DISCLOSURE (AND DISCLAIMER) PEDIATRIC PULMONARY HYPERTENSION PHARMACOTHERAPY · 2018-04-18 ·...

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PEDIATRIC PULMONARY HYPERTENSION PHARMACOTHERAPY

Angelica J. Ng, PharmD, BCPS, BCPPSPediatric Clinical Pharmacist UCSF Benioff Children’s Hospital

11th International Conference Neonatal & Childhood Pulmonary Vascular Disease ・April 19, 2018

Pediatric Pulmonary Hypertension Pharmacotherapy2

DISCLOSURE (AND DISCLAIMER)

I have no conflicts of interests to disclose

Unless otherwise noted, all medications to be discussed are off-label


OVERVIEW

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


UCSF BENIOFF CHILDREN’S HOSPITAL 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

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UCSF PEDIATRIC PULMONARY HYPERTENSION PROGRAM

Established 2011

1st PHA-Accredited Pediatric Center for Comprehensive Care on the west coast

149 – 200 patients being actively managed

- Most commonly associated diagnoses: congenital heart disease, congenital diaphragmatic hernia, idiopathic, bronchopulmonary dysplasia

20 – 29 patients on IV/SQ prostacyclin therapy

https://phassociation.org/phcarecenters/peds/ucsf/. Accessed March 29, 2018


PULMONARY HYPERTENSION

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


GOALS OF THERAPY

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


FDA APPROVAL TIMELINE

1995 2001 2002 2004 2005 2007 2008 2009 2012 2013 2015 2017

Epoprostenol(Flolan®)

Bosentan(Traceleer®)

Treprostinil(Remoudlin®)

Iloprost(Ventavis®)

Sildenafil (Revatio®)

Letairis(Ambrisentan®)

Epoprostenol(Veletri®)

Treprostinil(Tyvaso®)

Tadalafil(Adcirca®)

Sildenafil suspension (Revatio®)

Treprostinil(Orenitram®)

Riociguat(Adempas®)

Macitentan(Opsumit®)

Selexipag(Uptravi®)

Bosentan tablet for oral

suspension (Tracleer®)

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ENDOTHELIAL PATHWAYS

https://www.researchgate.net/figure/Key-pathways-involved-in-the-pathophysiology-of-pulmonary-hypertension-Three-main_fig1_49646627. Accessed March 26, 2018


ENDOTHELIN PATHWAY

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 PATHWAY

ET-1 – Endothelin 1ETA – Endothelin Receptor AETB – Endothelin Receptor B


ENDOTHELIN RECEPTOR ANTAGONISTS

Bosentan (Tracleer ®)Ambrisentan(Letairis ®)

Macitentan(Opsumit®)

Pediatric Data or FDA Approval

FDA approved 2017Phase III trial suspended*

Phase III trial recruiting

Dosing Frequency Twice daily Once daily Once daily

Teratogenic Yes Yes Yes

REMS program Yes Yes Yes

Adverse EffectsAnemiaElevated LFTsEdema

++++

+/--

++

+--

*as of March 30, 2018


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REMSRisk Evaluation and Mitigation Strategy

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 ToxicityCounsel patients on risk of liver toxicity

LFTs on initiation then monthlyN/A

TeratogenicityCounsel on teratogenicity

Pregnancy test before initiation and monthly thereafter (and 1 month after discontinuation); yearly pregnancy status update

BOSENTANTHE BASICS

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


BOSENTANDOSING

Dosing is no longer straightforward!

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


BOSENTANDOSING

New labeling:

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 ˃16-24 kg ˃24-40 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

http://www.tracleer.com/assets/PDFs/Tracleer_Full_Prescribing_Information.pdf. Accessed March 27, 2018.


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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)

BOSENTANDOSAGE FORMS & MED SAFETY

https://www.uspharmacist.com/article/bosentan-625-mg-ml-oral-suspension. Accessed March 27, 2018.

Lack of pediatric-friendly dosage form until very very recently!



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


Tablet for oral suspension

accompanied pediatric labeling September 2017


http://www.tracleer.com/px/about-tracleer. Accessed March 27, 2018.



Availability of 32 mg soluble tablet and dosing recommendations based on age and weight categories promote “cleaner” inpatient orders and

outpatient prescriptions (so far…)


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NITRIC OXIDE-cGMP PATHWAY


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)

NITRIC OXIDE-cGMP PATHWAY

Soluble Guanylate Cyclase Stimulator

+

NO – Nitric Oxide PDE – PhosphodiesteraseSGC – Soluble Guanylate Cyclase


NITRIC OXIDE-cGMP MEDICATIONS

Sildenafil (Revatio®) Tadalafil (Adcirca®) Riociguat (Adempas®)

Class PDE-5 Inhibitor PDE-5 Inhibitor SGC stimulator

Pediatric Data or FDA Approval

Phase III trials completed

Phase III trials in progress

Phase III trial in progress

Dosing Frequency Three times daily (usually)

Once daily N/A

Adverse Effects headache, nausea, myalgia, nasal

congestion, flushing

headache, nausea, myalgia, nasal

congestion, flushingN/A


SILDENAFILTHE BASICS

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?)


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SILDENAFILTHE BASICS

Adverse Reactions:

- headache, nausea, myalgia, nasal congestion, flushing

- Hypotension? Reflux? Vision changes?

Access: available through community pharmacies


SILDENAFILDOSING

Not straightforward either!

Generally: 1 mg/kg/dose TID

Titrate based on “tolerability” (ex. decrease to 0.75 mg/kg/dose Q6H)

Children and adolescents < 18 years oldWeight 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



SILDENAFILSTARTS-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 alon behalf of the STARTS-2 investigators


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SILDENAFILSTARTS-1 AND STARTS-2 – THE FALLOUT

August 2012 October 2012 March 2014


SILDENAFILDOSAGE FORMS & MED SAFETY (& ECONOMICS)

10 mg/mL (112 mL): $9,883.76 (~$8/mg)Generic Sildenafil tablets 25 mg (30): $1,993.91 (~$2.60/mg)

Discard 60 days after reconstitution


TADALAFILTHE BASICS

Phosphodiesterase-5 Inhibitor

Administration: oral/enteral

Pharmacokinetic and pharmacodynamics considerations:

- Half-life: 15 – 17.5 hours

- Metabolism: Hepatically via CYP3A4


TADALAFILTHE BASICS

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): $4,809.60 (~$4/mg)


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PROSTACYCLIN PATHWAY


Endogenous prostacyclin synthesized from arachidonic acid → increased cAMP → vasodilation (but also inhibits platelet activity and smooth muscle cell growth)

PROSTACYCLIN PATHWAY

PROSTACYCLIN THERAPY

PROSTACYCLIN ANALOGUES

PARENTERAL

Epoprostenol

Treprostinil

INHALED

Iloprost

Treprostinil

ORAL

Treprostinil

PROSTACYCLIN RECEPTOR AGONIST

Selexipag

Prostacyclin receptor agonist


PROSTACYCLIN MEDICATIONS

Epoprostenol(Flolan®, Veletri®)

Treprostinil(Remodulin®,

Tyvaso®, Orenitram®)

Iloprost(Ventavis®)

Selexipag(Uptravi®)

ClassProstacyclin

analogueProstacyclin

analogueProstacyclin

analogueProstayclin IP

Receptor Agonist

Pediatric Data or FDA Approval Clinical

data/experience

Clinical data/experience for inhaled/parenteral

routesPhase II trial for PO

Clinical data/experience

Minimal clinical data/experience

Routes IV (inhaled?) IV, SQ, inhaled, PO Inhaled PO


INHALED PROSTACYCLINS


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EPOPROSTENOLFLOLAN®, VELETRI® – THE BASICS

Synthetic prostacyclin

Administration: continuous IV infusion (requires central access)


- Metabolism: rapidly hydrolyzed

- Half-life: ≤ 6 mins → abrupt withdrawal or sudden large dose reductions can cause severe rebound pulmonary hypertension; possible death


EPOPROSTENOLFLOLAN®, VELETRI® – THE BASICS

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


EPOPROSTENOLFLOLAN®, VELETRI® – LOGISTICS

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)


TREPROSTINILREMODULIN® – THE BASICS

Synthetic prostacyclin analogue

Administration: IV, SQ


- Metabolism: hepatically via CYP2C8

- Half-life: ~4 hours


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TREPROSTINILREMODULIN® – THE BASICS

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


TREPROSTINILREMODULIN ® – LOGISTICS

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 PROSTACYCLINSUCSF PRACTICE

Primarily use SQ Remodulin®

- ”Soft max” rate of 0.03 mL/hr

Patients transitioned to hospital-supplied pump and medication

Requires use of order set; ordering privileges restricted to certain providers




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BEDSIDE RN COMPLETES SCREENING TOOL


Information obtained by nursing and pharmacy should be corroborated by orders

entered by provider

PHARMACY CONTACTS SPECIALTY PHARMACY



SQ site pain commonly reported pitfall of SQ Remodulin®

Can be managed with acetaminophen, ibuprofen, and opioids as well as topical medications



PERIOPERATIVE MANAGEMENT

PERIOPERATIVE PULMONARY HYPERTENSIVE CRISESMedication-related Recommendations from the AHA/ATS Guidelines on Pediatric PH

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

General postoperative strategies for avoiding PHC, including avoidance of hypoxia, agitation, and acidosis, should be used in children at high risk for PHCs

Class ILevel of Evidence B

Induction of alkalosis can be useful for treatment of PHCs Class IIaLevel of Evidence B

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



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PERIOPERATIVE PULMONARY HYPERTENSIVE CRISES

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 Pharmacotherapy49 Pediatric Pulmonary Hypertension Pharmacotherapy50

SUMMARY

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 pediatric-friendly dosage forms

Encouraging that data is coming out from individual centers but still need more robust clinical trials

Abman et al. Circulation. 2015.

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;132:2037-2099 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, 2013. Vol 187, Iss. 6, pp 572–575 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. 2009 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, 542–547 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;125:324-33 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. 2014 May 13;129(19):1914-23 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. 2016 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) 83 1734–1744 Dhariwal AK and Bavdekar SB. Sildenafil in pediatric pulmonary arterial hypertension. J Postgrad Med. 2015 Jul-Sep; 61(3): 181–192

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4943407/. Accessed March 26, 2018


REFERENCES

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, 391-405

Gallotti R, et al. Single-Center Experience Using Selexipag in a Pediatric Population. Pediatr Cardiol (2017) 38:1405–1409 Frank BS and Dunbar I. Diagnosis, Evaluation and Treatment of Pulmonary Arterial Hypertension in Children. Children. 2018 Mar 23;5(4) Galié N, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension Ivy, Dunbar. Advances in Pediatric Pulmonary Arterial Hypertension. Curr Opin Cardiol. 2012 March ; 27(2): 70–81 Kameny RJ, Fineman J, Adatia, I. Perioperative Management of Pediatric Pulmonary Hypertension. Advances in Pulmonary Hypertension: 2016, Vol. 15,

No. 2, pp. 87-91 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;119:2250-2294 Oishi P, Datar S, Fineman J. Pediatric pulmonary arterial hypertension: current and emerging therapeutic options. Expert Opinion on Pharmacotherapy,

12:12, 1845-1864 Siehr SL, et al. Hemodynamic Effects of Phenylephrine, Vasopressin, and Epinephrine in Children With Pulmonary Hypertension: A Pilot Study. Pediatr

Crit Care Med 2016; 17:428–437 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) 1129–1146 Takatsuki S and Calderbank M. Initial Experience With Tadalafil in Pediatric Pulmonary Arterial Hypertension. Pediatr Cardiol (2012) 33:683–688 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: e003896


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