Hostname: page-component-78c5997874-fbnjt Total loading time: 0 Render date: 2024-11-19T05:50:47.131Z Has data issue: false hasContentIssue false
  • English
  • Français

Subcutaneous fluid and drug delivery: safe, efficient and inexpensive

Published online by Cambridge University Press:  23 June 2015

Oscar Duems-Noriega  and
Sergio Ariño-Blasco
Oscar Duems-Noriega
Affiliation:
Servicio de Geriatría, Hospital General de Granollers, Granollers, Barcelona, Spain
Sergio Ariño-Blasco*
Affiliation:
Servicio de Geriatría, Hospital General de Granollers, Granollers, Barcelona, Spain
*
Address for correspondence: Dr Sergio Ariño-Blasco, Avda Frances Ribas sn, Granollers 08402, Barcelona, Spain. Email: [email protected]
Get access Rights & Permissions [Opens in a new window]

Summary

Patients with difficult venous access or oral intolerance and clinical situations with inadequate response to oral therapy have generated the need for alternative routes of delivery for drugs and fluids.

The purpose of this study was to conduct a systematic review examining the evidence for subcutaneous (SC) administration of drugs and/or fluids.

We used a broad search strategy using electronic databases CINAHL, EMBASE, PubMed and Cochrane library, key terms and ‘Medical Subject Headings’ (MeSH) such as ‘subcutaneous route’, ‘hypodermoclysis’ and the name/group of the most used drugs via this route (e.g. ‘ketorolac, morphine, ceftriaxone’, ‘analgesics, opioids, antibiotics’).

We conclude that the SC route is an effective alternative for rehydration in patients with mild–moderate dehydration and offers a number of potential advantages in appropriately selected scenarios. Experience of administering drugs by this route suggests that it is well tolerated and is associated with minimal side-effects.

Keywords

hypodermoclysissubcutaneous routealternative routesgeriatric
Type
Review Article
Information
Reviews in Clinical Gerontology , Volume 25 , Issue 2 , May 2015 , pp. 117 - 146
Copyright
Copyright © Cambridge University Press 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

1 Gallardo Avilés R GAF. Uso de la vía subcutánea en cuidados paliativos. Monografías SECPAL 2013; 4: 1–48.Google Scholar
2 Kinnunen, HM, Mrsny, RJ. Improving the outcomes of biopharmaceutical delivery via the subcutaneous route by understanding the chemical, physical and physiological properties of the subcutaneous injection site. J Controlled Release 2014; 182: 22–32.Google Scholar
3 Dychter, SS, Gold, DA, Haller, MF. Subcutaneous drug delivery: a route to increased safety, patient satisfaction, and reduced costs. J Infusion Nursing 2012; 35: 154–60.Google Scholar
4 Uitto, J, Olsen, DR, Fazio, MJ. Extracellular matrix of the skin: 50 years of progress. J Investigative Dermatology 1989; 92 (suppl): 61–77s.Google Scholar
5 Supersaxo, A, Hein, WR, Steffen, H. Effect of molecular weight on the lymphatic absorption of water-soluble compounds following subcutaneous administration. Pharmaceutical Res 1990; 7: 167–69.Google Scholar
6 Richter, WF, Bhansali, SG, Morris, ME. Mechanistic determinants of biotherapeutics absorption following SC administration. AAPS J 2012; 14: 559–70.Google Scholar
7 Schoenbeck, SL, McBride, K. Hypodermoclysis: easy, safe, cost-effective. J Practical Nursing 2010; 60: 7–8.Google Scholar
8 Justad, M. Continuous subcutaneous infusion: an efficacious, cost-effective analgesia alternative at the end of life. Home Healthcare Nurse 2009; 27: 140–47; quiz 8–9.Google Scholar
9 Dugas, R. [Practical advice. Subcutaneous drug administration. An alternative used in palliative care]. Canadian Family Physician 2001; 47: 266–67.Google Scholar
10 Barua, P, Bhowmick, BK. Hypodermoclysis – a victim of historical prejudice. Age Ageing 2005; 34: 215–17.Google Scholar
11 O’Keeffe, S, Geoghegan, M. Subcutaneous hydration in the elderly. Irish Medical J 2000; 93: 197–98.Google Scholar
12 Hussain, NA, Warshaw, G. Utility of clysis for hydration in nursing home residents. J Am Geriatrics Soc 1996; 44: 969–73.Google Scholar
13 Brown, MK, Worobec, F. Hypodermoclysis. Another way to replace fluids. Nursing 2000; 30: 58–59.Google Scholar
14 Slesak, G, Schnurle, JW, Kinzel, E, Jakob, J, Dietz, PK. Comparison of subcutaneous and intravenous rehydration in geriatric patients: a randomized trial. J Am Geriatrics Soc 2003; 51: 155–60.Google Scholar
15 Duems Noriega, O, Arino Blasco, S. [Efficacy of the subcutaneous route compared to intravenous hydration in the elderly hospitalised patient: a randomised controlled study]. Revista espanola de geriatria y gerontologia 2014; 49: 103–7.Google Scholar
16 Dasgupta, M, Binns, MA, Rochon, PA. Subcutaneous fluid infusion in a long-term care setting. J Am Geriatrics Soc 2000; 48: 795–99.Google Scholar
17 Challiner, YC, Jarrett, D, Hayward, MJ, al-Jubouri, MA, Julious, SA. A comparison of intravenous and subcutaneous hydration in elderly acute stroke patients. Postgraduate Medical J 1994; 70: 195–97.Google Scholar
18 Arinzon, Z, Feldman, J, Fidelman, Z, Gepstein, R, Berner, YN. Hypodermoclysis (subcutaneous infusion) effective mode of treatment of dehydration in long-term care patients. Archives Gerontology Geriatrics 2004; 38: 167–73.Google Scholar
19 Lanuke, K, Fainsinger, RL, DeMoissac, D. Hydration management at the end of life. J Palliative Medicine 2004; 7: 257–63.Google Scholar
20.Frisoli Junior, A, de Paula, AP, Feldman, D, Nasri, F. Subcutaneous hydration by hypodermoclysis. A practical and low cost treatment for elderly patients. Drugs Aging 2000; 16: 313–9.Google Scholar
21 Luk, J CF, Chu, L. Is hypodermoclysis suitahie for frail Chinese elderly? Asian J Gerontology Geriatrics 2008; 3: 49–50.Google Scholar
22 Lybarger, EH. Hypodermoclysis in the home and long-term care settings. J Infusion Nursing 2009; 32: 40–44.Google Scholar
23 Turner, T, Cassano, AM. Subcutaneous dextrose for rehydration of elderly patients – an evidence-based review. BMC Geriatrics 2004; 4: 2.Google Scholar
24 Dychter, SS, Ebel, D, Mead, TR, Yocum, RC. Comparison of the tolerability of recombinant human hyaluronidase + normal saline and recombinant human hyaluronidase + lactated Ringer solution administered subcutaneously: a phase IV, double-blind, randomized pilot study in healthy volunteers. Current Therapeutic Res 2009; 70: 421–38.Google Scholar
25 Mace, SE, Harb, G, Friend, K, Turpin, R, Armstrong, EP, Lebel, F. Cost-effectiveness of recombinant human hyaluronidase-facilitated subcutaneous versus intravenous rehydration in children with mild to moderate dehydration. Am J Emergency Med 2013; 31: 928–34.Google Scholar
26 Spandorfer, PR, Mace, SE, Okada, PJ, Simon, HK, Allen, CH, Spiro, DM et al. A randomized clinical trial of recombinant human hyaluronidase-facilitated subcutaneous versus intravenous rehydration in mild to moderately dehydrated children in the emergency department. Clinical Therapeutics 2012; 34: 2232–45.Google Scholar
27 Cockshott, WP, Thompson, GT, Howlett, LJ, Seeley, ET. Intramuscular or intralipomatous injections? New England J Med 1982; 307: 356–58.Google Scholar
28 Pramanick, S, Singodia, D, Chandel, V. Excipient selection in parenteral formulation development. Pharma Times 2013; 45: 65–77.Google Scholar
29 Carpenter, CP, Shaffer, CB. A study of the polyethylene glycols as vehicles for intramuscular and subcutaneous injection. J Pharm Sci 2006; 41: 27–29.Google Scholar
30 Soler Mieras, A, Santaeugenia Gonzalez, S, Montane Esteva, E. [Administration of subcutaneous antibiotics in patients on palliative care]. Medicina clinica 2007; 129: 236–37.Google Scholar
31 Robelet, A, Caruba, T, Corvol, A, Begue, D, Gisselbrecht, M, Saint-Jean, O et al. [Antibiotics given subcutaneously to elderly]. Presse medicale (Paris, France: 1983). 2009; 38: 366–76.Google Scholar
32 Farias Azevedo, E, De Bortoli, S. Administration of antibiotics subcutaneously: an integrative literature review. Acta Paul Enferm 2012; 25: 6.Google Scholar
33 Harb, G, Lebel, F, Battikha, J, Thackara, JW. Safety and pharmacokinetics of subcutaneous ceftriaxone administered with or without recombinant human hyaluronidase (rHuPH20) versus intravenous ceftriaxone administration in adult volunteers. Current Medical Res Opinion 2010; 26: 279–88.Google Scholar
34 Walker, P, Neuhauser, MN, Tam, VH, Willey, JS, Palmer, JL, Bruera, E et al. Subcutaneous administration of cefepime. J Pain Symptom Management 2005; 30: 170–74.Google Scholar
35 Champoux, N, Du Souich, P, Ravaoarinoro, M, Phaneuf, D, Latour, J, Cusson, JR. Single-dose pharmacokinetics of ampicillin and tobramycin administered by hypodermoclysis in young and older healthy volunteers. Br J Clin Pharmacol 1996; 42: 325–31.Google Scholar
36 Barbot, A, Venisse, N, Rayeh, F, Bouquet, S, Debaene, B, Mimoz, O. Pharmacokinetics and pharmacodynamics of sequential intravenous and subcutaneous teicoplanin in critically ill patients without vasopressors. Intensive Care Med 2003; 29: 1528–34.Google Scholar
37 Frasca, D, Marchand, S, Petitpas, F, Dahyot-Fizelier, C, Couet, W, Mimoz, O. Pharmacokinetics of ertapenem following intravenous and subcutaneous infusions in patients. Antimicrobial Agents Chemotherapy 2010; 54: 924–26.Google Scholar
38 Forestier, E, Gros, S, Peynaud, D, Levast, M, Boisseau, D, Ferry-Blanco, C et al. [Ertapenem administered intravenously or subcutaneously for urinary tract infections caused by ESBL producing enterobacteriacea]. Medecine et maladies infectieuses 2012; 42: 440–43.Google Scholar
39 Plantin, P, Mahe, M, Le Noac’h, E, Le Roy, JP. [Cutaneous necroses after subcutaneous injections of amikacin]. Presse medicale (Paris, France: 1983). 1993; 22: 1366.Google Scholar
40 Leng, B, Saux, MC, Latrille, J. [Comparative pharmacokinetics of amikacin after intravenous, intramuscular and subcutaneous administration]. La Nouvelle presse medicale 1979; 8: 3421–25.Google Scholar
41 Duterque, M, Hubert-Asso, AM, Corrard, A. [Necrotic lesions caused by subcutaneous injections of gentamycin and sisomicin]. Annales de dermatologie et de venereologie 1985; 112: 707–8.Google Scholar
42 Penso, D, Delfraissy, JF, Pham Van, T, Dormont, J. [Skin necrosis following administration of subcutaneous gentamicin]. Presse medicale (Paris, France: 1983). 1984; 13: 1575–76.Google Scholar
43 Doutre, MS, Beylot, C, Vendeaud-Busquet, M, Bioulac-Sage, P. [Cutaneous necrosis after subcutaneous administration of gentamycin]. Therapie 1985; 40: 266–67.Google Scholar
44 Courcol, RJ, Pol, A, Dufay, C, Lafitte, C, Martin, GR. Pharmacokinetics of netilmicin administered once or twice-daily by subcutaneous injection. J Antimicrobial Chemotherapy 1986; 18: 646–47.Google Scholar
45 Cree, M, Stacey, S, Graham, N, Wainwright, C. Fosfomycin – investigation of a possible new route of administration of an old drug. A case study. J Cystic Fibrosis 2007; 6: 244–46.Google Scholar
46 Verma, AK, da Silva, JH, Kuhl, DR. Diuretic effects of subcutaneous furosemide in human volunteers: a randomized pilot study. Annals Pharmacotherapy 2004; 38: 544–49.Google Scholar
47 Goenaga, MA, Millet, M, Sanchez, E, Garde, C, Carrera, JA, Arzellus, E. Subcutaneous furosemide. Annals Pharmacotherapy 2004; 38: 1751.Google Scholar
48 Tarabini-Castellani, C. Uso subcutáneo de furosemida en insuficiencia cardíaca terminal. Med Pal 2006; 13: 2.Google Scholar
49 Schein, RJ, Arieli, S. Administration of potassium by subcutaneous infusion in elderly patients. Br Med J 1982; 285: 1167–68.Google Scholar
50 Aries, PM, Schubert, M, Muller-Wieland, D, Krone, W. [Subcutaneous magnesium pump in a patient with combined magnesium transport defect]. Deutsche medizinische Wochenschrift 2000; 125: 970–72.Google Scholar
51 Walker, J, Lane, P, McKenzie, C. Evidence-based practice guidelines: a survey of subcutaneous dexamethasone administration. Int J Palliative Nursing 2010; 16: 494–98.Google Scholar
52 Russell, GM, Durant, C, Ataya, A, Papastathi, C, Bhake, R, Woltersdorf, W et al. Subcutaneous pulsatile glucocorticoid replacement therapy. Clinical Endocrinology 2014; 81: 289–93.Google Scholar
53 Oksnes, M, Bjornsdottir, S, Isaksson, M, Methlie, P, Carlsen, S, Nilsen, RM et al. Continuous subcutaneous hydrocortisone infusion versus oral hydrocortisone replacement for treatment of Addison's disease: a randomized clinical trial. J Clinical Endocrinol Metabolism 2014; 99: 1665–74.Google Scholar
54 Gagliardi, L, Nenke, MA, Thynne, TR, von der Borch, J, Rankin, WA, Henley, DE et al. Continuous subcutaneous hydrocortisone infusion therapy in Addison's disease: a randomized, placebo-controlled clinical trial. J Clinical Endocrinol Metabolism 2014; 99: 4149–57.Google Scholar
55 Lovas, K, Husebye, ES. Continuous subcutaneous hydrocortisone infusion in Addison's disease. European J Endocrinol 2007; 157: 109–12.Google Scholar
56 Hahner, S, Burger-Stritt, S, Allolio, B. Subcutaneous hydrocortisone administration for emergency use in adrenal insufficiency. European J Endocrinol 2013; 169: 147–54.Google Scholar
57 Pecking, M, Montestruc, F, Marquet, P, Wodey, E, Homery, MC, Dostert, P. Absolute bioavailability of midazolam after subcutaneous administration to healthy volunteers. Br J Clinical Pharmacol 2002; 54: 357–62.Google Scholar
58 Gremaud, G, Zulian, GB. Indications and limitations of intravenous and subcutaneous midazolam in a palliative care center. J Pain Symptom Management 1998; 15: 331–33.Google Scholar
59 Greenblatt, DJ, Blaskovich, PD, Nuwayser, ES, Harmatz, JS, Chen, G, Zinny, MA. Clonazepam pharmacokinetics: comparison of subcutaneous microsphere injection with multiple-dose oral administration. J Clinical Pharmacol 2005; 45: 1288–93.Google Scholar
60 Smales, OR, Smales, EA, Sanders, HG. Flunitrazepam in terminal care. J Paediatrics Child Health 1993; 29: 68–69.Google Scholar
61 Tanguy-Goarin, C, Cogulet, V. Drugs administration by subcutaneous injection within palliative care. Therapie 2010; 65: 525–31.Google Scholar
62 Kennett, A, Hardy, J, Shah, S, A’Hern, R. An open study of methotrimeprazine in the management of nausea and vomiting in patients with advanced cancer. Supportive Care in Cancer 2005; 13: 715–21.Google Scholar
63 Eisenchlas, JH, Garrigue, N, Junin, M, De Simone, GG. Low-dose levomepromazine in refractory emesis in advanced cancer patients: an open-label study. Palliative Medicine 2005; 19: 71–75.Google Scholar
64 McCabe, HL, Maraveyas, A. Subcutaneous levomepromazine rescue (SLR) for high grade delayed chemotherapy-induced emesis (DCIE). Anticancer Res 2003; 23: 5209–12.Google Scholar
65 O’Neill, J, Fountain, A. Levomepromazine (methotrimeprazine) and the last 48 hours. Hospital Medicine 1999; 60: 564–67.Google Scholar
66 Elsayem, A, Bush, SH, Munsell, MF, Curry, E 3rd, Calderon, BB, Paraskevopoulos, T et al. Subcutaneous olanzapine for hyperactive or mixed delirium in patients with advanced cancer: a preliminary study. J Pain Symptom Management 2010; 40: 774–82.Google Scholar
67 Lopez-Saca, JM, Vaquero, J, Larumbe, A, Urdiroz, J, Centeno, C. Repeated use of subcutaneous levetiracetam in a palliative care patient. J Pain Symptom Management 2013; 45: e7–8.Google Scholar
68 Remi, C, Lorenzl, S, Vyhnalek, B, Rastorfer, K, Feddersen, B. Continuous subcutaneous use of levetiracetam: a retrospective review of tolerability and clinical effects. J Pain Palliative Care Pharmacotherapy 2014; 28: 371–77.Google Scholar
69 Dosda, R, Marti-Bonmati, L, Ronchera-Oms, CL, Molla, E, Arana, E. Effect of subcutaneous butylscopolamine administration in the reduction of peristaltic artifacts in 1.5-T MR fast abdominal examinations. European Radiology 2003; 13: 294–98.Google Scholar
70De Conno, F, Caraceni, A, Zecca, E, Spoldi, E, Ventafridda, V. Continuous subcutaneous infusion of hyoscine butylbromide reduces secretions in patients with gastrointestinal obstruction. J Pain Symptom Management 1991; 6: 484–86.Google Scholar
71 Kintzel, PE, Chase, SL, Thomas, W, Vancamp, DM, Clements, EA. Anticholinergic medications for managing noisy respirations in adult hospice patients. Am J Health-system Pharmacy 2009; 66: 458–64.Google Scholar
72 Reichmann, JP, Kirkbride, MS. Reviewing the evidence for using continuous subcutaneous metoclopramide and ondansetron to treat nausea and vomiting during pregnancy. Managed Care 2012; 21: 44–47.Google Scholar
73 Klauser, CK, Fox, NS, Istwan, N, Rhea, D, Rebarber, A, Desch, C et al. Treatment of severe nausea and vomiting of pregnancy with subcutaneous medications. Am J Perinatology 2011; 28: 715–21.Google Scholar
74 Sadaba, B, del Barrio, A, Campanero, MA, Azanza, JR, Gomez-Guiu, A, Lopez-Picazo, JM et al. Randomized pharmacokinetic study comparing subcutaneous and intravenous palonosetron in cancer patients treated with platinum based chemotherapy. PloS One 2014; 9: e89747.Google Scholar
75 Gurpide, A, Sadaba, B, Martin-Algarra, S, Azanza, JR, Lopez-Picazo, JM, Campanero, MA et al. Randomized crossover pharmacokinetic evaluation of subcutaneous versus intravenous granisetron in cancer patients treated with platinum-based chemotherapy. The Oncologist 2007; 12: 1151–55.Google Scholar
76 Varma, S, Deakin, J, Claydon, PJ. Subcutaneous cyclizine. Anaesthesia 2001; 56: 919–20.Google Scholar
77 Vella-Brincat, JW, Begg, EJ, Jensen, BP, Chin, PK, Roberts, RL, Fairhall, M et al. The pharmacokinetics and pharmacogenetics of the antiemetic cyclizine in palliative care patients. J Pain Symptom Management 2012; 43: 540–48.Google Scholar
78 Desmidt, T, Constans, T. Subcutaneous infusion of esomeprazole in elderly patients in palliative care: a report of two cases. J Am Geriatrics Soc 2009; 57: 1724–25.Google Scholar
79 Agar, M, Webster, R, Lacey, J, Donovan, B, Walker, A. The use of subcutaneous omeprazole in the treatment of dyspepsia in palliative care patients. J Pain Symptom Management 2004; 28: 529–31.Google Scholar
80 Duncan, AR, Hardy, JR, Davis, CL. Subcutaneous ketorolac. Palliative Medicine 1995; 9: 77–78.Google Scholar
81 Menegaldo, L. [The subcutaneous administration of a NSAID in palliative care]. La Clinica terapeutica 1992; 141: 273–78.Google Scholar
82 Zeitlinger, M, Rusca, A, Oraha, AZ, Gugliotta, B, Muller, M, Ducharme, MP. Pharmacokinetics of a new diclofenac sodium formulation developed for subcutaneous and intramuscular administration. Int J Clin Pharmacol Therapeutics 2012; 50: 383–90.Google Scholar
83 Chiarello, E, Bernasconi, S, Gugliotta, B, Giannini, S. Subcutaneous injection of diclofenac for the treatment of pain following minor orthopedic surgery (DIRECT study): a randomized trial. Pain Practice: the official journal of World Institute of Pain. 2013.Google Scholar
84 Derry, CJ, Derry, S, Moore, RA. Sumatriptan (subcutaneous route of administration) for acute migraine attacks in adults. Cochrane Database Systematic Reviews 2012; 2: Cd009665.Google Scholar
85 Moore, JC, Miner, JR. Subcutaneous delivery of sumatriptan in the treatment of migraine and primary headache. Patient Preference and Adherence 2012; 6: 27–37.Google Scholar
86 Nelson, KA, Glare, PA, Walsh, D, Groh, ES. A prospective, within-patient, crossover study of continuous intravenous and subcutaneous morphine for chronic cancer pain. J Pain Symptom Management 1997; 13: 262–67.Google Scholar
87 Elsner, F, Radbruch, L, Loick, G, Gaertner, J, Sabatowski, R. Intravenous versus subcutaneous morphine titration in patients with persisting exacerbation of cancer pain. J Palliative Medicine 2005; 8: 743–50.Google Scholar
88 Anderson, SL, Shreve, ST. Continuous subcutaneous infusion of opiates at end-of-life. Annals Pharmacotherapy 2004; 38: 1015–23.Google Scholar
89 Hunt, R, Fazekas, B, Thorne, D, Brooksbank, M. A comparison of subcutaneous morphine and fentanyl in hospice cancer patients. J Pain Symptom Management 1999; 18: 111–19.Google Scholar
90 Thomas, JR, Wallace, MS, Yocum, RC, Vaughn, DE, Haller, MF, Flament, J. The INFUSE-Morphine study: use of recombinant human hyaluronidase (rHuPH20) to enhance the absorption of subcutaneously administered morphine in patients with advanced illness. J Pain Symptom Management 2009; 38: 663–72.Google Scholar
91 Walsh, D, Perin, ML, McIver, B. Parenteral morphine prescribing patterns among inpatients with pain from advanced cancer: a prospective survey of intravenous and subcutaneous use. Am J Hospice Palliative Care 2006; 23: 353–59.Google Scholar
92 Stuart-Harris, R, Joel, SP, McDonald, P, Currow, D, Slevin, ML. The pharmacokinetics of morphine and morphine glucuronide metabolites after subcutaneous bolus injection and subcutaneous infusion of morphine. Br J Clin Pharmacol 2000; 49: 207–14.Google Scholar
93 Kestenbaum, MG, Vilches, AO, Messersmith, S, Connor, SR, Fine, PG, Murphy, B et al. Alternative routes to oral opioid administration in palliative care: a review and clinical summary. Pain Medicine 2014; 15: 1129–53.Google Scholar
94 Watanabe, S, Pereira, J, Hanson, J, Bruera, E. Fentanyl by continuous subcutaneous infusion for the management of cancer pain: a retrospective study. J Pain Symptom Management 1998; 16: 323–26.Google Scholar
95 Miller, RS, Peterson, GM, Abbott, F, Maddocks, I, Parker, D, McLean, S. Plasma concentrations of fentanyl with subcutaneous infusion in palliative care patients. Br J Clin Pharmacol 1995; 40: 553–56.Google Scholar
96 Paix, A, Coleman, A, Lees, J, Grigson, J, Brooksbank, M, Thorne, D et al. Subcutaneous fentanyl and sufentanil infusion substitution for morphine intolerance in cancer pain management. Pain 1995; 63: 263–69.Google Scholar
97 Watanabe, S, Pereira, J, Tarumi, Y, Hanson, J, Bruera, E. A randomized double-blind crossover comparison of continuous and intermittent subcutaneous administration of opioid for cancer pain. J Palliative Med 2008; 11: 570–74.Google Scholar
98 Vadivelu, N, Hines, RL. Buprenorphine: a unique opioid with broad clinical applications. J Opioid Management 2007; 3: 49–58.Google Scholar
99 Khajavi, MR, Aghili, SB, Moharari, RS, Najafi, A, Mohtaram, R, Khashayar, P et al. Subcutaneous tramadol infiltration at the wound site versus intravenous administration after pyelolithotomy. Annals Pharmacotherapy 2009; 43: 430–35.Google Scholar
100 Rotshteyn, Y, Boyd, TA, Yuan, CS. Methylnaltrexone bromide: research update of pharmacokinetics following parenteral administration. Expert Opin Drug Metab Toxicol 2011; 7: 227–35.Google Scholar
101 Ladanyi, A, Temkin, SM, Moss, J. Subcutaneous methylnaltrexone to restore postoperative bowel function in a long-term opiate user. Int J Gynecol Cancer 2010; 20: 308–10.Google Scholar
102 Candy, B, Jones, L, Goodman, ML, Drake, R, Tookman, A. Laxatives or methylnaltrexone for the management of constipation in palliative care patients. Cochrane Database Systematic Reviews 2011; (1): Cd003448.Google Scholar
103 Raj, G, Kumar, R, McKinney, WP. Time course of reversal of anticoagulant effect of warfarin by intravenous and subcutaneous phytonadione. Archives Internal Med 1999; 159: 2721–24.Google Scholar
104 Mottice, BL, Soric, MM, Legros, E. Effect of intravenous versus subcutaneous phytonadione on length of stay for patients in need of urgent warfarin reversal. Am J Therapeutics 2014; published ahead of print.Google Scholar
105 Guerci, B, Sauvanet, JP. Subcutaneous insulin: pharmacokinetic variability and glycemic variability. Diabetes Metabolism 2005; 31: 4s7–4s24.Google Scholar
106 Gutniak, MK, Linde, B, Holst, JJ, Efendic, S. Subcutaneous injection of the incretin hormone glucagon-like peptide 1 abolishes postprandial glycemia in NIDDM. Diabetes Care 1994; 17: 1039–44.Google Scholar
107 Young, MA, Wald, JA, Matthews, JE, Scott, R, Hodge, RJ, Zhi, H et al. Clinical pharmacology of albiglutide, a GLP-1 receptor agonist. Postgraduate Med 2014; 126: 84–97.Google Scholar
108 Scott, LJ. Liraglutide: a review of its use in adult patients with type 2 diabetes mellitus. Drugs 2014; 74: 2161–74.Google Scholar
109 Sanford, M. Dulaglutide: first global approval. Drugs 2014; 74: 2097–103.Google Scholar
110 Jodar, E. [Characteristics and types of GLP-1 receptor agonists. An opportunity for individualized therapy]. Medicina clinica 2014; 143 (suppl 2): 12–7.Google Scholar
111 Gerich, J. Pathogenesis and management of postprandial hyperglycemia: role of incretin-based therapies. Int J General Med 2013; 6: 877–95.Google Scholar
112 Clarke, BL, Kay Berg, J, Fox, J, Cyran, JA, Lagast, H. Pharmacokinetics and pharmacodynamics of subcutaneous recombinant parathyroid hormone (1–84) in patients with hypoparathyroidism: an open-label, single-dose, phase I study. Clinical Therapeutics 2014; 36: 722–36.Google Scholar
113 Mystakidou, K, Befon, S, Hondros, K, Kouskouni, E, Vlahos, L. Continuous subcutaneous administration of high-dose salmon calcitonin in bone metastasis: pain control and beta-endorphin plasma levels. J Pain Symptom Management 1999; 18: 323–30.Google Scholar
114 Mercadante, S, Spoldi, E, Caraceni, A, Maddaloni, S, Simonetti, MT. Octreotide in relieving gastrointestinal symptoms due to bowel obstruction. Palliative Medicine 1993; 7: 295–99.Google Scholar
115 Leveque, D. Subcutaneous administration of anticancer agents. Anticancer Res 2014; 34: 1579–86.Google Scholar
116 Migliore, A, Bizzi, E, Bernardi, M, Picchianti Diamanti, A, Lagana, B, Petrella, L. Indirect comparison between subcutaneous biologic agents in ankylosing spondylitis. Clinical Drug Investigation 2014.Google Scholar
117 Torgerson, TR. Overview of routes of IgG administration. J Clin Immunol 2013; 33 (suppl 2): S87–89.Google Scholar
118 Jay, R. Methotrexate revisited: considerations for subcutaneous administration in RA. Clinical Rheumatology 2014.Google Scholar
119 Braun, J, Kastner, P, Flaxenberg, P, Wahrisch, J, Hanke, P, Demary, W et al. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheumatism 2008; 58: 73–81.Google Scholar
120 Gould, MK, Dembitzer, AD, Doyle, RL, Hastie, TJ, Garber, AM. Low-molecular-weight heparins compared with unfractionated heparin for treatment of acute deep venous thrombosis. A meta-analysis of randomized, controlled trials. Annals Internal Med 1999; 130: 800–9.Google Scholar
121 Remi, C, Albrecht, E. Subcutaneous use of baclofen. J Pain Symptom Management 2014; 48: e1–3.Google Scholar
122 Simons, FE, Gu, X, Simons, KJ. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clinical Immunol 2001; 108: 871–73.Google Scholar
123 Simpson, RG. Hyaluronidase in geriatric therapy. The Practitioner 1977; 219: 361–63.Google Scholar
124 Dychter, SS, Harrigan, R, Bahn, JD, Printz, MA, Sugarman, BJ, DeNoia, E et al. Tolerability and pharmacokinetic properties of ondansetron administered subcutaneously with recombinant human hyaluronidase in minipigs and healthy volunteers. Clinical Therapeutics 2014; 36: 211–24.Google Scholar
125 Sandoval, M, Coleman, P, Govani, R, Siddiqui, S, Todd, KH. Pilot study of human recombinant hyaluronidase-enhanced subcutaneous hydration and opioid administration for sickle cell disease acute pain episodes. J Pain Palliative Care Pharmacotherapy 2013; 27: 10–18.Google Scholar
126 Vaughn, DE, Muchmore, DB. Use of recombinant human hyaluronidase to accelerate rapid insulin analogue absorption: experience with subcutaneous injection and continuous infusion. Endocrine Practice 2011; 17: 914–21.Google Scholar
127 Muchmore, DB, Vaughn, DE. Accelerating and improving the consistency of rapid-acting analog insulin absorption and action for both subcutaneous injection and continuous subcutaneous infusion using recombinant human hyaluronidase. J Diabetes Science Technol 2012; 6: 764–72.Google Scholar
128 Frost, GI. Recombinant human hyaluronidase (rHuPH20): an enabling platform for subcutaneous drug and fluid administration. Expert Opinion Drug Delivery 2007; 4: 427–40.Google Scholar
129 Ward, WK, Castle, JR, Branigan, DL, Massoud, RG, El Youssef, J. Discomfort from an alkaline formulation delivered subcutaneously in humans: albumin at pH 7 versus pH 10. Clinical Drug Investigation 2012; 32: 433–38.Google Scholar
130 Laursen, T, Hansen, B, Fisker, S. Pain perception after subcutaneous injections of media containing different buffers. Basic Clinical Pharmacol Toxicol 2006; 98: 218–21.Google Scholar
131 Harbour, R, Miller, J. A new system for grading recommendations in evidence based guidelines. BMJ 2001; 323: 334–36.Google Scholar
132 Borner, K, Lode, H, Hampel, B, Pfeuffer, M, Koeppe, P. Comparative pharmacokinetics of ceftriaxone after subcutaneous and intravenous administration. Chemotherapy 1985; 31: 237–45.Google Scholar
133 Melin-Coviaux, F HL, Hurtel, AS, Andrejak, M, Grumbach, Y. Etude pharmaco-clinique comparative de la ceftriaxone par voie sous-cutanée et intraveineuse chez la personne âgée. Rev gériatr 2000; 25: 10.Google Scholar
134 Bricaire, F, Castaing, JL, Pocidalo, JJ, Vilde, JL. [Pharmacokinetics and tolerance of ceftriaxone after subcutaneous administration]. Pathologie-biologie 1988; 36: 702–5.Google Scholar
135 Gauthier, D, Schambach, S, Crouzet, J, Sirvain, S, Fraisse, T. Subcutaneous and intravenous ceftriaxone administration in patients more than 75 years of age. Medecine et maladies infectieuses 2014; 44: 275–80.Google Scholar
136 Tailandier. Nécroses cutanées induites par la gentamicine sous-cutanée. Presse Med 1984; 13: 2.Google Scholar
137 Doutre. Nécroses cutanées après administration sous-cutanée de gentamicine. Therapie 1985; 40: 2.Google Scholar
138 Farless, LB, Steil, N, Williams, BR, Bailey, FA. Intermittent subcutaneous furosemide: parenteral diuretic rescue for hospice patients with congestive heart failure resistant to oral diuretic. American J Hospice Palliative Care 2013; 30: 791–92.Google Scholar
139 Zacharias, H, Raw, J, Nunn, A, Parsons, S, Johnson, M. Is there a role for subcutaneous furosemide in the community and hospice management of end-stage heart failure? Palliative Medicine 2011; 25: 658–63.Google Scholar
140 Austin, J, Hockey, D, Williams, WR, Hutchison, S. Assessing parenteral diuretic treatment of decompensated heart failure in the community. Br J Community Nursing 2013; 18: 528, 30–34.Google Scholar
141 Zatarain-Nicolas, E, Lopez-Diaz, J, de la Fuente-Galan, L, Garcia-Pardo, H, Recio-Platero, A, San Roman-Calvar, JA. Subcutaneous infusion of furosemide administered by elastomeric pumps for decompensated heart failure treatment: initial experience. Revista espanola de cardiologia (English edn). 2013; 66: 1002–4.Google Scholar
142 Mulvenna, PM, Regnard, CF. Subcutaneous ondansetron. Lancet 1992; 339: 1059.Google Scholar
143 Myers, KG, Trotman, IF. Use of ketorolac by continuous subcutaneous infusion for the control of cancer-related pain. Postgraduate Medical J 1994; 70: 359–62.Google Scholar
144 Mathew, P, Storey, P. Subcutaneous methadone in terminally ill patients: manageable local toxicity. J Pain Symptom Management 1999; 18: 49–52.Google Scholar
145 Centeno, C, Vara, F. Intermittent subcutaneous methadone administration in the management of cancer pain. J Pain Palliative Care Pharmacotherapy 2005; 19: 7–12.Google Scholar
146 Jabalameli, M, Kalantari, F. Evaluation of the analgesic effect of subcutaneous methadone after cesarean section. Advanced Biomedical Res 2014; 3: 197.Google Scholar
147 Porteous, A, Robson, P, Lee, M. End-of-life management of patients who have been established on oral methadone for pain control. J Palliative Medicine 2013; 16: 820.Google Scholar
148 Kawamata, T, Sato, Y, Niiyama, Y, Omote, K, Namiki, A. Pain management after lumbar spinal fusion surgery using continuous subcutaneous infusion of buprenorphine. J Anesthesia 2005; 19: 199–203.Google Scholar
149 Kronenberg, RH. Ketamine as an analgesic: parenteral, oral, rectal, subcutaneous, transdermal and intranasal administration. J Pain Palliative Care Pharmacotherapy 2002; 16: 27–35.Google Scholar
150 Webster, LR, Walker, MJ. Safety and efficacy of prolonged outpatient ketamine infusions for neuropathic pain. Am J Therapeutics 2006; 13: 300–5.Google Scholar
151 Mercadante, S, Lodi, F, Sapio, M, Calligara, M, Serretta, R. Long-term ketamine subcutaneous continuous infusion in neuropathic cancer pain. J Pain Symptom Management 1995; 10: 564–68.Google Scholar
152 Oshima, E, Tei, K, Kayazawa, H, Urabe, N. Continuous subcutaneous injection of ketamine for cancer pain. Canadian J Anaesthesia 1990; 37: 385–86.Google Scholar
153 Thomas, JR, Yocum, RC, Haller, MF, von Gunten, CF. Assessing the role of human recombinant hyaluronidase in gravity-driven subcutaneous hydration: the INFUSE-LR study. J Palliative Medicine 2007; 10: 1312–20.Google Scholar
154 Pirrello, RD, Ting Chen, C, Thomas, SH. Initial experiences with subcutaneous recombinant human hyaluronidase. J Palliative Medicine 2007; 10: 861–64.Google Scholar
155 Allen, CH, Etzwiler, LS, Miller, MK, Maher, G, Mace, S, Hostetler, MA et al. Recombinant human hyaluronidase-enabled subcutaneous pediatric rehydration. Pediatrics 2009; 124: e858–67.Google Scholar
156 Yocum, RC, Kennard, D, Heiner, LS. Assessment and implication of the allergic sensitivity to a single dose of recombinant human hyaluronidase injection: a double-blind, placebo-controlled clinical trial. J Infusion Nursing 2007; 30: 293–99.Google Scholar
157 Thomas, JR, Yocum, RC, Haller, MF, Flament, J. The INFUSE-Morphine IIB study: use of recombinant human hyaluronidase (rHuPH20) to enhance the absorption of subcutaneous morphine in healthy volunteers. J Pain Symptom Management 2009; 38: 673–82.Google Scholar
158 Morrow, L, Muchmore, DB, Hompesch, M, Ludington, EA, Vaughn, DE. Comparative pharmacokinetics and insulin action for three rapid-acting insulin analogs injected subcutaneously with and without hyaluronidase. Diabetes Care 2013; 36: 273–75.Google Scholar
159 Garg, SK, Buse, JB, Skyler, JS, Vaughn, DE, Muchmore, DB. Subcutaneous injection of hyaluronidase with recombinant human insulin compared with insulin lispro in type 1 diabetes. Diabetes Obesity Metab 2014; 16: 1065–69.Google Scholar
160 Wilson, A, Patel, V, Chande, N, Ponich, T, Urquhart, B, Asher, L et al. Pharmacokinetic profiles for oral and subcutaneous methotrexate in patients with Crohn's disease. Alimentary Pharmacol Therapeutics 2013; 37: 340–45.Google Scholar
161 Schiff, MH, Jaffe, JS, Freundlich, B. Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses >/ = 15 mg may be overcome with subcutaneous administration. Annals Rheumatic Diseases 2014; 73: 1549–51./+=+15+mg+may+be+overcome+with+subcutaneous+administration.+Annals+Rheumatic+Diseases+2014;+73:+1549–51.>Google Scholar
162 Demary, W, Schwenke, H, Rockwitz, K, Kastner, P, Liebhaber, A, Schoo, U et al. Subcutaneously administered methotrexate for rheumatoid arthritis, by prefilled syringes versus prefilled pens: patient preference and comparison of the self-injection experience. Patient Preference Adherence 2014; 8: 1061–71.Google Scholar
163 Balis, FM, Mirro, J Jr, Reaman, GH, Evans, WE, McCully, C, Doherty, KM et al. Pharmacokinetics of subcutaneous methotrexate. Journal Clin Oncology 1988; 6: 1882–86.Google Scholar
164 Slevin, ML, Piall, EM, Johnston, A, Levison, DA, Aherne, GW, Tree, SB et al. The pharmacokinetics of subcutaneous bolus cytosine arabinoside in an arachis oil plus aluminium distearate suspension. Investigational New Drugs 1984; 2: 271–76.Google Scholar
165 Slevin, ML, Piall, EM, Aherne, GW, Johnston, A, Sweatman, MC, Lister, TA. The pharmacokinetics of subcutaneous cytosine arabinoside in patients with acute myelogenous leukaemia. Br J Clin Pharmacol 1981; 12: 507–10.Google Scholar
166 Slevin, ML, Piall, EM, Aherne, GW, Johnston, A, Lister, TA. Subcutaneous infusion of cytosine arabinoside. A practical alternative to intravenous infusion. Cancer Chemotherapy Pharmacol 1983; 10: 112–14.Google Scholar
167 Marcucci, G, Silverman, L, Eller, M, Lintz, L, Beach, CL. Bioavailability of azacitidine subcutaneous versus intravenous in patients with the myelodysplastic syndromes. J Clin Pharmacol 2005; 45: 597–602.Google Scholar
168 Juliusson, G, Samuelsson, H. Hairy cell leukemia: epidemiology, pharmacokinetics of cladribine, and long-term follow-up of subcutaneous therapy. Leukemia Lymphoma 2011; 52 (suppl 2): 46–49.Google Scholar
169 Moreau, P, Pylypenko, H, Grosicki, S, Karamanesht, I, Leleu, X, Grishunina, M et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. The Lancet Oncology 2011; 12: 431–40.Google Scholar
170 Moreau, P, Coiteux, V, Hulin, C, Leleu, X, van de Velde, H, Acharya, M et al. Prospective comparison of subcutaneous versus intravenous administration of bortezomib in patients with multiple myeloma. Haematologica 2008; 93: 1908–11.Google Scholar
171 Nemunaitis, J, Mita, A, Stephenson, J, Mita, MM, Sarantopoulos, J, Padmanabhan-Iyer, S et al. Pharmacokinetic study of omacetaxine mepesuccinate administered subcutaneously to patients with advanced solid and hematologic tumors. Cancer Chemotherapy Pharmacol 2013; 71: 35–41.Google Scholar
172 Lundin, J, Kimby, E, Bjorkholm, M, Broliden, PA, Celsing, F, Hjalmar, V et al. Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood 2002; 100: 768–73.Google Scholar
173 Stilgenbauer, S, Zenz, T, Winkler, D, Buhler, A, Schlenk, RF, Groner, S et al. Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncology 2009; 27: 3994–4001.Google Scholar
174 Wynne, C, Harvey, V, Schwabe, C, Waaka, D, McIntyre, C, Bittner, B. Comparison of subcutaneous and intravenous administration of trastuzumab: a phase I/Ib trial in healthy male volunteers and patients with HER2-positive breast cancer. J Clinical Pharmacol 2013.Google Scholar
175 Ismael, G, Hegg, R, Muehlbauer, S, Heinzmann, D, Lum, B, Kim, SB et al. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. The Lancet Oncology 2012; 13: 869–78.Google Scholar
176 Pivot, X, Gligorov, J, Muller, V, Curigliano, G, Knoop, A, Verma, S et al. Patients’ preferences for subcutaneous trastuzumab versus conventional intravenous infusion for the adjuvant treatment of HER2-positive early breast cancer: final analysis of 488 patients in the international, randomized, two-cohort PrefHer study. Annals Oncology 2014; 25: 1979–87.Google Scholar
177 Jackisch, C, Kim, S, Semiglazov, V, Melichar, B, Pivot, X, Hillenbach, C et al. Subcutaneous versus intravenous formulation of trastuzumab for HER2-positive early breast cancer: updated results from the phase III HannaH study. Annals Oncology 2014.Google Scholar