Medications used for targeted therapy in pediatric patients with pulmonary hypertension

Medication	US brand name	Dose/route	Side effects	Comments
PDE5 inhibitors
Sildenafil	Revatio	Age <1 year: 0.5 to 1 mg/kg per dose orally 3 times per day Age ≥1 year: <20 kg: 10 mg orally 3 times per day ≥20 kg: 20 mg orally 3 times per day Maximum dose: 20 mg orally 3 times per day	Headache, flushing, nasal congestion, epistaxis, dizziness, hypotension, peripheral edema, dyspepsia, diarrhea, priapism	Co-administration of nitrates is contraindicated Sensorineural hearing loss and ischemic optic neuropathy have been reported In extremely preterm infants, use should be delayed until retinal vascularization established
Tadalafil	Adcirca	Initial dose: 1 mg/kg/dose orally once daily Maximum dose: 40 mg/day	Similar to sildenafil	Co-administration of nitrates is contraindicated Sensorineural hearing loss has been reported Ischemic optic neuropathy has been reported Very limited information in children regarding dosing, safety, and efficacy
Calcium channel blockers*
Nifedipine		Initial dose: 0.1 to 0.2 mg/kg per dose orally 3 times per day; increase to 2 to 3 mg/kg/day total oral dose Maximum dose: 180 mg/day Extended release tablets preferred for patients able to swallow whole pills	Hypotension, bradycardia, flushing, headache, peripheral edema, dizziness, rash, gingival hyperplasia	Contraindicated with RV dysfunction Used in patients who demonstrate a response to AVT
Amlodipine		Initial dose: 0.1 to 0.3 mg/kg per dose orally once daily; may increase to 2.5 to 10 mg orally once daily Maximum dose: 10 mg/day	Similar to nifedipine	Contraindicated with RV dysfunction Used in patients who demonstrate a response to AVT
Diltiazem		Initial dose: 0.5 mg/kg/dose orally 3 times per day; increase to 2 to 5 mg/kg/day total oral dose Maximum dose: 360 mg/day Extended release formulations preferred for patients able to swallow whole pills	Similar to nifedipine	Contraindicated with RV dysfunction Used in patients who demonstrate a response to AVT
Endothelin receptor antagonists
Bosentan	Tracleer	Starting dose is one-half maintenance dose; increase to full maintenance after 2 to 4 weeks if LFTs and Hgb are stable Maintenance dose: <10 kg: 2 mg/kg/dose orally twice per day 10 to 20 kg: 31.25 mg orally twice per day 20 to 40 kg: 62.5 mg orally twice per day >40 kg: 125 mg orally twice per day Maximum dose: 125 mg orally twice per day	Abdominal pain, vomiting, extremity pain, fatigue, flushing, headache, edema, nasal congestion, anemia, decreased sperm count Potential risk of dose-dependent increases in aminotransaminase levels	Monitor LFTs and Hgb and adjust dose per manufacturer's recommendations Not recommended in patients with moderate or severe hepatic impairment Caution with concomitant use of CYP3A4 inducers and inhibitors Is a teratogen; pregnancy test required prior to use and for 1 month afterwards; 2 forms of contraception required Concurrent use of bosentan and sildenafil increases bosentan serum levels and decreases sildenafil levels
Ambrisentan	Letairis	Maintenance dose: <20 kg: 2.5 to 5 mg orally once daily >20 kg: 5 to 10 mg orally once daily Maximum dose: 10 mg/day	Peripheral edema, nasal congestion, headache, flushing, anemia, nausea, and decreased sperm count The incidence of serum aminotransferase elevation is low	Obtain baseline LFTs and Hgb, monitor after 1 month, then every 6 months or as clinically indicated Teratogenicity concerns as for bosentan Little efficacy and safety data for children; avoid use in neonates and infants
Macitentan	Opsumit	Pediatric dosing is not established Adult dosing: 10 mg orally daily	Nasal congestion, headache, flushing, anemia, decreased sperm count The incidence of serum aminotransferase elevation is low	Obtain baseline LFTs and Hgb and monitor as clinically indicated Teratogenicity as for other ERAs Infrequently used in children as there are no available data in pediatric patients
Prostacyclin analogues
Epoprostenol (IV)	Flolan Veletri	Initial infusion rate: 1 to 3 nanograms/kg/min; slowly increase infusion rate over weeks Maintenance infusion rate: 50 to 80 nanograms/kg/min, titrated to effect No clear maximum dose	Flushing, headache, nausea, diarrhea, jaw discomfort, rash, hypotension, thrombocytopenia	Potential risk of hypotension and bleeding in children receiving concomitant drugs such as anticoagulants, platelet inhibitors, or other vasodilators Bolus infusion can cause systemic hypotension Short elimination half-life (3 to 5 minutes); PH crises can occur rapidly if infusion is stopped Cooling is needed for Flolan but not Veletri Dose increases needed due to tachyphylaxis
Iloprost (inhaled)	Ventavis	Initial dose: 2.5 micrograms per inhalation 6 times a day Maintenance dose: 5 micrograms per inhalation 6 to 9 times per day Maximum dose: 45 mcg/day	Cough, wheeze, headache, flushing, jaw pain, diarrhea, rash, hypotension (at higher doses)	Elimination half-life 20 to 30 minutes Potential risk of exacerbating reactive airway disease symptoms Patient must be old enough to initiate breath from nebulizer
Treprostinil (IV/SC)	Remodulin	As for epoprostenol, but maintenance infusion rate may need to be higher	As for epoprostenol Pain and redness at SC infusion site	Stable at room temperature Elimination half-life 4 hours
Treprostinil (inhaled)	Tyvaso	Initial dose: 3 breaths (18 micrograms) 4 times a day Maintenance dose: 9 breaths (54 micrograms) 4 times a day	Cough, headache, nausea, dizziness, flushing, throat irritation	As for iloprost Elimination half-life 4 hours Potential risk of exacerbating reactive airway disease symptoms
Treprostinil diolamine (oral)	Orenitram	Initial dose: 0.125 to 3 times per day, or 0.25 mg orally twice per day Maintenance dose: Determined by tolerability	Headache, nausea, diarrhea, jaw pain, extremity pain, hypokalemia, abdominal discomfort, flushing	Must be taken with food Limited experience in pediatric patients Unlikely to be sufficient substitute for parenteral prostacyclin for patients requiring high-dose prostacyclin

This table summarizes medications used in the management of pediatric PH. Data on the efficacy, dosing, and safety of these agents in children are limited. Most of these agents (with the exception of sildenafil) are not specifically approved by the FDA or EMA for treatment of pediatric PH. Infants and children with PH should be managed in centers with the experience, special expertise, and multidisciplinary teams necessary to provide care for these patients. For additional details, refer to UpToDate topics on PH in children.

PDE5: phosphodiesterase type 5; RV: right ventricle; AVT: acute vasoreactivity testing; LFT: liver function test; Hgb: hemoglobin; CYP3A4: cytochrome P450 3A4; ERA: endothelin receptor antagonist; IV: intravenous; PH: pulmonary hypertension; SC: subcutaneous; FDA: Food and Drug Administration; EMA: European Medicines Agency.

* Calcium channel blockers play a limited role in management of pediatric PH. They are used selectively in patients who have vasoreactivity documented on cardiac catheterization. Refer to UpToDate topics on PH in children for details.

Adapted from: Abman SH, Hansmann G, Archer SL, et al. Pediatric pulmonary hypertension: Guidelines from the American Heart Association and American Thoracic Society. Circulation 2015; 132:2037.

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Medications used for targeted therapy in pediatric patients with pulmonary hypertension