Adempas riociguat tablets for PAH for CTEPH

Bayer

Important Safety Information
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. Continue reading below.

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WHO PH classification2:

The 5 Groups of Pulmonary Hypertension (PH) as Classified by the World Health Organization (WHO).

CTEPH

Clinical definition
CTEPH is a form of pulmonary hypertension (PH) and is designated as WHO Group 4. It can develop when a combination of persistent macrovascular obstruction, often associated with small vessel arteriopathy, and vasoconstriction in the pulmonary arteries result in PH (defined as mean pulmonary artery pressure [mPAP] >25 mm Hg).2,3

Pathogenesis
CTEPH may be caused by either single or recurrent pulmonary emboli, which incompletely resolve, resulting in endothelialized residua that obstruct or significantly narrow pulmonary arteries.3

CTEPH results from persistent macrovascular obstruction often associated with vasoconstrictor response that leads to a secondary small vessel arteriopathy. Small vessel arteriopathy is characterized by medial hypertrophy, intimal proliferation and thickening, microthrombi formation, and plexiform lesions.4

Some CTEPH risk factors5

  • Multiple episodes of PE
  • Larger perfusion defect
  • Idiopathic presentation of PE
  • Previous/recurrent thromboembolism

Diagnosis
CTEPH is under-diagnosed, resulting in delay of a potentially curative procedure1,6

  • All patients with suspected CTEPH should be assessed with a right heart catheter for presence of PH1,7
  • The V/Q (ventilation/perfusion) lung scan is the diagnostic tool of choice for verifying CTEPH1,8
  • American College of Cardiology and American Heart Association recommend a V/Q scan 3 months after a PE if patient is still symptomatic9
  • Multidetector CT (computed tomography) angiography is less sensitive at detecting CTEPH than a V/Q scan1,10

Incidence5,6

  • Estimated at 1-3% overall
  • 1% 6 months after PE
  • 3.8% 2 years after PE
  •  

Surgical Treatment

  • All CTEPH patients need to be assessed for operability as pulmonary endarterectomy (PEA)* is the only potentially curative treatment and is the treatment of choice for surgical candidates1
  • Of newly diagnosed patients in an International Prospective Registry, 36.6% were inoperable11
  • In a long-term follow-up of a UK CTEPH cohort study, 35% of patients had residual PH following PEA surgery12

*PEA, also known as pulmonary thromboendarterectomy (PTE).

Important Safety Information

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.

Contraindications

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).

Warnings and Precautions

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.

Most Common Adverse Reactions

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.

Indications

  • 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.

Reference(s):

  1. Kim NH, Delcroix M, Jenkins DP, et al. Chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol. 2013;62(25)(suppl D):D92–D99.
  2. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013;62(25)(suppl D):D34–D41.
  3. Piazza G, Goldhaber SZ. Chronic thromboembolic pulmonary hypertension. N Engl J Med. 2011;364:351-360.
  4. Fedullo P, Kerr KM, Kim NH, Auger WR. Chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med. 2011;183(12):1605-1613.
  5. Pengo V, Lensing AWA, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med. 2004;350(22):2257- 2264.
  6. Tapson VF, Humbert M. Incidence and prevalence of chronic thromboembolic pulmonary hypertension—from acute to chronic pulmonary embolism. Proc Am Thorac Soc. 2006;3(7):564-567.
  7. McNeil K, Dunning J. Chronic thromboembolic pulmonary hypertension (CTEPH). Heart. 2007;93(9):1152-1158.
  8. Hoeper MM, Barbera JA, Channick RN, et al. Diagnosis, assessment, and treatment of non-pulmonary arterial hypertension pulmonary hypertension. J Am Coll Cardiol. 2009;54(suppl 1):S85-S96.
  9. McLaughlin VV, Archer SL, Badesch BD, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension. A report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association. Developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation. 2009;119(16):2250-2294.
  10. Jenkins D, Mayer E, Screaton N, Madani M. State-of-the-art chronic thromboembolic pulmonary hypertension diagnosis and management. Eur Respir Rev. 2012;21(123):32-39.
  11. Pepke-Zaba J, Delcroix M, Lang I, et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation. 2011;124(18):1973-1981.
  12. Condliffe R, Kiely DG, Gibbs SR, et al. Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med. 2008;177:1122–1127.

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