Identification of the Component Part in an Epoetin Alfa Preparation That Causes Pain After Subcutaneous Injection

Frenken, L.A.M.; Lier, H. J. J. Van; Jordans, J.G.M.; Leunissen, Karel M.L.; Leusen, R. van; Verstappen, V.M.C.; Koene, R. A. P.

doi:10.1016/s0272-6386(12)80928-0

Cited by 46 publications

(20 citation statements)

References 5 publications

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“…43,53,54,58,80,81,86,111,114,117,118,123 If the drug itself is found to be responsible for the pain on injection or tissue damage, the formulator could use a prodrug or salt form; 70,102,120 formulate the drug as a suspension or emulsion rather than as a solution; 43,56,[59][60][61][62]75,85,125 encapsulate the drug in some type of biocompatible/biodegradable carrier such as liposomes, 133 microspheres, 134 or mixed micelles; 63 or develop other novel drug complexes. Formulation changes can also involve modifications in the type of buffer, cosolvents, or other excipients used in the product 70,102,106,125 or altering the final pH of the product. [68][69][70]102 If necessary, the drug product labeling may include a recommendation that a specific vehicle or local anesthetic or other protective agent be administered concurrently with the drug.…”

Section: Methods To Reduce or Eliminate Pain On Injectionmentioning

confidence: 99%

“…Buffers, cosolvents, antimicrobial preservatives, and chelating agents may, in some cases, be associated with injection site pain. 106,130,131 Final formulation factors such as pH, osmolarity, tonicity, solution temperature, drug concentration, and injection volume may be associated with pain upon injection. For peptides, it has been suggested that aggregation of proteins and particulates in general may contribute to pain.…”

Section: Drug and Formulation Factors Associated With Pain On Injectionmentioning

confidence: 99%

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Current Perspectives on Pain upon Injection of Drugs

Brazeau

Cooper

Svetic

et al. 1998

Journal of Pharmaceutical Sciences

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A limitation in the administration of parenteral products is the pain caused upon injection. Injection site pain has been predominately associated with intravenous, intramuscular, and subcutaneous administration. It becomes important for the formulation scientist to have a basic understanding of the physiology underlying the pain process, as well as the pharmaceutical factors associated with injection site pain. Initially, this review will provide the reader with a primer on the mediation of pain in the periphery and a compilation of those drugs that have been associated with pain on injection. In addition, this review will present important considerations and general formulation approaches or methods that have been used to overcome pain on injection. Finally, a brief overview of the various experimental systems used to investigate injection site pain is discussed.

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Section: Methods To Reduce or Eliminate Pain On Injectionmentioning

confidence: 99%

Section: Drug and Formulation Factors Associated With Pain On Injectionmentioning

confidence: 99%

Current Perspectives on Pain upon Injection of Drugs

Brazeau

Cooper

Svetic

et al. 1998

Journal of Pharmaceutical Sciences

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“…Pre-treatment with ice or a local anaesthetic cream (EMLA cream, Astra, Ontario, Canada) was not helpful. Not all preparations of rhEPO are painful, and recent studies [5] suggest that the pain is due to the citrate base used in Epoeitin Alpha Products -Epogen (Amgen, Calif., USA), Procrit (Ortho Pharm, N.J., USA), Eprex (Ortho Biotec, Ontario, Canada) or Eprex (Cilag, Switzerland). Less painful preparations such as Epogin (Chugai, Japan) and Recormon (Boehringer Mannheim, Germany) are used in Asia and Europe.…”

Section: Discussionmentioning

confidence: 99%

Intraperitoneal erythropoietin treatment of children with chronic renal failure

Steele

Vigneux

1995

Pediatr Nephrol

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Intraperitoneal erythropoietin was given to three children on chronic peritoneal dialysis. Doses between 100 and 150 units/kg were given undiluted into a dry cavity twice weekly and left for 10-12 h before resuming dialysis. Satisfactory haemoglobin levels were seen over a 6-month period and there were no complications. Intraperitoneal administration of erythropoietin is cost-effective and avoids the local pain of subcutaneous injections.

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“…Parenteral formulations using these buffers and other excipients have the potential to cause damage and/or pain following injection. Citrate buffer has been reported to cause significantly more pain than 0.9% NaCl injection after subcutaneous administration in patients (4). Furthermore, the degree of pain was related to the injected concentration of citrate buffer.…”

Section: Introductionmentioning

confidence: 94%

Assessment of the Myotoxicity of Pharmaceutical Buffers Using an In Vitro Muscle Model: Effect of pH, Capacity, Tonicity, and Buffer Type

Napaporn

Thomas

Svetic

et al. 2000

Pharmaceutical Development and Technology

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The purpose of the present study was to investigate the myotoxicity of three buffers containing carboxylic acid groups (i.e., acetate, succinate, and citrate) as a function of their pH, capacity, and tonicity. The myotoxicity of these buffers in the range of pH 2-6 and 0.001-0.1 M buffer capacity was assessed using cumulative creatine kinase (CK) release from an isolated rodent muscle model following injection. Phenytoin and 0.9% NaCl injection were used as positive and negative controls, respectively. Buffer solutions were prepared. A lower pH and higher buffer capacity was linked to increased myotoxicity for the acetate buffers. However, for succinate and citrate buffers, pH appeared to influence the extent of myotoxicity, whereas buffer capacity did not seem to have an effect. When either NaCl or trehalose was used as a tonicity-adjusting agent at pH 6, isotonic 0.01 M buffer solutions dramatically lowered the cumulative CK release compared to those that were not isotonic. Isotonic succinate buffers displayed the lowest myotoxicity, whereas citrate buffers displayed the highest values. Citrate buffers containing three carboxylic acid groups showed higher myotoxicity than succinate buffers and acetate buffers at 0.001 and 0.01 M buffer capacities, whereas acetate buffer produced higher cumulative CK release than citrate and succinate buffers at 0.1 M buffer capacity. The myotoxicity of pharmaceutical buffers containing carboxylic acid groups appears to be directly affected by lowering the pH of the solution.

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Identification of the Component Part in an Epoetin Alfa Preparation That Causes Pain After Subcutaneous Injection

Cited by 46 publications

References 5 publications

Current Perspectives on Pain upon Injection of Drugs

Current Perspectives on Pain upon Injection of Drugs

Intraperitoneal erythropoietin treatment of children with chronic renal failure

Assessment of the Myotoxicity of Pharmaceutical Buffers Using an In Vitro Muscle Model: Effect of pH, Capacity, Tonicity, and Buffer Type

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