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Home , Cilostazol, Defibrotide, Dipyridamole, Prasugrel, Ticagrelor, Vorapaxar

Texas Vendor Drug Program

Drug Use Criteria: Aggregation Inhibitors

Publication History ● Developed December 2016. ● Revised December 2020; March 2019 Notes: All criteria may be applied retrospectively. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document. listed in the tables and non-FDA approved indications that may be included in these retrospective criteria are not indicative of Vendor Drug Program formulary coverage. Prepared by: • Drug Information Service, UT Health San Antonio. • The College of Pharmacy, The University of Texas at Austin

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1 Dosage

1.1 Adults Platelet aggregation inhibitors (PAIs) are FDA-approved to reduce thrombotic cardiovascular events in patients with a history of ischemic , or to prevent stroke in patients with predisposing factors for or symptomatic cerebrovascular disease.1-12 PAIs work by interfering with pathways that promote normal platelet function: inhibiting cyclooxygenase-1 (e.g., ); inhibiting uptake into , resulting in increased cyclic-3’,5’- (cAMP) and adenosine levels (e.g., ); inhibiting the

(ADP) on the platelet surface and blocking activation of the glycoprotein GPIIb/IIIa complex (e.g., , , ); antagonizing protease-activated receptor 1 (PAR-1), which inhibits and agonist peptide activity (e.g., ); or inhibiting lll (e.g., ).2-4, 13

Aspirin is available in combination with , a proton pump inhibitor, to reduce the risk of aspirin-associated gastric ulcers in those patients requiring aspirin for secondary prevention of cardiovascular and cerebrovascular events.2-4, 10 Aspirin is also available as combination therapy with dipyridamole, pairing two antiplatelet agents with different mechanisms of action for secondary stroke prevention.2-4, 11 Maximum recommended adult dosages for PAIs are summarized in Tables 1 and 2. profiles identifying patients prescribed dosages exceeding these recommendations will be reviewed.

Table 1. Maximum Daily Adult Dosages for PAIs - Monotherapy1-3, 5-12 Maximum Treatment Dosage Form/ Drug Name Recommended Indication Strength Dosage

reduce risk of death and recurrent stroke or recurrent MI in patients with a history aspirin 162.5 mg extended- 162.5 mg of ischemic stroke or (Durlaza®)* release capsule once daily TIA, and/or a history of chronic ACS (STEMI, NSTE-ACS)

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Maximum Treatment Dosage Form/ Drug Name Recommended Indication Strength Dosage intermittent cilostazol 50 mg, 100 mg 100 mg twice claudication (generics) tablets daily

Initial: 300 mg or 600 mg loading dose, followed by 75 mg once ACS, including clopidogrel 75 mg, 300 mg daily for up UA/NSTEMI and (Plavix®, tablets to 12 months STEMI generics) in combination with aspirin, followed by aspirin indefinitely thromboembolism prophylaxis in patients with recent MI or stroke, or 75 mg/day established peripheral vascular disease

400 mg/day (divided prevention of doses, in postoperative combination thrombotic with dipyridamole 25 mg, 50 mg, 75 mg complications in ) or (generics) tablets patients with 400 mg/day prosthetic heart (divided valves doses, in combination with aspirin)

following a 60 mg ACS in patients to prasugrel loading dose, be managed with (Effient®, 5 mg, 10 mg tablets 10 mg/day+ PCI generics) in combination with aspirin reduce risk of death, MI, and following a 180 stroke in patients mg loading with ACS, history ticagrelor dose, 90 mg 60 mg, 90 mg tablets of MI, or acute (Brilinta®) twice daily^ in ischemic stroke/ combination high risk transient with aspirin ischemic attack

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Maximum Treatment Dosage Form/ Drug Name Recommended Indication Strength Dosage

reduce risk of first 60 mg twice MI or stroke in daily in patients with CAD combination at high risk of with aspirin events

MI, stroke, 2.08 mg/day in prophylaxis in vorapaxar 2.08 mg tablet combination patients with a (Zontivity®) with aspirin history of MI or or clopidogrel PAD ACS = ; CAD = coronary artery disease; MI = ; NSTE-ACS = non- ST-elevation acute coronary syndrome; NSTEMI = non-ST-elevation myocardial infarction; PAD = peripheral arterial disease; PCI = percutaneous coronary intervention; STEMI = ST-elevation myocardial infarction; TIA = transient ischemic attack; UA = * Durlaza is not currently available by the manufacturer. It is expected to be reintroduced to the U.S. market by the middle of 2021. +patients 75 years or older or weigh < 60 kg may use prasugrel 5 mg/day as maintenance therapy in combination with aspirin to reduce risk ^ticagrelor dosages are decreased to 60 mg twice daily after 12 months

Table 2. Maximum Daily Adult Dosages for PAIs – Combination Therapy1-3, 5-12 Maximum Treatment Dosage Form/ Drug Name Recommended Indication Strength Dosage

secondary prevention of cardiovascular and aspirin/ 81 mg/40 mg, 325 325 mg/40 cerebrovascular omeprazole mg/40 mg delayed- mg once events in patients (Yosprala®) release tablets daily predisposed to gastric ulcers

dipyridamole/ 200 mg/25 mg secondary stroke aspirin 200 mg/25 mg extended-release prevention (Aggrenox®, twice daily capsule generics)

1.2 Pediatrics Dipyridamole is FDA-approved for use in pediatric patients 12 years of age and older as adjunctive therapy to prevent thromboembolism following cardiac valve replacement. The maximum recommended dose is 100 mg four times daily in combination with warfarin. Dosages exceeding these recommendations will be reviewed.

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Aspirin as Durlaza®, cilostazol, prasugrel, ticagrelor, vorapaxar, aspirin/omeprazole, and dipyridamole/aspirin are not recommended for use in pediatric patients as safety and efficacy have not been established for these agents in this patient population. Although not FDA-approved, clopidogrel has effectively been used in pediatric patients to reduce thrombosis risk in infants and children with select types of heart disease, or as an alternative in patients with Kawasaki disease or ischemic stroke when aspirin is not tolerated.2, 3, 14-17

2 Duration of Therapy

There is no basis for limiting PAI therapy duration when prescribed to prevent thromboembolic events associated with cardiovascular or cerebrovascular disease. However, PAI therapy duration varies based on medication utilized and indication for use. PAI treatment durations are summarized in Tables 3 and 4.

Table 3. PAI Recommended Treatment Duration (Adults) - Monotherapy1-3, 5-12 Drug Maximum Treatment Treatment Indication Name Duration

reduce risk of death and recurrent stroke or recurrent MI in patients aspirin with a history of ischemic stroke indefinite (Durlaza®) or TIA, and/or a history of chronic CAD

cilostazol intermittent claudication indefinite

up to 1 year, in acute coronary syndrome (NSTE- combination with aspirin; clopidogrel ACS and STEMI) aspirin then continued

indefinitely+

thromboembolism prophylaxis indefinite

at least 12 months, in ACS in patients to be managed prasugrel combination with aspirin, with PCI after stent placement

90 mg twice daily x 1 year in combination with ticagrelor ACS aspirin; then, 60 mg twice daily in combination with aspirin indefinitely

MI, stroke, thrombosis indefinite, in combination vorapaxar prophylaxis in patients with a with aspirin or clopidogrel history of MI or PAD ACS = acute coronary syndrome; CAD = coronary artery disease; MI = myocardial infarction; NSTE-ACS = non- ST-elevation acute coronary syndrome; NSTEMI = non-ST-elevation myocardial infarction; PAD = peripheral 5 arterial disease; PCI = percutaneous coronary intervention; STEMI = ST-elevation myocardial infarction; TIA = transient ischemic attack +in patients with aspirin allergy, clopidogrel monotherapy may be continued indefinitely

Table 4. Adult PAI Recommended Combination Therapy Treatment Duration1-3, 5-12 Maximum Drug Name Treatment Indication Treatment Duration

secondary prevention of cardiovascular and cerebrovascular aspirin/omeprazole indefinite events in patients predisposed to gastric ulcers

dipyridamole/aspirin stroke prevention indefinite

3 Duplicative Therapy

Adjunctive therapy with aspirin and clopidogrel, dipyridamole, prasugrel, ticagrelor, or vorapaxar has documented efficacy for acute coronary syndrome or thrombotic event prevention; concurrent therapy with clopidogrel and ticagrelor or vorapaxar is also FDA-approved for thromboembolic event prophylaxis or acute coronary syndrome (see Tables 1-4).1-11,18-19

4 Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens that may result in clinically significant drug-drug interactions. Major drug-drug interactions considered clinically significant for platelet aggregation inhibitors are summarized in Table 5. Only those drug-drug interactions classified as clinical significance level 1/contraindicated or those considered life threatening which have not yet been classified will be reviewed.

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Table 5: Major Platelet Aggregation Inhibitor Drug-Drug Interactions1-3, 5-11, 20-22

Clinical Target Interacting Interaction Recommendation Significance Drug Drug Level avoid concurrent potential for aspirin use within 10 increased MTX days of high-dose serum levels, risk MTX; otherwise, use major of enhanced cautiously together; (DrugReax) aspirin pharmacologic/ (MTX) monitor for increased 1-severe (CP) toxic effects as myelosuppressive, GI NSAIDs can adverse effects; may reduce MTX consider using longer clearance leucovorin rescue contraindicated concurrent (DrugReax) administration cilostazol, riociguat dipyridamole: 1- may result in avoid concurrent use dipyridamole (Adempas®) severe; increased cilostazol: 3- risk moderate (CP) co-administration avoid use; ticagrelor may result in therapy should not be elevated serum initiated for at least 2 ticagrelor: concentrations of weeks after contraindicated; select platelet cilostazol, aggregation discontinuation; if vorapaxar: cilostazol, itraconazole, inhibitors (PAIs) adjunctive major ticagrelor, strong CYP3A4 and potential administration (DrugReax) vorapaxar inhibitors bleeding necessary, use ticagrelor: 1- complications as cautiously and severe; cilostazol, monitor patient cilostazol, ticagrelor, and closely for enhanced vorapaxar: 2- vorapaxar pharmacologic/ major (CP) metabolized by adverse effects, CYP3A4 especially bleeding adjunctive administration with clopidogrel (strong CYP2C8 dasabuvir/ inhibitor) ombitasvir/ contraindicated by paritaprevir/ manufacturer, as ritonavir dasabuvir (Viekira®) metabolized by clopidogrel avoid concurrent use 1-severe (CP) CYP2C8, which increases risk for dasabuvir-induced QT interval prolongation; ritonavir, a CYP3A4 inhibitor, may limit clopidogrel

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Clinical Target Interacting Interaction Recommendation Significance Drug Drug Level conversion to active metabolite strong CYP2C19 inhibitor (e.g. omeprazole) may result in reduced avoid concurrent major plasma use; consider (DrugReax) clopidogrel omeprazole concentrations of alternative proton 2-major (CP) clopidogrel active pump inhibitor (e.g.

metabolite and pantoprazole) diminish antiplatelet activity increased risk of hemorrhage when used adjunctively contraindicated PAIs with avoid concurrent use (DrugReax) / 1-severe (CP) fibrinolytic drugs like PAIs potential for additive bleeding avoid concurrent adverse effects; therapy, if possible; major, moderate PAIs inhibit PAIs, if drug combination (DrugReax) low molecular platelet including necessary, use 2-major, 3- weight aggregation and aspirin cautiously, monitor moderate (CP) have increased for signs/symptoms bleeding risk, of bleeding prolonged bleeding time increased selective bleeding risk with serotonin monitor for combined reuptake signs/symptoms of SSRIs –major; therapy; PAIs, inhibitors bleeding; may SNRIs-major SSRIs/SNRIs including (SSRIs)/, consider substituting (DrugReax) deplete platelet aspirin serotonin tricyclic 3-moderate (CP) serotonin, which norepinephrine antidepressant for may impair reuptake SSRI/SNRI platelet inhibitors (SNRIs) aggregation combined if combined therapy major PAIs, administration necessary, monitor (DrugReax) including may increase patients closely for 2-major, 3- aspirin bleeding risk, due bleeding moderate (CP) to additive effects signs/symptoms concurrent use nonsteroidal anti- monitor for signs of major may increase risk PAIs inflammatory bleeding with (DrugReax) for bleeding drugs (NSAIDs) concurrent use 3-moderate (CP) especially with

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Clinical Target Interacting Interaction Recommendation Significance Drug Drug Level chronic NSAID use strong inducers substantially reduce ticagrelor, strong CYP3A major ticagrelor, vorapaxar inducers (e.g., avoid use (DrugReax) vorapaxar exposure and rifampin) 2–major (CP) efficacy as both are CYP3A4 substrates adjunctive use may increase lovastatin, avoid lovastatin, simvastatin simvastatin doses serum levels as moderate simvastatin, higher than 40 mg; ticagrelor ticagrelor is (DrugReax) lovastatin observe for adverse CYP3A4 inhibitor 2–major (CP) effects if combined and lovastatin use necessary and simvastatin are metabolized by CYP3A4

5 References

1. DRUGDEX® System (electronic version). Truven Health Analytics, Greenwood Village, Colorado, USA. Available at: http://www.micromedexsolutions.com.libproxy.uthscsa.edu. Accessed December 22, 2020. 2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2020. Available at: http://www.clinicalpharmacology.com. Accessed December 22, 2020. 3. Facts and Comparisons eAnswers [database online]. Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2020. Available at: http://eanswers.factsandcomparisons.com.ezproxy.lib.utexas.edu/. Accessed December 22, 2020. 4. Cucchiara BL, Messé SR. Antiplatelet therapy for secondary prevention of stroke. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on December 22, 2020.) 5. Aspirin extended-release capsules (Durlaza®) package insert. New Haven Pharmaceuticals, September 2015. 6. Clopidogrel tablets (Plavix®) package insert. Sanofi-Aventis, April 2020.

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7. Prasugrel tablets (Effient®) package insert. , September 2020. 8. Ticagrelor (Brilinta®) package insert. AstraZeneca, November 2020. 9. Vorapaxar tablets (Zontivity®) package insert. Aralez Pharmaceuticals Us Inc., November 2019. 10.Aspirin/omeprazole extended-release tablets (Yosprala®) package insert. Aralez Pharmaceuticals US Inc., June 2018. 11.Aspirin/extended-release dipyridamole capsules (Aggrenox®) package insert. Pharmaceuticals, Inc., December 2019. 12.Lexicomp Online, Lexi-Drugs Online, Hudson, Ohio:Wolters Kluwer Clinical Drug Information, Inc.; 2020; December 22, 2020. 13.Coutre S. Congenital and acquired disorders of platelet function. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on December 22, 2020.) 14.Li JS, Yow E, Berezny KY, et al. Dosing of clopidogrel for platelet inhibition in infants and young children: primary results of the Platelet Inhibition in Children On cLOpidogrel (PICOLO) trial. Circulation 2008;117:553-9. 15.Soman T, Rafay MF, Hune S, et al. The risks and safety of clopidogrel in pediatric arterial ischemic stroke. Stroke. 2006;37(4):1120-2. 16.Giglia TM, Massicotte MP, Tweddell JS, et al., for the American Heart Association Congenital Heart Defects Committee of the Council on Cardiovascular Disease in the Young, Council on Cardiovascular and Stroke Nursing, Council on Epidemiology and Prevention, and Stroke Council. Prevention and treatment of thrombosis in pediatric and congenital heart disease: a scientific statement from the American Heart Association. Circulation. 2013;128:2622-2703. 17.McCrindle Brian W., Rowley Anne H., Newburger Jane W., et al. Diagnosis, treatment, and long-term management of kawasaki disease: a scientific statement for health professionals from the american heart association. Circulation. 2017;135(17):e927-e999. 18.DiDomenico RJ, Dobesh PP, Finks SW. Chapter 33. Acute coronary syndromes. (Chapter) In: DiPiro JT, Talbert RL, Yee GC, et al. (eds): Pharmacotherapy: a pathophysiologic approach. 11th edition. New York: McGraw-Hill; 2020. Access Pharmacy Website. Available at: http://accesspharmacy.mhmedical.com.ezproxy.lib.utexas.edu/book.aspx?bo okid=689. Accessed December 23, 2020. 19.Stacy Z, Chow S. Chapter 34. Peripheral arterial disease. (Chapter) In: DiPiro JT, Talbert RL, Yee GC, et al. (eds): Pharmacotherapy: a pathophysiologic approach. 11th edition. New York: McGraw-Hill; 2020. Access Pharmacy Website. Available at: http://accesspharmacy.mhmedical.com.ezproxy.lib.utexas.edu/book.aspx?bo okid=689. Accessed December 23, 2020. 20.Ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets co-packaged for oral use (Viekira Pak®) package insert. AbbVie Inc., November 2020. 21.Food and Drug Administration. Current and Resolved Drug Shortages and Discontinuations Reported to FDA: dasabuvir, ombitasvir, paritaprevir, and ritonavir extended-release tablets (Viekira XR). May 22, 2018. Available at: 10 https://www.accessdata.fda.gov/scripts/drugshortages/dsp_ActiveIngredient Details.cfm?AI=Dasabuvir%20Sodium;%20Ombitasvir;%20Paritaprevir;%20 Ritonavir%20(Viekira%20XR)%20Tablets&st=d. Accessed December 22, 2020.

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