6/21/2013 Disclosures � United Therapeutics, Speaker’s Bureau Daniela Brady, RN Research Nurse Clinician Pulmonary Hypertension Center Columbia University Medical Center PGI2: Mechanism of Action Prostacyclin pathway Prostacyclin (PGI2) Arachidonic acid Prostaglandin I 2 � Naturally occuring prostaglandin metabolite of arachidonic Prostacyclin acid (PGI2) derivatives Prostacyclin (PGI 2 ) + � Continuously produced by the vascular endothelium by cAMP prostacyclin synthase Vasodilation and � A relative deficiency of prostacyclin may contribute to the antiproliferation Pulmonary pathogenesis of PAH artery in Smooth muscle cells patient with PAH PGI2 and its derivatives have potent vasodilatory, antiproliferative and antithrombotic effects on vascular smooth muscle cells. 1
6/21/2013 Prostanoids Main Properties of Prostacyclin � Developed to mimic the favorable characteristics of � Systemic and pulmonary vasodilation via relaxation of vascular prostacyclin (PGI2) but offer alternate modes of smooth muscle cells delivery � Inhibition of platelet aggregation � Longer half-life or other features (e.g. thermostability) to improve risk-benefit ratio and/or � Inhibition of vascular cell migration and proliferation quality of life issues associated with epoprostenol delivery � Cytoprotective effect: prevention of ischemic cell injury � Improvement in pulmonary clearance of endothelin-1 � Possible inotropic effect Epoprostenol vs. Conventional Therapy Change from Baseline in 6-Minute Walk Test Intravenous Epoprostenol (PGI2) 80 � Rapidly hydrolyzed in circulation (t 1 / 2 = 3 min) 60 � Unstable at room temperature – requires ice packs 40 � thermo-stable formulation FDA approved; not tested in children Meters 20 � Many potential side effects 0 � Requires continuous IV infusion for sustained effect � PGI2 was first used as an acute vasodilator in 1980 in -20 a child with IPAH -40 Week 1 Weeks 8 and 12 (Mean) -60 Epoprostenol (11; 41) Conventional Therapy (14; 40) FDA approved 1995; FC III/IV PAH Rubin, et al. Ann Intern Med, 1990; Barst, et al. NEJM, 1996 2
6/21/2013 Pediatric PAH Survival and Treatment Epoprostenol and Survival in Children success in “Epo Era” K-M survival curves comparing survival of nonresponders (n=24) treated with long-term PGI2 with survival of nonresponders (n=22) for whom PGI2 was Kaplan-Meier curves for survival and treatment success in patients in more recent medical era (n=44) indicated but unavailable Yung, D. et al. Circulation 2004;110:660-665 Barst, RJ. et al. Circulation 1999 Epoprostenol delivery system IV/SQ Prostanoid Side Effects (CADD pump) � Flushing � Hypotension � Headache � Dizziness � Diarrhea � Syncope � Nausea/emesis � Delivery complications � Jaw pain � Site pain � Leg pain � Site reaction Vary according to drug and route of delivery Epoprostenol (Flolan) Epoprostenol –thermostable (Veletri) 3
6/21/2013 Epoprostenol Delivery System Epoprostenol Complications � Prostacyclin is effective in treating group 1 PAH � improve pulmonary hemodynamics � Local site infection � prolong survival � Catheter related bloodstream infections � improve symptoms � CADD pump malfunction � extend exercise tolerance � bolus effect � Caution � cessation phenomenon – due to short half life � numerous side effects of epoprostenol � inconvenience and risks with continuous infusion Pediatric PAH Indications for IV Treprostinil (remodulin) epoprostenol: general guidelines � Longer acting prostacyclin analogue � WHO FC III or IV patient (presence of right heart failure) � (t ½= 4 hours) � Non-responsive to AVT � Stable at room temperature � No ice packs or refrigeration required � Very young patients (<7yrs); maximize benefit during rapid lung development � Mixed cassettes last 48 hours � Syncope (particularly if already on oral tx) � SQ or IV form � Failed oral trial (how long do you wait?) � Consider a lower threshold knowing the natural history in children is worse than adults, untreated 4
6/21/2013 IV/SC Bioequivalence Study Treprostinil Delivery Systems ● IV Remodulin IV ▲ SC Remodulin SC Treprostinil concentration, ng/mL 10 0 � CADD Legacy 10 -1 � Chrono 5 Steady state � Minimed 407 C (IV/SQ) 10 -2 10 -3 0 12 24 36 48 60 72 84 96 Hour Laliberte et al. J Cardiovasc Pharmacol. 2004 . SQ Treprostinil Site Pain Considerations Treatment considerations: IV vs SQ � Provider/patient preferences � Financial considerations � PAH center experience � Family/care-giver support � Body image concerns � Low pain threshholds 5
6/21/2013 Site Pain Management Approaches: Pain Management Approaches: Local/Topical options Systemic options � Histamine H1 receptor antagonists � First line remedies � Loratadine, fexofenadine HCL, cetirizine HCL � Ice � Histamine H2 receptor antagonists � Warm bath with Epsom salts � Ranitidine, famotidine � Aloe vera gel, arnica oil, capsaicin cream � Non-opioid analgesics � Ibuprofen, acetaminophen � Anesthetic Agents � GABA analogs � Lidocaine 5% patches/lidocaine cream � Gabapentin, pregabalin � Caladryl lotion � Opioid analgesics (for severe pain) � Vasoconstrictive agents � Tramadol, fentanyl patch, hydrocodone with acetaminophen � Hemorrhoid ointment � Antidepressants � Amitriptyline � PLO Gel compounds IV Prostanoids: Minimizing risk for Catheter IV Epoprostenol to IV Treprostinil transition Related- Blood Stream Infections (CR-BSI) � Successful transition of 13 pediatric PAH pts � Single center experience using closed-hub system and from IV epo to IV treprostinil waterproofing precautions during showering with IV prostanoids in children to minimize CR-BSI � 2 deaths, 2 transitions to other therapies � 50 patients receiving prostanoids � Transitioned in hospital over 24 hours (rapid or slow) � Closed-hub system and maintenance of dry catheter hub � Patients maintained their exercise capacity connections significantly reduced the incidence of CR-BSI � Higher dose, fewer side effects (particularly infections caused by gram-negative pathogens) in � Several central line infections however, reported patients receiving intravenous treprostinil. before current recommendations for treprostinil line care were implemented Ivy DD, et al. Am J Cardiol, 2007 Ivy DD, et al. Infection Control and Hospital Epidemiology, 2009. 6
6/21/2013 Rates of CR-BSI pre and post implementation of SQ Treprostinil for PH associated Closed-Hub system with protected connections with CLD of infancy � Case series of 5 infants successfully treated (off-label) with SQ treprostinil at Columbia University Medical Center � General characteristics � CLD � Former premature infants (born at 23-26 weeks) � Birth weight range 470-635 grams � 4/5 patients were under 1 year of age at the time of initiation of therapy Ivy DD, et al. Infection Control and Hospital Epidemiology, 2009. Transition of Pediatric PAH Patients from IV SQ Treprostinil for PH associated with Epoprostenol to oral/inhaled agents CLD of infancy: Results � Retrospective review of all pediatric IPAH/FPAH � All patients had improvement in their respiratory and treated at Columbia (1987-2008) who transitioned off inotrope support after treprostinil initiation IV epo to oral/inhaled drugs � There were no local reactions at SC infusion site � General criteria for transition off included: � No evidence of pain or tenderness at infusion site � FC I/II � 4/5 patients are alive at present (one baby died from � Age > 6yrs suspected septic shock 2 weeks after initiation of � PAPm <35mmHg therapy) � Normal cardiac index � Hemodynamics and clinical data were assessed on peak epoprostenol dose vs. off epoprostenol Melnick L, et al., AJCardiol, 2010 7
6/21/2013 Transition of Pediatric PAH Patients from IV Summary: Prostanoids in Pediatric PAH Epoprostenol to oral/inhaled agents: Results � IV epoprostenol still remains the “gold standard” for the � 14/104 pediatric patients who met general criteria were treatment of advanced pediatric PAH transitioned off IV epoprostenol (over several months to � Newer agents have enabled initiation or transition to other years; 4/03-7/08) prostanoids and even to oral/inhaled agents in carefully � 13/14 remained off IV epo on oral/inhaled medications selected patients � Hemodynamics, exercise capacity (if able) and WHO � Close monitoring of side effects and diligent management are functional class remained stable off epo compared to important for patient compliance and treatment success peak epoprostenol dose. (f/u 7+6 mos); Further � Caution should be applied to delay in the institution of improvement in WHO FC was seen post epoprostenol prostanoid therapy when using novel oral agents (p<0.005) � As novel agents are developed so are new challenges in � All 13 patients are alive at present; (77% ERA, 69% decision making PDE-5 inhibitor, 38% CCB, 8% iloprost) Melnick L, et al., AJCardiol, 2010 8
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