Bayer's Adempas
On October 8, 2013, the FDA announced approval of Adempas (riociguat) tablets for treatment of persistent or recurrent chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH).1 The indication is limited to patients with CTEPH who have undergone surgical treatment, or patients with CTEPH who are not candidates for surgical treatment.
Adempas may help patients achieve improvements in exercise capacity and may delay clinical worsening of PAH. Use of Adempas is contraindicated in patients who are pregnant (category X), patients taking nitrates or nitric oxide donors, and patients using phosphodiesterase inhibitors. Adempas carries a black box warning for embryofetal toxicity. Use in females is regulated by a risk evaluation and mitigation strategy.2
PHARMACOLOGY AND PHARMACOKINETICS
Cyclic guanosine monophosphate (cGMP) is a signaling molecule that promotes vasodilation, modulates cell proliferation, and regulates inflammation. Riociguat directly stimulates an enzyme called “soluble guanylate cyclase” (sGC) to increase levels of cyclic cGMP. Riociguat also sensitizes sGC to nitric oxide, an endogenous activator of sGC that is often underproduced in cases of PAH. Improved sGC response to nitric oxide also improves cGMP production.2
After single-dose oral administration of Adempas, plasma concentrations peak within about 1.5 hours. Total exposure to riociguat, defined by area under the curve (AUC), varies by about 60% between patients, and may vary by about 30% between administrations of riociguat to a single individual. In healthy volunteers, elimination half-life is about 7 hours, increasing to approximately 12 hours in patients with PAH and CTEPH. Elimination occurs mainly through metabolism by several cytochrome (CYP) P450 isoenzymes, including CYP1A1, CYP3A, CYP2C8, and CYP2J2. Metabolism by CYP1A1 leads to formation of an active metabolite known as M1 with between one-third and onetenth the activity of the unchanged drug.2
Pharmacokinetic studies in patients with mild, moderate, and severe renal impairment indicate an approximately 2-fold increase in exposure to riociguat relative to patients with normal renal function. Despite this finding, the manufacturer does not recommend any dosage reduction in renal impairment. The manufacturer does not recommend use in patients with severe (Child-Pugh class C) hepatic impairment, in patients with a creatinine clearance lower than 15 mL/min, or in patients undergoing dialysis, because riociguat has not been evaluated in these populations.2
DOSAGE AND ADMINISTRATION
Adempas tablets are available in 0.5-mg, 1-mg, 1.5-mg, 2-mg, and 2.5-mg doses. The usual starting dose of Adempas is a 1-mg tablet taken orally 3 times a day, with or without food. However, patients who experience adverse events related to low blood pressure may start therapy with a lower dose of 0.5 mg 3 times a day. If tolerated, the prescriber may increase the dose in increments of 0.5 mg no more frequently than every 2 weeks. A typical dose escalation may follow a course of 1 mg 3 times a day for 2 weeks, 1.5 mg 3 times a day for 2 weeks, 2 mg 3 times a day for 2 weeks, and finally, 2.5 mg 3 times a day for 2 weeks. Interruption of treatment for 3 or more days requires retitration.2
CLINICAL TRIALS
Investigators evaluated the efficacy
of Adempas in 2 trials: Chronic Thromboembolic Pulmonary Hyper-tension Soluble Guanylate Cyclase—Stimulator Trial 1 (CHEST-1) and Pulmonary Arterial Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1 (PATENT-1).2-4
The CHEST-1 trial evaluated the efficacy of Adempas versus placebo in patients with 261 patients with CTEPH who were not candidates for surgical intervention (pulmonary endarterectomy) or had a suboptimal response 6 or more months after surgery. Patients with low systolic blood pressure (under 95 mm Hg) at baseline, and patients who did not meet criteria for high pulmonary vascular resistance (PVR) or pulmonary artery pressure (PAP), were excluded from the trial. Investigators allowed patients taking oral anticoagulants, diuretics, digitalis, calcium channel blockers, or oxygen to participate in the study, but excluded patients using endothelin receptor antagonists, prostacyclin analogues, or phosphodiesterase inhibitors. From baseline to the 16-week end point, mean 6-minute walk distance (6MWD) increased by 46 m (95% confidence interval [CI]: 25-67 m; P <.0001) in patients treated with Adempas. A significantly higher percentage of patients treated with Adempas experienced functional class improvement at the 16-week end point than patients receiving placebo (33% vs 15%; P = .0026).2,3
In CHEST-2, an open-label extension study of the CHEST-1 trial, 237 patients received Adempas for a mean duration of 582 days with a 94% survival rate. However, the study lacked a control group and did not prove a mortality benefit.2,3
The PATENT-1 study involved 443 patients with PAH defined by PVR and PAP measures. As in CHEST-1, patients with low systolic blood pressure (under 95 mm Hg) at baseline were excluded from the trial. Unlike patients enrolled in CHEST-1, patients enrolled in PATENT-1 received combination therapy with endothelin-receptor antagonists (44% of patients) or prostacyclin analogue (6% of patients). From baseline to the 12-week end point, mean 6MWD increased by 36 m (95% CI: 20-52 m; P <.0001) in patients treated with Adempas. A significantly lower percentage of patients treated with Adempas experienced clinical worsening at the 12-week end point than patients receiving placebo (1.2% vs 6.3%; P = .00285).2,4
In an open-label extension study of the PATENT-1 trial, 363 patients received Adempas for a mean duration of 663 days with a 93% survival rate. Again, the study lacked a control group and did not prove a mortality benefit.2,4
WARNINGS AND PRECAUTIONS
Patients using strong p-glycoprotein inhibitors, breast cancer resistance protein (BCRP) inhibitors, or strong CYP450 inhibitors (eg, ketoconazole, itraconazole, or ritonavir) should initiate treatment with the lowest dose of Adempas—0.5 mg 3 times a day. Because inorganic antacids may reduce absorption of Adempas, patients should receive instructions to avoid taking antacids within 1 hour before or after taking a dose of Adempas.
Polycyclic aromatic hydrocarbons in cigarette smoke may induce CYP1A1, which increases metabolism of Adempas to the less-active M1 metabolite. Patients who smoke should use the highest dose of Adempas, if tolerated—2.5 mg 3 times a day. Likewise, patients who stop smoking may require a dose reduction.2
Patients with symptomatic hypotension or bleeding may require dosage reductions or discontinuation of treatment with Adempas. Confirmed pulmonary edema in patients with pulmonary veno-occlusive disease requires discontinuation of treatment.2
In clinical trials, common adverse reactions occurring with higher incidence in patients receiving active treatment than in patients treated with placebo (by at least 3 percentage points) included headache, dizziness (20%), dyspepsia/gastritis (21%), nausea (14%), diarrhea (12%), hypotension (10%), vomiting (10%), anemia (7%), gastroesophageal reflux (5%), and constipation (5%).
For a complete discussion of potential adverse events and drug interactions, please consult the product package insert.2 SPT
References:
1. FDA approves Adempas to treat pulmonary hypertension. FDA website. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm370866.htm. Accessed October 2013.
2. Adempas (riociguat) tablets [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; 2013.
3. Ghofrani HA, D’Armini AM, Grimminger F, et al; CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369(4):319-329.
4. Ghofrani HA, Galiè N, Grimminger F, et al; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330-340.
About the Author
Michael R. Page, PharmD, RPh, earned his PharmD from the Ernest Mario School of Pharmacy at Rutgers University. He has worked as a community pharmacist at CVS Pharmacy and is currently clinical editor in clinical and scientific affairs at Pharmacy Times.
