heparin sodium (porcine)

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heparin sodium (porcine)

Classes

Heparins For Flushing
Unfractionated Heparins

Administration
Injectable Administration

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Use extreme caution during the preparation, dispensing, and administration of any heparin-containing products. Heparin injection is available in various concentrations, and the inadvertent administration of the incorrect concentration could result in devastating consequences. Fatal hemorrhages have occurred in pediatric patients (including neonates) due to medication errors in which concentrated 1 mL heparin injection vials were administered rather than 1 mL 'catheter lock flush' vials.
Do NOT administer via intramuscular injection due to risk of hematoma at the injection site.[41347]

Intravenous Administration

Intermittent IV Injection
Administer IV either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection.[41347] [56872]
 
Continuous IV Infusion
Dilute in 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or Lactated Ringer's Injection. Invert container at least 6 times after diluting to ensure adequate mixing. Periodically mix during the infusion.[56872]
ASHP Recommended Standard Concentrations for Adult Continuous Infusions: 100 units/mL.[64020]
ASHP Recommended Standard Concentrations for Pediatric Continuous Infusions: 50 units/mL or 100 units/mL.
Administer IV bolus doses over 10 minutes in pediatric patients.[51862]
Infuse intravenously via an electronic infusion pump. For systemic anticoagulation, adjust rate based on aPTT or plasma heparin concentration (by protamine titration or anti-factor Xa assay).[56872]

Subcutaneous Administration

Using a 25 to 27 gauge needle that is 3/8 to 5/8 inches in length, inject by deep subcutaneous injection into the lower abdomen; do not aspirate or massage injection site. Take care not to inject intradermally. Rotate injection sites frequently.
The initial dose should be sufficiently high to counteract the reduced bioavailability from subcutaneous administration. If an immediate effect is required, the initial dose should be proceeded by an IV bolus injection.

Adverse Reactions
Severe

bone fractures / Delayed / 2.0-3.0
hematemesis / Delayed / Incidence not known
retroperitoneal bleeding / Delayed / Incidence not known
intracranial bleeding / Delayed / Incidence not known
ocular hemorrhage / Delayed / Incidence not known
GI bleeding / Delayed / Incidence not known
myocardial infarction / Delayed / Incidence not known
pulmonary embolism / Delayed / Incidence not known
stroke / Early / Incidence not known
thromboembolism / Delayed / Incidence not known
thrombosis / Delayed / Incidence not known
anaphylactic shock / Rapid / Incidence not known
bronchospasm / Rapid / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
hyperkalemia / Delayed / Incidence not known
skin necrosis / Early / Incidence not known

Moderate

thrombocytopenia / Delayed / 0-30.0
hematuria / Delayed / Incidence not known
adrenocortical insufficiency / Delayed / Incidence not known
melena / Delayed / Incidence not known
vaginal bleeding / Delayed / Incidence not known
anemia / Delayed / Incidence not known
prolonged bleeding time / Delayed / Incidence not known
hyphema / Delayed / Incidence not known
bleeding / Early / Incidence not known
hematoma / Early / Incidence not known
subdural hematoma / Early / Incidence not known
osteoporosis / Delayed / Incidence not known
erythema / Early / Incidence not known
skin ulcer / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hyperlipidemia / Delayed / Incidence not known
priapism / Early / Incidence not known
vitamin D deficiency / Delayed / Incidence not known

Mild

epistaxis / Delayed / Incidence not known
petechiae / Delayed / Incidence not known
purpura / Delayed / Incidence not known
rhinitis / Early / Incidence not known
chills / Rapid / Incidence not known
vomiting / Early / Incidence not known
lacrimation / Early / Incidence not known
urticaria / Rapid / Incidence not known
headache / Early / Incidence not known
nausea / Early / Incidence not known
fever / Early / Incidence not known
alopecia / Delayed / Incidence not known
pruritus / Rapid / Incidence not known
injection site reaction / Rapid / Incidence not known

Common Brand Names

Hep-Lock, Hep-Lock U/P, Hepflush-10, Monoject Prefill Advanced Heparin Lock Flush, SASH Normal Saline and Heparin

Dea Class

Rx

Description

A glycosaminoglycan anticoagulant; its molecular weight ranges from 5,000-30,000 daltons; derived from porcine or bovine tissue; produces a less predictable anticoagulant response than LMWH; used to prevent and treat DVT and PE, to treat unstable angina or myocardial infarction.

Dosage And Indications
For the treatment of deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thromboembolism. Continuous Intravenous Infusion dosage (weight-based adjusted dose) Adults

80 units/kg IV bolus, then 18 units/kg/hour IV continuous infusion, initially. Adjust dose to maintain anti-factor Xa concentration of 0.3 to 0.7 units/mL or aPTT range that correlates to this anti-factor Xa range. Monitor anti-factor Xa concentration or aPTT every 6 hours, initially. If the aPTT is less than 35 (1.2 times normal), increase the dose by 4 units/kg/hour and rebolus with 80 units/kg IV. If aPTT is 35 to 45 (1.2 to 1.5 times normal), increase the dose by 2 units/kg/hour and rebolus with 40 units/kg IV. If aPTT is 46 to 70 (1.5 to 2.3 times normal), maintain current dose. If aPTT is 71 to 90 (2.3 to 3 times normal), reduce dose by 2 units/kg/hour. If aPTT is more than 90 (more than 3 times normal), hold infusion for 1 hour and reduce dose by 3 units/kg/hour.

Children and Adolescents

75 to 100 units/kg IV bolus, then 20 units/kg/hour continuous IV infusion, initially. Adjust dose to maintain anti-factor Xa concentration of 0.3 to 0.7 units/mL or an aPTT range that correlates to this anti-factor Xa range. Max: 1,000 units/hour.

Infants

75 to 100 units/kg IV bolus, then 28 units/kg/hour continuous IV infusion, initially. Adjust dose to maintain anti-factor Xa concentration of 0.3 to 0.7 units/mL or an aPTT range that correlates to this anti-factor Xa range.

Neonates

75 to 100 units/kg IV bolus, then 28 units/kg/hour continuous IV infusion, initially. Adjust dose to maintain anti-factor Xa concentration of 0.3 to 0.7 units/mL or an aPTT range that correlates to this anti-factor Xa range.

Continuous Intravenous Infusion dosage (fixed-dose) Adults

5,000 units IV bolus, then 1,000 units/hour continuous IV infusion.

Intravenous dosage (adjusted dose) Adults

10,000 units IV bolus, then 5,000 to 10,000 units IV every 4 to 6 hours. Adjust dose to maintain anti-factor Xa concentration of 0.3 to 0.7 units/mL or an aPTT range that correlates to this anti-factor Xa range.

Subcutaneous dosage (adjusted dose) Adults

10,000 to 20,000 units subcutaneously, then 8,000 to 10,000 units subcutaneously every 8 hours or 15,000 to 20,000 units subcutaneously every 12 hours. Adjust dose to maintain anti-factor Xa concentration of 0.3 to 0.7 units/mL or an aPTT range that correlates to this anti-factor Xa range.

Pregnant Persons†

10,000 units or more subcutaneously every 12 hours. Adjust dose to maintain aPTT in the therapeutic range (1.5 to 2.5 times the control).

Subcutaneous dosage (weight-based fixed-dose) Adults

333 units/kg subcutaneously, then 250 units/kg subcutaneously every 12 hours.

For thrombosis prophylaxis, including arterial thromboembolism prophylaxis, deep venous thrombosis (DVT) prophylaxis, pulmonary embolism prophylaxis, and mural thrombosis prophylaxis. For arterial thromboembolism prophylaxis in patients with prosthetic heart valves. Intravenous or Subcutaneous dosage Adults

80 units/kg IV bolus, then initial maintenance infusion of 18 units/kg/hour IV continuous infusion or 17,500 to 20,000 units subcutaneously every 12 hours, adjusted to prolong the aPTT 1.5 to 2 times control. Heparin (or LMWH) should be given initially with oral anticoagulants until the INR is within the therapeutic range for 2 consecutive days.

Pregnant females

Adjust doses of heparin subcutaneously every 12 hours throughout pregnancy to maintain a mid-interval aPTT at 2 times control or more or anti-Xa level maintained at 0.35 to 0.7 units/mL. Or, at the 13th week of pregnancy, change to warfarin until the middle of the third trimester then restart heparin or LMWH until delivery. Long-term anticoagulation should resume postpartum.

For thrombosis prophylaxis, including arterial thromboembolism prophylaxis, during extracorporeal circulation in patients undergoing open heart or other cardiovascular surgery. Intravenous dosage Adults

Initially, at least 150 units/kg IV. For procedures expected to last less than 60 minutes, doses up to 300 units/kg IV may be used. For procedures expected to last longer than 60 minutes, doses up to 400 units/kg IV may be used. Further dosage should be based on coagulation test results (e.g., activated clotting time (ACT)).

For thrombosis prophylaxis, including arterial thromboembolism prophylaxis, during hemodialysis. Intravenous dosage Adults

2,000 to 5,000 units IV bolus at the initiation of dialysis, followed by 10 to 20 units/kg/hour IV infusion directly into the arterial port of the dialysis circuit or repeated bolus doses as needed to maintain the activated clotting time (ACT) or whole blood partial thromboplastin time (WBPTT) at about 150% of baseline. The extent of anticoagulation is based on risk factors for bleeding and co-existing conditions. In patients at moderate risk for bleeding, administration of lower loading doses and lower maintenance infusion rates can be used to maintain the ACT or WBPTT at about 115% to 125% of baseline.

For deep venous thrombosis (DVT) prophylaxis. Subcutaneous dosage Adults with severely restricted mobility during acute illness

5,000 units subcutaneously every 8 to 12 hours.

Moderate risk adults undergoing surgery (e.g., minor procedure, with additional risk factors; non-major surgery for patients 40 to 60 years with no risk factors; major surgery in patients younger than 40 years with no risk factors

5,000 units subcutaneously every 8 to 12 hours, starting 1 to 2 hours before surgery, LMWH, intermittent pneumatic compression, or elastic stockings.

Higher risk adults undergoing surgery (e.g., non-major surgery in patients older than 60 years or with additional risk factors; major surgery in patients older than 40 years or with additional risk factors)

5,000 units subcutaneously every 8 hours, LMWH, or intermittent pneumatic compression (IPC). In all higher-risk general surgery patients, the use of mechanical prophylaxis with elastic stockings (ES) or IPC is recommended initially. In very high-risk general surgery patients with multiple risk factors, combination of pharmacologic (i.e., heparin or LMWH) and mechanical (i.e., ES or IPC) prophylaxis is recommended.

Adults undergoing major gynecologic surgery for benign disease, no additional risk factors

5,000 units subcutaneous every 12 hours, starting 1 to 2 hours prior to surgery.

Adults undergoing extensive gynecological surgery for malignancy

5,000 units subcutaneously every 8 hours, starting 1 to 2 hours prior to surgery.

Adults undergoing major open urologic procedure (including high-risk)

5,000 units subcutaneously every 8 to 12 hours, starting 1 to 2 hours prior to surgery, LMWH, elastic stockings (ES), or intermittent pneumatic compression (IPC). For patients at highest risk, heparin 5,000 units subcutaneously every 8 to 12 hours in combination with ES with or without IPC.

Adults undergoing hip replacement surgery or hip fracture surgery

5,000 units subcutaneously every 8 to 12 hours starting 2 hours before surgery. Continue prophylaxis for a minimum of 10 to 14 days after surgery; up to 35 days is recommended. Guidelines recommend heparin as an alternative to the preferred agent, low molecular weight heparin, as antithrombotic prophylaxis for patients undergoing hip fracture surgery.

Adults undergoing neurosurgery

5,000 units subcutaneously every 8 to 12 hours, starting 1 to 2 hours before surgery, as an alternative to elastic stockings (ES) or intermittent pneumatic compression (IPC) alone; however, use must be balanced with the clinically important risk of intracranial bleeding. Low-dose heparin may be offered in combination with ES or IPC for patients at high-risk and may be more effective than either modality alone.

Adults with acute myocardial infarction

7,500 units subcutaneously every 12 hours until fully ambulatory for all patients not receiving heparin for another reason.

Adults with acute ischemic stroke and impaired mobility

5,000 units subcutaneously every 8 to 12 hours, LMWH, or a heparinoid, if not contraindicated. Low-dose heparin should be restricted for 24 hours after thrombolytic administration. Low-dose heparin may be used safely in combination with aspirin. For patient with contraindications to anticoagulant therapy, intermittent pneumatic compression devices or elastic stockings are recommended.

For deep venous thrombosis (DVT) prophylaxis in pregnant females. Subcutaneous dosage Pregnant females with a history of DVT with a transient risk factor; no current risk factors

Surveillance and post partum anticoagulation.

Pregnant females with an episode of idiopathic DVT; thrombophilia (confirmed laboratory abnormality); no current long-term anticoagulation

Options include surveillance, heparin 5,000 units subcutaneously every 12 hours, adjusted dose heparin subcutaneously every 12 hours to maintain a target anti-Xa level of 0.1 to 0.3 units/mL, or LMWH with postpartum anticoagulation.

Pregnant females, no prior DVT; thrombophilia (confirmed laboratory abnormality); no current long-term anticoagulation

Options include surveillance, heparin 5,000 units subcutaneously every 12 hours, or LMWH with postpartum anticoagulation. Indication for active prophylaxis is strongest in antithrombin-deficient women.

Pregnant females with 2 or more episodes of DVT, and/or long-term anticoagulation (e.g., single episode of DVT, idiopathic or associated with thrombophilia)

Options include adjusted dose heparin subcutaneously every 12 hours to maintain a target anti-Xa level of 0.1 to 0.3 units/mL or LMWH with postpartum, long-term anticoagulation.

Pregnant females with mechanical heart valves

Adjusted doses of heparin subcutaneously every 12 hours throughout pregnancy to maintain a mid-interval aPTT at 2 times control or more or anti-Xa concentration maintained at 0.35 to 0.7 units/mL. Or, at the 13th week of pregnancy, change to warfarin until the middle of the third trimester then restart heparin or LMWH until delivery. Long-term anticoagulation should resume postpartum.

For thrombosis prophylaxis and/or for pulmonary embolism prophylaxis in patients at increased risk after sustaining an acute MI (e.g., Q-wave infarction, severe LV dysfunction, CHF, history of systemic or pulmonary embolism, 2D echo evidence of mural thrombus, or atrial fibrillation). Intravenous or Subcutaneous dosage Adults

In patients not receiving thrombolytic therapy, 75 units/kg IV bolus, followed by 1,250 units/hour IV, with a target aPTT of 1.5 to 2 times control (also see dosage for treatment of an evolving acute MI). For patients who have received heparin following thrombolytic therapy (see acute myocardial infarction indication for initial heparin dosage recommendations following thrombolytic therapy), continue IV heparin or change to subcutaneous heparin (initial dose about 17,500 units every 12 hours) beyond 48 hours to maintain the aPTT 1.5 to 2 times control, LMWH, or convert to oral anticoagulation.

For mural thrombosis prophylaxis in patients with an acute transmural anterior myocardial infarction. Subcutaneous dosage Adults

12,500 units subcutaneously every 12 hours for 10 days after an acute anterior MI. When compared to 5,000 units subcutaneously every 12 hours, left ventricular mural thrombosis was observed less frequently in the high-dose heparin group. There was no difference in the frequency of hemorrhagic complications between the 2 groups.

For thrombosis prophylaxis in pediatric patients requiring cardiac catheterization via an artery. Intravenous dosage Infants, Children, and Adolescents

100 units/kg IV bolus. Additional doses may be necessary for prolonged procedures.

Neonates

100 units/kg IV bolus. Additional doses may be necessary for prolonged procedures.

For intravascular catheter occlusion prophylaxis.
NOTE: The amount of heparin solution in each single dose is sufficient to prevent clotting within the lumen of the indwelling catheter for up to 24 hours. If the catheter is used for withdrawal of repeated blood samples for laboratory tests and the presence of heparin is likely to interfere with the test, the in situ heparin flush should be cleared from the catheter by aspirating and discarding a volume of solution equivalent to that of the indwelling catheter before the desired blood sample is drawn. If the drug to be administered is incompatible with heparin, the entire catheter or lumen should be flushed with sterile water or normal saline before and after the medication is administered. Following the second flush, the heparin flush solution may be reinstilled into the set.
To maintain patency of single and multiple-lumen catheters. Intravenous catheter Adults

Use heparin 100 units/mL. Instill enough volume to fill the lumen of the catheter (usually 2 to 5 mL) to the tip. Catheters should be flushed daily, with additional flushes given when stagnant blood is observed in the catheter. This solution should be replaced each time the catheter or lumen is used for drug or blood administration, and after blood withdrawal from the catheter.

Infants, Children, and Adolescents weighing more than 10 kg†

In general, heparin 100 units/mL is used for pediatric patients weighing more than 10 kg. Instill enough volume to fill the lumen of the catheter. Catheters should be flushed at least daily; certain types of catheters are more prone to clotting and require more frequent flushing. Refer to site-specific guidelines for details. Additional flushes should be administered when stagnant blood is observed in the catheter. This solution should be replaced each time the catheter or lumen is used for drug or blood administration, and after blood withdrawal from the catheter.

Infants and Children weighing less than 10 kg†

In general, heparin 10 units/mL is used for infants and small children (e.g., weight less than 10 kg). Instill enough volume to fill the lumen of the catheter. Catheters should be flushed at least daily; certain types of catheters are more prone to clotting and require more frequent flushing. Refer to site-specific guidelines for details. Additional flushes should be administered when stagnant blood is observed in the catheter. This solution should be replaced each time the catheter or lumen is used for drug or blood administration, and after blood withdrawal from the catheter.

Neonates†

0.5 units/kg/hour IV infused through the line is recommended for maintaining central venous access line patency in neonates. Use only preservative free solutions.

To maintain patency of peripheral catheters (i.e., heparin locks). Intravenous catheter Adults

Use heparin 100 units/mL. Instill enough volume to fill the lumen of the catheter. This solution should be replaced each time the catheter or lumen is used for drug or blood administration, and after blood withdrawal from the catheter.

Infants, Children, and Adolescents weighing more than 10 kg†

In general, heparin 100 units/mL is used for pediatric patients weighing more than 10 kg. Instill enough volume to fill the lumen of the catheter. Catheters should be flushed at least daily; certain types of catheters are more prone to clotting and require more frequent flushing. Refer to site-specific guidelines for details. Additional flushes should be administered when stagnant blood is observed in the catheter. This solution should be replaced each time the catheter or lumen is used for drug or blood administration, and after blood withdrawal from the catheter.

Infants and Children weighing less than 10 kg†

In general, heparin 10 units/mL is used for infants and small children (e.g., weight less than 10 kg). Instill enough volume to fill the lumen of the catheter. Catheters should be flushed at least daily; certain types of catheters are more prone to clotting and require more frequent flushing. Refer to site-specific guidelines for details. Additional flushes should be administered when stagnant blood is observed in the catheter. This solution should be replaced each time the catheter or lumen is used for drug or blood administration, and after blood withdrawal from the catheter.

Neonates†

0.5 units/kg/hour IV infused through the line is recommended for maintaining central venous access line patency in neonates. Use only preservative free solutions.

To maintain patency of arterial lines. Intraarterial catheter Adults

Use a final heparin concentration of 1 unit/mL (range: 0.5 to 2 units/mL). In order to avoid large total doses and systemic effects, use 0.5 units/mL in patients receiving multiple lines containing heparin.

Infants, Children, and Adolescents†

Use a final heparin concentration of 0.5 units/mL to run at 1 mL/hour IV.

Neonates†

Use a final heparin concentration of 0.5 units/mL running at a rate of 1 mL/hour IV for peripheral arterial catheters. A final heparin concentration of 0.25 to 1 unit/mL with a total heparin dose of 25 to 200 units/kg/day IV is recommended to maintain patency of umbilical artery catheters (UAC). Use only preservative free solutions.

To maintain line patency in patients receiving total parenteral nutrition (TPN). TPN solution additive Adults

A final heparin concentration of 1 unit/mL may be added to TPN solutions intended for central or peripheral administration.

Adolescents and Children†

A final heparin concentration of 1 unit/mL may be added to TPN solutions intended for central or peripheral administration.

Neonates and Infants†

A final concentration of heparin of 0.5 to 1 unit/mL added to peripheral or central TPN solutions. Lower concentrations may be used in small infants receiving larger TPN volumes to avoid systemic heparin effects.

For the prevention of pregnancy loss and/or thrombosis in patients with antiphospholipid antibody syndrome (APLA). In pregnant women with APLA and >= 2 early pregnancy losses, or >= 1 late pregnancy loss, or preeclampsia, or intrauterine growth restriction (IUGR), or abruption. Subcutaneous dosage Adult females

Antepartum aspirin and heparin 5000 Units subcutaneous every 12 hours or adjusted doses of heparin subcutaneous every 12 hours to maintain a anti-Xa level of 0.1—0.3 Units/mL, or LMWH.

In pregnant women with thrombophilic defects and recurrent miscarriages; a miscarriage during or after the second trimester; or preeclampsia, intrauterine growth restriction (IUGR), or abruption. Subcutaneous dosage Adult females

Consider low-dose aspirin with either heparin 5000 Units subcutaneous every 12 hours or adjusted doses of heparin subcutaneous every 12 hours to maintain a anti-Xa level of 0.1—0.3 Units/mL, or LMWH. Give anticoagulants postpartum.

In pregnant women with APLA and a history of venous thrombosis, with current long-term anticoagulation. Subcutaneous dosage Adult females

Adjusted doses of heparin subcutaneous every 12 hours to maintain a anti-Xa level of 0.1—0.3 Units/mL or LMWH. Give anticoagulants postpartum. Resume long-term oral anticoagulation therapy postpartum.

In women with antiphospholipid antibodies and no previous venous thrombosis and no pregnancy losses. Subcutaneous dosage Adult females

Options include surveillance, heparin 5000 Units subcutaneous every 12 hours, prophylactic LMWH, or low-dose aspirin.

For the treatment of disseminated intravascular coagulation (DIC). Continuous Intravenous Infusion dosage Adults

The use and the dosing of heparin in the management of DIC are controversial. For selected patients (i.e., those with clinically overt thromboembolism or extensive deposition of fibrin), low doses of heparin 300 to 1,000 units/hour or 15 units/kg/hour IV infusion have shown some benefit. Patients with antithrombin III levels less than 25% may not respond to heparin. In general, heparin should be continued until fibrinogen levels are more than 100 mg/dL and platelet counts are more than 100,000/mm3.

Children and Adolescents

75 to 100 units/kg IV load then 20 units/kg/hour IV as an initial maintenance dose. Adjust dose to maintain aPTT 60 to 85 seconds, assuming this reflects an antifactor Xa level of 0.3 to 0.7 units/mL.

Neonates and Infants

75 to 100 units/kg IV load then 28 units/kg/hour IV as an initial maintenance dose. Adjust dose to maintain aPTT 60 to 85 seconds, assuming this reflects an antifactor Xa level of 0.3 to 0.7 units/mL.

For coronary artery thrombosis prophylaxis in percutaneous coronary intervention (PCI), acute myocardial infarction, STEMI, acute myocardial infarction, NSTEMI, and unstable angina. For coronary artery thrombosis prophylaxis in STEMI in persons undergoing primary PCI with planned GP IIb/IIIa receptor antagonist administration. Intravenous dosage Adults

50 to 70 units/kg IV bolus as needed to achieve therapeutic ACT of 200 to 250 seconds.

For coronary artery thrombosis prophylaxis in STEMI in persons undergoing primary PCI without planned GP IIb/IIIa receptor antagonist administration. Intravenous dosage Adults

70 to 100 units/kg IV bolus as needed to achieve therapeutic ACT of 250 to 300 seconds by HemoTec device or 300 to 350 seconds by Hemochron device.

For coronary artery thrombosis prophylaxis in STEMI in persons undergoing reperfusion with fibrinolytic therapy. Intravenous dosage Adults

60 units/kg (Max: 4,000 units) IV bolus, then 12 units/kg/hour (Max: 1,000 units/hour) continuous IV infusion, initially. Adjust dose to maintain target anti-factor Xa concentration or aPTT. Continue infusion for at least 48 hours or until revascularization.

For coronary artery thrombosis prophylaxis in NSTEMI or unstable angina, including in persons undergoing PCI. Intravenous dosage Adults

60 units/kg (Max: 4,000 units) IV bolus, then 12 units/kg/hour (Max: 1,000 units/hour) continuous IV infusion, initially. Adjust dose to maintain target anti-factor Xa concentration or aPTT. Continue infusion for 48 hours or until PCI.[58787]

For coronary artery thrombosis prophylaxis in general PCI without prior anticoagulation administration. Intravenous dosage Adults

70 to 100 units/kg IV bolus to achieve therapeutic ACT of 250 to 300 seconds by HemoTec device or 300 to 350 seconds by Hemochron device.

For coronary artery thrombosis prophylaxis in general PCI with prior heparin administration. Intravenous dosage Adults

2,000 to 5,000 units IV bolus to achieve therapeutic ACT of 250 to 300 seconds by HemoTec device or 300 to 350 seconds by Hemochron device.

For the treatment and prevention of thromboembolic complications of atrial fibrillation. Continuous Intravenous Infusion dosage Adults

60 to 70 units/kg (Max: 5,000 units) IV, then 12 to 15 units/kg/hour (Max: 1,000 units/hour) continuous IV infusion, initially. Titrate dose to target coagulation parameter.[41347] [51249] [51288] [56966] [65847] [65848]

For periprocedural anticoagulation† (bridge therapy) in patients with atrial fibrillation, mechanical heart valve, or venous thrombosis who require an interruption in oral anticoagulant therapy. For patients taking direct-acting oral anticoagulants (DOACs) who require multiple procedures and/or are unable to tolerate oral medications post-procedure. Subcutaneous dosage Adults

5,000 to 7,500 units subcutaneously twice daily. DOACs have short half-lives; hence, alternative anticoagulation during temporary interruption is not needed in the majority of situations.

For patients taking warfarin at moderate or high risk for thromboembolism and with no significant bleed risk. Subcutaneous dosage (prophylactic dose) Adults

5,000 to 7,500 units subcutaneously twice daily. Stop warfarin approximately 5 days before procedure and initiate heparin 24 hours or more after the first missed dose of warfarin. Guidelines recommend starting heparin when INR is less than 2 in those with nonvalvular atrial fibrillation, or if INR is not measured, after omitting 2 to 3 doses of warfarin. Discontinue heparin 4 to 6 hours before procedure if the aPTT is within normal range. If necessary, residual anticoagulation can be assessed by checking the aPTT In most cases, warfarin can be restarted in the first 12 to 24 hours after the procedure at the patient's usual therapeutic dose; post-procedural bridging can be considered in patients with moderate or high risk of stroke or thromboembolic events.

Continuous Intravenous Infusion dosage (therapeutic dose) Adults

60 to 80 units/kg IV, then 12 to 18 units/kg/hour continuous IV infusion, initially. Titrate dose to target coagulation parameter. Stop warfarin approximately 5 days before procedure and initiate heparin 24 hours or more after the first missed dose of warfarin. Guidelines recommend starting heparin when INR is less than 2 in those with nonvalvular atrial fibrillation, or if INR is not measured, after omitting 2 to 3 doses of warfarin. Discontinue heparin 4 to 6 hours before procedure if the aPTT is within normal range. If necessary, residual anticoagulation can be assessed by checking the aPTT. In most cases, warfarin can be restarted in the first 12 to 24 hours after the procedure at the patient's usual therapeutic dose; post-procedural bridging can be considered in patients with moderate or high risk of stroke or thromboembolic events.

For the treatment of frostbite in combination with thrombolytic therapy†. Intravenous or Intra-Arterial dosage Adults

500 units/hour continuous IV or intra-arterial infusion concurrently with thrombolytic therapy.

†Indicates off-label use

Dosing Considerations
Hepatic Impairment

It appears that hepatic impairment does not affect the elimination of heparin; however, patients with hepatic disease may have increased risk of bleeding during heparin therapy.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

Drug Interactions

5-Aminosalicylates: (Moderate) Coadministration of 5-aminosalicylates and heparin may result in an increased risk of bleeding (i.e., hematomas) following neuraxial anesthesia. Discontinue 5-aminosalicylates prior to the initiation of heparin. If this is not possible, it is recommended to monitor patients closely for bleeding.
Abciximab: (Moderate) The use of abciximab within 7 days of use an oral anticoagulant is contraindicated unless the patient's prothrombin time is less than or equal to 1.2 times the control value. Because abciximab inhibits platelet aggregation, additive effects may be seen when abciximab is given in combination with other agents that affect hemostasis such as other platelet inhibitors (e.g., aspirin, ASA, clopidogrel, dipyridamole, ticlopidine), thrombolytic agents (e.g., alteplase, reteplase, streptokinase), and anticoagulants (e.g., heparin, warfarin). However, in clinical trials with abciximab, aspirin and heparin were administered concomitantly. The bleeding risk is significantly increased with concurrent abciximab and thrombolytic therapy; the risks of combination therapy should be weighed against the potential benefits. The GUSTO V study evaluated reduced-dose reteplase in combination with full dose abciximab, in comparison to full dose reteplase alone in patients with acute myocardial infarction (MI); all patients received concurrent aspirin and heparin therapy. The combination regimen was associated with a two-fold increase in moderate to severe non-intracranial bleeding complications, including spontaneous GI bleeding. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. Although NSAIDs lacks platelet inhibitory effects, an increased risk for GI bleeding is possible when NSAIDs are administered during abciximab therapy.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Acetaminophen; Aspirin: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Acetaminophen; Ibuprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Ado-Trastuzumab emtansine: (Moderate) Use caution if coadministration of anticoagulants with ado-trastuzumab emtansine is necessary due to reports of severe and sometimes fatal hemorrhage, including intracranial bleeding, with ado-trastuzumab emtansine therapy. Consider additional monitoring when concomitant use is medically necessary. While some patients who experienced bleeding during ado-trastuzumab therapy were also receiving anticoagulation therapy, others had no known additional risk factors.
Alprostadil: (Moderate) Caution is advised with the concomitant administration of alprostadil injection for dilation of the ductus arteriosis and heparin infusions. Coadministration resulted in a 140% increase in partial thromboplastin time and a 120% increase in thrombin time in a study of 12 healthy volunteers receiving alprostadil 90 mcg infusion over 3 hours and heparin 5000 units. Monitor patients for increased bleeding if these agents are used together.
Alteplase: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
Altretamine: (Moderate) Due to the thrombocytopenic effects of altretamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Aminosalicylate sodium, Aminosalicylic acid: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Amlodipine; Celecoxib: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Amlodipine; Valsartan: (Minor) Concomitant use of valsartan with other drugs that may increase potassium concentrations, such as heparin, may lead to increases in serum potassium.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Minor) Concomitant use of valsartan with other drugs that may increase potassium concentrations, such as heparin, may lead to increases in serum potassium.
Anagrelide: (Moderate) Although anagrelide inhibits platelet aggregation at high doses, there is a potential additive risk for bleeding if anagrelide is given in combination with other agents that effect hemostasis such as other anticoagulants. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. An in vivo interaction study in humans demonstrated that a single 1 mg dose of anagrelide administered concomitantly with a single dose of aspirin 900 mg was well tolerated; there was no effect on bleeding time, PT, or PTT. However, aspirin alone produced a marked inhibition of platelet aggregation ex vivo; anagrelide enhanced the platelet inhibition effects of aspirin slightly. Patients may be at increased risk of bleeding if anagrelide is administered with aspirin.
Antithrombin III: (Major) As a regulator of hemostasis, antithrombin III (AT III) may increase bleeding risk in patients receiving heparin concomitantly. The anticoagulant effect of heparin is enhanced by concurrent treatment with AT III in patients with hereditary AT III deficiency. In addition, the half-life of AT III may be altered during concomitant administration with anticoagulants. Thus, in order to avoid bleeding, the heparin dosage may need to be reduced during treatment with AT III. Coagulation tests (aPTT and anti-Factor Xa, when appropriate) should be performed regularly and especially in the first hours following the start or withdrawal of AT III therapy to ensure appropriate anticoagulation.
Apixaban: (Major) Avoid concomitant use of apixaban and with heparin due to the increased risk for bleeding. Short-term overlaps in anticoagulation therapy may be necessary for patients transitioning from one anticoagulant to another. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if the use of multiple anticoagulants is necessary.
Aprotinin: (Moderate) If an activated clotting time is used to determine the effectiveness of heparin anticoagulation, the prolongation of ACT by aprotinin may lead to an overestimation of the degree of anticoagulation, thereby leading to inadequate anticoagulation.
Argatroban: (Major) An additive risk of bleeding may be seen in patients receiving other anticoagulants in combination with heparin.
Aspirin, ASA: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Aspirin, ASA; Caffeine: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Aspirin, ASA; Carisoprodol: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Aspirin, ASA; Dipyridamole: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis.
Aspirin, ASA; Omeprazole: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Aspirin, ASA; Oxycodone: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Betrixaban: (Major) Avoid concurrent use of betrixaban with heparin due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if betrixaban and other anticoagulants are used concomitantly. Coadministration of betrixaban and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with betrixaban and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from betrixaban.
Bismuth Subsalicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Bivalirudin: (Major) An additive risk of bleeding may be seen in patients receiving or other anticoagulants in combination with heparin.
Bupivacaine; Meloxicam: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Caplacizumab: (Major) Avoid concomitant use of caplacizumab and anticoagulants when possible. Assess and monitor closely for bleeding if use together is necessary. Interrupt use of caplacizumab if clinically significant bleeding occurs.
Cardiac glycosides: (Minor) Digitalis (e.g., cardiac glycosides like digoxin or digitoxin) may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
Celecoxib: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Celecoxib; Tramadol: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Cetirizine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
Cetirizine; Pseudoephedrine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
Chlorambucil: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Choline Salicylate; Magnesium Salicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Cilostazol: (Moderate) The safety of cilostazol has not been established with concomitant administration of anticoagulants. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently.
Clofarabine: (Moderate) Due to the thrombocytopenic effects of clofarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Clopidogrel: (Moderate) Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other agents that affect hemostasis such as anticoagulants. In healthy volunteers receiving heparin, clopidogrel does not alter the effect of heparin on coagulation parameters or require adjustment of the heparin dose. In addition, heparin has no effect on inhibition of platelet aggregation induced by clopidogrel. Nevertheless, the safety of this combination has not been established and concomitant administration of clopidogrel with heparin should be undertaken with caution.
Collagenase: (Moderate) Cautious use of injectable collagenase by patients taking anticoagulants is advised. The efficacy and safety of administering injectable collagenase to a patient taking an anticoagulant within 7 days before the injection are unknown. Receipt of injectable collagenase may cause an ecchymosis or bleeding at the injection site.
Corticorelin, Ovine: (Major) The use of a heparin solution to maintain IV cannula patency during corticorelin stimulation tests is not recommended. A possible interaction between corticorelin and heparin may have been responsible for a major hypotensive reaction that occurred after corticorelin administration.
Cytarabine, ARA-C: (Moderate) Due to the thrombocytopenic effects of pyrimidine analogs, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Dabigatran: (Major) Avoid use of dabigatran with heparin due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if dabigatran and other anticoagulants are used concomitantly. Coadministration of dabigatran and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with dabigatran and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from dabigatran.
Dalteparin: (Major) An additive risk of bleeding may be seen in patients receiving other anticoagulants (e.g., heparin) in combination with dalteparin.
Danazol: (Major) Danazol can decrease hepatic synthesis of procoagulant factors, increasing the possibility of bleeding when used concurrently with anticoagulants.
Dasatinib: (Moderate) Monitor for evidence of bleeding if coadministration of dasatinib and anticoagulants is necessary. Dasatinib can cause serious and fatal bleeding. Concomitant anticoagulants may increase the risk of hemorrhage.
Deferasirox: (Moderate) Because gastric ulceration and GI bleeding have been reported in patients taking deferasirox, use caution when coadministering with other drugs known to increase the risk of peptic ulcers or gastric hemorrhage including anticoagulants.
Defibrotide: (Contraindicated) Coadministration of defibrotide with antithrombotic agents like anticoagulants is contraindicated. The pharmacodynamic activity and risk of hemorrhage with antithrombotic agents are increased if coadministered with defibrotide. If therapy with defibrotide is necessary, discontinue systemic antithrombotic agents (not including use for routine maintenance or reopening of central venous catheters) prior to initiation of defibrotide therapy. Consider delaying the onset of defibrotide treatment until the effects of the antithrombotic agent have abated.
Desirudin: (Major) Any agent which may enhance the risk of hemorrhage should generally be discontinued before initiating desirudin therapy, including anticoagulants. If coadministration cannot be avoided, close clinical and laboratory monitoring should be conducted. During prophylaxis of venous thromboembolism with desirudin, concomitant treatment with heparins [including unfractionated and low-molecular weight heparins (LMWHs)] or dextrans is not recommended. The effects of desirudin and unfractionated heparins on prolongation of aPTT are additive.
Desloratadine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
Desloratadine; Pseudoephedrine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
Desmopressin: (Minor) Desmopressin has been shown to have an additive effect on the anticoagulant activity of heparin. Caution should be used when coadministering these agents.
Dextran: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently.
Diclofenac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Diclofenac; Misoprostol: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Diflunisal: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Diphenhydramine; Ibuprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Diphenhydramine; Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Dipyridamole: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis.
Drospirenone: (Minor) Chronic heparin therapy may predispose a patient to develop hyperkalemia; this risk may be increased in patients receiving drospirenone concomitantly. Monitoring of serum potassium during the 1st month of concurrent therapy with drospirenone is recommended.
Drospirenone; Estetrol: (Minor) Chronic heparin therapy may predispose a patient to develop hyperkalemia; this risk may be increased in patients receiving drospirenone concomitantly. Monitoring of serum potassium during the 1st month of concurrent therapy with drospirenone is recommended.
Drospirenone; Estradiol: (Minor) Chronic heparin therapy may predispose a patient to develop hyperkalemia; this risk may be increased in patients receiving drospirenone concomitantly. Monitoring of serum potassium during the 1st month of concurrent therapy with drospirenone is recommended.
Drospirenone; Ethinyl Estradiol: (Minor) Chronic heparin therapy may predispose a patient to develop hyperkalemia; this risk may be increased in patients receiving drospirenone concomitantly. Monitoring of serum potassium during the 1st month of concurrent therapy with drospirenone is recommended.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Chronic heparin therapy may predispose a patient to develop hyperkalemia; this risk may be increased in patients receiving drospirenone concomitantly. Monitoring of serum potassium during the 1st month of concurrent therapy with drospirenone is recommended.
Edoxaban: (Major) Avoid concurrent use of edoxaban with heparin due to the increased bleeding risk. Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if edoxaban and other anticoagulants are used concomitantly. Coadministration of edoxaban and other anticoagulants may increase the risk of bleeding. Long-term concomitant treatment with edoxaban and other anticoagulants is not recommended; short-term use may be necessary for patients transitioning to or from edoxaban.
Eltrombopag: (Moderate) Use caution when discontinuing eltrombopag in patients receiving anticoagulants (e.g., warfarin, enoxaparin, dabigatran, rivaroxaban). The risk of bleeding and recurrent thrombocytopenia is increased in patients receiving these drugs when eltrombopag is discontinued.
Enoxaparin: (Major) An additive risk of bleeding may be seen in patients receiving enoxaparin in combination with other anticoagulants. If coadministration of 2 or more anticoagulants is necessary, patients should be closely monitored for evidence of bleeding.
Epoprostenol: (Moderate) When used concurrently with anticoagulants, epoprostenol may increase the risk of bleeding.
Eptifibatide: (Moderate) Concomitant use of eptifibatide and other agents that may affect hemostasis, such as anticoagulants, may be associated with an increased risk of bleeding. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. In clinical trials with eptifibatide, aspirin and heparin were administered concomitantly. Eptifibatide has been administered with a thrombolytic agent in a small number of patients. In the IMPACT II study, 15 patients received a thrombolytic agent with the 135/0.5 dosing regimen, 2 of whom experienced a major bleed. In the PURSUIT study, 40 patients who received eptifibatide (180 mcg/kg bolus, then 2 mcg/kg/min) also received a thrombolytic agent, 10 of whom experienced a major bleed. In another acute MI study (n=181), eptifibatide (180 mcg/kg bolus, then up to 2 mcg/kg/min for up to 72 hours) was administered concomitantly with streptokinase (1.5 mU over 60 min). At the highest studied infusion rates (1.3 to 2 mcg/kg/min), eptifibatide was associated with an increase in the incidence of bleeding and transfusions compared to the incidence seen with streptokinase alone.
Esterified Estrogens; Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
Etodolac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Factor Xa, Andexanet Alfa: (Major) Avoid use of factor Xa for the reversal of direct factor Xa inhibitors prior to heparinization. Use an alternative to heparin if anticoagulation is required after factor Xa use. Factor Xa may cause unresponsiveness to heparin anticoagulation.
Fenoprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Fexofenadine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
Fexofenadine; Pseudoephedrine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
Fish Oil, Omega-3 Fatty Acids (Dietary Supplements): (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
Flurbiprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Fondaparinux: (Major) Discontinue heparin before starting fondaparinux due to the increased bleeding risk, unless these agents are essential. If coadministration is necessary, monitor patients closely and promptly evaluate any signs or symptoms of bleeding.
Garlic, Allium sativum: (Moderate) Garlic produces clinically significant antiplatelet effects so additive risk of bleeding may occur if anticoagulants are given in combination. Avoid concurrent use of herbs which interact with anticoagulants when possible. If garlic dietary supplements are taken, monitor the INR or other appropriate parameters to attain clinical and anticoagulant endpoints. In regard to warfarin, published data are limited to a random case report; however, the product labeling for warfarin includes garlic as having potential for interaction due to additive pharmacologic activity. A case of spontaneous spinal epidural hematoma, attributed to dysfunctional platelets from excessive garlic use in a patient not receiving concomitant anticoagulation, has been reported.
Ginger, Zingiber officinale: (Moderate) Additive bleeding may occur if anticoagulants are given in combination with ginger, zingiber officinale. Ginger inhibits thromboxane synthetase (platelet aggregation inducer) and is a prostacyclin agonist. Patients taking ginger and an anticoagulant should be monitored closely for bleeding.
Ginkgo, Ginkgo biloba: (Moderate) Monitor for signs or symptoms of bleeding with coadministration of ginkgo biloba and heparin as an increased bleeding risk may occur. Although data are mixed, ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with ginkgo biloba, with or without concomitant drug therapy.
Green Tea: (Moderate) Green tea has demonstrated antiplatelet and fibrinolytic actions in animals. It is possible that the use of green tea may increase the risk of bleeding if co-administered with anticoagulants (e.g., enoxaparin, heparin, warfarin, and others), thrombolytic agents, or platelet inhibitors (e.g., aspirin, clopidogrel, cilostazol and others). Caution and careful monitoring of clinical and/or laboratory parameters are warranted if green tea is coadministered with any of these agents. Exogenous administration or occult sources of vitamin K may decrease or reverse the activity of warfarin; stability of the diet can be an important factor in maintaining anticoagulation goals. Occult sources of vitamin K include green tea and green tea dietary supplements. Published data are limited in regard to this interaction. A patient with previous INRs of 3.2 and 3.79 on a dose of 7.5mg daily of warfarin (goal INR 2.5 to 3.5) had an INR of 1.37. One month later, the patient's INR was 1.14. The patient admitted that he had started consuming 0.51 gallon of green tea daily approximately one week prior to the INR of 1.37. The patient denied noncompliance and other changes in diet, medications, or health. The patient discontinued green tea and one week later his INR was 2.55. While the amount of vitamin K in a single cup of brewed green tea may not be high (0.03 mcg/100 g), the actual amount may vary from cup to cup depending on the amount of tea leaves used, the length of time the tea bags are allowed to brew, and the volume of tea consumed. Additionally, if a patient drinks multiple cups of tea per day, the amount of vitamin K could reach significance. It is recommended that patients on warfarin maintain a stable intake of green tea.
Hemin: (Major) Because hemin has exhibited transient, mild anticoagulant effects during clinical studies, concurrent use of anticoagulants should be avoided. The extent and duration of the hypocoagulable state induced by hemin has not been established.
Hydrocodone; Ibuprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Ibritumomab Tiuxetan: (Major) During and after therapy, avoid the concomitant use of Yttrium (Y)-90 ibrutumomab tiuxetan with drugs that interfere with coagulation such as anticoagulants; the risk of bleeding may be increased. If coadministration with anticoagulants is necessary, monitor platelet counts more frequently for evidence of thrombocytopenia.
Ibrutinib: (Moderate) The concomitant use of ibrutinib and anticoagulant agents such as heparin may increase the risk of bleeding; monitor patients for signs of bleeding. Severe bleeding events have occurred with ibrutinib therapy including intracranial hemorrhage, GI bleeding, hematuria, and post procedural hemorrhage; some events were fatal. The mechanism for bleeding with ibrutinib therapy is not well understood.
Ibuprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Ibuprofen; Famotidine: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Ibuprofen; Oxycodone: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Ibuprofen; Pseudoephedrine: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Icosapent ethyl: (Moderate) Icosapent ethyl is an ethyl ester of the omega-3 fatty acid eicosapentaenoic acid (EPA). Because omega-3 fatty acids inhibit platelet aggregation, caution is advised when icosapent ethyl is used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 36 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant icosapent ethyl therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
Iloprost: (Moderate) When used concurrently with anticoagulants, inhaled iloprost may increase the risk of bleeding.
Indocyanine Green: (Moderate) Heparin products that contain sodium bisulfite may reduce the absorption peak of indocyanine green. Collection of blood samples for analysis should be performed with anticoagulants that do not contain sodium bisulfite.
Indomethacin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Inotersen: (Moderate) Use caution with concomitant use of inotersen and anticoagulants due to the potential risk of bleeding from thrombocytopenia. Consider discontinuation of anticoagulants in a patient taking inotersen with a platelet count of less than 50,000 per microliter.
Intravenous Lipid Emulsions: (Moderate) Drug interactions with fish oil, omega-3 fatty acids (Dietary Supplements) or fish oil, omega-3 fatty acids (FDA-approved) are unclear at this time. However, because fish oil, omega-3 fatty acids inhibit platelet aggregation, caution is advised when fish oils are used concurrently with anticoagulants, platelet inhibitors, or thrombolytic agents. Theoretically, the risk of bleeding may be increased, but some studies that combined these agents did not produce clinically significant bleeding events. In one placebo-controlled, randomized, double-blinded, parallel study, patients receiving stable, chronic warfarin therapy were administered various doses of fish oil supplements to determine the effect on INR determinations. Patients were randomized to receive a 4-week treatment period of either placebo or 3 or 6 grams of fish oil daily. Patients were followed on a twice-weekly basis for INR determinations and adverse reactions. There was no statistically significant difference in INRs between the placebo or treatment period within each group. There was also no difference in INRs found between groups. One episode of ecchymosis was reported, but no major bleeding episodes occurred. The authors concluded that fish oil supplementation in doses of 3-6 grams per day does not have a statistically significant effect on the INR of patients receiving chronic warfarin therapy. However, an increase in INR from 2.8 to 4.3 in a patient stable on warfarin therapy has been reported when increasing the dose of fish oil, omega-3 fatty acids from 1 gram/day to 2 grams/day. The INR decreased once the patient decreased her dose of fish oil to 1 gram/day. This implies that a dose-related effect of fish oil on warfarin may be possible. Patients receiving warfarin that initiate concomitant fish oil therapy should have their INR monitored more closely and the dose of warfarin adjusted accordingly.
Ketoprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Ketorolac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Levocetirizine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
Lithium: (Moderate) Moderate to significant dietary sodium changes, or changes in sodium and fluid intake, may affect lithium excretion. Systemic sodium chloride administration may result in increased lithium excretion and therefore, decreased serum lithium concentrations. In addition, high fluid intake may increase lithium excretion. For patients receiving sodium-containing intravenous fluids, symptom control and lithium concentrations should be carefully monitored. It is recommended that patients taking lithium maintain consistent dietary sodium consumption and adequate fluid intake during the initial stabilization period and throughout lithium treatment. Supplemental oral sodium and fluid should be only be administered under careful medical supervision.
Lomustine, CCNU: (Moderate) Due to the bone marrow suppressive and thrombocytopenic effects of lomustine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Loratadine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
Loratadine; Pseudoephedrine: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
Magnesium Salicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Meclofenamate Sodium: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Mefenamic Acid: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Meloxicam: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Methenamine; Sodium Salicylate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Methoxsalen: (Minor) Agents, such as anticoagulants, that decrease clotting could decrease the efficacy of photosensitizing agents used in photodynamic therapy.
Methylsulfonylmethane, MSM: (Moderate) Increased effects from concomitant anticoagulant drugs such as increased bruising or blood in the stool have been reported in patients taking methylsulfonylmethane, MSM. Although these effects have not been confirmed in published medical literature or during clinical studies, clinicians should consider using methylsulfonylmethane, MSM with caution in patients who are taking anticoagulants such as warfarin until data confirming the safety of MSM in patients taking these drugs are available. During one of the available, published clinical trials in patients with osteoarthritis, those patients with bleeding disorders or using anticoagulants or antiplatelets were excluded from enrollment. Patients who choose to consume methylsulfonylmethane, MSM while receiving warfarin should be observed for increased bleeding.
Methyltestosterone: (Moderate) Methyltestosterone can increase the effects of anticoagulants through reduction of procoagulant factor. Patients receiving oral anticoagulant therapy should be closely monitored, especially when methyltestosterone treatment is initiated or discontinued.
Mifepristone: (Contraindicated) When mifepristone is used for the termination of pregnancy, concurrent use of anticoagulants is contraindicated due to the risk of serious bleeding.
Miltefosine: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
Mycophenolate: (Moderate) Mycophenolate may causes thrombocytopenia and increase the risk for bleeding. Agents which may lead to an increased incidence of bleeding in patients with thrombocytopenia include anticoagulants.
Nabumetone: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Naproxen; Esomeprazole: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Naproxen; Pseudoephedrine: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Nebivolol; Valsartan: (Minor) Concomitant use of valsartan with other drugs that may increase potassium concentrations, such as heparin, may lead to increases in serum potassium.
Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
Nicotine: (Minor) Nicotine may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance in most patients since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
Nintedanib: (Moderate) Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients who are taking anticoagulants closely and adjust anticoagulation therapy as necessary. Use nintedanib in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
Nitroglycerin: (Minor) At high doses, nitroglycerin may interfere with the anticoagulant effect of heparin. Intravenous nitroglycerin can induce heparin resistance. Monitor for lack of heparin efficacy if these drugs are administered concurrently. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
Nonsteroidal antiinflammatory drugs: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Obinutuzumab: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
Omacetaxine: (Major) Avoid the concomitant use of omacetaxine and anticoagulants when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
Omidubicel: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently.
Oritavancin: (Contraindicated) Use of intravenous unfractionated heparin for 120 hours (5 days) after oritavancin administration is contraindicated. Although oritavancin has no effect on the coagulation cascade, it does interfere with some coagulation tests by binding to and preventing activation of coagulation by phospholipid reagents commonly used in laboratory tests. The activated partial throboplastin time (aPTT) is artificially elevated for up to 120 hours (5 days) after oritavancin dosing. Consider use of an alternate anticoagulant, as appropriate. For patients who require aPTT monitoring within 120 hours (5 days) after oritavancin use, a non-phospholipid dependent coagulation test, such as Factor Xa, which is chromogenic, may be considered.
Orlistat: (Moderate) Patients on chronic stable doses of anticoagulants, like heparin, should be monitored closely for changes in coagulation parameters when orlistat is prescribed. Reports of decreased prothrombin, increased INR, and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with orlistat and anticoagulants.
Oxandrolone: (Moderate) An increased effect of anticoagulants may occur with oxandrolone; the anticoagulant dosage may need adjustment downward with oxandrolone initiation or adjustment upward with oxandrolone discontinuation to maintain the desired clinical effect. Oxandrolone suppresses clotting factors II, V, VII, and X, which results in an increased prothrombin time. An increase in plasminogen-activator activity, and serum concentrations of plasminogen, protein C, and antithrombin III have occurred with several 17-alpha-alkylated androgens. For example, concurrent use of oxandrolone and warfarin may result in unexpectedly large increases in the INR or prothrombin time (PT). A multidose study of oxandrolone (5 or 10 mg PO twice daily) in 15 healthy individuals concurrently treated with warfarin resulted in significant increases in warfarin half-life and AUC; a 5.5-fold decrease in the mean warfarin dosage from 6.13 mg/day to 1.13 mg/day (approximately 80 to 85% dose reduction) was necessary to maintain a target INR of 1.5. According to the manufacturer, if oxandrolone therapy is initiated in a patient already receiving warfarin, the dose of warfarin may need to be decreased significantly to reduce the potential for excessive INR elevations and associated risk of serious bleeding events. The patient should be closely monitored with frequent evaluation of the INR and clinical parameter, and the dosage of warfarin should be adjusted as necessary until a stable target INR is achieved. Careful monitoring of the INR and necessary adjustment of the warfarin dosage are also recommended when the androgen therapy is changed or discontinued.
Oxaprozin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Palifermin: (Moderate) The co-administration of palifermin and unfractionated heparin may result in a 4 to 5-fold increase in palifermin exposure; however, this interaction does not appear to affect the pharmacodynamics of either drug. If heparin is used to maintain an IV line, rinse the line with saline prior to and after palifermin administration. The palifermin AUC value was increased by 5-fold and the mean clearance was decreased by 80% after a single 60 mcg/kg dose of palifermin was administered with therapeutic levels of unfractionated heparin compared with no heparin in 27 healthy subjects. The activated partial thromboplastin time (aPTT) was not affected by this interaction. The palifermin AUC value was increased by 425% and the palifermin clearance, volume of distribution, and half-life was decreased by 76.5%, 73.1%, and 38.8%, respectively, following the administration of palifermin 40 mcg/kg/day for 3 days in combination with therapeutic levels of unfractionated heparin compared with no heparin in 31 healthy subjects. Palifermin administration results in a dose-dependent epithelial cell proliferation that may be assessed by Ki67 immunohistochemical staining. In this study, the pharmacokinetics of palifermin did not affect Ki67 expression in buccal biopsies. The co-administration of palifermin and low-molecular weight heparins (LMWHs), such as enoxaparin and dalteparin, is expected to have a similar interaction.
Pentosan: (Major) Pentosan is a weak anticoagulant. Pentosan has 1/15 the anticoagulant activity of heparin. An additive risk of bleeding may be seen in patients receiving other anticoagulants (e.g., heparin, warfarin)

in combination with pentosan.
Piperacillin; Tazobactam: (Moderate) Some penicillins (e.g., piperacillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type, however, is relatively rare. The concomitant use of warfarin with many classes of antibiotics, including penicillins, may result in an increased INR thereby potentiating the risk for bleeding. Inhibition of vitamin K synthesis due to alterations in the intestinal flora may be a mechanism; however, concurrent infection is also a potential risk factor for elevated INR. Monitor patients for signs and symptoms of bleeding. Additionally, increased monitoring of the INR, especially during initiation and upon discontinuation of the antibiotic, may be necessary in patients receiving warfarin.
Piroxicam: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Prasterone (DHEA) is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Prasterone (DHEA) is contraindicated for use in patients with active deep vein thrombosis, pulmonary embolism or history of these conditions. Prasterone is also contraindicated in patients with active arterial thromboembolic disease (for example, stroke and myocardial infarction), or a history of these conditions. Thus, patients receiving anticoagulation due to a history of these conditions are not candidates for prasterone treatment. DHEA is converted to androgens and estrogens within the human body and thus may affect hemostasis via androgenic or estrogenic effects. Estrogens increase the production of clotting factors VII, VIII, IX, and X. Androgens, such as testosterone, increase the synthesis of several anticoagulant and fibrinolytic proteins. Because of the potential effects on coagulation, patients receiving prasterone or DHEA concurrently with preventative anticoagulants (e.g., warfarin or heparin) or other platelet inhibitors, including aspirin, ASA should be monitored for side effects or the need for dosage adjustments.
Prasugrel: (Moderate) Based on the mechanism of actions of prasugrel and unfractionated heparin or low-molecular weight heparins (LMWHs), patients receiving these medications in combination may be at increased risk of bleeding. The concurrent use of prasugrel and a single 100 unit/kg intravenous dose of heparin did not disrupt coagulation or the inhibition of platelet aggregation; however, the bleeding time increased compared with monotherapy of either medication. Use caution when administering prasugrel with medications that may increase the risk of bleeding, such as unfractionated heparin or LMWH.
Protamine: (Contraindicated) Upon contact with heparin, protamine forms a salt, neutralizing the anticoagulant effect of both drugs. Protamine, a strongly basic compound, forms complexes with heparin sodium or heparin calcium, which are acidic compounds. Formation of this complex can result in disruption of the heparin-antithrombin III complex responsible for the anticoagulant activity of heparin. Protamine is used therapeutically to reverse the activity of heparins.
Reteplase, r-PA: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
Rivaroxaban: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with heparin; the safety of concomitant use has not been studied. If heparin is used during therapeutic transition periods, closely observe patients and promptly evaluate any signs or symptoms of blood loss.
Sacubitril; Valsartan: (Minor) Concomitant use of valsartan with other drugs that may increase potassium concentrations, such as heparin, may lead to increases in serum potassium.
Salicylates: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Salsalate: (Moderate) An additive risk of bleeding may be seen in patients receiving platelet inhibitors (e.g., aspirin, ASA). Despite the potential drug-drug interaction between aspirin and heparin, heparin is frequently administered in combination with low-dose aspirin therapy to patients who have had an acute myocardial infarction and in other disease states. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
Sedating H1-blockers: (Minor) Antihistamines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
Selective serotonin reuptake inhibitors: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of selective serotonin reuptake inhibitors (SSRIs) and anticoagulants like heparin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Serotonin norepinephrine reuptake inhibitors: (Moderate) Advise patients of the increased bleeding risk associated with the concomitant use of serotonin norepinephrine reuptake inhibitors (SNRIs) and anticoagulants like heparin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
Sodium Iodide: (Moderate) Anticoagulants may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administrations.
Sulindac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Sumatriptan; Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Telavancin: (Contraindicated) Concomitant use of intravenous unfractionated heparin infusions and telavancin is contraindicated as the activated partial thromboplastin time (aPTT) test results are expected to be artificially prolonged for 0 to 18 hours after telavancin administration. Although telavancin does not increase bleeding risk and has no effect on platelet aggregation, it does interfere with some coagulation tests by binding to and preventing activation of coagulation by phospholipid reagents commonly used in laboratory tests. For patients who require aPTT monitoring while being treated with telavancin, a nonphospholipid dependent coagulation test, such as a Factor Xa (chromogenic) assay, or an alternative anticoagulant not requiring aPTT monitoring may be considered.
Tenecteplase: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
Tetracyclines: (Minor) Tetracyclines may partially counteract the anticoagulant actions of heparin, according to the product labels. However, this interaction is not likely of clinical significance in most patients since heparin therapy is adjusted to the partial thromboplastin time (aPTT) and other clinical parameters of the patient.
Thrombolytic Agents: (Major) An additive risk of bleeding may be seen in patients receiving thrombolytic agents and anticoagulants.
Ticagrelor: (Moderate) Because ticagrelor inhibits platelet aggregation, a potential additive pharmacodynamic effect for bleeding exists if ticagrelor is given in combination with other agents that affect hemostasis such as heparin. No significant pharmacokinetic changes were seen with ticagrelor was coadministered with heparin 100 international units and enoxaparin 1 mg/kg, and the manufacturer states ticagrelor may be administered with unfractionated heparin and low molecular weight heparins.
Ticlopidine: (Moderate) Because ticlopidine inhibits platelet aggregation, a potential additive risk for bleeding exists if ticlopidine is given in combination with other agents that affect hemostasis such as anticoagulants. In clinical trials of cardiac stenting, patients were treated with heparin and ticlopidine concomitantly for 12 hours. The tolerance and long term safety of coadministered ticlopidine with these drugs has not been established. Per the manufacturer of ticlopidine, if a patient is switched from an anticoagulant or a thrombolytic agent to ticlopidine, the former drug should be discontinued prior to the administration of ticlopidine.
Tipranavir: (Moderate) Caution should be used when administering tipranavir to patients receiving anticoagulants. In clinical trials, there have been reports of intracranial bleeding, including fatalities, in HIV infected patients receiving tipranavir as part of combination antiretroviral therapy. In many of these reports, the patients had other medical conditions (CNS lesions, head trauma, recent neurosurgery, coagulopathy, hypertension, or alcoholism/alcohol abuse) or were receiving concomitant medications, including anticoagulants, that may have caused or contributed to these events.
Tirofiban: (Moderate) Concomitant use of tirofiban and other agents that effect hemostasis, such as anticoagulants, other platelet inhibitors, NSAIDs, and thrombolytic agents, may be associated with an increased risk of bleeding. In addition, large doses of salicylates (>= 3 to 4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding. In clinical trials with tirofiban, many patients received aspirin and heparin concomitantly. In these studies, the combination of tirofiban with heparin and aspirin has been associated with an increase in bleeding compared to heparin and aspirin alone. While administering tirofiban and heparin, the aPTT should be checked 6 hours after the start of the heparin infusion; heparin should be adjusted to maintain the aPTT approximately 2-times control. No information is available about the concomitant use of tirofiban with thrombolytic agents.
Tolmetin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Tolvaptan: (Moderate) Coadministration of tolvaptan and hypertonic saline (e.g., 3% NaCl injection solution) is not recommended. The use of hypertonic sodium chloride in combination with tolvaptan may result in a too rapid correction of hyponatremia and increase the risk of osmotic demyelination (i.e., central pontine myelinolysis).
Trazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking trazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. It would be prudent for clinicians to monitor the INR and patient's clinical status closely if trazodone is added to or removed from the regimen of a patient stabilized on anticoagulant therapy.
Treprostinil: (Moderate) When used concurrently with anticoagulants, treprostinil may increase the risk of bleeding.
Valdecoxib: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
Valsartan: (Minor) Concomitant use of valsartan with other drugs that may increase potassium concentrations, such as heparin, may lead to increases in serum potassium.
Valsartan; Hydrochlorothiazide, HCTZ: (Minor) Concomitant use of valsartan with other drugs that may increase potassium concentrations, such as heparin, may lead to increases in serum potassium.
Vasopressin, ADH: (Minor) Heparin can decrease the antidiuretic response to vasopressin.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with anticoagulants is necessary due to the risk of decreased verteporfin efficacy. Verteporfin is a light-activated drug. Once activated, local damage to neovascular endothelium results in a release of procoagulant and vasoactive factors resulting in platelet aggregation, fibrin clot formation, and vasoconstriction. Concomitant use of drugs that decrease clotting could decrease the efficacy of verteporfin therapy.
Vilazodone: (Moderate) Patients should be instructed to monitor for signs and symptoms of bleeding while taking vilazodone concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Serotonergic agents may increase the risk of bleeding when combined with anticoagulants via inhibition of serotonin uptake by platelets; however, the absolute risk is not known. In addition, both vilazodone and warfarin are highly protein bound, which may result in displacement of warfarin from protein binding sites and an increased anticoagulant effect. It would be prudent for clinicians to monitor the INR and clinical status of the patient closely if vilazodone is added to or removed from the regimen of a patient stabilized on warfarin.
Vorapaxar: (Major) Avoid concomitant use of vorapaxar and warfarin or other anticoagulants. Because vorapaxar inhibits platelet aggregation, a potential additive risk for bleeding exists if vorapaxar is given in combination with other agents that affect hemostasis such as anticoagulants.
Vortioxetine: (Moderate) Platelet aggregation may be impaired by vortioxetine due to platelet serotonin depletion, possibly increasing the risk of a bleeding complication (e.g., gastrointestinal bleeding, ecchymoses, epistaxis, hematomas, petechiae, hemorrhage) in patients receiving anticoagulants. Bleeding events related to drugs that inhibit serotonin reuptake have ranged from ecchymosis to life-threatening hemorrhages. Patients should be instructed to monitor for signs and symptoms of bleeding while taking vortioxetine concurrently with anticoagulants and to promptly report any bleeding events to the practitioner. Co-administration of vortioxetine and warfarin has not been shown to significantly affect the pharmacokinetics of either agent.
Warfarin: (Major) An additive risk of bleeding may be seen in patients receiving other anticoagulants in combination with heparin. Heparin and warfarin therapies often overlap with no serious sequelae, although the risk of bleeding is nonetheless increased. It should be noted that heparin also can prolong prothrombin time. When heparin and warfarin are administered concomitantly, wait at least 5 hours after the last IV heparin dose or 24 hours after the last subcutaneous heparin dose before drawing blood to obtain prothrombin time.

How Supplied

Heparin Sodium (Porcine)/Heparin Sodium (Porcine), Dextrose/Heparin Sodium (Porcine), Sodium Chloride/Heparin Sodium (Porcine);Sodium Chloride/Hepflush-10/Hep-Lock/Hep-Lock U/P/Monoject Prefill Advanced Heparin Lock Flush/SASH Normal Saline and Heparin Intravenous Inj Sol: 0.5mL, 1mL, 2U, 10U, 100U, 1000U, 2000U, 2500U, 5000U, 10000U, 20000U, 100-0.45%, 100-0.9%, 100-5%, 2-0.9%, 40-5%, 50-0.45%, 50-5%
Heparin Sodium (Porcine)/Hepflush-10/Hep-Lock/Hep-Lock U/P/Monoject Prefill Advanced Heparin Lock Flush Subcutaneous Inj Sol: 0.5mL, 1mL, 10U, 1000U, 5000U, 10000U, 20000U

Maximum Dosage

NOTE: Since heparin-induced bleeding has been related to dose in addition to other patient specific factors, it would seem to be prudent to limit the dose of heparin, especially in high-risk patients.

Adults

Maintain the aPTT below levels that correlate with heparin concentrations of 0.4 units/mL (by protamine titration) or an anti-factor Xa concentration of 0.7 units/mL.

Geriatric

Maintain the aPTT below levels that correlate with heparin concentrations of 0.4 units/mL (by protamine titration) or an anti-factor Xa concentration of 0.7 units/mL.

Adolescents

Maintain the aPTT below levels that correlate with heparin concentrations of 0.4 units/mL (by protamine titration) or an anti-factor Xa concentration of 0.7 units/mL.

Children

Maintain the aPTT below levels that correlate with heparin concentrations of 0.4 units/mL (by protamine titration) or an anti-factor Xa concentration of 0.7 units/mL.

Infants

Maintain the aPTT below levels that correlate with heparin concentrations of 0.4 units/mL (by protamine titration) or an anti-factor Xa concentration of 0.7 units/mL.

Neonates

Maintain the aPTT below levels that correlate with heparin concentrations of 0.4 units/mL (by protamine titration) or an anti-factor Xa concentration of 0.7 units/mL.

Mechanism Of Action

Heparin exerts its anticoagulant action by accelerating the activity of antithrombin III (ATIII) to inactivate thrombin; however, heparin does not lyse existing clots. Approximately one-third of heparin molecules contain a unique pentasaccharide sequence with high-affinity binding to ATIII. The interaction of heparin with ATIII produces a conformational change in ATIII, which accelerates the ability of ATIII to inactivate thrombin (factor IIa), factor Xa, and factor IXa. Of these enzymes, thrombin is the most sensitive to inhibition by heparin/ATIII. Heparin catalyzes the ATIII inactivation of thrombin by acting as a template to which both thrombin and ATIII bind to form a ternary complex. The inactivation of factor Xa does not require the heparin/ATIII complex formation and occurs via binding of ATIII to factor Xa. Heparin molecules must be greater than 18 monosaccharides to bind to thrombin and ATIII simultaneously. Therefore, smaller heparin molecules (i.e., < 18 monosaccharides) are unable to accelerate the inactivation of thrombin by ATIII, but retain their ability to catalyze the inhibition of factor Xa by ATIII. Heparin is unable to inactivate fibrin-bound (i.e., surface) thrombin or factor Xa bound to phospholipid surfaces within the prothrombinase complex. The inability of heparin to inactivate surface-bound thrombin and factor Xa may explain its limited efficacy in patients with unstable angina, high-risk coronary angioplasty, and coronary thrombolysis. At doses higher than those required to stimulate the activity of ATIII, heparin catalyzes the inactivation of thrombin by heparin cofactor II, which does not require interaction with ATIII. Heparin also stimulates the inhibition of thrombin by plasminogen activator inhibitor I, protein C inhibitor, and protease nexin-1 and inhibition of factor Xa by tissue factor pathway inhibitor; however, these proteins are only present in the serum in very small quantities as compared to ATIII.
 
High doses of heparin also interfere with platelet aggregation, which, in turn, prolongs the bleeding time, although commonly used therapeutic doses heparin do not affect bleeding time. High-molecular-weight heparin fractions have a greater effect on platelet function. It has been shown that the platelet-aggregating activity of heparin can be directly related to its molecular weight.
 
Fibroblast growth factors (FGF) bind to heparin with high-affinity. Heparin potentiates the effects of FGF by promoting the binding of these factors to their receptors, a transmembrane tyrosine kinase. Fibroblast growth factors stimulate angiogenesis. As opposed to its anticoagulation effects, the activity of heparin on FGF is due to the degree of sulfation and not the size of the molecule.
 
The variability of anticoagulant response in individuals given fixed doses of heparin is thought to be due to differences between patients in their plasma concentrations of neutralizing plasma proteins and/or heparin-binding proteins (e.g., histidine-rich glycoprotein, vitronectin, lipoproteins, fibronectin, fibrinogen, platelet factor 4, and von Willebrand factor). The response of the aPTT ratio to heparin may be decreased in patients with high levels of factor VIII. These patients may have therapeutic plasma heparin levels at the usual dose of heparin when measured using anti-Xa activity or by protamine sulfate titration, but require very high doses of heparin (> 50,000 International Units/day) to achieve an aPTT > 1.5-times control. Patients with acquired antithrombin deficiency (< 25% normal concentration) may not respond to heparin.

Pharmacokinetics

Heparin is given parenterally, either intravenously or subcutaneously. Heparin is highly bound to antithrombin, fibrinogens, globulins, serum proteases, and lipoproteins. The Vd is 0.07 L/kg. Heparin does not undergo enzymatic degradation. It is primarily cleared from the circulation by liver and reticuloendothelial cells mediated uptake into extravascular space. Heparin undergoes biphasic clearance, first by a rapid, saturable, zero-order process, then via slower first order elimination. In the zero-order phase, heparin is bound to the surface of cells (e.g., proteins, endothelial cells, macrophages) where it is internalized and depolymerized. Low doses of heparin are cleared mostly by a saturable, rapid, zero-order process. Slower first order elimination usually occurs with very high doses of heparin and is dependent on renal function. Plasma half-life is dose-dependent and ranges from 0.5 to 2 hours.
 
Affected cytochrome P450 isoenzymes and drug transporters: none

Intravenous Route

Peak plasma concentration and onset of action are achieved immediately after intravenous administration.

Subcutaneous Route

Administration of low or moderate doses of subcutaneous heparin reduces the plasma recovery. However, plasma recovery is almost complete with use of high therapeutic doses of subcutaneous heparin (more than 35,000 units every 24 hours). After subcutaneous administration, approximately 22% to 40% of the administered dose is absorbed systemically as determined by anti-factor Xa assay. Subcutaneous heparin concentrations reach steady-state between 4 and 10 hours.

Pregnancy And Lactation
Pregnancy

In published reports, heparin exposure during pregnancy did not result in increased risk of adverse maternal or fetal outcomes in humans. No teratogenicity was seen in animal studies where animals were given approximately 10 times the maximum recommended human dose during organogenesis; however, increased resorptions were reported. Consider the benefits and risks of heparin to a pregnant woman and possible risks to the fetus when using heparin during pregnancy. Heparin does not cross the placental barrier. When indicated, use only preservative-free heparin formulations; benzyl alcohol has been associated with serious adverse events and death, particularly in neonates and infants.

There are no data on the presence of heparin in human milk, the effects on the breast-fed infant, or the effects on milk production. Due to its large molecular weight, heparin is not likely to be excreted in human breast milk, and any heparin in milk would not be orally absorbed by a nursing infant. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for heparin and any potential adverse effects on the breast-fed infant from heparin or from the underlying maternal condition. When indicated, use only preservative-free heparin formulations; benzyl alcohol has been associated with serious adverse events and death, particularly in neonates and infants.