1. Donor deferral due to intake of anti-platelet medication Sharyn Orton, Ph.D. Jaro Vostal, M.D., Ph.D. OBRR/CBER/FDA Blood Products Advisory Committee Meeting March 9, 2006

2. Background Draft “Guidance for Industry and FDA Review Staff: Collection of Platelets by Apheresis Methods”, published 9/30/2005. Included new proposed deferrals for some medications.

3. Changes in platelet transfusion practice that drive revision of donor deferrals due to NSAIDs or anti- platelet medication Higher percentage of single donor apheresis platelets transfused –if platelets are inactive could lead to decreased hemostatic performance when transfused Whole blood derived platelets are transfused as a pool –if one platelet unit out of the pool is inactive there will be less effect on the over-all performance of the pool –However pools are getting smaller (4-6 vs 6-10 units per pool) which could lead to a higher percentage of the pool being inactive if one donor has anti-platelet medication Lower transfusion triggers (5-10,000 vs 20,000)

4. Proposed Deferrals for Donors Aspirin (ASA) ASA-containing drugs 5 Non-steroidal Anti- inflammatory Drugs (NSAIDS) 3 Plavix (Clopidogrel)5 Ticlid (Ticlopidine)14 Medicine Days from last dose

5. Comments to the Docket Aspirin: Not based on current practice No observed adverse patient events from apheresis platelets collected 36 – 48 hours after aspirin ingestion (refs provided) Will result in significant donor loss 10-30% of unaffected platelets necessary for normal platelet function

6. continued NSAIDs: Reference not peer reviewed Platelet effect is reversible Some have no platelet effect Will result in donor loss Plavix, Ticlid: Deferral should be 24 and 48 hours

7. continued General: Too restrictive Donors willing to stop medications for a few days, but not likely more than 3

8. Reversibility of anti-platelet effect is based on whether the drug effect on target enzyme is reversible or irreversible In the donor (drug recipient) –Reversible: time to reversal of anti-platelet effect depends on last drug ingestion and 4-5 plasma T1/2 of drug –Irreversible: need to replace affected platelets (~10% per day) In the patient (platelet transfusion recipient) –Reversible: the effect on platelets depends on rate of elution of drug out of platelets –Irreversible: platelets will remain inhibited for duration of their life span.

9. Aspirin Aspirin-containing drugs Short plasma T1/2 (30 minutes) Irreversible inactivation of COX-1 and COX-2 Platelets have COX -1 and are inactivated for duration of their life span

10. Non aspirin containing non steroidal anti-inflammatory drugs Reversibly inhibit both COX-1 and COX-2 or are selective for COX-2 COX-2 selective inhibitors do not inhibit platelets Inhibition of COX-1 is reversed when drug is not present in plasma –4-5 plasma T1/2 s post last ingestion –If treated platelets are placed in medium that contains no inhibitors (i.e. transfused)

11. Anti platelet drugs Clopidogrel (Plavix) and Ticlopidine (Ticlid) Irreversibly block platelet ADP receptors and inhibit activation Plavix: Platelet effect to normal by 5 days Ticlid: Platelet effect to normal by 10 days

12. Assessment of ASA effect on platelets Aggregation –Inhibited by ASA –Aggregation alone is not predictive of platelet efficacy in vivo Skin bleeding time –Standard size cut on skin –Measure time to cessation of bleeding –Prolonged by ASA –Not predictive of surgical bleeding risk –Not used to predict platelet efficacy in vivo Clinical trial –Thrombocytopenic patients transfused with ASA inactivated platelets –Bleeding (WHO bleeding scale) as endpoint –S59 treated platelets (SPRINT Trial)

13. Time (minutes) % aggregation agonist UntreatedASA or NSAID treated Strong agonist (thrombin, dual agonist (Epi+ADP) Weak agonist (ADP or Epi alone) Agonist –induced platelet aggregation

14. Deferral of non-aspirin platelet inhibitors Ideally, deferral period should be based on time to reversal of platelet inhibition in the recipient. When this is not known, deferral should be based upon reversibility rate (rate at which platelet function becomes normal in the donor after discontinuation of the drug, i.e. 4-5 T1/2 of drug in plasma) Platelet function assessed by single agonist induced aggregation

15. Zeiler, Thomas, Gritzka, Debora, Karger, Ralf & Kretschmer, Volker The effect of ASA on platelet activation during apheresis and on in-vitro properties of stored platelet concentrates. Transfusion 44 (9), 1300-1305, 2004. AgonistBefore donationAfter donation + ASA Group A Control Group B + ASA Group A Control Group B ADP (4 uM)39+1073+1034+1477+8 ADP (10 uM) 50+977+748+1376+6 Collagen (4 ug/ml) 63+676+562+1277+7 Arachidonic acid (500 ug/ml) 10+270+1910+270+19 Donors Apheresis Products Group A = 500 mg ASA 12 hours prior to donation Group B = no meds

16. Stuart et al. Platelet function in recipient of platelets from donors ingesting aspirin. NEJM 287; 1105-1109, 1972 Transfused platelets from donors with ASA exposure Post 600 mg ASA Epinephrine-induced Aggregation (2 nd wave) Present 10 0 0 3 10 Equivocal 0 0 2 4 0 Absent 0 10 8 3 0 Donors Thrombocytopenic patients one hour post transfusion

17. Croneberg, S et al. Effect on platelet aggregation of oral administration of 10 non-steroidal analgesics to humans. Scand. J. Haematology 33: 155-159, 1984 Number of donors with full single agonist-induced aggregation Time after medicine discontinuation Before1hr3 hr6 hr1 d2 d3 d5-8 d Aspirin50000 5 Piroxicam4000004 Naproxen40002 Indometh acin 50005 Ibuprofen52124

18. MedicationT ½Reversibility rate Nabumetone, RelafenNANo plt effect Ibuprofen2 hrsAlmost immediately Cataflam, Diclofenac, Volteran 2 hrs24 hrs Difunisal, Dolobid8-12 hrs24 hrs Indocin, Indomethacin4.5 hrs50% at 24 hrs Toradol, Ketorolac5.3 hrs24 – 48 hrs

19. MedicationT ½Reversibility rate Anaprox, Naprosyn, Naproxen 12-17 hrs 2 days Feldene, Piroxicam50 hr3 days Clinoral, Sulindac8 hrsUnknown Meclofenamate, Meclomen, Mefanamic acid 2 hrsUnknown

20. Non steroidal anti- inflammatory COX-1 Aspirin (ASA) ASA-containing drugs 35 Proprionic acid derivatives (Motrin group) None All others (except Feldene) 1 Piroxicam (Feldene)3 COX-2None Anti-plateletPlavix (Clopidogrel)55 Ticlid (Ticlopidine)1014 Revised Proposed Deferrals Drugs Days post last ingestion Revised Proposed 3

21. NOTE: FDA does not believe it is appropriate for individuals to stop taking medications prescribed for clinical conditions, in order to donate

22. Question to the Committee Does the BPAC agree with the revised proposed donor deferral criteria: Aspirin: 3 days Motrin group: no deferral All other COX-1 reversible inhibitors: 1 day except Feldene3 days COX-2 inhibitors: no deferral Plavix: 5 days Ticlid: 10 days

23. Stuart et al. Platelet function in recipient of platelets from donors ingesting aspirin. NEJM 287; 1105-1109, 1972 “Only in situations in which all platelets administered are from donors who have taken aspirin within 36 hours of donation, and in which the patient will make an inconsequential contribution to the total circulating platelet pool, should aspirin ingestion prove a problem to the recipient.”