Consumer medicine information

Pergoveris Solution for Injection

Follitropin alfa; Lutropin alfa

BRAND INFORMATION

Brand name

Pergoveris Solution for Injection

Active ingredient

Follitropin alfa; Lutropin alfa

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Pergoveris Solution for Injection.

What is in this leaflet

This leaflet answers some common questions about PERGOVERIS.

It does not contain all the available information.

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

All medicines have benefits and risks. Your doctor has weighed the risks of you using PERGOVERIS against the benefits it is expected to have for you.

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

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

What PERGOVERIS is used for

PERGOVERIS is a medicine containing follitropin alfa, a recombinant follicle stimulating hormone (FSH) and lutropin alfa, a recombinant luteinising hormone (LH), which are essentially similar to the hormones found naturally in humans, but they are made by means of biotechnology. They belong to the family of hormones called gonadotrophins, which are involved in the normal control of reproduction.

PERGOVERIS is for the treatment of women who have been shown to produce very low levels of some of the hormones involved in the natural reproductive cycle. PERGOVERIS is used to bring about the development of a single mature follicle. Follicles are structures in the ovaries that mature the eggs (ova). Once adequate follicular development is achieved, a single injectable dose of human chorionic gonadotrophins (hCG) is given, which leads to the release of an egg from the follicle (ovulation).

Ask your doctor if you have any questions about why PERGOVERIS has been prescribed for you. You doctor may have prescribed it for another reason.

PERGOVERIS is available only on a doctor's prescription.

PERGOVERIS is not habit-forming.

Before you are given PERGOVERIS

When you must not use it

Do not use PERGOVERIS if:

  • you have a history of allergy to gonadotrophins or to any of the ingredients listed at the end of this leaflet.

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 PERGOVERIS 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
  • you have tumours of the pituitary gland or hypothalamus.

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

Do not use this medicine after the expiry date (month/year) on the packaging has passed, or if the packaging is torn or shows signs of tampering. If your medicine has expired or is damaged, return it to your pharmacist or clinic for disposal.

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

Before you start to use it

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

Tell your doctor if you are breastfeeding. PERGOVERIS should not be used while you are breastfeeding.

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

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

  • premature menopause
  • disorders of the thyroid gland
  • disorders of the adrenal glands
  • high prolactin levels in the blood
  • fibroid tumours in your uterus which would make pregnancy impossible
  • if you have been through menopause
  • kidney disease
  • liver disease
  • you or your family have increased risk factors for developing blood clots, e.g. stroke, heart attacks.
  • porphyria or a family history of porphyria.

Treatment with PERGOVERIS 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 using ultrasound and blood tests to help determine if you are likely to develop OHSS.

If necessary, your doctor will delay or cancel your PERGOVERIS injection. You may also be advised to refrain from sexual intercourse or use barrier methods until the end of the cycle if this occurs.

Compared to natural conception, the frequency of multiple pregnancies and births is increased in patients receiving treatments that stimulate follicle growth for ovulation induction. The majority of these are twins. Your doctor will monitor your ovarian response to minimise the chance of multiple pregnancies, because of the greater risks they carry for mothers and babies. However, this risk can be minimised by using the recommended dose and time of injections.

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.

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

Taking other medicines

Tell your doctor if you are taking any other medicines:

  • all prescription medicines
  • all medicines, vitamins, herbal supplements or natural therapies you buy without a prescription from your pharmacy, supermarket, naturopath or health food shop.

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

How PERGOVERIS 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 PERGOVERIS should be started under the supervision of a specialist doctor experienced in fertility treatment.

PERGOVERIS is given as a course of daily injections. You should have your injection at the same time each day.

PERGOVERIS should not be given in the same injection with other medicines. If needed, PERGOVERIS solution for injection may be administered along with follitropin alfa as separate injections.

Do not use PERGOVERIS on anyone else. It is for your use only.

How much to inject

Your treatment should be tailored according to your individual response.

Your doctor will tell you how much PERGOVERIS to use and when to inject it.

It is usually recommended that your treatment with PERGOVERIS starts with 150 IU of follitropin alfa/75 IU of lutropin alfa once a day.

If needed, your doctor may increase your dose of follitropin alfa by 37.5 - 75 IU, preferably at 7-14 day intervals.

How to inject

PERGOVERIS is given as a subcutaneous (under your skin) injection in the lower abdominal area or thigh, each day for up to 3 weeks.

Your doctor may decide to extend the treatment to up to 5 weeks.

PERGOVERIS is intended to be injected by you or by your partner.

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 a nurse will teach you the injection technique.

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

PERGOVERIS 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 discolouration.

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

If you forget to inject PERGOVERIS

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 trouble remembering to inject your medicine.

If you injected too much

Immediately contact your doctor or the Poisons Information Centre (telephone 131 126) if you are concerned that you have given yourself too much or someone else has injected themselves with PERGOVERIS.

While you are using PERGOVERIS

Your doctor will carefully monitor your response using ultrasound and blood tests before and during treatment with PERGOVERIS.

Things you must do

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

Tell your doctor immediately if you become pregnant while using PERGOVERIS.

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

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

Tell all the doctors, dentists and pharmacists who are treating you that you are using PERGOVERIS.

Things you must not do

If you are self-injecting do not:

  • Stop using PERGOVERIS without telling your doctor.
  • 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 prevent the medicine 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.

Things to be careful of

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

Side effects

Tell your doctor as soon as possible if you do not feel well while using PERGOVERIS.

All medicines can have side effects. Sometimes they are serious, most of the time they are not.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

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

Tell your doctor immediately, or go to the Accident and Emergency section of your nearest hospital if you experience any of the following:

  • signs of allergic reactions, including 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
  • vaginal bleeding
  • inflammation, swelling or pain in your legs
  • 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
  • warning signs of stroke or heart attack
  • warning signs of blood clots (such as pain, warmth, redness, numbness or tingling in arm or leg).

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

  • headache, dizziness
  • nausea, vomiting, diarrhoea, abdominal discomfort, abdominal distension, abdominal pain
  • ovarian cysts, ovarian enlargement, breast pain, pelvic pain
  • local reactions at the injection site, such as bruising, pain, redness, itching or swelling.

Ectopic pregnancy (embryo implanted outside the womb) may occur, especially in women with a history of prior tubal disease.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some patients.

After using PERGOVERIS

Storage

Prior to using, store PERGOVERIS in the original package at 2°C to 8°C (Refrigerate. Do not freeze). Protect from light.

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

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

Do not use the product after the expiry date printed on the label.

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

Do not store it or any other medicine in the bathroom or near a sink.

Do not leave it in the car.

Keep this medicine where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

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

If you have any PERGOVERIS that has expired or is left over from your treatment, refer this to your clinic.

Product description

What it looks like

PERGOVERIS solution for injection contains sterile, clear, colourless to slightly yellow solution for injection in a cartridge, pre-assembled in a disposable pen.

PERGOVERIS solution for injection is available in the following presentations and pack sizes*:

  • 300 IU of follitropin alfa and 150 IU of lutropin alfa in 0.48 mL.
    The pack contains 1 cartridge of solution for injection pre-assembled in a disposable pen and 5 needles for administration.
  • 450 IU of follitropin alfa and 225 IU of lutropin alfa in 0.72 mL.
    The pack contains 1 cartridge of solution for injection pre-assembled in a disposable pen and 7 needles for administration.
  • 900 IU of follitropin alfa and 450 IU of lutropin alfa in 1.44 mL.
    The pack contains 1 cartridge of solution for injection pre-assembled in a disposable pen and 14 needles for administration.

* Not all presentations and pack sizes may be marketed.

Ingredients

Active ingredient:

  • Follitropin alfa (rch)
  • Lutropin alfa (rch)

Inactive ingredients:

  • Poloxamer
  • Arginine hydrochloride
  • Phenol
  • Dibasic sodium phosphate dihydrate
  • Monobasic sodium phosphate monohydrate
  • Methionine
  • Sucrose
  • Phosphoric acid
  • Sodium hydroxide
  • Water for injections

Supplier

PERGOVERIS solution for injection 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]
For enquiries call: 1800 633 463

Australian Registration Number

PERGOVERIS follitropin alfa (rch)/lutropin alfa (rch) 300 IU/150 IU in 0.48 mL solution for injection cartridge pre-assembled in a pen: AUST R 288927

PERGOVERIS follitropin alfa (rch)/lutropin alfa (rch) 450 IU/225 IU in 0.72 mL solution for injection cartridge pre-assembled in a pen: AUST R 288928

PERGOVERIS follitropin alfa (rch)/lutropin alfa (rch) 900 IU/450 IU in 1.44 mL solution for injection cartridge pre-assembled in a pen: AUST R 288929

Date of preparation

This leaflet was prepared in February 2020

A004-0220

Published by MIMS April 2020

BRAND INFORMATION

Brand name

Pergoveris Solution for Injection

Active ingredient

Follitropin alfa; Lutropin alfa

Schedule

S4

 

1 Name of Medicine

Follitropin alfa (rch)/lutropin alfa (rch).

2 Qualitative and Quantitative Composition

Pergoveris contains follitropin alfa (recombinant human follicle stimulating hormone (r-hFSH)) and lutropin alfa (recombinant human luteinising hormone (r-hLH)) produced by genetically engineered Chinese Hamster Ovary (CHO) cells.
Each cartridge of Pergoveris contains:
300 IU (equivalent to 21.84 microgram) of follitropin alfa (r-hFSH) and 150 lutropin alfa (equivalent to 6 microgram) of lutropin alfa (r-hLH) in 0.48 mL solution; or
450 IU (equivalent to 32.76 microgram) of follitropin alfa (r-hFSH) and 225 IU (equivalent to 9 microgram) of lutropin alfa (r-hLH) in 0.72 mL; or
900 IU (equivalent to 65.52 microgram) of follitropin alfa (r-hFSH) and 450 IU (equivalent to 18 microgram) of lutropin alfa (r-hLH) in 1.44 mL solution.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Pergoveris is presented as a sterile solution for injection in a cartridge, pre-assembled in a disposable pen.

4 Clinical Particulars

4.1 Therapeutic Indications

Pergoveris is indicated for the stimulation of follicular development in women with severe LH and FSH deficiency.

4.2 Dose and Method of Administration

Treatment with Pergoveris should be initiated under the supervision of a physician experienced in the treatment of fertility problems. The injection site should be alternated daily to prevent lipoatrophy. Self-administration of Pergoveris should only be performed by patients who are well-motivated, adequately trained and with access to expert advice.
In LH and FSH deficient women, the objective of Pergoveris therapy is to promote follicular development followed by final maturation after the administration of human chorionic gonadotrophin (hCG). Pergoveris should be given as a course of daily injections. If the patient is amenorrhoeic and has low endogenous oestrogen secretion, treatment can commence at any time. Nevertheless, the possibility of pregnancy should be first excluded by clinical or other means.
Pergoveris is intended for daily subcutaneous administration.
A treatment regimen commences with the recommended dose of Pergoveris containing 150 IU r-hFSH/75 IU r-hLH once daily. If less than the recommended dose of Pergoveris daily is used, the follicular response may be unsatisfactory because the amount of lutropin alfa may be insufficient. Treatment should be tailored to the individual patient's response as assessed by measuring (i) follicle size by ultrasound and (ii) oestrogen response.
The majority of the women with very low LH levels (< 1.2 IU/L as used in clinical studies, but this may vary from laboratory to laboratory) will have a poor ovarian response to r-hFSH alone. However, some women may have adequate follicular response. Clinicians will need to decide on a case by case basis whether to commence ovulation induction with r-hFSH alone or in combination with r-hLH.
The efficacy studies have suggested that the minimum effective daily dose of lutropin alfa is 37.5 IU. However, dose titration is recommended according to individual patient response.
If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7 to 14 day intervals and preferably by 37.5 to 75 IU increments using a licensed follitropin alfa preparation. It may be acceptable to extend the duration of stimulation in any one cycle up to 5 weeks.
When an optimal response is obtained, a single injection of 250 microgram of recombinant hCG or 5,000 IU to 10,000 IU hCG should be administered 24 to 48 hours after the last Pergoveris injection. The patient is recommended to have coitus on the day of, and on the day following, hCG administration. Alternatively, intrauterine insemination (IUI) or another medically assisted reproduction procedure may be performed based on the physician's judgement of the clinical case. Luteal phase support should be considered since lack of endogenous gonadotrophins after ovulation may lead to premature failure of the corpus luteum.
If an excessive response is obtained, treatment with Pergoveris should be stopped and the trigger hCG injection withheld. Treatment should recommence in the next cycle at an FSH dosage lower than that of the previous cycle.
Pergoveris is for individual patient use only.

4.3 Contraindications

Pergoveris is contraindicated in patients with:
hypersensitivity to gonadotrophins or to any of the excipients;
ovarian, uterine or mammary carcinoma;
tumours of the hypothalamus or pituitary gland;
ovarian enlargement or cyst of unknown aetiology;
gynaecological haemorrhages of unknown origin;
pregnancy and lactation.

4.4 Special Warnings and Precautions for Use

Before starting treatment, the couple's infertility should be assessed as appropriate and putative contraindications for pregnancy evaluated. It is recommended that Pergoveris is not used in conditions where an effective response is usually not expected, such as primary ovarian failure, malformation of the sexual organs or fibroid tumours of the uterus that are incompatible with pregnancy. In addition, patients should be evaluated for hypothyroidism, adrenocortical deficiency and hyperprolactinemia, and appropriate specific treatment given.

Ovarian hyperstimulation syndrome (OHSS).

A certain degree of ovarian enlargement is an expected effect of controlled ovarian stimulation. It is more commonly seen in women with polycystic ovarian syndrome and usually regresses without treatment.
Distinct from uncomplicated ovarian enlargement, OHSS is a condition that can manifest itself with various 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 cavity, pleural, and rarely, in the pericardial cavities.
Mild to moderate OHSS is a common adverse effect of ovulation induction with gonadotrophins; the risk should be considered and discussed with women prior to treatment.
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 and oliguria. Clinical evaluation may reveal signs such as hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, pleural effusions or acute pulmonary distress. Very rarely, severe OHSS may be complicated by ovarian torsion or thromboembolic events, such as pulmonary embolism, ischaemic stroke or myocardial infarction.
Independent risk factors for developing OHSS include young age, lean body mass, polycystic ovarian syndrome (PCOS), higher doses of exogenous gonadotrophins, 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 Assisted Reproductive Technology (ART) cycles. In clinical trials, lutropin alfa has been associated with higher oestradiol levels than follitropin alfa alone.
Adherence to recommended Pergoveris and FSH dosage and regimen of administration and careful monitoring of therapy will minimise the incidence of OHSS. Monitoring of stimulation cycles by ultrasound scans, as well as oestradiol measurements, is recommended to identify risk factors early.
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.
There is evidence to suggest that hCG plays a key role in triggering OHSS and that the syndrome may be more severe and more protracted if pregnancy occurs. Therefore, if monitoring results indicate a high risk of OHSS or if signs of ovarian hyperstimulation occur, it is recommended that hCG be withheld and the patient be advised to refrain from coitus or use barrier contraceptive methods for at least 4 days. 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 usually resolves spontaneously with the onset of menses. If severe OHSS occurs, it is recommended that treatment be stopped, the patient be hospitalised and appropriate therapy started. Treatment 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 monitored in the following manner: 1) fluid intake and output, 2) weight, 3) haematocrit, 4) serum and urinary electrolytes, 5) urine specific gravity 6) Blood Urea Nitrogen (BUN) and creatinine levels 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.

Multiple pregnancy.

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.
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 than following natural conception.

Thromboembolic events.

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 carry an increased risk of thromboembolic events.
In very rare instances, thromboembolism has been associated with gonadotrophin therapy.

Porphyria.

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

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 foetal development, parturition or postnatal development, ovulation induction agents cannot be excluded as a contributing factor.

Use in hepatic or renal impairment.

Caution should be used and close monitoring considered when administering Pergoveris to patients with renal or hepatic impairment. There are currently no data available on the use of Pergoveris in patients with hepatic or renal impairment.

Use in the elderly.

No data available.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pergoveris solution for injection in a pre-filled pen must not be administered as a mixture with other medicinal products in the same injection.
Pergoveris solution for injection in a pre-filled pen may be administered concomitantly with follitropin alfa as separate injections.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

See Section 4.1 Therapeutic Indications.
(Category D)
Pergoveris should not be administered during pregnancy as it may cause foetal harm when given to a pregnant woman (see Section 4.3 Contraindications).
Treatment of pregnant rats and rabbits with r-hLH at subcutaneous doses of 10 IU/kg/day and above was associated with embryonic resorptions (approximately 0.4x and 0.8x clinical exposure at the maximum recommended clinical dose of 225 IU/day, based on body surface area, respectively). Teratogenicity was not observed in pregnant rats and rabbits dosed with r-hLH at subcutaneous doses up to 20 IU/kg/day (approximately 0.8x and 1.6x clinical exposure, based on body surface area, respectively). Administration of 10 IU/kg/day r-hLH to rats from late gestation to weaning resulted in adverse effects on the post-natal survival and growth of offspring.
In rats and rabbits, follitropin alfa caused dystocia and marked post implantation 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.
 Pergoveris should not be administered during lactation (see Section 4.3 Contraindications). Secretion of r-hLH and/or its degradation products has been shown to occur in lactating rats. 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.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive or 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)

Pergoveris is a fixed dose combination product, containing lutropin alfa and follitropin alfa. In this context, undesirable effects may be due to either or both of these substances, or to their pharmacodynamic consequences.
In clinical trials with lutropin alfa, a maximal score of all mild and moderate injection site reactions (bruising, pain, redness, itching or swelling) was reported in 12.7% (mild) and 2.7% (moderate) of the 2282 injections in 271 treatment cycles, respectively. Among the 170 patients treated, only 2 patients (1.2%) reported a severe injection site reaction.
OHSS was observed in 3.9% of treatment cycles with lutropin alfa. Six serious OHSS reports (2.3%) occurred in 259 treatment cycles.
In very rare instances, thromboembolisms have been associated with human menopausal gonadotrophin therapy. Although these adverse events were not observed, there is a possibility that they may also occur with Pergoveris. Ovarian cysts and enlargements are common. Complications including adnexal torsion and haemoperitoneum have been reported rarely with human menopausal gonadotrophin therapy.
Ectopic pregnancy may also occur, especially in women with a history or prior tubal disease.
The reported undesirable effects are consistent with those reported for other hLH-containing products.
The reactions reported below are classified according to frequency of occurrence as follows (see Table 1).

General disorders and administration site conditions.

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

Reproductive system and breast disorders.

Very common: ovarian cyst, mild to moderate ovarian enlargement.
Common: mild or moderate OHSS (including symptomatology), breast pain, pelvic pain.
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.

Very rare: thromboembolism, usually associated with severe OHSS.

Respiratory, thoracic and mediastinal disorders.

Very rare: exacerbation or aggravation of asthma.

Immune system disorders.

Very rare: mild to severe hypersensitivity reactions including anaphylactic reactions and shock.
See Section 4.4 Special Warnings and Precautions for Use for information on symptoms and management of OHSS.

Reporting of 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 in Australia, or at https://nzphvc.otago.ac.nz/reporting/ in New Zealand.

4.9 Overdose

The effects of overdosage of Pergoveris are unknown, nevertheless there is a possibility that OHSS may occur which is further described in Section 4.4 Special Warnings and Precautions for Use.
Single doses of up to 40,000 IU of lutropin alfa have been administered to healthy female volunteers without serious adverse events and were well tolerated.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia) or 0800 764 766 (New Zealand).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Luteinising hormone binds on the ovarian theca (and granulosa) cells and testicular Leydig cells to a receptor shared with human chorionic gonadotrophin hormone (hCG). This LH/hCG transmembrane receptor is a member of the super-family of G protein-coupled receptors and has a large extracellular domain. The in vitro binding affinities of r-hLH, pituitary hLH and hCG to the LH/hCG receptor on murine Leydig tumour cells are of similar orders of magnitude.
Luteinising hormone (LH) and follicle stimulating hormone (FSH) are secreted from the anterior pituitary gland in response to gonadotropin-releasing hormone (GnRH) and play a complementary role in follicle development and ovulation. In theca cells, LH stimulates the secretion of androgens that are transferred to granulosa cells to be converted to oestradiol (E2) by aromatase. In granulosa cells, FSH stimulates the development of ovarian follicles, while LH action is involved in follicle development, maturation and steroidogenesis.
In the stimulation of follicular development in anovulatory women deficient in LH and FSH, the primary effect resulting from administration of r-hLH is an increase in oestradiol secretion by the follicles, while administration of r-hFSH primarily stimulates the growth and maturation of the follicles.

Clinical trials.

The safety and efficacy of the combination of follitropin alfa and lutropin alfa have been examined in five studies for induction of ovulation in women with hypogonadotropic hypogonadism (HH).
Pivotal studies. The safety and efficacy of the combination of follitropin alfa and lutropin alfa administered concomitantly, subcutaneously, in women with HH for ovulation induction was assessed and confirmed in the following two international pivotal studies.
In clinical trials (studies 6253 and 21008), patients were defined by an endogenous serum LH level < 1.2 IU/L as measured in a central laboratory. However, it should be taken into account that there are variations between LH measurements performed in different laboratories.

Study 6253.

Study 6253 was a Phase II randomised, open-label, dose-finding study to determine the minimal effective dose and assess the safety of r-hLH to support r-hFSH-induced follicular development in LH and FSH deficient anovulatory women. Patients were randomised to treatment with 0, 25, 75 or 225 IU r-hLH concomitant with 150 IU of r-hFSH for up to 3 treatment cycles. Thirty-eight patients were enrolled and treated in a total of 53 treatment cycles.
The proportion of patients who fulfilled the primary efficacy endpoint criteria (at least one follicle ≥ 17 mm; E2 ≥ 400 picomol/L; mid-luteal phase P4 ≥ 25 nanomol/L) was related to the dose of r-hLH, both when excessive follicular development was not included as a success (0.0%, 14.3%, 44.4% and 50.0% for treatment with 0, 25, 75 and 225 IU r-hLH, respectively; p=0.0124) and when excessive follicular development was included as a success (0.0%, 14.3%, 66.7% and 80.0% for treatment with 0, 25, 75 and 225 IU r-hLH, respectively; p=0.0001).

Study 21008.

The safety and efficacy of lutropin alfa 75 IU administered subcutaneously in conjunction with follitropin alfa for induction of ovulation in women with HH and severe gonadotrophin deficiency was assessed in this Phase III double-blind, placebo-controlled, randomised trial of 39 women.
The primary efficacy parameter in this single-cycle study was follicular development as defined by: (i) at least one follicle with a mean diameter of ≥ 17 mm, (ii) pre-ovulatory serum E2 level ≥ 109 picogram/mL (400 picomol/L) and (iii) mid-luteal phase P4 level ≥ 7.9 nanogram/mL (25 nanomol/L). Patients with excessive follicular development or who became pregnant were considered treatment successes from the perspective of the analysis.
The efficacy results for Study 21008 are summarised in Table 2.
The efficacy results for the same study are also assessed when the risk of OHSS is considered as an efficacy failure in Table 3.
In studies 6253 and 21008, achievement of an adequate follicular development as the optimal well-established, surrogate marker of conception was consistently found in 66.7% of patients with LH < 1.2 IU treated with 150 IU follitropin alfa and 75 IU lutropin alfa. This result was based on Studies 6253 [66.7%] and 21008 [66.7%] and was calculated when risk of ovarian hyperstimulation syndrome (OHSS) and pregnancy outcome were considered as treatment successes. When patients with risk of OHSS were considered as a treatment failure, adequate follicular development was found in 43.2% of patients (combined analysis of follicular development in Studies 6253 and 21008).
Other studies. The safety and efficacy of lutropin alfa administered subcutaneously concomitantly with follitropin alfa for ovulation induction in women with HH was also investigated in three additional studies.
Study 6905 was a Phase II/III open-label, randomised, multicentre study to determine the minimal effective dose and assess the safety of lutropin alfa administered with follitropin alfa to induce follicular development in anovulatory women with hypogonadotropic hypogonadism and moderate gonadotrophin deficiency. Forty patients were enrolled and treated.
Study 7798 was a Phase III multicentre study to assess the efficacy and safety of lutropin alfa administered with follitropin alfa for up to three treatment cycles in induction of follicular development in LH and FSH deficient anovulatory women and enrolled 15 patients.
Study 8297 was a Phase III multicentre, non-comparative study to assess the efficacy and safety of lutropin alfa administered with follitropin alfa for up to three treatment cycles in induction of follicular development in LH and FSH-deficient anovulatory women and enrolled 38 patients.
Among the 170 patients with HH enrolled in the 5 lutropin alfa development studies, 154 were seeking fertility and of these 127 were treated with lutropin alfa. Overall 41 of 127 (32%) lutropin alfa treated patients (all doses) and 31 of 100 (31%) in the lutropin alfa 75 IU dose group achieved a pregnancy over a total of 205 treatment cycles (see Table 4).

5.2 Pharmacokinetic Properties

Follitropin alfa and lutropin alfa combination has shown the same pharmacokinetic profile as follitropin alfa and lutropin alfa separately.

Follitropin alfa.

Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life 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.

Lutropin alfa.

The pharmacokinetics of lutropin alfa have been studied in pituitary desensitised female volunteers from 75 IU up to 40,000 IU.
The pharmacokinetic profile of lutropin alfa is similar to that of urinary-derived hLH. Following intravenous administration, lutropin alfa is rapidly distributed with an initial half-life of approximately one hour and eliminated from the body with a terminal half-life of about 10-12 hours. The steady state volume of distribution is around 10-14 L. Lutropin alfa shows linear pharmacokinetics, as assessed by AUC, which is directly proportional to the dose administered. Total clearance is around 2 L/h, and less than 5% of the dose is excreted in the urine. The mean residence time is approximately 5 hours.
Following subcutaneous administration, the absolute bioavailability is approximately 60%; the terminal half-life is slightly prolonged. The lutropin alfa pharmacokinetics following single and repeated administration of lutropin alfa are comparable and the accumulation ratio of lutropin alfa minimal. There is no pharmacokinetic interaction with follitropin alfa when administered simultaneously.
A phase I, open label, randomised, two-period, two-sequence crossover study was conducted to assess the bioequivalence of Pergoveris powder for injection and Pergoveris solution for injection formulations, administered subcutaneously in pituitary suppressed healthy premenopausal female subjects. In this study, 900 IU r-hFSH and 450 IU r-hLH of each formulation was given as a single dose of two injections (450 IU/225 IU each). The total volume given for the corresponding total dose (900 IU/450 IU) was 1.44 mL and 1.4 mL for solution for injection and powder for injection formulations, respectively. The reference solution was given by administering two injections each of 0.7 mL diluent with three vials (150 IU r-hFSH and 75 IU r-hLH each) of the current powder for injection formulation.
A summary of the key pharmacokinetic parameters after subcutaneous administration of both formulations is shown in Table 5.
The statistical analysis showed that the mean ratios and 90% confidence intervals for Cmax and AUC0-t were within the acceptance range of 0.80 to 1.25 for both r-hFSH and r-hLH, thus bioequivalence of Pergoveris powder for injection and Pergoveris solution for injection formulations can be concluded.

5.3 Preclinical Safety Data

Genotoxicity.

Lutropin alfa was inactive in in vitro tests for gene mutation and chromosomal damage, and in an in vivo mouse micronucleus test. Follitropin alfa showed no genotoxic activity in a series of assays performed to evaluate its potential to cause gene mutations (Salmonella typhimurium, E. 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 and lutropin alfa.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sucrose, arginine hydrochloride, poloxamer, methionine, phenol, dibasic sodium phosphate dihydrate, monobasic sodium phosphate monohydrate, sodium hydroxide, phosphoric acid and water for injections.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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

Store at 2°C to 8°C (Refrigerate. Do not freeze). Protect from light.
After the first injection, Pergoveris solution for injection 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

Solution for injection in a clear glass cartridge (Type I) with a grey bromobutyl rubber plunger and a crimp cap with a grey rubber stopper septum and aluminium, pre-assembled in a pre-filled pen.
Pergoveris solution for injection is available in the following strengths and pack sizes*.
300 IU r-hFSH/150 IU r-hLH in 0.48 mL nominal volume. Each pen is sufficient for two doses of 150 IU r-hFSH/75 IU r-hLH. One pack contains 1 cartridge of solution for injection pre-assembled in a disposable pen and 5 needles for administration.
450 IU r-hFSH/225 IU r-hLH in 0.72 mL nominal volume. Each pen is sufficient for three doses of 150 IU r-hFSH/75 IU r-hLH. One pack contains 1 cartridge of solution for injection pre-assembled in a disposable pen and 7 needles for administration.
900 IU r-hFSH/450 IU r-hLH in 1.44 mL nominal volume. Each pen is sufficient for six doses of 150 IU r-hFSH/75 IU r-hLH. One pack contains 1 cartridge of solution for injection pre-assembled in a disposable pen and 14 needles for administration.
*Not all strengths and pack sizes may be marketed.

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.

Pergoveris contains recombinant human follicle stimulating hormone (follitropin alfa (rch)) and recombinant human luteinising hormone (lutropin alfa (rch)).
Human follicle stimulating hormone (hFSH) is a glycoprotein (Molecular Weight (MW) about 30,000 Da) and is characterised by two amino acid chains known as α and β.
Recombinant human follicle stimulating hormone (r-hFSH) is a human gonadotrophin hormone of 203 amino acids, which consists of two non-covalently linked, non-identical protein components designated as the α- and β-subunits. The α-subunit is formed by 92 amino acids and possesses two sites of N-linked glycosylation (Asn-52 and Asn-78). Five disulphide bonds contribute to its tertiary structure. The β-subunit is formed by 111 amino acids carrying two carbohydrate moieties linked to Asn-7 and Asn-24 and containing six disulphide bonds.
Human luteinising hormone (hLH) is a glycoprotein (MW about 29,000 Da) that consists of two non-covalently linked, non-identical protein components designated as the α- and β-subunits.
Recombinant human luteinising hormone (r-hLH) is a human gonadotrophin hormone, composed of two non-covalently linked, non-identical subunits, designated as the α- and β-subunits. The α-subunit is identical to the one described above. The β-subunit, which is hormone specific, is 121 amino acids in length and possesses a single site of N-linked glycosylation (Asn-30). It contains six disulphide bridges.
For both r-hFSH and r-hLH, the α-chain is common to all gonadotrophin family, with specificity residing in the β-chain. The β-chain confers biological activity.
The physicochemical, immunological and biological activities of r-hLH are comparable to those of human menopausal urinary-hLH (u-hLH).
The main difference between u-hLH and r-hLH is that the u-hLH carbohydrate moieties are essentially capped with sulphate groups, while in r-hLH it is with sialic acid. Preclinical and clinical experience, however, indicate that this has no significant impact on the pharmacokinetic characteristics of these molecules.

CAS number.

CAS-146479-72-3 (follitropin alfa); CAS-152923-57-4 (lutropin alfa); CAS-56832-30-5 (α-subunit, lutropin alfa); CAS-53664-53-2 (β-subunit, lutropin alfa).

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes