Lutropin Alfa

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

Treatment with Pergoveris should be initiated under the supervision of a physician experienced in the treatment of fertility disorders. Posology 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 gonadotropin (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. A treatment regimen commences with the recommended dose of Pergoveris containing 150 IU r-hFSH/75 IU r-hLH daily.

1). Treatment should be tailored to the individual patient’s response as assessed by measuring follicle size by ultrasound and oestrogen response. 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 to up to 5 weeks.

When an optimal response is obtained, a single injection of 250 micrograms of r-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 or another medically assisted reproduction procedure may be performed based on the physician’s judgment of the clinical case. Luteal phase support may be considered since lack of substances with luteotrophic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum.

If an excessive response is obtained, treatment should be stopped and hCG withheld. ). Special populations Elderly There is no relevant indication for the use of Pergoveris in the elderly population. Safety and efficacy of this medicinal product in elderly patients have not been established.

Renal and hepatic impairment Safety, efficacy, and pharmacokinetics of this medicinal product in patients with renal or hepatic impairment have not been established. Paediatric population There is no relevant use of this medicinal product in the paediatric population.

Method of administration Pergoveris is intended for subcutaneous administration. The first injection should be performed under direct medical supervision. Self-administration should only be performed by patients who are well motivated, adequately trained and with access to expert advice.

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g. pain, erythema, haematoma, swelling and/or irritation at the site of injection). Mild or moderate OHSS has been commonly reported and should be considered as an intrinsic risk of the stimulation procedure. 4). 4). Tabulated list of adverse reactions Adverse reactions are listed below by MedDRA system organ class and by frequency.

The frequency categories used are: 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), not known (cannot be estimated from the available data). g. pain, erythema, haematoma, bruising, swelling and/or irritation at the site of injection) Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

1 • tumours of the hypothalamus and pituitary gland • ovarian enlargement or ovarian cyst unrelated to polycystic ovarian disease and of unknown origin • gynaecological haemorrhages of unknown origin • ovarian, uterine or mammary carcinoma Pergoveris must not be used when an effective response cannot be obtained, such as: • primary ovarian failure • malformations of sexual organs incompatible with pregnancy • fibroid tumours of the uterus incompatible with pregnancy

AND CLINICAL USE ...................................................................................... 3 CONTRAINDICATIONS ............................................................................................................

4 WARNINGS AND PRECAUTIONS .......................................................................................... 4 ADVERSE REACTIONS ............................................................................................................

9 DRUG INTERACTIONS........................................................................................................... 14 DOSAGE AND ADMINISTRATION ......................................................................................

14 OVERDOSAGE ......................................................................................................................... 15 ACTION AND CLINICAL PHARMACOLOGY .....................................................................

16 STORAGE AND STABILITY .................................................................................................. 17 DOSAGE FORMS, COMPOSITION AND PACKAGING ...................................................... 19 PHARMACEUTICAL INFORMATION ..................................................................................

19 CLINICAL TRIALS .................................................................................................................. 20 DETAILED PHARMACOLOGY .............................................................................................

23 TOXICOLOGY .......................................................................................................................... 24 REFERENCES ...........................................................................................................................

0 mL of lutropin alfa (recombinant human luteinizing hormone, r-hLH) Sucrose, L-methionine, disodium phosphate dihydrate, sodium dihydrogen phosphate monohydrate, and Polysorbate 20. For a complete listing see Dosage Forms, Composition and Packaging section DESCRIPTION LUVERIS® (lutropin alfa for injection) is a recombinant human luteinizing hormone (r-hLH), a heterodimeric glycoprotein consisting of two non-covalently linked subunits (designated alpha and beta) of 92 and 121 amino acids, respectively.

Lutropin alfa is produced by recombinant DNA technology in a Chinese Hamster Ovary (CHO) mammalian cell expression system. 2 IU/L). A definitive effect on pregnancy in this population has not been demonstrated. The safety and effectiveness of concomitant administration of LUVERIS with any other preparation of recombinant human FSH or urinary human FSH is unknown.

Geriatrics (>60 years of age):

LUVERIS is not indicated in geriatric patients. Safety and effectiveness in these patient populations have not been established.

Pediatrics (<16 years of age):

LUVERIS is not indicated in pediatric patients. Safety and effectiveness in these patient populations have not been established. LUVERIS® Product Monograph Page 4 of

 Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition and Packaging section of the product monograph;  Patients with uncontrolled thyroid or adrenal failure;  Patients with active, untreated tumours of the hypothalamus and pituitary gland;  Patients who are pregnant or lactating;  Ovarian, uterine, or mammary carcinoma;  Ovarian enlargement or ovarian cyst unrelated to polycystic ovarian disease and of unknown origin;  Abnormal uterine bleeding of unknown origin LUVERIS must not be used when a condition exists which would make a normal pregnancy impossible, such as:  Primary ovarian failure  Malformations of sexual organs incompatible with pregnancy  Fibroid tumours of the uterus incompatible with pregnancy WARNINGS AND PRECAUTIONS General LUVERIS should only be used by physicians who are thoroughly familiar with the treatment of hypogonadotropic hypogonadism (HH) and its management.

Possible contraindications for pregnancy should be evaluated. In particular, patients should be evaluated for hypothyroidism, adrenocortical insufficiency, hyperprolactinemia and pituitary or hypothalamic tumours, and appropriate specific treatment instituted.

Patients undergoing stimulation of follicular growth are at an increased risk of developing hyperstimulation in view of possible excessive estrogen response and multiple follicular development. In patients with porphyria or a family history of porphyria, Gonadotropins may increase the risk of an acute attack.

Deterioration or a first appearance of this condition may require cessation of treatment. The porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio- synthetic pathway. They manifest either by neurological complications or cutaneous disorders or occasionally both.

Symptoms of porphyria attacks may include abdominal pain, nausea/vomiting, personality changes or mental disorders. Acute attacks of porphyria are usually ascribed to environmental factors, certain drugs, infections, alcohol, fasting and stress.

Sex hormones have also been described as playing a key role in the onset of porphyria attacks. Women are at least three times more likely than men to LUVERIS® Product Monograph Page 5 of 30 experience an acute attack and in some women (10-30%), attacks are clearly related to the pre- menstrual phase of the menstrual cycle.

As LUVERIS and GONAL-F are both associated with supra-physiological levels of estrogens, there is a theoretical risk that both gonadotropins would precipitate attack of porphyria. Only isolated cases have been reported after ovarian stimulation by gonadotropins.

The patient should be informed:  Of the duration of treatment and monitoring of their condition that will be required  Of her personal risk of ovarian hyperstimulation syndrome  That there is a potential risk of multiple births Carcinogenesis and Mutagenesis Long-term studies to evaluate the carcinogenic potential of LUVERIS in animals have not been performed.

In vitro mutagenicity testing of LUVERIS in bacteria and mammalian cell lines, chromosome aberration assay in human lymphocytes and in vivo mouse micronucleus have shown no indication of genetic defects. Impaired fertility has been reported in animals exposed to high doses of lutropin alfa; increased pre- and post-implantation losses were observed in female rats and rabbits given lutropin alfa at doses of 10 IU/kg/day and higher.

Cardiovascular As with other gonadotropin products, a potential for arterial thromboembolism exists.

Thromboembolic Events:

In women with recent or ongoing thromboembolic disease or with generally recognised risk factors for thrombo-embolic events, such as personal or family history, treatment with gonadotropins may further increase the risk for aggravation or occurrence of such events.

In these women, the benefits of gonadotropin administration need to be weighed against the risks. It should be noted however, that pregnancy itself, as well as ovarian hyperstimulation syndrome (OHSS), also carries an increased risk of thrombo-embolic events.

Sexual Function/Reproduction Ovarian Enlargement:

Mild to moderate uncomplicated ovarian enlargement, which may be accompanied by abdominal distension and/or abdominal pain, may occur in patients treated with gonadotropins such as LUVERIS. These conditions generally regress without treatment within two or three weeks.

Careful monitoring of ovarian response can further minimize the risk of overstimulation. If the ovaries are abnormally enlarged on the last day of therapy with LUVERIS and GONAL-F, human chorionic gonadotropin (hCG) should not be administered in this course of therapy.

This will reduce the risk of development of OHSS.

LUVERIS® Product Monograph Page 6 of 30 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. OHSS is a medical event distinct from uncomplicated ovarian enlargement.

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. Severe OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event. It is characterized by an increase in vascular permeability, which can result in a rapid accumulation of fluid in the peritoneal cavity, thorax, and potentially, the pericardium.

Clinical evaluation may reveal hypovolemia, hemoconcentration, electrolyte imbalances, ascites, hemoperitoneum, pleural effusions, hydrothorax, acute pulmonary distress. Very rarely, […]

Luveris in association with a follicle stimulating hormone (FSH) preparation is indicated for the stimulation of follicular development in adult women with severe luteinising hormone (LH) and FSH deficiency.

Treatment with Luveris should be initiated under the supervision of a physician experienced in the treatment of fertility disorders. Posology In LH and FSH deficient women, the objective of Luveris therapy in association with FSH is to promote follicular development followed by final maturation after the administration of human chorionic gonadotropin (hCG).

Luveris should be given as a course of daily injections simultaneously with FSH. If the patient is amenorrhoeic and has low endogenous estrogen secretion, treatment can commence at any time. Luveris should be administered concomitantly with follitropin alfa.

e. one vial of Luveris) daily with 75 to 150 IU FSH. Treatment should be tailored to the individual patient’s response as assessed by measuring follicle size by ultrasound and estrogen response. In clinical trials, Luveris has been shown to increase the ovarian sensitivity to follitropin alfa.

5 IU to 75 IU increments. It may be acceptable to extend the duration of stimulation in any one cycle to up to 5 weeks. 3 When an optimal response is obtained, a single injection of 250 micrograms of r-hCG or 5 000 IU to 10 000 IU hCG should be administered 24 to 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 or another medically assisted reproduction procedure may be performed based on the physician’s judgment of the clinical case.

Luteal phase support may be considered since lack of substances with luteotrophic activity (LH/hCG) after ovulation may lead to premature failure of the corpus luteum. If an excessive response is obtained, treatment should be stopped and hCG withheld.

). Special populations Elderly There is no relevant use of Luveris in the elderly population. Safety and efficacy of Luveris in elderly patients have not been established. Renal and hepatic impairment Safety, efficacy and pharmacokinetics of Luveris in patients with renal or hepatic impairment have not been established.

Paediatric population There is no relevant use of Luveris in the paediatric population. Method of administration Luveris is intended for subcutaneous use. The first injection of Luveris should be performed under direct medical supervision.

The powder should be reconstituted immediately prior to use with the solvent provided. Self-administration of this medicinal product should only be performed by patients who are well-motivated, adequately trained and with access to expert advice.

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Summary of the safety profile Luveris is used for the stimulation of follicular development in association with follitropin alfa. In this context, it is difficult to attribute adverse reactions to any one of the substances used. 9% of the injections, respectively.

No severe injection site reactions were reported. Ovarian hyperstimulation syndrome (OHSS) was observed in less than 6% of patients treated with Luveris. 4). In rare instances, adnexal torsion (a complication of ovarian enlargement), and haemoperitoneum have been associated with human menopausal gonadotropin therapy.

Although these adverse reactions were not observed, there is the possibility that they may also occur with Luveris. Ectopic pregnancy may also occur, especially in women with a history of prior tubal disease. List of adverse reactions 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), frequency not known (cannot be estimated from the available data).

The following adverse reactions may be observed after administration of Luveris. g. pain, erythema, haematoma, swelling and/or irritation at the site of injection) Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation 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 via the national reporting system listed in Appendix V.

1. • tumours of the hypothalamus and pituitary gland • ovarian enlargement or ovarian cyst unrelated to polycystic ovarian disease and of unknown origin • gynaecological haemorrhages of unknown origin • ovarian, uterine, or mammary carcinoma Luveris must not be used when a condition exists which would make a normal pregnancy impossible, such as: • primary ovarian failure • malformations of sexual organs incompatible with pregnancy • fibroid tumours of the uterus incompatible with pregnancy