Consumer medicine information

Puregon

Follitropin beta

BRAND INFORMATION

Brand name

Puregon Solution for injection

Active ingredient

Follitropin beta

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Puregon.

What is in this leaflet

This leaflet answers some common questions about PUREGON.

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 PUREGON against the benefits they expect it will have for you.

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

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

What PUREGON is used for

PUREGON solution for injection contains follitropin beta, a hormone known as follicle stimulating hormone (FSH).

FSH belongs to the group of gonadotrophins, which play an important role in human fertility and reproduction. FSH is needed in women for the growth and development of follicles in the ovaries. Follicles are small round sacs that contain the egg cells.

In men, FSH is needed for the production of sperm.

PUREGON is used to treat infertility in any of the following situations:

Women:

  • PUREGON can be used to cause ovulation in women who have not responded to treatment with clomiphene citrate.
  • PUREGON can be used to bring about the development of multiple follicles in women undergoing assisted reproduction technologies (ART) such as in vitro fertilisation (IVF).

Men:
PUREGON can be used for the production of sperm in men who are infertile due to a hormonal deficiency.

PUREGON is not addictive.

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

Before you use PUREGON

When you must not use it

Do not use PUREGON if you:

  • are allergic (hypersensitive) to follitropin beta or to any of the ingredients in PUREGON listed at the end of this leaflet
  • have a tumour of the ovary, breast, uterus, testis, or brain (pituitary gland or hypothalamus)
  • are pregnant or think you may be pregnant
  • are breast feeding
  • have heavy or irregular vaginal bleeding where the cause is not known
  • suffer from primary ovarian failure
  • have ovarian cysts or enlarged ovaries not caused by polycystic ovarian disease (PCOD)
  • have malformations of the sexual organs which make a normal pregnancy impossible
  • have fibroid tumours in the uterus which make a normal pregnancy impossible
  • suffer from primary testicular failure.

Take special care with Puregon

Tell your doctor if you:

  • have experienced an allergic reaction to neomycin and/or streptomycin (antibiotics) in the past. PUREGON may contain traces of these antibiotics
  • have ever had ovarian hyperstimulation syndrome (OHSS)
  • are pregnant or think that you may be pregnant
  • have ever had stomach (abdominal) surgery
  • have ever had a twisting of an ovary
  • have past or current cysts in your ovary or ovaries
  • you have uncontrolled pituitary gland or hypothalamic problems
  • have an underactive thyroid gland (hypothyroidism)
  • have adrenal glands that are not working properly (adrenocortical insufficiency)
  • have high prolactin levels in the blood (hyperprolactinemia)
  • have been told by a doctor that pregnancy would be dangerous for you
  • have any other medical conditions (for example, diabetes, heart disease, or any other long-term disease).

In Women
Close supervision by your doctor is very important. Usually ultrasound scans of the ovaries are regularly made. Your doctor may also check blood hormone levels. The results of these tests allow your doctor to choose the correct dose of PUREGON from day to day. This is very important since too high a dose of FSH may lead to rare but serious complications in which the ovaries are overly stimulated and the growing follicles become larger than normal.

This serious medical condition is called ovarian hyperstimulation syndrome (OHSS).

In rare cases, severe OHSS may be life-threatening. OHSS causes fluid to build up suddenly in your stomach and chest areas and can cause blood clots to form.

Call your doctor right away if you have:

  • severe abdominal swelling
  • pain in the stomach (abdomen), even if this occurs dome days after the last injection has been given
  • nausea (feeling sick)
  • vomiting
  • sudden weight gain
  • diarrhoea
  • decreased urine output
  • trouble breathing.

Regular monitoring of the response to FSH-treatment helps to prevent ovarian overstimulation.

Ovarian Torsion
Ovarian torsion has occurred after treatment with gonadotrophins including PUREGON. Ovarian torsion is the twisting of an ovary. Twisting of the ovary could cause the blood flow to the ovary to be cut off.

Before starting this medicine it is important to inform your doctor if you:

  • have ever had ovarian hyperstimulation syndrome (OHSS)
  • are pregnant or think that you may be pregnant
  • have ever had stomach (abdominal) surgery
  • have ever had a twisting of an ovary
  • have past or current cysts in your ovary or ovaries

Treatment with PUREGON (like pregnancy itself) may increase the risk of having a blood clot (thrombosis). Thrombosis is the formation of a blood clot in a blood vessel.

Blood clots can lead to serious medical conditions, such as:

  • blockage in your lungs (pulmonary embolus)
  • stroke
  • heart attack
  • blood vessel problems (thrombophlebitis)
  • a lack of blood flow (deep venous thrombosis) that may result in a loss of your arm or leg.

Please discuss this with your doctor, before starting treatment, especially if:

  • you already know you have an increased risk of thrombosis
  • you, or anyone in your immediate family, have ever had a thrombosis
  • you are severely overweight.

Ovarian and other reproductive system tumours
There have been reports of ovarian and other reproductive system tumours in women who have had infertility treatment. It is not known if treatment with fertility medicines increases the risk of these tumours in infertile women.

Other medical conditions
You have been told by a doctor that pregnancy would be dangerous for you.

In Men
Elevated FSH blood levels are indicative of testicular damage. PUREGON is usually not as effective in such cases. To monitor your treatment, your doctor may ask you for a semen analysis to be performed 4 to 6 months after the beginning of treatment.

Do not use PUREGON if the packaging is torn or shows signs of tampering.

Do not use PUREGON after the expiry date printed on the pack has passed.

If it has expired or is damaged, return it to your pharmacist or clinic for disposal.

Talk to your doctor if you are not too sure about using PUREGON.

Before you start to use it

You and your partner's fertility should be assessed to see if PUREGON is appropriate for you.

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

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

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

  • thyroid disorder
  • adrenal gland disorder
  • ovarian cyst
  • cancer or a tumour of the breast, ovary, uterus, prostate, hypothalamus or pituitary gland
  • polycystic ovarian disease (irregular or no periods, acne, obesity, excess hair growth)
  • unexplained vaginal bleeding.

If you have any of the above conditions, tell your doctor before you start to use PUREGON.

Tell your doctor if you have or have had any other medical conditions.

Pregnancy:
After treatment with gonadotrophic preparations, there is an increased risk of having multiple pregnancies, even when only one embryo is transferred into the uterus. Multiple pregnancies carry an increased health risk for both the mother and her babies around the time of birth.

Furthermore, multiple pregnancies and characteristics of the patients undergoing fertility treatment (e.g age of the female, sperm characteristics, genetic background of both parents) may be associated with an increased risk of birth defects.

Generally in women undergoing fertility treatment there may be a slightly higher risk of miscarriage.

There is a slightly increased risk of a pregnancy outside of the uterus (an ectopic pregnancy). Therefore, your doctor should perform an early ultrasound examination to exclude the possibility of pregnancy outside the uterus.

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.

How PUREGON is given

The very first injection of PUREGON should be given by a health professional.

PUREGON solution for injection in cartridges has been developed for use in the PUREGON Pen. The separate instructions for using the pen must be followed carefully. Do not use the cartridge if the solution contains particles or if the solution is not clear.

Using the pen, injections just under the skin (in the stomach or thigh) can be given by you or your partner. Your doctor will tell you when and how to do this. When the instructions are followed carefully, PUREGON will be administered properly and with minimal discomfort.

How much to inject

Your doctor will decide on the dose of PUREGON to be given. This dose may be adjusted as your treatment progresses.

There are large differences between women in the response of the ovaries to FSH. This makes it impossible to set a dosage schedule which is suitable for all patients. To find the right dosage, follicle growth is checked by means of ultrasound scanning and measurement of the amount of oestradiol (female sex hormone) in the blood.

The following is a guide to the usual dose:

Women who are not ovulating
The dose usually starts at 75-150 IU daily. The dose is continued for at least 5 to 7 days. If there is no response, the daily dose will be gradually increased until an adequate response is obtained. The daily dose is then maintained until a follicle of adequate size is present.

An hCG injection (to stimulate ovulation) is given after the last PUREGON injection.

Women undergoing assisted reproductive technologies
The dose usually starts at 75 to 300 IU daily. The dose may be adjusted according to your response. When a sufficient number of follicles of adequate size are present, the final phase of maturation of the follicles is induced by administration of hCG. Oocyte (egg) retrieval is performed 34-35 hours later.

Men
PUREGON is usually prescribed at a dose of 75 IU daily or 2-3 times a week, in combination with another hormone (hCG) for at least 3 months.

If you forget to use PUREGON

If you forget an injection or are not sure what to do, contact your doctor or nurse immediately for advice. Do not double the dose on any day.

If you inject too much

Immediately contact your doctor, or for Australia, the Poisons Information Centre (telephone 13 11 26), or for New Zealand, National Poisons Centre (telephone 0800 POISON or 0800 764 766) for advice.

In females, too high a dose may cause overstimulation of the ovaries (Ovarian Hyperstimulation Syndrome, OHSS) (see Side Effects).

While you are using PUREGON

Things you must do

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

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

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

Tell all doctors and dentists who are treating you that you are using PUREGON.

Things you must not do

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

As far as is known, PUREGON has no effect on alertness and concentration.

Do not stop using PUREGON without telling your doctor.

Do not change the dose unless your doctor tells you to.

Changing your dose without telling your doctor can increase your risk of unwanted side effects or can prevent the drug from working properly.

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

Side Effects

Tell your doctor as soon as possible if you do not feel well while you are using PUREGON. All medicines can have side effects. Sometimes they are serious, most of the time they are not.

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

  • Bruising, pain, redness, swelling and itching at the injection site
  • Skin rash

If any of the following happen, tell your doctor immediately or go to the Emergency Department at your nearest hospital:

  • 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.

For women
If any of the following happen, tell your doctor immediately or go to the Emergency Department at your nearest hospital:

  • Signs of a blood clot such as pain, warmth, redness, numbness, or tingling in your arm or leg; confusion, extreme dizziness or severe headache. This condition is rare.

Common side effects (likely to affect 1 to 10 users in 100):

  • Headache
  • Injection site reactions (such as bruising, pain, redness, swelling and itching)
  • Ovarian hyperstimulation syndrome (OHSS)
  • Pelvic pain
  • Stomach pain and/or bloating

Uncommon side effects (likely to affect 1 to 10 users in 1,000):

  • Ovarian torsion (twisting of the ovary) resulting in extreme lower stomach pain
  • Breast complaints (including tenderness)
  • Diarrhoea, constipation or stomach discomfort
  • Enlargement of the uterus
  • Feeling sick
  • Hypersensitivity reactions (such as rash, redness, hives and itching)
  • Ovarian cysts or enlargement of the ovaries
  • Vaginal bleeding

A complication with FSH treatment is unwanted 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
  • In rare cases blood clots. Signs of a blood clots include pain, warmth, redness, numbness, or tingling in your arm or leg; confusion, extreme dizziness or severe headache.

Tell your doctor immediately or go to the Emergency Department at your nearest hospital if you have stomach pains or any of the other symptoms of ovarian hyperstimulation, even if they develop some days after the last injection has been given.

The following side effects are not considered to be related to the use of PUREGON, but to Assisted Reproductive Technology (ART) or subsequent pregnancy:

  • Miscarriage
  • Ectopic pregnancy (pregnancy that occurs outside the uterus)
  • Multiple pregnancies.

For men
Common side effects (likely to affect 1 to 10 users in 100):

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

  • Acne
  • Hardening of the injection site
  • Headache
  • Rash
  • Some breast development
  • Testicular cyst

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

Other side effects not listed in this leaflet also occur in some people.

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

After using PUREGON

Storage

  1. Store PUREGON in the refrigerator (2°C-8°C). Do not freeze. Use until the expiry date printed on the label.
    OR
  2. Store at room temperature (at or below 25°C) for a single period of not more than 3 months. Make a note of when you start storing PUREGON out of the refrigerator.

Storage after first dose:
Once you have started using a cartridge, store below 25°C (do not freeze) for a maximum of 28 days.

Disposal

Do not use PUREGON after the expiry date stated on the label after the term 'Expiry Date'.

Return any unused medicine to your pharmacist.

Ingredients

Active ingredient
Follitropin beta, a hormone known as follicle-stimulating hormone (FSH), at a strength of 833 IU/mL aqueous solution per cartridge.

One cartridge of PUREGON contains the following amounts of PUREGON solution:

  • 0.480 equal to a net dose of 300 IU
  • 0.840 equal to a net dose of 600 IU
  • 1.230 mL equal to a net dose of 900 IU

Other ingredients

  • sucrose
  • sodium citrate
  • methionine
  • polysorbate 20
  • benzyl alcohol
  • water for injections.

The pH may have been adjusted with sodium hydroxide and/or hydrochloric acid anhydrous.

PUREGON 300 IU, 600 IU and 900 IU is available in packs containing one cartridge.

Supplier

Merck Sharp & Dohme (Australia) Pty Limited
Level 1, Building A
26 Talavera Road
Macquarie Park, NSW 2113
Australia

Merck Sharp & Dohme (New Zealand) Ltd
PO Box 99 851
Newmarket
Auckland 1149
New Zealand

Australian Registration Numbers:
PUREGON 300 IU: AUST R 76436
PUREGON 600 IU: AUST R 76437
PUREGON 900 IU: AUST R 116843

This leaflet was prepared in December 2014.

BRAND INFORMATION

Brand name

Puregon Solution for injection

Active ingredient

Follitropin beta

Schedule

S4

 

Name of the medicine

Follitropin-β (recombinant human follicle stimulating hormone (rec FSH)).

Excipients

Sucrose, sodium citrate, methionine, polysorbate 20 and benzyl alcohol in water for injections. The pH may have been adjusted with sodium hydroxide and/or hydrochloric acid.

Description

Puregon contains the active ingredient follitropin-β (rch). This is produced by a Chinese hamster ovary cell line transfected with the human FSH subunit genes (i.e. by recombinant DNA technology).

Pharmacology

Pharmacodynamic properties.

Pharmacotherapeutic group: gonadotrophins; ATC code: G03G A06.
Puregon contains follitropin-β, a recombinant human FSH. FSH is indispensable in normal gamete growth and maturation, and gonadal steroid production.

In the female.

The amount of FSH is critical for the onset and duration of follicular development, and consequently for the timing and number of follicles reaching maturity. Puregon can thus be used to stimulate follicular development and steroid production in selected cases of disturbed gonadal function.
Furthermore Puregon can be used to promote multiple follicular development in medically assisted reproduction programs (e.g. in vitro fertilisation/ embryo transfer (IVF/ET), gamete or zygote intrafallopian transfer (GIFT/ZIFT)).
In the absence of an endogenous LH surge, treatment with Puregon is generally followed by administration of hCG to induce the final phase of follicle maturation, leading to ovulation.

In the male.

In deficient spermatogenesis due to hypogonadotrophic hypogonadism, Puregon is given to substitute FSH for the stimulation of the Sertoli cells. The high LH activity needed to stimulate the Leydig cells is provided by an hCG preparation given in addition.

Pharmacokinetic properties.

After subcutaneous administration of Puregon, high concentrations of follitropin-β are reached within about 12 hours. Due to the sustained release from the injection site, and the relatively long elimination half-life of about 40 hours (ranging from 12 to 70 hours), follitropin-β levels remain high for 24-48 hours.
Due to the relatively long elimination half-life, after repeated administration, plasma concentrations of follitropin-β are approximately 1.5-2.5 times higher than after single administration. This increase contributes to reach therapeutic follitropin-β FSH concentrations.
Since follitropin-β (recombinant FSH) is very similar to endogenous FSH, it is expected that it would be distributed, metabolised, and excreted in the same way.
A bioequivalence study was performed to compare the pharmacokinetics of FSH after subcutaneous single dose injection of Puregon with a conventional syringe as dissolved freeze dried cake (2 x 75 IU) versus administration of Puregon solution (150 IU) with pen injector.
Due to the precision of the device, it can be assumed that exactly 150 IU was injected with the pen injector. The dose injected with the syringe was actually lower than the anticipated 150 IU, which is due to losses while filling the syringe and/or removing excess air and to the void volume of the syringe. After correction of the dose by a factor of 1.18, bioequivalence was demonstrated for all relevant pharmacokinetic parameters (see Table 1). Since the daily dose of Puregon is determined by the patient's individual ovarian response, the slightly higher dose delivered by the pen is unlikely to affect clinical outcome. Table 1 shows the main pharmacokinetic results of the study.

Indications

In the female.

Anovulatory infertility.
Controlled ovarian hyperstimulation to induce the development of multiple follicles in medically assisted reproduction programs (e.g. in vitro fertilisation and related procedures).

In the male.

For the treatment of deficient spermatogenesis due to hypogonadotrophic hypogonadism.

Contraindications

Hypersensitivity to the active substance or any of the excipients.
Tumours of ovarium, breasts, uterus, testes, hypothalamus and pituitary gland.
Pregnancy and during lactation.
Unexplained vaginal bleeding.
Ovarian cysts or enlarged ovaries, not related to polycystic ovarian disease (PCOD).
Puregon is contraindicated when an effective response cannot be obtained, such as: primary ovarian failure such as indicated by high levels of FSH; organic disorders of the reproductive organs incompatible with pregnancy such as congenital malformations of the uterus and fibroids.
Any condition in which a pregnancy (including multiple pregnancy) would be particularly hazardous (e.g. extremes of weight disorders and uterine abnormalities).
Primary testicular failure.
Puregon should not be used in the elderly or in children.

Precautions

Before starting treatment, the couple's infertility should be assessed as appropriate. In particular, patients should be evaluated for hypothyroidism, adrenocortical insufficiency, hyperprolactinemia and pituitary or hypothalamic tumours, and appropriate specific treatment given.
Prior to treating patients for inadequate gonadal function, the following should be assessed.
1. Careful clinical examination to determine general, pelvic or genital pathology.
2. Serum gonadotrophin levels concentrations to exclude gonadal failure.
3. Thyroid function, serum prolactin to exclude endocrinopathies that may be responsible.
4. A semen analysis of the partner.
Ovarian torsion has been reported after treatment with gonadotrophins, including Puregon. Ovarian torsion may be associated with other risk factors such as ovarian hyperstimulation syndrome (OHSS), pregnancy, previous abdominal surgery, past history of ovarian torsion, previous or current ovarian cyst and polycystic ovaries. Damage to the ovary due to reduced blood supply can be limited by early diagnosis and immediate detorsion.
Multiple pregnancies and births have been reported for all gonadotrophin treatments, including Puregon. Multiple gestations, especially high order, carry an increased risk of adverse maternal (pregnancy and delivery complications) and perinatal (low birth weight) outcomes. For anovulatory women undergoing ovulation induction, monitoring follicular development with transvaginal ultrasonography is important for minimising the risk of multifoetal gestations. The concurrent determination of serum oestradiol levels may also be useful. The parents should be advised of the potential risks of multiple births before starting treatment.
In women undergoing assisted reproductive technologies (ART) procedures, the risk of a multiple pregnancy is mainly related to the number of embryos transferred. When used for an ovulation induction cycle, appropriate FSH dose adjustment(s) should prevent multiple follicle development.
The first injection of Puregon should be performed under direct medical supervision.
Infertile women undergoing ART, have an increased incidence of ectopic pregnancies. Early ultrasound confirmation that a pregnancy is intrauterine is therefore important.
The incidence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This slightly higher incidence is thought to be related to differences in parental characteristics (e.g. maternal age, sperm characteristics) and to the higher incidence of multiple gestations after ART. Analysis of pooled data does not indicate that the use of gonadotrophins in ovulation induction and medically assisted reproduction programs carries an increased risk of congenital malformations.
There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple drug regimens for infertility treatment. It is not established whether or not treatment with gonadotrophins increases the risk of these tumours in infertile women.
Puregon would not be expected to be effective in the absence of endogenous luteinising hormone (LH). The presence of spontaneous or progestogen withdrawal menstruation is suggestive of adequate endogenous LH.
Thromboembolic events, both in association with and separate from OHSS, have been reported following treatment with gonadotrophins, including Puregon. Intravascular thrombosis, which may originate in venous or arterial vessels, can result in reduced blood flow to vital organs or the extremities. In women with generally recognised risk factors for thromboembolic events, such as personal or family history, severe obesity or thrombophilia, treatment with gonadotrophins, including Puregon, may further increase this risk. In these women the benefits of gonadotrophin administration, including Puregon, need to be weighed against the risks. It should be noted however that pregnancy itself also carries an increased risk of thrombosis.
Puregon may contain traces of streptomycin and/or neomycin. These antibiotics may cause hypersensitivity reactions in susceptible persons.
Elevated endogenous FSH levels in men are indicative of primary testicular failure. Such patients are unresponsive to Puregon/ hCG therapy.
In men, semen analysis is recommended 4 to 6 months after the beginning of treatment in assessing the response.
Medical conditions that contraindicate pregnancy should be evaluated before starting treatment with Puregon.

Overstimulation of the ovary during Puregon therapy.

Ovarian enlargement.

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 Puregon and hCG and generally regresses without treatment within two or three weeks.
In order to minimise the hazard associated with the occasional abnormal ovarian enlargement which may occur with Puregon-hCG therapy, the lowest dose consistent with expectation of good results should be used. Careful monitoring of ovarian response can further minimise the risk of overstimulation.
If the ovaries are abnormally enlarged on the last day of Puregon therapy, hCG should not be administered in this course of therapy; this will reduce the chances of development of the ovarian hyperstimulation syndrome.

The ovarian hyperstimulation syndrome (OHSS).

OHSS is a medical event distinct from uncomplicated ovarian enlargement. OHSS may progress rapidly to become a serious medical event. It is characterised by an apparent dramatic increase in vascular permeability which can result in a rapid accumulation of fluid in the peritoneal cavity, thorax and potentially, the pericardium. Clinical signs and symptoms of mild and moderate OHSS are abdominal pain, nausea, diarrhoea, mild to moderate enlargement of ovaries and ovarian cysts. Severe OHSS may be life threatening. Clinical signs and symptoms of severe OHSS are large ovarian cysts, acute abdominal pain, ascites, pleural effusion, hydrothorax, dyspnoea, oliguria, haematological abnormalities and weight gain. In rare instances, venous or arterial thromboembolism may occur in association with OHSS. Transient liver function test abnormalities suggestive of hepatic dysfunction with or without morphologic changes on liver biopsy have also been reported in association with OHSS. The early warning signs of development of OHSS are severe pelvic pain, nausea, vomiting and weight gain. The following symptomatology has been seen with cases of OHSS: abdominal pain, abdominal distension, gastrointestinal symptoms including nausea, vomiting and diarrhoea, severe ovarian enlargement, weight gain, dyspnoea and oliguria. Clinical evaluation may reveal hypovolaemia, haemoconcentration, electrolyte imbalances, ascites, haemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress and thromboembolic events (see Pulmonary and vascular complications).
OHSS may be caused by administration of human chorionic gonadotrophin (hCG) and by pregnancy (endogenous hCG). Early OHSS usually occurs within 10 days after hCG administration and may be associated with an excessive ovarian response to gonadotrophin stimulation. Late OHSS occurs more than 10 days after hCG administration, as a consequence of the hormonal changes with pregnancy. Because of the risk of developing OHSS, patients should be monitored for at least two weeks after hCG administration. OHSS occurs uncommonly in patients when the recommended dose is administered and is more common in patients when higher than recommended doses are administered. Cases of OHSS are more common, more severe and more protracted if pregnancy occurs. Most often, OHSS occurs after treatment has been discontinued and reaches its maximum at about seven to ten days following treatment. Usually, OHSS resolves spontaneously with the onset of menses. If there is evidence that OHSS may be developing prior to hCG administration, the hCG should be withheld.
Women with known risk factors for a high ovarian response may be especially prone to the development of OHSS during or following treatment with Puregon. For women having their first cycle of ovarian stimulation, for whom risk factors are only partially known, close observation for early signs and symptoms of OHSS is recommended.
To reduce the risk of OHSS, ultrasound assessments of follicular development should be performed prior to treatment and at regular intervals during treatment. The concurrent determination of serum oestradiol levels may also be useful. In ART there is an increased risk of OHSS with 18 or more follicles of 11 mm or more in diameter. When there are 30 or more follicles in total it is advised to withhold hCG administration.
Depending on the ovarian response, the following measures can be considered to reduce the risk of OHSS:
withhold further stimulation with a gonadotrophin for a maximum of 3 days (coasting); withhold hCG and cancel the treatment cycle; administer a dose lower than 10,000 IU of urinary hCG for triggering final oocyte maturation, e.g. 5,000 IU urinary hCG or 250 microgram rec-hCG (which is equivalent to approximately 6,500 IU of urinary hCG); cancel the fresh embryo transfer and cryopreserve embryos; avoid administration of hCG for luteal phase support.
If OHSS develops, standard and appropriate management of OHSS should be implemented and followed.
If OHSS occurs, treatment should be stopped and the patient hospitalised. 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 the pericardial cavity has been seen to occur and should be thoroughly assessed in the following manner: fluid intake and output, weight, haematocrit, serum and urinary electrolytes, urine specific gravity, BUN and creatinine, and abdominal girth. These determinations are to be performed daily or more often if the need arises.
With OHSS there is an increased risk of injury to the ovary. The ascitic, pleural and pericardial fluid 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. 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.
The management of OHSS may be divided into three phases: an acute, a chronic and a resolution phase. Because the use of diuretics can accentuate the diminished intravascular volume, diuretics should be avoided except in the late phase of resolution as described below.

Acute phase.

Management during the acute phase should be designed to prevent haemoconcentration due to loss of intravascular volume to the third space and to minimise the risk of thromboembolic phenomena and kidney damage. Treatment is designed to normalise electrolytes while maintaining an acceptable but somewhat reduced intravascular volume. Full correction of the intravascular volume deficit may lead to an unacceptable increase in the amount of third space fluid accumulation. Management includes administration of limited intravenous fluids, electrolytes, and human serum albumin. Monitoring for the development of hyperkalaemia is recommended.

Chronic phase.

After stabilising the patient during the acute phase, excessive fluid accumulation in the third space should be limited by instituting severe potassium, sodium and fluid restriction.

Resolution phase.

A fall in haematocrit and an increasing urinary output without an increased intake are observed due to the return of third space fluid to the intravascular compartment. Peripheral and/or pulmonary oedema may result if the kidneys are unable to excrete third space fluid as rapidly as it is mobilised. Diuretics may be indicated during the resolution phase if necessary to combat pulmonary oedema.

Pulmonary and vascular complication.

Serious pulmonary conditions (e.g. atelectasis, acute respiratory distress syndrome) have been reported. In addition, thromboembolic events both in association with, and separate from the ovarian hyperstimulation syndrome are possible following Puregon therapy. Intravascular thrombosis, which may originate in venous or arterial vessels, can result in reduced blood flow to vital organs or the extremities. Sequelae of such events have included venous thrombophlebitis, pulmonary embolism, pulmonary infarction, cerebral vascular occlusion (stroke) and arterial occlusion resulting in loss of limb. In rare cases, pulmonary complications and/or thromboembolic events could result in death.

Multiple births.

In the majority of patients, the pregnancies following treatment with Puregon resulted in single births. For patients undergoing IVF treatment the risk of multiple pregnancy following assisted reproductive technologies is related to the number of oocytes/ embryos replaced, in other patients the incidence of multiple pregnancies is increased by Puregon, as with other agents used to stimulate ovulation. However, the majority of multiple conceptions are twins.
Pregnancy loss is higher than that in the normal population, but comparable with the rates found in women with other fertility problems.

Carcinogenicity and mutagenicity.

Long-term studies in animals have not been performed to evaluate the carcinogenic potential of follitropin-β. Follitropin-β showed no genotoxic activity in a series of assays performed to evaluate its potential to cause gene mutations (Salmonella typhimurium and E. coli) and chromosomal damage (human lymphocytes in vitro).

Use in pregnancy.

(Category B2)
Follitropin-β is not intended for use during pregnancy (see Contraindications). There are no available data from studies in which Puregon was administered to pregnant animals. In case of inadvertent exposure during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of recombinant FSH.

Use in lactation.

It is not known whether follitropin-β is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in the nursing infant from Puregon, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Effects on ability to drive and use machines.

As far as known this medicine has no influence on alertness and powers of concentration.

Interactions

Concurrent use of Puregon and clomiphene may enhance the follicular response. After pituitary desensitisation effected by a GnRH agonist, a higher dose of Puregon may be necessary to elicit an adequate follicular response.

Incompatibilities.

No relevant incompatibilities are known.

Adverse Effects

Unwanted ovarian hyperstimulation, ovarian hyperstimulation syndrome. Signs and symptoms of ovarian hyperstimulation syndrome were reported in 3% of women treated with Puregon in clinical trials.
Multiple pregnancy (including higher order multiplets than twins).

Body system disorders.

See Table 2.

Application site disorders.

Bruising*, pain, redness, swelling, itching.
(*In one study of 195 women undergoing superovulation for IVF, comparing intramuscular and subcutaneous routes of administration no differences between the two routes of administration were significant apart from bruising which was more common in the subcutaneous group.)
Generalised hypersensitivity reactions which may include erythema, urticaria, rash and pruritus have been observed uncommonly.

In the female.

Headache (in up to 1.0% of the women treated with Puregon).
Ovarian torsion has been reported (see Precautions).
In rare instances, thromboembolism has been associated with Puregon/ hCG treatment as with other gonadotrophins.
Characteristic symptoms of ovarian hyperstimulation and the ovarian hyperstimulation syndrome are included under Precautions.
Adverse effects related to the hyperstimulation syndrome are breast complaints, (including breast tenderness, pain and/or engorgement (uncommonly)) and ovarian enlargement.

In the male.

Occasionally gynecomastia and acne may occur during Puregon/ hCG therapy. These are known effects of hCG treatment.

Dosage and Administration

Treatment with Puregon should be initiated under the supervision of a physician experienced in the treatment of fertility problems.

Dosage in the female.

Anovulation/ defective follicle ripening and/or corpus luteum insufficiency.

There are great interindividual and intraindividual variations in the response of the ovaries to exogenous gonadotrophins. This makes it impossible to set a uniform dosage scheme. The dosage should, therefore, be adjusted individually depending on the ovarian response. This requires ultrasound assessment of follicular development. The concurrent determination of serum oestradiol levels may also be useful.
In general, a sequential treatment scheme is recommended. This starts with daily administration of 75-150 IU FSH. This dose is maintained for 5-7 days. If there is no apparent ovarian response, the daily dose is gradually increased until oestrogen levels start to rise.
A daily ascent rate of 40-100% is considered to be optimal. The daily effective dose is then maintained until preovulatory conditions are reached. If oestrogen levels rise too rapidly, i.e. more than a daily doubling for 2 or 3 consecutive days, the daily dose should be decreased.
Preovulatory conditions are reached when plasma oestradiol levels of 300-900 picogram/mL (1000 to 3000 picomol/L), or a total urinary oestrogen excretion of 75-200 microgram (250-650 nanomol)/24 hours are attained, and/or when there is ultrasonographic evidence of a dominant follicle of at least 18 mm in diameter. The administration of Puregon is then discontinued and ovulation can be induced by administering human chorionic gonadotrophin (hCG) in a dose of 5000-10,000 IU. Two to three injections of 1000-3000 IU hCG each may be given within the following 9 days to prevent insufficiency of the corpus luteum.
Since follicles of over 15 mm may produce pregnancies, a maximum of two additional follicles exceeding 15 mm is acceptable. If this limit is exceeded, hCG should be withheld and pregnancy should be avoided in order to prevent large multiple gestations.
In women with polycystic ovarian disease, induction of a hypogonadotrophic state by a GnRH agonist before and during treatment with Puregon may result in better pregnancy rates than without the use of an agonist.

Controlled ovarian hyperstimulation in medically assisted reproduction programs.

Various stimulation protocols are applied. Stimulation of follicular growth is generally achieved by daily administration of 75-300 IU FSH. Puregon can be given either alone, or in combination with clomiphene citrate to stimulate the endogenous production of gonadotrophins, or in combination with a GnRH agonist, in particular to prevent premature luteinization.
Maturation of follicles is monitored by ultrasound assesment. The concurrent determination of serum oestradiol levels may also be useful. When ultrasound assessment indicates the presence of at least three follicles of 16-20 mm, and there is evidence of a good oestradiol response (plasma levels of about 300-400 picogram/mL (1000-1300 picomol/L) for each follicle with a diameter greater than 18 mm), the final phase of maturation of the follicles is induced 30-40 hours after the last administration of Puregon by administration of hCG in a dose of 5000-10,000 IU. Oocyte retrieval is performed 34-35 hours later.
After embryo transfer, up to three repeat injections of 1000 to 3000 IU hCG each may be given within the following 9 days to provide luteal phase support.

Dosage in the male.

75 IU FSH injections are given daily or 2-3 times a week. These injections should be combined with a simultaneous dose of 1000-2000 IU hCG, 2-3 times a week to make up the necessary LH activity. This treatment should be continued for at least three months before any improvement in spermatogenesis can be expected. During this treatment testosterone replacement therapy should be suspended. Once achieved, the improvement may in some cases be maintained by hCG alone.

Paediatric population.

There is no relevant indication for use of Puregon in children.

Method of administration.

Puregon solution for injection in cartridges has been developed for use in the Puregon pen and should be administered subcutaneously. The injection site should be alternated to prevent lipoatrophy.
Using the pen, injection of Puregon can be carried out by the patient or partner, provided proper instructions are given by the physician. Self administration of Puregon should only be performed by women who are well motivated, adequately trained and with access to expert advice.
Do not use if the solution contains particles or if the solution is not clear.
Empty cartridges must not be refilled. Puregon cartridges are not designed to allow any other drug to be mixed in the cartridges.

Overdosage

The acute toxicity of gonadotrophin preparations has been shown to be very low. However, too high a dosage for more than one day may lead to hyperstimulation of the ovaries (see Precautions, Unwanted hyperstimulation).

Presentation

Solution for injection, 150 IU/0.18 mL extractable volume (≡ Puregon solution 0.270 mL, AUST R 116842): 1's*; 300 IU/0.36 mL extractable volume (≡ Puregon solution 0.480 mL, AUST R 76436): 1's; 600 IU/0.72 mL extractable volume (≡ Puregon solution 0.840 mL, AUST R 76437): 1's; 900 IU/1.08 mL extractable volume (≡ Puregon solution 1.230 mL, AUST R 116843): 1's (clear glass cartridge with rubber stoppers).
*Not currently marketed in Australia.

Storage

Protect from light.
Pharmacy: store at 2°C to 8°C (refrigerate, do not freeze) until expiry date on carton.
Patient: store at 2°C to 8°C (refrigerate, do not freeze) until expiry date on carton, or alternatively store below 25°C for a maximum of 3 months.
The product should not be kept above 25°C, refrigerate if necessary.
After commencement of use, Puregon may be stored below 25°C (do not freeze) for a maximum of 28 days. Each cartridge is for individual patient use only.

Poison Schedule

S4.