ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS

Transcription

1 ANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1

2 1. NAME OF THE MEDICINAL PRODUCT Flebogammadif 50 mg/ml solution for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One ml contains 50 mg of human normal immunoglobulin (IVIg) of which at least 97% is IgG. The percentage of IgG subclasses is approximately 66.6% IgG 1, 28.5% IgG 2, 2.7% IgG 3 and 2.2% IgG 4. It contains trace amounts of IgA (lower than 0.05 mg/ml). Excipient: One ml contains 50 mg of D-sorbitol. For a full list of excipients, see section PHARMACEUTICAL FORM Solution for infusion. The solution is clear or slightly opalescent and colourless or pale yellow. 4. CLINICAL PARTICULARS 4.1. Therapeutic indications Flebogammadif is indicated for: Replacement therapy in: Primary immunodeficiency syndromes such as: - congenital agammaglobulinaemia and hypogammaglobulinaemia - common variable immunodeficiency - severe combined immunodeficiency - Wiskott Aldrich syndrome Myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections. Children with congenital AIDS and recurrent infections. Immunomodulation Idiopathic thrombocytopenic purpura (ITP), in children or adults at high risk of bleeding or prior to surgery to correct the platelet count. Guillain Barré syndrome. Kawasaki disease. Allogeneic bone marrow transplantation. 2

3 4.2. Posology and method of administration Posology The dose and dosage regimen is dependent on the indication. In replacement therapy the dosage may need to be individualised for each patient dependent on the pharmacokinetic and clinical response. The following dosage regimens are given as a guideline. Replacement therapy in primary immunodeficiency syndromes The dosage regimen should achieve a trough level of IgG (measured before the next infusion) of at least 4-6 g/l. Three to six months are required after the initiation of therapy for equilibration to occur. The recommended starting dose is g/kg followed by at least 0.2 g/kg every three weeks. The dose required to achieve a trough level of 6 g/l is of the order of g/kg/month. The dosage interval when steady state has been reached varies from 2-4 weeks. Trough levels should be measured in order to adjust the dose and dosage interval. Replacement therapy in myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections; replacement therapy in children with AIDS and recurrent infections. The recommended dose is g/kg every three to four weeks. Idiopathic thrombocytopenic purpura For the treatment of an acute episode, g/kg on day one, which may be repeated once within 3 days, or 0.4 g/kg daily for two to five days. The treatment can be repeated if relapse occurs. Guillain Barré syndrome 0.4 g/kg/day for 3 to 7 days. Experience in children is limited. Kawasaki disease g/kg should be administered in divided doses over two to five days or 2.0 g/kg as a single dose. Patients should receive concomitant treatment with acetylsalicylic acid. Allogeneic bone marrow transplantation Human normal immunoglobulin treatment can be used as part of the conditioning regimen and after the transplant. For the treatment of infections and prophylaxis of graft versus host disease, dosage is individually tailored. The starting dose is normally 0.5 g/kg/week, starting seven days before transplantation and for up to 3 months after transplantation. In case of persistent lack of antibody production, dosage of 0.5 g/kg/month is recommended until antibody level returns to normal. 3

4 The dosage recommendations are summarised in the following table: Replacement therapy in primary immunodeficiency Indication Dose Frequency - starting dose: g/kg - thereafter: g/kg every 2-4 weeks to obtain IgG trough level of at least 4-6 g/l Replacement therapy in secondary immunodeficiency Children with AIDS Immunomodulation: Idiopathic thrombocytopenic purpura Guillain Barré syndrome Kawasaki disease Allogeneic bone marrow transplantation: - treatment of infections and prophylaxis of graft versus host disease - persistent lack of antibody production Method of administration g/kg g/kg g/kg or 0.4 g/kg/d 0.4 g/kg/d g/kg or 2 g/kg 0.5 g/kg 0.5 g/kg every 3-4 weeks to obtain IgG trough level of at least 4-6 g/l every 3-4 weeks on day 1, possibly repeated once within 3 days for 2-5 days for 3-7 days in several doses for 2-5 days in association with acetylsalicylic acid in one dose in association with acetylsalicylic acid every week from day -7 up to 3 months after transplantation every month until antibody levels return to normal Flebogammadif should be infused intravenously at an initial rate of ml/kg/min for the first thirty minutes. If well tolerated, the rate of administration may gradually be increased to a maximum of 0.1 ml/kg/min Contraindications Hypersensitivity to any of the components (see section 4.4). Hypersensitivity to homologous immunoglobulins, especially in very rare cases of IgA deficiency, when the patient has antibodies against IgA. Fructose intolerance (see section 4.4) Special warnings and precautions for use Certain severe adverse drug reactions may be related to the rate of infusion. The recommended infusion rate given under 4.2. Posology and method of administration must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. 4

5 Certain adverse reactions may occur more frequently - in case of high rate of infusion, - in patients with hypo- or agammaglobulinaemia with or without IgA deficiency, - in patients who receive human normal immunoglobulin for the first time, or in rare cases, when the human normal immunoglobulin product is switched or when there has been a long interval since the previous infusion. True hypersensitivity reactions are rare. They can occur in the very seldom cases of IgA deficiency with anti-iga antibodies. Rarely, human normal immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin. Potential complications can often be avoided by ensuring: - that patients are not sensitive to human normal immunoglobulin by first injecting the product slowly at an initial rate of ml/kg/min; - that patients are carefully monitored for any symptoms throughout the infusion period. In particular, patients naive to human normal immunoglobulin, patients switched from an alternative IVIg product or when there has been a long interval since the previous infusion should be monitored during the first infusion and for the first hour after the first infusion, in order to detect potential adverse signs. All other patients should be observed for at least 20 minutes after administration. There is clinical evidence of an association between IVIg administration and thromboembolic events such as myocardial infarction, stroke, pulmonary embolism and deep vein thromboses which is assumed to be related to a relative increase in blood viscosity through the high influx of immunoglobulin in at-risk patients. Caution should be exercised in prescribing and infusing IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events (such as advanced age, hypertension, diabetes mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilisation, severely hypovolemic patients, and patients with diseases which increase blood viscosity). Cases of acute renal failure have been reported in patients receiving IVIg therapy. In most cases, risk factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolemia, overweight, concomitant nephrotoxic medicinal products or age over 65. In case of renal impairment, IVIg discontinuation should be considered. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IVIg products, those containing sucrose as a stabiliser accounted for a disproportionate share of the total number. In patients at risk, the use of IVIg products that do not contain sucrose may be considered. In patients at risk for acute renal failure or thromboembolic adverse reactions, IVIg products should be administered at the minimum rate of infusion and dose practicable. In all patients, IVIg administration requires: - adequate hydration prior to the initiation of the infusion of IVIg - monitoring of urine output - monitoring of serum creatinine levels - avoidance of concomitant use of loop diuretics In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped. The treatment required depends on the nature and severity of the side effect. 5

6 In case of shock, standard medical treatment for shock should be implemented. Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens. The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped viruses HAV and parvovirus B19. There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to viral safety. It is strongly recommended that every time Flebogammadif is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product. Special warnings about excipients: This medicinal product contains 50 mg of sorbitol per ml as excipient. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Special precautions should be taken with babies and young children because this fructose intolerance may not yet be diagnosed and may be fatal. Interferences with determination of blood glucose levels are not expected Interaction with other medicinal products and other forms of interaction Live attenuated virus vaccines Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of this product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. Therefore patients receiving measles vaccine should have their antibody status checked. Interference with serological testing After injection of immunoglobulin the transitory rise of the various passively transferred antibodies in the patients blood may result in misleading positive results in serological testing. Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D, may interfere with some serological tests for red cell antibodies, for example the antiglobulin test (Coomb s test) Pregnancy and lactation The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials and therefore should only be given with caution to pregnant women and breast-feeding mothers. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected. Immunoglobulins are excreted into the milk and may contribute to the transfer of protective antibodies to the neonate. 6

7 4.7. Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed. Since Flebogammadif might induce dizziness, patients should be cautioned when driving or operating machines Undesirable effects Adverse reactions such as chills, headache, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally. Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration. Cases of reversible aseptic meningitis, isolated cases of reversible haemolytic anaemia/haemolysis and rare cases of transient cutaneous reactions, have been observed with human normal immunoglobulin. Increase in serum creatinine level and/or acute renal failure have been observed. Very rarely: Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thromboses. Two multicenter clinical trials were performed, one of them in children and adults with primary immune deficiency and the second one in patients with chronic immune thrombocytopenic purpura in acute phase. Forty-six patients were included in the first trial and 41 completed the study. They were followed during 1 year of treatment at a dose of mg/kg every 3 to 4 weeks. A total of 20 patients were included in the second study. Patients received a total dose of 400 mg/kg body weight for 5 consecutive days and were followed for 3 months. Therefore, a total of 66 patients have been exposed to Flebogammadif and they have received 806 infusions. Data from both studies indicate a good tolerability of the product as incidence of adverse events was low and most of them were mild to moderate in intensity. Of the 806 infusions administered in patients enrolled in both studies 10.8% (1-sided 95% CI upper bound = 12.9%) were associated with an adverse event suspected to be related to the product. No patients died, only 6 patients withdrew from the studies but none of them because of potentially related adverse events. Four patients experienced 8 serious adverse events that were considered not related to the study medicinal product. Pyrexia and headache were the most frequently reported adverse events potentially related to the medicinal product in both studies. The adverse drug reactions reported in the 2 trials by at least the 5% of the patients are summarised and categorised according to the MedDRA system organ class in the table below: Frequency has been determined using the following criteria: - 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.) Within each frequency grouping, undesirable effects are presented in order of decreasing of seriousness. 7

8 System Organ Class Investigations Nervous system disorder Respiratory, thoracic and mediastinal disorder Gastrointestinal disorders Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorder Vascular disorders General disorders & administration site conditions Body System Preferred Term Coombs test positive, blood pressure systolic decreased, blood pressure systolic increased, body temperature increased Headache Dizziness Bronchitis, cough, wheezing Diarrhoea, nausea, vomiting, abdominal pain, abdominal pain upper Urticaria, rash pruritic, dermatitis contact Back pain, arthralgia, myalgia, muscle cramp Hypotension, hypertension, diastolic hypertension, blood pressure fluctuations Pyrexia, injection site reaction Rigors, asthenia, pain, infusion site inflammation, injection site oedema, injection site pain, injection site pruritus, injection site swelling, migration of implant ADR frequency evaluation Uncommon Common Uncommon Uncommon Uncommon Uncommon Uncommon Uncommon Common Uncommon For safety with respect to transmissible agents, see section Overdose Overdose may lead to fluid overload and hyper viscosity, particularly in patients at risk, including elderly patients or patients with renal impairment. 5. PHARMACOLOGICAL PROPERTIES 5.1. Pharmacodynamic properties Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration, ATC code: J06BA02. Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents. Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1000 donors. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma. Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range. 8

9 The mechanism of action in indications other than replacement therapy is not fully elucidated, but includes immunomodulatory effects. A significant increase in median platelet levels was achieved in a clinical trial in chronic ITP patients (64,000/µl) although it did not reach normal levels. Two clinical trials were performed with Flebogammadif, one for replacement therapy in patients with primary immunodeficiency (both in adults and in children above 10 years) and another for immunomodulation in adults patients with immune thrombocytopenic purpura Pharmacokinetic properties Human normal immunoglobulin is immediately and completely bioavailable in the recipient s circulation after intravenous administration. It is distributed relatively rapidly between plasma and extravascular fluid, after approximately 3-5 days equilibrium is reached between the intra- and extravascular compartments. Flebogammadif has a half-life of about days. This half-life may vary from patient to patient, in particular in primary immunodeficiency. IgG and IgG-complexes are broken down in cells of the reticuloendothelial system Preclinical safety data Single dose toxicity studies were carried out in rats and mice. The absence of mortality in the non-clinical studies performed with Flebogammadif with dosages up to 2500 mg/kg, and the lack of any confirmed relevant adverse sign affecting respiratory, circulatory and central nervous system, of the treated animals supports the safety of Flebogammadif. Repeated dose toxicity testing and embryo-foetal toxicity studies are impracticable due to induction of, and interference with antibodies. Effects of the product on the immune system of the newborn have not been studied. 6. PHARMACEUTICAL PARTICULARS 6.1. List of excipients D-sorbitol Water for injections 6.2. Incompatibilities This medicinal product must not be mixed with other medicinal products or intravenous fluids. It should be administered by a separate intravenous line Shelf life 2 years Special precautions for storage Do not store above 30 ºC. Do not freeze. 9

10 6.5. Nature and contents of container 10 ml, 50 ml, 100 ml, 200 ml or 400 ml solution in a vial (type II glass) with stopper (chloro-butylrubber). Pack size: 1 vial Not all pack sizes may be marketed Special precautions for disposal and other handling The product should be brought to room or body temperature before use. The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have deposits. Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Barcelona - Spain 8. MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT Detailed information on this product is available on the website of the European Medicines Agency (EMEA) 10

11 ANNEX II A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OF THE MARKETING AUTHORISATION 11

12 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substance Polígono Levante Can Guasch, 2, E Parets del Vallès Barcelona, Spain Name and address of the manufacturer responsible for batch release Instituto Grifols S.A. Polígono Levante Can Guasch, 2 E Parets del Vallès Barcelona, Spain B. CONDITIONS OF THE MARKETING AUTHORISATION CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON THE MARKETING AUTHORISATION HOLDER Medicinal product subject to medical prescription. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT Not applicable. OTHER CONDITIONS Pharmacovigilance system The MAH must ensure that the system of pharmacovigilance, as described in version 1.0 presented in Module of the Marketing Authorisation Application, is in place and functioning before and whilst the product is on the market. Risk Management Plan The MAH commits to performing the pharmacovigilance activities detailed in the Pharmacovigilance Plan, as agreed in version 1.1 of the Risk Management Plan (RMP) presented in Module of the Marketing Authorisation Application and any subsequent updates of the RMP agreed by the CHMP. As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, an updated RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR). In addition, an updated RMP should be submitted When new information is received that may impact on the current Safety Specification, Pharmacovigilance Plan or risk minimisation activities Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached At the request of the EMEA 12

13 Official batch release: in accordance with Article 114 Directive 2001/83/EC as amended, the official batch release will be undertaken by a state laboratory or a laboratory designated for that purpose. 13

14 ANNEX III LABELLING AND PACKAGE LEAFLET 14

15 A. LABELLING 15

16 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON (0.5 g, 2.5 g, 5 g, 10 g and 20 g) 1. NAME OF THE MEDICINAL PRODUCT Flebogammadif 50 mg/ml solution for infusion Human normal immunoglobulin 2. STATEMENT OF ACTIVE SUBSTANCE(S) One ml contains 50 mg of human normal immunoglobulin (IVIg) of which at least 97% is IgG. 3. LIST OF EXCIPIENTS D-sorbitol, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for infusion. 0.5 g in 10 ml 2.5 g in 50 ml 5 g in 100 ml 10 g in 200 ml 20 g in 400 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous 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 8. EXPIRY DATE EXP 16

17 9. SPECIAL STORAGE CONDITIONS Do not store above 30 ºC. Do not freeze. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Barcelona - Spain 12. MARKETING AUTHORISATION NUMBER(S) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted 17

18 PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING VIAL LABEL (2.5 g, 5 g, 10 g and 20 g) 1. NAME OF THE MEDICINAL PRODUCT Flebogammadif 50 mg/ml solution for infusion Human normal immunoglobulin 2. STATEMENT OF ACTIVE SUBSTANCE(S) One ml contains 50 mg of human normal immunoglobulin (IVIg) of which at least 97% is IgG. 3. LIST OF EXCIPIENTS D-sorbitol, water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Solution for infusion 2.5 g in 50 ml 5 g in 100 ml 10 g in 200 ml 20 g in 400 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use Read the package leaflet before use. To hang pull here 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 8. EXPIRY DATE EXP 18

19 9. SPECIAL STORAGE CONDITIONS Do not store above 30 ºC. Do not freeze. 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Barcelona - Spain 12. MARKETING AUTHORISATION NUMBER(S) 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY Medicinal product subject to medical prescription. 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted 19

20 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL LABEL (0.5 g) 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION Flebogammadif 50 mg/ml solution for infusion Human normal immunoglobulin For intravenous use 2. METHOD OF ADMINISTRATION Read the package leaflet before use. 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 0.5 g in 10 ml 6. OTHER 20

21 B. PACKAGE LEAFLET 21

22 PACKAGE LEAFLET: INFORMATION FOR THE USER Flebogammadif 50 mg/ml solution for infusion Human normal immunoglobulin (IVIg) 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 your doctor or pharmacist. In this leaflet: 1. What Flebogammadif is and what it is used for 2. Before you use Flebogammadif 3. How to use Flebogammadif 4. Possible side effects 5. How to store Flebogammadif 6. Further information 1. WHAT FLEBOGAMMADIF IS AND WHAT IT IS USED FOR Flebogammadif is one of the group of medicines called intravenous immunoglobulins. These are used to treat conditions where the body s defence system against disease is not working properly. It is used to raise antibody levels in your blood. A lower than normal level of antibodies in your blood results in the incorrect functioning of your body s defence (immune) system. The low levels of antibodies may be inherited or may have developed as you have grown older. Other medical conditions such as myeloma or chronic lymphocytic leukaemia can also reduce the level of antibodies in your blood. Raising antibody levels by regular injections of Flebogammadif will help your body fight off infections. It is used to treat Guillain Barré syndrome, where the immune system damages the nerves and hinders them from working properly. It is used to treat Kawasaki disease, an illness in children where the blood vessels (arteries) in the body become enlarged. It is used in bone marrow transplantation, when you are given bone narrow cells from another person. The antibodies in Flebogammadif help to stop infections and help to stop your body rejecting the new cells. It is used to treat a condition called idiopathic thrombocytopenic purpura (ITP), where the number of platelets in your blood stream is greatly reduced. Platelets form an important part of the clotting process and a reduction in their numbers may cause unwanted bleeding and bruising. Injection of Flebogammadif results in an increase in the number of platelets, and an improvement in your condition. In children with the acquired immune deficiency syndrome (AIDS), it can be used to prevent troublesome infections. If you have any question about use of Flebogammadif please ask your doctor. 22

23 2. BEFORE YOU USE FLEBOGAMMADIF Do not use Flebogammadif - if you are allergic (hypersensitive) to human normal immunoglobulin or any of the other ingredients of Flebogammadif (see special warnings about excipients at the end of this section). - if you have immunoglobulin A (IgA) deficiency with anti-iga antibodies. - fructose intolerance. Take special care with Flebogammadif Certain adverse reactions may occur more frequently: in case of high rate of infusion. if you have hypo- or agammaglobulinaemia (a condition implying low immunoglobulin levels in your blood) with or without IgA deficiency. if you are having Flebogammadif for the first time, or it is a long time since your last infusion (e.g. several weeks). You will be watched carefully until an hour after the infusion to detect potential adverse signs. True hypersensitivity reactions are rare. They can occur in the very seldom cases of IgA deficiency with anti-iga antibodies. Rarely, human normal immunoglobulin can induce a fall in blood pressure with allergic reaction, even if you had tolerated previous treatment with human normal immunoglobulin. Patient with pre-existing risk factors Please tell your doctor if you have any other condition and/or illness, as caution is required. In particular, tell your doctor if you have: diabetes high blood pressure history of vascular disease or thrombosis overweight blood volume decrease diseases which increase blood viscosity advanced age Patients with a kidney problem If you have a kidney problem, your doctor should consider whether to stop treatment since cases of acute renal failure have been reported in patients receiving IVIg therapy, generally in patients with risk factors. Tell your doctor, even when any of the above-mentioned circumstances had happened to you in the past. Special safety warning When medicines are made from human blood or plasma, certain measures are put in place to prevent infections being passed on to patients. These include careful selection of blood and plasma donors to make sure those at risk of carrying infections are excluded, and the testing of each donation and pools of plasma for signs of virus/infections. Manufacturers of these products also include steps in the processing of the blood or plasma that can inactivate or remove viruses. Despite these measures, when 23

24 medicines prepared from human blood or plasma are administered, the possibility of passing on infection cannot be totally excluded. This applies to any unknown or emerging viruses or other types of infections. The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus and hepatitis C virus, and for the non-enveloped hepatitis A and parvovirus B19 viruses. Immunoglobulins have not been associated with hepatitis A or parvovirus B19 infections possibly because the antibodies against these infections, which are contained in the product, are protective. Taking 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. Effects on vaccines: Flebogammadif may reduce the effectiveness of certain type of vaccines such as measles, rubella, mumps and varicella. Effects on blood tests If you are having a blood test after receiving Flebogammadif, please tell the analyst or your doctor that you have been given this medicine. The level of certain antibodies can rise. Pregnancy and breast feeding Ask your doctor or pharmacist for advice before taking any medicine. If you are pregnant or breast-feeding you must tell your doctor. Your doctor will decide if Flebogammadif can be used during pregnancy and lactation. Driving and using machines Dizziness can sometimes occur and might affect the ability to drive and use machines. Important information about some of the ingredients of Flebogammadif Special warnings about ingredients: This medicine contains 50 mg of sorbitol per ml as excipient. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. Special precautions should be taken with babies and young children because this intolerance may not yet be diagnosed and may be fatal. 3. HOW TO USE FLEBOGAMMADIF Flebogammadif is given by injection into your veins (intravenous administration). It may be self administered if you have been fully trained by hospital staff. You must make up the infusion in exactly the way you have been shown in order to stop germs getting in. You must never self administer it alone; a responsible adult must be always present. The dose that you will be given will depend on your weight and will be worked out by your doctor. At the beginning of your infusion you will receive Flebogammadif at a slow rate ( ml/kg/min). Depending on how comfortable you feel, your doctor may then gradually increase the infusion rate (up to 0.1 ml/kg/min). 24

25 The solution should be clear or slightly opalescent. Do not use Flebogammadif if you notice that the solution is cloudy or has deposits. If you use more Flebogammadif than you should If you get more Flebogammadif than you should, your body may take on too much fluid. Tell your doctor immediately. If you forget to use Flebogammadif Tell your doctor or pharmacist immediately and follow his/her instructions. You must not be given a double dose to make up for a forgotten dose. 4. POSSIBLE SIDE EFFECTS Like all medicines, Flebogammadif can cause side effects, although not everybody gets them. Tell your doctor if any of the following side effects happen during or after the infusion: Chills Headache Fever Nausea Vomiting Allergic reaction Joint pain Low blood pressure Moderate low back pain Rare side effects, which are likely to occur in fewer than 1 in 1,000 patients, are: A sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even if you have shown no hypersensitivity to previous administration. Cases of temporary meningitis (reversible aseptic meningitis). Cases of temporary reduction in the number of the red cells in the blood (reversible haemolytic anaemia/haemolysis). Cases of transient cutaneous reactions. Increase in serum creatinine level and/or acute renal failure. Very rare side effects, which are likely to occur in fewer than 1 in 10,000 patients or which cannot be estimated from the available data, are: Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thromboses. 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 FLEBOGAMMMADIF Keep out of the reach and sight of children. Do not use Flebogammadif after the expiry date which is stated on the label and carton after EXP. The expiry date refers to the last day of that month. Do not store above 30 ºC. Do not freeze. 25

26 Any unused product or waste material should be disposed of in accordance with local requirements. Medicines should not be disposed via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Flebogammadif contains - The active substance is human normal immunoglobulin (IVIg). One ml contains 50 mg of human normal immunoglobulin, of which at least 97% is IgG. The percentage of IgG subclasses is approximately 66.6% IgG 1, 28.5% IgG 2, 2.7% IgG 3 and 2.2% IgG 4. It contains trace amounts of IgA (lower than 0.05 mg/ml). - The other ingredients are sorbitol and water for injections (see section 2. Before you use Flebogammadif for further information about ingredients). What Flebogammadif looks like and contents of the pack Flebogammadif is a solution for infusion. The solution is clear or slightly opalescent and colourless or pale yellow. Flebogammadif is supplied as 0.5 g/10 ml, 2.5 g/50 ml, 5 g/100 ml, 10 g/200 ml and 20 g/400 ml vials. Pack size of 1 vial. Not all sizes may be marketed. Marketing Authorisation Holder and Manufacturer Barcelona - Spain For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Tél/ България Česká republika Grifols S.R.O. Zitná 2 CZ Praha 2 Tel: Luxembourg/Luxemburg Tél/ Magyarország Malta 26

27 Danmark Tél/ Deutschland Grifols Deutschland GmbH Siemensstraße 32 D Langen Tél/Tel: Eesti Ελλάδα España France Grifols France, SARL Parc Technologique Sainte Victoire Bâtiment 10, 1er étage F Meyreuil Tél/Tel: Ireland Ísland Italia Grifols Italia S.p.A. Via Carducci, 62 d I Ghezzano (Pisa) Tel: Nederland Norge Tél/ Österreich Polska Grifols Polska Sp. z o. o. UL. Nowogrodzka 68 PL Warsaw Tel: Portugal Grifols Portugal, Lda. Rua de São Sebastião, nº 2 Zona Industrial de Cabra Figa P Río de Mouro Tel: România Slovenija Slovenská republika Grifols Internacional, S.A. Trnavská cesta , Bratislava Tel: Suomi/Finland 27

28 Κύπρος Latvija Sverige United Kingdom Grifols UK Ltd. Byron House Cambridge Business Park Cambridge, CB4 0WZ Tel: Lietuva This leaflet was last approved in Detailed information on this medicine is available on the European Medicines Agency (EMEA) website: The following information is intended for medical or healthcare professionals only: Posology and method of administration The dose and dosage regimen is dependent on the indication. In replacement therapy the dosage will be adapted dependent on your pharmacokinetic and clinical response. The following dosage regimens are given as a guideline: The dosage recommendations are summarised in the following table: Indication Dose Frequency - starting dose: g/kg - thereafter: g/kg Replacement therapy in primary immunodeficiency every 2-4 weeks to obtain IgG trough level of at least 4-6 g/l Replacement therapy in secondary immunodeficiency Children with AIDS g/kg g/kg every 3-4 weeks to obtain IgG trough level of at least 4-6 g/l every 3-4 weeks 28

29 Immunomodulation: Idiopathic thrombocytopenic purpura Guillain Barré syndrome Kawasaki disease Allogeneic bone marrow transplantation: - treatment of infections and prophylaxis of graft versus host disease - persistent lack of antibody production g/kg or 0.4 g/kg/d 0.4 g/kg/d g/kg or 2 g/kg 0.5 g/kg 0.5 g/kg on day 1, possibly repeated once within 3 days for 2-5 days for 3-7 days in several doses for 2-5 days in association with acetylsalicylic acid in one dose in association with acetylsalicylic acid every week from day -7 up to 3 months after transplantation every month until antibody levels return to normal Flebogammadif should be infused intravenously at an initial rate of ml/kg/min for the first thirty minutes. If well tolerated, the rate of administration may gradually be increased to a maximum of 0.1 ml/kg/min. A significant increase in median platelet levels was achieved in a clinical trial in chronic ITP patients (64,000/µl) although it did not reach normal levels. Incompatibilities Flebogammadif should not be mixed with other medicines or intravenous solutions and it should be administered by a separate intravenous line. Special precautions It is strongly recommended that every time Flebogammadif is administered, the name and batch number of the product is recorded in order to maintain a record of the batches used. Instructions for handling and disposal The product should be brought at room temperature (no more than 30 ºC) before use. The solution should be clear or slightly opalescent. Do not use Flebogammadif if you notice that the solution is cloudy or has deposits. Any unused product or waste material should be disposed of in accordance with local requirements 29