Consumer medicine information

What is in this leaflet

This leaflet answers some common questions about REKOVELLE. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

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

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

Keep this leaflet with the medicine. You may need to read it again.

What REKOVELLE is used for

REKOVELLE contains follitropin delta, which is a recombinant human follicle-stimulating hormone (FSH) produced in a human cell line (PER.C6®) by recombinant DNA technology.

REKOVELLE belongs to a class of hormones called gonadotropins. FSH is necessary for the growth and development of egg sacs (follicles) in women.

This medicine is used for controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technologies (ART) such as an in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycle.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is not addictive.

It is available only with a doctor's prescription.

This medicine is not expected to affect your ability to drive a car or operate machinery.

Before you use REKOVELLE

When you must not use it

Do not use REKOVELLE if you have an allergy to:

• any medicine containing the active substance
• any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

• shortness of breath
• wheezing or difficulty breathing
• swelling of the face, lips, tongue or other parts of the body
• rash, itching or hives on the skin.

Do not use REKOVELLE if any of the following apply to you:

• tumours of the hypothalamus or pituitary gland
• ovarian enlargement or ovarian cyst not due to polycystic ovarian syndrome
• bleeding from the vagina without a known cause
• ovarian, uterine or breast cancer
• experienced early menopause
• your ovaries have failed.

Do not use this medicine if you are already pregnant. It may affect your developing baby if you use it during pregnancy.

Do not breast-feed if you are taking this medicine.

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

If you are not sure whether you should start using this medicine, talk to your doctor.

Before you start to use it

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 REKOVELLE.

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

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.

Tell your doctor if you are already pregnant or are breast-feeding.

Treatment with REKOVELLE 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 symptoms are lower abdominal pain, discomfort or swelling. 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 REKOVELLE 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 REKOVELLE 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 REKOVELLE.

Taking other medicines

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

Some medicines and REKOVELLE may interfere with each other.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How REKOVELLE is given

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

Treatment with REKOVELLE should be initiated under the supervision of a physician experienced in the treatment of fertility problems. You must be educated on how to use the REKOVELLE injection pen and to perform injections

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to inject

The dosage of REKOVELLE is individualised for each patient. The dosage requirement can be influenced by a woman's body weight and her ovarian reserve, which is reflected in her serum anti- Müllerian hormone (AMH) concentration. Your doctor may measure and record your body weight and serum AMH concentration to assist in determining your REKOVELLE dosage requirement.

Women with low AMH levels are likely to have low ovarian reserve.

REKOVELLE is dosed in micrograms and not in international units (IU) of biological activity. The dosing regimen is specific for REKOVELLE and the microgram dose cannot be applied to other gonadotropins.

Your doctor will decide on the dose of REKOVELLE to be given. Your doctor will individualise your treatment cycle of REKOVELLE.

How to use it

REKOVELLE is to be injected under the skin, preferably in the abdominal wall. Supervision by a trained health practitioner is required for the first injection.

Self-administration of REKOVELLE should only be performed if you are well motivated, adequately trained and have access to expert advice.

For instructions on the administration with the REKOVELLE injection pen, see the 'Instructions for Use' in the pack.

It is important that you do not try to give yourself the injection unless you have received special training from your doctor or nurse.

When to use it

Dosing with REKOVELLE should be initiated day 2 or 3 after start of menstrual bleeding, and continue until adequate follicular development has been achieved as assessed by monitoring with ultrasound alone or in combination with measurement of serum estradiol levels.

How long to use it

Adequate follicular development is achieved on average by the ninth day of treatment (range 5 to 20 days).

Continue using your medicine for as long as your doctor tells you.

If you forget to use REKOVELLE

If you forget an injection or are not sure what to do, contact your doctor or nurse immediately for advice.

If you inject too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have used too much REKOVELLE.

While you are using REKOVELLE

Things you must do

See your doctor regularly so you can be monitored closely throughout your treatment.

Tell your doctor, nurse and pharmacist that you are using REKOVELLE if you are about to be started on any new medicine.

Tell any other doctors who treat you that you are taking this medicine.

Tell your doctor immediately if you become pregnant while taking this medicine.

Things you must not do

Do not use REKOVELLE to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using REKOVELLE.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

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

• headache
• nausea
• pelvic discomfort
• pelvic pain
• fatigue.

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

Tell your doctor as soon as possible if you notice any of the following:

• mood swings
• sleepiness/drowsiness
• dizziness
• diarrhoea
• constipation
• abdominal discomfort
• vaginal bleeding
• breast pain
• breast tenderness.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital, even if they develop some days after the final injection:

• signs of an allergic reaction such as shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin

A complication with FSH treatment is unwanted overstimulation of the ovaries. Contact your doctor if you experience any symptoms of overstimulation of the ovaries. The first symptoms of ovarian overstimulation may be noticed as pain in the stomach (abdomen), feeling sick or diarrhoea.

Ovarian overstimulation may develop into a serious medical condition called ovarian hyperstimulation syndrome (OHSS).

Signs and symptoms of severe OHSS may include:

• acute stomach pain, weight gain (due to the accumulation of fluid in the abdomen and/or chest), shortness of breath and passing less urine
• pain, warmth, redness, numbness, or tingling in your arm or leg; confusion, extreme dizziness or severe headache (signs of a blood clot).

If you get any side effects, talk to you doctor, pharmacist or nurse.

This also includes any possible side effects not listed above.

Tell your doctor if you notice anything that worries you or that is making you feel unwell.

After using REKOVELLE

Storage

• Keep REKOVELLE in a refrigerator at a temperature of 2°C to 8°C.
• Do not freeze.
• REKOVELLE may be removed from the refrigerator and stored at or below 25°C for up to 3 months and must be discarded afterwards.
• Before use: store in the original package in order to protect from light.
• Do not use this medicine if you notice that it is cloudy or there are particles in it.
• After the first injection: the pre- filled pen can be stored at or below 25°C and it must be discarded after 28 days.
• Keep REKOVELLE out of sight and reach of children.

Disposal

Once you have injected REKOVELLE, do not re-use the needle.

Discard the used needle into an approved, puncture-resistant sharps container and keep it out of the reach of children.

Never put a used needle into your normal household rubbish bin.

Dispose of this medicine as instructed by your doctor, nurse or pharmacist.

Product description

What it looks like

REKOVELLE is a clear and colourless solution for injection presented in a pre-filled multidose pen with a dose selection knob, display window and cap. Each pen contains an integrated non- replaceable cartridge containing the solution for injection. Each pack contains 1 pre-filled multidose pen and a number of injection needles.

REKOVELLE is available in 3 strengths.

REKOVELLE 12 micrograms pack contains:

• 1 x pre-filled multidose pen containing 12 micrograms follitropin delta (rhu) in 0.36 mL of solution for injection
• 3 x injection needles

REKOVELLE 36 micrograms pack contains:

• 1 x pre-filled multidose pen containing 36 micrograms follitropin delta (rhu) in 1.08 mL of solution for injection
• 6 x injection needles

REKOVELLE 72 micrograms pack contains:

• 1 x pre-filled multidose pen containing 72 micrograms follitropin delta (rhu) in 2.16 mL of solution for injection
• 9 x injection needles

Each mL of the solution contains 33.3 micrograms of follitropin delta.

Ingredients

The active ingredient in REKOVELLE is follitropin delta.

Other ingredients are:

• phenol
• polysorbate 20
• methionine
• sodium sulfate
• dibasic sodium phosphate dodecahydrate
• phosphoric acid
• sodium hydroxide
• Water for Injections.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

REKOVELLE is supplied in Australia by:

Ferring Pharmaceuticals Pty Ltd
Suite 2, Level 1, Building 1
20 Bridge Street
Pymble, NSW 2073, Australia.

AUST R 289310 - REKOVELLE
12 micrograms/0.36 mL solution for injection in a pre-filled pen.

AUST R 289311 - REKOVELLE
36 micrograms/1.08 mL solution for injection in a pre-filled pen.

AUST R 289312 - REKOVELLE
72 micrograms/2.16 mL solution for injection in a pre-filled pen.

This leaflet was prepared in April 2017. #45471-v1A

REKOVELLE® is a registered trademark of Ferring B.V.

® = Registered Trademark

Published by MIMS June 2018

1 Name of Medicine

Follitropin delta*.

2 Qualitative and Quantitative Composition

* Follitropin delta (rhu) is a recombinant human follicle-stimulating hormone (FSH) produced in a human cell line (PER.C6) by recombinant DNA technology.
Rekovelle 12 micrograms: contains 12 micrograms follitropin delta (rhu) in 0.36 mL. One pre-filled multidose pen contains 12 micrograms follitropin delta (rhu)* in 0.36 mL solution.
Rekovelle 36 micrograms: contains 36 micrograms follitropin delta (rhu) in 1.08 mL. One pre-filled multidose pen contains 36 micrograms follitropin delta (rhu)* in 1.08 mL solution.
Rekovelle 72 micrograms: contains 72 micrograms follitropin delta (rhu) in 2.16 mL. One pre-filled multidose pen contains 72 micrograms follitropin delta (rhu)* in 2.16 mL solution.
For all products, one mL of the solution contains 33.3 micrograms of follitropin delta (rhu).
This medicinal product contains less than 1 mmol (23 mg) sodium per dose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Follitropin delta is a recombinant human follicle-stimulating hormone (FSH) produced in a human cell line (PER.C6) by recombinant DNA technology.
The average molecular weights of the glycosylated α and β subunits are approximately 15,200 and 18,500 Daltons (Da), respectively. Thus, approximately 40% of the total molecular weight of the molecule is due to glycosylation. No animal-derived materials are used in the Rekovelle manufacturing processes.
Solution for injection in a pre-filled multidose pen with injection needles.
Clear and colourless solution. The pH of the solution is 6.0-7.0.

4 Clinical Particulars

4.1 Therapeutic Indications

Controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technologies (ART) such as an in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycle.

4.2 Dose and Method of Administration

Treatment with Rekovelle should be initiated under the supervision of a physician experienced in the treatment of fertility problems. Patients must be educated on how to use the Rekovelle injection pen and to perform injections.
The dosage of Rekovelle is individualised for each patient to obtain an ovarian response with favourable safety/efficacy profile (see Section 5.1 Pharmacodynamic Properties). Rekovelle is dosed in micrograms and not in international units (IU) of biological activity (see Section 5.1 Pharmacodynamic Properties). The dosing regimen is specific for Rekovelle and the microgram dose cannot be applied to other gonadotropins.
For the first treatment cycle, the individual daily dose will be determined on the basis of the woman's serum anti-Müllerian hormone (AMH) concentration, which is a biomarker of ovarian response to gonadotropins, and her body weight. The dose should be based on a recent (i.e. within the last 12 months) determination of AMH concentration measured by one of the following diagnostic tests: Elecsys AMH Plus immunoassay from Roche (i.e. assay used in clinical development trials) or, alternatively, the Access AMH Advanced immunoassay from Beckman Coulter.
The dosing recommendations (based on AMH concentration and body weight) are presented in Table 1. These dosing recommendations rely on the use of the Roche Elecsys AMH Plus or the Beckman Coulter Access AMH Advanced immunoassays. The use of other AMH assays for this purpose is not recommended, as there is currently no standardisation of available AMH assays.
Patients with low AMH levels are likely to have low ovarian reserve.
The individual daily dose is to be maintained throughout the stimulation period. For women with AMH < 15 picomol/L the daily dose is 12 micrograms, irrespective of body weight. For women with AMH ≥ 15 picomol/L the daily dose decreases from 0.19 to 0.10 micrograms/kg by increasing AMH concentration (Table 1). The dose is to be rounded off to the nearest 0.33 micrograms to match the dosing scale on the injection pen. The maximum daily dose for the first treatment cycle is 12 micrograms.
The AMH concentration is to be expressed in picomol/L and is to be rounded off to the nearest integer (Table 1). If the AMH concentration is in nanogram/mL, the concentration should be converted to picomol/L by multiplying by 7.14 (nanogram/mL x 7.14 = picomol/L) before use.
For calculation of the Rekovelle dose, body weight is to be measured without shoes and overcoat just prior to start of stimulation.
Dosing with Rekovelle should be initiated on day 2 or 3 after start of menstrual bleeding in a protocol using a gonadotropin-releasing hormone (GnRH) antagonist, or approximately 2 weeks after the start of agonist treatment in a protocol using down-regulation with a GnRH agonist. Treatment should continue until adequate follicular development has been achieved as assessed by monitoring with ultrasound alone or in combination with measurement of serum oestradiol levels. Adequate follicular development is achieved on average by the ninth or tenth day of treatment (range 5 to 20 days). As soon as ≥ 3 follicles ≥ 17 mm are observed, a single injection of 250 micrograms recombinant human chorionic gonadotropin (hCG) or 5,000 IU hCG is administered to induce final follicular maturation.
In patients with excessive ovarian response at risk of ovarian hyperstimulation syndrome (OHSS), in GnRH antagonist cycles, administration of a GnRH agonist instead of hCG could be considered for triggering of final follicular maturation. Administration of GnRH agonist can reduce, but not eliminate, the risk for OHSS and is applicable only for GnRH antagonist cycles. In case of GnRH agonist administration, embryos should not be replaced in the fresh cycle but cryopreserved for later use. In patients with excessive ovarian response of > 35 follicles with a diameter ≥ 12 mm, triggering of final follicular maturation should not be performed and the cycle cancelled.
For subsequent treatment cycles, the daily dose of Rekovelle should be maintained or modified according to the patient's ovarian response in the previous cycle. The maximum daily dose is 24 micrograms.
If the patient had adequate ovarian response in the previous cycle without developing OHSS, the same daily dose of Rekovelle should be used.
In case of ovarian hypo-response in the previous cycle, the daily dose of Rekovelle in the subsequent cycle should be increased by 25% or 50%, according to the extent of response observed.
In case of ovarian hyper-response in the previous cycle, the daily dose of Rekovelle in the subsequent cycle should be decreased by 20% or 33%, according to the extent of response observed.
In patients who developed OHSS or were at risk of OHSS in a previous cycle, the daily dose of Rekovelle for the subsequent cycle is 33% lower than the dose used in the cycle where OHSS or risk of OHSS occurred.

Patients with AMH > 35 picomol/L.

Patients with renal and hepatic impairment.

Polycystic ovarian syndrome patients with anovulatory disorders.

Elderly (more than 65 years).

Paediatric population.

Method of administration.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in Section 6.1 List of Excipients.
Tumours of the hypothalamus or pituitary gland.
Ovarian enlargement or ovarian cyst not due to polycystic ovarian syndrome.
Gynaecological haemorrhages of unknown aetiology.
Ovarian, uterine or mammary carcinoma.
Pregnancy and lactation.
Rekovelle must not be used when an effective response cannot be obtained, such as:
primary ovarian failure;
malformations of sexual organs incompatible with pregnancy;
fibroid tumours of the uterus incompatible with pregnancy.

4.4 Special Warnings and Precautions for Use

Rekovelle contains a potent gonadotropic 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.
Gonadotropin therapy requires time commitment by physicians and supportive healthcare professionals, as well as the availability of appropriate monitoring facilities. Safe and effective use of Rekovelle calls for monitoring of ovarian response with ultrasound alone, or in combination with measurement of serum oestradiol levels, on a regular basis. The dose of Rekovelle is individualised for each patient to obtain an ovarian response with a favourable safety/efficacy profile. There may be a degree of inter-patient variability in response to FSH administration, with poor response to FSH in some patients and exaggerated response in others.
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 and hyperprolactinaemia, and the appropriate specific treatment should be given.
Patients undergoing stimulation of follicular growth may experience ovarian enlargement and may be at risk of developing ovarian hyperstimulation syndrome. Adherence to the Rekovelle dose and regimen of administration and careful monitoring of therapy will minimise the incidence of such events.

Ovarian hyperstimulation syndrome (OHSS).

Thromboembolic events.

Ovarian torsion.

Multiple pregnancy.

Pregnancy loss.

Ectopic pregnancy.

Reproductive system neoplasms.

Congenital malformation.

Other medical conditions.

Sodium content.

Use in women over 40 years of age.

Use in the elderly.

Paediatric use.

Effects on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed with Rekovelle. With pituitary desensitisation caused by a GnRH agonist, a longer duration of stimulation and therefore a higher total dose of Rekovelle may be necessary to achieve adequate follicular response.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

4.7 Effects on Ability to Drive and Use Machines

Rekovelle is expected to have no or negligible influence on the ability to drive and use machines.

4.8 Adverse Effects (Undesirable Effects)

Table 2 combines all three controlled ovarian stimulation (COS) cycles in the ESTHER trials and thus provides the most frequent adverse events based on 1,012 treatment cycles with Rekovelle and 1,015 treatment cycles with GONAL-F in the phase 3 program conducted in IVF/ICSI patients.

Summary of safety profile.

ADRs from clinical trials.

ADRs from post-marketing sources.

Reporting suspected adverse effects.

4.9 Overdose

The effect of an overdose in humans is unknown, nevertheless, there is a risk 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 131 126 (Australia).
Advise your patients to immediately contact their doctor or the Poisons Information Centre (telephone 131 126) if they are concerned that they have given themselves too much Rekovelle.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Sex hormones and modulators of the genital systems, gonadotropins and other ovulation stimulants, gonadotropins.
ATC code: G03GA10.

Mechanism of action.

Pharmacodynamic effects compared to follitropin alfa.

Factors influencing response.

Clinical trials.

Ovarian response and total FSH dose.

Safety - OHSS risk management.

Safety - immunogenicity.

5.2 Pharmacokinetic Properties

The pharmacokinetic profile of Rekovelle has been investigated in healthy female subjects and in in vitro fertilisation (IVF)/intracytoplasmic sperm injection (ICSI) patients undergoing controlled ovarian stimulation (COS). Following repeated daily subcutaneous administration, Rekovelle reaches steady-state within 6 to 7 days with a three-fold higher concentration compared with the concentration after the first dose. Circulating levels of Rekovelle are inversely related to the body weight, which supports individualised dosing based on body weight.
Within the therapeutic dose range, exposure to Rekovelle increases proportionally with the dose.

Absorption.

Distribution.

Metabolism.

Excretion.

5.3 Preclinical Safety Data

Genotoxicity.

Carcinogenicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

Rekovelle solution for injection contains the following excipients: phenol, polysorbate 20, methionine, sodium sulfate decahydrate, dibasic sodium phosphate dodecahydrate, phosphoric acid (for pH adjustment), sodium hydroxide (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

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store in a refrigerator (2°C-8°C). Do not freeze.
Within its shelf life, Rekovelle may be removed from the refrigerator, without being refrigerated again, and stored at or below 25°C for up to 3 months and must be discarded afterwards.

Before use.

After the first injection.

6.5 Nature and Contents of Container

Rekovelle is a clear and colourless solution for injection presented in a pre-filled multidose pen with a dose selection knob, display window and cap. Each pen contains an integrated non-replaceable cartridge containing the solution for injection.

12 micrograms.

36 micrograms.

72 micrograms.

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.

CAS number.

7 Medicine Schedule (Poisons Standard)

(S4) Prescription Only Medicine.

Summary Table of Changes