Indications: Riociguat 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.
- Pulmonary Arterial Hypertension (PAH) (WHO Group 1) to improve exercise capacity, improve WHOfunctional class and to delay clinical worsening.
Mechanism: Riociguat is a stimulator of soluble guanylate cyclase (sGC), an enzyme in the cardiopulmonary system and the receptor for nitric oxide (NO). When NO binds to sGC, cyclic guanosine monophosphate (cGMP) is synthesized. Intracellular cGMP plays an important role in regulating processes that influence vascular tone, proliferation, fibrosis and inflammation. Pulmonary hypertension is associated with endothelial dysfunction, impaired synthesis of nitric oxide, and insufficient stimulation of the NO-sGC-cGMP pathway. Riociguat stimulates the NO-sGC-cGMP pathway and leads to increased generation of cGMP with subsequent vasodilation.
Dosing: Initiate treatment at 1 mg taken three times a day. For patients who may not tolerate the hypotensive effect of riociguat, consider a starting dose of 0.5 mg, three times a day. Increase dosage by 0.5 mg at intervals of no sooner than 2-weeks as tolerated to a maximum of 2.5 mg three times a day.
Efficacy:
Chronic-Thromboembolic Pulmonary Hypertension
A double-blind, multi-national, multi-center, study (CHEST-1) was conducted in 261 patients with CTEPH. Patients were randomized to Adempas titrated up to 2.5 mg three times a day (n=173) or placebo (n=88). Stable dosages of oral anticoagulants, diuretics, digitalis, calcium channel blockers and oxygen were allowed, but not concomitant therapy with NO donors, endothelin receptor antagonists, prostacyclin analogues, specific PDE-5 inhibitors (such as, sildenafil, tadalafil, or vardenafil), and nonspecific phosphodiesterase inhibitors (for example, dipyridamole or theophylline).
The primary endpoint of the study was change from baseline in six minute walking distance (6MWD) after 16 weeks. The mean age of the patients enrolled was 59 years (range 18–80 years). In the study, 72% of patients had inoperable CTEPH, 28% had recurrent or persisting pulmonary hypertension following pulmonary
endarterectomy. The majority of patients had a World Health Organization (WHO) Functional Class II (31%) or III (64%) at baseline. The mean baseline 6MWD was 347 meters. In the study, 77% of patients were titrated to the maximum dose of 2.5 mg three times a day; 13%, 6%, 4%, and 1% of patients were titrated to riociguat doses of 2 mg, 1.5 mg, 1 mg, and 0.5 mg three times a day, respectively.
Results of the 6MWD over 16 weeks for the CHEST-1 study are shown in Figure 1.
Improvements in walking distance were apparent from Week 2 onward. At Week 16, the placebo adjusted mean increase in 6MWD within the Adempas group was 46 m (95% confidence interval [CI]: 25 m to 67 m; p<0.0001). For CHEST-1, the median difference (Hodges-Lehmann non-parametric estimate) in 6MWD was 39 m (95% CI, 25 m to 54 m).
Improvements in WHO Functional Class are shown in Table 1.
Long-Term Treatment of CTEPH
An open-label extension study (CHEST-2) included 237 patients who had completed CHEST-1. At the cut-off date in the CHEST-2 study, the mean treatment duration for the total population was 582 days (± 317). The probabilities of survival at 1 and 2 years were 97% and 94%, respectively. Without a control group, however, these data must be interpreted cautiously.
Pulmonary Arterial Hypertension
A double-blind, multi-national, multi-center study (PATENT-1) was conducted in 443 patients with PAH as defined by PVR >300 dyn*sec*cm-5 and a PAP mean >25 mmHg. Patients were randomized to one of three treatment groups: Adempas titrated up to 1.5 mg (n=63), 2.5 mg (n=254) or placebo (n=126) three times a day. Oral anticoagulants, diuretics, digitalis, calcium channel blockers, and oxygen were allowed. In this study, 50% of the patients were treatment- naive with respect to PAH therapy, 44% were pre-treated with an endothelin receptor antagonist (ERA) and 6% were pre-treated with a prostacyclin analogue (inhaled, oral or subcutaneous). Pre-treated patients were defined as patients on stable treatment for 3 months with either an ERA or PCA; Adempas was added in combination to these background therapies.
The primary endpoint of the study was change from baseline and placebo in 6MWD after 12 weeks in the 2.5 mg group. The mean age of all patients was 51 years and approximately 80% were female. PAH etiologies were either idiopathic (61%) or familial PAH (2%), PAH associated with connective tissue disease (25%), congenital heart disease (8%), portal hypertension (3%), or anorexigen or amphetamine use (1%). The majority of patients had a World Health Organization (WHO) Functional Class II (42%) or III (54%) at baseline. The overall mean baseline 6MWD was 363 meters. Approximately 75% of patients were up-titrated to receive the maximum dose of 2.5 mg three times a day by week 12; 15%, 6%, 3%, and 2% were titrated to doses of 2 mg, 1.5 mg, 1 mg, and 0.5 mg 3 times a day, respectively.
Results of the 6MWD over 12 weeks for the PATENT-1 study are shown in Figure 2.
Improvements 6MWD were apparent from Week 2 onward. At Week 12, the placebo-adjusted mean increase in 6MWD within the Adempas group was 36 m (95% CI: 20 m to 52 m; p<0.0001). For PATENT-1, the median difference in 6MWD was 29 m (95% CI, 17 m to 40 m).
WHO Functional Class improvements in the IDT (individual dose titration) arm of the PATENT-1 trial are shown in Table 2.
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. Effects of Adempas in PATENT-1 on events of clinical worsening are shown in Table 3.
*p-value=0.0285 (Mantel-Haeuszel estimate)
Note: Patients may have had one or more than one event of clinical worsening.
Adempas-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p=0.0046). Significantly fewer events of clinical worsening up to week 12 (last visit) were observed in patients treated with Adempas (1.2%) compared to placebo (6.3%) (p=0.0285).
Adempas-treated patients experienced a significant delay in time to clinical worsening versus placebo-treated patients (p=0.0046). Significantly fewer events of clinical worsening up to week 12 (last visit) were observed in patients treated with Adempas (1.2%) compared to placebo (6.3%) (p=0.0285).
The Kaplan-Meier plot of time to clinical worsening is presented in Figure 3.
Long-Term Treatment of PAH
An open-label extension study (PATENT-2) included 363 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 663 days (± 319). The probabilities of survival at 1 and 2 years were 97% and 93%, respectively. Without a control group, these data must be interpreted cautiously.
Adverse Events: Adverse reactions occurring more frequently (≥3%) on Adempas compared to placebo are headache, dizziness, dyspepsia/gastritis, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux, and constipation.
Warnings:
- EMBRYO-FETAL TOXICITY-Do not administer Adempas to a pregnant female because it may cause fetal harm. Exclude pregnancy before start of treatment, monthly during treatment, and 1 month after treatment discontinuation in females of reproductive potential. Prevent pregnancy during treatment and for one month after treatment discontinuation by use of acceptable methods of contraception. For females, Adempas is available only through a restricted program called the Adempas REMS Program.
- Symptomatic Hypotension-Riociguat reduces blood pressure. Consider potential symptomatic hypotension or ischemia in patients with hypovolemia, sever left ventricular outflow obstruction, resting hypotension, autonomic dysfunction, or concominant antihypertensive therapy.
- Bleeding-serious bleeding, serious hemoptysis and other hemorrhagic events have occurred with riociguat.
- Pulmonary Edema-reported in patients with pulmonary veno-occlusive disease. If confirmed, discontinue treatment with riociguat.
Contraindications: Pregnancy, use with nitrates or nitric oxide donors in any form, and use with phosphodiesterase (PDE) inhibitors are contraindications to use of riociguat.
Metabolism/Drug interactions: Riociguat is mainly cleared by metabolism by CYP1A1, CYP3A, CYP2C8 and CYP2J2.
- Nitrates-co-administration of Adempas with nitrates or nitric oxide donors (such as amyl nitrite) in any form is contraindicated because of hypotension.
- PDE Inhibitors- co-administration of Adempas with phosphodiesterase (PDE) inhibitors, including specific PDE-5 inhibitors (such as sildenafil, tadalafil, or vardenafil) and nonspecific PDE inhibitors (such as dipyridamole or theophylline), is contraindicated because of hypotension.
- Strong CYP and P-gp/BCRP inhibitors-consider a starting dose of 0.5 mg three times a day. Monitor for hypotension.
- Antacids-separate administration by at least 1 hour.
Access Program: Riociguat is only available to patients through certified pharmacies registered with the Adempas REMS (Risk Evaluation and Mitigation Strategy) Program. This program is required by FDA and informs patients and healthcare providers about the serious risks of birth defects while taking Adempas.
All females must enroll in the Adempas REMS Program to receive Adempas. Information on the Adempas REMS program may be found at https://www.adempasrems.com/#MainContent/!Home.
- Females must not be pregnant when they start taking Adempas become pregnant during treatment, or become pregnant for one month after stopping Adempas treatment.
- All healthcare providers must enroll in the Adempas REMS Program and agree to the REMS requirements to prescribe Adempas.
- All female patients must enroll in the Adempas REMS Program and agree to the REMS requirements to receive Adempas.
- A limited number of certified pharmacies will dispense Adempas for outpatients. They must enroll in the Adempas REMS Program and agree to the REMS requirements to provide Adempas for outpatient use.
- Inpatient pharmacies must enroll in the Adempas REMS Program and agree to the REMS requirements to stock Adempas for inpatient use.
Patient Enrollment form: https://www.adempasrems.com/Resources/PDF/PatientEnrollConsentForm.pdf
Bayer offers patient assistance through the Adempas Aim Support Center program, which will assist with obtaining coverage and patient support of Adempas. Patients and providers may contact the program at 1-855-4ADEMPAS or visit http://www.adempas-us.com/hcp/aim-patient-support-program/ for more information
Full US Prescribing Information can be found here:
http://labeling.bayerhealthcare.com/html/products/pi/Adempas_PI.pdf
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