Tadalafil for Pulmonary Hypertension

Tadalafil is a once-daily oral phosphodiesterase-5 inhibitor for pulmonary arterial hypertension (PAH, group 1), often combined with an endothelin receptor antagonist. Start only in a PAH centre after right heart catheterisation.

Classification. Phosphodiesterase-5 inhibitor, pulmonary vasodilator.

Mechanism. Blocks cyclic GMP breakdown in pulmonary vascular smooth muscle, enhancing nitric oxide-mediated vasodilatation.

Pharmacokinetics. Bioavailability not changed by food. Peak at 2 to 4 hours. Metabolised by CYP3A4. Half-life about 35 hours. Excreted mainly in faeces.

Specialist, PAH, adults. 40 mg (two 20 mg tablets) once daily. Where tolerability is a concern, start 20 mg once daily and increase to 40 mg once daily after 2 to 4 weeks.

Initial combination. Tadalafil 20 mg once daily with ambrisentan 5 mg once daily, raising tadalafil to 40 mg after 4 weeks if tolerated.

Fixed combination. Tadalafil 40 mg with macitentan 10 mg once daily, where licensed.

Children. Not licensed in many regions; specialist use only with weight-banded dosing.

Emergency. Not used.

Titration and loading. One step from 20 mg to 40 mg. No loading dose.

Contraindications. All nitrates and nitric oxide donors, riociguat, hypersensitivity, recent stroke or myocardial infarction, severe hypotension, and pulmonary veno-occlusive disease.

Serious adverse effects. Hypotension, non-arteritic anterior ischaemic optic neuropathy, sudden hearing loss, priapism, epistaxis.

Common adverse effects. Headache, myalgia, back pain, flushing, dyspepsia, nasal congestion.

Interactions.

• Nitrates: contraindicated.

• Ritonavir: if already on ritonavir for at least a week, start 20 mg once daily. If starting ritonavir in a patient already on tadalafil, stop tadalafil 24 hours before and restart at 20 mg once daily after at least a week.

• Rifampicin lowers tadalafil exposure by about 85%; avoid.

• Bosentan lowers tadalafil exposure by about 40%.

• Alpha-blockers and antihypertensives add hypotension.

Common prescribing errors. Giving with nitrates. Missing the ritonavir adjustment. Giving with rifampicin without review. Using in left heart disease.

Special groups.

• Pregnancy: avoid unless needed; limited data. Breastfeeding: no data; avoid.

• Older adults: no adjustment.

• Kidney impairment: GFR 31 to 80 mL/min, start 20 mg once daily and raise to 40 mg if tolerated. GFR under 30 mL/min and dialysis: avoid. Liver impairment: mild to moderate, start 20 mg once daily. Severe: avoid.

• East Africa: rifampicin-containing tuberculosis regimens and ritonavir-boosted antiretroviral regimens are the key interactions. Caution in sickle cell pulmonary hypertension, as with sildenafil.

Formulations. Tablets 20 mg for PAH. Other strengths (2.5, 5, 10 mg) are for other conditions.

Administration. Once daily at the same time, with or without food.

Baseline. Blood pressure, right heart catheter results, functional class, 6 minute walk distance, NT-proBNP, nitrate use, eye history.

Monitoring. Blood pressure, visual and hearing symptoms, functional class and 6 minute walk distance every 3 to 6 months.

Stop and reduce rules. Stop for sudden visual or hearing loss, priapism over 4 hours or symptomatic hypotension. Therapeutic drug monitoring is not used.

Referral and escalation. Manage in a PAH centre. Refer urgently for syncope, right heart failure or visual loss.