ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1

2 1. NAME OF THE MEDICINAL PRODUCT Pergoveris 150 IU/75 IU powder and solvent for solution for injection. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One vial contains 150 IU (equivalent to 11 micrograms) of follitropin alfa (r-hfsh) and 75 IU (equivalent to 3.0 micrograms) of lutropin alfa (r-hlh). The reconstituted solution contains 150 IU r-hfsh and 75 IU r-hlh per milliliter. Follitropin alfa and lutropin alfa are produced in genetically engineered Chinese Hamster Ovary (CHO) cells. Excipients: sucrose, disodium phosphate dihydrate, sodium dihydrogen phosphate monohydrate. For a full list of excipients, see section PHARMACEUTICAL FORM Powder and solvent for solution for injection. Powder: white lyophilised pellet. Solvent: clear colourless solution. The ph of the reconstituted solution is CLINICAL PARTICULARS 4.1 Therapeutic indications Pergoveris is indicated 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 level < 1.2 IU/l. 4.2 Posology and method of administration Treatment with Pergoveris should be initiated under the supervision of a physician experienced in the treatment of fertility problems. Pergoveris is intended for subcutaneous administration. The powder should be reconstituted immediately prior to use with the solvent provided. In LH and FSH deficient women (hypogonadotrophic hypogonadism), the objective of Pergoveris therapy is to develop a single mature Graafian follicle from which the oocyte will be liberated after the administration of human chorionic gonadotrophin (hcg). Pergoveris should be given as a course of daily injections. Since these patients are amenorrhoeic and have low endogenous oestrogen secretion, treatment can commence at any time. Treatment should be tailored to the individual patient s response as assessed by measuring follicle size by ultrasound and oestrogen response. A recommended regimen commences with one vial of Pergoveris daily. If less than one vial of Pergoveris daily is used, the follicular response may be unsatisfactory because the amount of lutropin alfa may be insufficient (see section 5.1). If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by IU increments using a licensed follitropin alfa preparation. It may 2

3 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 5,000 IU to 10,000 IU hcg should be administered hours after the last Pergoveris injection. The patient is recommended to have coitus on the day of, and on the day following, hcg administration. Alternatively, intrauterine insemination (IUI) may be performed. 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. Treatment should recommence in the next cycle at a dose of FSH lower than that of the previous cycle. In clinical trials, patients with severe FSH and LH deficiency 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 the ovulation rate per cycle was 70-75%. 4.3 Contraindications Pergoveris is contraindicated in patients with: hypersensitivity to the active substances follitropin alfa and lutropin alfa or to any of the excipients case of tumours of the hypothalamus and pituitary gland ovarian enlargement or cyst not due to polycystic ovarian disease gynaecological haemorrhages of unknown aetiology 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 4.4 Special warnings and precautions for use Pergoveris contains potent gonadotrophic substances capable of causing mild to severe adverse reactions, and should only be used by physicians who are thoroughly familiar with infertility problems and their management. Gonadotrophin therapy requires a certain time commitment by physicians and supportive health professionals, as well as the availability of appropriate monitoring facilities. In women, safe and effective use of Pergoveris calls for monitoring of ovarian response with ultrasound, alone or preferably in combination with measurement of serum oestradiol levels, on a regular basis. There may be a degree of interpatient variability in response to FSH/LH administration, with a poor response to FSH/LH in some patients. The lowest effective dose in relation to the treatment objective should be used in women. Self-administration of Pergoveris should only be performed by patients who are well motivated, adequately trained and with access to expert advice. The first injection of Pergoveris should be performed under direct medical supervision. Patients with porphyria or a family history of porphyria should be closely monitored during treatment with Pergoveris. Deterioration or a first appearance of this condition may require cessation of treatment. 3

4 Pergoveris contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially sodium-free. Pergoveris contains 30 mg of sucrose per dose. This should be taken into account in patients with diabetes mellitus. Before starting treatment, the couple's infertility should be assessed as appropriate and putative contraindications for pregnancy evaluated. In particular, patients should be evaluated for the following: hypothyroidism adrenocortical deficiency hyperprolactinemia and pituitary or hypothalamic tumours Appropriate specific treatment should be given. Patients undergoing stimulation of follicular growth are at an increased risk of developing hyperstimulation in view of possible excessive oestrogen response and multiple follicular development. In clinical trials, lutropin alfa in combination with follitropin alfa has been shown to increase the ovarian sensitivity to gonadotropins. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be at 7-14 day intervals and preferably with IU increments using a licensed follitropin alfa preparation. Ovarian Hyperstimulation Syndrome (OHSS) is a medical event distinct from uncomplicated ovarian enlargement. OHSS is a syndrome 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. The following symptomatology may be observed in severe cases of OHSS: abdominal pain abdominal distension severe ovarian enlargement weight gain dyspnoea oliguria and gastrointestinal symptoms including nausea, vomiting and diarrhoea. Clinical evaluation may reveal: hypovolaemia haemoconcentration electrolyte imbalances ascites haemoperitoneum pleural effusions hydrothorax acute pulmonary distress, and thromboembolic events. Very rarely, severe OHSS may be complicated by pulmonary embolism, ischemic stroke and myocardial infarction. Excessive ovarian response seldom gives rise to significant hyperstimulation unless hcg is administered to induce ovulation. Therefore in cases of ovarian hyperstimulation it is prudent to withhold hcg in such cases and advise the patient to refrain from coitus or use barrier methods for at least 4 days. OHSS may progress rapidly (within 24 hours to several days) to become a serious medical event, therefore patients should be followed for at least two weeks after hcg administration. To minimise the risk of OHSS or of multiple pregnancy (see below), ultrasound scans as well as oestradiol measurements are recommended. In anovulation the risk of OHSS is increased by a serum 4

5 oestradiol level > 900 pg/ml (3,300 pmol/l) and by the presence of more than 3 follicles of 14 mm or more in diameter. Adherence to recommended Pergoveris and FSH dosage and regimen of administration and careful monitoring of therapy will minimise the incidence of ovarian hyperstimulation and multiple pregnancy (see below). OHSS may be more severe and more protracted if pregnancy occurs. Most often, OHSS occurs after hormonal 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 severe OHSS occurs, gonadotrophin treatment should be stopped if still ongoing. The patient should be hospitalised and specific therapy for OHSS started. This syndrome occurs with higher incidence in patients with polycystic ovarian disease. In patients undergoing induction of ovulation, the incidence of multiple pregnancies and births is increased compared with natural conception. The majority of multiple conceptions are twins. To minimise the risk of multiple pregnancy, careful monitoring of ovarian response is recommended. The patients should be advised of the potential risk of multiple births before starting treatment. The incidence of pregnancy wastage by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction than in the normal population. When risk of OHSS or multiple pregnancies is assumed, treatment discontinuation should be considered. Women with a history of tubal disease are at risk of ectopic pregnancy, whether the pregnancy is obtained by spontaneous conception or with fertility treatments. The prevalence of ectopic pregnancy after IVF was reported to be 2 to 5%, as compared to 1 to 1.5% in the general population. 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 yet established whether or not treatment with gonadotrophins increases the baseline risk of these tumours in infertile women. The prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions. This is thought to be due to differences in parental characteristics (e.g. maternal age, sperm characteristics) and multiple pregnancies. In women with generally recognised risk factors for thrombo-embolic events, such as personal or family history, treatment with gonadotrophins may further increase the risk. In these women, the benefits of gonadotrophin administration need to be weighed against the risks. It should be noted however, that pregnancy itself also carries an increased risk of thrombo-embolic events. 4.5 Interaction with other medicinal products and other forms of interaction Pergoveris should not be administered as a mixture with other medicinal products, in the same injection, except follitropin alfa. 4.6 Pregnancy and lactation Pergoveris should not be used during pregnancy or lactation. 4.7 Effects on ability to drive and use machines 5

6 No studies on the effects on the ability to drive and use machines have been performed. 4.8 Undesirable effects Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Nervous system disorders Respiratory, thoracic and mediastinal disorders Very Common ( 1/10) Common ( 1/100 to <1/10) Very rare (<1/10,000) Headache Somnolence Exacerbation or worsening of asthma Gastrointestinal disorders Common ( 1/100 to <1/10) Abdominal pain and gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal cramps and bloating Vascular disorders Very rare (<1/10,000) Thromboembolism, usually associated with severe ovarian hyperstimulation syndrome (OHSS) General disorders and administration site conditions Very Common ( 1/10) Mild to severe injection site reaction (pain, redness, bruising, swelling and/or irritation at the site of injection) Immune system disorders Very rare (<1/10,000) Mild systemic allergic reactions (e.g. mild forms of erythema, rash, facial swelling, urticaria, oedema, difficulty breathing). Serious cases of allergic reactions, including anaphylactic reactions, have also been reported. Reproductive system and breast disorders Very Common ( 1/10) Ovarian cysts Common ( 1/100 to <1/10) Uncommon ( 1/1,000 to <1/100) Rare ( 1/10,000 to <1/1,000) Breast pain, pelvic pain, mild to moderate OHSS Severe OHSS Ovarian torsion, a complication of OHSS 4.9 Overdose The effects of an overdose of Pergoveris are unknown. Nevertheless one could expect ovarian hyperstimulation syndrome to occur, which is further described in section PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Gonadotrophins, ATC code: G03GA05 / G03GA07. Pergoveris is a preparation of follicle stimulating hormone and luteinising hormone produced by genetically engineered Chinese Hamster Ovary (CHO) cells. 6

7 In clinical trials the efficacy of the combination of follitropin alfa and lutropin alfa has been demonstrated in women with hypogonadotropic hypogonadism. In the stimulation of follicular development in anovulatory women deficient in LH and FSH, the primary effect resulting from administration of lutropin alfa is an increase in oestradiol secretion by the follicles, the growth of which is stimulated by FSH. In one clinical study of women with hypogonadotrophic hypogonadism and an endogenous serum LH concentration below 1.2 IU/L the appropriate dose of r-hlh (lutropin alfa) was investigated. A dose of 75 IU r-hlh daily (in combination with 150 IU follitropin alfa (r-hfsh)) resulted in adequate follicular development and oestrogen production. A dose of 25 IU r-hlh daily (in combination with 150 IU follitropin alfa) resulted in insufficient follicular development. Therefore, administration of less than one vial of Pergoveris daily may provide too little LH-activity to ensure adequate follicular development. 5.2 Pharmacokinetic properties Follitropin alfa and lutropin alfa have shown the same pharmacokinetic profile as follitropin alfa and lutropin alfa separately. Follitropin alfa Following intravenous administration, follitropin alfa is distributed to the extracellular fluid space with an initial half-life of around 2 hours and eliminated from the body with a terminal half-life of about one day. The steady state volume of distribution and total clearance are 10 l and 0.6 l/h, respectively. One-eighth of the follitropin alfa dose is excreted in the urine. Following subcutaneous administration, the absolute bioavailability is about 70%. Following repeated administration, follitropin alfa accumulates 3-fold achieving a steady-state within 3-4 days. In women whose endogenous gonadotrophin secretion is suppressed, follitropin alfa has nevertheless been shown to effectively stimulate follicular development and steroidogenesis, despite unmeasurable LH levels. Lutropin alfa 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 hours. The steady state volume of distribution is around l. Lutropin alfa shows linear pharmacokinetics, as assessed by AUC which is directly proportional to the dose administered. Total clearance is around 2 l/h, and less than 5% of the dose is excreted in the urine. The mean residence time is approximately 5 hours. Following subcutaneous administration, the absolute bioavailability is approximately 60%; the terminal half-life is slightly prolonged. The lutropin alfa pharmacokinetics following single and repeated administration of lutropin alfa are comparable and the accumulation ratio of lutropin alfa is minimal. There is no pharmacokinetic interaction with follitropin alfa when administered simultaneously. 5.3 Preclinical safety data Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients 7

8 Powder: Sucrose Polysorbate 20 Methionine Disodium phosphate dihydrate Sodium dihydrogen phosphate monohydrate Phosphoric acid, concentrated for ph adjustment Sodium hydroxide for ph adjustment Solvent: Water for Injections 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section Shelf life 3 years. For immediate and single use following first opening and reconstitution. 6.4 Special precautions for storage Do not store above 25 C. Store in the original package in order to protect from light. 6.5 Nature and contents of container Powder: 3 ml vials (Type I glass) with a stopper (bromobutyl rubber) and aluminium flip-off cap. 1 vial contains 11 micrograms r-hfsh and 3 micrograms r-hlh. Solvent: 3 ml vials (Type I glass) with a Teflon coated rubber stopper and aluminium flip-off cap. 1 vial of solvent contains 1 ml of water for injections. The medicinal product is supplied in pack sizes of 1, 3 and 10 vials with the corresponding number of 1, 3 and 10 vials of solvent. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling For single use only. Pergoveris must be reconstituted with the solvent before use. The reconstituted solution should not be administered if it contains particles or is not clear. Pergoveris may be mixed with follitropin alfa and co-administered as a single injection. Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 8

9 7. MARKETING AUTHORISATION HOLDER Serono Europe Limited 56 Marsh Wall London E14 9TP United Kingdom 8. MARKETING AUTHORISATION NUMBERS 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT 9

10 ANNEX II A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCES AND MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OF THE MARKETING AUTHORISATION C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING AUTHORISATION HOLDER 10

11 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCES AND MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substances Laboratoires Serono S.A. Zone Industrielle de l Ouriettaz 1170 Aubonne Switzerland Name and address of the manufacturer responsible for batch release Industria Farmaceutica Serono SpA Zona Industriale di Modugno Bari Italy B. CONDITIONS OF THE MARKETING AUTHORISATION CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON THE MARKETING AUTHORISATION HOLDER Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, section 4.2) CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT Not applicable. OTHER CONDITIONS The Marketing Authorisation Holder must ensure that the system of pharmacovigilance is in place and functioning prior to placing the product on the market. 11

12 ANNEX III LABELLING AND PACKAGE LEAFLET 12

13 A. LABELLING 13

14 PARTICULARS TO APPEAR ON THE OUTER PACKAGING BOX OF 1, 3, 10 VIALS OF POWDER AND SOLVENT 1. NAME OF THE MEDICINAL PRODUCT Pergoveris 150 IU/75 IU powder and solvent for solution for injection. Follitropin alfa/lutropin alfa 2. STATEMENT OF ACTIVE SUBSTANCE(S) One vial contains 150 IU (equivalent to 11 micrograms) of follitropin alfa (r-hfsh) and 75 IU (equivalent to 3.0 micrograms) of lutropin alfa (r-hlh). 3. LIST OF EXCIPIENTS Other ingredients: disodium phosphate dihydrate, sodium dihydrogen phosphate monohydrate, methionine, polysorbate 20. Sucrose: See leaflet before use. Solvent: water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Powder and solvent for solution for injection. 1 vial of powder (11 µg r-hfsh and 3 µg r-hlh). 1 vial of solvent (1 ml). 3 vials of powder. 3 vials of solvent. 10 vials of powder. 10 vials of solvent. 5. METHOD AND ROUTE OF ADMINISTRATION Subcutaneous use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY 14

15 8. EXPIRY DATE EXP (powder) EXP (solvent) 9. SPECIAL STORAGE CONDITIONS Do not store above 25 C. Store in the original package in order to protect from light. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE Any unused product or waste material should be disposed of in accordance with local requirements. 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Serono Europe Limited 56 Marsh Wall London E14 9TP United Kingdom 12. MARKETING AUTHORISATION NUMBER(S) EU/0/00/000/000 EU/0/00/000/000 EU/0/00/000/000 1 vial of powder for solution for injection. 1 vial of solvent. 3 vials of powder for solution for injection. 3 vials of solvent. 10 vials of powder for solution for injection. 10 vials of solvent. 13. BATCH NUMBER Batch Solvent Batch 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE pergoveris 15

16 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS PERGOVERIS 150 IU/75 IU VIAL LABEL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Pergoveris 150 IU/75 IU powder for solution for injection Follitropin alfa/lutropin alfa Subcutaneous use 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Batch 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 150 IU r-hfsh-75 IU r-hlh 6. OTHER 16

17 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS SOLVENT VIAL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Solvent for Pergoveris Water for injections 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Batch 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 1 ml 6. OTHER 17

18 B. PACKAGE LEAFLET 18

19 PACKAGE LEAFLET: INFORMATION FOR THE USER PERGOVERIS 150 IU/75 IU powder and solvent for solution for injection Follitropin alfa/lutropin alfa Read all of this leaflet carefully before you start using this medicine. - Keep this leaflet. You may need to read it again. - If you have any further questions, ask your doctor or pharmacist. - This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. - If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell you doctor or pharmacist. In this leaflet: 1. What Pergoveris is and what it is used for 2. Before you use Pergoveris 3. How to use Pergoveris 4. Possible side effects 5. How to store Pergoveris 6. Further information 1. WHAT PERGOVERIS IS AND WHAT IT IS USED FOR Pergoveris belongs to the family of hormones called gonadotrophins, which are involved in the normal control of reproduction. Pergoveris is a medicine containing follitropin alfa and lutropin alfa, which is made in laboratories by special recombinant DNA techniques. The medicine should only be used under the strict supervision of a physician. In women who are not ovulating due to very low production of the fertility hormones (FSH and LH) by their pituitary gland, Pergoveris is used to cause ovulation. 2. BEFORE YOU USE PERGOVERIS You and your partner's fertility should be evaluated before the treatment is started. Do not use Pergoveris if you are allergic (hypersensitive) to follicle stimulating hormone, luteinising hormone or any of the other ingredients of Pergoveris, if you have tumours of the hypothalamus and pituitary gland, if you have ovarian enlargement or cyst not due to polycystic ovarian disease, if you have gynaecological bleeding of unknown cause, if you have ovarian, uterine or breast cancer. The medicine must not be used when a condition exists which would make a normal pregnancy impossible, such as : premature menopause, malformation of sexual organs, specific tumours of the womb. 19

20 Take special care with Pergoveris Inform you doctor if you have porphyria or a family history of porphyria (a disorder that may be passed on from parents to children). The use of certain medications may trigger an attack of the illness. Tell your doctor if you notice the following: your skin becoming fragile and easily blistered (especially areas that are frequently exposed to sunlight) and/or you have stomach or limb pain. Your doctor who may recommend that you stop treatment. This treatment stimulates your ovaries sometimes leading to excessive growth of the follicles, which may be associated with the risk of excessive increase of ovarian size. This can lead to the so called ovarian hyperstimulation syndrome (OHSS) (see 4. Possible side effects). However, if you are not ovulating and the recommended dose and schedule of administration are adhered to, the occurrence of severe OHSS is uncommon (likely to occur in fewer than 1 in 100 patients). Pergoveris treatment seldom gives rise to significant OHSS unless the medicine used to induce final follicular maturation (containing human chorionic gonadotrophin - hcg) is administered. It is therefore prudent to withhold administration of hcg in cases where OHSS is developing (see 4. Possible side effects) and not to have sexual intercourse or use barrier methods for at least four days. In patients undergoing induction of ovulation, the incidence of multiple pregnancies and births is increased compared with natural conception. However, this can be minimised by using the recommended dose and schedule of administration. To minimise the risk of OHSS or of multiple pregnancy, ultrasound scans as well as oestradiol measurements are recommended. Miscarriages are higher than in the normal population, but comparable with the rates found in women with fertility problems. Women with a history of tubal disease are at risk of pregnancy where the embryo is implanted outside the womb (ectopic pregnancy), whether the pregnancy is obtained by spontaneous conception or with fertility treatments. There have been reports of tumors to the ovary and other reproductive organs, both benign and malignant, in women who have undergone multiple drug regimens for infertility treatment. There have been isolated reports of non-serious allergic reactions to Pergoveris. If you had this type of reaction to similar medicines, inform your doctor. Using other medicines Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Pergoveris should not be administered as a mixture with other medicinal products in the same injection, except for follitropin alfa, if prescribed by your doctor. Pregnancy and breast-feeding Pergoveris is not indicated if you are pregnant or are breast-feeding. Driving and using machines 20

21 No studies on the effects on the ability to drive and use machines have been performed. Important information about some of the ingredients of Pergoveris Pergoveris contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially sodium-free. Pergoveris contains 30 mg of sucrose per dose. This should be taken into account in patients with diabetes mellitus. 3. HOW TO USE PERGOVERIS Always use Pergoveris exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Pergoveris is intended for subcutaneous use, that means it is given by injection just under the skin. It is for single use only. The usual dose is one vial of Pergoveris used every day for up to three weeks. According to your response, your doctor may increase your dose of follitropin alfa by preferably IU at 7 to 14- day intervals. Your physician may decide to extend your treatment up to 5 weeks. When the desired response has been obtained, a single injection of hcg is given hours after the last injections of Pergoveris. You are recommended to have sexual intercourse on the day of, and the day following administration of the hcg. Alternatively, intrauterine insemination (IUI) may be performed. If an excessive response is obtained, treatment should be stopped and hcg withheld (see 4. Possible side effects). For the following cycle, your doctor will prescribe follitropin alfa at a lower dose than that of the previous cycle. If you administer Pergoveris to yourself, please carefully read the following instructions: Wash your hands. It is important that your hands and the items you use be as clean as possible. Assemble and lay out on a clean surface everything you need: - one vial containing Pergoveris powder - one solvent vial - two alcohol swabs - one syringe - one needle for reconstitution and a fine bore needle for subcutaneous injection - sharp container Remove the protective cap from the solvent vial. Attach the reconstitution 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. 21

22 Prepare the injection solution: Remove the protective cap from the Pergoveris powder vial, pick up your syringe and slowly inject the solvent into the vial of powder. Swirl gently without removing the syringe. Do not shake. After the powder has dissolved (which usually occurs immediately), check that the resulting solution is clear and does not contain any particles. Turn the vial upside down, gently draw the solution back into the syringe. 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. 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. Dispose of all used items: Once you have finished your injection, immediately discard all needles and empty glass containers in the sharp container provided. Any unused solution must be discarded. If you use more Pergoveris than you should The effects of an overdose of Pergoveris are unknown, nevertheless one could expect ovarian hyperstimulation syndrome to occur, which is further described in the Possible side effects Section. However this will only occur if hcg is administered (see 2. Before you use Pergoveris). If you forget to take Pergoveris Do not take a double dose to make up for a forgotten dose, please contact your doctor. 4. POSSIBLE SIDE EFFECTS Like all medicines, Pergoveris can cause side effects, although not every body gets them. The very commun (likely to occur in more than 1 in 10 patients) reported side effects are: ovarian cysts headache Other commun (likely to occur in fewer than 1 in 100 patients) side effects are: abdominal pain pelvic pain breast pain nausea vomiting diarrhoea abdominal cramp 22

23 bloating somnolence (sleepiness) and local reactions at the injection site (pain, redness, itching, bruising, swelling and/or irritation). Following treatment with Pergoveris when human chorionic gonadotrophin is administered, a condition called ovarian hyperstimulation syndrome (see 2. Before you use Pergoveris) can occur. This syndrome is characterised by large ovarian cysts. The following are first symptoms of ovarian hyperstimulation: pain in the lower abdominal region, possibly in combination with nausea vomiting and weight gain. Should the above mentioned symptoms occur, a careful medical examination is indicated as soon as possible. In serious, but rare cases (likely to occur in fewer than 1 in 1000 patients), an ovarian hyperstimulation syndrome with clearly enlarged ovaries, can go hand in hand with possible accumulation of fluid in the abdomen or thorax as well as ovarian torsion or more serious thromboembolic complications. In rare cases the latter can also be found independently of ovarian hyperstimulation syndrome. In view of the above, to prevent such events, when the ovarian response is excessive, treatment with Pergoveris could be discontinued by your physician and the treatment with hcg abandoned. Rarely (likely to occur in fewer than 1 in 1000 patients) blood clots in blood vessels (abnormal blood clottings) have been seen to occur with similar medicines.therefore, this could possibly occur with Pergoveris / hcg therapy. Very rare (likely to occur in fewer than 1 in patients)cases of allergic reactions to follitropin alfa have occurred causing redness of the skin, rash, swelling, hives and difficulty in breathing. These reactions can sometimes be serious. Very rarely (likely to occur in fewer than 1 in patients) patients with asthma may experience worsening of their condition. Pregnancy where the embryo is implanted outside the womb (ectopic pregnacy) may occur especially in women with a history of prior tubal disease. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. HOW TO STORE PERGOVERIS Keep out of the reach and sight of children. Do not use Pergoveris after the expiry date which is stated on the vials and the carton after EXP. The expiry date refers to the last day of that month. Do not store above 25 C. Store in the original package in order to protect from light. The medicine must be administered immediately after reconstitution. Do not use Pergoveris if you notice any visible signs of deterioration. The reconstituted solution should not be administered if it contains particles or is not clear. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 23

24 6. FURTHER INFORMATION What Pergoveris contains The active substances are follitropin alfa and lutropin alfa. One vial of powder contains 150 IU follitropin alfa and 75 IU lutropin alfa. The other ingredients are sucrose, disodium phosphate dihydrate, sodium dihydrogen phosphate monohydrate, methionine, polysorbate 20, concentrated phosphoric acid and sodium hydroxide. The solvent is water for injections. What Pergoveris looks like and contents of the pack Pergoveris is presented as a powder and solvent for solution for injection. The powder is a white lyophilised pellet. The solvent is a clear colourless solution. One vial of powder contains 150 IU of follitropin alfa and 75 IU of lutropin alfa. One vial of solvent contains 1 ml of Water for Injections. The medicine is supplied in packs of 1, 3 and 10 vials with the corresponding number of 1, 3 and 10 vials of solvent. Not all pack sizes may be marketed. Marketing Authorisation Holder Serono Europe Limited, 56 Marsh Wall, London E14 9TP, United Kingdom Manufacturer Industria Farmaceutica Serono S.p.A., Zona Industriale di Modugno, I Bari, Italy For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder. 24

25 België/Belgique/Belgien Serono Benelux BV Heizel Esplanade Heysel - b11 B-1020 Brussel/Bruxelles/Brüssel Tél./Tel.: България Serono Austria GmbH Floridsdorfer Hauptstraße 1 A-1210 Виена Австрия Teл.: Česká republika Serono Austria GmbH Floridsdorfer Hauptstraße 1 A-1210 Vídeň Rakousko Tel: Danmark Serono Nordic Strandvejen 102 B, 4, th. DK-2900 Hellerup Tlf: Deutschland Serono GmbH Freisinger Straße 5 D Unterschleißheim Tel: Eesti Serono Austria GmbH Floridsdorfer Hauptstraße 1 A-1210 Viin Austria Tel: Ελλάδα Serono Hellas A.E. Κηφισίας 41-45, Κτήριο Β GR Μαρούσι Αθήνα Tηλ: España Serono España S.A. María de Molina, 40 E Madrid Línea de Información Serono: Tel: Luxembourg/Luxemburg Serono Benelux BV Esplanade Heysel - b11 B-1020 Bruxelles/Brüssel Belgique/Belgien Tél./Tel.: Magyarország Serono Austria GmbH Floridsdorfer Hauptstraße 1 A-1210 Bécs Ausztria Tel.: Malta Cherubino LTD Delf Building Sliema Road MT-GZR 06 Gzira Malta Tel: /1/2/3/4 Nederland Serono Benelux BV Alexanderstraat 3-5 NL-2514 JL Den Haag Tel: Norge Serono Nordic Luhrtoppen 2 N-1470 Lørenskog Tlf: Österreich Serono Austria GmbH Floridsdorfer Hauptstraße 1 A-1210 Wien Tel: Polska Serono Austria GmbH Floridsdorfer Hauptstraße 1 A-1210 Wiedeń Austria Tel.: Portugal Serono Portugal Lda Rua Tierno Galvan, n 16B Amoreiras, Torre 3, Piso 16, Esc. 1 P Lisboa Tel:

26 France Serono France S.A. 738, rue Yves Kermen F Boulogne Cedex Numéro vert : Tél: Ireland Serono Ltd. Bedfont Cross, Stanwell Road Feltham, Middlesex TW 14 8NX - UK United Kingdom Tel: Ísland Gróco ehf. Þverholti 14 IS-105 Reykjavík Sími: Italia Industria Farmaceutica Serono S.p.A. Via Casilina 125 I Roma Tel: Κύπρος Akis Panayiotou & Son LTD Γιάννου Κρανιδιώτη 4 CY , Λευκωσία Τηλ: Latvija Serono Austria GmbH Floridsdorfer Hauptstraße 1 A-1210 Vīne Austrija Tel: România Serono Austria GmbH Floridsdorfer Hauptstraße 1 A-1210 Viena Austria Tel: Slovenija Serono Austria GmbH Floridsdorfer Hauptstraße 1 A-1210 Dunaj Avstrija Tel: Slovenská republika Serono Austria GmbH Floridsdorfer Hauptstraße 1 A-1210 Viedeň Rakúsko Tel: Suomi/Finland Serono Nordic Rajatorpantie 41B FIN Vantaa Puh/Tel: Sverige Serono Nordic AB S Stockholm Tel: United Kingdom Serono Ltd. Bedfont Cross, Stanwell Road Feltham, Middlesex TW 14 8NX - UK Tel: Lietuva Serono Austria GmbH Floridsdorfer Hauptstraße 1 A-1210 Viena Austrija Tel: This leaflet was last approved in 26