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Adempas

Generic Name: Riociguat
Class: Vasodilating Agents
Chemical Name: N - [4,6 - Diamino - 2 - [1 - [(2 - fluorophenyl)methyl] - 1H - pyrazolo[3,4 - b]pyridin - 3 - yl] - 5 - pyrimidinyl] - N - methyl - carbamic acid, methyl ester
Molecular Formula: C20H19FN8O2
CAS Number: 625115-55-1

Warning(s)

  • Teratogenicity
  • May cause fetal harm; contraindicated in females who are pregnant.1

  • Exclude pregnancy in females of childbearing potential before initiation of therapy and prevent thereafter by using acceptable methods of contraception during and for 1 month following discontinuance of therapy.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions and also see Advice to Patients.)

  • Distribution of riociguat is restricted in all female patients.1 (See Restricted Distribution Program under Dosage and Administration.)

REMS:

FDA approved a REMS for riociguat to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of riociguat and consists of the following: medication guide, elements to assure safe use, and implementation system. See the FDA REMS page () or the ASHP REMS Resource Center (). See also Restricted Distribution Program under Dosage and Administration.

Introduction

Vasodilator; a soluble guanylate cyclase (sGC) stimulator.1 6 7 10

Uses for Adempas

Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Management of CTEPH (WHO group 4 pulmonary hypertension) to improve exercise capacity and NYHA/WHO functional class in patients with inoperable disease or persistent/recurrent pulmonary hypertension after surgery (i.e., pulmonary endarterectomy).1 2 20

Standard treatment for patients with CTEPH is pulmonary endarterectomy.2 7 8 9 Because such surgery is potentially curative, an experienced clinician should assess patients to determine suitability for surgery before medical therapy is considered.2 8 9 12 13 20

Has been designated an orphan drug by FDA for treatment of CTEPH.4

Pulmonary Arterial Hypertension (PAH)

Management of PAH (WHO group 1 pulmonary hypertension) to improve exercise capacity and NYHA/WHO functional class and to delay clinical worsening.1 3

Efficacy established principally in patients with NYHA/WHO functional class II or III PAH (idiopathic, heritable, or associated with connective tissue diseases) receiving the drug as monotherapy or in combination with an endothelin-receptor antagonist or a prostanoid.1 3

Recommended as one of several treatment options for initial management of PAH in patients with NYHA/WHO functional class II, III, or IV symptoms who are not candidates for calcium-channel blocker therapy or in whom such therapy failed.40 Individualize choice of therapy; consider factors such as disease severity, route of administration, potential adverse effects and costs of treatment, clinician experience, and patient preference.27 38 40

In patients with inadequate response to initial monotherapy, may consider combination therapy with a prostanoid or endothelin-receptor antagonist (added sequentially);40 however, concomitant use of riociguat and phosphodiesterase (PDE) type 5 inhibitors is contraindicated.1 40 (See Cardiovascular Effects under Cautions.) By targeting different pathophysiologic pathways of the disease, such combination therapy may provide additive and/or synergistic benefits.24 25 29 40

Has been designated an orphan drug by FDA for treatment of PAH.4

Adempas Dosage and Administration

General

  • Restricted Distribution Program
  • Distribution of riociguat to female patients is restricted; available only through the Adempas REMS program.1 5 (See Boxed Warning and also see REMS.)

  • All female patients (regardless of childbearing potential), clinicians, and pharmacies must enroll in the program in order to receive, prescribe, and dispense the drug, respectively; in addition, females of childbearing potential must comply with pregnancy testing and contraception requirements.1 Male patients do not need to enroll.1 Additional information available at or 855-423-3672.1

Administration

Oral Administration

Administer orally without regard to meals.1

If a dose is missed, take next dose at the regularly scheduled time; if treatment is interrupted for ≥3 days, retitrate dosage.1

Dosage

Adults

CTEPH
Oral

Initially, 1 mg 3 times daily (doses approximately 6–8 hours apart); consider reduced initial dosage of 0.5 mg 3 times daily in patients who may not tolerate the hypotensive effects of the drug.1 41

Adjust dosage based on response and tolerance.1 In patients without manifestations of hypotension and in whom systolic BP >95 mm Hg, may titrate dosage up to maximum of 2.5 mg 3 times daily.1 Adjust dosage in increments of 0.5 mg 3 times daily at intervals of at least 2 weeks.1 If symptoms of hypotension occur at any time, reduce dosage by 0.5 mg 3 times daily.1

In patients receiving concomitant therapy with potent inhibitors of CYP and P-glycoprotein (P-gp)/breast cancer resistance protein (BCRP), consider reduced initial dosage of 0.5 mg 3 times daily.1 Monitor for hypotension upon initiation of and during such concomitant therapy.1 (See Drugs Affecting Hepatic Microsomal Enzymes and Efflux Transport Systems under Interactions.)

PAH
Oral

Initially, 1 mg 3 times daily (doses approximately 6–8 hours apart).1 41

Consider reduced initial dosage of 0.5 mg 3 times daily in patients who may not tolerate the hypotensive effects of the drug.1

Adjust dosage based on response and tolerance.1 In patients without manifestations of hypotension and in whom systolic BP >95 mm Hg, may titrate dosage up to maximum of 2.5 mg 3 times daily.1 Adjust dosage in increments of 0.5 mg 3 times daily at intervals of at least 2 weeks.1 If symptoms of hypotension occur at any time, reduce dosage by 0.5 mg 3 times daily.1

In patients receiving concomitant therapy with potent inhibitors of CYP and P-gp/BCRP, consider reduced initial dosage of 0.5 mg 3 times daily.1 Monitor for hypotension upon initiation of and during such concomitant therapy.1 (See Drugs Affecting Hepatic Microsomal Enzymes and Efflux Transport Systems under Interactions.)

Prescribing Limits

Adults

CTEPH
Oral

Maximum recommended dosage 2.5 mg 3 times daily; consider higher dosages in patients who smoke.1

PAH
Oral

Maximum recommended dosage 2.5 mg 3 times daily; consider higher dosages in patients who smoke.1

Special Populations

Smokers

Smoking can reduce plasma concentrations of riociguat; may consider titration to maximum dosages >2.5 mg 3 times daily in patients who smoke.1 6 19 (See Specific Drugs under Interactions.) Such dosage recommendations based on pharmacokinetic modeling; safety and efficacy not established in smokers.1 Dosage reduction may be required in patients who stop smoking.1 19

Hepatic Impairment

No specific dosage recommendations at this time.1

Renal Impairment

No specific dosage recommendations at this time.1

Geriatric Patients

Dosage adjustments based solely on age not necessary.1

Cautions for Adempas

Contraindications

  • Pregnancy.1

  • Concomitant therapy with nitrates or nitric oxide donors in any form (e.g., amyl nitrite, nitroglycerin).1

  • Concomitant therapy with PDE inhibitors, including specific PDE type 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) and nonspecific PDE inhibitors (e.g., dipyridamole, theophylline).1

Warnings/Precautions

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity and embryotoxicity demonstrated in animals.1 (See Boxed Warning and also see Restricted Distribution Program under Dosage and Administration.)

Exclude pregnancy prior to initiation of therapy; perform monthly pregnancy tests during therapy and at 1 month following discontinuance of therapy.1

Females of childbearing potential must use acceptable methods of contraception during and for 1 month following cessation of therapy.1 (See Advice to Patients.)

If riociguat is used during pregnancy or patient becomes pregnant during therapy, apprise of potential fetal hazard.1

Cardiovascular Effects

Risk of hypotension.1 Consider potential for symptomatic hypotension or ischemia in patients with predisposing risk factors (e.g., hypovolemia, severe left-ventricular outflow obstruction, resting hypotension, autonomic dysfunction, concomitant use of antihypertensive agents or drugs that can increase exposure to riociguat).1 (See Interactions.)

Concomitant use of nitrates, nitric oxide donors, or phosphodiesterase inhibitors can potentiate hypotensive effects of riociguat.1 (See Contraindications under Cautions.)

If manifestations of hypotension occur at any time, reduce dosage.1 (See Dosage under Dosage and Administration.)

Bleeding

Bleeding (e.g., hemoptysis, vaginal bleeding, catheter site bleeding, subdural hematoma, hematemesis, intra-abdominal bleeding) reported, including at least 1 death.1

Pulmonary Effects

If acute pulmonary edema occurs, consider possibility of pulmonary veno-occlusive disease; if confirmed, discontinue riociguat.1

Specific Populations

Pregnancy

Category X.1 (See Fetal/Neonatal Morbidity and Mortality and also Contraindications, under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

No overall differences in safety or efficacy relative to younger patients.1

Hepatic Impairment

Safety and efficacy not established in patients with severe hepatic impairment (Child-Pugh class C).1

Renal Impairment

Safety and efficacy not established in patients with severe renal impairment (Clcr<15 mL/minute) or in those undergoing dialysis.1

Common Adverse Effects

Headache,1 2 3 dyspepsia/gastritis,1 2 3 dizziness,1 2 3 nausea,1 2 3 diarrhea,1 2 3 hypotension,1 2 3 vomiting,1 2 anemia,1 3 GERD,1 3 constipation.1 2

Interactions for Adempas

Metabolized by CYP1A1, 3A, 2C8, and 2J2.1 Both drug and active metabolite are potent inhibitors of CYP1A1.19

Substrate of P-gp and BCRP.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A4 inhibitors or inducers: Potential pharmacokinetic interaction (increased or decreased riociguat concentrations, respectively); caution is advised and dosage adjustments may be necessary.1 19

CYP1A1 inhibitors or inducers: Potential pharmacokinetic interaction (increased or decreased riociguat concentrations, respectively); caution is advised and dosage adjustments may be necessary.1 19

CYP1A1 substrates: Clinically important interactions are possible.19

Drugs Affecting Efflux Transport Systems

Pharmacokinetic interactions possible with inhibitors or inducers of P-gp and BCRP.1 19 (See Specific Drugs under Interactions.)

Drugs Affecting Hepatic Microsomal Enzymes and Efflux Transport Systems

Concomitant use of potent inhibitors of both CYP and P-gp/BRCP is expected to substantially increase exposure to riociguat and, thus, risk of hypotension.1 Dosage adjustments may be required.1 (See Dosage and Administration: Dosage.)

Specific Drugs

Drug

Interaction

Comments

Antacids (aluminum hydroxide and magnesium hydroxide)

Possible reduced absorption and bioavailability of riociguat1 19

Do not administer antacids within 1 hour of taking riociguat1 19

Antihypertensive agents

Possible additive hypotensive effects1

Aspirin

No substantial pharmacokinetic or pharmacodynamic (bleeding time or platelet aggregation) interactions observed1

No dosage adjustments necessary1

Azole antifungals (e.g., itraconzole, ketoconazole)

Increased exposure to riociguat and risk of hypotension1

Concomitant use not recommended; however, if necessary, consider reduced initial dosage of riociguat and monitor for hypotension1

Anticonvulsants (carbamazepine, phenobarbital, phenytoin)

Potential decreased plasma concentrations of riociguat1

Use concomitantly with caution19

Bosentan

Potential decrease in plasma riociguat concentrations; however, efficacy of combination not likely to be affected1 19

No dosage adjustments necessary1

Clarithromycin

Increased systemic exposure to riociguat and its major active metabolite; no substantial change in peak plasma concentrations of riociguat1

Use concomitantly with caution; no dosage adjustments necessary1 19

Cyclosporine

Potential increased exposure to riociguat19

Use concomitantly with caution19

H2-receptor antagonists (e.g., ranitidine)

Potential decreased bioavailability of riociguat due to increased gastric pH induced by H2-receptor antagonists1 19

Ranitidine: Slightly reduced peak plasma concentrations and systemic exposure of riociguat19

HIV protease inhibitors (e.g., ritonavir)

Increased exposure to riociguat and risk of hypotension1

Concomitant use not recommended; however, if necessary, consider reduced initial dosage of riociguat and monitor for hypotension1

Midazolam

Pharmacokinetics of midazolam not altered1

Nitrates and nitric oxide donors (e.g., nitroglycerin, amyl nitrate)

Possible additive hypotensive effects; syncope also reported1

Concomitant use contraindicated1

Proton-pump inhibitors (e.g., omeprazole)

Potential decreased bioavailability of riociguat due to increased gastric pH induced by proton-pump inhibitors1 19

Omeprazole: Modest decrease in peak plasma concentrations and systemic exposure of riociguat1 19

No dosage adjustments necessary1 19

PDE inhibitors, including specific PDE type 5 inhibitors (sildenafil, tadalafil) and nonspecific PDE inhibitors (e.g., dipyridamole, theophylline)

Possible additive hypotensive effects1

Concomitant use contraindicated1

Rifampin

Possible decreased plasma concentrations of riociguat1

Use concomitantly with caution19

Smoking

Decreased plasma concentrations of riociguat by approximately 50–60%1

Consider increasing dosage to >2.5 mg 3 times daily if necessary1

St. John's wort

Possible decreased plasma concentrations of riociguat1

Use concomitantly with caution19

Tyrosine kinase inhibitors (e.g., erlotinib, gefitinib)

Clinically important CYP1A1-mediated interactions possible19

Use concomitantly with caution19

Warfarin

No substantial change in pharmacodynamics (e.g., PT) or pharmacokinetics of warfarin; increased peak plasma concentrations of riociguat, but not clinically important1 14

No dosage adjustments necessary1 14

Adempas Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration; peak plasma concentrations attained in approximately 0.5–1.5 hours.1 7 15 Plasma concentrations of the active M-1 metabolite are about 50% of those of the parent drug.1

Food

Food does not affect absorption.1

Distribution

Plasma Protein Binding

Approximately 95%.1

Elimination

Metabolism

Principally undergoes hepatic metabolism by CYP1A1, 3A, 2C8, and 2J2.1 Converted to major active M-1 metabolite by CYP1A1, then further metabolized to inactive N-glucuronide conjugate.1

Elimination Route

Following oral administration of radiolabeled dose, approximately 40 and 53% of total radioactivity recovered in urine and feces, respectively.1

Half-life

Elimination half-life about 7 hours in healthy individuals and 12 hours in patients with pulmonary hypertension.1 15 16

Special Populations

In geriatric patients, systemic exposure to riociguat may be increased.1

In patients with mild to moderate hepatic impairment (Child-Pugh class A or B), systemic exposure to riociguat may be increased.1

In patients with renal impairment, systemic exposure to riociguat may be increased.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Actions

  • Promotes vasodilation via effects on the nitric oxide-sGC-cyclic guanosine monophosphate (cGMP) pathway.1 6 7 10 Impairment of this nitric oxide signaling pathway, including decreased synthesis of nitric oxide and insufficient stimulation of sGC, demonstrated in patients with pulmonary hypertension.1 7 10 18

  • Dual mechanism of action; increases sensitivity of sGC to endogenous nitric oxide and also directly stimulates sGC independent of nitric oxide, resulting in increased levels of cGMP and subsequent vasodilation.1 7 10

  • In patients with pulmonary hypertension, improves hemodynamics (e.g., pulmonary vascular resistance, pulmonary artery pressure, cardiac output) and concentrations of N-terminal prohormone of brain (pro-brain) natriuretic peptide, a biomarker of heart function.1 2 3 7 15 16

  • Some antiproliferative and antifibrotic effects also observed.1 2 17

Advice to Patients

  • Risk of fetal harm; importance of advising females of childbearing potential to avoid pregnancy and to use acceptable methods of contraception during and for 1 month following discontinuance of riociguat therapy.1 41 Acceptable methods of contraception include one highly effective form of contraception (intrauterine device [IUD], progesterone implant, or tubal sterilization) or a combination of methods (either one hormonal and one barrier method or 2 barrier methods where one form is the male condom).1 41 Acceptable hormonal methods of contraception include estrogen-progestin combination oral contraceptives or transdermal contraceptive systems, vaginal ring, and progesterone injections.1 41 Acceptable barrier methods include male condoms, diaphragms with spermicide, and cervical caps with spermicide.1 41 Even if the partner has had a vasectomy, an additional hormonal or barrier method must be used.1 41

  • Advise females to inform their clinician immediately if a menstrual period is missed or pregnancy is suspected; clinicians should provide counseling on the use of emergency contraception in the event of unprotected sexual intercourse or contraceptive failure.1 Apprise patient of potential risk to fetus if pregnancy occurs.1

  • Importance of monthly pregnancy testing.1

  • Importance of all female patients (regardless of childbearing potential) enrolling in the Adempas REMS program and complying with contraceptive and pregnancy testing requirements.1 Importance of monitoring reproductive status of prepubertal females and immediately reporting changes to clinician.1 41

  • Risk of hemoptysis; importance of advising patients to report any potential manifestations of hemoptysis to their clinician.1 41

  • Importance of advising patients that smoking during riociguat therapy may decrease concentrations of the drug and reduce efficacy; importance of informing clinician if smoking is started or stopped during riociguat therapy as riociguat dosage adjustment may be needed.1 41

  • Importance of advising patients to not take antacids within 1 hour of riociguat administration and to avoid use of nitrates, nitric oxide donors, and PDE inhibitors while undergoing riociguat therapy.1 41

  • Risk of dizziness; importance of advising patients to avoid driving or operating machinery until effects of the drug on the individual are known and to consult their clinician, if necessary.1 41

  • Importance of taking riociguat as prescribed and of not discontinuing therapy or altering dosage without consulting a clinician.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription (e.g., azole antifungal agents, HIV protease inhibitors) and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of riociguat is restricted.1 (See Restricted Distribution Program under Dosage and Administration.)

Riociguat

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

0.5 mg

Adempas

Bayer

1 mg

Adempas

Bayer

1.5 mg

Adempas

Bayer

2 mg

Adempas

Bayer

2.5 mg

Adempas

Bayer

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814. Review Date: September 06, 2016.

References

1. Bayer. Adempas (riociguat) tablets prescribing information. Whippany, NJ; 2013 Oct.

2. Ghofrani HA, D'Armini AM, Grimminger F et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013; 369:319-29. [PubMed 23883377]

3. Ghofrani HA, Galiè N, Grimminger F et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013; 369:330-40. [PubMed 23883378]

4. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97-414). Rockville, MD; [January 7, 2014]. From FDA web site.

5. Adempas (riociguat) risk evaluation and mitigation strategy (REMS). Available from FDA web site. Accessed 2014 Jan 13.

6. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 204819Orig1s000: Summary Review. From FDA website.

7. Conole D, Scott LJ. Riociguat: first global approval. Drugs. 2013; 73:1967-75. [PubMed 24218053]

8. Tanabe N, Sugiura T, Tatsumi K. Recent progress in the diagnosis and management of chronic thromboembolic pulmonary hypertension. Respir Investig. 2013; 51:134-46. [PubMed 23978639]

9. Wilkens H, Lang I, Behr J et al. Chronic thromboembolic pulmonary hypertension (CTEPH): updated Recommendations of the Cologne Consensus Conference 2011. Int J Cardiol. 2011; 154 Suppl 1:S54-60.

10. Schermuly RT, Janssen W, Weissmann N et al. Riociguat for the treatment of pulmonary hypertension. Expert Opin Investig Drugs. 2011; 20:567-76. [PubMed 21391889]

11. Ghofrani HA, Hoeper MM, Halank M et al. Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J. 2010; 36:792-9. [PubMed 20530034]

12. Archer SL. Riociguat for pulmonary hypertension--a glass half full. N Engl J Med. 2013; 369:386-8. [PubMed 23883383]

13. Auger WR, Jamieson SW, Pulmonary Thromboendarterectomy Program at University of California, San Diego. Riociguat for pulmonary hypertension. N Engl J Med. 2013; 369:2266.

14. Frey R, Mück W, Kirschbaum N et al. Riociguat (BAY 63-2521) and warfarin: a pharmacodynamic and pharmacokinetic interaction study. J Clin Pharmacol. 2011; 51:1051-60. [PubMed 20801938]

15. Frey R, Mück W, Unger S et al. Single-dose pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase stimulator BAY 63-2521: an ascending-dose study in healthy male volunteers. J Clin Pharmacol. 2008; 48:926-34. [PubMed 18519919]

16. Grimminger F, Weimann G, Frey R et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J. 2009; 33:785-92. [PubMed 19129292]

17. Lang M, Kojonazarov B, Tian X et al. The soluble guanylate cyclase stimulator riociguat ameliorates pulmonary hypertension induced by hypoxia and SU5416 in rats. PLoS One. 2012; 7:e43433.

18. Klinger JR, Abman SH, Gladwin MT. Nitric oxide deficiency and endothelial dysfunction in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013; 188:639-46. [PubMed 23822809]

19. Bayer. Whippany, NJ; Personal communication.

20. Kim NH, Delcroix M, Jenkins DP et al. Chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol. 2013; 62(25 Suppl):D92-9. [PubMed 24355646]

24. Channick RN. Combination therapy in pulmonary arterial hypertension. Am J Cardiol. 2013; 111(8 Suppl):16C-20C. [PubMed 23558025]

25. Zhu B, Wang L, Sun L et al. Combination therapy improves exercise capacity and reduces risk of clinical worsening in patients with pulmonary arterial hypertension: a meta-analysis. J Cardiovasc Pharmacol. 2012; 60:342-6. [PubMed 22691882]

27. Barst RJ, Gibbs JS, Ghofrani HA et al. Updated evidence-based treatment algorithm in pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54(1 Suppl):S78-84.

29. Gokhman R, Smithburger PL, Kane-Gill SL et al. Pharmacologic and Pharmacokinetic Rationale for Combination Therapy in Pulmonary Arterial Hypertension. J Cardiovasc Pharmacol. 2010; :. [PubMed 20838230]

38. McLaughlin VV, Archer SL, Badesch DB 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. J Am Coll Cardiol. 2009; 53:1573-619. [PubMed 19389575]

40. Galiè N, Corris PA, Frost A et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol. 2013; 62(25 Suppl):D60-72. [PubMed 24355643]

41. Bayer. Adempas (riociguat) tablets medication guide. Whippany, NJ; 2013 Oct.

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