VI.2 ELEMENTS FOR A PUBLIC SUMMARY (VOLUVEN 10%)

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1 VI.2 ELEMENTS FOR A PUBLIC SUMMARY (VOLUVEN 10%) VI.2.1 OVERVIEW OF DISEASE EPIDEMIOLOGY Hypovolaemia is a state of decreased or reduced circulating blood volume which can be caused by a number of medical events including fluid loss as a consequence of surgical interventions or injury (trauma). Injury (trauma) with its accompanying blood loss is one of the major causes of decreased blood volume (hypovolaemia). Trauma remains the leading cause of death [world-wide] with bleeding as the primary cause of preventable death during the first 24 hours following trauma (Maegele et al. 2013) 2. Balancing hypovolaemia quickly is of importance to solve the immediate threat to organ function and life. In the context of surgery hypovolaemia may occur very frequently. However, the rate of occurrence is difficult to estimate as hypovolaemia may have several different causes (Wu and Wang) 3. Therefore, the rate of occurrence of hypovolaemia is not available.

2 Hypovolaemia may occur in different patient populations from neonates to elderly from different gender and ethnic origin. Risk factors for hypovolaemia include medical conditions such as blood loss, extensive loss of body fluids (dehydration), due to e.g. vomiting, diarrhoea, and fluid loss from burns. VI.2.2 SUMMARY OF TREATMENT BENEFITS Voluven 10% is an artificial infusion solution comprising hydroxyethyl starch (HES), a substance similar to waxy-maize starch, as well as sodium chloride for volume replacement. Voluven 10% is hyperoncotic, this means that the increase in blood volume exceeds the volume of the solution infused. Infusion of 500 ml of Voluven 10% in 30 minutes results in a relative increase of the subjects blood volume by 20 % and an increase of the subjects plasma volume by 32%. This effect is maintained for approximately 5 to 6 hours. VI.2.3 UNKNOWNS RELATING TO TREATMENT BENEFITS The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) noted for HES products, that the available data from studies in surgical and trauma patients are limited in size and duration of follow-up and that some reassurance is needed that the risks of increased mortality and renal injury in surgical and trauma patients may be lower than those in the critically ill and septic patients. Therefore, two phase IV randomised clinical trials will need to be conducted with HES to provide more evidence on the efficacy and safety in surgery and trauma patients including the risk of increased mortality and renal failure, in perioperative and trauma populations. C O N F I D E N T I A L Page 237 of 355

3 VI.2.4 SUMMARY OF SAFETY CONCERNS Table 56 Summary of Safety Concerns Safety Concern What is known Preventability Important Identified Risks Intolerance (Hypersensitivity) Severe intolerance (hypersensitivity) due to allergic or allergy-like (anaphylactic/anaphylactoid) reactions have been observed with the use of HES. Delayed function of tissue or organs (grafts) that were transplanted to patients from a donor (Delayed graft function in organ transplant patients) Kidney injury dialysis up to 90 days after use of HES may be required (Renal injury - need for renal replacement therapy up to 90 days after HES administration) Delayed function of the transplanted tissue/organs after use of HES has been reported in literature. 43,47 Frequency not known (cannot be estimated from the available data) The reported incidence of renal injury is extremely low (< 1 per million patients treated). Compared to patients suffering Partly, the use of HES is contraindicated in patients with intolerance (hypersensitivity) to the active substance. The first ml should be infused slowly and under careful monitoring of the patient so that any intolerance (hypersensitivity) reaction can be detected as early as possible. Because of the risk of intolerance (hypersensitivity) reactions, the patient should be monitored closely and the infusion instituted at a low rate. Yes, HES is contraindicated in organ transplant patients. Yes, according to the new Summary of Product Characteristic (SmPC) the dosage of all HES products is restricted. Further, the duration of treatment is restricted to 24 hours. With these limitations a clinical relevant tissue storage can be C O N F I D E N T I A L Page 238 of 355

4 Safety Concern What is known Preventability Increased mortality in patients suffering from serious generalised infection (sepsis) and critically ill patients Increased bleeding in patients with blood clotting (coagulation) disorders, severely impaired liver (hepatic) function, bleeding in the skull or brain (intracranial or cerebral haemorrhage) and open heart surgery in association with a heart-lung machine assisting in pumping the patient s blood during the surgery (cardiopulmonary bypass) from serious generalised infection (sepsis) treated with crystalloids, an increased need of dialysis (renal replacement therapy) up to 90 days after HES administration was observed in 3 published investigator-initiated 34,35,36 studies. Results of a clinical trial 34 with a similar product (HES 130/0.42) revealed a significant increased risk of death at 90 days or dependence on dialysis after HES administration compared with Ringer s acetate (RR 1.17, 95% CI: ; p = 0.03). The risk of bleeding is increased in patients with disturbances of blood clotting and impaired liver function due to a decreased production of clotting factors. excluded. Furthermore, HES is contraindicated in patients with pre-existing kidney impairment or need for dialysis (renal replacement therapy), patients suffering from serious generalised infection (sepsis), burns, and critically ill patients. Monitoring of renal function is recommended for at least 90 days. Yes, HES is contraindicated in patients suffering from serious generalised infection (sepsis) and in critically ill patients. Yes, HES is contraindicated in patients with bleeding in the skull or brain. The use is not recommended in patients undergoing open heart surgery in association with a heart-lung machine assisting in pumping the patient s blood during the surgery due to the risk of excess bleeding. Particular caution should be exercised when treating patients with impaired liver function or in patients with blood clotting disorders. In the case of repeated administration, blood clotting values should be monitored carefully. C O N F I D E N T I A L Page 239 of 355

5 Safety Concern What is known Preventability The use of HES must be discontinued at the first sign of blood clotting disorders. Severe dilution of the blood (haemodilution) due to high doses of HES Liver (hepatic) injury Fluid overload (hyperhydration) and excessive fluid accumulation in body tissues (oedema) due to water/sodium overload may occur, in particular in patients with conditions associated with sodium retention, e.g. elevated blood pressure, heart failure, oedema of the extremities or lung (peripheral or pulmonary oedema), impaired kidney function Long lasting itching Depending on the dosage, HES may cause dilution of the blood and coating of blood cells whose function - along with the blood clotting factors - is to stop bleeding (thrombocytes) Frequency not known (cannot be estimated from the available data) The reported incidence of liver injury is extremely low (< 1 per million patients treated). Patients with conditions associated with sodium retention are at a higher risk to develop fluid overload. Prolonged administration of high dosages of HES may cause itching (pruritus), that may be therapy-resistant and persist over months. Yes, severe dilution of the blood can be avoided by consideration of the dose restrictions. Yes, according to the new Summary of Product Characteristic (SmPC) the dosage of all HES products is restricted. Further, the duration of treatment is restricted to 24 hours. With these limitations a clinically relevant tissue storage of HES in the liver can be excluded. Yes, HES is contraindicated in patients with pre-existing fluid overload, fluids in the lung, and heart failure. In patients who are at higher risk to develop fluid overload, the dosage must be adjusted carefully, particularly in patients with problems of the lung, the heart and the blood circulation (cardiocirculatory problems). Serum salts (electrolytes), fluid balance and kidney function should be monitored closely. Yes, according to the new Summary of Product Characteristic (SmPC) the dosage of all HES products is restricted. Further, the C O N F I D E N T I A L Page 240 of 355

6 Safety Concern What is known Preventability Off-label use Important Potential Risks Use outside the treatment indication that is foreseen in the SmPC may occur duration of treatment is restricted to 24 hours. With these limitations a clinically relevant tissue storage of HES in the skin can be excluded. Yes, by consideration of the contraindications, warnings and precautions in the Summary of Product Characteristic (SmPC) Increased mortality in patients with burns Wrong diagnosis of pancreas inflammation (pancreatitis) due to elevated levels of a digestic substance in the blood which is released by the pancreas (serum amylase) l Missing Information Long-term data in surgical (particularly perioperative) and trauma patients Results of a clinical trial 34 with a similar product (HES 130/0.42) revealed a significant increased risk of death at 90 days after HES administration compared with Ringer s acetate (RR 1.17, 95% CI: ; p = 0.03). The concentration of serum amylase, a digestic substance released by the pancreas, can rise during administration of HES and can interfere with the diagnosis of inflammation of the pancreas. This harmless effect should be considered with the diagnostics of pancreas inflammation. There is a lack of robust long term safety data in patients undergoing surgical procedures and in patients with trauma. Yes, HES is contraindicated in patients with burns. Not possible, but the effect is harmless. No case has been reported since first authorisation of the product. Not amylase but another digestic substance (lipase) is the main diagnostic value for inflammation of the pancreas. Thus, it is considered to be a theoretical risk only. The expected benefit of treatment should be carefully weighed against uncertainty with regard to long term safety. Other available treatment options should be considered. C O N F I D E N T I A L Page 241 of 355

7 Safety Concern What is known Preventability Use in paediatric population Data are limited in children. It is recommended not to use HES products in this population. Use in pregnancy Use in lactation (excretion of HES in human breast milk) Impact of tissue storage in organs other than the skin, kidney, and liver There are limited clinical study data available from the use of a single dose of HES 130/0.4 (Voluven 6%) in pregnant women undergoing caesarean section with spinal anaesthesia. No negative influence of Voluven 6% on patient safety could be detected; a negative influence on the neonate could also not be detected. Animal studies with HES 130/0.4 (Voluven 6%) do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/foetal development, birth or development after delivery. Death of embryos was observed with HES in rabbits at 50 ml/kg BW/day. For HES 200/0.5 there is currently no clinical data available on the use during pregnancy There are currently no clinical data available on the use of HES in breast-feeding women. It is unknown whether HES is excreted in human breast milk. The excretion of HES in milk has not been studied in animals. In animal studies intake of 10% HES 130/0.4 into liver and kidney cells was observed HES should be used during pregnancy only if the potential benefit justifies the potential risk to the embryo/foetus. A decision on whether to continue/discontinue breastfeeding or to continue/discontinue therapy with HES should be made taking into account the benefit of breast-feeding to the child and the benefit of HES therapy to the woman. Yes, according to the new SmPC the dosage of all HES products is restricted. Further, C O N F I D E N T I A L Page 242 of 355

8 Safety Concern What is known Preventability in microscopic examinations of tissues after infusion of enormous amounts of fluid (up to 90 ml/kg within short time (3 hours) in healthy rats and dogs daily for 13 weeks). Further, 2 case reports are available on a fatal case of liver storage 49 and with persistent renal failure 37, respectively, after infusion of large amounts of HES. Tissue storage in the skin has been observed with HES 130/0.4 in an observational trial in 70 patients with hearing (otological) disorders, surgery, trauma, and other indications 57. the duration of treatment is restricted to 24 hours. With these limitations a clinically relevant tissue storage can be excluded. VI.2.5 SUMMARY OF RISK MINIMISATION MEASURES BY SAFETY CONCERN The Summary of Product Characteristics and the Package Leaflet for Voluven 10% contain information about routine risk minimisation measures. One of the outcomes of the 107i referral was that the Co-ordination Group for Mutual Recognition and Decentralised Procedures - human (CMDh) also decided that the direct healthcare professional communication (DHPC) should be submitted to the NCAs where HES products are marketed, within one week of the CMDh adopted position as per agreed communication plan. Therefore the translations of the DHPCs were sent to the different NCAs by 30 October 2013 for approval and were distributed by Fresenius Kabi to the customers directly by 12 November 2013 according to the CMDh position C O N F I D E N T I A L Page 243 of 355

9 Table 57 Summary of Risk Minimisation Measures by Safety Concern (Voluven 10%) Safety Concerns: Renal injury, increased bleeding/haemodilution, fluid overload, increased mortality in septic and critically ill patients, potentially increased mortality in patients with burns Dear Healthcare Professional Communication (DHPC) Information on Restriction of Use of HES Summary description Summary of the new recommendations - HES products should only be used for the treatment of hypovolaemia due to acute blood loss when crystalloids alone are not considered sufficient - HES products should be used at the lowest effective dose for the shortest period of time. Treatment should be guided by continuous haemodynamic monitoring so that the infusion is stopped as soon as appropriate haemodynamic goals have been achieved - (HES) products are now contraindicated in o Sepsis o Burns o Renal impairment or renal replacement therapy o Intracranial or cerebral haemorrhage o Critically ill patients (typically admitted to the ICU) o Hyperhydrated patients, including patients with pulmonary oedema o Dehydrated patients o Severe coagulopathy o Severely impaired hepatic function - There is a lack of robust long term safety data in patients undergoing surgical procedures and in patients with trauma. The expected benefit of treatment should be carefully weighed against the uncertainties with regard to long term safety and other available treatment options should be considered. - Large randomised clinical trials have reported an increased risk of renal dysfunction in the critically ill, including patients with sepsis. Therefore HES should no longer be used in these patients. - Monitoring of renal function in patients receiving HES is recommended and HES must be discontinued at the first sign of renal injury. Further information on the safety concern: Infusion solutions containing HES belong to the class of colloids. In the EU, HES-containing C O N F I D E N T I A L Page 244 of 355

10 solutions for infusion are approved via national procedures. Recently, the results of two clinical trials in critically ill patients, mainly with sepsis, have been published (1,2) compared with crystalloids. The studies showed a greater risk of adverse renal effects in patients treated with HES. The study of patients with sepsis (1) also showed a greater risk of mortality in patients treated with HES. Based on the results of these randomised controlled trials, the European Medicines Agency (EMA) in November 2012 initiated a safety review of all HES-containing products on the EU market. The review included data from the scientific literature, data submitted by the companies, data from the authors of the studies and from the stakeholders. In June 2013, the EMA s Pharmacovigilance Risk Assessment Committee (PRAC) recommended that the benefits of HES solutions no longer outweigh their risks and that HES containing products should be suspended from the market in the EU. Since then, the PRAC has analysed and considered new evidence that was not available at the time of the initial recommendation, including new studies and new proposals for additional risk minimisation measures. The companies have also committed to conduct additional studies to examine efficacy and long-term safety. On the basis of the data available to date, the PRAC has now concluded that HES products should only be used in a restricted patient population. New contraindications and warnings are being introduced and the marketing authorisation holders are required to perform further studies. The product information will be updated with the new information. Call for reporting Healthcare professionals should report any suspected adverse reactions associated with use of hydroxyethyl starch in accordance with the national requirements via the national spontaneous reporting system <detailed information of national spontaneous reporting system> Company contact point : <Contact point details for access to further information, including relevant website address(es), telephone numbers and a postal address> C O N F I D E N T I A L Page 245 of 355

11 VI.2.6 PLANNED POST-AUTHORISATION DEVELOPMENT PLAN All studies described in the table below are conditions of the marketing authorisation. Table 58 Planned post-authorisation developmental plan Study / activity Type, title and category (1-3) Study Code Objectives Safety concerns addressed Status (planned) Date for submission of interim or final reports (planned) Drug Utilisation Study (DUS) to investigate the Usage of Hydroxyethyl starch (HES)- containing Infusion Solutions in Hospitals HE CNI Category 1 The primary objective is to assess the adherence of the hospital physicians to the revised European Summary of Product Characteristics (SmPC)/Package Leaflet for HEScontaining medicinal products concerning indication, posology and method of administration, contraindications, special warnings and precautions for use. Please refer to column Objectives 1. Submission of final study protocol 2. Submission of final study report Jun 2014 (within 6 months of EC decision dated 19 Dec 2013) Note: The protocol of the DUS will be submitted to the PRAC who will initiate an Article 107 n-q procedure according to Directive 2001/83/EC months after protocol agreement Sample Size (planned): to be entered after protocol agreement C O N F I D E N T I A L Page 246 of 355

12 Study / activity Type, title and category (1-3) Study Code Objectives Safety concerns addressed Status (planned) Date for submission of interim or final reports (planned) Efficacy and safety of 6% HES 130/0.4 in isotonic electrolyte solution (Volulyte ) vs. crystalloid solution in elective abdominal surgery patients VOLU-024- CP4 Category 1 To assess the safety and efficacy of 6% HES 130/0.4 in isotonic electrolyte solution (Volulyte ) vs. crystalloid (Ringer s lactate) in patients undergoing elective abdominal surgery. The study aims to demonstrate non-inferiority of 6% HES 130/0.4 versus crystalloid solution. Renal injury, mortality 1. Submission of final clinical study protocol 2. Submission of final clinical study report Jun 2014 (within 6 months of EC decision dated 19 Dec 2013) Note: For the study design Fresenius Kabi and the other concerned MAHs have sought Scientific Advice at the EMA. The full validated application was submitted at DLP of this RMP. The study protocol will be submitted to the NCAs via Type IIB variation months after protocol agreement Efficacy and safety of 6% HES 130/0.4 in saline (Voluven ) vs. crystalloid solution in trauma patients HE CP4 Category 1 To assess the safety and efficacy of 6% HES 130/0.4 in saline solution (Voluven ) vs. crystalloid (NaCl 0.9%) in patients with blunt trauma. The study aims to demonstrate noninferiority of 6% HES 130/0.4 versus crystalloid solution. Renal mortality injury, 1. Submission of final clinical study protocol Jun 2014 (within 6 months of EC decision dated 19 Dec 2013) Note: For the study design Fresenius Kabi and the other concerned MAHs have sought Scientific Advice at the EMA. The full validated application was submitted at DLP of this RMP. The study protocol will be submitted to the NCAs via Type IIB variation. C O N F I D E N T I A L Page 247 of 355

13 Study / activity Type, title and category (1-3) Study Code Objectives Safety concerns addressed Status (planned) Date for submission of interim or final reports (planned) 2. Submission of final clinical study report months after protocol agreement VI.2.7 SUMMARY OF CHANGES TO THE RISK MANAGEMENT PLAN OVER TIME Not applicable. C O N F I D E N T I A L Page 248 of 355