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Lining Up to Infuse Excellence Subcutaneous Route for Drugs and Fluids Annette O. Arthur PharmD Department of Emergency Medicine University of Oklahoma School of Community Medicine

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Lining Up to Infuse Excellence Disclosures Co-investigator on a study funded by Halozyme Therapeutics, the manufacturer of the FDA approved human recombinant hyaluronidase (Hylenex). The manufacturer had no control over the study design or reporting content.

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Lining Up to Infuse Excellence Objectives 1.Compare the pharmacokinetics of IV, IM and SC administration of fluids and medications 2.Discuss the emerging methods of SC infusion 3.Discuss proper SC technique

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Lining Up to Infuse Excellence Contents Introduction Pharmacokinetics Therapies Historical uses Emerging uses SC access technique Advantages/Limitations

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Lining Up to Infuse Excellence Intravenous (IV) Intramuscular (IM) Intraosseous (IO) Subcutaneous (SC) Introduction: Parenteral Routes

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Lining Up to Infuse Excellence Introduction: Hypodermoclysis Old term for Subcutaneous (SC) fluid infusion Common in early to mid 1900s Interstitial matrix a barrier to diffusion Adverse events with hypertonic solutions Development of modern IV catheter

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Lining Up to Infuse Excellence Introduction: Skin Structure

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Lining Up to Infuse Excellence Introduction: Extracellular matrix Located in the hypodermis Maintains architecture and controls fluid flow Collagen fibrils and elastin structure Viscoelastic gel fluid flow - Glycosaminoglycans -Hyaluronic Acid Limits SC injection to no more than 2mls Tissue distortion Increases injection pressure

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Lining Up to Infuse Excellence Introduction: Hyaluronidase Found in nature to increase the dispersion of substances (sperm, toxins, venoms, bacteria) Initially derived from bovine testes Use traced back to 1928 Many impurities leading to increased capillary permeability and allergic reactions Human recombinant hyaluronidase HRH FDA approved 2005

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Lining Up to Infuse Excellence Introduction: Hyaluronidase

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Lining Up to Infuse Excellence Introduction: Hyaluronidase HRH Facilitated Drug Therapy 1.Dexamethasone 2.Famotidine 3.Glycopyrrolate 4.Haloperidol 5.Hydromorphone 6.Lidocaine 7.Magnesium 8.Midazolam 9.Ondansetron 10.Potassium 11.Sufentanil

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Lining Up to Infuse Excellence Pharmacokinetics: Terms C max - maximum concentration T max time to maximum concentration t 1/2 elimination half-life AUC Area under the serum concentration-time curve Bioavailability (F) the proportion of drug absorbed into the circulation and available for physiologic action

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Lining Up to Infuse Excellence Pharmacokinetics: IM vs SC Similarity in the absorption and efficacy between IM and SC administration C max AUC T max t 1/2 IM may have variable absorption depending on blood flow and muscle mass IM absorption is unpredictable in infants Insufficient muscle tone Insufficient vascularity

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Lining Up to Infuse Excellence C max Higher IV than SC T max Faster IV than SC AUC IV and SC similar t 1/2 IV and SC similar Bioavailability SC injected meds are generally Pharmacokinetics: IV vs SC

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Lining Up to Infuse Excellence Pharmacokinetics Time (hrs) Concentration (mcg/ml) IV SC

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Lining Up to Infuse Excellence Pharmacokinetics: SC with HRH C max Increased T max Faster AUC Increased Bioavailability Increased Moves SC PKs closer to IV

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Lining Up to Infuse Excellence Pharmacokinetics: SC with HRH

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Lining Up to Infuse Excellence Therapies: Historical uses Pediatric rehydration Palliative care (fluids and pain meds) Deferoxamine Iron chelating agent Haemochromatosis Pts/caregivers start SC access and administer med w/ ambulatory pump over 8-10 hours 5-7 days/wk

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Lining Up to Infuse Excellence Therapies: Emerging mAbs Trastuzumab 1998 FDA approved HER2+ breast cancer, early and metastatic HannaH study, 2012, Ismael et al Wynne et al study, 2013 PrefHer, 2013, Pivot et al Rituximab 2006 FDA approved Targets CD20; indicated for non-Hodgkins lymphoma and chronic lymphocytic leukemia SABRINA study, 2013, Davies et al

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Lining Up to Infuse Excellence Therapies: Emerging ABX Ceftriaxone Third-generation cephalosporin Broad spectrum; gram (-) and gram (+) activity Once daily dosing Typically administered IV or IM IV more costly, inconvenient (hospital or Dr. visit) IM costly, inconvenient, and painful Study published in 2010, Harb et al Safety and PKs of IV & SC SC w/ HRH and without

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Lining Up to Infuse Excellence Therapies: Emerging ABX, cont. Ertapenem Long-acting, parenteral carbapenem Mainly indicated for community/hospital- acquired infections (not Pseudomonas or Acinetobactor) Daily dosing, IM or IV administration Study in France by Frasca, 2010 Compare PKs after 30 min IV & SC infusions SC did not include HRH

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Lining Up to Infuse Excellence Therapies: Emerging IgG 1952 IgG replacement Tx first given 1950s 1970s IgG given by IM injection 1980s IV became the most common route 2006 SC formulation FDA approved 2010 higher concentration SC FDA approved 2013 IgG + HRH in clinical trials SC IM IV SC

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Lining Up to Infuse Excellence Therapies: Emerging IgG cont. IGIV monthly infusions IGSC weekly home infusions, multiple sites IGHy monthly infusions, single site, at home Wasserman study, 2012 IGHy bioequivalent to IGIV Main AE with IGHy local Systemic AE IGIV (25%) > IGHy (8.3%) HA, fatigue, n/v, fever, chills

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Lining Up to Infuse Excellence Therapies: Emerging Pain Mngt Morphine Sulfate Moderate to severe pain Pt controlled analgesia (PCA) SC vs IV INFUSE Morphine study, Thomas et al SC Morphine + Ketoprofen Moselli et al, 2010 Continuous SC MS w/w/o Ketoprofen for cancer pain

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Lining Up to Infuse Excellence Therapies: Emerging Anti-Emetic Ondansetron Selective serotonin-blocking agent IM, IV, PO formulas Approved for n/v Study of SC use in Pregnancy (Klauser, 2011) AEs mild and transient PKs similar to other discussed drugs

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Lining Up to Infuse Excellence Therapies: Emerging Hydration Pediatric ORT is first line treatment for dehydration 15% - 20% unable to perform ORT SC + HRH infusion of fluids safe & effective SC + HRH more cost-effective than IV Adult Most studies were conducted in the 1980s- 1990s Studies in 2005 and 2 in 2007 SC+HRH is safe, well-tolerated, and cost effective

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Lining Up to Infuse Excellence Therapies: Emerging Insulin Hompesch, 2011 Type 1 diabetes mellitus patients Prandial insulins - Lispro & Regular human insulin Peak exposure incd 35% and 66% with HRH Time to peak decd significantly Morrow, 2013 Healthy volunteers HRH + lispro/aspart/glulisine insulins

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Lining Up to Infuse Excellence Therapies: Mass Casualty Events Ease of SC access Minimal training required; no special equipment Adverse conditions in the field Poor lighting, cramped spaces, moving vehicles # Pts > # medical providers MCI injuries often require quick fluids/meds A variety of injuries and illnesses Crush injuries

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Lining Up to Infuse Excellence Case report: Severe Hemorrhage 57-yr old lady, with secondary progressive MS ED weakness, clammy, fever Dx right basal pneumonia Tx IV Abx, fluids, prophylactic LMWH Swallow assessment signs of silent aspiration Oral feedings unable to maintain hydration SC fluid infusion replace fluids Day 30 started bleeding at site Pt died 7 hours later

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Lining Up to Infuse Excellence 1.Choose site, prep skin, pinch 2.Insert IV cath (22-24 g); 45 angle 3.Secure catheter with tape/transparent drsg 4.if using Inject HRH, 150 units/1 ml 5.Attach Standard IV tubing & secure 6.Begin to infuse fluids a/o meds 7.Rate gravity driven 8.Dont be surprised by some soft swelling at the site of the infusion; this is normal Technique: Overview

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Lining Up to Infuse Excellence Technique: Locations

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Lining Up to Infuse Excellence Technique: Skin pinch

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Lining Up to Infuse Excellence Technique: Skin pinch

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Lining Up to Infuse Excellence Technique: Skin pinch, cont.

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Lining Up to Infuse Excellence Technique: Catheter placement

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Lining Up to Infuse Excellence Technique: Catheter placement

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Lining Up to Infuse Excellence Technique: Secure catheter

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Lining Up to Infuse Excellence Advantages: SC vs IV/IM 1.Smaller needle/IV catheter 2.Less pain 3.More sites for injection/infusion 4.Less frequent site change 5.Avoids infusion reactions 6.Systemic infection, less concern 7.Administration at home 8.Less cost

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Lining Up to Infuse Excellence Limitations: SC vs IV/IM 1.Limited volume (1-2mls) 2.Drug trapping 3.Irritants 4.Retention 5.Home administration

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Lining Up to Infuse Excellence Current studies Psoriasis Asthma Osteoporosis Crohns Dz RA Breast Cancer Hodgkins lymphoma CLL Multiple sclerosis Alzheimers Dz Pain management Diabetic kidney Dz Bone healing SLE TTP Etc.

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Lining Up to Infuse Excellence Conclusion Hypodermoclysis has been used for many decades Pharmacokinetics are well understood Bioavailability similar to IV administration HRH co-administration improves PK Uses: fluid resuscitation, mAbs, ABXs, IgG replacement, insulin, pain management, anti-emetics, and MCI Simple technique Advantages/disadvantages

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Lining Up to Infuse Excellence Q UESTIONS ?