Riociguat (Adempas, Bayer Healthcare Pharmaceuticals Inc.) was approved by FDA on October 8, 2013 for two patient groups. It is intended for patients with pulmonary arterial hypertension (PAH) World Health Organization (WHO) group 1 to improve exercise capacity, improve WHO functional class, and delay clinical worsening. It is also approved for patients with pulmonary hypertension (PH) WHO Group IV who have inoperable or persistent/recurrent postoperative chronic thromboembolic pulmonary hypertension (CTEPH), with the intent of improving exercise capacity and WHO functional class.
Riociguat (Adempas, Bayer Healthcare Pharmaceuticals Inc.) was approved by FDA on October 8, 2013 for 2 patient groups. It is intended for patients with pulmonary arterial hypertension (PAH) World Health Organization (WHO) group 1 to improve exercise capacity, improve WHO functional class, and delay clinical worsening. It is also approved for patients with pulmonary hypertension (PH) WHO Group IV who have inoperable or persistent/recurrent postoperative chronic thromboembolic pulmonary hypertension (CTEPH), with the intent of improving exercise capacity and WHO functional class.
Riociguat is the first drug approved in the new class of soluble guanylate cyclase (sGC) stimulators. Soluble guanylate cyclase is an enzyme that, when stimulated, catalyzes the synthesis of cyclic guanosine monophosphate (cGMP) in the cardiopulmonary system.
The mechanism of action of riociguat is twofold. It binds sGC, resulting in vasodilation in the lungs from the stabilization of nitrous oxide (NO) binding to sGC, which sensitizes this pathway. In addition, it directly stimulates sGC independent of NO. Both mechanisms increase intracellular cGMP and relaxation of vascular tone.
A boxed warning accompanies the drug to alert prescribers to the risk of embryo-fetal toxicity. An Adempas REMS program restricts the distribution of the drug. Prescribers must enroll in the program and complete required training. Women can receive the drug only through participation in the program. Female patients must enroll and comply with both pregnancy testing (before starting the drug, monthly, and for one month after discontinuation of riociguat) and the defined contraception requirements. Pharmacies must also be certified with the program and dispense the medication only to patients authorized to receive it. A list of certified pharmacies can be found at www.adempasrems.com and by calling 855-4-ADEMPAS.
FDA approved riociguat on the results of two phase 3, double-blind, multinational, multicenter, randomized, placebo-controlled trials, CHEST-1 and PATENT-1. CHEST-1 assessed use in patients (n=261) with CTEPH who were deemed inoperable and demonstrated PH at least 90 days after initiation of anticoagulation or who demonstrated recurrent/persistent PH at least 180 days postoperatively. PATENT-1 assessed riociguat use in patients (n=433) with PH WHO group 1. Patients were excluded from either trial if they demonstrated a systolic blood pressure <95 mmHg.
Both trials permitted the use of stable doses of oral anticoagulants, digitalis, diuretics, calcium channel blockers, and oxygen therapy in addition to riociguat. CHEST-1 did not allow the use of concomitant nitrous oxide donors, endothelin receptor antagonists, prostacyclin analogues, or phosphodiesterase inhibitors. Both trials initiated riociguat in the treatment groups at a dose of 1 mg 3 times daily. Doses were titrated up every 2 weeks as permitted, based on systolic blood pressure and signs and symptoms of hypertension, to a maximum dose of 2.5 mg 3 times daily.
The primary end point of the trials was the change in 6-minute walking distance (6MWD). Improvements in walking distance were demonstrated from week 2 onward for participants taking riociguat in both trials. In the CHEST-1 trial, 83% of participants receiving riociguat demonstrated improvement in 6MWD compared to 57% receiving placebo, with a median difference of 46 m at 16 weeks. In PATENT-1, the results were 76% and 59%, respectively, and a median difference of 29 m at 12 weeks. Participants taking riociguat in both trials demonstrated a significant improvement over placebo in WHO functional class. In addition, participants in PATENT-1 taking riociguat demonstrated a significant delay in time to clinical worsening compared to placebo.
Owing to the similarity of the CHEST-1 and PATENT-1 trials, FDA pooled the safety data from both trials for analysis. Warnings/precautions attached to this drug include hypotension, bleeding, and pulmonary edema in patients with pulmonary veno-occlusive disease. Riociguat must be discontinued in patients with confirmed pulmonary veno-occlusive disease.
Adverse reactions occurring with a frequency at least 3% greater with riociguat compared to placebo include hypotension, headache, dizziness, gastrointestinal disturbances (dyspepsia/gastritis, GERD, nausea, vomiting, diarrhea, constipation), and anemia. Other adverse events with greater frequency than placebo include palpitations, nasal congestion, epistaxis, dysphagia, abdominal distension, and peripheral edema.
Patients should be routinely monitored for hypotension and counseled to use caution when driving or operating machinery because of the possibility of dizziness and syncope, which may occur when initiating or increasing riociguat therapy. Riociguat is contraindicated in patients who are pregnant, due to its teratogenic effects. Patients taking nitrates or nitric oxide donors should not take riociguat; co-administration will potentiate its blood-pressure-lowering effects. Because of the additive blood-pressure-lowering effects, patients should not take phosphodiesterase inhibitors (specific and nonspecific) while on riociguat. This is important to note, as phosphodiesterase-5 inhibitors are considered a therapy option for treatment of patients with PH.
The recommended starting dose of riociguat is 1 mg three times daily. It is titrated up by 0.5 mg (per dose) no sooner than every 2 weeks to a maximum of 2.5 mg 3 times daily. There is no specific recommendation for dosing riociguat in elderly patients, a patient group that has demonstrated a greater exposure to riociguat. However, initiation of riociguat at 0.5 mg 3 times daily is recommended for patients who may be intolerant to hypotensive effects of the medication. This lower starting dose is also recommended for patients taking strong P-glycoprotein/breast cancer resistance protein or cytochrome P450 inhibitors. Patients taking strong CYP3A inducers may experience significantly lowered riociguat exposure. However, no data currently exist to guide dosing. Dose increases, perhaps greater than the recommended maximum dose, may be necessary for active smokers, as the plasma drug concentration can be lowered by 50% to 60% in these patients. Patients who quit smoking while taking riociguat may require a dose reduction to avoid adverse effects. The safety and efficacy of riociguat has not been demonstrated for patients on dialysis, those with a creatinine clearance <15 mL/min, or those with severe hepatic impairment (Child Pugh C). Riociguat may be taken without regard to meals, but antacids should not be taken within one hour of riociguat administration to avoid the potential for decreased absorption. Riociguat is 95% plasma-protein-bound.
1. Adempas [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc., 2013.
2. FDA approved risk evaluation and mitigation strategies. Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM370907.pdf Accessed January 21, 2014.
3. Ghofrani HA, D’Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369:319-329.