Meds for Pulmonary Arterial Hypertension

Drug

Benefits

Good to Know

Calcium channel blockers block arterial calcium channels.

Amlodipine, diltiazem, or nifedipine⁴

Only for patients deemed vasoreactive on vasoreactivity testing.^1,2

Amlodipine or nifedipine are preferred over diltiazem if bradycardia is a concern.⁴

Calcium channel blockers can lose effectiveness over time.⁷

High doses are used (e.g., titrated to total daily doses of nifedipine ER 120 to 240 mg, diltiazem ER
240 to 960 mg, amlodipine 20 mg to 30 mg).^2,4,8

Phosphodiesterase 5 inhibitors increase cGMP in the pulmonary vascular smooth muscle.

Sildenafil (Revatio)

Generic available in U.S.

Improves exercise capacity and delays clinical worsening.

Dosed TID. Instruct patient to take doses four to six hours apart (Canada: six to eight hours apart).

Avoid with nitrates (contraindicated) and strong CYP3A4 inhibitors (may cause dangerous hypotension; Canada: contraindicated). CYP3A4 inducers significantly reduce sildenafil concentrations. Grapefruit may increase levels.⁹

Advise patients to report sudden loss of vision or hearing, or an erection lasting >4 hrs.

Adding sildenafil to bosentan does not improve exercise capacity.

Available as a tablet (U.S.: $42.95 per month for 20 mg TID [generic]), oral suspension (U.S.), and injection.

The injection is for patients prescribed sildenafil who are temporarily unable to take oral tablets. An intravenous dose of 10 mg is about equal to 20 mg orally.

Tadalafil (Adcirca)

Improves exercise capacity. With ambrisentan, reduces risk of clinical disease progression and hospitalization.

Dosed once daily. If patient is taking 40 mg (two 20 mg tablets), instruct patient to take both tablets once daily; do not divide the dose.

Dose cautiously (start with 20 mg once daily) if CrCl 31 to 80 mL/min, or patient has mild to moderate liver impairment. Avoid if CrCl <30 mL/min, and in patients with severe liver impairment.

Avoid with nitrates (contraindicated), strong CYP3A4 inhibitors (may cause dangerous hypotension), and CYP3A4 inducers (may reduce efficacy). Grapefruit may increase levels.

Advise patients to report sudden loss of vision or hearing, or an erection lasting >4 hrs.

Available as a tablet (U.S.: $3,318.50 per month for 40 mg once daily).

Endothelin receptor antagonists block endothelin-mediated vasoconstriction, vascular hypertrophy, fibrosis, and inflammation.

Ambrisentan (Letairis [U.S.], Volibris [Canada])

Improves exercise capacity and delays clinical worsening. With tadalafil, reduces risk of clinical disease progression and hospitalization.

Teratogenic. U.S.: Available only through a restricted program called Letairis REMS to ensure effective contraception and monthly pregnancy tests. The prescriber, female patient, and pharmacy must be certified/enrolled in the program. Canada: requires baseline pregnancy test, reliable contraception, and pregnancy testing as clinically indicated.

More frequent side effects: peripheral edema, flushing, nasal congestion, sinusitis.

Peripheral edema that may require diuretics, fluid restriction, or hospitalization may occur. More common when used with tadalafil. Symptoms must be distinguished from other causes, such as worsening PAH.

May also cause pulmonary edema with pulmonary veno-occlusive disease, which requires discontinuation.

Not recommended in moderate or severe liver impairment (Canada: contraindicated).

Canada: check liver function tests at baseline, monthly in at-risk patients, and in any patient as clinically indicated.

Measure hemoglobin at baseline, one month after starting, and periodically.

Available as a tablet. Available only from specialty pharmacies (U.S.).

Bosentan (Tracleer)

Generic available in Canada.

Improves exercise capacity and delays clinical worsening.

Teratogenic. U.S.: Available only through a restricted program called Tracleer REMS to ensure effective contraception and monthly pregnancy tests. The prescriber, patient, and pharmacy must be certified/enrolled in the program. Canada: requires baseline pregnancy test and reliable contraception. Monthly pregnancy testing is recommended.

More frequent side effects: anemia, respiratory tract infection.

Must check liver function tests at baseline and monthly (U.S.: weekly for the first four weeks if taking rifampin). This is a component of the Tracleer REMS. Avoid in moderate or severe liver impairment (Canada: contraindicated).

Avoid use with a CYP2C9 inhibitor plus strong or moderate CYP3A4 inhibitor (Canada: avoid use with a potent CYP2C9 inhibitor plus CYP3A4 inhibitor).

Induces CYP2C9 and CYP3A4. May render hormonal contraceptives ineffective, and reduce efficacy of CYP3A4-metabolized statins (e.g., atorvastatin, lovastatin, simvastatin).

Cyclosporine is contraindicated.

Contraindicated with glyburide due to liver enzyme elevation.

Peripheral edema that may require diuretics, fluid restriction, or hospitalization may occur. Symptoms must be distinguished from other causes, such as worsening PAH.

May also cause pulmonary edema with pulmonary veno-occlusive disease, which requires discontinuation.

Measure hemoglobin after one and three months, then every three months.

Available as a tablet. Available only from specialty pharmacies (U.S.)

Macitentan (Opsumit)

Delays clinical disease progression (e.g., worsening symptoms, reduced exercise capacity, need for a prostacyclin) and reduces hospitalization.

Teratogenic. U.S.: Available only through a restricted program called Opsumit REMS to ensure effective contraception and monthly pregnancy tests. The prescriber, female patient, and pharmacy must be certified/enrolled in the program. Canada: requires baseline pregnancy test and reliable contraception during treatment and for one month afterward. Monthly pregnancy testing is recommended.

More frequent side effects: anemia, nasopharyngitis, pharyngitis, bronchitis, flu, urinary tract infection.

Avoid strong CYP3A4 inhibitors (Canada: use caution) and inducers.

May cause pulmonary edema with pulmonary veno-occlusive disease, which requires discontinuation.

U.S.: Check liver function tests and hemoglobin at baseline and as clinically indicated. Canada: Check hemoglobin at baseline, at one month, and as clinically indicated. Check liver function tests at baseline, monthly for the first year, and as clinically indicated.

Available as a tablet. Available only from specialty pharmacies (U.S.).

Soluble guanylate cyclase inhibitor stimulates the receptor for nitric oxide.

Riociguat (Adempas)

Improves exercise capacity, improves WHO functional class, and delays clinical worsening.

Teratogenic. U.S.: Available only through a restricted program called Adempas REMS to ensure effective contraception and monthly pregnancy tests. The prescriber, female patient, and pharmacy must be certified/enrolled in the program. Canada: women should be advised to use effective contraception.

More frequent side effects: headache, stomach upset, reflux, dizziness, hypotension, nausea, vomiting, diarrhea, constipation, anemia.

Contraindicated with nitrates or phosphodiesterase 5 inhibitors.

• Stop sildenafil at least 24 hrs before, and tadalafil at least 48 hrs before, starting riociguat. Stop riociguat at least 24 hrs before starting a phosphodiesterase 5 inhibitor.

Increases risk of bleeding, hypotension, and pulmonary veno-occlusive disease, which requires discontinuation.

For patient receiving strong CYP and P-gp/BCRP inhibitors (e.g. azoles, protease inhibitors), consider starting with only 0.5 mg TID. Monitoring for hypotension.

Smokers may require a dose higher than the maximum dose (U.S.). A dose reduction may be needed if the patient stops smoking.

Separate from antacids by at least one hour. Canada: take antacids at least one hour after riociguat.

Available as a tablet. Available only from specialty pharmacies (U.S.).

Prostacyclins cause vasodilation and have antiplatelet effects.

Epoprostenol (Flolan, Veletri [U.S.], Caripul [Canada])

Generic Flolan available in U.S.

Improves exercise capacity.

Continuous intravenous infusion. Requires central access. Peripheral line may be used temporarily until central access obtained. Initiate in facility with access to emergency care. Thereafter, can be administered with an ambulatory infusion pump.

More frequent side effects (caused by vasodilation): headache, musculoskeletal and jaw pain, nausea, vomiting, diarrhea, anxiety. More common during initiation or dose escalation are hypotension, dizziness, flushing, chest pain, tachycardia, bradycardia, dyspnea, and abdominal pain.

Increases bleeding risk. Canada: monitor platelet counts and prothrombin time.

Discontinue if pulmonary edema occurs.

Discontinuation requires tapering to prevent rebound increase in pulmonary artery pressure.

Preferred over treprostinil.¹

Postmarketing reports of hyperthyroidism.

Available only from specialty pharmacies (U.S.).

Limited stability once reconstituted. See product labeling for storage and administration time limits.

Iloprost (Ventavis [U.S.])

Improves exercise tolerance and symptoms, and stabilizes clinical disease progression.

Inhalation therapy. Used with the I-neb AAD system.

Frequent dosing (six to nine times daily). Consider extending dosing interval in patients with moderate or severe liver impairment.

Increases bleeding risk.

More frequent side effects: flushing, cough, hemoptysis, pneumonia, headache, trismus, muscle cramps, back pain, insomnia, nausea, vomiting, hypotension, syncope, increased alkaline phosphatase or GGT (gamma-glutamyl transferase), muscle cramps, tongue pain, palpitations

May cause bronchospasm. Not studied in patients with asthma, COPD, or pulmonary infection.

Due to risk of syncope, do not initiate in patients with systolic blood pressure <85 mmHg.

Discontinue in the event of pulmonary edema.

Available only from specialty pharmacies (U.S.).

Treprostinil (U.S.) (Remodulin, Tyvaso, Orenitram)

Improves exercise capacity.

Available as a solution for continuous subcutaneous or intravenous infusion (Remodulin), inhalation (Tyvaso), and extended-release tablet (Orenitram).

More frequent side effects:

• Remodulin: infusion site reactions, headache, nausea, diarrhea, jaw pain, edema, hypotension.
• Tyvaso: cough, headache, nausea, diarrhea, flushing, dizziness, throat irritation or pain.
• Orenitram: headache, diarrhea, nausea, flushing.

Other notable product-specific information:

• Remodulin: discontinuation requires tapering to prevent rebound increase in pulmonary artery pressure. Requires initial dose reduction in liver impairment. Reduces the rate of clinical deterioration in patients who require transition from Flolan. Has not been studied with epoprostenol or bosentan.
• Tyvaso: use only with the Tyvaso Inhalation System. Increases bleeding risk. May cause symptomatic hypotension.
• Orenitram: increases bleeding risk. Discontinuation requires tapering to prevent rebound increase in pulmonary artery pressure. Contraindicated in severe liver impairment. Avoid in moderate hepatic impairment. Reduce initial and titration dose in mild hepatic impairment. Tablets may become lodged in a diverticulum. Use with blood pressure meds increases risk of hypotension. Orenitram has only a small effect on exercise. It has not been shown to provide added benefit if given with other vasodilator therapy. Product labeling provides information on switching to/from Remodulin.

Available only from specialty pharmacies (U.S.).

Prostacyclin receptor agonists reduce pulmonary vascular resistance by binding to prostacyclin receptors.

Selexipag
(Uptravi)

Delays clinical progression and reduces risk of hospitalization

Available as a tablet.

More frequent side effects: headache, nausea, vomiting, diarrhea, pain in jaw or extremity, myalgias, flushing.

Requires dose reduction for moderate liver impairment. Avoid use in severe liver impairment.

U.S.: Avoid with strong CYP2C8 inhibitors. Canada: use with strong inhibitors of CYP2C8, inhibitors of UGT1A3 or UGT2B7, or inducers of these enzymes (e.g., rifampin) is not recommended.

Canada: may cause hypotension or hyperthyroidism.

Available only from specialty pharmacies (U.S.).