OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Riociguat – Adempas®

DRUG CLASS

Pulmonary Arterial Hypertension Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Riociguat	625115-55-1	C20-H19-F-N8-O2

ANNOTATED BIBLIOGRAPHY

References updated: 04 June 2018

Abbreviations used: PAH, pulmonary arterial hypertension.

• Zimmerman HJ. Acetaminophen toxicity. Syndromes of environmental hepatotoxicity. In, Zimmerman, HJ. Hepatotoxicity. The adverse effects of drugs and other chemicals upon the liver. 2nd edition. Philadelphia. Lippincott, 1999. pp 337-46.

  (Textbook of drug induced liver injury published in 1999 before the availability of riociguat).
• Barnes PJ. Pharmacotherapy of pulmonary arterial hypertension. Pulmonary Pharmacology. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1059-61.

  (Textbook of pharmacology and therapeutics).
• Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, et al. PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369:330–40. [PubMed: 23883378]

  (Among 443 patients with pulmonary arterial hypertension [PAH] treated with riociguat or placebo for 12 weeks, exercise capacity improved with riociguat and side effects included headache, dyspepsia, peripheral edema, nausea, dizziness and diarrhea, and one patient required early discontinuation of therapy because of serum enzyme elevations, but no details provided).
• Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, et al. CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013;369(4):319–29. [PubMed: 23883377]

  (Among 261 patients with chronic thromboembolic PAH treated with riociguat or placebo for 16 weeks, exercise capacity improved with riociguat and side effects included headache, dizziness, dyspepsia, sinusitis, nausea, vomiting, diarrhea and hypotension; there were no liver related serious adverse events).
• Riociguat (Adempas) for pulmonary hypertension. Med Lett Drugs Ther. 2014;56(1437):17–9. [PubMed: 24589497]

  (Concise review of the mechanism of action, clinical efficacy, safety and costs of riociguat shortly after its approval for use in the US mentions the common side effects and teratogenicity, but makes no mention of ALT elevations or hepatotoxicity).
• Rubin LJ, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh A, et al. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Respir J. 2015;45:1303–13. [PubMed: 25614164]

  (Among 396 patients with PAH who were treated with riociguat or placebo in a randomized controlled trial and were then continued or started riociguat, improvements in exercise capacity persisted for the year of therapy and side effects included hypotension, syncope, dizziness and headache; no mention of ALT elevations or hepatotoxicity).
• Hill NS, Badesch D, Benza RL, D'Eletto TA, Farber HW, Gomberg-Maitland M, Hassoun PM, Preston I. Perspectives on oral pulmonary hypertension therapies recently approved by the U.S. Food and Drug Administration. Ann Am Thorac Soc. 2015;12:269–73. [PubMed: 25590376]

  (Review of recently approved drugs for PAH including macitentan, riociguat and oral treprostinil mentions that riociguat can cause significant hypotension and is embryotoxic; no mention of ALT elevations or hepatotoxicity).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, one was attributed to bosentan, but none to riociguat or other agents used primarily to treat pulmonary artery hypertension).
• Ghofrani HA, Grimminger F, Grünig E, Huang Y, Jansa P, Jing ZC, Kilpatrick D, et al. Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial. Lancet Respir Med. 2016;4:361–71. [PubMed: 27067479]

  (Among 396 patients with PAH who had participated in a placebo controlled trial and then were treated with open label riociguat, exercise capacity was maintained for the duration of therapy [up to 2 years] and no new side effects were evident; no mention of serum ALT elevations or clinically apparent liver injury).
• Simonneau G, D'Armini AM, Ghofrani HA, Grimminger F, Jansa P, Kim NH, Mayer E, et al. Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial. Lancet Respir Med. 2016;4:372–80. [PubMed: 27067478]

  (Among 237 patients with chronic thromboembolic PAH who had participated in a placebo controlled trial and then were treated with open label riociguat, exercise capacity was maintained for the duration of therapy [up to 2 years] and no new side effects were evident; no mention of serum ALT elevations or clinically apparent liver injury).
• Humbert M, Coghlan JG, Ghofrani HA, Grimminger F, He JG, Riemekasten G, Vizza CD, et al. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. Ann Rheum Dis. 2017;76:422–6. [PMC free article: PMC5284330] [PubMed: 27457511]

  (Analysis of 111 patients with connective tissue disease associated PAH from previous controlled trials of riociguat [Ghofrani et al 2013 and 2016] found similar rates of improvements and side effects as found in the entire treated population; no mention of ALT elevations or hepatotoxicity).
• Halank M, Hoeper MM, Ghofrani HA, Meyer FJ, Stähler G, Behr J, Ewert R, et al. Riociguat for pulmonary arterial hypertension and chronic thromboembolic pulmonary ypertension: Results from aphase II long-term extension study. Respir Med. 2017;128:50–6. [PubMed: 28610669]

  (Among 68 patients with PAH treated with riociguat in a long term extension study following a controlled trial [Ghofrani 2013], clinical improvements were maintained and no new adverse events were found; no mention of ALT levels or hepatotoxicity).
• McLaughlin VV, Jansa P, Nielsen-Kudsk JE, Halank M, Simonneau G, Grünig E, Ulrich S, et al. Riociguat in patients with chronic thromboembolic pulmonary hypertension: results from an early access study. BMC Pulm Med. 2017;17:216. [PMC free article: PMC5745920] [PubMed: 29282032]

  (Among 262 patients with recurrent or persistent chronic thromboembolic PAH treated with riociguat in an open access study for an average of 1 year, common adverse events included dizziness, headache, syncope, peripheral edema and gastrointestinal symptoms; no mention of ALT elevations or hepatotoxicity).