Sildenafil Dosing in Pediatric Patients
For pediatric pulmonary arterial hypertension, use weight-based dosing: infants <1 year receive 0.5-1 mg/kg three times daily; children <20 kg receive 10 mg three times daily; and children >20 kg receive 20 mg three times daily, but avoid higher doses due to increased mortality risk demonstrated in the STARTS-2 study. 1
Age and Weight-Based Dosing Algorithm
Infants Under 1 Year
- Starting dose: 0.5-1 mg/kg orally three times daily 1
- Critical caveat: Delay use in extremely preterm infants until retinal vascularization is established to avoid potential vision complications 1
Children by Weight Categories
- Weight <20 kg: 10 mg orally three times daily 1
- Weight >20 kg: 20 mg orally three times daily 1
- Dosing interval: Administer every 4-6 hours (three times daily) 2
Critical Safety Warning: Avoid High-Dose Therapy
The FDA issued a warning against sildenafil use in children aged 1-17 years, specifically cautioning against high-dose therapy. 1 The STARTS-2 study demonstrated a hazard ratio of 3.5 (p=0.015) for mortality with high-dose compared to low-dose sildenafil monotherapy in children with idiopathic pulmonary arterial hypertension. 1, 3 This finding led to the recommendation that chronic use of sildenafil, particularly at higher doses, is not recommended in children. 3
Dose Escalation Strategy
When initiating therapy, always uptitrate from the lower end of the dosing range: 1
- Initial dose: Start at 0.5 mg/kg three times daily 4, 5
- Escalation if needed: Can increase to 1.0 mg/kg, then 1.5 mg/kg, and maximum 2.0 mg/kg per dose 4, 5
- Key finding: Research demonstrates that 0.5 mg/kg every 4 hours is therapeutically as effective as 2.0 mg/kg every 4 hours for reducing pulmonary artery pressure, making lower doses preferable 5
Pharmacokinetic Considerations
Plasma levels in children receiving therapeutic doses are comparable to adults: 4
- After 0.5 mg/kg dose: 109±87 ng/ml at 1 hour
- After 1.0 mg/kg dose: 150±62 ng/ml at 1 hour
- After 2.0 mg/kg dose: 368±200 ng/ml at 1 hour, declining to 211±106 ng/ml at 3 hours
Common Side Effects and Monitoring
Side effects occur in approximately 30% of pediatric patients on sildenafil. 6 The incidence by system includes:
- Gastrointestinal: 37% overall (24% monotherapy, 48% combination therapy) 6
- Vascular: 35% overall (21% monotherapy, 45% combination therapy), including headache, nasal congestion, flushing, and hypotension 1, 6
- Neurologic: 22% overall (18% monotherapy, 25% combination therapy), including agitation 1, 6
- Serious but rare: Vision and hearing loss, priapism 1
- Respiratory: Airway spasm with desaturation (rare, led to discontinuation in 2 of 269 patients) 7
Patients on combination therapy with endothelin receptor antagonists or prostacyclins experience significantly higher rates of side effects compared to monotherapy. 6
Special Clinical Contexts
Persistent Pulmonary Hypertension of the Newborn (PPHN)
- Intravenous sildenafil improves oxygenation index in PPHN patients treated with or without inhaled nitric oxide 1
- Important caveat: Sildenafil infusion can increase intrapulmonary shunting and worsen hypoxemia in postoperative congenital heart disease patients 1
Congenital Heart Disease
- Same weight-based dosing applies 1
- Monitor carefully for increased intrapulmonary shunting in postoperative patients 1
Bronchopulmonary Dysplasia (BPD)
- Standard weight-based dosing 7
- Favorable prognosis: 45% of BPD patients can discontinue sildenafil due to improvement in pulmonary hypertension 7
Regulatory Status and Approval
- FDA approval: Approved for adult PAH in 2005; intravenous formulation approved in 2009 1
- Pediatric use: Approved in Europe and Canada but carries FDA warning for children 1-17 years of age 1
- Current status: Used off-label in pediatric patients in the United States 8
Long-Term Management Considerations
Sildenafil monotherapy is likely insufficient with disease progression, requiring close surveillance and frequent monitoring. 8 In a large cohort study with median follow-up of 3.1 years: 7
- 37% remained on sildenafil or transitioned to tadalafil
- 35% discontinued due to improvement in pulmonary hypertension
- 20% died (18 PH-related deaths, 36 from other causes)
- Overall survival was significantly lower in WHO group 3 PH (BPD and congenital diaphragmatic hernia) compared to group 1 (idiopathic PAH and congenital heart disease)