Pharmacological Treatment Options for Venous Thromboembolism Prevention & Treatment
Marie Meyer, PharmD Candidate 2007
Unfractionated Heparin(UFH) / Low Molecular Weight Heparin (LMWH) / Vitamin K antagonist / Platelet Inhibitors / Selective Anti-Xa Inhibitor / Direct Thrombin Inhibitors
Product Availability
Generic (Brand) / Heparin sodium, porcine
(Hep-Lock)
Infusions:
1,000 units/500ml
2,000 units/1,000ml
10,000 units/100ml
12,500 units/250ml
25,000 units /250ml
25,000 units/500ml
Injections:
10 units/ml
100 units/ml
1,000 units/ml
5,000 units/ml
10,000 units/ml
20,000 units/ml
Generic available / Dalteparin (Fragmin)
10,000 units/ml
25,000 units/ml
2500 units/0.2ml
5000 units/0.2ml
7500 units/0.3ml
Enoxaparin (Lovenox)
Prefilled syringes:
30mg/0.3ml
40mg/0.4ml
60mg/0.6ml
80mg/0.8ml
100mg/ml
120mg/0.8ml
150mg/ml
Multidose solution
100mg/ml (3ml)
Tinzaparin (Innohep)
20,000 units/ml (2ml)
No generics available / Warfarin (Coumadin, Jantoven)
Injection, powder for resuspension
Tablets
1mg, 2mg, 2.5mg, 3mg, 4mg, 5mg, 6mg, 7.5mg, 10mg
Generic available / Aspirin
generic available
tablets 81, 325, 500mg
Ticlopidine (Ticlid)
Generic available
tablet 250mg
Clopidogrel (Plavix)
No generics available
tablet 75 mg / Fondaparinux (Arixtra)
2.5mg/0.5ml
5mg/0.4ml
7.5mg/0.6ml
10mg/0.8ml
No generics available / Lepirudin (Refludan)
50 mg powder for injection
Bivalirudin (Angiomax)
250 mg powder for injection
argatroban
100mg/ml injection
No generics available
Mechanism
of Action / Indirect anticoagulant. Binds to antithrombinIII (ATIII) and accelerates ATIII activity. ATIII inactivates thrombin (IIa) and factor Xa. Prevents conversion of fibrinogen to fibrin. / Same as UFH but with little to no IIa activity – mainly inactivates Xa / Inhibits hepatic synthesis of vitamin K-dependent clotting factors (II, VII, IX, X). Inhibits the conversion of vitamin K to clotting factors, slows production of clotting factors. / Aspirin
Inhibit prostaglandin synthetase enzyme preventing formation of thromboxaneA2 (platelet aggregator)
Ticlopidine (Ticlid)
Inhibit platelet function
Clopidogrel (Plavix)
Block ADP receptor, prevents fibrinogen binding, reduces platelet adhesion aggregation. / Synthetic pentascccharide (mimics the active moiety of heparins). Factor Xa neutralization via ATIII-mediated selective inhibition of factor Xa.
Interrupts coagulation cascade, inhibits thrombin formation. / Bind directly to thrombin – prevent formation of fibrin.
Unfractionated Heparin
(UFH) / Low Molecular Weight Heparin (LMWH) / Vitamin K antagonist / Platelet Inhibitors / Selective Anti-Xa Inhibitor / Direct Thrombin Inhibitors
EFFICACY
(Indication/ Use, Clinical Data Support) / Treatment or prevention of VTE / Treatment or prevention of DVT / Treatment or prevention of DVT
Prevention of stroke in patients with A.fib.
Takes 10-14 days for therapeutic effect because of the t ½ of existing clotting factors. Takes 12 days to reach maximal effect. / Aspirin
Stroke/MI prevention
Ticlopidine (Ticlid)
Reduce risk of thrombotic stroke in patients who have had a stroke – reserved for patients who failed or cannot tolerate aspirin
Clopidogrel (Plavix)
Reduce atherosclerotic events / Prevention of DVT
Treatment of PE or DVT / Limited indications
Lepirudin nticoagulation in patients with HIT associated thrombo-embolic disease in order to prevent further thromboembolic complications
BivalirudinAnticoagulant used in conjunction with aspirin for patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA) or percutaneous coronary intervention (PCI) with provisional glycoprotein IIb/IIIa inhibitor; anticoagulant used in patients undergoing PCI with (or at risk of) HIT / thrombosis syndrome (HITTS)
argatroban Prophylaxis or treatment of thrombosis in adults with HIT; adjunct to percutaneous coronary intervention (PCI) in patients who have or are at risk of thrombosis associated with HIT
Unfractionated Heparin
(UFH) / Low Molecular Weight Heparin (LMWH) / Vitamin K antagonist / Platelet Inhibitors / Selective Anti-Xa Inhibitor / Direct Thrombin Inhibitors
SAFETY
(Major Drug Interactions,
Pre-cautions, Contra-indications,
Adverse Effects,
Pregnancy Risk Category) / Cephaolosporins, platelet acting drugs, penicillins, thrombolytics, warfarin, antihistamines, tetracyclines, quinine, nicotine, digoxin, cat's claw, dong quai, evening primrose, feverfew, red clover, horse chestnut, garlic, green tea, ginseng, ginkgo may all increase bleed risk.
Nitroglycerin may decrease heparin effect.
AE: bleeding, bruising, nausea, constipation, elevated LFTs, injection site irritation, allergic rxn,
thrombocytopenia (HIT)
CI: previous HIT, severe bleeding, suspected intracranial hemorrhage
Pregnancy category C / Dalteparin (Fragmin)
Platelet inhibitors, thrombolytics, warfarin may increase bleeding
AE: bleeding, injection site rxn, thrombo-cytopenia, allergic rxn,
CI: pork allergy, previous dalteparin thrombocytopenia
Pregnancy category B
Enoxaparin (Lovenox)
AE: bleeding, fever, nausea, injection site rxn, thrombocytopenia
CI: pork allergy, previous enoxaparin thrombocytopenia
Pregnancy category B
Tinzaparin (Innohep)
AE: bleeding, injection site rxn, elevated LFTs, thrombocytopenia, allergic rxn,
CI: pork allergy, previous HIT
Pregnancy category B / CYP1A2, 2C9, 2C19, 3A4 substrate
CYP2C9, 2C19 inhibitor
Too many drug interactions to list
AE: bleeding, fever, lethargy, vasculitis, edema, rash, anorexia, nausea, vomiting, taste disturbance, jaundice, skin necrosis/gangrene (rare)
CI: anything that increases risk of bleeding, poor compliance, alcoholism, history of warfarin induced necrosis
Pregnancy category X / Aspirin
Increased bleed risk with heparin, NSAIDs, platelet inhibitors, warfarin. Interaction with ACEi, buspirone, carbonic anhydrase inhibitors, corticosteroids, methotrexate, probenecid, sulfonyureas, valproic acid, verapamil.
AE: anaphylaxis, rash, acidosis, GI upset, ulcer, tinnitus, bronchospasm,
CI: salicylate or NSAID hypersensitivity, asthma, rhinitis, nasal polyps, bleeding disorder, children, 3rd trimester pregnancy
Pregnancy category C/D
Ticlopidine (Ticlid)
Interactions: antacids, anticogulants, anti-platelets, carbamazepine, cimetidine, cyclosporine, digoxin, phenytoin, theophylline
AE: bleeding, neutropenia, thrombocytopenia, agranulocytosis, increases cholesterol, diarrhea, dizziness, rash, UTI, GI upset
CI: allergy, bleeding, liver dysfunction, hematopoietic disorders
Pregnancy category B
Clopidogrel (Plavix)
Interactions: anticoagulants, aspirin, atorvastatin, drotrecogin alpha, macrolides, NSIADs, rifampin, thrombolytics.
AE: bleeding, GI upset, chest pain, headache, dizziness, rash, increased cholesterol, UTI, arthralgia, respiratory problems, flu-like symptoms, agranulocytosis,
CI: bleeding, coagulation disorders
Pregnancy category B / Anticoagulants, antiplatelets, NSAIDs, salicylates, thrombolytics may increase bleed risk.
AE: bleeding, fever, nausea, edema, rash, constipation, thrombocytopenia, elevated LFTs, injection site rxn
CI: ClCr < 30 ml/min, body weight < 50 kg, active bleed, bacterial endocarditis, previous fondparinux thrombocytopenia
Pregnancy category B / Lepirudin
Interactions: cephalosporins, platelet drugs, penicillins, thrombolytics, warfarin
AE: bleeding, anemia, hematoma, heart failure, fever, elevated LFTs, bronchospasm, angio-edema, thrombocytopenia
CI: bleeding, hypersensitivity
Pregnancy category B
Bivalirudin
Interactions: aspirin, anticoagulants, trepostinil
AE: bleeding HoTN, nausea, back pain, angina, urinary retention, thrombocytopenia, injection site reaction, pelvic pain
CI: bleeding, hypersensitivity
Pregnancy category B
argatroban
Interactions: platelet drugs, erythromycin, heparin, thrombolytics, warfarin
AE: bleeding, chest pain, UTI, fever, decreased Hgb Hct, back pain, GI upset, difficulty breathing, infection, sepsis
CI: bleeding, hypersensitivity
Pregnancy category B
Dosage & Administ-ration
(Include renal and/or hepatic adjustments) / IV continuous infusion
IV Heparin lock injection
SQ injection, but absorption is unpredictable
CANNOT be given IM
Prevention – 5000 units subcutaneously q 8-12h
Treatment of DVT/PE – IV push 80 units/kg then continuous infusion of 18 units/kg/hour (20,000-40,000 units daily)
Treatment of DVT – 17,500 units subcutaneously q12h
Elderly – dose lowering may be required / Must be given SQ
Dalteparin (Fragmin)
Prevention
2500 units/day low risk; 5000 units/day high risk or s/p hip surgery
Treatment of DVT
100 units/kg bid
Enoxaparin (Lovenox)
Prevention
30mg bid
40mg bid high risk
Treatment
1mg/kg q12h,
Tinzaparin (Innohep)
Treatment
175 anti-Xa units/kg/day / Individualized dosing.
Oral
Start 5-10 mg daily x 2 days, adjust dose based on INR
IV
2-5 mg daily as slow bolus / Aspirin
30 - 325 mg daily
Ticlopidine (Ticlid)
250mg bid
Clopidogrel (Plavix)
75 mg daily / Must be given SQ
Prevention of DVT
2.5 mg once daily 6-8 hours post surgery x 5-9 days
Treatment of VTE
5mg, 7.5mg, or 10mg once daily (weight based) x 5-9 days
caution in patients with ClCr 30-50 ml/min
contraindicated if ClCr <30 ml/min / must be given IV
Lepirudin (Refludan)
Weight-based not to exceed 0.21 mg/kg/h
Reduce 50% if ClCr <60ml/min
Bivalirudin (Angiomax)
7.5mg/kg bolus, then 1.5 mg/kg/hr up to 4 h post procedure
reduce to 1mg/kg/hr id ClCr <30 ml/min
argatroban
2mcg/kg/min
reduce in hepatic impairment
Unfractionated Heparin
(UFH) / Low Molecular Weight Heparin (LMWH) / Vitamin K antagonist / Platelet Inhibitors / Selective Anti-Xa Inhibitor / Direct Thrombin Inhibitors
Monitoring
(Efficacy and Toxicity Parameters) / Platelets, hemoglobin, hematocrit, signs of bleeding,
Activated partial thromboplastin time (aPTT) / Prothrombin time (PT)
International normalized ratio (INR), signs of bleeding, / Prothrombin time (PT), hematocrit,
International normalized ratio, signs of bleeding, / s/sx bleeding, Hg Hct
Ticlopidine (Ticlid)
CBC with differential q 2 weeks, LFTs, / CBC, SCr, fecal occult blood test
Anti-factor Xa activity (only valid if fondaparinux is used as the calibrator – do not use international standards of heparin or LMWH as calibrators) / aPTT, PT, Hgb, Hct, s/sx bleeding, ACT
Patient Education / This drug must be given by infusion or injection. Avoid new Rx, OTC, herbals while in heparin. Beware of increased risk of bleeding. Report chest pain, trouble breathing, fever, persistent nausea, visual changes, or injection site reactions. / This drug must be given by injection. Follow self-administer instructions carefully and dispose of needle properly. Beware of increased risk of bleeding. Report chest pain, trouble breathing, fever, persistent nausea, or injection site reactions. / Do not take with food, take at the same time every day. Do not change diet drastically. Keep consistant dietary intake of vitamin K. Food high in vitamin K inhibit this drug’s effect. Avoid large portions of of alfalfa, asparagus, broccoli, brussel sprouts, cabbage, cauliflower, green teas, kale, lettuce, liver, spinach, turnip greens, watercress. You will need regular blood tests while on this drug. Tell your doctor and pharmacist of all Rx, OTC, and herbal products you take. If you miss a dose take it right away but never double doses. Avoid alcohol. Be careful about increased tendency to bleed while taking this drug. / Aspirin
Take with food or milk, may upset stomach, avoid alcohol and NSAIDs, may cause GI bleeding/ulcers, stop taking if you get ringing ears, persistent stomach pain, difficulty breathing, unusual bruising/bleeding, rash
Ticlopidine (Ticlid)
Be careful about increased tendency to bleed while taking this drug. Do not use aspirin. Report unusual bleeding or bruising, flu-like symptoms, changes in mentall status; blood in urine, stool, or vomitus; delayed healing of any wounds; skin rash; yellowing of skin or eyes; changes in color of urine or stool; pain or burning on urination; respiratory difficulty.
Clopidogrel (Plavix)
Take without regard to meals. May cause headache, dizziness, nausea, vomiting, back pain. Be sure your physicians and dentists know you are taking this medication. Report chest pain, trouble breathing, rash, unusual bleeding. / This medication must be given by injection under the skin. Tell your caregiver about injection site pain, burning, redness, or swelling and about any unusual bleeding or bruising, pain in joints or back, fever, severe headache.
Be careful about increased tendency to bleed while taking this drug. May cause nausea, vomiting, dizziness, headache. / This drug can only be given by injection (bivalirudin) or infusion (lepirudin, argatroban). You will need blood tests to monitor therapy. Be aware of increased bleed risk. Do not start any new medication without consent of your doctor. Report severe GI upset, headache, confusion, bleeding, trouble breathing, back pain.
Cost
(1-month) / Injection solution:
1000units/ml = $5 (10ml)
5000units/ml = $30 (25ml) / Dalteparin (Fragmin)
10,000 units/ml
1ml = $65
Enoxaparin (Lovenox)
30mg x 10 syr = $201
40mg x 10 syr = $262
60mg x 10 syr = $397
80mg x 10 syr = $495
100mg/ml x 10 = $658
150mg/ml x 10 = $987
Multidose solution
100mg/ml (3ml) = $208
Tinzaparin (Innohep)
20,000 units/ml (2ml)
expensive / 30 tablets generic
1 mg = $14
2 mg = $15
2.5 mg = $15
3 mg = $16
4 mg = $15
5 mg = $14
6 mg = $24
7.5 mg = $23
10 mg = $24 / Aspirin
Generic 81 mg <$2
Generic 325 mg <$1
Ticlopidine (Ticlid)
Generic 1 month $86
Clopidogrel (Plavix)
Brand 1 month $117 / Prefilled syringe:
7.5mg/0.6ml, 1 dose = $105 / argatroban
100mg/ml (2.5ml) = $942
References
1. The SeventhACCP Conference on Antithrombotic and Thrombolytic Therapy.Chest 2004;126
2. Lexi-Comp Online. Copyright © 1978-2006 Lexi-Comp, Inc.
3. Drugstore.com
Marie Meyer, PharmD Candidate 2007Pharmacotherapy Presentation – Pharmaceutical Care Rotation
University of MarylandSchool of PharmacyHappy Harry’s PharmacyPatientCareCenter, Perryville, MD