4/18/2018 DISCLOSURE (AND DISCLAIMER)

Transcription

1 DISCLOSURE (AND DISCLAIMER) PEDIATRIC PULMONARY HYPERTENSION PHARMACOTHERAPY 11th International Conference Neonatal & Childhood Pulmonary Vascular Disease April 19, 2018 I have no conflicts of interests to disclose Unless otherwise noted, all medications to be discussed are off-label Angelica J. Ng, PharmD, BCPS, BCPPS Pediatric Clinical Pharmacist UCSF Benioff Children s Hospital 2 OVERVIEW UCSF BENIOFF CHILDREN S HOSPITAL Brief overview of pulmonary hypertension as a disease state Pharmacologic management of pulmonary hypertension targeted therapies - Medication safety and regulatory considerations Pharmacotherapeutic considerations in the perioperative management of pediatric pulmonary hypertension 183-bed quaternary care teaching hospital - 24 pediatric cardiac ICU/ TCU beds, 32 PICU/TCU beds and 58 NICU beds Nationally ranked in pediatric cardiology and pulmonology (US News & World Report 3 4 1

2 UCSF PEDIATRIC PULMONARY HYPERTENSION PROGRAM PULMONARY HYPERTENSION Established st PHA-Accredited Pediatric Center for Comprehensive Care on the west coast patients being actively managed - Most commonly associated diagnoses: congenital heart disease, congenital diaphragmatic hernia, idiopathic, bronchopulmonary dysplasia patients on IV/SQ prostacyclin therapy Defined as an increase in mean pulmonary arterial pressure 25 mmhg at rest as assessed by right heart catheterization Pediatrics: - Same definition, (slightly) different etiologies - Catch-22: worse outcomes if left untreated but lack of data for pediatric-specific therapeutic strategies Accessed March 29, GOALS OF THERAPY FDA APPROVAL TIMELINE selective pulmonary vasodilation, restoration of normal endothelial function, and reversal of remodeling of the pulmonary vasculature reduce right ventricular afterload and prevent right ventricular failure Ultimately, improved survival and allowance of normal activities of childhood without the need to self-limit Epoprostenol (Flolan ) Bosentan Treprostinil Iloprost (Traceleer ) (Remoudlin ) (Ventavis ) Sildenafil Letairis Epoprostenol (Revatio ) (Ambrisentan ) (Veletri ) Treprostinil (Tyvaso ) Tadalafil (Adcirca ) Sildenafil suspension (Revatio ) Treprostinil (Orenitram ) Riociguat (Adempas ) Macitentan (Opsumit ) Selexipag (Uptravi ) Bosentan tablet for oral suspension (Tracleer ) 7 8 2

3 ENDOTHELIAL PATHWAYS ENDOTHELIN PATHWAY Accessed March 26, ENDOTHELIN PATHWAY ET-1 Endothelin 1 ETA Endothelin Receptor A ETB Endothelin Receptor B Endothelin 1 is a potent vasoconstrictor - ET-1 + ETA vasoconstriction Endothelin Receptor Antagonists - Bosentan (Tracleer ) non-selective - Ambrisentan (Letairis ) selective for ETA - Macitentan (Opsumit ) non-selective Biology of ET-1 and ET receptors is complex - Is selectivity better? ENDOTHELIN RECEPTOR ANTAGONISTS Bosentan (Tracleer ) Ambrisentan (Letairis ) Macitentan (Opsumit ) Pediatric Data or FDA Phase III trial FDA approved 2017 Approval suspended* Phase III trial recruiting Dosing Frequency Twice daily Once daily Once daily Teratogenic Yes Yes Yes REMS program Yes Yes Yes Adverse Effects Anemia Elevated LFTs Edema *as of March 30, /

4 REMS Risk Evaluation and Mitigation Strategy BOSENTAN THE BASICS FDA requirement for manufacturers; ensures that benefit of a medication outweigh its risks Provider must be enrolled in REMS program; restricted distribution In a nutshell: Bosentan Ambrisentan, Macitentan Patient enrollment Male and female patients enrolled Female patients enrolled Liver Toxicity Counsel patients on risk of liver toxicity LFTs on initiation then monthly N/A Teratogenicity Counsel on teratogenicity Pregnancy test before initiation and monthly thereafter (and 1 month after discontinuation); yearly pregnancy status update Non-selective endothelin receptor antagonist Administration: oral/enteral Pharmacokinetic and pharmacodynamic considerations: - Bioavailability: ~50% - Metabolism: Hepatically via CYP2C9 and CYP3A4 (active metabolite) - Drug Interactions: Induces CYP2C9 (weak) and CYP3A4 (moderate) Adverse Reactions: hepatic dysfunction, anemia, edema Access: only available through specialty pharmacies BOSENTAN DOSING BOSENTAN DOSING Dosing is no longer straightforward! New labeling: Historically (UCSF Practice): - Initial: 1 mg/kg/dose BID, maintenance: 2 mg/kg/dose BID FUTURE-1 study: Bosentan plasma concentrations achieved in children are lower than those in adults (even at 4 mg/kg/dose BID) FUTURE-3 study: can dose Bosentan up to three times daily Initial (4 weeks) Maintenance Patients >12 years of age and >40 kg 62.5 mg twice daily 125 mg twice daily Patients >12 years of age and <40 kg 62.5 mg twice daily 62.5 mg twice daily Patients 12 years of age 4-8 kg 8-16 kg kg kg 16 mg twice daily 32 mg twice daily 48 mg twice daily 64 mg twice daily 16 mg twice daily 32 mg twice daily 48 mg twice daily 64 mg twice daily Accessed March 27,

5 BOSENTAN DOSAGE FORMS & MED SAFETY BOSENTAN DOSAGE FORMS & MED SAFETY Lack of pediatric-friendly dosage form until very very recently! Conundrum: hazardous medication that needs to be compounded AND needs to be provided by a specialty pharmacy cannot prescribe as a suspension (since outpatient pharmacy only able to provide tablets) To split or not to split tablets? Patient education sheet developed by UCSF Pediatric Pulmonary Hypertension Program Required constant vigilance at transitions of care to make sure correct dose/instructions ordered Accessed March 27, BOSENTAN DOSAGE FORMS & MED SAFETY BOSENTAN DOSAGE FORMS & MED SAFETY Tablet for oral suspension accompanied pediatric labeling September Accessed March 27, Availability of 32 mg soluble tablet and dosing recommendations based on age and weight categories promote cleaner inpatient orders and outpatient prescriptions (so far )

6 NITRIC OXIDE-cGMP PATHWAY NITRIC OXIDE-cGMP PATHWAY + Soluble Guanylate Cyclase Stimulator Increasing cgmp production stimulates vasodilation and antiproliferation Achieved by: - Stimulating cgmp production (inhaled NO, SGC stimulator) - Preventing cgmp breakdown by PDE-5 (PDE-5 Inhibitors) NO Nitric Oxide PDE Phosphodiesterase SGC Soluble Guanylate Cyclase NITRIC OXIDE-cGMP MEDICATIONS SILDENAFIL THE BASICS Sildenafil (Revatio ) Tadalafil (Adcirca ) Riociguat (Adempas ) Class PDE-5 Inhibitor PDE-5 Inhibitor SGC stimulator Pediatric Data or FDA Approval Dosing Frequency Adverse Effects Phase III trials completed Three times daily (usually) headache, nausea, myalgia, nasal congestion, flushing Phase III trials in progress Once daily headache, nausea, myalgia, nasal congestion, flushing Phase III trial in progress N/A N/A Phosphodiesterase-5 Inhibitor Administration: oral/enteral (IV in some cases) Pharmacokinetic and pharmacodynamic considerations: - Bioavailability: ~40% (tablets and suspension are bioequivalent) - Metabolism: Hepatically via CYP2C9 and CYP3A4 - Drug Interactions: weak inhibitor of CYP2C9; major substrate of CYP3A4 (remember bosentan?)

7 SILDENAFIL THE BASICS SILDENAFIL DOSING Adverse Reactions: Not straightforward either! - headache, nausea, myalgia, nasal congestion, flushing Generally: 1 mg/kg/dose TID - Hypotension? Reflux? Vision changes? Titrate based on tolerability (ex. decrease to 0.75 mg/kg/dose Q6H) Access: available through community pharmacies Children and adolescents < 18 years old Weight Dose 8 to 20 kg 10 mg three times daily >20 kg to 45 kg 20 mg three times daily >45 kg 40 mg three times daily SILDENAFIL STARTS-1 AND STARTS-2 TRIALS In summary, although children randomized to [high sildenafil] had an unexplained increased mortality compared to [lower sildenafil], multiple analyses raised uncertainty about the survival/dose relationship; all dose groups displayed favorable survival for children with PAH. STARTS-1 efficacy results and the long-term survival rates favor use of lower sildenafil doses. Barst RJ et al on behalf of the STARTS-2 investigators

8 SILDENAFIL STARTS-1 AND STARTS-2 THE FALLOUT SILDENAFIL DOSAGE FORMS & MED SAFETY (& ECONOMICS) Discard 60 days after reconstitution August 2012 October 2012 March 2014 Generic Sildenafil tablets 25 mg (30): $1, (~$2.60/mg) 10 mg/ml (112 ml): $9, (~$8/mg) TADALAFIL THE BASICS TADALAFIL THE BASICS Phosphodiesterase-5 Inhibitor Administration: oral/enteral Pharmacokinetic and pharmacodynamics considerations: - Half-life: hours - Metabolism: Hepatically via CYP3A4 Adverse Reactions: - headache, nausea, myalgia, nasal congestion, flushing Access: available through community pharmacies Dosing: 1 mg/kg/dose once daily Tadalafil tablets 20 mg (60): $4, (~$4/mg)

9 PROSTACYCLIN PATHWAY PROSTACYCLIN PATHWAY Prostacyclin receptor agonist Endogenous prostacyclin synthesized from arachidonic acid increased camp vasodilation (but also inhibits platelet activity and smooth muscle cell growth) PROSTACYCLIN THERAPY PROSTACYCLIN ANALOGUES PROSTACYCLIN RECEPTOR AGONIST PARENTERAL Epoprostenol Treprostinil INHALED Iloprost Treprostinil ORAL Treprostinil Selexipag PROSTACYCLIN MEDICATIONS INHALED PROSTACYCLINS Epoprostenol (Flolan, Veletri ) Treprostinil (Remodulin, Tyvaso, Orenitram ) Iloprost (Ventavis ) Selexipag (Uptravi ) Class Pediatric Data or FDA Approval Prostacyclin analogue Clinical data/experience Prostacyclin analogue Clinical data/experience for inhaled/parenteral routes Phase II trial for PO Prostacyclin analogue Clinical data/experience Prostayclin IP Receptor Agonist Minimal clinical data/experience Routes IV (inhaled?) IV, SQ, inhaled, PO Inhaled PO

10 EPOPROSTENOL FLOLAN, VELETRI THE BASICS EPOPROSTENOL FLOLAN, VELETRI THE BASICS Synthetic prostacyclin Administration: continuous IV infusion (requires central access) Pharmacokinetic and pharmacodynamic considerations: - Metabolism: rapidly hydrolyzed - Half-life: 6 mins abrupt withdrawal or sudden large dose reductions can cause severe rebound pulmonary hypertension; possible death Initiate at 2 ng/kg/min and titrate upwards as tolerated Dose-limiting side effects: nausea, diarrhea, vomiting, hypotension, headache, jaw pain Access: only available through specialty pharmacies EPOPROSTENOL FLOLAN, VELETRI LOGISTICS TREPROSTINIL REMODULIN THE BASICS Central access increased risk of infection Flolan only stable for 8 hours at room temperature (needs ice packs for 24-hour administration) Flolan only compatible with Flolan -specific diluent Veletri is room-temperature stable but limited data in pediatrics Very short half-life need back ups of everything! (i.e. medication, IV access, pump and associated supplies) Synthetic prostacyclin analogue Administration: IV, SQ Pharmacokinetic and pharmacodynamic considerations: - Metabolism: hepatically via CYP2C8 - Half-life: ~4 hours

11 TREPROSTINIL REMODULIN THE BASICS TREPROSTINIL REMODULIN LOGISTICS Initial infusion rates vary (typically 1.25 ng/kg/min); pediatric patients may require higher starting rates (2-4 ng/kg/min) Titrate upwards as tolerated - Dose-limiting side effects similar to epoprostenol Access: only available through specialty pharmacies Longer half-life (~4 hours) and room-temperature stable - No back-up cassette/cartridge - Does not have to be refrigerated or hung with ice packs Flexibility of IV or SQ administration Benefits of SQ administration - Less risk of infection - May change cartridges as infrequently as Q72hours PARENTERAL PROSTACYCLINS UCSF PRACTICE PARENTERAL PROSTACYCLINS UCSF PRACTICE Primarily use SQ Remodulin - Soft max rate of 0.03 ml/hr Patients transitioned to hospitalsupplied pump and medication Requires use of order set; ordering privileges restricted to certain providers

12 PARENTERAL PROSTACYCLINS UCSF PRACTICE PARENTERAL PROSTACYCLINS UCSF PRACTICE BEDSIDE RN COMPLETES SCREENING TOOL PHARMACY CONTACTS SPECIALTY PHARMACY Information obtained by nursing and pharmacy should be corroborated by orders entered by provider SQ site pain commonly reported pitfall of SQ Remodulin Can be managed with acetaminophen, ibuprofen, and opioids as well as topical medications PERIOPERATIVE PULMONARY HYPERTENSIVE CRISES Medication-related Recommendations from the AHA/ATS Guidelines on Pediatric PH PERIOPERATIVE MANAGEMENT General postoperative strategies for avoiding PHC, including avoidance of hypoxia, agitation, and acidosis, should be used in children at high risk for PHCs Induction of alkalosis can be useful for treatment of PHCs Administration of opiates, sedatives, and muscle relaxants is recommended for reducing postoperative stress response and the risk for or severity of PHCs In addition to conventional postoperative care, ino and/or inhaled PGI2 should be used as the initial therapy for PHCs and failure of the right side of the heart Sildenafil should be prescribed to prevent rebound PH in patients who have evidence of a sustained increase in PAP on withdrawal of ino and require reinstitution of ino despite gradual weaning of ino dose In patients with PHCs, inotropic/pressor therapy should be used to avoid RV ischemia caused by systemic hypotension Class I Level of Evidence B Class IIa Level of Evidence B Class I Level of Evidence B Class I Level of Evidence B Class I Level of Evidence B Class I Level of Evidence B Death or pulmonary hypertensive crises occur in 4.5% of pediatric pulmonary hypertension patients undergoing catheterizations and/or non-cardiac surgeries Inciting factors: acidosis, agitation, pain, hypoxia, or tracheal suctioning

13 PERIOPERATIVE PULMONARY HYPERTENSIVE CRISES SUMMARY Possibility of compromised perfusion s/p cardiac surgery = decreased absorption of SQ Remodulin? No data; UCSF practice has been to convert to IV pre-operatively Pediatric pulmonary hypertension is a rare disease state; requires lot of extrapolation from adult algorithms Common pitfalls in managing pediatric pulmonary hypertension: lack of data, lack of pediatricfriendly dosage forms Encouraging that data is coming out from individual centers but still need more robust clinical trials Abman et al. Circulation REFERENCES REFERENCES Abman SH. Role of Endothelin Receptor Antagonists in the Treatment of Pulmonary Arterial Hypertension. Annu Rev Med. 2009;60:13-23 Abman SH et al. Pediatric Pulmonary Hypertension: Guidelines From the American Heart Association and American Thoracic Society. Circulation. 2015;132: Abman SH, et al. Implications of the U.S. Food and Drug Administration Warning against the Use of Sildenafil for the Treatment of Pediatric Pulmonary Hypertension. Am J Respir Crit Care Med. March 15, Vol 187, Iss. 6, pp Aggarwal M and Grady RM. Treatment of Pediatric Pulmonary Hypertension. Curr Treat Options Cardio Med (2018) 20: 8 Aypar E, et al. Clinical efficacy and safety obr J Clin Pharmacol Dec;68(6):948-55f switch from bosentan to macitentan in children and young adults with pulmonary arterial hypertension. Cardiology in the Young (2018), 28, Barst RJ et al. A Randomized, Double-Blind, Placebo-Controlled, Dose-Ranging Study of Oral Sildenafil Citrate in Treatment-Naive Children With Pulmonary Arterial Hypertension. Circulation. 2012;125: Barst RJ, et al. STARTS-2: Long-Term Survival With Oral Sildenafil Monotherapy in Treatment-Naïve Pediatric Pulmonary Arterial Hypertension. Beghetti M, et al. Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study. Circulation May 13;129(19): Berger RMF, et al. FUTURE-2: Results from an open-label, long-term safety and tolerability extension study using the pediatric FormUlation of bosentan in pulmonary arterial hypertension. Int J Cardiol Jan 1;202:52-8 Berger RMF, et al. A bosentan pharmacokinetic study to investigate dosing regimens in paediatric patients with pulmonary arterial hypertension: FUTURE-3. Br J Clin Pharmacol (2017) Dhariwal AK and Bavdekar SB. Sildenafil in pediatric pulmonary arterial hypertension. J Postgrad Med Jul-Sep; 61(3): Accessed March 26, 2018 Dingemanse J, et al. Efficacy, safety and clinical pharmacology of macitentan in comparison to other endothelin receptor antagonists in the treatment of pulmonary arterial hypertension. Expert Opinion on Drug Safety, 13:3, Gallotti R, et al. Single-Center Experience Using Selexipag in a Pediatric Population. Pediatr Cardiol (2017) 38: Frank BS and Dunbar I. Diagnosis, Evaluation and Treatment of Pulmonary Arterial Hypertension in Children. Children Mar 23;5(4) Galié N, et al ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension Ivy, Dunbar. Advances in Pediatric Pulmonary Arterial Hypertension. Curr Opin Cardiol March ; 27(2): Kameny RJ, Fineman J, Adatia, I. Perioperative Management of Pediatric Pulmonary Hypertension. Advances in Pulmonary Hypertension: 2016, Vol. 15, No. 2, pp Lexicomp Online, Pediatric & Neonatal Lexi-Drugs, Hudson, Ohio: Lexi-Comp, Inc.; March 1 30, 2018 McLaughlin VV, et al. ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension Circulation. 2009;119: Oishi P, Datar S, Fineman J. Pediatric pulmonary arterial hypertension: current and emerging therapeutic options. Expert Opinion on Pharmacotherapy, 12:12, Siehr SL, et al. Hemodynamic Effects of Phenylephrine, Vasopressin, and Epinephrine in Children With Pulmonary Hypertension: A Pilot Study. Pediatr Crit Care Med 2016; 17: Spreemann T, et al. First-in-child use of the oral soluble guanylate cyclase stimulator riociguat in pulmonary arterial hypertension. Pulmonary Circulation 2017; 8(3) 1 6 Steinhorn RH. Pharmacotherapy for Pulmonary Hypertension. Pediatr Clin N Am 59 (2012) Takatsuki S and Calderbank M. Initial Experience With Tadalafil in Pediatric Pulmonary Arterial Hypertension. Pediatr Cardiol (2012) 33: Wei A, et al. Clinical Adverse Effects of Endothelin Receptor Antagonists: Insights From the Meta-Analysis of 4894 Patients From 24 Randomized Double-Blind Placebo-Controlled Clinical Trials. J Am Heart Assoc. 2016;5: e

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