovaleap with other agents used to stimulate ovulation may potentiate the follicular response, whereas concurrent use of a GnRH agonist or antagonist to induce pituitary desensitisation may increase the dosage of Ovaleap needed to elicit an adequate ovarian response.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

See Section 4.1 Therapeutic Indications.
(Category D)
Follitropin alfa is not intended for use during pregnancy (see Section 4.3 Contraindications). In rats and rabbits, follitropin alfa caused dystocia and marked postimplantation loss at subcutaneous doses of greater than 5 IU/kg/day, indicating that it is embryotoxic and fetotoxic. Follitropin alfa was not teratogenic at subcutaneous doses up to 320 IU/kg/day in rats or 5 IU/kg/day in rabbits.
 It is not known whether follitropin alfa is excreted in human milk. In lactating rats, follitropin alfa at doses up to 40 IU/kg did not influence lactation or have any effects on the postnatal growth and development of the offspring. Follitropin alfa was measured in the milk in early lactation.
Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the nursing infant from Ovaleap, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the drug to the mother.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. However, adverse events of these medicines include dizziness which could affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

The reactions reported below are classified according to frequency of occurrence as follows:
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.

Treatment in general.

Immune system disorders.

Very rare: mild to severe hypersensitivity reactions including anaphylactic reactions and shock.

Respiratory, thoracic and mediastinal disorders.

Very rare: exacerbation or aggravation of asthma.

General disorders and administration site conditions.

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

Treatment in women.

The following adverse events have been reported during gonadotrophin therapy:

Reproductive system and breast disorders.

Very common: ovarian cyst, mild to moderate ovarian enlargement.
Common: mild or moderate OHSS (including symptomatology), intermenstrual bleeding.
Uncommon: severe OHSS (including symptomatology).
Rare: complications of severe OHSS, ectopic pregnancy, adnexal torsion associated with ovarian enlargement.

Gastrointestinal disorders.

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

Nervous system disorders.

Very common: headache, dizziness.

Vascular disorders.

Rare: thromboembolism.
See Section 4.4 Special Warnings and Precautions for Use for information on symptoms and management of OHSS.

Treatment in men.

Reproductive system and breast disorders.

Common: gynaecomastia.

Skin and subcutaneous tissue disorders.

Common: acne.

Investigations.

Common: weight gain.

Reporting suspected adverse reactions.

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.

4.9 Overdose

The effects of an overdose of follitropin alfa are unknown, nevertheless, there is the possibility that OHSS may occur (see Section 4.4 Special Warnings and Precautions for Use).
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

In females, the most important effect resulting from parenteral administration of FSH is the development of mature Graafian follicles. To complete follicular maturation and to stimulate ovulation in the absence of an endogenous luteinising hormone (LH) surge, human chorionic gonadotrophin (hCG) is given once monitoring of the patient indicates that sufficient follicular development has occurred. There may be a degree of inter-patient variability in response to FSH administration, with lack of response to FSH in some patients. In males, FSH stimulates spermatogenesis without significant effect on the androgen secreting interstitial cells.

Clinical trials.

Clinical trials with Gonal-f.

WHO group II anovulatory infertile women.

In a controlled study involving 222 randomised patients, cumulative ovulation rate was not significantly different between follitropin alfa and urofollitropin or urinary-derived hFSH (uhFSH) groups whether analysed on an intention-to-treat or evaluable patient basis. The ovulation rate in each cycle was also not different between the two medicines.

Superovulation in assisted reproduction techniques (ART).

Study 21884.

The safety and efficacy of follitropin alfa (r-hFSH; filled-by-mass) versus u-hFSH and its equivalence as compared to follitropin alfa old formulation (filled by bioactivity), all administered subcutaneously, were assessed in a multicentre, randomised, single blind, phase III study in infertile women undergoing in vitro fertilisation (IVF) and embryo transfer. All patients underwent pituitary desensitisation (down-regulation) with a gonadotrophin-releasing hormone (GnRH) agonist prior to and during stimulation of multiple follicular development with one of the three study treatments. Randomisation occurred when pituitary downregulation was confirmed by an E2 level of < 50 picogram/mL.
The primary efficacy parameter in this study was the number of fertilised oocytes retrieved per patient. 837 patients entered the study, of whom 713 were randomised. Of these, 711 received at least one dose of FSH: 237 patients received follitropin alfa (r-hFSH; filled-by-mass), 237 patients received u-hFSH, and 237 patients received follitropin alfa old formulation (filled by bioactivity). The number of oocytes retrieved was similar in all treatment groups. The efficacy of follitropin alfa (r-hFSH; filled-by-mass) although not superior, led to statistically higher response rates in the number of fertilised oocytes as compared to u-hFSH. The efficacy results are summarised in Tables 1 and 2.
441 of 713 patients experienced 1474 adverse events: 145 patients in the follitropin alfa (rhFSH; filled-by-mass) group, 143 patients in the u-hFSH group and 153 patients in the old follitropin alfa (filled by bioactivity) group. Most of the reported events were less in the follitropin alfa (r-hFSH; filled-by-mass) group when compared to the old follitropin alfa (filled by bioactivity) group. Overall, the pattern of adverse events was similar between treatment groups and was consistent with the profile of events reported in this indication.

Men with hypogonadotrophic hypogonadism.

Male hypogonadotrophic hypogonadism (HH) is a rare condition therefore study sizes are limited. Two phase III (open and non-comparative) studies were conducted to assess the efficacy and safety of follitropin alfa in combination with hCG in inducing spermatogenesis in men with HH. The primary efficacy endpoint was the achievement of a mature sperm density of > 1.5 x 106/mL. Follitropin alfa was administered subcutaneously at a dosage of 150 IU three times a week in combination with hCG (> 2000 IU twice weekly) for up to 18 months.
The first study was conducted in university clinical centres in France, Germany and UK. A total of 32 patients with complete, primary isolated HH were recruited into this study. They were azoospermic before entering the study, remained so after the pre-treatment phase and none had prior treatment with FSH or GnRH. In the pre-treatment phase, the patients were treated with hCG alone (2000 IU twice weekly for 3 - 6 months) to first normalise serum testosterone levels before initiating the treatment with follitropin alfa. Of 26 patients who received follitropin alfa, 19 patients were found to be eligible for efficacy evaluation.
The primary endpoint of a sperm density of > 1.5 x 106/mL was achieved in 12/19 (63%) patients. Overall 15/19 (79%) patients achieved some spermatogenesis. The median time to initiate spermatogenesis was 9 months.
The second study was conducted in 2 university clinical centres in Australia. A total of 10 patients with severe HH entered the study, but only 8 patients completed the follitropin alfa treatment phase. Similar results to the first study were obtained.
The primary endpoint of a sperm density of > 1.5 x 106/mL were achieved in 5/8 (63%) patients. Overall 7/8 (88%) patients achieved some spermatogenesis. The median time to initiate spermatogenesis was 6 months. The studies also demonstrated that follitropin alfa has a good safety profile and is well tolerated over the treatment period of up to 18 months.

Comparability of Ovaleap with Gonal-f.

Therapeutic equivalence of Ovaleap and Gonal-f was demonstrated in a multi-national, multicentre, randomised, controlled, assessor-blind, parallel-group study in women undergoing controlled ovarian hyperstimulation for ART.
The primary efficacy endpoint was the number of oocytes retrieved. Equivalence of Ovaleap and Gonal-f was considered to be shown if the two-sided 0.95 CI for the differences in the number of oocytes retrieved lied entirely within the equivalence range of [-3 oocytes, + 3 oocytes].
Secondary endpoints included total r-hFSH dose and dose adaptation; duration of r-hFSH stimulation; follicle size distribution, serum oestradiol and endometrial thickness on Stimulation Day 6 and on the day of hCG administration; cancellation rate prior to oocyte retrieval; oocyte maturity (ICSI); oocyte quality; fertilisation rate; and clinical pregnancy rate; and confirmed no clinically meaningful differences between Ovaleap and Gonal-f.

5.2 Pharmacokinetic Properties

Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and eliminated from the body with a terminal half-life of about 1 day. The steady state volume of distribution and total clearance are 10 L (0.17 L/kg) and 0.6 L/h (0.01 L/h/kg), respectively. One-eighth of the follitropin alfa dose is excreted in the urine.
Following subcutaneous administration, the absolute bioavailability is about 70%. Following repeated administration, follitropin alfa accumulates 3-fold at steady state within 3 - 4 days. In women whose endogenous gonadotrophin secretion is suppressed, follitropin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels.
A phase I (study IMP 23572), open, randomised, 2-way crossover study to assess the relative bioavailability and the tolerability of r-hFSH of a reference follitropin alfa as a monodose freeze-dried formulation and a new multidose liquid formulation, administered subcutaneously in male and pre-menopausal female volunteers with pituitary gonadotrope cell down regulation was conducted. The pharmacokinetic parameters from this study can be seen in Table 3.
Following the subcutaneous administration of both formulations, the 90% confidence intervals of the mean ratios for the bioavailability metrics, Cmax and AUClast lie within the pre-defined limits of 0.8 - 1.25 showing bioequivalence of liquid (test) and freeze dried (reference) formulations. Because the observed variability (< 10%) was much lower than expected a priori, the study allowed the detection of a small difference between the two formulations in rate (about 8%) and extent (about 5%). Suppression of endogenous FSH production was incomplete, probably more so in period 2 compared to period 1 and this probably explains the significant period effect observed. The significant difference seen on tmax is probably a function of the diverse mechanisms by which the drug enters the systemic circulation. In subjects where the diffusion processes from the subcutis to the adjacent small blood vessels dominate, earlier tmax is observed, whereas, in subjects where flow of FSH through the lymph to the systemic circulation is dominant, a later tmax probably occurs. This latter process may be non-linear generating an apparent zero order input over sustained periods in some subjects. The mixture of these processes in the population leads to very high variability in tmax so a larger study would be necessary to truly assess the relative magnitude of this parameter for the two formulations.

Comparability of Ovaleap with Gonal-f.

Equivalent pharmacokinetic (PK) profiles of Ovaleap and Gonal-f have been demonstrated in a randomised, open label, two-way cross-over phase I study in 36 healthy, down-regulated (suppression of endogenous pituitary gonadotrophin release with a gonadotrophin-releasing hormone (GnRH) agonist prior to stimulation with either Gonal-f or Ovaleap) women. The results of comparative statistical evaluation of the pharmacokinetic parameters are summarized in Table 4.

5.3 Preclinical Safety Data

Genotoxicity.

Follitropin alfa showed no genotoxic activity in a series of assays performed to evaluate its potential to cause gene mutations (Salmonella typhimurium, Escherichia coli and Chinese hamster lung cells) and chromosomal damage (human lymphocytes and mouse micronucleus test).

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

Monobasic sodium phosphate dihydrate, sodium hydroxide (2 M) (for pH adjustment), mannitol, Methionine, polysorbate 20, benzyl alcohol, benzalkonium chloride 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. The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store at 2°C to 8°C (Refrigerate. Do not freeze). Protect from light.
Should refrigeration be unavailable, Ovaleap cartridge can be stored below 25°C for up to 3 months. Ovaleap must be discarded if it has not been used after 3 months.
After first using the Ovaleap cartridge with the supplied pen, Ovaleap may be stored below 25°C for a maximum of 28 days. Store the pen with the cap on, in order to protect the product from light.

6.5 Nature and Contents of Container

Ovaleap is available in the following strengths and pack sizes:

Ovaleap 300 IU/0.5 mL solution for injection.

Cartridge (type I glass) with a rubber piston (bromobutyl rubber) and a crimp-cap (aluminium) with a septum (bromobutyl rubber), containing 0.5 mL of solution.
Injection needles (stainless steel; 0.33 mm x 12 mm, 29 G x ½").
Pack size of 1 cartridge and 10 injection needles.

Ovaleap 450 IU/0.75 mL solution for injection.

Cartridge (type I glass) with a rubber piston (bromobutyl rubber) and a crimp-cap (aluminium) with a septum (bromobutyl rubber), containing 0.75 mL of solution.
Injection needles (stainless steel; 0.33 mm x 12 mm, 29 G x ½").
Pack size of 1 cartridge and 10 injection needles.

Ovaleap 900 IU/1.5 mL solution for injection.

Cartridge (type I glass) with a rubber piston (bromobutyl rubber) and a crimp-cap (aluminium) with a septum (bromobutyl rubber), containing 1.5 mL of solution.
Injection needles (stainless steel; 0.33 mm x 12 mm, 29 G x ½").
Pack size of 1 cartridge and 20 injection needles.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Human follicle stimulating hormone (FSH) is a glycoprotein (Molecular Weight is about 30,000 Da) and is characterised by two amino acid chains known as α and β. The β-chain confers biological activity. The α-chain is common to all gonadotrophins with specificity residing in the β-chain.

CAS number.

146479-72-3.

7 Medicine Schedule (Poisons Standard)

Prescription Only Medicine - Schedule 4.

Summary Table of Changes