The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 3 November 2010

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 3 November 2010 Examination of the dossier of the proprietary medicinal product included on the list for a limited time in accordance with the Decree of 27 October 1999 (Official Gazette 30 October 1999) and the Decision of 1 December 2006 (Official Gazette 21 December 2006) FERRISAT 50 mg/ml, solution for injection or infusion B/5 x 2 ml ampoules (CIP code: ) B/10 x 2 ml ampoules (CIP code: ) B/10 x 5 ml ampoules (CIP code: ) Applicant: PHARMACOSMOS Iron (III) hydroxide and dextran complex ATC code : B03AC06 List I For hospital prescription Date of Marketing Authorisation: 1 October 2007 (mutual recognition procedure) Reason for request: Reassessment of the AB in accordance with article R of the Social Security Code. Medical, Economic and Public Health Assessment Division 1/8

2 1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient Iron (III) hydroxide and dextran complex 1.2. Indications FERRISAT is indicated for the treatment of iron deficiency in the following indications: When oral iron preparations cannot be used, e.g. due to intolerance, or in case of demonstrated lack of effect of oral iron therapy. Where there is a clinical need to deliver iron rapidly to iron stores. The diagnosis of iron deficiency must be based on appropriate laboratory tests (e.g. serum ferritin, serum iron, transferrin saturation and hypochromic red cells) For use in adults only Dosage The normal recommended dosage schedule is mg iron corresponding to 2-4 ml, two or three times a week depending on the haemoglobin level. However, if clinical circumstances require rapid delivery of iron to the body iron stores, FERRISAT may be administered as a total dose infusion up to a total replacement dose corresponding to 20 mg iron/kg body weight. Subsequent doses may be administered by intravenous infusion, intravenous injection, infusion of the total dose or by injection in an extracorporeal circuit. 2 REMINDER OF THE COMMITTEE S OPINIONS AND CONDITIONS OF INCLUSION Opinion of 19 December 2007 Inclusion on the list of medicines approved for use by hospitals The efficacy/adverse effects ratio of FERRISAT 50 mg/ml solution for injection is considerable. The actual benefit conferred by FERRISAT in the treatment of anaemia related to iron deficiency in patients who have been found to be intolerant of oral iron preparations, where oral iron treatment has been shown to be ineffective, or where there is a clinical need to deliver iron to iron stores rapidly, is high. 2/8

3 3 SIMILAR MEDICINAL PRODUCTS 3.1. ATC Classification (2010) B B03 B03A B03A C B03AC06 : Blood and blood-forming organs : Antianaemic preparations : Iron preparations : Iron trivalent, parenteral preparations : Ferric oxide dextran complexes 3.2. Medicines in the same pharmaco-therapeutic category Comparator medicines VENOFER 100 mg/5 ml, solution for injection (IV) FERINJECT 50 mg/ml solution for injection for infusion (not yet on the market) 4 UPDATING OF AVAILABLE DATA SINCE THE PREVIOUS OPINION The Afssaps pharmacovigilance committee conducted a review in January 2010 of the risks of serious allergic reactions with iron dextran (FERRISAT) compared to the ferric hydroxide - sucrose complex (VENOFER). The pharmacovigilance committee analysed data from the PSURs 1 and the French pharmacovigilance database. These sources of information show that allergic accidents are more common and more serious in patients being treated with FERRISAT than with patients being treated with VENOFER. The PSURs show that, according to estimates of number of patients treated, the rate of reports of potentially allergic reactions was 14.1 per 100,000 patients treated in the case of FERRISAT and 3.9 per 100,000 patients treated in the case of VENOFER (a ratio of 3.6 to 1), and the rate of potentially life-threatening allergic reactions was 2.9 per 100,000 patients treated in the case of FERRISAT versus 0.26 per 100,000 patients treated in the case of VENOFER (a ratio of 11.2 to 1). Similarly, the French pharmacovigilance database showed the number of allergic adverse effects in relation to the number of years that the products had been on the market to be higher for FERRISAT than for VENOFER. The time to onset of allergic reactions was also shorter and the clinical picture more serious in the case of FERRISAT than in the case of VENOFER. On 27 May 2010 the EMA pharmacovigilance working party decided to take steps to warn healthcare professionals about the risk of serious allergic reactions and the need to take precautions when administering this product. In France, a letter was sent to prescribing physicians in May 2010 from the pharmaceutical company and Afssaps, reminding them of the need to administer a trial dose before the first therapeutic dose of FERRISAT, to stop the infusion immediately if signs of hypersensitivity appear, and to have cardiorespiratory resuscitation equipment to hand when administering FERRISAT. 1 National pharmacovigilance committee discussion on 26 January Update on the risk of serious allergic reactions with iron dextran (FERRISAT) compared to the ferric iron - sucrose complex (VENOFER). 3/8

4 This data confirms the analysis of data published by Chertow 2 in the United States based on WHO data from 2004 comparing the reported adverse effects of VENOFER and FERRISAT administered by the intravenous route between 2001 and This analysis showed that between 2001 and 2003 more serious adverse effects were reported with FERRISAT than with VENOFER. Table 1: Adverse effects reported between 2001 and 2003 following parenteral administration of iron (according to Chertow 1 ) Adverse effects VENOFER n = 8,837,000 FERRISAT n = 6,690,000 Odds Ratio VENOFER versus FERRISAT total (0.4; 0.6) serious (0.1; 0.4) The pharmaceutical company has submitted a bibliographical review of new tolerance data. It includes in particular three comparative clinical trials 3,4,5 and a systematic review 6 covering the period from 1996 to The clinical trials were conducted on cohorts of 60, 110 and 979 patients treated with FERRISAT, while the systematic review examined 60 studies involving 2,000 patients taking FERRISAT and 4,000 taking VENOFER. No serious adverse effect was found. However, the cohort sizes and the methodology (systematic review) were not sufficient to highlight any significant difference in respect of rare effects. In addition, dextrans have been associated with a risk of fœtal death 7 if used during pregnancy. The possibility that the dextran contained in FERRISAT might also lead to this risk cannot be ruled out. 5 DRUG USAGE DATA According to data published by Afssaps in on the basis of annual reports of sales by marketing authorisation holders, 21,000 boxes of FERRISAT were sold in Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmén J. On the relative safety of parenteral iron formulations. Nephrol Dial Transplant 2004; 19: Moniem KA, Tolerability and efficacy of parenteral iron therapy in haemodialysis patients, a comparison of preparation. TATM 2007, 9: Sav T, Is there a difference between the allergic potencies of the iron sucrose and low molecular weight iron dextran? Ren Fail 2007, 29: Sinha S. Comparison of intravenous iron sucrose versus low molecular weight dextran in chronic kidney diseases. J Ren Care 2009, Critchley J. Adverse events associated with intravenous iron infusion (low-molecular-weight dextran and iron sucrose): a systematic review. TATM 2007; 9: C. Bodiou et al. Dextran et accouchement. [Dextran and labour] Souffrance fœtale majeure. [Major foetal distress] Rech Gynécol. Sept 89, 1 ; Sales of medicines in dispensaries and hospitals in France. Key figures. Afssaps report, October /8

5 6 TRANSPARENCY COMMITTEE CONCLUSIONS Iron deficiency anaemia can impair patients quality of life depending on how severe it is. The efficacy/adverse effects ratio of FERRISAT 50 mg/ml solution for injection is poor. Alternative substances for venous administration exist. This proprietary medicinal product is intended as curative therapy for iron deficiency anaemia. The public health burden due to iron deficiency anaemia is significant. The need for an iron treatment given by venous administration is met by VENOFER. In the light of the data available, particularly the tolerance data, FERRISAT would have no additional impact on reducing morbidity related to iron deficiency compared to VENOFER, and a negative impact cannot be ruled out. As a result, FERRISAT is not expected to benefit public health. In the light of the treatments currently available, and due to the Transparency Committee s concerns following the pharmacovigilance report on the tolerance of FERRISAT, which appears to be more hazardous than VENOFER for comparable efficacy, FERRISAT seems to be inferior in performance to VENOFER and cannot therefore be retained on the list of refundable medicines. Consequently, the actual benefit of FERRISAT in its indications is insufficient. 5/8

6 APPENDIX: NATIONAL PHARMACOVIGILANCE COMMITTEE, 26 JANUARY 2010 Extract III - REVIEW OF THE RISK OF SERIOUS ALLERGIC REACTIONS WITH DEXTRAN IRON (FERRISAT) COMPARED TO FERRIC HYDROXIDE/SUCROSE COMPLEX (VENOFER) Trade name FERRISAT VENOFER INN Pharmaceutical form Pharmacological class Marketing authorisation procedure MA holder MA operator Ferric hydroxidedextran complex IV route (2-ml and 10-ml ampoules (50 mg/ml) since March 08 and April 09 respectively. Anti-anaemia preparations B03AC06 ferric oxide dextran complex mutual recognition (Denmark= reference Member State) Pharmacosmos HAC pharma Ferric hydroxidesucrose complex IV route 100 mg/50 ml ampoule since June 1999 Anti-anaemia preparations B03AC02 ferric oxide/ sucrose national Vifor Dates reviewed by the pharmacovigilance technical committee: 13/10/2009 and 04/01/ Introduction IV iron is indicated for the treatment of patients with iron deficiency when the oral route is inadequate or poorly tolerated (in particular, patients with chronic renal failure and also patients who are about to undergo surgery or have recently had surgery, or patients with intestinal absorption disorders). The Caen Regional Pharmacovigilance Centre (CRPV) was asked to conduct this review of the risk of serious allergic accidents reported with FERRISAT compared to VENOFER at the meeting of the technical committee held in February Method Caen CRPV examined the files of the French national pharmacovigilance database up to 30 September 2009, looking for reports of serious incidents where a link with FERRISAT or VENOFER was suspected. Data submitted by the pharmaceutical firms was also analysed: - The PSURs covering the period from 01/03/2007 to 28/02/2009 for VENOFER (two years). French data from the PSURs for the first two years of sale (1999 and 2000) and French reports from the start of 2001 to the end of 2006 were submitted subsequently. - The PSURs covering the period from 01/05/2006 to 31/08/2008 for FERRISAT and the period from 01/02/2009 to 06/05/2009 (line listings submitted for these periods), a total 6/8

7 duration of two years and seven months. The PSURs for COSMOFER/FERRISAT covering the period from 01/09/2009 to 31/01/2009 were submitted subsequently. Caen CRPV investigated reports which mentioned an immediate hypersensitivity reaction to these two drugs (anaphylactoid or anaphylactic reaction, or symptoms pointing to an allergic reaction), classified in severity grades I to IV according to the Ring and Messmer system. Reporting rates were calculated for all countries in which these products are sold and for France on the basis of sales figures submitted to Afssaps by the pharmaceutical companies. 3 Results and Discussion Data from the French national pharmacovigilance database (up to 15/07/2009): The main differences between FERRISAT and VENOFER are: - A higher number of cases with FERRISAT in relation to the number of years that it has been on the market. - The time to onset of symptoms is much shorter with FERRISAT (66% of cases occur within approximately 10 minutes, and around 75% within an hour after the start of infusion; the corresponding figures for Vénofer are 9% and 18%). This translates into a higher proportion of cases being attributable to FERRISAT, with 93% C3S1. - The allergic syndromes associated with FERRISAT are more severe; 33% are grade III (lifethreatening), compared to 6% for Vénofer. 22% of the reports of allergic adverse effects to FERRISAT concerned life-threatening incidents (data for the period up to 30 September 2009, when the product had been on the market in France for 19 months), as against 6% for Vénofer (which had been on the market for over 10 years). It should be noted that all patients had a favourable outcome. PSU data: - The number of reports received each year for VENOFER is higher, but that needs to be seen in the context of the much larger number of patients treated with VENOFER. - 20% of the anaphylactoid incidents reported with VENOFER are due to an error in the administration speed or dosage. - There is no identifiable difference in terms of time to onset of symptoms as this parameter is very rarely reported. - However, there is a significant difference in terms of severity: 20.5% of cases reported for iron-dextran are life-threatening, as opposed to 6.6% for iron-sucrose. According to estimates of numbers of patients treated during the periods under investigation, the rate of potentially allergic reactions reported per 100,000 patients is 14.1 for FERRISAT and 3.9 for Vénofer (a ratio of 3.6 to 1). According to international data, the rate of life-threatening allergic reactions reported per 100,000 patients treated is 2.9 for FERRISAT versus 0.26 for VENOFER (a ratio of 11.2 to 1). The estimate of the rate of allergic reaction reports in France clearly indicates a higher risk with FERRISAT compared to VENOFER, both in terms of the number and severity of cases. 7/8

8 FERRISAT from March 2008 to June 2009 VENOFER from January 1999 to December 2000 VENOFER in 2008 VENOFER in VENOFER from 1999 to February 2009 Rate of reports of allergic events Rate of reports of life-threatening allergic events 125/100, to 61 / 100, /100, to 15.3 / 100, /100, /100, /100, /100,000 1/100,000 Bibliographical data: The bibliographical review, which looked at articles reporting the results of an investigation of the FDA pharmacovigilance database, prospective clinical trials and European guidelines (Locatelli F et al., Nephrol Dial Transplant, 2004), found that iron-dextran, even a low molecular weight formulation, was associated with a greater allergic risk. 4 Rapporteur s conclusions and proposals Allergic accidents are found to be more common and more serious in patients being treated with FERRISAT than in patients being treated with VENOFER. Rapporteur s proposals: - Prescribing doctors should be clearly informed of this risk associated with FERRISAT, which is close to that found with dextran filling solutions (where the rate of reports of life-threatening adverse effects is 22/100,000). - The use of FERRISAT should be restricted to indications where it is likely to offer benefits over VENOFER, i.e. for patients with chronic renal failure or other patients needing IV iron on a regular basis. - The rate of reports of allergic reactions with FERRISAT from July 2009 to the end of 2010 should be monitored in order to evaluate the trend and the potential impact on reporting rates of the product being placed on the market. - The potential for foetal damage of prescribing iron-dextran to pregnant women should be evaluated, as dextran filling solutions had been contraindicated in France after the 1989 pharmacovigilance investigation (risk of foetal death in the event of a maternal anaphylactic or anaphylactoid reaction linked to uterine hypertension triggered by the release of prostaglandins: Paris saint-vincent de Paul CRPV). 8/8