ADEMPAS

What it is

ADEMPAS contains the active ingredient riociguat and is available as film-coated tablets in strengths of 0.5 mg, 1 mg, 1.5 mg, 2 mg, and 2.5 mg. Riociguat is a stimulator of soluble guanylate cyclase, an enzyme found in most tissues and the receptor for nitric oxide. It has a dual mode of action: it sensitises the enzyme to endogenous nitric oxide by stabilising the nitric oxide-enzyme binding, and it also directly stimulates the enzyme via a different binding site, independently of nitric oxide.

Approved indications

— Idiopathic pulmonary arterial hypertension, as monotherapy or in combination with approved PAH treatments (endothelin receptor antagonists or inhaled or subcutaneous prostanoids), in adult patients with WHO functional Class II, III or IV symptoms. — Heritable pulmonary arterial hypertension, as monotherapy or in combination with approved PAH treatments (endothelin receptor antagonists or inhaled or subcutaneous prostanoids), in adult patients with WHO functional Class II, III or IV symptoms. — Pulmonary arterial hypertension associated with connective tissue diseases, as monotherapy or in combination with approved PAH treatments (endothelin receptor antagonists or inhaled or subcutaneous prostanoids), in adult patients with WHO functional Class II, III or IV symptoms. — Pulmonary arterial hypertension associated with congenital heart disease, as monotherapy or in combination with approved PAH treatments (endothelin receptor antagonists or inhaled or subcutaneous prostanoids), in adult patients with WHO functional Class II, III or IV symptoms. — Persistent or recurrent chronic thromboembolic pulmonary hypertension (CTEPH) after surgical treatment, in adult patients with WHO functional Class II, III or IV symptoms. — Inoperable CTEPH, in adult patients with WHO functional Class II, III or IV symptoms.

Dosing overview

Treatment should only be initiated and monitored by a physician experienced in the treatment of CTEPH or PAH. Tablets should be taken three times daily approximately 6 to 8 hours apart. The recommended starting dose is 1.0 mg three times daily for 2 weeks, though a starting dose of 0.5 mg three times daily may be considered for patients who may not tolerate the hypotensive effect. Dosage should be increased in 2-week intervals by 0.5 mg increments to a maximum of 2.5 mg three times daily, if systolic blood pressure is ≥ 95 mmHg and the patient has no signs or symptoms of hypotension. The maximum total daily dose is 7.5 mg.

Key safety warnings

ADEMPAS reduces blood pressure. The potential for symptomatic hypotension or ischaemia should be considered in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong multi-pathway CYP and P-gp/BCRP inhibitors. While the risk of hypotension is greater during titration it may occur during maintenance therapy. Dose reduction should be considered if the patient develops signs or symptoms of hypotension. In patients with pulmonary hypertension, there is increased likelihood for respiratory tract bleeding, particularly among patients receiving anticoagulation therapy. Bleeding risk should be carefully evaluated before initiating ADEMPAS therapy, and patients should be monitored periodically, particularly in patients taking anticoagulants. The prescriber should regularly assess the benefit-risk with each individual patient. The risk of serious and fatal bleeding, including respiratory tract bleeding, may be further increased under treatment with ADEMPAS, especially in the presence of risk factors such as recent episodes of serious haemoptysis including those managed by bronchial arterial embolization. Riociguat should be avoided in patients with a history of serious haemoptysis or who have previously undergone bronchial arterial embolization. Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease. Therefore, administration of ADEMPAS to these patients is not recommended. Should signs of pulmonary oedema occur, the possibility of associated PVOD should be considered and treatment with ADEMPAS should be discontinued.

Contraindications

ADEMPAS may cause birth defects and is contraindicated in pregnancy and lactation. Co-administration of ADEMPAS with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated. Co-administration of ADEMPAS with specific PDE-5-inhibitors (such as sildenafil, tadalafil, or vardenafil) or nonspecific PDE inhibitors (such as dipyridamole or theophylline) is contraindicated. ADEMPAS is contraindicated in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias (PH-IIP).

PBS listing

ADEMPAS is listed on the PBS in strengths of 0.5 mg, 1 mg, 1.5 mg, 2 mg, and 2.5 mg. Each strength has 4 PBS items and requires authority. The ex-manufacturer price is A$1631.82 per item.

Regulatory history

ADEMPAS (riociguat) was first registered on the ARTG on 14 April 2014 in all five strengths (0.5 mg, 1 mg, 1.5 mg, 2 mg, and 2.5 mg). The TGA approved ADEMPAS on 7 April 2014 for the treatment of adult patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) who present with WHO functional class II, III or IV symptoms. In March 2016, the PBAC recommended listing of riociguat under Section 100 (Highly Specialised Drugs Program) for the treatment of patients with inoperable CTEPH or persistent CTEPH subsequent to pulmonary endarterectomy, finding that riociguat provides a significant improvement in efficacy over placebo for some patients. In November 2021, the PBAC recommended an amendment to authority requirements.