Nanik Hatsakorzian Pharm.D/MPH

Transcription

1 Pharm.D/MPH Therapeutics FDA indication & Dosing Clinical Pearls Anticoagulants Heparin Antiphospholipid antibody syndrome Cerebral thromboembolism Prosthetic heart valve Acute coronary syndrome - STEMI/NSTEMI/UA: Initial bolus of 60 units/kg (maximum: 4000 units), then 12 units/kg/hour (maximum: 1000 units/hour) as continuous infusion Percutaneous coronary intervention - No prior anticoagulant therapy: If no GPIIb/IIIa inhibitor use planned: Initial bolus of units/kg or units/kg if planning GPIIb/IIIa inhibitor use Thromboprophylaxis: SubQ: 5000 units every 8-12hours. Note: ACCP recommends a minimum of days for patients undergoing total hip arthroplasty, total knee arthroplasty, or hip fracture surgery. DVT/PE*: I.V.: 80 units/kg (or alternatively 5000 units) I.V. push followed by continuous infusion of 18 units/kg/hour (or alternatively 1000 units/hour) Treatment of Venous thromboembolism: Note: Start warfarin on the first or second treatment day and continue heparin until INR is 2 for at least 24 hours (usually 5-7 days). Enoxaparin (Lovenox) Acute coronary syndrome DVT/PE treatment and prophylaxis - Prophylaxis: Twice- daily dosing: 30 mg every 12 hours, with initial dose within hours after surgery, and every 12 hours for at least 10 days or until risk of DVT has diminished or the patient is adequately anticoagulated on warfarin. Once- daily dosing: 40 mg once daily, with initial dose within 9-15 hours before surgery, and daily for at least 10 days (or up to 35 days postoperatively) or until risk of DVT has diminished or the patient is adequately anticoagulated on warfarin. - Treatment: (Acute): SubQ: Note: Start warfarin on the first or second treatment day and continue enoxaparin until INR is 2 for at least 24 hours (usually 5-7 days) - Inpatient treatment (with or without pulmonary embolism): 1 Due to large molecular size, Ok in pregnancy and breastfeeding. No dosage adjustment is necessary in renal impairment No dosage adjustment is necessary in hepatic impairment, but bleeding risks might be higher Moderate- severe risk of hyperkalemia in patient on ACEI or any potassium sparing diuretic Antidote is protamine 1mg neutralizes about 100 units of heparin Preferred in pregnancy over UFH d/t less HIT risk No dosage adjustment is necessary in hepatic impairment Dosage adjustment is necessary in renally impaired patients with CrCl <= 30ml/min Closer monitoring of anti Xa is required in morbidly obese patients (BMI 30-48; marginally higher anti Xa at steady state when compared with non obese patients on 1.5 mg/kg SC daily) Antidote is protamine 1mg neutralizes about 1mg of enoxaparin

2 Fondaparinu x (Arixtra) mg/kg/dose every 12 hours or 1.5 mg/kg once daily. - Outpatient treatment (without pulmonary embolism): 1 mg/kg/dose every 12 hours. PCI* Antiphospholipid antibody syndrome* Cerebral thromboembolism* DVT/PE prophylaxis: SubQ: Adults 50 kg: 2.5 mg once daily DVT/PE treatment - SubQ: Note: Start warfarin on the first or second treatment day and continue fondaparinux until INR is 2 for at least 24 hours (usually 5-7 days) <50 kg: 5 mg once daily kg: 7.5 mg once daily >100 kg: 10 mg once daily. Usual duration: 5-9 days (has been administered up to 26 days) DVT prophylaxis with the history of HIT* SubQ: 2.5 mg once daily Acute coronary syndrome* Direct Xa inhibitor (Anti Xa) Xarelto DVT/PE treatment: Initial: 15 mg twice daily with food (rivaroxaban) for 3 weeks followed by 20 mg once daily with food Reduction in risk of reoccurrence of DVT/PE: 20 mg once daily with food Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism): 20 mg once daily with the evening meal Postoperative thromboprophylaxis: Note: Initiate therapy after hemostasis has been established, 6-10 hours postoperatively. Knee replacement: 10 mg once daily; Total duration of therapy: days; extended duration of up to 35 days suggested. Hip replacement: 10 mg once daily; total duration of therapy: 35 days. Eliquis (Apixaban) Nonvalvular atrial fibrillation (to prevent stroke and systemic embolism): Oral: 5 mg twice daily unless patient has any 2 of the following: Age 80 years, body weight 60 kg, or serum creatinine 1.5 mg/dl, then reduce dose to 2.5 mg twice daily. Per the American Heart Association, the following apixaban doses have been recommended: Pregnancy and lactation: Enoxaparin is preferred over fondaparinux Hepatic impairment: mild to moderate consider closer monitoring for risk of bleeding. For severe hepatic impairment dose adjustment is not available from manufacturer Renal impairment: contraindicated in CrCl <30. CrCl= clearance is decrease ~40%. 50% reduction is recommended Contraindicated in patient <50kg for DVT prophylaxis Weight based dosing in acute DVT/PE treatment Fondaparinux should be discontinued 24 hours prior to CABG No antidote available Conversion from warfarin: Discontinue warfarin and initiate rivaroxaban as soon as INR falls to <3.0 Conversion from continuous infusion UFH: Initiate rivaroxaban at the time of heparin discontinuation Conversion to continuous infusion UFH: Initiate continuous infusion UFH 24 hours after discontinuation of rivaroxaban Discontinue current anticoagulant and initiate rivaroxaban 2 hours prior to the next regularly scheduled evening dose of the discontinued anticoagulant. Conversion to other anticoagulants (other than warfarin): Initiate the anticoagulant 24 hours after discontinuation of rivaroxaban Safety and efficacy have not been established in patients with prosthetic heart valves or significant rheumatic heart disease Contraindicated with strong CYP3A4 inducers and inhibitors Contraindicated with CrCl<30 Use with caution in moderate liver impairment (Child- Pugh class B) Conversion from warfarin to apixaban: Discontinue warfarin and initiate apixaban when INR is <2.0 Conversion from apixaban to warfarin: Apixaban affects the INR; measuring the INR during coadministration with warfarin therapy may not be useful for determining an appropriate dose of warfarin. Conversion between apixaban and other non- warfarin anticoagulants: Discontinue anticoagulant being taken and begin the other at

3 Pharm.D/MPH Patients with 1 additional risk factor for stroke and 1 of the following: Age 80 years, weight 60 kg, or serum creatinine 1.5: Alternative to aspirin or warfarin depending on suitability of vitamin K antagonist (VKA) therapy: 5 mg twice daily - Patients with 1 additional risk factor for stroke and 2 of the following: Age 80 years, weight 60 kg, or serum creatinine 1.5: Alternative to aspirin or warfarin depending on suitability of vitamin K antagonist (VKA) therapy: 2.5 mg twice daily Venous thromboembolism (DVT or PE) treatment* Oral: Initial treatment: 10 mg twice daily for 7 days followed by 5 mg twice daily for 6 months Antiplatelets agents (Thienopyridine) Effient (Prasugrel) Prasugrel is a prodrug. The active metabolite irreversibly blocks the P2Y 12 component of ADP receptors on the platelet, which prevents activation of the GPIIb/IIIa receptor complex, thereby reducing platelet activation and aggregation. Percutaneous coronary intervention (PCI) for ACS: Loading dose: 60 mg administered promptly (as soon as coronary anatomy is known or before if risk for bleeding is low and need for CABG considered unlikely) and no later than 1 hour after PCI; Maintenance dose: 10 mg once daily (in combination with aspirin mg/day day; 81 mg/day recommended). STEMI, a loading dose may also be administered if PCI is performed >24 hours after treatment with a fibrin- specific thrombolytic (ie, alteplase, reteplase, tenecteplase) Duration of prasugrel (in combination with aspirin) after stent placement: Premature interruption of therapy may result in stent thrombosis with subsequent fatal or nonfatal MI. Those with ACS receiving either stent type [BMS] or [DES] or those receiving a DES for a non- ACS indication, prasugrel for at least 12 months is recommended. Those receiving a BMS for a non- ACS indication should be given at least 1 month and ideally up to 12 months; if patient is at increased risk of bleeding, give for a minimum of 2 weeks. Duration>12 months, regardless of indication, may be considered in patients with DES placement. Maintenance dosing in low body weight (ie, <60 kg) the next scheduled dose. U.S. labeling: Dual strong CYP3A4 and P- glycoprotein inhibitors 2.5 mg twice daily; Note: Avoid concomitant use if patient is already taking apixaban 2.5 mg twice daily or patient meets 2 of the following criteria: Age 80 years, body weight 60 kg, or serum creatinine 1.5 Use not recommended when ClCr < 25 Use with caution in moderate liver impairment (Child- Pugh class B) Use with caution in patients with severe hepatic impairment Elderly: [U.S. Boxed Warning]: In patients 75 years of age, use is not recommended due to increased risk of fatal and intracranial bleeding and uncertain benefit; use may be considered in high- risk situations (eg, patients with diabetes or history of MI). Risk of bleeding is increased in older adults (Beers Criteria). Monitoring Parameters: Hemoglobin and hematocrit periodically Inhibition is irreversible; on discontinuation of prasugrel, normal platelet function returns only when new platelets are released from the bone marrow. Normal platelet function will occur within 5-9 days of discontinuation. There is no scientific evidence to warrant the discontinuance of prasugrel prior to dental surgery Vitamin E may enhance anti- platelet properties Less complicated DDI profile

4 Clopidogrel (Plavix) individuals: Due to a higher incidence of bleeding in patients weighing <60 kg, a maintenance dose of 5 mg once daily may be considered. Recent MI, recent stroke, or established peripheral arterial disease (PAD) or Coronary artery disease (CAD): Oral: 75 mg once daily Secondary prevention of cardioembolic stroke (patient not candidate for oral anticoagulation): Oral: 75 mg once daily (in combination with aspirin) UA/NSTEMI: Initial: 300 mg loading dose, followed by 75 mg once daily for up to 12 months (in combination with aspirin indefinitely) STEMI: 75 mg once daily (in combination with aspirin mg initially followed by mg/day Atrial fibrillation (in patients not candidates for warfarin and at a low risk of bleeding) * Oral: 75 mg once daily (in combination with aspirin mg once daily). Note: Combination may also be used as an alternative for patients with atrial fibrillation and mitral stenosis Carotid artery stenosis, symptomatic (including recent carotid endarterectomy)*: Oral: 75 mg once daily Antiplatelet agent (cyclopentyltriazolopyrimidine) Ticagrelor ACS: 180 mg loading dose (with a loading dose of aspirin (Brilinta) 325 mg; Maintenance: 90 mg twice daily; initiated 12 hours after initial loading dose (with low- dose aspirin mg/day or 81 mg/day in patients with UA/NSTEMI In patients with DES/BMS duration of therapy is at least 12 months or longer. If patient has increased risk of bleeding then for 2 weeks. Bleeding: Clopidogrel increases the risk of bleeding. Use is contraindicated in patients with active pathological bleeding or intracranial hemorrhage. Age 75 years, propensity to bleed (eg, recent trauma or surgery, recent or recurrent GI bleeding, active PUD, severe hepatic impairment), body weight <60 kg Thienopyridine hypersensitivity: Because of structural similarities, cross- reactivity is possible among the thienopyridines (clopidogrel, prasugrel, and ticlopidine); use with caution or avoid in patients with previous thienopyridine hypersensitivity Hepatic impairment: Use with caution in patients with severe hepatic impairment Renal impairment: Use with caution in patients with severe renal impairment CYP2C19 inhibitors: Concurrent use with drugs known to inhibit CYP2C19 (eg, proton pump inhibitors) may reduce levels of active metabolite and subsequently reduce clinical efficacy and increase the risk of cardiovascular events; if possible, avoid concurrent use of moderate- to- strong CYP2C19 inhibitors. In patients requiring antacid therapy, consider use of ranitidine/famotidine or with less CYP2C19 inhibition. Avoid concurrent use of omeprazole (even when scheduled 12 hours apart) or esomeprazole. Reduced CYP2C19 function: [U.S. Boxed Warning]: Patients with one or more copies of the variant CYP2C19*2 and/or CYP2C19*3 alleles (and potentially other reduced- function variants) may have reduced conversion of clopidogrel to its active thiol metabolite. Lower active metabolite exposure may result in reduced platelet inhibition and, thus, a higher rate of cardiovascular events following MI or stent thrombosis following PCI. Conversion from clopidogrel to ticagrelor: May initiate ticagrelor 90 mg twice daily beginning 24 hours after last clopidogrel dose Dose change is not necessary for renaly impaired patients Contraindicated in severe hepatic impairments Tablets can be crushed to create suspension if patient cannot swallow or NG tube use Hyperuricemia: Use with caution in patients with a history of hyperuricemia or gouty arthritis Maintenance doses of aspirin greater than 100 mg/day reduce the efficacy of ticagrelor and should be avoided Caution with CYP3A4 inhibitors or inducers- risk X avoid combination Avoid using doses of simvastatin greater than 40 mg/day with ticagrelor MoA: Reversibly and noncompetitively binds the adenosine diphosphate (ADP) P2Y 12 receptor on the platelet surface, which prevents ADP- mediated activation of the GPIIb/IIIa reducing platelet aggregation. Due to the reversible antagonism of the P2Y 12 receptor, recovery of platelet function is likely to depend on serum concentrations of ticagrelor and its active metabolite.

5 Pharm.D/MPH Direct Thrombin Inhibitors Dabigatran Nonvalvular atrial fibrillation (to prevent stroke and (Pradaxa) systemic embolism): Oral: 150 mg twice daily. American College of Chest Physicians (ACCP) suggests dabigatran over warfarin for primary and secondary prevention of nonvalvular atrial fibrillation- induced cardioembolic stroke or TIA. For secondary prevention, initiate therapy within 1-2 weeks after stroke onset or earlier in patients at low bleeding risk Reversible, DTI that inhibits both free and fibrin- bound thrombin. Inhibits coagulation by preventing thrombin- mediated effects, including cleavage of fibrinogen to fibrin monomers, activation of factors V, VIII, XI, and XIII, and inhibition of thrombin- induced platelet aggregation. Existing AHA Recommendations for use of dabigatran: Dabigatran is useful as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent AF and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (CrCl <15 ml/min), or advanced liver disease (impaired baseline clotting function) Conversion from a parenteral anticoagulant: Initiate dabigatran 2 hours prior to the time of the next scheduled dose of the parenteral anticoagulant (eg, enoxaparin) or at the time of discontinuation for a continuously administered parenteral drug (eg, I.V. heparin); discontinue parenteral anticoagulant at the time of dabigatran initiation. Conversion to a parenteral anticoagulant: U.S. labeling: Wait 12 hours (Cl cr 30) or 24 hours (Cl cr <30) after the last dose of dabigatran before initiating a parenteral anticoagulant. Conversion from warfarin: Discontinue warfarin and initiate dabigatran when INR <2.0 Conversion to warfarin: Start time must be adjusted based on Cl cr: Cl cr >50: Initiate warfarin 3 days before discontinuation of dabigatran Cl cr 31-50: Initiate warfarin 2 days before discontinuation of dabigatran Cl cr 15-30: Initiate warfarin 1 day before discontinuation of dabigatran Cl cr <15 ml/minute: No recommendations provided in the U.S. manufacturer s labeling. Note: Since dabigatran contributes to INR elevation, warfarin s effect on the INR will be better reflected only after dabigatran has been stopped for 2 days Patients 80 years: Use with extreme caution or consider other treatment options; no dosage adjustment provided in manufacturer s labeling; however, numerous cases of hemorrhage, including hemorrhagic stroke, have been reported postmarketing, particularly in this age group of octogenarians Dabigatran is contraindicated in patients with severe renal impairment (Cl cr 30 ml/minute) Not recommended for patients with coexisting prosthetic heart valve Atorvastatin and Antacids: May decrease the serum concentration of Dabigatran Proton Pump Inhibitors: May decrease serum concentrations of the active metabolite of Dabigatran Verapamil: May increase serum concentrations of the active metabolite(s) of Dabigatran Amiodarone: May increase the serum concentration of Dabigatran