Tadalafil 20 mg to 40 mg Given Every Second Day Is Effective in Secondary Pulmonary Hypertensio
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The primary endpoint was time to first clinical failure event, defined as time from randomisation to the first occurrence of death (all-cause), hospitalisation for worsening PAH, disease progression or unsatisfactory long-term clinical response (events adjudicated by an independent, blinded committee). Analysis of the time to first individual component of clinical failure indicates the treatment effect observed was primarily driven by a reduction in hospitalisations. No new safety signals were detected with the combination of ambrisentan and tadalafil than have been observed with either medicine alone. Adverse events occurring more frequently in the combination arm than in each monotherapy arm were peripheral oedema (combination: 46%; ambrisentan: 33%; tadalafil: 28%), headache (combination: 42%; ambrisentan: 33%; tadalafil: 35%), nasal congestion (combination: 21%; ambrisentan: 15 %; tadalafil: 12 %) and anaemia (combination: 15%; ambrisentan: 6%; tadalafil: 12%). GSK commercialises ambrisentan under the tradename Volibris® in territories outside of the United States and Gilead commercialises ambrisentan under the tradename Letairis® in the U.S. Ambrisentan has been granted orphan drug status for the treatment of PAH in Australia, Europe, Japan, Korea and United States. GSK also has an exclusive license from Eli Lilly and Company to promote tadalafil for PAH under the tradename Adcirca® in Europe. For the approved indications and EU summaries of product characteristics for ambrisentan and tadalafil, please visit Letairis and Volibris are registered trademarks of Gilead Sciences, Inc or one of its related companies.
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Carlo Russo, Senior Vice President, Head of GSK Rare Diseases Research & Development. “We thank all the investigators, study teams and especially the patients for diligently participating in this study that lasted for 3.5 years and we now look forward to submitting an application to regulatory authorities in the coming months.” The combination use of ambrisentan and tadalafil is not approved anywhere in the world. Preclinical data suggested these therapies may have synergistic effects. Ambrisentan, a selective endothelin type-A receptor antagonist, and tadalafil, a PDE-5 inhibitor, are each approved in the EU and other countries as once-daily treatments for PAH, (WHO Group 1) in patients with WHO/NYHA functional class II and III symptoms. In the EU, ambrisentan is indicated for the treatment of adult patients with PAH classified as WHO functional class II and III, to improve exercise capacity. Adcirca is a registered trademark of Eli Lilly and Company. The following Important Safety Information is based on a summary of the Summary of Product Characteristics for both ambrisentan and tadalafil. Please consult the full Summary of Product Characteristics for all the labelled safety information for ambrisentan and tadalafil. Ambrisentan is contraindicated in patients with hypersensitivity to the active substance, to soya or any of the excipients Animal studies have shown that ambrisentan is teratogenic. Women receiving ambrisentan must be advised of the risk of foetal harm and alternative therapy initiated if pregnancy occurs. It is not known whether ambrisentan is excreted in human breast milk. The excretion of ambrisentan in milk has not been studied in animals.
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Rates of serious adverse events and events leading to discontinuation were similar across treatment arms. Detailed results from the study (Abstract #2916) were presented today during an oral session at the annual meeting of the European Respiratory Society (ERS). “The data provided by the AMBITION study represent one of the most important steps forward in the treatment of patients with PAH” said Nazzareno Galiè, MD, Professor of Cardiology and Head of the Pulmonary Hypertension Centre, University of Bologna, Italy; Principal Investigator and Co-Chair of the AMBITION Steering Committee. “The 50% risk reduction for clinical failure achieved with upfront combination therapy as compared to upfront monotherapy, indicates that this combination treatment strategy could potentially become the standard of care in treatment naïve PAH patients with WHO/NYHA functional class II and III symptoms.” The companies now plan to seek approval for this combination indication by submitting the data from the AMBITION study to regulators in the United States (US), European Union (EU) and the rest of the world. “As part of our efforts to further help patients who suffer with this rare and debilitating lung disease, GSK and Gilead took a major step to jointly sponsor the first study to investigate whether there was an advantage to use upfront combination of ambrisentan and tadalafil compared to first-line monotherapy with either medicine” said Dr. Therefore breast-feeding is contraindicated in patients taking ambrisentan In males, the development of testicular tubular atrophy in male animals has been linked to the chronic administration of endothelin receptor antagonists (ERAs), including ambrisentan. Ambrisentan has not been studied in a sufficient number of patients to establish the benefit/risk balance in WHO functional class I PAH. Liver function abnormalities have been associated with PAH. Cases consistent with autoimmune hepatitis, including possible exacerbation of underlying autoimmune hepatitis, hepatic injury and hepatic enzyme elevations potentially related to therapy have been observed with ambrisentan. Therefore hepatic aminotransferases (ALT and AST) should be evaluated prior to initiation of ambrisentan and treatment should not be initiated in patients with baseline values of ALT and/or AST>3xULN.
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PAH afflicts approximately 200,000 patients worldwide. The AMBITION study was co-sponsored by GSK and Gilead. Eli Lilly and Company also provided funding and tadalafil drug supply for the trial. AMBITION was a randomised, double-blind phase IIIb/IV study designed to compare the safety and efficacy of investigational first-line combination therapy (ambrisentan and tadalafil) to first-line monotherapy (ambrisentan or tadalafil) in treatment-naïve patients with WHO/NYHA functional class II and III PAH. In the study, 500 patients were randomised (2:1:1) to receive ambrisentan and tadalafil combination (n=253) or monotherapy with ambrisentan (n=126) or tadalafil (n=121) (titrated from 5 mg to 10 mg once-daily and from 20 mg to 40 mg once-daily for ambrisentan and tadalafil, respectively). Peripheral oedema, fluid retention and headache (including sinus headache, migraine) were the most common adverse reactions observed with ambrisentan. Tadalafil is contraindicated in patients with hypersensitivity to the active substance or to any of the excipients. Tadalafil is contraindicated in patients that have experienced acute myocardial infarction within the last 90 days and in patients that have severe hypotension (<90/50 mm Hg).
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Tadalafil is indicated in adults for the treatment of PAH classified as WHO functional class II and III, to improve exercise capacity. PAH is a debilitating disease characterised by constriction of the blood vessels in the lungs leading to high pulmonary arterial pressures. These high pressures make it difficult for the heart to pump blood through the lungs to be oxygenated. Patients with PAH suffer from shortness of breath as the heart struggles to pump against these high pressures, causing such patients to ultimately die of heart failure. PAH can occur with no known underlying cause, or it can occur secondary to diseases such as connective tissue disease, congenital heart defects, cirrhosis of the liver and HIV infection. In clinical studies, tadalafil was shown to augment the hypotensive effects of nitrates. This is thought to result from the combined effects of nitrates and tadalafil on the nitric oxide/cGMP pathway. Therefore, administration of tadalafil to patients who are using any form of organic nitrate is contraindicated. Tadalafil is contraindicated in patients who have loss of vision in one eye because of non-arteritic anterior ischaemic optic neuropathy (NAION), regardless of whether this episode was in connection or not with previous PDE5 inhibitor exposure. Visual defects and cases of NAION have been reported in connection with the intake of tadalafil and other PDE5 inhibitors. The patient should be advised that in case of sudden visual defect, to consult a physician immediately. Patients with known hereditary degenerative retinal disorders, including retinitis pigmentosa, were not included in the clinical studies, and use in these patients is not recommended. The following groups of patients with cardiovascular disease were not included in PAH clinical studies: Patients with clinically significant aortic and mitral valve disease Since there are no clinical data on the safety of tadalafil in these patients, the use of tadalafil is not recommended. Due to increased tadalafil exposure (AUC), limited clinical experience, and the lack of ability to influence clearance by dialysis, tadalafil is not recommended in patients with severe renal impairment. Patients with severe hepatic cirrhosis (Child-Pugh Class C) have not been studied and therefore dosing of tadalafil is not recommended. For patients chronically taking potent inducers of CYP3A4, such as rifampicin, the use of tadalafil is not recommended. For patients taking concomitant potent inhibitors of CYP3A4, such as ketoconazole or ritonavir, the use of tadalafil is not recommended. The safety and efficacy of combinations of tadalafil and other PDE5 inhibitors or other treatments for erectile dysfunction have not been studied. Patients should be informed not to take tadalafil with these medicinal products. The efficacy and safety of tadalafil co-administered with prostacyclin or its analogues has not been studied in controlled clinical studies. Therefore, caution is recommended in case of co-administration. The efficacy of tadalafil in patients already on bosentan therapy has not been conclusively demonstrated.