Peer Review Report #1. Desmopressin. (1) Does the application adequately address the issue of the public health need for the medicine?

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1 20 th Expert Committee on Selection and Use of Essential Medicines Peer Review Report #1 Desmopressin (1) Does the application adequately address the issue of the public health need for the medicine? Desmopressin is a synthetic analogue of the antidiuretic hormone that is mainly used to treat diabetes insipidus. Section 8 reports the prevalence of other main clinical conditions in which D is being used, i.e. mild or moderate hemophilia A (HA), the relative deficiency of the coagulation FVIII affecting 1/5000 males, and type 1von Willebrand Disease (vwd), the mild quantitative deficiency of a normal vw Factor (vwf) affecting 1% of the general population. D is also used in certain situations for patients with other coagulation disorders or platelet disorders and in female carriers of HA, 10% of whom have a higher risk of bleeding. (2) Have all important studies that you are aware of been included in the application? The application includes guidelines of the relevant scientific societies: the World Federation of Hemophila (WFH), the European Society of Anaesthesiology (ESA) and with regard to vwd the British Committee for Standards in Haematology (BCSH) and the National Heart, Lung, and Blood Institute (NHLBI). The application also includes reviews of the available studies addressing the efficacy and safety of D in different clinical conditions. (3) Does the application provide adequate evidence of efficacy/effectiveness of the medicine for the proposed use? Guidelines and suggestions of the authors of the reviews submitted mostly rely on case series or uncontrolled studies. Therefore the experimental evidence backing those recommendations is limited and can be summarized as follows: Clinical condition Current use of D Level of evidence* Grading of recommendation* Mild haemophilia A Established 2 -/-/3/3 -/-/-/B VWD type 1 1 and 2N Established 2 2a/Low/-/3 B/Strong/-/B notes 1

2 Congenital defect of Possible -/Low/-/4 -/Weak/-/C platelet function Uremia Possible -/Low/-/4 -/Weak/-/C Liver cirrhosis Possible -/-/-4 -/-/-/C Drug-induced bleeding Possible -/-/-4 -/-/-/C Surgery in vwd 3 Doubtful -/Low/-/- -/-/Weak/-/- Cardiac surgery Doubtful -/-/-1 -/-/-/A There is no evidence that D Orthopaedic surgery Doubtful -/-/-1 -/-/-/A minimises perioperative allogeneic blood transfusion; nor that its use reduces the need for allogeneic blood or improves health outcomes during or after surgery 4 * scores of NHLBI/ESA/WHF/ Mannucci/ 1. with normal platelet count 2. According to Mannucci...autologous replacement of the deficient factors [by D in these clinical indications] is so clear that no randomised controlled trial was ever necessary. 3. accrding to ESA There is no convincing evidence that D minimises perioperative bleeding or perioperative allogeneic blood transfusion in patients without a congenital bleeding disorder 4. Cochrane SR: (4) Is there evidence of efficacy in diverse settings and/or populations? Obvious advantages of D over plasma products are the much lower cost and the absence of any risk of transmission of viral infections. However, it is not reported whether D treatment is effective in ethnic groups other than Caucasian people and can be safely administered in disadvantage setting, considering the possible difficulties in identifying the suitable target patients and in testing and monitoring their response to D (see Section (6)). D seems to be effective as home-based therapy. Two prospective studies (Rodeghiero, Thromb Haemost, 1996; and Leissinger, Haemophilia, 2001) evaluated the efficacy of D used to treat spontaneous bleeding in over 500 outpatients with bleeding disorders (276 with vwd, 216 with HA, and 10 with other bleeding disorders). Both studies included children and adults. Good or excellent hemostatic responses were achieved in 91 96% of all bleeding episodes, and no significant AEs were reported. (5) Has the application adequately considered the safety and adverse effects of the medicine? Are there any adverse effects of concern, or that may require special monitoring? refers to the 1st Q refers to the 2nd Q Minor AEs of D are common and include facial flushing, transient hypertension or hypotension, headache or gastrointestinal upset but these effects rarely limit clinical use. Water retention after a dose of D, with an increase in urinary osmolality, is universal; however, decreased serum sodium in otherwise healthy adults is variable and is related to 2

3 multiple doses. In the case of repeated dosing, all patients should be instructed to limit fluid intake to maintenance levels for 24 h. Prophylactic use of D complicates the management of fluids and electrolytes for surgery or during childbirth. Seizures have been associated with hyponatraemia after D administration, primarily in young children. Most paediatric hematologists do not use D in children <2 years old. Myocardial infarction after treatment with D has been reported, although rarely, in patients with mild hemophilia A. D should be avoided in patients who are at very high risk for cardiovascular or cerebrovascular disease, especially the elderly, as underlying inhibition of plasminogen activation with D-related vasoconstriction contributes additional prothrombotic effects in these patients. Because of reported complications in other patient populations, D should be used with caution for brain, ocular and coronary artery surgeries, and vwf concentrate replacement generally is used in these settings. Pregnancy is not an absolute contraindication but use of D is rarely indicated and should be avoided in pre-eclampsia and eclampsia because of the already high levels of vwf. Data are limited on the use of D for vwd in pregnancy. However, in the lower doses used to treat diabetes insipidus, D is generally thought to be safe for mother and fetus. In a review of 53 women who were pregnant and were administered with D ( microg/day) for diabetes insipidus, no adverse maternal or neonatal effects were attributable to the medication. In an in vitro placenta model, D did not cross the placenta in detectable amounts. ADDITIONAL CONSIDERATIONS: (6) Are there special requirements or training needed for the safe, effective and/or appropriate use of the medicine? Treatment with D requires preliminary tests to identify plasma FVIII or vvf deficiency and to monitor their response to D. Tests include aptt, vwf:rco (vwf ristocetin cofactor activity, functional), vwf:ag (immunoassay), and FVIII activity (functional). This tests are also useful to assess the potential response of patients in the recommended preliminary trials. (7) Are there any issues regarding the registration of the medicine by regulatory authorities? (e.g., recent registration, new indications, off-label use) In US D (Stimate Nasal Spray) is approved for patients with hemophilia A with Factor VIII coagulant activity levels greater than 5% and for patients with mild to moderate classic von Willebrand's disease (Type I) with Factor VIII levels greater than 5%. In EU D has not been approved through the centralized procedure by the EMA. However, the Agency s guidelines recognize its value as a first choice treatment of mild vwd 3

4 ( pdf). This recognition is not clearly stated for mild hemophilia A (8) Is the medicine recommended for use in a current WHO GRC-approved Guideline (i.e., post 2008)? D is mentioned in the WHO handbook The clinical use of blood for the treatment of patients with mild to moderate hemophilia A and to increase endogenous vwf levels. (9) Please comment briefly on issues regarding cost and affordability of this medicine. D is a safe and affordable alternative to plasma products and fresh blood components for patients with moderate and mild hemophilia, vwd and other hereditary bleeding disorders in the developed world and particularly in developing countries. (10) Any additional comments? This reviewer could not find the reason why D was removed from the WHO EML in 2002 after being included in (11) Please summarise the action you propose the Expert Committee takes. It is the opinion of this reviewer that D should not be considered as an essential drug. However, it could be included in the Complementary List. The reason for allowing D onto the Complementary List is that there is long-lasting experience in its use and empirical evidence of its efficacy, safety and cost-effectiveness in the prevention and treatment of bleeding in patients with mild hemophilia A and type 1 vwd. D could help avoid the potential danger and/or cost of blood derivatives and clotting factor concentrates or recombinant coagulation factors. The reasons not to allow D onto the Master List are that (a) the evidence of its efficacy and safety in most clinical settings only relies on case series and uncontrolled trials; (b) its use is mostly recommended in subsamples of patients with two coagulation disorders; (c) it is questionable whether D could be safely adopted in disadvantaged contexts of care, where 4

5 the facilities needed to diagnose these diseases and preliminary test the individual response to D might not be available/affordable. 5

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