RHOPHYLAC 300 MICROGRAMS / 2 ML SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE

PACKAGE LEAFLET: INFORMATION FOR THE PATIENT

Rhophylac 300 micrograms / 2 ml, solution for injection in pre filled syringe
Active substance: Human anti D immunoglobulin Please read all of this leaflet carefully before you are given this medicine
Keep this leaflet. You may need to read it again. If you have further questions, please ask your doctor or healthcare professional. 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 healthcare professional.

In this leaflet: 1. What Rhophylac is and what it is used for 2. Before you are given Rhophylac 3. How Rhophylac will be administered 4. Possible side effects 5. How to store Rhophylac 6. Further information

when it is likely that your baby's red blood cells have passed over into your own blood circulation (transplacental haemorrhage resulting from antepartum haemorrhage). This may, for example, happen when you experience vaginal bleedings during pregnancy; when your doctor needs to perform testing methods for foetal deformities (amniocentesis, chorionic biopsy); when your doctor or midwife needs to try moving the baby from outside (e.g., external version of the baby or other obstetric manipulative procedures); when you have an accident hurting your stomach or gut (abdominal trauma). B) You are a Rh(D) negative person, who has accidentally received infusions (transfusions) of Rh(D) positive blood (mismatched transfusion). This also applies to any blood products containing Rh(D) positive red blood cells.

2. BEFORE YOU ARE GIVEN RHOPHYLAC 1. WHAT RHOPHYLAC IS AND WHAT IT IS USED FOR
What is Rhophylac? Rhophylac is a ready to use solution for injection, which comes in a pre filled syringe. The solution contains special proteins, isolated from human blood plasma. These proteins belong to the class of so called immunoglobulins, also called antibodies. The active ingredient of Rhophylac is a specific antibody called anti D (Rh) immunoglobulin. This antibody works against Rhesus factor type D. What is Rhesus factor type D? Rhesus factors are special characteristics of human red blood cells. About 85% of the population carry the so called Rhesus factor type D (abbreviated Rh(D)). These people are called Rh(D)-positive. People who do not carry Rhesus factor type D are called Rh(D)-negative. What is anti D (Rh) immunoglobulin? Anti D (Rh) immunoglobulin is an antibody, which works against Rhesus factor type D and is produced by the human immune system. When a Rh(D) negative person receives Rh(D) positive blood, her/his immune system will recognise the Rh(D) positive red blood cells as foreign to her/his body, and will attempt to destroy them. For this purpose, the immune system will build specific antibodies against Rhesus factor type D. This process is called immunisation and it usually takes some time (23 weeks). Therefore, the Rh(D) positive red blood cells will not be destroyed upon the first contact, and no signs or symptoms are usually seen then. But when the same Rh(D) negative person receives Rh(D) positive blood a second time, the antibodies will be ready at hand and her/his immune system will destroy the foreign red blood cells immediately. How Rhophylac works If a Rh(D) negative person is given a sufficient amount of human anti D (Rh) immunoglobulin, immunisation against Rhesus factor type D can be prevented. To achieve this, treatment with Rhophylac should commence before or early enough after the first contact to Rh(D) positive red blood cells. The anti D (Rh) immunoglobulins contained in Rhophylac will then destroy the foreign Rh(D) positive red blood cells immediately. Thus, the person's immune system will not be prompted to build up its own antibodies. What Rhophylac is used for Rhophylac is used in two distinct situations: A) You are a Rh(D) negative pregnant woman, who carries a Rh(D) positive baby In this special situation you may be immunised by red blood cells from your baby passing over into your own blood circulation. If this happens, the first baby is not usually affected and fully healthy. But in the next Rh(D) positive baby, the mother's antibodies would destroy the baby's red blood cells already during pregnancy. This may lead to complications with the baby, including his/her possible death.


Special care should be taken with Rhophylac P For protecting Rh(D) negative women after delivery of a Rh(D) positive baby, Rhophylac is always given to the mother, not to the newborn baby. P Rhophylac is not intended for use in Rh(D) positive persons. P Rhophylac may trigger hypersensitivity reactions (allergic responses). Early signs of hypersensitivity reactions may appear as small itching bubbles on your skin (hives) or all over your body (generalised urticaria), tightness of the chest, wheezing, fall in blood pressure (hypotension) or a shock like state (anaphylaxis). Please keep those signs in mind, and if such symptoms occur, please tell your doctor or healthcare professional immediately. They will then stop the administration of the product and treat you depending on the nature and severity of the side effect. P Rhophylac may also contain human immunoglobulins (antibodies) of the IgA type. Persons who have low levels of the IgA type immunoglobulins are thus more likely to experience a hypersensitivity reaction. Should you have low levels of the IgA type immunoglobulins, please tell your doctor or healthcare professional. Your doctor will then very thoroughly weigh the benefit of treatment with Rhophylac against the increased risk of hypersensitivity reactions. P For your safety, your doctor or healthcare professional will observe you for at least 20 minutes after receiving Rhophylac. Information on safety with respect to infections Rhophylac is made from human blood plasma (this is the liquid part of the blood). 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.

As a Rh(D)-negative pregnant woman, you may receive anti-D (Rh) immunoglobulins in the following situations: when you carry or have just delivered a Rh(D) positive baby; when you lose a Rh(D) positive baby (miscarriage, threatened miscarriage or abortion); when your pregnancy is severely complicated (ectopic pregnancy or hydatidiform mole); Tear here

Perforation

FOR HEALTHCARE PROFESSIONALS ONLY

SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT Rhophylac 300 micrograms / 2 ml, solution for injection in pre filled syringe 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Human Anti D immunoglobulin Each 2 ml solution in pre filled syringe contains: Human anti D immunoglobulin 1500 IU (300 micrograms) Corresponding to a concentration of 750 IU (150 micrograms) per ml The product contains a maximum of 30 mg/ml of human plasma proteins of which 10 mg/ml is human albumin as stabiliser. At least 95% of the other plasma proteins are IgG. Rhophylac contains not more than 5 micrograms/ml IgA. For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Solution for injection in pre filled syringe 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Prevention of Rh(D) immunisation in Rh(D) negative women Pregnancy/delivery of a Rh(D) positive baby Abortion/threatened abortion, ectopic pregnancy or hydatidiform mole Transplacental haemorrhage (TPH) resulting from antepartum haemorrhage (AMH), amniocentesis, chorionic biopsy or obstetric manipulative procedures e.g. external version, or abdominal trauma. Treatment of Rh(D) negative persons after incompatible transfusions of Rh(D) positive blood or other products containing red blood cells 4.2 Posology and method of administration Posology The following dose schedules are recommended based on the clinical studies performed with Rhophylac, however consideration must be given to professional guidelines for the use of anti D IgG in the individual EU member states. Prevention of Rh(D) immunisation in Rh(D) negative women: Antepartum prophylaxis: The recommended dose is a single dose of 300 micrograms (1500 IU) administered by intravenous or intramuscular injection at 2830 weeks of gestation. Postpartum prophylaxis: For intravenous administration, 200 micrograms (1000 IU) is a sufficient dose. If administered intramuscularly, 200 micrograms (1000 IU) to 300 micrograms (1500 IU) is recommended. Rhophylac should be administered as soon as possible within 72 hours of delivery. The post partum dose must be given even when antepartum prophylaxis has been administered. If a large foeto maternal haemorrhage (greater than 4 ml (0.7%0.8% of women)) is suspected, e.g., in the event of foetal anaemia or intrauterine foetal death, its extent should be determined by a suitable method, e.g., Kleihauer Betke test, and additional doses of anti D should be administered as indicated (20 micrograms/100IU for each 1 ml of foetal red blood cells). Prophylaxis following complications of pregnancy: Interventions and incidents occurring up to 12 weeks gestation: 200 micrograms (1000 IU) should be administered by intravenous or intramuscular injection as soon as possible and not later than 72 hours after the at risk event. Interventions and incidents occurring after 12 weeks of gestation: at least 200 micrograms (1000 IU) should be administered by intravenous or intramuscular injection as soon as possible and not later than 72 hours after the at risk event. Chorionic villus sampling: 200 micrograms (1000 IU) should be administered by intravenous or intramuscular injection as soon as possible and not later than 72 hours after the at risk event. Incompatible transfusions: The recommended dose is 20 micrograms (100 IU) anti D immunoglobulin per 2 ml of transfused Rh(D) positive blood or per 1 ml of erythrocyte concentrate. The intravenous administration is recommended. If given by intramuscular administration the large doses should be applied over a period of several days. A maximum dose of 3000 micrograms is sufficient in the case of larger incompatible transfusions independent of whether the transfusion volume is greater than 300 ml of Rh(D) positive blood. Method of administration Rhophylac can be administered by intravenous or intramuscular injection. In case of haemorrhagic disorders where intramuscular injections are contraindicated, Rhophylac should be administered intravenously. If large doses (>5 ml) are required and intramuscular injection is chosen, it is advisable to administer them in divided doses at different sites. 4.3 Contraindications Hypersensitivity to any of the components. The intramuscular injection is contraindicated in persons with severe thrombocytopenia or other disorders of haemostasis. 4.4 Special warnings and precautions for use In the case of postpartum use, anti D immunoglobulin is intended for maternal administration. It should not be given to the newborn infant. The product is not intended for use in Rh(D) positive individuals. Patients should be observed for at least 20 minutes after administration. If symptoms of allergic or anaphylactic type reactions occur, immediate discontinuation of the administration is required. Allergic responses to anti D immunoglobulin may occur. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. The treatment required depends on the nature and severity of the side effect. If necessary, the current medical standards for shock treatment should be observed. The concentration of IgA in Rhophylac was found to be below the detection limit of 5 micrograms/ml. Nevertheless, the product may contain trace amounts of IgA. Although anti D immunoglobulin has been used successfully to treat selected IgA deficient patients, individuals who are deficient in IgA have the potential for developing IgA antibodies and may have anaphylactic reactions after administration of blood components containing IgA. The physician must therefore weigh the benefit of treatment with Rhophylac against the potential risks of hypersensitivity reactions. Information on safety with respect to transmissible agents 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 HIV, HBV and HCV. They may be of limited value against non enveloped viruses such as HAV or parvovirus B19. There is reassuring clinical experience regarding the lack of hepatits A or parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to the viral safety. It is strongly recommended that every time that Rhophylac 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 product.



You should not receive Rhophylac P If you are hypersensitive (allergic) to human immunoglobulins, to human albumin or to any of the other ingredients of Rhophylac (please see section 6 of this leaflet for a full statement of all ingredients). Please tell your doctor or healthcare professional prior to treatment about any medicine or food which you have not well tolerated earlier. P You must not receive injections into a muscle, if you suffer from a severe reduction in the number of platelets (thrombocytopenia), any other severe blood clotting disorder. Please tell your doctor or healthcare professional prior to treatment if this applies to you. In this case Rhophylac may be given to you only by injection into a vein.

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 medicines prepared from human blood or plasma are administered, the possibility of passing on infection cannot be totally excluded. This also applies to any unknown or emerging viruses and other types of infections. The measures taken for Rhophylac are considered effective for enveloped viruses such as human immunodeficiency virus (HIV, the AIDS virus), hepatitis B virus and hepatitis C virus. The measures may be of limited value against non enveloped viruses such as hepatitis A virus and parvovirus B19. Immunoglobulins like Rhophylac have not been associated with hepatitis A or parvovirus B19 infections. This is possibly because antibodies against these infections are also present in immunoglobulins. These antibodies may help preventing hepatitis A or parvovirus B19 infections. It is strongly recommended that every time you receive a dose of Rhophylac the name and batch number of the product are recorded in order to maintain a record of the batches used. Taking other medicines P Always tell your doctor or healthcare professional if you are taking or have recently taken any other medicines. This also applies to medicines obtained without a prescription. Interactions of Rhophylac with other treatments have not been investigated in clinical studies. The information given in this section is derived from the literature and from current guidelines. Vaccinations Rhophylac may impair the efficacy of vaccinations with live virus vaccines, for example against measles, mumps, rubella (German measles) or varicella (chicken pox). P Such vaccinations should therefore not be given until 3 months after you were last given Rhophylac. Please inform your vaccinating doctor about your treatment with Rhophylac. P If you have just had a vaccination within the last 24 weeks Please tell your doctor or healthcare professional prior to treatment. Please also inform your vaccinating doctor after the treatment. He can then plan to check the efficacy of your vaccination. Laboratory tests After you were given Rhophylac, the results of some blood tests (serological testing) may be altered for a certain period of time. If you are a mother having received Rhophylac before delivery, the results of some blood tests in your newborn baby may also be affected. P Should you or your newborn baby have such blood tests, please inform your doctor or healthcare professional that you were treated with Rhophylac. Pregnancy and breast feeding This medicinal product is used in pregnancy or early after delivery. In clinical studies with 432 mothers who received Rhophylac before delivery, no side effects were seen in their children. Driving and operating machines No effects of Rhophylac on the ability to drive and use machines are expected.

4. POSSIBLE SIDE EFFECTS
Like all medicines, Rhophylac can cause side effects, although not everybody gets them. If you are given Rhophylac into a muscle, you may feel local pain and tenderness at the injection site. The following side effects may occur occasionally (between 1 in 100 and 1 in 1,000 persons treated): fever and chills (shivering), generally feeling unwell (malaise), headache, skin reactions. The following side effects may occur rarely (between 1 in 1,000 and 1 in 10,000 persons treated): nausea and/or vomiting, low blood pressure (hypotension), rapid heartbeat or pulse rate (tachycardia), hypersensitivity reactions (allergic or anaphylactic type), including difficulty in breathing (dyspnoea) and shock. Please note the early signs of hypersensitivity reactions given in section 2 of this leaflet. If such symptoms occur, please tell your doctor or healthcare professional immediately. Such side effects may occur even when you have previously received human immunoglobulins and had tolerated them well. P Please tell your doctor or healthcare professional if any of the side effects gets serious, or if you notice any side effects not listed in this leaflet.

5. HOW TO STORE RHOPHYLAC
P P P P Keep out of the reach and sight of children. Store in a refrigerator (+2 to +8 C). Do not freeze. Keep the syringe in the outer carton (in its sealed plastic pack) in order to protect from light.

Do not use Rhophylac after the expiry date. It is stated on the outer carton and the syringe label in the format MM.YYYY (M = month, Y = year). The expiry date refers to the last day of that month. Do not use Rhophylac if you notice that the solution is cloudy or has deposits.

6. FURTHER INFORMATION
What Rhophylac contains The active substance is human anti D (Rh) immunoglobulin (antibodies of the IgG type against the so called Rhesus factor type D). The other ingredients are human albumin, glycine and sodium chloride. This product contains a maximum of 30 mg/ml of human plasma proteins of which 10 mg/ml is human albumin as stabiliser. At least 95% of the other plasma proteins are human immunoglobulins (antibodies) of the IgG type. Rhophylac contains not more than 5 micrograms/ml human immunoglobulins (antibodies) of the IgA type. What Rhophylac looks like and contents of the pack Rhophylac is a clear or slightly pearly solution for injection. It comes in a glass syringe pre filled with 2 ml of solution containing 1,500 IU (300 micrograms) of anti D immunoglobulin. The pack contains 1 pre filled syringe and 1 injection needle, both packed in one blister pack (a clear plastic container sealed with a paper foil). Marketing Authorisation Holder and Manufacturer CSL Behring GmbH Emil von Behring Strasse 76 D 35041, Marburg Germany This leaflet was last approved in 03/2010

3. HOW TO USE RHOPHYLAC
P Rhophylac will be injected by your doctor or healthcare professional into a muscle or directly into a vein. P Your doctor will decide how much Rhophylac you should receive and which is the appropriate route of administration. P The syringe should be brought to room or body temperature before use. P One syringe should be used for one patient only (even if product is left over then). Please note the early signs of hypersensitivity reactions given in section 2 of this leaflet. If such symptoms occur, please tell your doctor or healthcare professional immediately. If you receive more Rhophylac than the usual dose If you are treated with Rhophylac after a mismatched transfusion, you may receive quite a large amount of the product (up to 3,000 micrograms, equivalent to 20 ml or 10 syringes). In this case there is an increased risk for a special complication called haemolytic reaction. This results from the intended destruction of the foreign Rh(D) positive red blood cells. For this reason your doctor or healthcare professional will monitor you closely and may need to do special blood tests. In other Rh(D) negative people more frequent or more severe side effects are not expected, even after large amounts of Rhophylac (overdosage).

4.5 Interaction with other medicinal products and other forms of interaction Interactions of Rhophylac with other treatments have not been investigated. The information given in this section is derived from the literature and current guidelines. Active immunisation with live virus vaccines (e.g. measles, mumps, rubella or varicella) should be postponed until 3 months after the last administration of anti D immunoglobulin, as the efficacy of the live virus vaccine may be impaired. If anti D immunoglobulin needs to be administered within 24 weeks of a live virus vaccination, then the efficacy of such a vaccination may be impaired. 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 for red blood cell antibodies e.g. Coombs test in the neonate. Rhophylac can contain antibodies to other Rh antigens, e.g. anti Rh(C) antibodies, which might be detected by sensitive serological test methods following administration of the product. 4.6 Pregnancy and lactation This medicinal product is used in pregnancy. No study drug related adverse events were reported for the children delivered of 432 patients who received antepartum administration of Rhophylac. 4.7 Effects on ability to drive and use machines No effects on ability to drive and use machines have been observed. 4.8 Undesirable effects When anti D immunoglobulins are administered by the intramuscular route, local pain and tenderness can be observed at the injection site. Occasionally fever, malaise, headache, cutaneous reactions and chills occur. In rare cases, nausea, vomiting, hypotension, tachycardia, and allergic or anaphylactic type reactions, including dyspnoea and shock, are reported, even when the patient has shown no hypersensitivity to previous administration. For viral safety with respect to transmissible agents, see section 4.4. 4.9 Overdose No data are available on overdosage. Patients in receipt of an incompatible transfusion who receive very large doses of anti D immunoglobulin should be monitored clinically and by biological parameters because of the risk of haemolytic reaction. In other Rh(D) negative individuals overdosage should not lead to more frequent or more severe undesirable effects than the normal dose. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: immune sera and immunoglobulins: Anti D (Rh) immunoglobulin. ATC Code: J06BB01. Rhophylac contains specific IgG antibodies against the Rh(D) antigen of human erythrocytes. During pregnancy, and especially at the time of childbirth, foetal red blood cells may enter the maternal circulation. When the woman is Rh(D) negative and the foetus Rh(D) positive, the women might become immunised to the Rh(D) antigen and may produce anti Rh(D) antibodies which cross the placenta and may cause haemolytic disease of the newborn. Passive immunisation with anti D immunoglobulin prevents Rh(D) immunisation in more than 99% of cases provided that a sufficient dose of anti D immunoglobulin is administered early enough after exposure to Rh(D) positive foetal red blood cells. The mechanism by which anti D immunoglobulin suppresses immunisation to Rh(D) positive red cells is not known. Suppression may be related to the clearance of the red cells from the circulation before they reach immunocompetent sites or, it may be due to more complex mechanisms involving recognition of foreign antigen and antigen presentation by the appropriate cells at the appropriate sites in the presence or absence of antibody. In Rh(D) negative healthy male volunteers, both the intravenous and intramuscular administration of 200 micrograms (1000 IU) of Rhophylac at 48 hours after injection of 5 ml of Rh(D) positive red blood cells resulted in an almost complete clearance of Rh(D) positive red blood cells within 24 hours. While the intravenous administration of Rhophylac caused an instant onset of red blood cell disappearance, the onset

of elimination of red blood cells following intramuscular administration was delayed as anti D IgG had to be first absorbed from the injection site. On an average, 70% of injected red cells were cleared 2 hours after intravenous administration of Rhophylac. After intramuscular administration, a similar degree of red cell clearance was measured after 12 hours. Furthermore, the efficacy, safety and pharmacokinetics of Rhophylac are supported by the results of three clinical studies in patients. Rhophylac 200 micrograms (1000 IU) was administered postpartum in 139 per protocol patients. Rhophylac 300 micrograms (1500 IU) was administered antepartum as well as postpartum in 446 and 256 per protocol patients, respectively. None of the patients included in these studies developed antibodies against the Rh(D) antigen. Clinical studies with Rhophylac at doses below 200 micrograms (1000 IU) have not been performed. 5.2 Pharmacokinetic properties Measurable levels of antibodies are obtained approximately 4 hours after intramuscular injection. Peak serum levels are usually achieved 5 days later. Measurable levels of antibodies are obtained immediately after intravenous injection. The mean half life in the circulation of pregnant women with normal IgG levels was 17 days. IgG and IgG complexes are broken down in cells of the reticuloendothelial system. 5.3 Preclinical safety data There are no preclinical data of relevance for anti D immunoglobulin. Repeated dose testing and embryo foetal toxicity studies have not been conducted and are impracticable due to induction of, and interference with antibodies. The potential for mutagenic effects of immunoglobulins have not been studied. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Human albumin Glycine Sodium chloride 6.2 Incompatibilities In the absence of compatibility studies, Rhophylac must not be mixed with other medicinal products. 6.3 Shelf life 3 years 6.4 Special precautions for storage Store in a refrigerator (+2 C to +8 C). Do not freeze Keep the syringe (originally blistered) in the outer carton in order to protect from light. Store out of the reach and sight of children. 6.5 Nature and contents of containers Glass syringe (type I glass) pre filled with 2 ml solution for injection (1500 IU anti D IgG). Pack size: 1 blister pack contains 1 pre filled syringe and 1 injection needle. 6.6 Special precautions for disposal Rhophylac should be brought to room or body temperature before use. The solution should be clear or slightly opalescent. Do not use solutions which are cloudy or have deposits. Use only once (one syringe one patient). Any unused product or waste material should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER CSL Behring GmbH Emil von Behring Strasse 76 35041 Marburg Germany 8. MARKETING AUTHORISATION NUMBER(S) UK: PL 15036/0019, IE: PA 800/6/2 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION UK: 01 June 2006, IE: 17 October 2003 / 20 February 2006 10. DATE OF REVISION OF THE TEXT 21 September 2007

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