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Identification of the Component Part in an Epoetin Alfa Preparation That Causes Pain After Subcutaneous Injection
Identification of the Component Part in an Epoetin Alfa Preparation That Causes Pain After Subcutaneous Injection LAM. Frenken, MD, H.J.J. van Lier, MSc, J.G.M. Jordans, MD, PhD, K.M.L. Leunissen, MD, PhD, R. van Leusen, MD, PhD, V.M.e. Verstappen, MD, and RAP. Koene, MD, PhD • The subcutaneous administration of epoetin alfa preparations may cause pain at the injection site. To identify the pain-causing substance in these formulations we performed two double-blind, placebo-controlled, randomized order, cross-over studies. Differences in pain experienced after subcutaneous injection of an epoetin alfa solution and its vehicle were assessed in 36 patients. The vehicle and its component parts, albumin and citrate, were compared in 36 volunteers. Normal saline served as a placebo control in both studies. Pain scores were obtained from visual analogue pain scales with no divisions and from five point verbal descriptive pain scales. Both the epoetin alfa solution and its vehicle caused significantly more pain than normal saline (P < 0.0001) in the patients studied. In volunteers the pain scores with the vehicle or its citrate component were significantly higher (P < 0.0001) when compared with normal saline or with the albumin component of the vehicle. In conclusion, the local pain experienced after subcutaneous administration of epoetin alfa preparations is mainly caused by the citrate component of the buffered solution. Epoetin alfa and the albumin component of the preparation do not playa role in this phenomenon. © 1993 by the National Kidney Foundation, Inc. INDEX WORDS: Erythropoietin; subcutaneous administration; pain; citrate.
T
HE TREATMENT of the anemia of chronic renal failure with recombinant human erythropoietin (epoetin) is now well established. Subcutaneous administration of epoetin is convenient and is suitable for self-administration at home. In addition, dose requirements are lower when compared with the intravenous route, even in hemodialysis patients. I Therefore, subcutaneous administration of epoetin is widely accepted as the preferred route. However, local pain at the injection site is a common adverse event,2 sometimes precluding self-administration. 3 Preparations of epoetin alfa cause significantly more pain when compared with preparations containing epoetin beta. 3-6 Epoetin alfa and epoetin beta are recombinant human erythropoietin products from two independent manufacturers, and do not show major differences. Yet, the two drugs differ in their formulation excipients. Epoetin alfa is diluted in an aqueous solution containing sodium chloride, citrate buffer, and human serum albumin. Solutions containing epoetin beta are phosphate buffered, and in most brands polysorbatum 20 is present instead of albumin. We report the results of two studies aimed to determine the substance in epoetin alfa solutions that is responsible for the pain after subcutaneous injection. In the first study, which included chronic renal failure patients, we examined whether epoetin alfa itself plays a major role. The second study included volunteers and examined the component parts separately. Both studies
were designed as a double-blind, randomized, cross-over study. Normal saline served as an inert placebo. PATIENTS AND METHODS
First Study Thirty-six adult chronic renal failure patients in five hemodialysis centers were asked to participate in the study. The patients were all treated with epoetin alfa (Eprex; Cilag NY, Brussels, Belgium), but had never received the drug via the subcutaneous route. The study was designed to examine differences in pain experienced after subcutaneous injection of three different solutions, at a fixed volume of I mL. The three solutions tested were Eprex, Eprex-placebo (both provided by Cilag NY), and saline 0.9% (B. Braun Melsungen AG, Melsungen. Germany). Eprex contained 4,000 U /mL epoetin alfa and 2.5 mg/mL human serum albumin. The buffered solution was composed of sodium chloride, citrate buffer, and water for injection. Eprex-placebo was identical to Eprex, except that it did not contain epoetin alfa. From the Department o/Medicine, Division o/Nephrology, and the Department o/Medical Statistics, University Hospital Nijmegen, Nijmegen, The Netherlands; the Department 0/ Medicine, Nledisch Spectrum Twente. Hospital Enschede. Enschede, The Netherlands; the Department 0/ Medicine, University Hospital Maastricht. Maastricht, The Netherlands; the Department o/Medicine. Hospital Rijnstate. Arnhem, The Netherlands; and the Department 0/ Medicine, St Maartensgasthuis, Venlo. The Netherlands. Received March 19, 1993; accepted in revised form May 18, 1993. Address reprint requests to L.A.M. Frenken, MD, Department 0/ Medicine, University Hospital Nijmegen, Division 0/ Nephrology. Geert Grooteplein8, NL-6525 GA Nijmegen, The Netherlands. © 1993 by the National Kidney Foundation, Inc. 0272-6386/93/2204-0009$3.00/0
American Journal of Kidney Diseases, Vol 22, No 4 (October), 1993: pp 553-556
553
FRENKEN ET AL
554 Table 1. Characteristics of Patients and Volunteers
No. of subjects Median age (yr) (range) Female/male Mean ± SO weight (kg) Median skinfold thickness (mm) (quartiles) Median no. of months on dialysis (quartiles) (n = 35)
Second Study To assess which of the component parts of the Eprex formulation, human serum albumin or citrate buffer, causes pain following subcutaneous injection, a study including 36 healthy volunteers was done. The study was approved by the local hospital ethics committee, and written informed consent was obtained from the participants. Eprex-placebo and saline 0.9% are described in the previous section. A sterile aqueous solution of 2.5 mg/mL human albumin was obtained by diluting Albuminar-25 (Armour Pharmaceutical Company, Kankakee, IL) in normal saline. This brand of albumin is also used in Eprex. Sodium citrate 0.58% and citric acid 0.0057% in sterile water were used as the component parts in tl)e citrate solution, their concentrations being identical to those in Eprex. The osmolality of both the albumin and citrate solution was adjusted with saline to be identical with Eprex-placebo. The solutions were prepared by the hospital pharmacy of the University Hospital Nijmegen. The solutions were allowed to equilibrate at ambient room temperature before being prepared and injected. Standard disposable polypropylene syringes and 0.4 X 12 mm needles were used. A single experienced study nurse gave the injections by standard subcutaneous injection technique. All subjects received 1 mL of each solution subcutaneously alternating in the outer part of the upper arms. The order of the solutions to be injected was randomized, and both the nurse and the study subjects were blinded to their identity. Two pain scales were used by the patients and volunteers to assess the pain after the injection. 7 These included a visual analogue scale (VAS), a 10-cm vertical line without gradations, and a verbal descriptive scale (VDS), five horizontally placed
Patients
Volunteers
36 53.0 (19.0, 81.3) 20/16 60.7 ± 13.4 7 (5,11) 2.5 (1.5, 9.6)
36 28.9 (17.6,53.3) 24/12 70.3 ± 10.3 Not done Not applicable
boxes with adjacent descriptors. The end points of the VAS ranged from "no pain" (0 cm) to "pain as bad as it could be" (10 cm). The categories of the VDS were "no pain," "mild pain," "moderate pain," "severe pain," and "unbearable pain." Following each of the injections, the two pain scales, of which the randomized sequence was blinded for the nurse, were separately marked by the participant as explained to him or her previously. The differences in VAS scores for pain were analyzed with the signed rank test. The proportions of patients and volunteers who replied "no pain" or "mild pain" on the VDS were compared by McNemar's tests. Spearman correlation coefficients were calculated to look for correlations of age, body weight, skinfold thickness, and duration of hemodialysis therapy with pain scores. Differences were considered significant at the 0.05 level.
RESULTS
First Study The main characteristics of the patients are given in Table 1. Thirty-four patients were treated with hemodialysis and regularly received Eprex intravenously. One patient treated with continuous ambulatory peritoneal dialysis and one predialysis patient were new users of Eprex. The pain scores assessed by the VAS are given in Table 2. There was a significant difference in pain scores between injection of saline 0.9% and
Table 2. Pain Scores on the Visual Analogue Scale (Maximum = 10 cm) and Response on the Verbal Descriptive Scale After the Subcutaneous Injection of Eprex, Eprex-Placebo, or Saline 0.9% in Patients Eprex
Visual analogue scale (cm) Median (second and third quartiles) Range Verbal descriptive scale Percentage (no.) with mild or no pain Percentage (no.) with moderate to unbearable pain
2.7 (0.7,4.5) 0.0-8.3 52.8 (19) 47.2 (17)
, P < 0.0001 for difference between saline and Eprex or Eprex-placebo. t P < 0.0001 for difference between saline and Eprex. :j: P < 0.005 for difference between saline and Eprex-placebo.
Eprex-Placebo
2.0 (0.2, 3.9) 0.0-9.0 63.9 (23) 36.1 (13)
Saline 0.9%
0.0 (0.0, 0.7)' 0.0-3.0 94.4 (34)t':j: 5.6 (2)
PAIN AND SUBCUTANEOUS EPOETIN ALFA
555
Eprex or Eprex-placebo. The proportion of patients who marked "mild" or "no pain" on the VDS also was significantly lower with injection of saline 0.9% (see Table 2). There was no difference between Eprex and Eprex-placebo. Within each group of solutions there was no relationship between pain experienced and age, sex, body weight, skin fold thickness at the injection site, or duration of dialysis or epoetin alfa therapy. In some patients (n = 3) an immediate erythema at the location of the injection of Eprexplacebo (n = 2) or Eprex (n = 2) was observed. The sharply demarcated erythema had a diameter of 1 to 2 cm and was irregular in shape. The erythema did not disappear during the observation period of 4 hours. The pain that was felt with Eprex or Eprex-placebo was described by most patients as burning or itching and was different from the pain occasionally felt after the injection of saline. In most patients the pain had disappeared after 10 to 15 minutes. One patient who reported to have ingested 250 mg naproxen before the study and another patient receiving regular 5 mg/d prednisone therapy did not differ in their pain scores when compared with the other patients.
Second Study The characteristics of the 36 healthy volunteers are given in Table 1. The pain scores assessed by the VAS after injection of Eprex-placebo or after injection of the citrate solution were significantly higher when compared with injection of the albumin solution or of normal saline (Table 3). Similar results were obtained by the VDS with regard to the proportion of volunteers scoring "moderate" to "unbearable" pain (see Table 3).
There was no difference in pain scores between Eprex-placebo and the citrate solution, nor between the albumin solution and normal saline. DISCUSSION
Differences in pain sensation after subcutaneous injection between epoetin alfa and epoetin beta preparations suggested that the inactive ingredients of the epoetin alfa formulation are involved in this phenomenon. 3-6 The results of our first study show that the epoetin alfa formulation and its vehicle cause significantly more pain than the relatively inert saline solution. The observed percentage pain scores are similar to those found in other studies. 3 ,4 In addition, the results do not suggest that epoetin alfa itself contributes highly to the degree of pain after subcutaneous injection of its solvent. The second study, in which the inactive ingredients of the preparation were directly compared, demonstrates a similar distribution of pain scores for the epoetin alfa vehicle and the citrate solution. The injection of the solution containing albumin, which was of the same brand as used in Eprex, did not cause more pain than the injection of normal saline. The observed differences substantiate that local pain after subcutaneous injection of epoetin alfa solutions is mainly caused by the citrate buffer contained in the vehicle. There are no reports on the effects of longterm subcutaneous administration of preparations containing citrate buffers. The erythematous reaction seen in some patients suggests that the injection of epoetin alfa may cause a local vasodilation or inflammatory response. It is not known how these reactions influence the pharmacokinetic profile of subcutaneous epoetin alfa.
Table 3. Pain Scores on the Visual Analogue Scale (Maximum = 10 cm) and Response on the Verbal Descriptive Scale After the Subcutaneous Injection of Eprex-Placebo, Citrate Solution, Albumin Solution, or Saline 0.9% in Volunteers Eprex-Placebo
Visual analogue scale (cm) Median (second and third quartiles) Range Verbal descriptive scale Percentage (no.) with mild or no pain Percentage (no.) with moderate to unbearable pain *P
4.8 (2.1, 6.4) 0.3-9.0 25.0 (9) 75.0 (27)
Citrate
4.2 (2.3, 7.3) 0.2-9.4 22.2 (8) 77.8 (28)
< 0.0001 for difference between Eprex-placebo or citrate and albumin or saline.
Albumin
0.6 (0.0, 1.8)* 0.0-7.5 80.6 (29)* 19.4 (7)
Saline
0.7 (0.2, 2.9)* 0.0-6.6 83.3 (30)* 16.7 (6)
FRENKEN ET AL
556
In addition, it raises the question of chronic inflammatory changes at the injection sites after long-term use. However, it is reassuring in this regard that the current widespread experience with subcutaneous Eprex has not revealed harmful effects. Currently only single-use vials of epoetin are available, which mostly have a volume of I mL. Due to the cost of epoetin, dosing regimens often are based on the prescription of whole vials. Therefore, in our studies a standard injection volume of I mL was used. Vials with different concentrations of epoetin alfa all contain the same concentration of inactive ingredients. It is possible that the degree of pain is related to the amount of citrate buffer injected. If so, the pain problem might be reduced by using the currently available l-mL vials with high concentrations of epoetin alfa, allowing for the injection of volumes of 0.1 to 0.2 mL. However, to keep such a therapy practical and cost-effective the development of multiple-dose vials or low-volume single-use vials of higher concentrations is required. ACKNOWLEDGMENT We thank the patients and the nursing staff in the participating hemodialysis centers for their cooperation, and C. Pans for her skilful assistance. J. Schindler from the R.W. Johnson Pharmaceutical Research Institute, Bassersdorf, Switzerland,
and F. Deckers from Cilag Benelux NV, Brussels, Belgium, are acknowledged for providing the epoetin alfa preparation and its component parts. E. Wuis, pharmacist at the Department of Clinical Pharmacy of the University Hospital Nijmegen, arranged the preparation of the solutions tested.
REFERENCES 1. Bommer J, Samtleben W, Koch KM, Baldamus CA, Griitzmacher P, Scigalla P: Variations of recombinant human erythropoietin application in hemodialysis patients. Contrib Nephrol 76:149-158, 1989 2. Piraino B, Johnston JR: The use of subcutaneous erythropoietin in CAPO patients. Clin Nephrol 33:200-202, 1990 3. Frenken LAM, van Lier HJ, Gerlag PGG, den Hartog M, Koene RAP: Assessment of pain after subcutaneous injection of erythropoietin in patients receiving hemodialysis. BMJ 303:288, 1991 4. Granolleras C, LeskopfW, Sha1don S, Fourcade J: Experience of pain after subcutaneous administration of different preparations of recombinant human erythropoietin: A randomized, double-blind crossover study. Clin Nephrol 36:294298, 1991 5. Hendriks MW, Peters FP, Hooymans PM, Van de Wiel TW, Janknegt 0, Janknegt R, Lohman JJ: Is Recormon less painful than Eprex after subcutaneous administration? Pharm Weekbl [Sci] 14:55-58, 1992 6. Veys N, Van holder 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 12:68-72, 1992 7. Machin 0, Lewith GT, Wylson S: Pain measurement in randomized clinical trials. A comparison of two pain scales. Clin J Pain 4:161-168.1988
T
HE TREATMENT of the anemia of chronic renal failure with recombinant human erythropoietin (epoetin) is now well established. Subcutaneous administration of epoetin is convenient and is suitable for self-administration at home. In addition, dose requirements are lower when compared with the intravenous route, even in hemodialysis patients. I Therefore, subcutaneous administration of epoetin is widely accepted as the preferred route. However, local pain at the injection site is a common adverse event,2 sometimes precluding self-administration. 3 Preparations of epoetin alfa cause significantly more pain when compared with preparations containing epoetin beta. 3-6 Epoetin alfa and epoetin beta are recombinant human erythropoietin products from two independent manufacturers, and do not show major differences. Yet, the two drugs differ in their formulation excipients. Epoetin alfa is diluted in an aqueous solution containing sodium chloride, citrate buffer, and human serum albumin. Solutions containing epoetin beta are phosphate buffered, and in most brands polysorbatum 20 is present instead of albumin. We report the results of two studies aimed to determine the substance in epoetin alfa solutions that is responsible for the pain after subcutaneous injection. In the first study, which included chronic renal failure patients, we examined whether epoetin alfa itself plays a major role. The second study included volunteers and examined the component parts separately. Both studies
were designed as a double-blind, randomized, cross-over study. Normal saline served as an inert placebo. PATIENTS AND METHODS
First Study Thirty-six adult chronic renal failure patients in five hemodialysis centers were asked to participate in the study. The patients were all treated with epoetin alfa (Eprex; Cilag NY, Brussels, Belgium), but had never received the drug via the subcutaneous route. The study was designed to examine differences in pain experienced after subcutaneous injection of three different solutions, at a fixed volume of I mL. The three solutions tested were Eprex, Eprex-placebo (both provided by Cilag NY), and saline 0.9% (B. Braun Melsungen AG, Melsungen. Germany). Eprex contained 4,000 U /mL epoetin alfa and 2.5 mg/mL human serum albumin. The buffered solution was composed of sodium chloride, citrate buffer, and water for injection. Eprex-placebo was identical to Eprex, except that it did not contain epoetin alfa. From the Department o/Medicine, Division o/Nephrology, and the Department o/Medical Statistics, University Hospital Nijmegen, Nijmegen, The Netherlands; the Department 0/ Medicine, Nledisch Spectrum Twente. Hospital Enschede. Enschede, The Netherlands; the Department 0/ Medicine, University Hospital Maastricht. Maastricht, The Netherlands; the Department o/Medicine. Hospital Rijnstate. Arnhem, The Netherlands; and the Department 0/ Medicine, St Maartensgasthuis, Venlo. The Netherlands. Received March 19, 1993; accepted in revised form May 18, 1993. Address reprint requests to L.A.M. Frenken, MD, Department 0/ Medicine, University Hospital Nijmegen, Division 0/ Nephrology. Geert Grooteplein8, NL-6525 GA Nijmegen, The Netherlands. © 1993 by the National Kidney Foundation, Inc. 0272-6386/93/2204-0009$3.00/0
American Journal of Kidney Diseases, Vol 22, No 4 (October), 1993: pp 553-556
553
FRENKEN ET AL
554 Table 1. Characteristics of Patients and Volunteers
No. of subjects Median age (yr) (range) Female/male Mean ± SO weight (kg) Median skinfold thickness (mm) (quartiles) Median no. of months on dialysis (quartiles) (n = 35)
Second Study To assess which of the component parts of the Eprex formulation, human serum albumin or citrate buffer, causes pain following subcutaneous injection, a study including 36 healthy volunteers was done. The study was approved by the local hospital ethics committee, and written informed consent was obtained from the participants. Eprex-placebo and saline 0.9% are described in the previous section. A sterile aqueous solution of 2.5 mg/mL human albumin was obtained by diluting Albuminar-25 (Armour Pharmaceutical Company, Kankakee, IL) in normal saline. This brand of albumin is also used in Eprex. Sodium citrate 0.58% and citric acid 0.0057% in sterile water were used as the component parts in tl)e citrate solution, their concentrations being identical to those in Eprex. The osmolality of both the albumin and citrate solution was adjusted with saline to be identical with Eprex-placebo. The solutions were prepared by the hospital pharmacy of the University Hospital Nijmegen. The solutions were allowed to equilibrate at ambient room temperature before being prepared and injected. Standard disposable polypropylene syringes and 0.4 X 12 mm needles were used. A single experienced study nurse gave the injections by standard subcutaneous injection technique. All subjects received 1 mL of each solution subcutaneously alternating in the outer part of the upper arms. The order of the solutions to be injected was randomized, and both the nurse and the study subjects were blinded to their identity. Two pain scales were used by the patients and volunteers to assess the pain after the injection. 7 These included a visual analogue scale (VAS), a 10-cm vertical line without gradations, and a verbal descriptive scale (VDS), five horizontally placed
Patients
Volunteers
36 53.0 (19.0, 81.3) 20/16 60.7 ± 13.4 7 (5,11) 2.5 (1.5, 9.6)
36 28.9 (17.6,53.3) 24/12 70.3 ± 10.3 Not done Not applicable
boxes with adjacent descriptors. The end points of the VAS ranged from "no pain" (0 cm) to "pain as bad as it could be" (10 cm). The categories of the VDS were "no pain," "mild pain," "moderate pain," "severe pain," and "unbearable pain." Following each of the injections, the two pain scales, of which the randomized sequence was blinded for the nurse, were separately marked by the participant as explained to him or her previously. The differences in VAS scores for pain were analyzed with the signed rank test. The proportions of patients and volunteers who replied "no pain" or "mild pain" on the VDS were compared by McNemar's tests. Spearman correlation coefficients were calculated to look for correlations of age, body weight, skinfold thickness, and duration of hemodialysis therapy with pain scores. Differences were considered significant at the 0.05 level.
RESULTS
First Study The main characteristics of the patients are given in Table 1. Thirty-four patients were treated with hemodialysis and regularly received Eprex intravenously. One patient treated with continuous ambulatory peritoneal dialysis and one predialysis patient were new users of Eprex. The pain scores assessed by the VAS are given in Table 2. There was a significant difference in pain scores between injection of saline 0.9% and
Table 2. Pain Scores on the Visual Analogue Scale (Maximum = 10 cm) and Response on the Verbal Descriptive Scale After the Subcutaneous Injection of Eprex, Eprex-Placebo, or Saline 0.9% in Patients Eprex
Visual analogue scale (cm) Median (second and third quartiles) Range Verbal descriptive scale Percentage (no.) with mild or no pain Percentage (no.) with moderate to unbearable pain
2.7 (0.7,4.5) 0.0-8.3 52.8 (19) 47.2 (17)
, P < 0.0001 for difference between saline and Eprex or Eprex-placebo. t P < 0.0001 for difference between saline and Eprex. :j: P < 0.005 for difference between saline and Eprex-placebo.
Eprex-Placebo
2.0 (0.2, 3.9) 0.0-9.0 63.9 (23) 36.1 (13)
Saline 0.9%
0.0 (0.0, 0.7)' 0.0-3.0 94.4 (34)t':j: 5.6 (2)
PAIN AND SUBCUTANEOUS EPOETIN ALFA
555
Eprex or Eprex-placebo. The proportion of patients who marked "mild" or "no pain" on the VDS also was significantly lower with injection of saline 0.9% (see Table 2). There was no difference between Eprex and Eprex-placebo. Within each group of solutions there was no relationship between pain experienced and age, sex, body weight, skin fold thickness at the injection site, or duration of dialysis or epoetin alfa therapy. In some patients (n = 3) an immediate erythema at the location of the injection of Eprexplacebo (n = 2) or Eprex (n = 2) was observed. The sharply demarcated erythema had a diameter of 1 to 2 cm and was irregular in shape. The erythema did not disappear during the observation period of 4 hours. The pain that was felt with Eprex or Eprex-placebo was described by most patients as burning or itching and was different from the pain occasionally felt after the injection of saline. In most patients the pain had disappeared after 10 to 15 minutes. One patient who reported to have ingested 250 mg naproxen before the study and another patient receiving regular 5 mg/d prednisone therapy did not differ in their pain scores when compared with the other patients.
Second Study The characteristics of the 36 healthy volunteers are given in Table 1. The pain scores assessed by the VAS after injection of Eprex-placebo or after injection of the citrate solution were significantly higher when compared with injection of the albumin solution or of normal saline (Table 3). Similar results were obtained by the VDS with regard to the proportion of volunteers scoring "moderate" to "unbearable" pain (see Table 3).
There was no difference in pain scores between Eprex-placebo and the citrate solution, nor between the albumin solution and normal saline. DISCUSSION
Differences in pain sensation after subcutaneous injection between epoetin alfa and epoetin beta preparations suggested that the inactive ingredients of the epoetin alfa formulation are involved in this phenomenon. 3-6 The results of our first study show that the epoetin alfa formulation and its vehicle cause significantly more pain than the relatively inert saline solution. The observed percentage pain scores are similar to those found in other studies. 3 ,4 In addition, the results do not suggest that epoetin alfa itself contributes highly to the degree of pain after subcutaneous injection of its solvent. The second study, in which the inactive ingredients of the preparation were directly compared, demonstrates a similar distribution of pain scores for the epoetin alfa vehicle and the citrate solution. The injection of the solution containing albumin, which was of the same brand as used in Eprex, did not cause more pain than the injection of normal saline. The observed differences substantiate that local pain after subcutaneous injection of epoetin alfa solutions is mainly caused by the citrate buffer contained in the vehicle. There are no reports on the effects of longterm subcutaneous administration of preparations containing citrate buffers. The erythematous reaction seen in some patients suggests that the injection of epoetin alfa may cause a local vasodilation or inflammatory response. It is not known how these reactions influence the pharmacokinetic profile of subcutaneous epoetin alfa.
Table 3. Pain Scores on the Visual Analogue Scale (Maximum = 10 cm) and Response on the Verbal Descriptive Scale After the Subcutaneous Injection of Eprex-Placebo, Citrate Solution, Albumin Solution, or Saline 0.9% in Volunteers Eprex-Placebo
Visual analogue scale (cm) Median (second and third quartiles) Range Verbal descriptive scale Percentage (no.) with mild or no pain Percentage (no.) with moderate to unbearable pain *P
4.8 (2.1, 6.4) 0.3-9.0 25.0 (9) 75.0 (27)
Citrate
4.2 (2.3, 7.3) 0.2-9.4 22.2 (8) 77.8 (28)
< 0.0001 for difference between Eprex-placebo or citrate and albumin or saline.
Albumin
0.6 (0.0, 1.8)* 0.0-7.5 80.6 (29)* 19.4 (7)
Saline
0.7 (0.2, 2.9)* 0.0-6.6 83.3 (30)* 16.7 (6)
FRENKEN ET AL
556
In addition, it raises the question of chronic inflammatory changes at the injection sites after long-term use. However, it is reassuring in this regard that the current widespread experience with subcutaneous Eprex has not revealed harmful effects. Currently only single-use vials of epoetin are available, which mostly have a volume of I mL. Due to the cost of epoetin, dosing regimens often are based on the prescription of whole vials. Therefore, in our studies a standard injection volume of I mL was used. Vials with different concentrations of epoetin alfa all contain the same concentration of inactive ingredients. It is possible that the degree of pain is related to the amount of citrate buffer injected. If so, the pain problem might be reduced by using the currently available l-mL vials with high concentrations of epoetin alfa, allowing for the injection of volumes of 0.1 to 0.2 mL. However, to keep such a therapy practical and cost-effective the development of multiple-dose vials or low-volume single-use vials of higher concentrations is required. ACKNOWLEDGMENT We thank the patients and the nursing staff in the participating hemodialysis centers for their cooperation, and C. Pans for her skilful assistance. J. Schindler from the R.W. Johnson Pharmaceutical Research Institute, Bassersdorf, Switzerland,
and F. Deckers from Cilag Benelux NV, Brussels, Belgium, are acknowledged for providing the epoetin alfa preparation and its component parts. E. Wuis, pharmacist at the Department of Clinical Pharmacy of the University Hospital Nijmegen, arranged the preparation of the solutions tested.
REFERENCES 1. Bommer J, Samtleben W, Koch KM, Baldamus CA, Griitzmacher P, Scigalla P: Variations of recombinant human erythropoietin application in hemodialysis patients. Contrib Nephrol 76:149-158, 1989 2. Piraino B, Johnston JR: The use of subcutaneous erythropoietin in CAPO patients. Clin Nephrol 33:200-202, 1990 3. Frenken LAM, van Lier HJ, Gerlag PGG, den Hartog M, Koene RAP: Assessment of pain after subcutaneous injection of erythropoietin in patients receiving hemodialysis. BMJ 303:288, 1991 4. Granolleras C, LeskopfW, Sha1don S, Fourcade J: Experience of pain after subcutaneous administration of different preparations of recombinant human erythropoietin: A randomized, double-blind crossover study. Clin Nephrol 36:294298, 1991 5. Hendriks MW, Peters FP, Hooymans PM, Van de Wiel TW, Janknegt 0, Janknegt R, Lohman JJ: Is Recormon less painful than Eprex after subcutaneous administration? Pharm Weekbl [Sci] 14:55-58, 1992 6. Veys N, Van holder 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 12:68-72, 1992 7. Machin 0, Lewith GT, Wylson S: Pain measurement in randomized clinical trials. A comparison of two pain scales. Clin J Pain 4:161-168.1988