Roche Pharmaceuticals

Study Shows Subcutaneous Injection With MIRCERA is Significantly Less Painful Than With SC Aranesp

    Basel, Switzerland (ots/PRNewswire) - A new study on pain published today has found that subcutaneous (SC) injections of the new renal anaemia therapy MIRCERA is associated with significantly less pain immediately after injection than SC darbepoetin-alfa (Aranesp).(1) These findings are important because to date there has been minimal data regarding SC injection site pain in adults with different erythropoiesis-stimulating agents (ESAs), despite such pain being a common adverse event and a burden for patients with chronic kidney disease (CKD).

    Complaints of pain with subcutaneous injections of traditional ESAs is known to cause physicians to treat their CKD patients via the intravenous route(2),(3) despite the fact that subcutaneous use can be more convenient and may ultimately improve compliance and persistence.

    "These study findings provide important information for physicians when they are choosing ESA therapy for their patients. Repeated painful injections of what is often life-long treatment in these chronically ill kidney disease patients may affect compliance and could result in poor control of their anaemia. The statistically significant difference in pain experienced by the study participants given MIRCERA subcutaneously compared to darbepoetin alfa along with the less frequent dosing intervals MIRCERA has in its label(4) are important factors that physicians should consider when determining the treatment options for their patients," said Dr Frank Dougherty, Clinical Science Leader at Roche.

    In the Roche-sponsored study, half of participants (53%) rated injection with darbepoetin alfa as more painful than MIRCERA injections.

    The study

    In a randomized, placebo-controlled, single centre, single blind study, healthy subjects (81 completed the study) received one of six potential treatment sequences (ABC/ ACB/ BAC/ BCA/ CBA/ CAB), involving SC injection on days 1, 29, and 57 of: (A) MIRCERA. 50 micrograms; (B) darbepoetin alfa 50 micrograms and (C) placebo (saline solution, 0.5mL).

    The design of this trial ensured that any observed differences would not be a result of variation in subjects' pain perception. In addition, the trial methodology was standardized where possible to ensure that any observed differences in pain perception between SC treatments were unlikely to result from properties of the final preparation (e.g., drug concentration, injection volume) or injection procedure (e.g., needle size or sharpness, location of injection site, and staff's administration technique). Furthermore, all patients were blindfolded.

    Subjects assessed their SC injection site pain immediately after dosing on two scales: the visual analogue scale (VAS) and the verbal rating scale (VRS).(5) The primary endpoint was pain VAS immediately after the SC administration and the secondary endpoints were pain VAS 1 hour after dosing; VRS immediately and at one hour after dosing, safety and tolerability. On the 100-mm VAS, subjects rated their pain from 0 mm ('no pain') to 100 mm ('pain as bad as it could be'). The 6-point VRS was a categorical scale where 0 = 'no pain', 1 = 'minimal pain', 2= 'slightly painful', 3='moderately painful', 4='very painful', and 5='extremely painful'.

    Study Findings

    Using both the VAS and VRS systems, MIRCERA was associated with significantly less pain.

    - The least square mean VAS was 21.5 following SC administration of MIRCERA compared to 33.4 following SC darbepoetin alfa, which was statistically significant. Placebo was associated with the lowest mean VAS value (16.0).

    - In most subjects, pain VAS 1 hour after administration was 0 mm ("no pain").

    - Using the VRS, just over half of subjects (53% - 43 out of 81) rated darbepoetin alfa as more painful than MIRCERA. Only 12% rated MIRCERA with a higher VRS score than darbepoetin alfa.

    - 34% of subjects gave MIRCERA and darbepoetin alfa equal VRS scores.

    - None of the MIRCERA treated subjects gave a rating of 'very painful' (VRS score 4) compared with 13% of subjects who were administered darbepoetin alfa.

    - One hour after administration, most subjects rated their pain VRS as 0 "no pain".

    MIRCERA

    MIRCERA was approved in the EU in July and in Switzerland and Norway in September. It has already been launched in Austria, Sweden, Germany and the UK. It is the first ESA in the EU that offers a convenient dosing schedule of once every two weeks to correct anaemia in all CKD patient types not previously treated. MIRCERA is also the first ESA in the EU approved to directly convert all CKD patients types previously treated with any ESA to once-monthly dosing. The capacity of MIRCERA to correct and sustain haemoglobin levels in patients with CKD-related anaemia, coupled with a reduced dosing frequency that is associated with less pain on injection offers physicians and patients a new treatment option. The safety and efficacy of MIRCERA in other indications has not been established.

    CKD and Anaemia

    Anaemia is a frequent complication of CKD and untreated patients suffer fatigue, reduced quality of life, and an increased risk of cardiovascular events.(6),(7),(8),(9),(10) The introduction of ESAs has substantially improved the management of renal anaemia and these treatments have become widely accepted as a replacement for red blood cell transfusions. However, a drawback with traditional ESAs is that they require frequent dosing in the majority of patients to maintain efficacy and injection site pain is a common adverse event.(11),(12),(13),(14),(15),(16),(17),(18),(19),(20),(21),(22) The unique activity of MIRCERA at the receptor involved in stimulating red blood cell production, coupled with its longer half-life compared to traditional ESAs, is believed to play an essential role in providing smooth and predicable control of anaemia with as few as 12 injections per year.

    About Roche

    For more information please visit http://www.roche.com

    Notes to the Editor:

    Additionally another study, regarding the mechanism of action of MIRCERA, has just been published in the journal Pharmacology. The article describes the different receptor binding properties of MIRCERA that may enable continuous stimulation of erythropoiesis and, combined with a long half-life and slow systemic clearance, permit administration at extended intervals. The abstract and manuscript for this study are available at http://content.karger.com/ProdukteDB/prod ukte.asp?Aktion=Ausgabe&Ausgabe=233751&ProduktNr=224274.

    For video content from Roche related to anaemia please log on to http://www.thenewsmarket.com/roche, where you can order broadcast-standard video to be received digitally or by tape. Registration and video is free to the media.

    Additional information about renal anaemia is available on the Internet at http://www.AnaemiaWorld.com.

    All trademarks used or mentioned in this release are protected by law.

    References

    ---------------------------------

    (1) Pannier A et al. Subcutaneous injection pain with C.E.R.A., a continuous erythropoietin receptor activator, compared with darbepoetin alfa. Current Medical Research and Opinion. 2007 23; 12: 3025-3032

    (2) Weiss, L. Flexible dosing schemes for recombinant human erythropoietin - lessons from our daily practice. Nephrol Dial Transplant (2001) 16: (Suppl 7): 15 - 19.

    (3) Veys N Ringoir S. The subcutaneous administration route of epoetin: advantages, pain at the injection site and patient acceptance. Int J Artifl Organs 1993 16; 1: 1-3.

    (4) For patients not currently treated with an erythropoiesis stimulating agent (ESA), the recommended starting dose is 0.6 microgram/kg body weight, administered once every two weeks as a single intravenous or subcutaneous injection in order to increase the haemoglobin to greater than 11 g/dl (6.83 mmol/l). Patients currently treated with an ESA can be converted to MIRCERA administered once a month as a single intravenous or subcutaneous injection. The starting dose of methoxy polyethylene glycol-epoetin beta is based on the calculated previous weekly dose of darbepoetin alfa or epoetin at the time of substitution. Summary of Product Characteristics for MIRCERA in the EU, http://www.emeaeuropa.eu. Darbepoetin alfa in the correction phase, the initial dose by subcutaneous or intravenous administration is 0.45 microgram/kg body weight, as a single injection once weekly. Alternatively,  in patients not on dialysis, an initial dose of 0.75 microgram/kg may be administered subcutaneously as a single injection once every two weeks.  In the maintenance phase, Aranesp may continue to be administered as a single injection once weekly or once every two weeks. In patients not on dialysis,  once the target haemoglobin has been achieved with once every two week dosing, Aranesp may be administered subcutaneously once monthly using an  initial dose equal to twice the previous once every two week dose.

    (5) Machin D, Lewith GT, Wylson S. Pain measurement in randomized clinical trials. A comparison of two pain scales. Clinical Journal of Pain. 1988;4:161-168.

    (6) National Kidney Foundation web site. Available at: http://www.kidney.org. Accessed August 9, 2007.

    (7) Jurkovitz CT, Abramson JL, Vaccarino LV, Weintraub WS, McClellan WM. Association of high serum creatinine and anemia increases the risk of coronary events: results from the prospective community-based atherosclerosis risk in communities (ARIC) study. J Am Soc Nephrol. 2003;14:2919-2925.

    (8) Pisoni RL, Bragg-Gresham JL, Young EW, et al. Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2004;44:94-111.

    (9) Perlman RL, Finkelstein FO, Liu L, et al. Quality of life in chronic kidney disease (CKD): a cross-sectional analysis in the Renal Research Institute-CKD study. Am J Kidney Dis. 2005;45:658-666.

    (10) Evans RW, Rader B, Manninen DL. The quality of life of hemodialysis recipients treated with recombinant human erythropoietin. Cooperative Multicenter EPO Clinical Trial Group. JAMA. 1990;263:825-830.

    (11) Stevens JM, Auer J, Strong CA, et al. Stepwise correction of anaemia by subcutaneous administration of human recombinant erythropoietin in patients with chronic renal failure maintained by continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant. 1991;6:487-494.

    (12) Brazeau GA, Cooper B, Svetic KA, Smith CL, Gupta P. Current perspectives on pain upon injection of drugs. J Pharm Sci. 1998;87:667-677.

    (13) Frenken LA, van Lier HJ, Gerlag PG, den Hartog M, Koene RA. Assessment of pain after subcutaneous injection of erythropoietin in patients receiving haemodialysis. BMJj. 1991;303:288.

    (14) Lui SF, Leung CB, Li PK, Lai KN. Pain after subcutaneous injection of erythropoietin. BMJ. 1991;303:856.

    (15) Granolleras C, Leskopf W, Shaldon S, Fourcade J. Experience of pain after subcutaneous administration of different preparations of recombinant human erythropoietin: a randomized, double-blind crossover study. Clin Nephrol. 1991;36:294-298.

    (16) Veys N, Vanholder R, Lameire N. Pain at the injection site of subcutaneously administered erythropoietin in maintenance hemodialysis patients: a comparison of two brands of erythropoietin. Am J Nephrol. 1992;12:68-72.

    (17) Bommer J, Weinreich T, Ritz E, Zeier M, Bommer G. Efficacy of subcutaneous or intravenous recombinant human erythropoietin therapy in dialysis patients (Abstract). Nephrol Dial Transplant. 1989;4:471.

    (18) Veys N, Dhondt A, Lameire N. Pain at the injection site of subcutaneously administered erythropoietin: phosphate-buffered epoetin alpha compared to citrate-buffered epoetin alpha and epoetin beta. Clin Nephrol. 1998;49:41-44.

    (19) Yu AW, Leung CB, Li PK, Lui SF, Lai KN. Pain perception following subcutaneous injections of citrate-buffered and phosphate-buffered epoetin alpha. Int J Artif Organs. 1998;21:341-343.

    (20) Frenken LA, van Lier HJ, Jordans JG, et al. Identification of the component part in an epoetin alfa preparation that causes pain after subcutaneous injection. Am J Kidney Dis. 1993;22:553-556.

    (21) Frenken LA, van Lier HJ, Koene RA. Analysis of the efficacy of measures to reduce pain after subcutaneous administration of epoetin alfa. Nephrol Dial Transplant. 1994;9:1295-1298.

    (22) Morris KP, Hughes C, Hardy SP, Matthews JN, Coulthard MG. Pain after subcutaneous injection of recombinant human erythropoietin: does Emla cream help? Nephrol Dial Transplant. 1994;9:1299-1301.

ots Originaltext: Roche Pharmaceuticals
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