Consumer medicine information

Luveris 75 IU

Lutropin alfa

BRAND INFORMATION

Brand name

Luveris 75 U

Active ingredient

Lutropin alfa

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Luveris 75 IU.

What is in this leaflet

This leaflet answers some common questions about Luveris.

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 Luveris 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 Luveris is used for

Luveris is a medicine containing lutropin alfa, a recombinant luteinising hormone (LH), which is essentially similar to the hormone found naturally in humans, but it is made by means of biotechnology. It belongs to the family of hormones called gonadotrophins, which are involved in the normal control of reproduction.

Luveris 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. The medicine is used together with another hormone called follicle stimulating hormone (FSH) also known by the brand name GONAL-f, to bring about the development of follicles which are in the ovaries, the structures maturing the eggs (ova). It is followed by treatment with a single dose of human chorionic gonadotrophins (hCG), which leads to the release of an egg from the follicle (ovulation).

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

Luveris is available only on a doctor's prescription.

Luveris is not habit-forming.

Before you are given Luveris

When you must not use it

Do not use Luveris 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 Luveris 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 Luveris, 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 Luveris.

Tell your doctor if you are breastfeeding. Luveris 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 adrenal glands
  • disorders of the thyroid gland
  • 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 Luveris may increase your risk of developing a condition called ovarian hyperstimulation syndrome (OHSS). This is when the ovaries overreact to the hormonal treatment and become larger.

The most common symptom is lower abdominal pain. During stimulation your doctor will monitor your treatment using ultrasound and blood tests to help determine if you are likely to develop OHSS. If necessary, your doctor will delay or cancel your Luveris 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 this treatment. 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.

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 Luveris.

Taking other medicines

Tell your doctor if you are taking any other medicines, including:

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

Some medicines may be affected by Luveris or may affect how well it works.

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

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

Luveris is given as a course of daily subcutaneous (under the skin) injections at the same time as another medicine, follitropin alfa (GONAL-f).

How much to inject

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

It is recommended that your treatment with Luveris starts at 75 IU daily along with 75 IU to 150 IU GONAL-f but your doctor may adjust your dose of Luveris or GONAL-f depending on your individual response to treatment. Clinical results have shown the minimal effective dose of Luveris is 37.5 IU.

Each vial is for single use in one patient only. Discard any residue.

How to inject

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

Luveris 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

Luveris is usually given in the lower abdominal area (except around the navel and waistline) or the front of your thigh.

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 Luveris

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 (In Australia telephone 131 126. In New Zealand telephone 0800 764 766) if you are concerned that you have given yourself too much or someone else has injected themselves with Luveris.

While you are using Luveris

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

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 Luveris.

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

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

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

Things you must not do

If you are self-injecting do not:

  • Stop using Luveris 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 Luveris affects you.

Side effects

Tell your doctor as soon as possible if you do not feel well while taking Luveris. 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 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
  • nausea, vomiting, diarrhoea, abdominal discomfort or abdominal pain
  • ovarian cysts, breast pain and pelvic pain
  • local reactions at the injection site, such as pain, redness 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 Luveris

Storage

Prior to reconstitution keep the vials in a cool dry place where the temperature is below 25°C.

Store in the original package in order to protect from light. Once the Luveris powder is dissolved with the solvent provided, it should be injected immediately. This is due to the solvent not containing preservative. Any solution that is left over must be discarded.

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

Do not use the product after the expiry date printed on the label. Do not use Luveris if you notice any visible signs of deterioration or damage to the container.

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

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.

Each vial of medicine is for single use only. Any medicine left over after injecting should be discarded.

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

Product description

What it looks like

Luveris is a sterile white powder in a vial.

Each vial of Luveris contains 75 IU lutropin alfa.

Luveris is available in packs of 1 vial. Each pack also contains a vial of 1 mL Water for Injections.

Ingredients

Active ingredient:

  • Lutropin alfa (rch)

Inactive ingredients:

  • Polysorbate 20
  • Dibasic sodium phosphate dihydrate
  • Monobasic sodium phosphate monohydrate
  • Methionine
  • Sucrose
  • Phosphoric acid
  • Sodium hydroxide.

Supplier

Luveris is supplied in Australia by:

Merck Healthcare Pty Ltd
Suite 1, Level 1, Building B
11 Talavera Road
Macquarie Park NSW 2113
For enquiries call: 1800 633 463
E-mail: [email protected]

Luveris is supplied in New Zealand by:

Healthcare Logistics
58 Richard Pearse Drive
Airport Oaks, Auckland
For enquiries call: 0800 426 252
E-mail: [email protected]

Australian Registration Number

AUST R 95042

This leaflet was prepared in February 2020.

A012-0220

INSTRUCTIONS FOR USE

How should I administer Luveris 75 IU

Luveris is given by injection under the skin. Each vial is for single use only.

Sometimes the injection will be given to you by a doctor or nurse, or you or your partner may be trained to give the injection at home.

If you administer Luveris to yourself, please carefully read the following instructions:

Follow the directions below for mixing and injecting Luveris.

  1. Wash your hands.
    It is important that your hands and the items you use be as clean as possible.
  2. Assemble everything you need.
    Please note that alcohol swabs, syringes and needles are not contained in the package. Find a clean area and lay out everything:
  • two alcohol swabs,
  • one solvent vial,
  • one vial containing the medicinal product,
  • one syringe,
  • one big needle for reconstitution,
  • a fine-bore needle for subcutaneous injection.
  1. Drawing up the solvent:

Remove the protective cap from the solvent vial. Attach the needle for reconstitution (the bigger needle) to the syringe and draw up some air into the syringe by pulling the plunger to approximately the 1 mL mark. Then, insert the needle into the vial, push the plunger to expel the air, turn the vial upside down and gently draw up all the solvent.
Set the syringe down carefully on the work-surface taking care not to touch the needle.
  1. Preparing the injection solution:

Remove the protective cap from the Luveris powder vial, pick up your syringe and slowly inject the solvent into the vial of Luveris. Swirl gently without removing the syringe. Do not shake. The powder should dissolve into a clear solution immediately. Do not use if the solution is not clear. Up to 3 containers of powder may be dissolved in 1 mL of solvent.

Turn the vial upside down, gently draw the solution back into the syringe.
  1. Injection:

Change the needle for the fine-bore needle and remove any air bubbles: If you see air bubbles in the syringe, hold the syringe with the needle pointing upwards and gently flick the syringe until all the air collects at the top. Gently push the plunger until the air bubbles are gone.

Immediately inject the solution: Your doctor or nurse will have already advised you where to inject (e.g. tummy, front of thigh). Wipe the chosen area with an alcohol swab. Firmly pinch the skin together and insert the needle at a 45° to 90° angle using a dart-like motion. Inject under the skin, as you were taught. Do not inject directly into a vein. Inject the solution by pushing gently on the plunger. Take as much time as you need to inject all the solution. Immediately withdraw the needle and clean the skin with an alcohol swab using a circular motion.
  1. Dispose of all used items:
    Once you have finished your injection, immediately discard all needles and empty glass containers in a sharps container. Any unused solution must be discarded.

Published by MIMS April 2020

BRAND INFORMATION

Brand name

Luveris 75 U

Active ingredient

Lutropin alfa

Schedule

S4

 

1 Name of Medicine

Lutropin alfa (rch).
rch = Recombinant Chinese hamster.

6.7 Physicochemical Properties

Chemical structure.

Lutropin alfa is a recombinant human luteinising hormone (r-hLH). r-hLH is a human gonadotrophin hormone, composed of two non-covalently linked, non-identical protein components designated as the α- and β-subunits. It is a glycoprotein hormone with molecular weight (MW) of about 29,000 Da. The α-subunit is common to all four members of the gonadotropin hormone family. 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, 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.
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-152923-57-4 (lutropin alfa); CAS-56832-30-5 (α-subunit); CAS-53664-53-2 (β subunit).

2 Qualitative and Quantitative Composition

Lutropin alfa is a recombinant human luteinising hormone (r-hLH) derived from a Chinese Hamster Ovary cell line that has been modified by the addition of human genes encoding the LH α- and β-chains.
Each vial of Luveris contains 75 IU of lutropin alfa as lyophilised powder.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Powder for injection in vial(s).
Luveris is available as a sterile, lyophilised powder.
It is intended for co-administration with follitropin alfa as subcutaneous injection after reconstitution with sterile water for injections.

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 it 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.
In the ovaries, during the follicular phase, LH stimulates the theca cells to secrete androgens, which will be used as the substrate by granulosa cell aromatase enzyme to produce oestradiol, to support follicle stimulating hormone (FSH) action in inducing follicular development. At mid-cycle, high levels of LH trigger corpus luteum formation and ovulation. After ovulation, LH stimulates progesterone production in the corpus luteum by increasing the conversion of cholesterol to pregnenolone.
In the stimulation of follicular development in anovulatory women deficient in LH and FSH, the primary effect resulting from administration of Luveris is an increase in oestradiol secretion by the follicles, the growth of which is stimulated by r-FSH.
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.
In these trials, achievement of an adequate follicular development as the optimal well established and surrogate marker of conception was consistently found in 66.7% of patients with LH < 1.2 IU treated with FSH and 75 IU Luveris. 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 risk of OHSS was 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).

Clinical trials.

The safety and efficacy of Luveris have been examined in five studies for induction of ovulation in women with hypogonadotropic hypogonadism (HH).

Pivotal studies.

The safety and efficacy of Luveris administered subcutaneously and concomitantly with recombinant human FSH (r-hFSH) for ovulation induction in women with HH was assessed and confirmed in the following 2 international pivotal studies.

Study 6253.

Study 6253 was a Phase II randomized, open-label, dose-finding study to determine the minimal effective dose and assess the safety of Luveris to support r-hFSH-induced follicular development in LH and FSH deficient anovulatory women. Patients were randomized to treatment with 0, 25, 75 or 225 IU Luveris 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 Luveris, 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 Luveris, 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 Luveris, respectively; p=0.0001).

Study 21008.

The safety and efficacy of Luveris 75 IU administered subcutaneously for induction of ovulation in women with HH and severe gonadotrophin deficiency was assessed in this Phase III double-blind, placebo-controlled, randomized 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 summarized in Table 1.
The efficacy results for the same study are also assessed when risk of OHSS is considered as an efficacy failure in Table 2.

Other studies.

The safety and efficacy of Luveris administered subcutaneously concomitantly with r-hFSH for ovulation induction in women with HH was also investigated in 3 additional studies.
Study 6905 was a Phase II/III open-label, randomized, multicenter study to determine the minimal effective dose and assess the safety of Luveris administered with r-hFSH to induce follicular development in anovulatory women with HH and moderate gonadotrophin deficiency. Forty patients were enrolled and treated.
Study 7798 was a Phase III multicenter study to assess the efficacy and safety of Luveris administered with r-hFSH for induction of follicular development in LH and FSH deficient anovulatory women and enrolled 15 patients.
Study 8297 was a Phase III multicenter, non-comparative study to assess the efficacy and safety of Luveris administered with r-hFSH for 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 Luveris development studies, 154 were seeking fertility and of these 127 were treated with Luveris. Overall 41 of 127 (32%) Luveris treated patients (all doses) and 31 of 100 (31%) in the Luveris 75 IU dose group achieved a pregnancy over a total of 205 treatment cycles (see Table 3).
No direct comparison of r-hLH and r-hFSH versus human menopausal gonadotrophin (hMG) has been performed. Comparison with historical data suggests that the ovulation rate with the combination is similar to what can be obtained with hMG.

5.2 Pharmacokinetic Properties

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 Luveris are comparable and the accumulation ratio of lutropin alfa minimal. There is no pharmacokinetic interaction with follitropin alfa when administered simultaneously.

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.

Carcinogenicity.

Long-term carcinogenicity studies have not been carried out.

4 Clinical Particulars

4.1 Therapeutic Indications

Luveris in association with a recombinant follicle stimulating hormone (FSH) preparation is recommended for the stimulation of follicular development in women with severe LH and FSH deficiency. In clinical trials, these patients were defined by an endogenous serum LH of less than 1.2 IU/L.

4.3 Contraindications

Luveris is contraindicated in patients with:
hypersensitivity to gonadotrophins or to any of the excipients;
ovarian, uterine or mammary carcinoma;
active, untreated 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 Luveris 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 increasing degrees of severity. It comprises marked ovarian enlargement, high serum sex steroids, and an increase in vascular permeability which can result in an accumulation of fluid in the peritoneal, pleural and, rarely, in the pericardial cavities.
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.
Independent risk factors for developing OHSS include young age, lean body mass, polycystic ovarian syndrome, 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.
Adherence to recommended Luveris and FSH dosage and regimen of administration can minimise the risk of ovarian hyperstimulation. Monitoring of stimulation cycles by ultrasound scans, as well as oestradiol measurements, is recommended to identify risk factors early.
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 OHSS occur, it is recommended that hCG be withheld and the patient be advised to refrain from coitus or use barrier methods of contraception for at least 4 days. As OHSS may progress rapidly (within 24 hours) or over several days to become a serious medical event, patients should be followed for at least two weeks after hCG administration.
Mild manifestations of OHSS may include abdominal pain, abdominal discomfort and distension, or enlarged ovaries. Moderate OHSS may additionally present with nausea, vomiting, ultrasound evidence of ascites or marked ovarian enlargement. Severe OHSS further includes symptoms such as severe ovarian enlargement, weight gain, dyspnoea or 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.
Mild or moderate OHSS usually resolves spontaneously. If severe OHSS occurs, it is recommended that gonadotrophin treatment be stopped, the patient be hospitalised and appropriate therapy be started.

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.

Porphyria.

In patients with porphyria or a family history of porphyria, gonadotrophins 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 Luveris to patients with renal or hepatic impairment. There are currently no data available on the use of Luveris 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

Luveris should not be administered as a mixture with other medicines in the same injection, except follitropin alfa, for which studies have shown that co-administration does not significantly alter the activity, stability, pharmacokinetic nor pharmacodynamic properties of the active substances.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

See Section 4.1 Therapeutic Indications.
(Category B3)
Luveris should not be administered during pregnancy as it may cause fetal harm when given to a pregnant woman (see Section 4.3 Contraindications). Data on a limited number of human pregnancies exposed inadvertently following controlled ovarian stimulation indicate no adverse reactions of gonadotrophins on pregnancy, embryonal or foetal development, parturition or postnatal development. In the case of inadvertent administration during pregnancy, clinical data are not sufficient to exclude a teratogenic effect of Luveris.
Treatment of pregnant rats and rabbits with Luveris at doses of 10 IU/kg/day SC 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 Luveris at doses up to 20 IU/kg/day SC (approximately 0.8x and 1.6x clinical exposure, based on body surface area, respectively). Administration of 10 IU/kg/day Luveris to rats from late gestation to weaning resulted in adverse effects on the post-natal survival and growth of offspring.
Luveris 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.

4.8 Adverse Effects (Undesirable Effects)

Luveris is used for the stimulation of follicular development in association with follitropin alfa. In this context, undesirable effects may be due to either or both of the substances used, or to their pharmacodynamic consequences.
There is considerable post-marketing safety experience with human luteinising hormone (hLH) containing products of urinary origin. The safety profile of Luveris is expected to be very similar to that of urine derived hLH, with the exception of hypersensitivity reactions and application site disorders.
In clinical trials, 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 Luveris. Six serious OHSS reports (2.3%) occurred in 259 treatment cycles.
Ovarian cysts and enlargement 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 of prior tubal disease.
The following definitions apply to the frequency terminology used hereafter: Very Common ≥ 1/10; Common ≥ 1/100 to < 1/10; Uncommon ≥ 1/1,000 to < 1/100; Rare ≥ 1/10,000 to < 1/1,000; Very Rare < 1/10,000.

General disorders and administration site condition.

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

Nervous system disorders.

Common: headache.

Gastrointestinal disorders.

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

Reproductive system and breast disorders.

Common: mild or moderate OHSS (including associated symptomatology), ovarian cyst, breast pain, pelvic pain.

Vascular disorders.

Very rare: thromboembolism, usually associated with severe OHSS.

Immune system disorders.

Very rare: mild to severe hypersensitivity reactions including anaphylactic reactions and shock.
The reported undesirable effects are in agreement with those reported for other hLH containing products.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems in Australia, or at https://nzphvc.otago.ac.nz/reporting/ in New Zealand.

4.2 Dose and Method of Administration

Treatment with Luveris should be initiated under the supervision of a physician experienced in the treatment of fertility problems. Self-administration of Luveris 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 Luveris therapy, in association with FSH is to develop a single mature Graafian follicle from which the oocyte will be liberated following administration of human chorionic gonadotrophin (hCG). Luveris should be given as a course of daily injections concomitantly with FSH. Since these patients are amenorrhoeic and have low endogenous oestrogen secretion, treatment can commence at any time. Nevertheless, the possibility of pregnancy should be first excluded by clinical or other means.
All clinical experience to date with Luveris in this indication has been gained with concomitant daily administration of follitropin alfa.
Luveris is intended for daily subcutaneous administration. The powder should be reconstituted, immediately prior to use, with the solvent provided.
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 Luveris.
The efficacy studies have suggested that the minimum effective dose of Luveris is 37.5 IU. However, dose titration is recommended according to individual patient response.
Treatment should be tailored to the individual patient's response as assessed by measuring: (i) follicle size by ultrasound and (ii) oestrogen response. A recommended regimen commences at 75 IU of Luveris daily with 75-150 IU FSH.
Clinical studies have employed doses of up to 225 IU of lutropin alfa and 150 IU follitropin alfa per day to induce follicular development. If a patient fails to respond after 3 weeks of treatment, the cycle should be abandoned and the patient should recommence treatment with a higher starting dose of follitropin alfa and/or Luveris than in the abandoned cycle.
If there is insufficient follicular growth, it is reasonable to increase the FSH dose, but if there is good follicular development with a low oestradiol level, this suggests that more LH may be required.
In clinical trials, Luveris has been associated with higher oestradiol levels than follitropin alfa alone. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably with 37.5-75 IU increments.
When an optimal response is obtained, a single injection of 250 microgram of recombinant hCG (r-hCG) or 5,000 IU to 10,000 IU hCG should be administered 24-48 hours after the last Luveris and FSH injections. The patient is recommended to have coitus on the day of, and on the day following, hCG administration. Alternatively, intrauterine insemination (IUI) may be performed. 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 should be stopped and hCG withheld. Treatment should recommence in the next cycle at a FSH dosage lower than that of the previous cycle.
Product is for single use in one patient only. Discard any residue.

4.7 Effects on Ability to Drive and Use Machines

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

4.9 Overdose

The effects of overdosage of Luveris are unknown; nevertheless, there is a possibility that OHSS may occur (see Section 4.4 Special Warnings and Precautions for Use).
Single doses of up to 40,000 IU of Luveris 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).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sucrose, dibasic sodium phosphate dihydrate, methionine, monobasic sodium phosphate monohydrate, polysorbate 20, sodium hydroxide, phosphoric acid and sodium hydroxide for pH adjustment.

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

The lyophilised product must be stored below 25°C. Protect from light.
The reconstituted solution must be injected immediately as it contains no antimicrobial agent.

6.5 Nature and Contents of Container

Luveris is supplied in packs of 1, 3 or 10 vials* with the corresponding number of vials containing 1 mL water for injections.
* Not all pack sizes are available.

6.6 Special Precautions for Disposal

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

Summary Table of Changes