Heparin is a parenteral anticoagulant widely used in clinical medicine. It is a glycosaminoglycan composed of chains of alternating residues of D-glucosamine and an uronic acid; its molecular weight ranges from 5,000-30,000 daltons, with a mean of 15,000 daltons (about 50 monosaccharide chains). Commercially, heparin is derived from porcine or bovine tissue, and is available as the calcium or sodium salt. Full therapeutic doses of heparin prolong clotting time; however, bleeding time is usually unaffected by heparin. The response to heparin is variable since only about one-third of the molecules have anticoagulant activity, and its activity and clearance is dependent upon the length and size of the heparin molecules. The preferential clearance of larger molecules in vivo leads to accumulation of lower-molecular weight species that have a reduced ratio of antithrombin to antifactor Xa activity. Compared with low molecular weight heparins, unfractionated heparin produces a less predictable anticoagulant response due primarily to its reduced bioavailability after subcutaneous administration of low doses, its dose-dependent clearance, and differences among patients in the nonspecific binding of heparin to proteins and cells. Heparin was discovered in 1916 and was approved by the FDA in 1939.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific 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.
Intravenous Administration
Intermittent IV Injection
-Administer IV either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection.
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.
-ASHP Recommended Standard Concentrations for Adult Continuous Infusions: 100 units/mL.
-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.
-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).
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.
The most serious adverse reaction associated with heparin therapy is bleeding, which can occur at any site. This can involve minor bleeding, such as bleeding from the gums or hematuria, or frank hemorrhage. Repeated flushing of a catheter device with heparin can result in systemic effects, including anticoagulation and bleeding. Withdrawing the drug can usually control an overly prolonged bleeding time or minor bleeding during therapy. Adverse bleeding events include epistaxis, GI bleeding, hematoma, purpura, petechiae, unexplained bruising, heavy menstrual/vaginal bleeding, or prolonged bleeding from cuts or wounds. Back pain, abdominal pain, anemia, hematuria, melena, hematochezia, and hematemesis can indicate internal hemorrhage. If bleeding is serious, heparin therapy should be discontinued, and protamine can be administered as a heparin antagonist. Retroperitoneal bleeding, intracranial bleeding (e.g., subdural hematoma), or ovarian (corpus luteum) hemorrhage can be difficult to detect. Adrenal hemorrhage, with resultant acute adrenocortical insufficiency, has occurred during anticoagulant therapy. Therefore, discontinue heparin treatment in patients who develop signs and symptoms of acute adrenal hemorrhage and insufficiency. Do not delay initiation of corrective therapy for laboratory confirmation, as any delay in treatment during an acute situation may result in death. Although rare, massive ocular hemorrhage has been reported in patients with pre-existing disciform macular degeneration receiving systemic anticoagulants, such as heparin. Subconjunctival hemorrhage and spontaneous hyphema have also been reported.
Thrombocytopenia is a well-known complication of heparin therapy. The reported incidence of thrombocytopenia during heparin therapy is 30% or less. Some data suggest that heparin from bovine sources is associated with a higher incidence of thrombocytopenia than is heparin from porcine origin. Thrombocytopenia can present in 2 forms: an early, benign, reversible nonimmune thrombocytopenia and a late, more serious IgG-mediated immune thrombocytopenia. Mild nonimmune thrombocytopenia generally occurs about days 2 to 4 of therapy. In nonimmune heparin-associated thrombocytopenia, the decrease in platelet count may be mild and of no obvious clinical significance; the platelet count may recover despite continued heparin treatment. In contrast, the immune form of heparin-induced thrombocytopenia (HIT) is characterized by IgG-mediated platelet activation and usually occurs after the fifth day of therapy. Although the precise frequency of immune-mediated HIT is uncertain, data in orthopedic patients indicate a frequency of about 5% for unfractionated heparin, compared to about 1% with low molecular weight heparin. In patients previously unexposed to heparin, the platelet count usually begins to decline 5 to 10 days after starting heparin therapy in a patient with immune-mediated HIT. However, thrombocytopenia may occur within 24 hours of initiation of heparin in patients who have been previously exposed to heparin therapy, especially if heparin was administered within the previous 3 months. A platelet decrease of greater than 50% from baseline is considered indicative of HIT. In patients with immune-mediated HIT, platelet aggregation is greatly increased and the patient can develop thrombotic complications (white-clot syndrome). Thrombosis development shortly after documenting thrombocytopenia is a characteristic finding in approximately half of all patients with HIT. Thrombosis can occur while the platelet count is declining, but before the onset of overt thrombocytopenia, which may occur a few days later. Therefore, thrombosis may be the initial manifestation of HIT and may be accompanied by severe thromboembolic complications such as erythematous skin plaques, epidermal necrosis, gangrene of extremities that may lead to amputation, myocardial infarction, pulmonary embolism, stroke, thrombus formation on a prosthetic cardiac valve, and possibly death. HIT-associated thrombosis occurs in about 1% of patients who receive therapeutic doses of IV heparin for 5 days or more. An even higher frequency (2.4%) has been reported in orthopedic patients receiving heparin prophylaxis. Venous thromboembolism is more common than arterial (approximate ratio 4:1). Venous limb gangrene is characterized by distal tissue losses associated with extensive venous thrombosis that involves both large veins and small venules. Bilateral adrenal hemorrhagic necrosis can occur in patients with HIT and should be considered in any patient who complains of abdominal pain or unexplained low blood pressure during heparin therapy. If the platelet count falls in a manner consistent with immune-mediated HIT, all heparin therapy (including heparin flushes) should be stopped and an alternative management strategy initiated. Avoid future heparin use in patients with a diagnosis of HIT, especially within 3 to 6 months of diagnosis and while patients test positive for antibodies. After discontinuation of heparin, the median time to platelet count recovery to normal is about 4 days; about 90% of patients recover by 1 week, although in rare cases, the platelet count may not return to normal for several weeks. HIT can occur up to several weeks after the discontinuation of heparin therapy, and patients presenting with thrombocytopenia or thrombosis after heparin discontinuation should also be evaluated for HIT. Because the incidence of thrombosis is high even after discontinuation of heparin, consideration should be given to using an alternate anticoagulant.
Generalized hypersensitivity reactions have been reported with heparin use. Fever, chills, and urticaria are the most common manifestations; however, bronchospasm, rhinitis, lacrimation, headache, nausea, vomiting, and anaphylactoid reactions, including anaphylactic shock, may also occur. Itching and burning, especially on the plantar site of the feet, may occur. Histamine-like reactions have been observed at the site of heparin injection. Also, episodes of painful, ischemic, and cyanosed limbs have been reported and attributed to allergic vasospastic reactions; it is unclear whether these reactions are separate from or related to thrombocytopenia-associated reactions.
Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia. The risk of hyperkalemia appears to increase with duration of therapy; however, it is usually reversible upon discontinuation of heparin. Measure plasma potassium in persons at risk of hyperkalemia prior to initiation of heparin therapy and periodically in all persons receiving heparin for more than 5 days or sooner if clinically indicated.
Osteoporosis has been reported in patients receiving long-term administration of high doses of heparin ; this is particularly concerning during infancy, childhood, and adolescence, periods of active bone development. When possible, the chronic use of unfractionated heparin should be avoided in pediatric patients. There have been a few reports of heparin-induced osteoporosis in pediatric patients; however, these reports were complicated by additional risk factors. Significant reduction in bone density has been reported in about 30% of adult patients and symptomatic bone fractures occur in 2% to 3% of adult patients receiving heparin for 1 month or more. In animal studies, unfractionated heparin has been found to stimulate bone resorption in addition to decreasing bone formation.
Dermatologic reactions that may occur during heparin therapy include skin ulcer, hematoma, erythema, skin plaques, and skin necrosis. Pruritus and burning, especially on the plantar side of the feet may occur. Delayed, transient alopecia has been reported. Although skin lesions usually occur at the sites of heparin injection (i.e., injection site reaction), there have been rare reports of necrosis at sites remote from heparin injection. Severe injection site reactions are more commonly associated with intramuscular injections or deep subcutaneous injections. Skin lesions usually develop 5 days or more following subcutaneous heparin administration. The delayed onset is consistent with an immunologic reaction. Some patients with skin lesions have tested positive for HIT-IgG even though they did not develop thrombocytopenia. Patients who develop these delayed-onset skin lesions may be at increased risk for serious systemic reactions or thrombotic events, accompanied by an abrupt fall in platelet count, if they are given IV heparin.
Rebound hyperlipidemia on discontinuation of heparin therapy has been reported. Significantly elevated hepatic enzymes (AST and ALT) have occurred in persons receiving heparin. Hepatic enzyme elevations usually resolve upon heparin discontinuation. Elevated hepatic enzymes in persons receiving heparin therapy should be interpreted with caution.
Priapism has been reported with the use of heparin. However, it is unclear if the priapism was related to heparin administration or to the underlying thrombotic condition.
Heparin inhibits the formation of 1,25(0H)2D by the kidneys and may lead to vitamin D deficiency. Monitoring of vitamin D concentrations and supplementation with vitamin D may be necessary with prolonged therapy (i.e., greater than 1 month).
Do not use therapeutic heparin when appropriate blood coagulation tests for monitoring cannot be performed at appropriate intervals. Discontinue heparin immediately if the coagulation test is excessively prolonged or hemorrhage occurs. Monitor platelet counts, hematocrit, and occult blood in stool throughout the course of therapy, regardless of the route of administration.
Use caution when interpreting the clinical implications of elevated hepatic enzymes in patients receiving heparin. Significant elevations in aminotransferases (AST and ALT) have occurred in a high percentage of patients (including healthy subjects) who received heparin.
Heparin may prolong the one-stage prothrombin time. Hence, when given with warfarin, allow at least 5 hours after the last IV dose or 24 hours after the last subcutaneous dose of heparin to elapse before blood is drawn to obtain an accurate prothrombin time.
Heparin is contraindicated in patients with known heparin hypersensitivity; reserve heparin in these patients for clearly life-threatening situations. Heparin is derived from porcine tissue; therefore, use of heparin is contraindicated in patients with porcine protein hypersensitivity. Because heparin is derived from animal tissue, monitor for signs and symptoms of hypersensitivity when it is used in patients with a history of allergy. Heparin solutions containing dextrose may be contraindicated in patients with corn hypersensitivity. Some heparin preparations contain sulfites, which can induce a life-threatening allergic response in some patients. Use such heparin products with extreme caution in patients with known sulfite hypersensitivity; sulfite sensitivity reactions tend to occur more frequently in patients with asthma. Some heparin preparations contain benzyl alcohol as a preservative; avoid these formulations in patients with benzyl alcohol hypersensitivity.
Heparin is contraindicated in patients with severe thrombocytopenia and in those with a history of heparin-induced thrombocytopenia (HIT), heparin-induced thrombocytopenia and thrombosis (HITT), or thrombocytopenia with pentosan polysulfate. Heparin may be used safely in patients with mild nonimmune thrombocytopenia (platelets more than 100,000/mm3), which may remain stable or reverse with continued treatment. However, use an alternative anticoagulant and avoid all sources of heparin in patients with a history of immune-mediated HIT because these patients can develop thrombotic complications during heparin therapy. Because it may not be possible to differentiate asymptomatic, nonimmune thrombocytopenia from immune-mediated thrombocytopenia, monitor the platelet count closely. If the platelet count falls below 100,000/mm3 or recurrent thrombosis develops, promptly discontinue heparin, evaluate for HIT and HITT, and, if necessary, administer an alternative anticoagulant. Thrombosis in association with thrombocytopenia may indicate white-clot syndrome, which can lead to severe thromboembolic complications. HIT or HITT can occur up to several weeks after the discontinuation of heparin therapy; evaluate patients presenting with thrombocytopenia or thrombosis after heparin discontinuation for HIT or HITT. Avoid future heparin use in patients with a diagnosis of HIT or HITT, especially within 3 to 6 months of diagnosis and while patients test positive for antibodies.
Heparin is contraindicated in patients with uncontrollable bleeding (with the exception of bleeding associated with disseminated intravascular coagulation). Avoid use of heparin in the presence of major bleeding, unless the benefits of therapy outweigh the potential risks. Fatal hemorrhages have occurred with the use of heparin. Hemorrhage can occur at virtually any site in patients receiving heparin. Blood coagulation tests should be performed before and regularly during therapy. Consider the possibility of a hemorrhagic event with an unexplained fall in hematocrit, hypotension, or any other unexplained symptom. Use heparin with extreme caution in a patient with conditions that might increase the risk of hemorrhage. These may include subacute bacterial endocarditis; dissecting aortic aneurysm; peptic ulcer disease; diverticulitis; inflammatory bowel disease; liver disease; coagulopathy; hemophilia; thrombocytopenia; menstruation; threatened abortion or other abnormal vaginal bleeding; severe hypertension; head trauma; major surgery or trauma, especially involving eye, brain, or spinal cord; during or immediately after a lumbar puncture or spinal anesthesia; tube drainage of stomach or small intestine; and increased capillary permeability. Patients with hereditary antithrombin III deficiency receiving antithrombin III therapy are also at risk for hemorrhage with concurrent heparin use; reduce the heparin dose during concomitant use to reduce the risk of bleeding. Monitor all patients receiving heparin closely for easy bruising or petechiae, which can precede signs of hemorrhage such as nosebleed, hematuria, or tarry stools.
In patients with acute intracranial bleeding, the American College of Chest Physicians (ACCP) recommends the initial use of pneumatic compression devices for prevention of DVT and PE. In stable patients, low-dose subcutaneous heparin may be initiated as soon as the second day after the onset of intracranial hemorrhage (ICH). This represents a Grade 2C recommendation by ACCP, and assumes a relatively low degree of risk aversion.
Increased resistance to heparin is frequently encountered in patients with fever, thrombosis, thrombophlebitis, infection with thrombosing tendencies, myocardial infarction, neoplastic disease, postsurgical patients, and patients with antithrombin III deficiency. Consider measurement of anti-thrombin concentrations if heparin resistance is suspected. Monitor coagulation tests closely in such patients; heparin dose adjustments based on anti-factor Xa concentrations and/or partial thromboplastin time may be necessary.
Use heparin cautiously in patients with underlying hepatic disease as these patients often have coagulopathies and are at increased risk for anticoagulant-associated bleeding. Patients with inherited antithrombin deficiency usually have antithrombin concentrations 40% to 60% of normal but may have resistance to heparin and require higher doses to achieve the desired therapeutic response. Patients with acquired antithrombin deficiency, as seen with severe hepatic disease (e.g., cirrhosis), renal disease (e.g., nephrotic syndrome), or disseminated intravascular coagulation (DIC), may not respond to heparin.
When using heparin lock flush solutions to maintain catheter patency, the 100 unit/mL concentration should not be used in neonates or in infants who weigh less than 10 kg because of the risk of systemic anticoagulation. While systemic anticoagulation is not common with the use of heparin flushes for line patency in general, clinicians should use caution and carefully monitor small infants and other at risk patients receiving multiple flushes per day regardless of the heparin concentrations used. Extreme caution should be used during the preparation, dispensing, and administration of heparin flushes, heparin-containing fluids, and therapeutic doses of heparin for pediatric patients. Heparin injection is available in a wide range of concentrations. 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. To confirm correct vial choice during preparation and prior to administration, carefully inspect labels of heparin injection vials. Use preservative-free heparin formulations in neonates. Multiple dose vials contain benzyl alcohol as a preservative and should be avoided in this population. A 'gasping syndrome' characterized by CNS depression, metabolic acidosis, and gasping respirations has been associated with benzyl alcohol dosages more than 99 mg/kg/day in neonates. However, the minimum amount of benzyl alcohol at which toxicity may occur is unknown and low-birth weight and premature neonates may be more likely to develop toxicity. Normal therapeutic heparin doses would deliver benzyl alcohol at amounts lower than those reported with 'gasping syndrome'; however, the clinician should be aware of the toxic potential, especially if other drugs containing benzyl alcohol are administered.
Geriatric patients, especially females, may have higher plasma concentrations of heparin and longer activated partial thromboplastin time (aPTT) compared to patients younger than 60 years of age following similar doses. A higher incidence of bleeding in elderly patients older than 60 years, especially females, has been reported. Elderly patients may require lower doses of heparin.
Heparin is not intended for intramuscular administration. Severe large hematomas caused by accidental puncture of an IM vein may occur. Avoid intramuscular injections of other medications to patients receiving heparin. IM injections may cause bleeding, bruising, or hematomas.
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.
Heparin can suppress adrenal secretion of aldosterone leading to hyperkalemia, particularly in persons with diabetes mellitus, chronic renal failure, preexisting metabolic acidosis, a raised plasma potassium (e.g., preexisting hyperkalemia), or taking potassium sparing medications. The risk of hyperkalemia appears to increase with duration of therapy; however, it is usually reversible upon discontinuation of heparin. Measure plasma potassium in persons at risk of hyperkalemia prior to initiation of heparin therapy and periodically in all persons receiving heparin for more than 5 days or sooner if clinically indicated.
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.
Converting to Oral Anticoagulants
-When converting from heparin to warfarin, continue therapeutic heparin therapy for several days after warfarin initiation until the INR (prothrombin time) is within a stable therapeutic range. At that point, heparin may be discontinued without tapering. NOTE: Heparin may prolong the one-stage prothrombin time. When heparin is given with warfarin, prothrombin time is most accurate at least 5 hours after the last IV dose or 24 hours after the last subcutaneous dose of heparin.
-When converting from heparin to oral anticoagulants other than warfarin, stop the heparin infusion immediately after administering the first dose of oral anticoagulant. If the patient is receiving intermittent IV heparin, discontinue heparin and administer the oral anticoagulant 0 to 2 hours before the time that the next dose of heparin would have been administered.
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 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 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 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 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 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 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 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.
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 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.
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.
Therapeutic Drug Monitoring:
-The activated partial thromboplastin time (aPTT) is usually used to monitor heparin therapy since it is sensitive to the inhibitory effects of heparin on thrombin, factor Xa and factor IXa; although, only about 40% of the variation in plasma heparin levels is actually reflected by changes in aPTT. An aPTT ratio of 1.5-2.5 times baseline is traditionally regarded as the therapeutic target in the clinical treatment of thromboembolic disease with heparin. However, because the activity of thromboplastin reagents differ, the therapeutic aPTT range varies among different brands and lots of reagents. Therefore, the American College of Chest Physicians recommends that the therapeutic range for each aPTT reagent be calibrated to be equivalent to a plasma heparin concentration (by protamine titration) of 0.2-0.4 International Units/ml or to an anti-factor Xa concentration of about 0.3-0.6 International Units/ml. Alternatively, heparin treatment can be monitored by a chromogenic anti-factor Xa heparin assay with a targeted range of 0.3-0.7 International Units/ml. In patients with a subtherapeutic aPTT response despite high doses of heparin, further increases in heparin dosage may not be necessary if the heparin level is therapeutic (i.e., 0.3-0.7 International Units/ml by anti-factor Xa assay). Potency does not differ between calcium and sodium salts of heparin.
-Dosage should be adjusted to produce a therapeutic aPTT or heparin concentration by protamine titration at 6 hours after a SC or IV dose or infusion rate change. The measurement of anti-factor Xa levels, if available, approximately 4 hours after SC injection has been recommended.
-The aPTT is sensitive over a heparin range of 0.1-1 International Units/ml. However, in high-risk angioplasty patients or in patients having cardiac bypass surgery the aPTT is unsuitable for monitoring heparin dosage since these patients often require heparin levels > 1 International Units/ml (5 International Units/ml for CABG patients). For these procedures, the activated clotting time (ACT) is usually used to monitor heparin therapy since this test shows a graded response to heparin concentrations in the range of 1-5 International Units/ml.
Maximum Dosage Limits:
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.
Patients with Hepatic Impairment Dosing
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.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
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. (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.
Acetaminophen; Caffeine; Pyrilamine: (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.
Acetaminophen; Chlorpheniramine: (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.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (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.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (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.
Acetaminophen; Chlorpheniramine; Dextromethorphan; 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.
Acetaminophen; Chlorpheniramine; Phenylephrine : (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.
Acetaminophen; Dextromethorphan; Doxylamine: (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.
Acetaminophen; Diphenhydramine: (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.
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.
Acetaminophen; Pamabrom; Pyrilamine: (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.
Acrivastine; 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.
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.
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; 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.
Balsalazide: (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.
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 Subcitrate Potassium; Metronidazole; Tetracycline: (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.
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. (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.
Bivalirudin: (Major) An additive risk of bleeding may be seen in patients receiving or other anticoagulants in combination with heparin.
Brompheniramine: (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.
Brompheniramine; Dextromethorphan; Phenylephrine: (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.
Brompheniramine; Phenylephrine: (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.
Brompheniramine; 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.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (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.
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.
Carbinoxamine: (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.
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.
Chlophedianol; Dexbrompheniramine: (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.
Chlophedianol; Dexchlorpheniramine; 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.
Chlorcyclizine: (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.
Chlorpheniramine: (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.
Chlorpheniramine; Codeine: (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.
Chlorpheniramine; Dextromethorphan: (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.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (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.
Chlorpheniramine; Dextromethorphan; 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.
Chlorpheniramine; Hydrocodone: (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.
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. (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.
Chlorpheniramine; Phenylephrine: (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.
Chlorpheniramine; 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.
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.
Citalopram: (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.
Clemastine: (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.
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.
Cyproheptadine: (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.
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.
Demeclocycline: (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.
Deoxycholic Acid: (Moderate) Use deoxycholic acid with caution in patients receiving anticoagulants. Excessive bruising or bleeding may occur in and around the treatment area.
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.
Desvenlafaxine: (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.
Dexbrompheniramine: (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.
Dexbrompheniramine; 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.
Dexchlorpheniramine: (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.
Dexchlorpheniramine; Dextromethorphan; 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.
Dextran: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently.
Dextromethorphan; Diphenhydramine; Phenylephrine: (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.
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.
Digoxin: (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.
Dimenhydrinate: (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.
Diphenhydramine: (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.
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. (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.
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. (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.
Diphenhydramine; Phenylephrine: (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.
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.
Doxycycline: (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.
Doxylamine: (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.
Doxylamine; Pyridoxine: (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.
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.
Duloxetine: (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.
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.
Escitalopram: (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.
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.
Fluoxetine: (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.
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.
Fluvoxamine: (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.
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.
Hydroxyzine: (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.
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.
Levomilnacipran: (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.
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.
Meclizine: (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.
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.
Mesalamine, 5-ASA: (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.
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.
Milnacipran: (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.
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.
Minocycline: (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.
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.
Olanzapine; Fluoxetine: (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.
Olsalazine: (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.
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.
Omadacycline: (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.
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.
Paroxetine: (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.
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.
Pseudoephedrine; Triprolidine: (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.
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.
Sarecycline: (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.
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.
Sertraline: (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.
Sodium Iodide: (Moderate) Anticoagulants may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administrations.
Sulfasalazine: (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.
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.
Tetracycline: (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.
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.
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.
Triprolidine: (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.
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.
Venlafaxine: (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.
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.
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.
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
-Route-Specific Pharmacokinetics
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.
-Special Populations
Hepatic Impairment
The rate of clearance of unfractionated heparin may be decreased in persons with hepatic impairment and plasma heparin concentrations may be higher compared to persons with normal hepatic function.
Renal Impairment
The rate of clearance of unfractionated heparin may be decreased in persons with renal impairment and plasma heparin concentrations may be higher compared to persons with normal renal function.
Pediatrics
Neonates
Premature neonates (n = 25, gestational age 25 to 36 weeks) had a significantly shorter plasma half-life (35.5 to 41.6 minutes), larger volume of distribution (57.8 to 81 mL/kg), and faster clearance (1.37 to 1.49 mL/kg/minute) after an IV bolus dose of 100 units/kg compared to adults receiving an IV bolus dose of 75 units/kg (half-life = 63.3 minutes, Vd = 36.6 mL/kg, CL = 0.43 mL/kg/minute).
Geriatric
Persons older than 60 years may have higher plasma concentrations of heparin and longer activated partial thromboplastin times (aPTTs) compared with younger persons after similar doses of heparin.