Public Assessment Report. Albiomin 5% Albiomin 20% Human Albumin DE/H/0482/ /MR. Applicant: Biotest Pharma GmbH

Transcription

1 Public Assessment Report Albiomin 5% Albiomin 20% Human Albumin DE/H/0482/ /MR Applicant: Biotest Pharma GmbH This module reflects the scientific discussion for the approval of Albiomin 5% and Albiomin 20%. The procedure has been finalised at For information on changes after this date please refer to the module Update. Albiomin 5% and 20% DE/H/0482/ /MR EPAR 1/26

2 TABLE OF CONTENTS I. EXECUTIVE SUMMARY 4 I.1 General comments on the submitted dossier 4 I.2 General comments on compliance with GMP, GLP, GCP and agreed ethical principles 5 II. SCIENTIFIC OVERVIEW 5 III. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION 7 IV. SUMMARY OF PRODUCT CHARACTERISITCS 10 V. PACKAGE LEAFLET: INFORMATION FOR THE USER 18 Albiomin 5% and 20% DE/H/0482/ /MR EPAR 2/26

3 INFORMATION OF THE INITIAL PROCEDURE 1. Type of application Bibliographic application according to article 10a Directive 2001/83/EC on grounds for well- established used. 2. Active substance Human Albumin 3. Form Solution for infusion 4. Strength 50 g/l and 200 g/l 5. Marketing Authorisation Holder Biotest Pharma GmbH Landsteinerstraße Dreieich Germany 6. Reference Member State Paul-Ehrlich-Institut Germany 7. Concerned Member States Albiomin 5%: AT, ES, HU, IT, RO, UK Albiomin 20%: AT, BG, EL, ES, HU, IT, MT, PL, PT, RO, UK 8. Procedure-number DE/H/0482/ /MR 9. Timetable submission of application: start of procedure: termination of procedure: Albiomin 5% and 20% DE/H/0482/ /MR EPAR 3/26

4 I. EXECUTIVE SUMMARY Human albumin, as the most important oncotically active protein in plasma and a substantial extracellular protein, has a variety of unique physiological functions. The most important of these are the replacement of intracellular and extracellular volume, the maintenance of the oncotic gradient and specific binding capacities. Albiomin 5% and Albiomin 20% are human plasma derived normal albumin solutions for intravenous infusion and are intended for the restoration and maintenance of circulating blood volume where volume deficiency has been demonstrated, and use of a colloid is appropriate. Albiomin 5% and Albiomin 20% are purified albumin preparations complying with the Ph. Eur. monograph no on Human Albumin Solutions. The manufacturing process is a modification of the cold plasma fraction according to Cohn. Starting material is human plasma for fractionation complying with the Ph. Eur. monograph no Albiomin 5% (20%) is a biologic product at 5% (20%) (w/v) protein concentration with an albumin content of at least 96 %. The drug product of Albiomin 5% is presented as a solution of 250 ml (12.5 g protein). The drug product of Albiomin 20% is presented as a solution of 50 ml (10 g protein) or 100 ml (20 g protein) in glass type II vials. Albiomin 5% and Albiomin 20% belong to the pharmacotherapeutic group of plasma substitutes and plasma protein fractions (ATC code: B05AA01). The most important physiological functions of albumin result from its contribution to oncotic pressure of the blood and transport function. Albumin stabilises circulating blood volume and is a carrier of hormones, enzymes, medicinal products and toxins. Albiomin 5% is mildly hypooncotic to normal plasma. Albiomin 20% has a corresponding hyperoncotic effect. Albiomin 5% and Albiomin 20% are indicated for the restoration and maintenance of circulating blood volume where volume deficiency has been demonstrated and the use of a colloid is appropriate. I.1 General comments on the submitted dossier The present application is a bibliographic application according to Directive 2001/83/EC, Art. 10a on grounds for well established used. The purification of human serum albumin was first described in the thirties of last century. Since then, many studies have been performed investigating the structure of this protein. Purified albumin is a little modified protein, which production methods have developed only marginally since the introduction of Cohn fractionation. Due to the long term clinical use of human serum albumins the applicant has not performed own pharmacological and toxicological studies with Albiomin. This is considered to be appropriate because the applicant summarized sufficiently the general knowledge and essential data of clinical experience with human serum albumin in the published literature. Albiomin 5% and 20% DE/H/0482/ /MR EPAR 4/26

5 I.2 General comments on compliance with GMP, GLP, GCP and agreed ethical principles The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product prior to granting its National authorisation. II. SCIENTIFIC OVERVIEW Quality Albiomin 5% and Albiomin 20% are purified albumin preparations complying with the Ph. Eur. monograph no on Human Albumin Solutions. The production process is a modification of the cold plasma fraction according to Cohn. Starting material is human plasma for fractionation complying with the Ph. Eur. monograph no The classical cold ethanol fractionation of cryo-poor plasma leads to the rich albumin fraction V, which is obtained by precipitation and separation of fraction I/II/III and fraction IV-1/IV- 4 and removal of these fractions by centrifugation. Biotest has established a manufacturing process for human albumin using filtration for the separation of fractions in the presence of filter aid instead of centrifugation steps. This method with slightly modified parameters for precipitation of the plasma fractions results in a higher yield and therefore in a better exploit of the human plasma. The manufacturing steps of the drug substances are identical for Albiomin 5% and Albiomin 20%. Adventitious Agents Albiomin 5% and 20% is produced from human plasma (Austria, Belgium, Germany, the Netherlands and the USA) by established cold ethanol fractionation followed by pasteurisation according to Ph. Eur. Four steps of the production process (precipitation and separation of intermediate fraction I/II/III, precipitation and separation of intermediate fraction IV-1/IV-4, tempering at 58 o C for 5.25 hrs and pasteurisation (10 h at 60 C) were validated for their virus inactivation/removing capacity including robustness studies for precipitation and separation of intermediate fraction IV-1/IV-4, tempering at 58 o C for 5.25 hrs, and pasteurisation. Enveloped viruses such as HIV and PRV are effectively inactivated at precipitation and separation of intermediate fraction IV-1/IV-4 and pasteurisation. BVDV was effectively inactivated at pasteurisation. Non enveloped viruses such as HAV and PPV have been demonstrated to be removed in the range of 2-4 log 10 during the fractionation steps and approx. 2 log 10 HAV were inactivated during pasteurisation. No animal-derived TSE-risk material which is added at production was identified. In summary, the virus safety of Albiomin 5% and 20% is adequately demonstrated. Albiomin 5% and 20% DE/H/0482/ /MR EPAR 5/26

6 Non-clinical aspects Human serum albumin represents more than half of the total protein in native plasma and about 10 % of protein synthesis activity in the liver and thus is quantitatively the most important protein in human plasma. It fulfils several biological functions in the body, the most important being its influence on the oncotic pressure of the blood (i.e. stabilization of the circulating volume of blood) and its transport function (i.e. the transport of hormones, enzymes, pharmaceuticals and toxins). The purification of human serum albumin was first described in the thirties of last century. Since then, many studies have been performed regarding the structure of this protein. Because of the central role regarding oncotic pressure, because albumin is a little modified protein and because albumin production methods have developed only marginally since the introduction of Cohn fractionation, the applicant has not performed own pharmacological and toxicological studies with Albiomin. Thus, the review of the non-clinical properties of human serum albumin is based on available scientific publications. The review of available literature regarding non-clinical properties of human serum albumin revealed no signs for a toxicological risk within the clinical use of Albiomin in the claimed indications. Clinical aspects The relevant reviews and the important article of the SAFE study have been listed and described regarding the controversial discussion of albumin administration in the treatment of critically ill patients of the recent years, which started in 1998 with the suggestion of the Cochrane Injuries Group that albumin administration may increase mortality. A few years later Wilkes et al. (2001) detected no difference in mortality between patients treated with albumin and patients treated with other fluids. In 2004 the results of the SAFE study, which was an adequately designed large-scale clinical trial, were published and displayed no evidence that 4% human albumin solution causes excess mortality compared with normal saline when used for intravascular volume resuscitation. According to this study it can be concluded that albumin and saline may be considered therapeutically equivalent treatments for intravascular volume resuscitation in criticallyill patients. A subgroup analysis of the SAFE study displayed a higher mortality for patients with brain-injury treated with albumin, which has been verified in a follow-up study, and in contrast a trend towards a better outcome with albumin in patients with severe sepsis. The published meta-analysis of Vincent et al. (2004) showed a significant reduction of the overall morbidity for albumin infusions and especially a statistically significant benefit in terms of morbidity in ascites. But in general, the beneficial effects of albumin in comparison to other fluids are regarded as still unclear. In addition, there is still a lack of evidence from randomised trials to determine whether the routine use of albumin infusion, in paediatric patients including preterm infants with low serum albumin, reduces mortality or morbidity. According to these published data, the use of Albiomin 5%/20% is regarded to be efficient just like other fluids (saline/ artificial colloids) under the indication to restore and maintain circulating blood volume where volume deficiency has been demonstrated and use of colloid is appropriate. Albiomin 5% and 20% DE/H/0482/ /MR EPAR 6/26

7 Overall, the safety profiles of Albiomin 5% and Albiomin 20% appear favourable and allow the assumption that no specific adverse drug reactions will occur after treatment with Albiomin 5% and Albiomin 20% other than the well-described class effects. III. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION The use of albumin therapy in different clinical situations and its influence on morbidity and mortality have been reviewed in multiple randomized controlled trials and metaanalysis. Appropriately powered randomized, controlled trials have shown albumin to be safe in broad groups of critically ill patients. The reviews seem to have documented advantage of albumin therapy in the management of ascites and clarified the use of albumin in volume resuscitation. Although the observed very low incidence of adverse events may be underestimated due to under-reporting, the safety profile of Albiomin 5% and Albiomin 20% appears favourable. Based on the data on quality and combining the published efficacy and safety data of albumin preparations and post-marketing experience of Biotest`s albumin solutions, the risk/benefit ratio of Albiomin 5% and Albiomin 20% can be regarded positive in the indication intended for use. Albiomin 5% and 20% DE/H/0482/ /MR EPAR 7/26

8 IV. Summary of Product Characteristics 1. NAME OF THE MEDICINAL PRODUCT Albiomin 5% (50 g/l), solution for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Human albumin Albiomin 5% (50 g/l) is a solution containing 50 g/l of total protein of which at least 95% is human albumin. The product has a mildly hypooncotic effect. For excipients, see PHARMACEUTICAL FORM Solution for infusion. A clear, slightly viscous liquid; it is almost colourless, yellow, amber or green. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Restoration and maintenance of circulating blood volume where volume deficiency has been demonstrated and use of a colloid is appropriate. The choice of albumin rather than artificial colloid will depend on the clinical situation of the individual patient, based on official recommendations. 4.2 Posology and method of administration The concentration of the albumin preparation, dosage and the infusion-rate should be adjusted to the patient's individual requirements. Posology The dose required depends on the size of the patient, the severity of trauma or illness and on continuing fluid or protein losses. Measures of adequacy of circulating volume and not plasma albumin levels should be used to determine the dose required. If human albumin is to be administered, haemodynamic performance should be monitored regularly; this may include: arterial blood pressure and pulse rate central venous pressure pulmonary artery wedge pressure urine output electrolyte haemaotcrit / haemoglobin Method of administration Human albumin can be directly administered by the intravenous route. Albiomin 5% and 20% DE/H/0482/ /MR EPAR 8/26

9 The infusion rate should be adjusted according to the individual circumstances and the indication. In plasma exchange the infusion-rate should be adjusted to the rate of removal. 4.3 Contraindications Hypersensitivity to albumin preparations or to any of the excipients. 4.4 Special warnings and precautions for use Suspicion of allergic or anaphylactic type reactions requires immediate discontinuation of the injection. In case of shock, standard medical treatment for shock should be implemented. Albumin should be used with caution in conditions where hypervolaemia and its consequences or haemodilution could represent a special risk for the patient. Examples of such conditions are: Decompensated cardiac insufficiency Hypertension Oesophageal varices Pulmonary oedema Haemorrhagic diathesis Severe anaemia Renal and post-renal anuria Albumin solutions must not be diluted with water for injections as this may cause haemolysis in recipients. If comparatively large volumes are to be replaced, controls of coagulation and haematocrit are necessary. Care must be taken to ensure adequate substitution of other blood constituents (coagulation factors, electrolytes, platelets and erythrocytes). Hypervolaemia may occur if the dosage and rate of infusion are not adjusted to the patient's circulatory situation. At the fist clinical signs of cardiovascular overload (headache, dyspnoea, jugular vein congestion), or increased blood pressure, raised venous pressure and pulmonary oedema, the infusion is to be stopped immediately. 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. There are no reports of virus transmissions with albumin manufactured to European Pharmacopoeia specifications by established processes. It is strongly recommended that every time that Albiomin 5% (50 g/l) 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. 4.5 Interaction with other medicinal products and other forms of interaction No specific interactions of human albumin with other products are known. Albiomin 5% and 20% DE/H/0482/ /MR EPAR 9/26

10 4.6 Pregnancy and lactation The safety of Albiomin 5% (50 g/l) for use in human pregnancy has not been established in controlled clinical trials. However, clinical experience with albumin suggests that no harmful effects on the course of pregnancy, or on the fetus and the neonate are to be expected. Experimental animal studies are insufficient to assess the safety with respect to reproduction, development of the embryo or fetus, the course of gestation and peri- and postnatal development. However, human albumin is a normal constituent of human blood. 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 Mild reactions such as flush, urticaria, fever and nausea occur rarely. These reactions normally disappear rapidly when the infusion rate is slowed down or the infusion is stopped. Very rarely, severe reactions as far as shock may occur. In these cases, the infusion should be stopped and an appropriate treatment should be initiated. For safety with respect to transmissible agents, see Overdose Hypervolaemia may occur if the dosage and rate of infusion are too high. At the first clinical signs of cardiovascular overload (headache, dyspnoea, jugular vein congestion), or increased blood pressure, raised central venous pressure and pulmonary oedema, the infusion should be stopped immediately and the patient's haemodynamic parameters carefully monitored. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: plasma substitutes and plasma protein fractions, ATC code: B05AA01. Human albumin accounts quantitatively for more than half of the total protein in the plasma and represents about 10% of the protein synthesis activity of the liver. Physiochemical data: Human albumin 40 to 50 g/l is mildly hypooncotic to normal plasma. The most important physiological functions of albumin results from its contribution to oncotic pressure of the blood and transport function. Albumin stabilises circulating blood volume and is a carrier of hormones, enzymes, medicinal products and toxins. 5.2 Pharmacokinetic properties Under normal situations the total exchangeable albumin pool is 4-5 g/kg body weight, of which 40-45% is present intravascularly and 55-60% in the extravascular space. Increased capillary permeability will alter albumin kinetics and abnormal distribution may occur in conditions such as severe burns or septic shock. Under normal conditions the half-life of albumin is on average about 19 days. The balance between synthesis and breakdown is normally achieved by feed-back regulation. Elimination is predominantly intracellular and due to lysosome proteases. Albiomin 5% and 20% DE/H/0482/ /MR EPAR 10/26

11 In healthy subjects, less than 10% of infused albumin leaves the intravascular compartment during the first 2 hours following infusion. There is considerable individual variation in the effect on plasma volume. In some patients the plasma volume can remain increased for some hours. However, in critically ill patients, albumin can leak out of the vascular space in substantial amounts at an unpredictable rate. 5.3 Preclinical safety data Human albumin is a normal constituent of the human plasma and acts like the physiological albumin. In animals, single dose toxicity testing is of little relevance and does not permit the evaluation of toxic or lethal doses or of a dose-effect relationship. Repeated dose toxicity testing is impracticable due to the development of antibodies to heterologous protein in animal models. To date, human albumin has not been reported to be associated with embryo-foetal toxicity, oncogenic or mutagenic potential. No signs of acute toxicity have been described in animal models. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Caprylate (4 mmol/l), N-acetyl-DL-tryptophanate (4 mmol/l), sodium ions (145 mmol/l), water for injections ad 1000 ml. 6.2 Incompatibilities Human albumin must not be mixed with other medicinal products (except the recommended diluent), whole blood and packed red blood cells. 6.3 Shelf life 3 years 6.4 Special precautions for storage Do not store above 25 C. Do not freeze. Keep the container in the outer carton in order to protect from light. 6.5 Nature and contents of container 250 ml of a solution in a vial (Type II glass) with a grey rubber stopper (bromobutyl) and a cap (aluminium) pack size of one vial. 6.6 Special precautions for disposal and other handling The solution can be directly administered by the intravenous route. Albumin solutions must not be diluted with water for injections as this may cause haemolysis in recipients. If large volumes are administered, the product should be warmed to room or body temperature before use. Albiomin 5% and 20% DE/H/0482/ /MR EPAR 11/26

12 The solution should be clear or slightly opalescent. Do not use solutions which are cloudy or have deposits. This may indicate that the protein is unstable or that the solution has become contaminated. Once the container has been opened, the contents should be used immediately. Any unused product should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Biotest Pharma GmbH Landsteinerstraße Dreieich Germany 8. MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT December 2008 Albiomin 5% and 20% DE/H/0482/ /MR EPAR 12/26

13 1. NAME OF THE MEDICINAL PRODUCT Albiomin 20% (200 g/l), solution for infusion 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Human albumin Albiomin 20% (200 g/l) is a solution containing 200 g/l of total protein of which at least 95% is human albumin. The product has a hyperoncotic effect. For excipients, see PHARMACEUTICAL FORM Solution for infusion. A clear, slightly viscous liquid; it is almost colourless, yellow, amber or green. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Restoration and maintenance of circulating blood volume where volume deficiency has been demonstrated and use of a colloid is appropriate. The choice of albumin rather than artificial colloid will depend on the clinical situation of the individual patient, based on official recommendations. 4.2 Posology and method of administration The concentration of the albumin preparation, dosage and the infusion-rate should be adjusted to the patient's individual requirements. Posology The dose required depends on the size of the patient, the severity of trauma or illness and on continuing fluid or protein losses. Measures of adequacy of circulating volume and not plasma albumin levels should be used to determine the dose required. If human albumin is to be administered, haemodynamic performance should be monitored regularly; this may include: arterial blood pressure and pulse rate central venous pressure pulmonary artery wedge pressure urine output electrolyte haemaotcrit / haemoglobin Method of administration Human albumin can be directly administered by the intravenous route, or it can also be diluted in an isotonic solution (e.g. 0.9% sodium chloride). The infusion rate should be adjusted according to the individual circumstances and the indication. Albiomin 5% and 20% DE/H/0482/ /MR EPAR 13/26

14 In plasma exchange the infusion-rate should be adjusted to the rate of removal. 4.3 Contraindications Hypersensitivity to albumin preparations or to any of the excipients. 4.4 Special warnings and precautions for use Suspicion of allergic or anaphylactic type reactions requires immediate discontinuation of the injection. In case of shock, standard medical treatment for shock should be implemented. Albumin should be used with caution in conditions where hypervolaemia and its consequences or haemodilution could represent a special risk for the patient. Examples of such conditions are: Decompensated cardiac insufficiency Hypertension Oesophageal varices Pulmonary oedema Haemorrhagic diathesis Severe anaemia Renal and post-renal anuria The colloid-osmotic effect of human albumin 200 g/l is approximately four times that of blood plasma. Therefore, when concentrated albumin is administered, care must be taken to ensure adequate hydration of the patient. Patients should be monitored carefully to guard against circulatory overload and hyperhydration g/l human albumin solutions are relatively low in electrolytes compared to the g/l human albumin solutions. When albumin is given, the electrolyte status of the patient should be monitored (see section 4.2) and appropriate steps taken to restore or maintain the electrolyte balance. Albumin solutions must not be diluted with water for injections as this may cause haemolysis in recipients. If comparatively large volumes are to be replaced, controls of coagulation and haematocrit are necessary. Care must be taken to ensure adequate substitution of other blood constituents (coagulation factors, electrolytes, platelets and erythrocytes). Hypervolaemia may occur if the dosage and rate of infusion are not adjusted to the patient's circulatory situation. At the fist clinical signs of cardiovascular overload (headache, dyspnoea, jugular vein congestion), or increased blood pressure, raised venous pressure and pulmonary oedema, the infusion is to be stopped immediately. 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. Albiomin 5% and 20% DE/H/0482/ /MR EPAR 14/26

15 There are no reports of virus transmissions with albumin manufactured to European Pharmacopoeia specifications by established processes. It is strongly recommended that every time that Albiomin 20% (200 g/l) 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. 4.5 Interaction with other medicinal products and other forms of interaction No specific interactions of human albumin with other products are known. 4.6 Pregnancy and lactation The safety of Albiomin 20% (200 g/l) for use in human pregnancy has not been established in controlled clinical trials. However, clinical experience with albumin suggests that no harmful effects on the course of pregnancy, or on the fetus and the neonate are to be expected. Experimental animal studies are insufficient to assess the safety with respect to reproduction, development of the embryo or fetus, the course of gestation and peri- and postnatal development. However, human albumin is a normal constituent of human blood. 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 Mild reactions such as flush, urticaria, fever and nausea occur rarely. These reactions normally disappear rapidly when the infusion rate is slowed down or the infusion is stopped. Very rarely, severe reactions as far as shock may occur. In these cases, the infusion should be stopped and an appropriate treatment should be initiated. For safety with respect to transmissible agents, see Overdose Hypervolaemia may occur if the dosage and rate of infusion are too high. At the first clinical signs of cardiovascular overload (headache, dyspnoea, jugular vein congestion), or increased blood pressure, raised central venous pressure and pulmonary oedema, the infusion should be stopped immediately and the patient's haemodynamic parameters carefully monitored. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: plasma substitutes and plasma protein fractions, ATC code: B05AA01. Human albumin accounts quantitatively for more than half of the total protein in the plasma and represents about 10% of the protein synthesis activity of the liver. Physiochemical data: Human albumin 40 to 50 g/l is mildly hypooncotic to normal plasma. Human albumin 200 g/l has a corresponding hyperoncotic effect. Albiomin 5% and 20% DE/H/0482/ /MR EPAR 15/26

16 The most important physiological functions of albumin results from its contribution to oncotic pressure of the blood and transport function. Albumin stabilises circulating blood volume and is a carrier of hormones, enzymes, medicinal products and toxins. 5.2 Pharmacokinetic properties Under normal situations the total exchangeable albumin pool is 4-5 g/kg body weight, of which 40-45% is present intravascularly and 55-60% in the extravascular space. Increased capillary permeability will alter albumin kinetics and abnormal distribution may occur in conditions such as severe burns or septic shock. Under normal conditions the half-life of albumin is on average about 19 days. The balance between synthesis and breakdown is normally achieved by feed-back regulation. Elimination is predominantly intracellular and due to lysosome proteases. In healthy subjects, less than 10% of infused albumin leaves the intravascular compartment during the first 2 hours following infusion. There is considerable individual variation in the effect on plasma volume. In some patients the plasma volume can remain increased for some hours. However, in critically ill patients, albumin can leak out of the vascular space in substantial amounts at an unpredictable rate. 5.3 Preclinical safety data Human albumin is a normal constituent of the human plasma and acts like the physiological albumin. In animals, singledose toxicity testing is of little relevance and does not permit the evaluation of toxic or lethal doses or of a dose-effect relationship. Repeateddose toxicity testing is impracticable due to the development of antibodies to heterologous protein in animal models. To date, human albumin has not been reported to be associated with embryo-fetal toxicity, oncogenic or mutagenic potential. No signs of acute toxicity have been described in animal models. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Caprylate (16 mmol/l), N-acetyl-DL-tryptophanate (16 mmol/l), sodium ions (122 mmol/l), water for injections ad 1000 ml. 6.2 Incompatibilities Human albumin must not be mixed with other medicinal products (except the recommended diluent), whole blood and packed red blood cells. 6.3 Shelf life 3 years Albiomin 5% and 20% DE/H/0482/ /MR EPAR 16/26

17 6.4 Special precautions for storage Do not store above 25 C. Do not freeze. Keep the glass vials in the outer carton in order to protect from light. 6.5 Nature and contents of container 50 ml or 100 ml of a solution in a vial (Type II glass) with a grey rubber stopper (bromobutyl) and a cap (aluminium) pack size of one vial. 6.6 Special precautions for disposal and other handling The solution can be directly administered by the intravenous route, or it can be diluted in an isotonic solution (e.g. 0.9% sodium chloride). Albumin solutions must not be diluted with water for injections as this may cause haemolysis in recipients. If large volumes are administered, the product should be warmed 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. This may indicate that the protein is unstable or that the solution has become contaminated. Once the container has been opened, the contents should be used immediately. Any unused product should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER Biotest Pharma GmbH Landsteinerstraße Dreieich Germany 8. MARKETING AUTHORISATION NUMBER(S) 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 10. DATE OF REVISION OF THE TEXT December 2008 Albiomin 5% and 20% DE/H/0482/ /MR EPAR 17/26

18 V. PACKAGE LEAFLET: INFORMATION FOR THE USER Albiomin 5% (50 g/l), solution for infusion Human albumin Read this entire leaflet carefully before you start using this medicine. Keep this leaflet. You may need to read it again. If you have further questions, please ask your doctor or your 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 Albiomin 5% (50 g/l) is and what it is used for 2. Before you are given Albiomin 5% (50 g/l) 3. How you are given Albiomin 5% (50 g/l) 4. Possible side effects 5. How to store Albiomin 5% (50 g/l) 6. Further information 1. WHAT ALBIOMIN 5% (50 g/l) IS AND WHAT IT IS USED FOR Albiomin 5% (50 g/l) is a solution for infusion (into a vein) ml solution contains 50 g human plasma protein of which at least 95 % is human albumin. Albiomin 5% (50 g/l) is used to restore and maintain circulating blood volume where there is a low blood volume and the use of a colloid, such as albumin, is required. 2. BEFORE YOU ARE GIVEN ALBIOMIN 5% (50 g/l) You will not receive Albiomin 5% (50 g/l) if: you are allergic (hypersensitive) to albumin preparations or to any of the other ingredients (these are listed in section 6 of this leaflet). Special care will be taken with Albiomin 5% (50 g/l): Suspicion of allergic or anaphylactic type reactions requires an immediate stop of the injection. In case of shock, standard medical treatment for shock should be applied. The infusion will also be stopped if you develop any of the following conditions as a sign of cardiovascular overload (hypervolaemia): - headache - dyspnoea (difficulties in breathing) - jugular vein congestion (a build up of fluid in a neck vein) - increased blood pressure - raised venous pressure (increased pressure in the veins) - pulmonary oedema (water on the lungs) Albiomin 5% and 20% DE/H/0482/ /MR EPAR 18/26

19 You should tell your doctor if you suffer from any of the following conditions: Decompensated cardiac insufficiency (heart failure) Hypertension (high blood pressure) Oesophageal varices (enlarged veins in the gullet) Pulmonary oedema (water on the lungs) Haemorrhagic diathesis (tendency to abnormal or spontaneous bleeding) Severe anaemia (reduced red blood cells) Renal and post-renal anuria (decreased or absent urine production) He/She will take the appropriate precautions. You will also be monitored by your doctor to check your circulatory situation with the electrolyte balance and blood volume. 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 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 or other types of infections. There are no reports of virus infections with albumin manufactured to European Pharmacopoeia specifications by established processes. It is strongly recommended that every time you receive a dose of Albiomin 5% (50 g/l) the name and batch number of the product are recorded in order to maintain a record of the batches used. Taking other medicines Please tell your doctor if you are taking, or have recently taken, any other medicines including any that you may have bought without a prescription from a chemist or supermarket. Pregnancy and breast-feeding If you are pregnant, planning a family, or breast-feeding ask your doctor or pharmacist for advice before taking any medicine. If you have already told your doctor then follow any instructions that may have been given to you. Driving and using machines Albiomin 5% (50 g/l) has no known effects on the ability to drive or use machines. 3. HOW YOU ARE GIVEN ALBIOMIN 5% (50 g/l) Albiomin 5% (50 g/l) treatment will usually be given in hospital by a doctor or a nurse. Human albumin can be given directly into a vein. Dosage and Frequency of Administration Albiomin 5% and 20% DE/H/0482/ /MR EPAR 19/26

20 The amount of Albiomin 5% (50 g/l) you receive depends on your size, the illness, and on fluid or protein losses. Your doctor will calculate the dose of Albiomin 5% (50 g/l) and how often you will receive it to obtain the correct levels in your blood. If you are given more Albiomin 5% (50 g/l) than you should This is very unlikely but your doctor will know what to do if this happens. If you have any further questions on the use of the product, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS Like all medicines, Albiomin 5% (50 g/l) can cause side effects, although not everybody gets them. The following side effects have been reported: flush, urticaria (nettle rash), fever and nausea (feeling sick). These occur rarely. Very rarely, severe reactions such as shock may occur. If this happens the infusion will be stopped and the appropriate treatment will be started. 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 ALBIOMIN 5% (50 g/l) Albiomin 5% (50 g/l) should be kept in the outer carton to protect it from light. Albiomin 5% (50 g/l) should not be stored above 25ºC. Do not freeze. Keep out of the reach and sight of children. Do not use Albiomin 5% (50 g/l) after the expiry date which is stated on label and outer carton. The expiry date refers to the last day of that month. The product, once opened, should be used immediately. Immediately before administration, check that the solution is clear. The product must not be used if any cloudiness or particles are visible. Medicines should not be disposed of via wastewater or household water. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Albiomin 5% (50 g/l) contains Each vial with 250 ml solution contains 12.5 g of human plasma protein. It also contains the other ingredients caprylate, N-acetyl-DL-tryptophanate, sodium ions, and water for injections. Albiomin 5% and 20% DE/H/0482/ /MR EPAR 20/26

21 What Albiomin 5% (50 g/l) looks like and contents of the pack A clear, slightly viscous liquid; it is almost colourless, yellow, amber or green. Glass vial with 250 ml Marketing Authorisation Holder and Manufacturer Biotest Pharma GmbH Landsteinerstraße Dreieich Germany Tel.: Fax: und -727 info@biotest.de This medicinal product is authorised in the Member States of the EU under the following trade names: Germany: Albiomin 5% This leaflet was last approved in December 2008 THE FOLLOWING INFORMATION IS INTENDED FOR MEDICAL OR HEALTHCARE PROFESSIONALS ONLY: Special warnings and special precautions for use Albumin solutions must not be diluted with water for injections as this may cause haemolysis in recipients. If comparatively large volumes are to be replaced, controls of coagulation and haematocrit are necessary. Care must be taken to ensure adequate substitution of other blood constituents (coagulation factors, electrolytes, platelets and erythrocytes). Hypervolaemia may occur if the dosage and rate of infusion are not adjusted to the patient's circulatory situation. There are no reports of virus infections with albumin manufactured to European Pharmacopoeia specifications by established processes. It is strongly recommended that every time a dose of Albiomin 5% (50 g/l) is administered the name and batch number of the product are recorded in order to maintain a record of the batches used. Interactions with other medicinal products and other forms of interactions No specific interactions of human albumin with other products are known. Dosage instructions and mode of administration Dosage Measures of adequacy of circulating volume and not plasma albumin levels should be used to determine the dose required. Albiomin 5% and 20% DE/H/0482/ /MR EPAR 21/26

22 If human albumin is to be administered, haemodynamic performance should be monitored regularly; this may include: arterial blood pressure and pulse rate central venous pressure pulmonary artery wedge pressure urine output electrolyte haematocrit / haemoglobin Mode of administration In plasma exchange the infusion-rate should be adjusted to the rate of removal. Storage and notes for the handling If large volumes are administered, the product should be warmed to room or body temperature before use. Albiomin 5% and 20% DE/H/0482/ /MR EPAR 22/26

23 Albiomin 20% (200 g/l), solution for infusion Human albumin Read this entire leaflet carefully before you start using this medicine. Keep this leaflet. You may need to read it again. If you have further questions, please ask your doctor or your 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 Albiomin 20% (200 g/l) is and what it is used for 2. Before you are given Albiomin 20% (200 g/l) 3. How you are given Albiomin 20% (200 g/l) 4. Possible side effects 5. How to store Albiomin 20% (200 g/l) 6. Further information 1. WHAT ALBIOMIN 20% (200 g/l) IS AND WHAT IT IS USED FOR Albiomin 20% (200 g/l) is a solution for infusion (into a vein) ml solution contains 200 g human plasma protein of which at least 95% is human albumin. Albiomin 20% (200 g/l) is used to restore and maintain circulating blood volume where there is a low blood volume and the use of a colloid, such as albumin, is required. 2. BEFORE YOU ARE GIVEN ALBIOMIN 20%(200 g/l) You will not receive Albiomin 20% (200 g/l) if: you are allergic (hypersensitive) to albumin preparations or to any of the other ingredients (these are listed in section 6 of this leaflet). Special care will be taken with Albiomin 20% (200 g/l): Suspicion of allergic or anaphylactic type reactions requires an immediate stop of the injection. In case of shock, standard medical treatment for shock should be applied. The infusion will also be stopped if you develop any of the following conditions as a sign of cardiovascular overload (hypervolaemia): - headache - dyspnoea (difficulties in breathing) - jugular vein congestion (a build up of fluid in a neck vein) - increased blood pressure - raised venous pressure (increased pressure in the veins) - pulmonary oedema (water on the lungs) You should tell your doctor if you suffer from any of the following conditions: Decompensated cardiac insufficiency (heart failure) Hypertension (high blood pressure) Oesophageal varices (enlarged veins in the gullet) Pulmonary oedema (water on the lungs) Haemorrhagic diathesis (tendency to abnormal or spontaneous bleeding) Severe anaemia (reduced red blood cells) Albiomin 5% and 20% DE/H/0482/ /MR EPAR 23/26

24 Renal and post-renal anuria (decreased or absent urine production) He/She will take the appropriate precautions. You will also be monitored by your doctor to check your circulatory situation with the electrolyte balance and blood volume. 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 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 or other types of infections. There are no reports of virus infections with albumin manufactured to European Pharmacopoeia specifications by established processes. It is strongly recommended that every time you receive a dose of Albiomin 20% (200 g/l) the name and batch number of the product are recorded in order to maintain a record of the batches used. Taking other medicines Please tell your doctor if you are taking, or have recently taken, any other medicines including any that you may have bought without a prescription from a chemist or supermarket. Pregnancy and breast-feeding If you are pregnant, planning a family, or breast-feeding ask your doctor or pharmacist for advice before taking any medicine. If you have already told your doctor then follow any instructions that may have been given to you. Driving and using machines Albiomin 20% (200 g/l) has no known effects on the ability to drive or use machines. 3. HOW YOU ARE GIVEN ALBIOMIN 20% (200 g/l) Albiomin 20% (200 g/l) treatment will usually be given in hospital by a doctor or a nurse. Human albumin can be given directly into a vein or diluted in 0.9% sodium chloride. Dosage and Frequency of Administration The amount of Albiomin 20% (200 g/l) you receive depends on your size, the illness, and on fluid or protein losses. Your doctor will calculate the dose of Albiomin 20% (200 g/l)and how often you will receive it to obtain the correct levels in your blood. If you are given more Albiomin 20% (200 g/l) than you should This is very unlikely but your doctor will know what to do if this happens If you have any further questions on the use of the product, ask your doctor or pharmacist. 4. POSSIBLE SIDE EFFECTS Like all medicines, Albiomin 20% (200 g/l) can cause side effects, although not everybody gets them. The following side effects have been reported: flush, urticaria (nettle rash), fever and nausea (feeling sick). Albiomin 5% and 20% DE/H/0482/ /MR EPAR 24/26

25 These occur rarely. Very rarely, severe reactions such as shock may occur. If this happens the infusion will be stopped and the appropriate treatment will be started. 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 ALBIOMIN 20% (200 g/l) Albiomin 20% (200 g/l) should be kept in the outer carton to protect it from light. Albiomin 20% (200 g/l) should not be stored above 25ºC. Do not freeze. Keep out of the reach and sight of children. Do not use Albiomin 20% (200 g/l) after the expiry date which is stated on label and outer carton. The expiry date refers to the last day of that month. The product, once opened, should be used immediately. Immediately before administration, check that the solution is clear. The product must not be used if any cloudiness or particles are visible. Medicines should not be disposed of via wastewater or household water. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. FURTHER INFORMATION What Albiomin 20% (200 g/l) contains Each vial with 50 ml solution contains 10 g of human plasma protein. Each vial with 100 ml solution contains 20 g of human plasma protein. It also contains the other ingredients caprylate, N-acetyl-DL-tryptophanate, sodium ions, and water for injections. What Albiomin 20% (200 g/l) looks like and contents of the pack A clear, slightly viscous liquid; it is almost colourless, yellow, amber or green. Glass vial with 50 ml Glass vial with 100 ml Marketing Authorisation Holder and Manufacturer Biotest Pharma GmbH Landsteinerstraße Dreieich Germany Tel.: Fax: und -727 info@biotest.de This medicinal product is authorised in the Member States of the EU under the following trade names: Germany: Albiomin 20% This leaflet was last approved in December 2008 Albiomin 5% and 20% DE/H/0482/ /MR EPAR 25/26

26 THE FOLLOWING INFORMATION IS INTENDED FOR MEDICAL OR HEALTHCARE PROFESSIONALS ONLY: Special warnings and special precautions for use The colloid-osmotic effect of human albumin 200 g/l is approximately four times that of blood plasma. Therefore, when concentrated albumin is administered, care must be taken to ensure adequate hydration of the patient. Patients should be monitored carefully to guard against circulatory overload and hyperhydration. Albumin solutions must not be diluted with water for injections as this may cause haemolysis in recipients. If comparatively large volumes are to be replaced, controls of coagulation and haematocrit are necessary. Care must be taken to ensure adequate substitution of other blood constituents (coagulation factors, electrolytes, platelets and erythrocytes). Hypervolaemia may occur if the dosage and rate of infusion are not adjusted to the patient's circulatory situation. There are no reports of virus infections with albumin manufactured to European Pharmacopoeia specifications by established processes. It is strongly recommended that every time a dose of Albiomin 20% (200 g/l) is administered the name and batch number of the product are recorded in order to maintain a record of the batches used. Interactions with other medicinal products and other forms of interactions No specific interactions of human albumin with other products are known Dosage instructions and mode of administration Dosage Measures of adequacy of circulating volume and not plasma albumin levels should be used to determine the dose required. If human albumin is to be administered, haemodynamic performance should be monitored regularly; this may include: arterial blood pressure and pulse rate central venous pressure pulmonary artery wedge pressure urine output electrolyte haematocrit / haemoglobin Mode of administration In plasma exchange the infusion-rate should be adjusted to the rate of removal. Storage and notes for the handling If large volumes are administered, the product should be warmed to room or body temperature before use. Albiomin 5% and 20% DE/H/0482/ /MR EPAR 26/26