Adempas demonstrated efficacy for PAH adult patients in both WHO functional class II and III by 4 parameters1:
*Time to clinical worsening was a combined endpoint defined as death (all-cause mortality), heart/lung transplantation, atrial septostomy, hospitalization due to persistent worsening of pulmonary hypertension, start of new PAH-specific treatment, persistent decrease in 6-minute walk distance (6MWD) and persistent worsening of WHO functional class.
NT-proBNP=N-terminal pro-brain natriuretic peptide; PVR=pulmonary vascular resistance
PATENT-1 STUDY DESIGN1,2
Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (PATENT-1)
was a randomized, double-blind, multinational, multicenter, placebo-controlled, 12-week phase 3 study.
FC=functional class; mPAP=mean pulmonary arterial pressure; SBP=systolic blood pressure
36 m improvement (mean) in 6-minute walk distance (6MWD) over placebo at Week 12 (95% confidence interval (CI): 20 m-52 m; p<0.0001) for adults with PAH (WHO Group 1).
IMPROMENTS IN 6MWD
AT WEEK 12
Right-heart catheterization was performed at the beginning and end of the study period in 339 patients.
Adempas, n=254; placebo, n=126
IN THE 12-WEEK TRIAL
4% for Adempas (n=9/254)
14% for placebo (n=18/125)
76% for Adempas (n=192/254)
71% for placebo (n=89/125)
WITHIN 12 WEEKS
Time to clinical worsening was a combined endpoint defined as death (all-cause mortality), heart/lung transplantation, atrial septostomy, hospitalization due to persistent worsening of pulmonary hypertension, start of new PAH-specific treatment, persistent decrease in 6MWD and persistent worsening of WHO functional class.
DATA FOR PAH PATIENTS
An open-label extension PATENT-2 study included 396 patients who had completed PATENT-1. At the cut-off date in the PATENT-2 study, the mean treatment duration for the total population was 1146 days (±479). Without a control group, these data must be interpreted cautiously.
Other events that were seen more frequently in Adempas compared to placebo and potentially related to treatment were:
- Nasal congestion
- Abdominal distention
- Peripheral edema
WARNING: EMBRYO-FETAL TOXICITY
Do not administer Adempas (riociguat) tablets to a pregnant female because it may cause fetal harm.
Females of reproductive potential: Exclude pregnancy before the start of treatment, monthly during treatment, and one month after stopping treatment. To prevent pregnancy, females of reproductive potential must use effective forms of contraception during treatment and for one month after stopping treatment.
For all female patients, Adempas is available only through a restricted program called the Adempas Risk Evaluation and Mitigation Strategy (REMS) Program.
Adempas is contraindicated in:
- Pregnancy. Based on data from animal reproduction studies, Adempas may cause fetal harm when administered to a pregnant woman and is contraindicated in females who are pregnant. Adempas was consistently shown to have teratogenic effects when administered to animals. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.
- Co-administration with nitrates or nitric oxide donors (such as amyl nitrite) in any form.
- Concomitant administration with specific phosphodiesterase (PDE)-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) or nonspecific PDE inhibitors (such as dipyridamole or theophylline) is contraindicated. Do not administer within 24 hours of sildenafil. Do not administer 24 hours before or within 48 hours after tadalafil.
- Patients with Pulmonary Hypertension associated with Idiopathic Interstitial Pneumonias (PH-IIP).
Embryo-Fetal Toxicity. Based on data from animal reproduction studies, Adempas may cause embryo-fetal toxicity when administered to a pregnant female and is contraindicated in females who are pregnant. Advise females of reproductive potential of the potential risk to a fetus. Obtain a pregnancy test before the start of treatment, monthly during treatment, and for one month after stopping treatment. Advise females of reproductive potential to use effective contraception during treatment with Adempas and for at least one month after the last dose.
For females, Adempas is only available through a restricted program under the Adempas REMS Program.
Adempas REMS Program. Females can only receive Adempas through the Adempas REMS Program, a restricted distribution program.
Important requirements of the Adempas REMS Program include the following:
- Prescribers must be certified with the program by enrolling and completing training.
- All females, regardless of reproductive potential, must enroll in the Adempas REMS Program prior to initiating Adempas. Male patients are not enrolled in the Adempas REMS Program.
- Female patients of reproductive potential must comply with the pregnancy testing and contraception requirements.
- Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive Adempas.
Further information, including a list of certified pharmacies, is available at www.AdempasREMS.com or 1-855-4ADEMPAS.
Hypotension. Adempas reduces blood pressure. Consider the potential for symptomatic hypotension or ischemia in patients with hypovolemia, severe left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concomitant treatment with antihypertensives or strong CYP and P-gp/BCRP inhibitors. Consider a dose reduction if patient develops signs or symptoms of hypotension.
Bleeding. In the placebo-controlled clinical trials, serious bleeding occurred in 2.4% of patients taking Adempas compared to 0% of placebo patients. Serious hemoptysis occurred in 5 (1%) patients taking Adempas compared to 0 placebo patients, including one event with fatal outcome. Serious hemorrhagic events also included 2 patients with vaginal hemorrhage, 2 with catheter-site hemorrhage, and 1 each with subdural hematoma, hematemesis, and intra-abdominal hemorrhage.
Pulmonary Veno-Occlusive Disease. Pulmonary vasodilators may significantly worsen the cardiovascular status of patients with pulmonary veno-occlusive disease (PVOD). Therefore, administration of Adempas to such patients is not recommended. Should signs of pulmonary edema occur, the possibility of associated PVOD should be considered and if confirmed, discontinue treatment with Adempas.
The most common adverse reactions occurring more frequently (≥3%) on Adempas than placebo were headache (27% vs 18%), dyspepsia/gastritis (21% vs 8%), dizziness (20% vs 13%), nausea (14% vs 11%), diarrhea (12% vs 8%), hypotension (10% vs 4%), vomiting (10% vs 7%), anemia (7% vs 2%), gastroesophageal reflux disease (5% vs 2%), and constipation (5% vs 1%).
Other events that were seen more frequently in Adempas compared to placebo and potentially related to treatment were palpitations, nasal congestion, epistaxis, dysphagia, abdominal distension, and peripheral edema.
- Adempas (riociguat) tablets is indicated for the treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) (WHO Group 4) after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class.
- Adempas is indicated for the treatment of adults with pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise capacity, improve WHO functional class, and to delay clinical worsening.*
Efficacy was shown in patients on Adempas monotherapy or in combination with endothelin receptor antagonists or prostanoids. Studies establishing effectiveness included predominantly patients with WHO functional class II–III and etiologies of idiopathic or heritable PAH (61%) or PAH associated with connective tissue diseases (25%).
*Time to clinical worsening was a combined endpoint defined as death (all-cause mortality), heart/lung transplantation, atrial septostomy, hospitalization due to persistent worsening of pulmonary hypertension, start of new PAH-specific treatment, persistent decrease in 6MWD, and persistent worsening of WHO functional class.
For important risk and use information, please see the full Prescribing Information, including Boxed Warning.
- Adempas Prescribing Information. Whippany, NJ. Bayer Pharmaceuticals Inc., 2018.
- Ghofrani HA, Galiè N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330-340.
- Data on file, 2018. Bayer.