PRESCRIBING INFORMATION UK AND IRELAND Please refer to the Summary of Product Characteristics for further information

Transcription

1 PRESCRIBING INFORMATION UK AND IRELAND Please refer to the Summary of Product Characteristics for further information Cetrotide 0.25 mg powder and solvent for solution for injection cetrorelix acetate. Presentation: Cetrotide 0.25 mg vial contains 0.25 mg/ml cetrorelix after reconstitution with the 1 ml of solvent provided. Indications: Prevention of premature ovulation in patients undergoing controlled ovarian stimulation followed by oocyte pick-up and assisted reproductive techniques. Dosage and administration: Cetrotide should only be prescribed by a specialist experienced in this field. The first administration of Cetrotide should be performed under the supervision of a physician and under conditions where treatment of possible allergic/pseudo-allergic reactions (including life-threatening anaphylaxis) is immediately available. The following injections may be self-administered as long as the patient is made aware of the signs and symptoms that may indicate hypersensitivity, the consequences of such a reaction and the need for immediate medical intervention. Cetrotide is administered by subcutaneous injection into the lower abdominal wall. Cetrotide 0.25 mg is administered once daily either in the morning, commencing on day 5 or 6 of ovarian stimulation with gonadotrophins and is continued throughout the gonadotrophin treatment period including the day of ovulation induction, or in the evening commencing on day 5 of ovarian stimulation with gonadotrophins and continued throughout the gonadotrophin treatment period until the evening before the day of ovulation induction. Contraindications: Hypersensitivity to the active substance or any structural analogue of GnRH, extrinsic peptide hormones or to any other excipients. During pregnancy and lactation. In patients with severe renal impairment. Precautions: Cases of allergic/pseudoallergic reactions, including life-threatening anaphylaxis with the first dose have been reported. Take special care in women with signs and symptoms of active allergic conditions or known history of allergic predisposition. Treatment with Cetrotide is not advised in women with severe allergic conditions. During or following ovarian stimulation, ovarian hyperstimulation syndrome (OHSS) can occur. There is limited experience with Cetrotide during repeated ovarian stimulation procedures. Use in repeat cycles only after careful risk / benefit evaluation. The prevalence of congenital anomalies with assisted reproductive technologies (ART) may be slightly higher than after spontaneous conception but it is unclear whether related to factors inherent to couple s infertility or to ART. Limited data from clinical follow-up studies in 316 newborns of women administered cetrorelix for infertility treatment, suggest that cetrorelix does not increase the risk of congenital anomalies. Exercise caution in patients with hepatic impairment or mild to moderate renal impairment. The possibility of drug interactions with gonadotropins or products that induce histamine release in susceptible individuals, cannot be excluded. Side effects: Common: Local injection site reactions e.g., erythema, pruritus and swelling. Mild to moderate OHSS. Serious adverse events include severe OHSS and systemic allergic/pseudo-allergic reactions including life threatening anaphylaxis. Prescribers should consult the summary of product characteristics in relation to other side-effects. Legal Category: POM.

2 Basic NHS Price: 1 x 0.25 mg Cetrotide Marketing Authorisation Holder and Numbers: Merck Serono Europe Ltd, 56 Marsh Wall, London, E14 9TP; EU/1/99/100/001 For further information, including price queries, contact: UK: Merck Serono Ltd, Bedfont Cross, Stanwell Road, Feltham, Middlesex, TW14 8NX. Tel: Republic of Ireland: Merck Serono, 4045 Kingswood Road, Citywest Business Campus, Dublin 24. Tel: Date of Preparation: April Job Bag No: CET (1) Adverse events should be reported. Reporting forms and information can be found at In the Republic of Ireland information can be found at Adverse events should also be reported to Merck Serono Limited - Tel: +44 (0) or medinfo.uk@merckgroup.com

3 PRESCRIBING INFORMATION - IRELAND Please refer to the Summary of Product Characteristics for further information Crinone 8% Progesterone Vaginal Gel. Presentation: Each single use applicator is designed to deliver g of gel containing 90 mg of progesterone. Pack of 15 single use Crinone 8% applicators. Indications: Infertility due to inadequate luteal phase. Dosage and administration: Treatment of infertility due to inadequate luteal phase: Intravaginal application - one application (1.125 g) daily, starting after documented ovulation or arbitrarily on day of cycle. Contraindications: Known hypersensitivity to progesterone or any of the excipients, undiagnosed vaginal bleeding, porphyria, known or suspected malignancy of the breast or genital organs.thrombophlebitis, thromboembolic disorders, cerebral apoplexy or history of these conditions, missed abortion. Precautions: In cases of breakthrough bleeding, non-functional causes should be considered. Sorbic acid may cause local skin reactions. Pregnancy and Lactation: In case of corpus luteum deficiency, Crinone can be used during the first month of pregnancy. Do not use during lactation. Side effects: Headache, somnolence, breast tenderness, intermenstrual bleeding (spotting), vaginal irritation, hypersensitivity reactions usually manifesting as skin rash, and other mild application site reactions. Legal Category: POM. Marketing Authorisation Holder and Number: Merck Serono Limited, Bedfont Cross, Stanwell Road, Feltham, Middlesex, TW14 8NX, United Kingdom; PA 654/21/1. For further information, including price queries, contact: Republic of Ireland: Merck Serono, 4045 Kingswood Road, Citywest Business Campus, Dublin 24. Tel: Date of Preparation: May Job Bag No: CRI Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Merck Serono Limited Tel: +44(0) or medinfo.uk@merckgroup.com.

4 PRESCRIBING INFORMATION - UK Please refer to the Summary of Product Characteristics for further information Crinone 8% Progesterone Vaginal Gel. Presentation: Each single use applicator is designed to deliver g of gel i.e. 90 mg of progesterone. Indications: Treatment of infertility due to inadequate luteal phase. For use during in vitro fertilisation (IVF), where infertility is mainly due to tubal, idiopathic or endometriosis linked sterility associated with normal ovulatory cycles. Dosage and Administration: Intravaginal application. Treatment of infertility due to inadequate luteal phase: one application daily, starting after documented ovulation or arbitrarily on day of cycle. Use during IVF: daily application of Crinone 8% gel should be continued for 30 days if there is laboratory evidence of pregnancy. Contraindications: Known hypersensitivity to progesterone or any of the excipients, undiagnosed vaginal bleeding, porphyria, known or suspected progesterone-sensitive malignant tumours, thrombophlebitis, thromboembolic disorder, cerebral apoplexy, or patients with a history of these conditions, missed abortion. Precautions: Pre-treatment physical examination should include special reference to breast and pelvic organs, as well as Papanicolaou smear. Use with caution in severe hepatic insufficiency. Crinone should not be used concurrently with other intravaginal therapy. Treatment should be discontinued in the event of a missed abortion. Be alert to the early manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorder, pulmonary embolism and retinal thrombosis). If these symptoms occur or are suspected, discontinue the drug immediately. Carefully observe patients who have risk factors for thrombotic disorders. In women with generally recognised risk factors for thrombo-embolic events, such as personal or family history, treatment with Crinone may further increase the risk. In these women, the benefits of Crinone administration need to be weighed against the risks. Carefully observe patients with conditions that might be influenced by fluid retention (e.g, epilepsy, migraine, asthma, cardiac or renal dysfunction). Carefully observe patients with a history of depression and discontinue the drug if the depression recurs to a serious degree. Carefully observe diabetic patients while receiving progestin therapy. The excipient sorbic acid may cause local skin reactions (e.g. contact dermatitis) or vaginal irritation. In case of corpus luteum deficiency, Crinone can be used during the first month of pregnancy. Do not use during lactation. Side Effects: Common: Headache, somnolence, abdominal pain, breast tenderness, vaginal itching or burning. Post-marketing reports: intermenstrual bleeding (spotting), vaginal irritation and mild application site reactions. Hypersensitivity reactions usually manifesting as skin rash including rare events such as urticaria and pruritis. Prescribers should consult the summary of product characteristics in relation to other side-effects. Legal Category: POM.

5 Basic NHS Price: Pack of 15 single use applicators: Marketing Authorisation Holder and Number: Merck Serono Limited, Bedfont Cross, Stanwell Road, Feltham, Middlesex, TW14 8NX, United Kingdom; PL 11648/0261. For further information, including price queries, contact: UK: Merck Serono Ltd, Bedfont Cross, Stanwell Road, Feltham, Middlesex, TW14 8NX, UK Tel: Date of Preparation: November Job Bag: CRI Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Merck Serono Limited - Tel: +44(0) or medinfo.uk@merckgroup.com

6 PRESCRIBING INFORMATION UK AND IRELAND Please refer to the Summary of Product Characteristics for further information GONAL-f 75 IU (5.5 mcg), 450 IU/0.75 ml (33 mcg/0.75 ml), 1050 IU/1.75 ml (77 mcg/1.75 ml) powder and solvent for solution for injection. follitropin alfa. Presentation: Vials containing follitropin alfa, recombinant human follicle stimulating hormone (r-hfsh). Indications: (1) Anovulation (including polycystic ovarian syndrome, PCOS) in adult women who have been unresponsive to treatment with clomiphene citrate. (2) Stimulation of multifollicular development in adult women undergoing superovulation for assisted reproductive technologies (ART). (3) In association with a luteinising hormone (LH) preparation for stimulation of follicular development in adult women with severe LH and FSH deficiency. (4) Stimulation of spermatogenesis in adult men who have congenital or acquired hypogonadotrophic hypogonadism with concomitant human Chorionic Gonadotropin (hcg) therapy. Dosage and administration: For subcutaneous injection. Women with anovulation (including PCOS): Daily injections, starting by Day 7 of the cycle. Treatment should be tailored to the patient s response. Treatment typically commences at IU FSH daily and is increased preferably by 37.5 or 75 IU at 7 or preferably 14-day intervals if required. Maximum daily dose is usually not higher than 225 IU FSH. If a patient fails to respond after 4 weeks of treatment, that cycle should be abandoned and treatment may recommence at a higher starting dose. When an optimal response is obtained, a single injection of 250 mcg r-hcg or 5,000 IU to 10,000 IU hcg should be administered hours after the last GONAL-f injection. The patient is recommended to have coitus on the day of and day following, hcg administration. Alternatively intrauterine insemination (IUI) may be performed. If the response is excessive, treatment should be stopped and the hcg withheld (see precautions). Women undergoing ovarian stimulation for multiple follicular development prior to in vitro fertilisation or other assisted reproductive technologies: A commonly used regimen for superovulation involves the administration of IU of GONAL-f daily, commencing on day 2 or 3 of the cycle. Continue treatment until adequate follicular development has been achieved, with the dose adjusted according to the patient s response. Maximum daily dose is usually not higher than 450 IU daily. A single injection of 250 mcg r-hcg or 5,000 IU up to 10,000 IU hcg is administered hours after the last GONAL-f injection to induce final follicular maturation. Down-regulation with a gonadotropin-releasing hormone (GnRH) agonist or antagonist is commonly used in order to suppress the endogenous LH surge and to control tonic levels of LH. GONAL-f is started approximately 2 weeks after the start of agonist treatment, both being continued until adequate follicular development is achieved. Women with anovulation resulting from severe LH and FSH deficiency: Treatment should be tailored according to response. Treatment may commence at 75 IU of lutropin alfa daily with 75 IU-150 IU FSH. If appropriate, the FSH dose should be adapted after 7-14 day intervals and by 37.5 IU-75 IU increments for up to 5 weeks. When an optimal response is obtained, a single injection of 250 mcg r-hcg or 5,000 IU to 10,000 IU hcg should be administered hours after the last lutropin alfa and GONAL-f injections. The patient is recommended to have coitus on the day of, and on the day following, hcg administration. Alternatively, IUI may be performed. Men with hypogonadotrophic hypogonadism: 150 IU GONAL-f should be given three times a week, concomitantly with hcg, for a minimum of 4 months. If after this period, the patient has not responded, the combination treatment may be continued. Current clinical experience indicates that treatment for at least 18 months may be necessary to achieve spermatogenesis. Contraindications: Hypersensitivity to follitropin alfa, FSH or to any of the excipients, tumours of the hypothalamus or pituitary gland. In women, ovarian enlargement or cyst not due to polycystic ovarian syndrome,

7 gynaecological haemorrhages of unknown aetiology, ovarian, uterine or mammary carcinoma or when an effective response cannot be obtained. In men, primary testicular insufficiency. Precautions: Treatment with GONAL-f should be initiated under the supervision of a physician experienced in the treatment of infertility problems. Self-administration should only be performed by patients adequately trained and with access to expert advice. The first injection should be performed under direct medical supervision. Patients with porphyria or a family history of porphyria should be closely monitored during treatment with GONAL-f. Assess couple s infertility and putative contraindications for pregnancy before starting treatment. Monitor for ovarian enlargement or hyperstimulation. Excessive ovarian response to gonadotropin treatment can give rise to ovarian hyperstimulation syndrome (OHSS) with varying degrees of severity. Risk factors for OHSS include PCOS, as well as high or rapidly rising serum oestradiol levels. To minimise the risk of OHSS, adherence to recommended doses and administration schedule is important. Monitoring with ultrasound scans as well as oestradiol measurements are also recommended. There is evidence that hcg can trigger OHSS, and that the syndrome may be more severe and more protracted if pregnancy occurs. If signs of OHSS occur, withhold hcg and advise the patient to avoid coitus or use barrier methods of contraception for at least 4 days. Very rarely, severe OHSS may be complicated by ovarian torsion, pulmonary embolism, ischaemic stroke and myocardial infarction. Patients should be advised of the potential risk of multiple births before starting treatment. Ectopic pregnancy is more common following ART and may occur in patients with prior tubal disease. Pregnancy loss is higher than in the normal population. Prevalence of congenital malformations may be slightly higher than after spontaneous conceptions. In women with recent or ongoing thromboembolic disease or those with generally recognised risk factors for thromboembolic events, treatment with gonadotropins increases the risk. There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility treatment. It is not yet established whether or not treatment with gonadotropins increases the risk of these tumours in infertile women. Gonal-f should not be used during breastfeeding. In men, semen analysis is recommended 4 6 months after the beginning of the treatment in assessing the response. Gonal-f should not be used in men when an effective response cannot be obtained. Side effects: Women: Very common: ovarian cysts, injection site reactions (pain, erythema, haematoma, swelling and/or irritation at site of injection), headache. Common: mild to moderate OHSS, abdominal pain, abdominal distension and gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal discomfort. Serious: severe OHSS, ovarian torsion (a complication of OHSS), thromboembolism (both in association with and separate from OHSS), allergic reactions, including anaphylactic reactions and exacerbation or aggravation of asthma. Men: Very common: injection site reactions (pain, erythema, haematoma, swelling and/or irritation at the site of injection). Common: gynaecomastia, varicocele, acne and weight gain. Serious: allergic reactions including anaphylactic shock reactions and shock and exacerbation or aggravation of asthma. Prescribers should consult the summary of product characteristics in relation to other side-effects. Legal category: POM. Basic NHS price: 75 IU vial and solvent x IU/0.75 ml vial and solvent IU/1.75 ml vial and solvent

8 Marketing Authorisation Holder and Numbers: Merck Serono Europe Ltd, 56 Marsh Wall, London, E14 9TP; EU/1/95/001/025, EU/1/95/001/031, EU/1/95/001/021. For further information, including price queries, contact: UK: Merck Serono Ltd, Bedfont Cross, Stanwell Road, Feltham, Middlesex, TW14 8NX. Tel: Republic of Ireland: Merck Serono, 4045 Kingswood Road, Citywest Business Campus, Dublin 24. Tel: Date of preparation: April Job Bag Number: UK&IE/GON/0417/0005 Adverse events should be reported. Reporting forms and information can be found at In the Republic of Ireland information can be found at Adverse events should also be reported to Merck Serono Limited - Tel: +44(0) or medinfo.uk@merckgroup.com

9 PRESCRIBING INFORMATION UK AND IRELAND Please refer to the Summary of Product Characteristics for further information GONAL-f 300 IU/0.5 ml (22 mcg/0.5 ml), 450 IU/0.75 ml (33 mcg/0.75 ml), 900 IU/1.5 ml (66 mcg/1.5 ml) solution for injection in a pre-filled pen. follitropin alfa. Presentation: Pre-filled pens containing follitropin alfa, recombinant human follicle stimulating hormone (r-hfsh). Indications: (1) Anovulation (including polycystic ovarian syndrome, PCOS) in adult women who have been unresponsive to treatment with clomiphene citrate. (2) Stimulation of multifollicular development in adult women undergoing superovulation for assisted reproductive technologies (ART). (3) In association with a luteinising hormone (LH) preparation for stimulation of follicular development in adult women with severe LH and FSH deficiency. (4) Stimulation of spermatogenesis in adult men who have congenital or acquired hypogonadotrophic hypogonadism with concomitant human Chorionic Gonadotropin (hcg) therapy. Dosage and administration: For subcutaneous injection. Women with anovulation (including PCOS): Daily injections, starting by Day 7 of the cycle. Treatment should be tailored to the patient s response. Treatment typically commences at IU FSH daily and is increased preferably by 37.5 or 75 IU at 7 or preferably 14-day intervals if required. Maximum daily dose is usually not higher than 225 IU FSH. If a patient fails to respond after 4 weeks of treatment, that cycle should be abandoned and treatment recommenced at a higher starting dose. When an optimal response is obtained, a single injection of 250 mcg r-hcg or 5,000 IU to 10,000 IU hcg should be administered hours after the last GONAL-f injection. The patient is recommended to have coitus on the day of, and day following, hcg administration. Alternatively intrauterine insemination (IUI) may be performed. If the response is excessive, treatment should be stopped and the hcg withheld (see precautions). Women undergoing ovarian stimulation for multiple follicular development prior to in vitro fertilisation or other assisted reproductive technologies: A commonly used regimen for superovulation involves the administration of IU of GONAL-f daily, commencing on day 2 or 3 of the cycle. Continue treatment until adequate follicular development has been achieved. Maximum daily dose is usually not higher than 450 IU daily. A single injection of 250 mcg r-hcg or 5,000 IU up to 10,000 IU hcg is administered hours after the last GONAL-f injection to induce final follicular maturation. Down-regulation with a gonadotropin-releasing hormone (GnRH) agonist or antagonist is commonly used in order to suppress the endogenous LH surge and to control tonic levels of LH. GONAL-f is started approximately 2 weeks after the start of agonist treatment, both being continued until adequate follicular development is achieved. Women with anovulation resulting from severe LH and FSH deficiency: Treatment should be tailored according to response. Treatment may commence at 75 IU of lutropin alfa daily with 75 IU-150 IU FSH. If appropriate, the FSH dose should be adapted after 7-14 day intervals and by 37.5 IU-75 IU increments for up to 5 weeks. When an optimal response is obtained, a single injection of 250 mcg r-hcg or administer 5,000 IU to 10,000 IU hcg hours after the last lutropin alfa and GONAL-f injections.the patient is recommended to have coitus on the day of, and on the day following, hcg administration. Alternatively, IUI may be performed. Men with hypogonadotrophic hypogonadism: 150 IU GONAL-f should be given three times a week, concomitantly with hcg, for a minimum of 4 months. If after this period the patient has not responded, the combination treatment may be continued. Current clinical experience indicates that treatment for at least 18 months may be necessary to achieve spermatogenesis. 1

10 Contraindications: Hypersensitivity to follitropin alfa, FSH or to any of the excipients, tumours of the hypothalamus or pituitary gland. In women, ovarian enlargement or cyst not due to polycystic ovarian syndrome, gynaecological haemorrhages of unknown aetiology, ovarian, uterine or mammary carcinoma or when an effective response cannot be obtained. In men, primary testicular insufficiency. Precautions: Treatment with GONAL-f should be initiated under the supervision of a physician experienced in the treatment of infertility problems. Self-administration should only be performed by patients adequately trained and with access to expert advice. The first injection should be performed under direct medical supervision. Patients with porphyria or a family history of porphyria should be closely monitored during treatment with GONAL-f. Assess couple s infertility and putative contraindications for pregnancy before starting treatment. Monitor for ovarian enlargement or hyperstimulation. Excessive ovarian response to gonadotropin treatment can give rise to ovarian hyperstimulation syndrome (OHSS) with varying degrees of severity. Risk factors for OHSS include PCOS, as well as high or rapidly rising serum oestradiol levels. To minimise the risk of OHSS, adherence to recommended doses and administration schedule is important. Monitoring with ultrasound scans as well as oestradiol measurements are also recommended. There is evidence that hcg can trigger OHSS, and that the syndrome may be more severe and more protracted if pregnancy occurs. If OHSS occurs, withhold hcg and advise the patient to avoid coitus or use barrier methods of contraception for at least 4 days. Very rarely, severe OHSS may be complicated by ovarian torsion, pulmonary embolism, ischaemic stroke and myocardial infarction. Patients should be advised of the potential risk of multiple births before starting treatment. Ectopic pregnancy is more common following ART and may occur in patients with prior tubal disease. Pregnancy loss is higher than in the normal population. Prevalence of congenital malformations may be slightly higher than after spontaneous conceptions. In women with recent or ongoing thromboembolic disease or those with generally recognised risk factors for thromboembolic events, treatment with gonadotropins increases the risk. There have been reports of ovarian and other reproductive system neoplasms, both benign and malignant, in women who have undergone multiple treatment regimens for infertility treatment. It is not yet established whether or not treatment with gonadotropins increases the risk of these tumours in infertile women. Gonal-f should not be used during breastfeeding. In men, semen analysis is recommended 4 6 months after the beginning of the treatment in assessing the response. Gonal-f should not be used in men when an effective response cannot be obtained. Side effects: Women: Very common: ovarian cysts, injection site reactions (pain, erythema, haematoma, swelling and/or irritation at the site of injection), headache. Common: mild to moderate OHSS, abdominal pain, abdominal distension, abdominal discomfort and gastrointestinal symptoms such as nausea, vomiting, diarrhoea. Serious: severe OHSS, ovarian torsion (a complication of OHSS), thromboembolism (both in association with and separate from OHSS), allergic reactions, including anaphylactic reactions and exacerbation or aggravation of asthma. Men: Very common: injection site reactions (pain, erythema, haematoma, swelling and/or irritation at the site of injection). Common: gynaecomastia, varicocele, acne and weight gain. Serious: allergic reactions including anaphylactic reactions and shock and exacerbation or aggravation of asthma. Prescribers should consult the summary of product characteristics in relation to other side-effects. Legal category: POM. Basic NHS price: 2

11 300 IU/0.5 ml pre-filled pen x 1: IU/0.75 ml pre-filled pen x 1: IU/1.5 ml pre-filled pen x 1: Marketing Authorisation Holder and Numbers: Merck Serono Europe Ltd, 56 Marsh Wall, London, E14 9TP; EU/1/95/001/ For further information, including price queries, contact: UK: Merck Serono Ltd, Bedfont Cross, Stanwell Road, Feltham, Middlesex, TW14 8NX. Tel: Republic of Ireland: Merck Serono, 4045 Kingswood Road, Citywest Business Campus, Dublin 24. Tel: Date of preparation: April Job Bag No: UK&IE/GON/0417/0006 Adverse events should be reported. Reporting forms and information can be found at In the Republic of Ireland information can be found at Adverse events should also be reported to Merck Serono Limited - Tel: +44(0) or medinfo.uk@merckgroup.com. 3

12 PRESCRIBING INFORMATION - UK AND IRELAND Please refer to the Summary of Product Characteristics for further information LUVERIS 75 IU, powder and solvent for solution for injection lutropin alfa. Presentation: One vial contains 75 IU of lutropin alfa (recombinant human luteinising hormone, r-hlh). Indications: Luveris in association with a Follicle Stimulating Hormone (FSH) preparation is recommended for the stimulation of follicular development in adult women with severe LH and FSH deficiency. Dosage and administration: Treatment with Luveris should be initiated under the supervision of a physician experienced in the treatment of fertility problems. Self-administration should only be performed by patients who are well-motivated, adequately trained and with access to expert advice. Safety, efficacy, and pharmacokinetics have not been established in patients with renal or hepatic impairment. Luveris should be given as a course of daily injections simultaneously with FSH. Treatment can commence at any time. Luveris is intended for subcutaneous administration. 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. Treatment should be tailored to the individual patient s response. A recommended regimen commences at 75 IU of lutropin alfa (ie. one vial of Luveris) daily with IU FSH. Luveris has been shown to increase the ovarian sensitivity to follitropin alfa. If an FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by 37.5 IU-75 IU increments. 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 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 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. Contraindications: Hypersensitivity to gonadotrophins or to any of the excipients; ovarian, uterine, or mammary carcinoma; tumours of the hypothalamus and pituitary gland; ovarian enlargement or cyst unrelated to polycystic ovarian disease and of unknown origin; gynaecological haemorrhages of unknown origin. Do not use when a normal pregnancy is impossible (e.g. primary ovarian failure, malformation of the sexual organs incompatible with pregnancy or fibroid tumours of the uterus incompatible with pregnancy).

13 Precautions: In patients with porphyria or a family history of porphyria Luveris may increase the risk of an acute attack. Deterioration or a first appearance of this condition may require cessation of treatment. Assess couple's infertility and putative contraindications for pregnancy before starting treatment. Evaluate for hypothyroidism, adrenocortical deficiency and hyperprolactinemia and provide appropriate specific treatment. The first injection should be performed under direct medical supervision. A certain degree of ovarian enlargement is expected in women undergoing controlled ovarian stimulation, but excessive enlargement is associated with ovarian hyperstimulation syndrome (OHSS) and can become a serious medical event. Risk factors for OHSS include young age, lean body mass, polycystic ovarian syndrome, higher doses of exogenous gonadotropins, high absolute or rapidly rising serum estradiol levels and history of OHSS, large number of developing ovarian follicles and oocytes retrieved in ART cycles. Mild or moderate OHSS usually resolves spontaneously. In severe cases it is recommended that gonadotropin treatment be stopped and the patient hospitalised. To minimise the risk of OHSS or of multiple pregnancy, ultrasound scans as well as estradiol measurements are recommended during stimulation therapy. Adherence to recommended Luveris and FSH dosage, regimen of administration and careful monitoring of therapy can minimise the risk of ovarian hyperstimulation and multiple pregnancy. 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. Multiple pregnancy, especially high order, carry an increased risk of adverse maternal and perinatal outcomes. Pregnancy loss by miscarriage or abortion is higher in patients undergoing stimulation of follicular growth for ovulation induction than following natural conception. Women with a history of tubal disease are at risk of ectopic pregnancy. Reproductive system neoplasms, both benign and malignant, have been reported in women who have had multiple cycles of fertility treatment. It is not known if treatment with gonadotrophins increases the risk in infertile women. Prevalence of congenital malformations after ART may be slightly higher than after spontaneous conceptions, possibly due to parental factors, ART procedures and multiple pregnancies. Treatment with gonadotrophins may increase the risk of thromboembolic events in women with recognised risk factors. However, pregnancy itself, as well as OHSS, also carries an increased risk of thromboembolic events. Luveris should not be used during pregnancy and lactation. Side effects: Common adverse drug reactions are injection site reactions, headache, nausea, vomiting, abdominal pain/discomfort, diarrhoea, pelvic pain, mild or moderate ovarian hyperstimulation syndrome and associated symptoms, ovarian cyst, breast pain. Rare possibility of adnexal torsion and haemoperitoneum. Very rare: Mild to severe hypersensitivity reactions including anaphylactic reactions and shock. Thromboembolism.

14 Prescribers should consult the summary of product characteristics in relation to other side-effects. Legal category: POM. Basic NHS price: 1 vial pack size: Marketing Authorisation Holder and Numbers: Merck Serono Europe Ltd, 56 Marsh Wall, London, E14 9TP; EU/1/00/155/004. For further information, including price queries, contact: UK: Merck Serono Ltd, Bedfont Cross, Stanwell Road, Feltham, Middlesex, TW14 8NX. Tel: Republic of Ireland: Merck Serono, 4045 Kingswood Road, Citywest Business Campus, Dublin 24. Tel: Date of Preparation: May Job Bag No: LUV Adverse events should be reported. Reporting forms and information can be found at In the Republic of Ireland information can be found at Adverse events should also be reported to Merck Serono Limited - Tel: +44(0) or medinfo.uk@merckgroup.com

15 PRESCRIBING INFORMATION- UK AND IRELAND Please refer to the Summary of Product Characteristics for further information OVITRELLE 250 micrograms/0.5 ml, solution for injection in a pre-filled pen choriogonadotropin alfa. Presentation: One pre-filled pen contains 250 micrograms choriogonadotropin alfa in 0.5 ml (equivalent to approximately 6,500 IU) in 0.5 ml solution. Indications: (i) Adult women undergoing superovulation prior to assisted reproductive techniques such as in vitro fertilisation (IVF): Ovitrelle is administered to trigger final follicular maturation and luteinisation after stimulation of follicular growth. (ii) Anovulatory or oligo-ovulatory adult women: Ovitrelle is administered to trigger ovulation and luteinisation in anovulatory or oligo-ovulatory patients after stimulation of follicular growth. Dosage and administration: For subcutaneous administration. Treatment with Ovitrelle should be performed under the supervision of a physician experienced in the treatment of fertility problems. The maximum dose is 250 micrograms. The following dosing regimen should be applied: (i) (ii) Women undergoing superovulation prior to assisted reproductive techniques: One pre-filled pen of Ovitrelle (250 micrograms) is administered 24 to 48 hours after the last administration of an FSH- or hmg preparation, i.e. when optimal stimulation of follicular growth is achieved. Anovulatory or oligo-ovulatory women: One pre-filled pen of Ovitrelle (250 micrograms) is administered 24 to 48 hours after optimal stimulation of follicular growth is achieved. The patient is recommended to have coitus on the day of, and the day after, Ovitrelle injection. Contraindications: Tumours of the hypothalamus and pituitary gland, hypersensitivity to the active substance or to any of the excipients, ovarian enlargement or cyst not due to polycystic ovarian disease, gynaecological haemorrhages of unknown aetiology, ovarian, uterine or mammary carcinoma, extrauterine pregnancy in the previous 3 months, active thromboembolic disorders. Ovitrelle must not be used when an effective response cannot be obtained. Precautions: Self-administration of Ovitrelle should only be performed by patients who are adequately trained and have access to expert advice.

16 Assess couple's infertility and putative contraindications for pregnancy before starting treatment.evaluate for hypothyroidism, adrenocortical deficiency, hyperprolactinaemia and pituitary or hypothalamic tumours, and appropriate specific treatment given. Safety, efficacy, and pharmacokinetics have not been established in patients with renal or hepatic impairment. Patients undergoing ovarian stimulation are at an increased risk of developing ovarian hyperstimulation syndrome (OHSS). OHSS may become a serious medical event however this can be avoided by withholding hcg. To minimise the risk of OHSS, ultrasound scans as well as estradiol measurements are recommended prior to and during stimulation therapy. In anovulation, the risk of OHSS is increased by a serum estradiol level > 1,500 pg/ml (5,400 pmol/l) and more than 3 follicles of 14 mm or more in diameter. In assisted reproductive techniques, there is an increased risk of OHSS with a serum estradiol > 3,000 pg/ml (11,000 pmol/l) and 18 or more follicles of 11 mm or more in diameter. When the estradiol level is > 5,500 pg/ml (20,000 pmol/l) and/or when there are 30 or more follicles in total, it is recommended to withhold hcg administration. Rarely, severe OHSS may be complicated by haemoperitoneum, acute pulmonary distress, ovarian torsion and thromboembolism. Adherence to recommended Ovitrelle dosage, regimen of administration and careful monitoring of therapy will minimise the risk of OHSS and multiple pregnancy.in patients undergoing induction of ovulation, the incidence of multiple pregnancy and births is increased compared with natural conception. The majority of multiple conceptions are twins. The risk of multiple pregnancy following ART is related to the number of embryos replaced. The rate of miscarriage, in both anovulatory patients and women undergoing ART is higher than that found in the normal population, but comparable to women with other fertility problems. Women with a history of tubal disease are at risk of ectopic pregnancy. The incidence of congenital malformations after Assisted Reproduction Techniques (ART) may be slightly higher than after spontaneous conceptions, possibly due to parental factors and multiple pregnancies. Treatment with gonadotrophins may increase the risk of thromboembolic events in women with recognised risk factors. However, pregnancy itself, as well as OHSS, also carry an increased risk of thromboembolic events. The administration of Ovitrelle may interfere (for up to 10 days) with immunological determination for serum or uninary hcg leading to a false positive pregnancy test result. Minor thyroid stimulation is possible during therapy. Ovitrelle should not be used during pregnancy and lactation. Side effects: Common adverse drug reactions are injection site reactions, headache, tiredness, vomiting/nausea, abdominal pain, mild or moderate ovarian hyperstimulation syndrome.

17 Serious adverse events are allergic reactions including anaphylactic reactions and shock, and severe ovarian hyperstimulation syndrome. Rare possibility of thromboembolisms. Ectopic pregnancy, ovarian torsion and other complications have been reported after hcg administration and are considered concomitant effects related to ART. Prescribers should consult the summary of product characteristics in relation to other side-effects. Legal category: POM. Basic NHS price: 1 pre-filled pen Marketing Authorisation Holder and Numbers: Merck Serono Europe Ltd, 56 Marsh Wall, London, E14 9TP; EU/1/00/165/008. For further information, including price queries, contact: UK: Merck Serono Ltd, Bedfont Cross, Stanwell Road, Feltham, Middlesex, TW14 8NX. Tel: Republic of Ireland: Merck Serono, 4045 Kingswood Road, Citywest Business Campus, Dublin 24. Tel: Date of Preparation: May Job Bag No: OVI Adverse events should be reported. Reporting forms and information can be found at In the Republic of Ireland information can be found at Adverse events should also be reported to Merck Serono Limited - Tel: +44(0) or medinfo.uk@merckgroup.com

18 PRESCRIBING INFORMATION - UK AND IRELAND Please refer to the Summary of Product Characteristics for further information OVITRELLE 250 micrograms/0.5 ml, solution for injection in a pre-filled syringe choriogonadotropin alfa. Presentation: One pre-filled syringe contains 250 micrograms choriogonadotropin alfa (equivalent to approximately 6,500 IU) in 0.5 ml solution. Indications: (i) Adult women undergoing superovulation prior to assisted reproductive techniques such as in vitro fertilisation (IVF): Ovitrelle is administered to trigger final follicular maturation and luteinisation after stimulation of follicular growth. (ii) Anovulatory or oligo-ovulatory adult women: Ovitrelle is administered to trigger ovulation and luteinisation in anovulatory or oligo-ovulatory patients after stimulation of follicular growth. Dosage and administration: For subcutaneous administration. Treatment with Ovitrelle should be performed under the supervision of a physician experienced in the treatment of fertility problems. The maximum dose is 250 micrograms. The following dosing regimen should be applied: (i) (ii) Women undergoing superovulation prior to assisted reproductive techniques: One pre-filled syringe of Ovitrelle (250 micrograms) is administered 24 to 48 hours after the last administration of an FSH- or hmg preparation, i.e. when optimal stimulation of follicular growth is achieved. Anovulatory or oligo-ovulatory women: One pre-filled syringe of Ovitrelle (250 micrograms) is administered 24 to 48 hours after optimal stimulation of follicular growth is achieved. The patient is recommended to have coitus on the day of, and the day after, Ovitrelle injection. Contraindications: Tumours of the hypothalamus and pituitary gland, hypersensitivity to the active substance or to any of the excipients, ovarian enlargement or cyst not due to polycystic ovarian disease, gynaecological haemorrhages of unknown aetiology, ovarian, uterine or mammary carcinoma, extrauterine pregnancy in the previous 3 months, active thromboembolic disorders. Ovitrelle must not be used when an effective response cannot be obtained. Precautions: Self-administration of Ovitrelle should only be performed by patients who are adequately trained and have access to expert advice.

19 Assess couple's infertility and putative contraindications for pregnancy before starting treatment. Evaluate for hypothyroidism, adrenocortical deficiency, hyperprolactinaemia and pituitary or hypothalamic tumours, and appropriate specific treatment given. Safety, efficacy, and pharmacokinetics have not been established in patients with renal or hepatic impairment. Patients undergoing ovarian stimulation are at an increased risk of developing ovarian hyperstimulation syndrome (OHSS). OHSS may become a serious medical event however this can be avoided by withholding hcg administration. To minimise the risk of OHSS, ultrasound scans as well as estradiol measurements are recommended prior to and during stimulation therapy. In anovulation, the risk of OHSS is increased by a serum estradiol level > 1,500 pg/ml (5,400 pmol/l) and more than 3 follicles of 14 mm or more in diameter. In assisted reproductive techniques, there is an increased risk of OHSS with a serum estradiol > 3,000 pg/ml (11,000 pmol/l) and 18 or more follicles of 11 mm or more in diameter. When the estradiol level is > 5,500 pg/ml (20,000 pmol/l) and/or when there are 30 or more follicles in total, it is recommended to withhold hcg administration. Rarely, severe OHSS may be complicated by haemoperitoneum, acute pulmonary distress, ovarian torsion and thromboembolism. Adherence to recommended Ovitrelle dosage, regimen of administration and careful monitoring of therapy will minimise the risk of OHSS and multiple pregnancy. In patients undergoing induction of ovulation, the incidence of multiple pregnancy and births is increased compared with natural conception. The majority of multiple conceptions are twins. The risk of multiple pregnancy following ART is related to the number of embryos replaced. The rate of miscarriage, in both anovulatory patients and women undergroing ART is higher than that found in the normal population, but comparable to women with other fertility problems. Women with a history of tubal disease are at risk of ectopic pregnancy. The incidence of congenital malformations after Assisted Reproduction Techniques (ART) may be slightly higher than after spontaneous conceptions, possibly due to parental factors and multiple pregnancies. Treatment with gonadotrophins may increase the risk of thromboembolic events in women with recognised risk factors. However, pregnancy itself as well as OHSS also carry an increased risk of thromboembolic events. The administration of Ovitrelle may interfere (for up to 10 days) with immunological determination for serum or uninary hcg leading to a false positive pregnancy test result. Minor thyroid stimulation is possible during therapy. Ovitrelle should not be used during pregnancy and lactation. Side effects: Common adverse drug reactions are injection site reactions, headache, tiredness, vomiting/nausea, abdominal pain, mild or moderate ovarian hyperstimulation syndrome.

20 Serious adverse events are allergic reactions including anaphylactic reactions and shock, and severe ovarian hyperstimulation syndrome. Rare possibility of thromboembolisms. Ectopic pregnancy, ovarian torsion and other complications have been reported after hcg administration and are considered concomitant effects related to ART. Prescribers should consult the summary of product characteristics in relation to other side-effects. Legal category: POM. Basic NHS price: 1 pre-filled syringe Marketing Authorisation Holder and Numbers: Merck Serono Europe Ltd, 56 Marsh Wall, London, E14 9TP; EU/1/00/165/007. For further information, including price queries, contact: UK: Merck Serono Ltd, Bedfont Cross, Stanwell Road, Feltham, Middlesex, TW14 8NX. Tel: Republic of Ireland: Merck Serono, 4045 Kingswood Road, Citywest Business Campus, Dublin 24. Tel: Date of Preparation: May Job Bag No: OVI Adverse events should be reported. Reporting forms and information can be found at In the Republic of Ireland information can be found at Adverse events should also be reported to Merck Serono Limited Tel: +44(0) or medinfo.uk@merckgroup.com

21 PRESCRIBING INFORMATION UK AND IRELAND Please refer to the Summary of Product Characteristics for further information Pergoveris 150 IU/75 IU powder and solvent for solution for injection follitropin alfa and lutropin alfa. Presentation: One vial contains 150 IU (equivalent to 11 micrograms) of follitropin alfa (r-hfsh) and 75 IU (equivalent to 3 micrograms) of lutropin alfa (r-hlh). Indications: Pergoveris is indicated for the stimulation of follicular development in adult women with severe LH and FSH deficiency. In clinical trials, these patients were defined by an endogenous serum LH level < 1.2 IU/l. Dosage and administration: Treatment should be initiated under the supervision of a physician experienced in the treatment of fertility problems. Pergoveris is intended for subcutaneous administration. The first injection of Pergoveris should be administered under direct medical supervision. The powder should be reconstituted immediately prior to use with the solvent provided. Treatment should be tailored to the individual patient s response. A recommended regimen commences with one vial of Pergoveris daily. If a FSH dose increase is deemed appropriate, dose adaptation should preferably be after 7-14 day intervals and preferably by 37.5 IU 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 human chorionic gonadotrophin (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. If an excessive response is obtained, treatment should be stopped and hcg withheld. Treatment should restart in the next cycle using a lower dose of FSH. Contraindications: Hypersensitivity to the active substances or to any of the excipients, 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 or when an effective response cannot be obtained such as: primary ovarian failure, malformation of the sexual organs incompatible with pregnancy or fibroid tumours of the uterus incompatible with pregnancy. Precautions: Monitor patients for ovarian response with ultrasound alone or preferably in combination with measurement of serum oestradiol levels on a regular basis. Patients with porphyria or a family history of porphyria should be closely monitored during treatment with Pergoveris. In these patients, Pergoveris may increase the risk of an acute attack. Deterioration or first appearance of this condition may require cessation of treatment. Assess couple s infertility and putative contraindications for pregnancy before starting treatment. In particular, evaluate patients for hypothyroidism, adrenocortical deficiency, hyperprolactinaemia, and appropriate specific treatment should be given. 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. In distinction to 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. 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.