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    Fractionated Heparins (LMWHs)

    BOXED WARNING

    Bleeding, coagulopathy, diabetic retinopathy, endocarditis, epidural anesthesia, GI bleeding, hemophilia, hepatic disease, hypertension, lumbar puncture, peptic ulcer disease, scoliosis, spinal anesthesia, stroke, surgery

    Dalteparin is contraindicated in patients with active major bleeding. Use dalteparin with extreme caution in patients who have an increased risk of hemorrhage, including those with severe uncontrolled hypertension, bacterial endocarditis, congenital or acquired coagulopathy, such as hemophilia, active peptic ulcer disease, angiodysplastic GI disease, hemorrhagic stroke, or those with recent brain, spinal, or ophthalmological surgery. Dalteparin may increase the risk of bleeding in patients with platelet defects, severe renal or hepatic disease, hypertensive or diabetic retinopathy, and recent GI bleeding. Do not use dalteparin as treatment for unstable angina and non-Q-wave myocardial infarct or for prolonged venous thromboembolism prophylaxis in patients undergoing spinal anesthesia or epidural anesthesia. Spinal or epidural hemorrhage and subsequent hematomas can occur with the use of LMWH and neuraxial (spinal/epidural) anesthesia or spinal puncture. Risk is higher with the use of postoperative indwelling catheters, the concomitant use of additional drugs affecting hemostasis (e.g., NSAIDs, platelet inhibitors, other anticoagulants), with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity (e.g., scoliosis). Placement or removal of an epidural catheter or lumbar puncture is best performed when dalteparin's anticoagulant effect is low; however, optimal timing between administration of dalteparin and neuraxial procedures is not known. For patients receiving preoperative thromboprophylaxis, the first postoperative thromboprophylaxis dose should be given 6 to 8 hours postoperatively. Give the second postoperative dose not sooner than 24 hours after the first dose. Delay catheter placement or removal for at least 12 hours after administration of 2,500 International Units once daily, at least 15 hours after administration of 5,000 International Units once daily, and at least 24 hours after administration of higher doses (200 International Units/kg once daily or 120 International Units/kg twice daily). These delays are not a guarantee that neuraxial hematoma will be avoided. Although a specific recommendation for timing of a subsequent dalteparin dose after catheter removal cannot be made, consider delaying this next dose for at least 4 hours. For those with a CrCl less than 30 mL/minute, consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed doses (2,500 or 5,000 International Units/day) and at least 48 hours for the higher doses (200 International Units/kg once daily or 120 International Units/kg twice daily). If it is decided to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor the patient frequently for signs and symptoms of neurological impairment (e.g., midline back pain, sensory and motor deficits, bowel or bladder dysfunction). If spinal hematoma is suspected, initiate urgent diagnosis and treatment.

    DEA CLASS

    Rx

    DESCRIPTION

    Low molecular weight heparin
    Used for DVT prophylaxis, treatment of VTE, and prophylaxis of ischemic complications in unstable angina and non-Q-wave MI
    Consists of heparin molecules ranging in size from 2,000 to 9,000 daltons (14% to 26% are more than 8,000 daltons)

    COMMON BRAND NAMES

    Fragmin

    HOW SUPPLIED

    Fragmin Subcutaneous Inj Sol: 0.2mL, 0.3mL, 0.5mL, 0.6mL, 0.72mL, 1mL, 2500IU, 5000IU, 7500IU, 10000IU, 12500IU, 15000IU, 18000IU, 25000IU

    DOSAGE & INDICATIONS

    For the treatment of venous thromboembolism (VTE) including acute deep venous thrombosis (DVT) or pulmonary embolism (PE).
    For extended treatment of symptomatic VTE in adult patients with cancer.
    Subcutaneous dosage
    Adults

    200 International Units/kg/dose subcutaneously once daily (Max: 18,000 International Units/dose) for 1 month, then 150 International Units/kg/dose subcutaneously once daily (Max: 18,000 International Units/dose) for months 2 through 6. Administer the prefilled syringe that contains the closest calculated dalteparin dose. In patients with concomitant cancer, ACCP guidelines recommend treatment of a DVT or PE with LMWH for at least 3 to 6 months followed by anticoagulation therapy (LMWH or vitamin K antagonist therapy) indefinitely or until the cancer has resolved. If the platelet count falls between 50,000 and 100,000/mm3, reduce the daily dose by 2,000 International Units until the platelet count recovers to 100,000/mm3 or more. If the platelet count falls below 50,000/mm3, discontinue therapy until the platelet count recovers to above 50,000/mm3.

    For the treatment of DVT† or PE†.
    Subcutaneous dosage
    Adults

    200 International Units/kg/dose subcutaneously once daily (Max: 18,000 International Units/dose) with warfarin starting on day 1. Stop dalteparin after at least 5 days of combined therapy once the targeted INR is reached; routine anti-Xa monitoring is not recommended. Studies have shown dalteparin 100 International Units/kg/dose subcutaneously every 12 hours or 200 International Units/kg/dose subcutaneously once daily is safe and effective in the inpatient or outpatient treatment of DVT or PE. A study comparing once daily and twice daily dalteparin in high-risk patients with iliofemoral DVT suggested greater benefit with the twice daily regimen; however, further research is needed to confirm these findings. Consider monitoring anti-Xa activity in morbidly obese patients (e.g., 120 to 140 kg).

    Infants, Children, Adolescents

    129 International Units/kg/dose subcutaneously once daily; adjust dose to maintain an anti-Xa concentration of 0.5 to 1 International Units/mL drawn 4 hours after dalteparin injection. Younger children may require higher doses than older children. In children and older infants, initial treatment should be for 5 to 10 days, until a therapeutic INR is achieved if the patient is to continue anticoagulation therapy with warfarin. Initial anticoagulation with LMWH should be longer in patients with a massive PE or extensive DVT. Dalteparin or a vitamin K antagonists (VKA) can be given for the duration of anticoagulation, which is for 6 months or longer in patients with idiopathic VTE or, in patients with secondary thromboembolism, until the risk factor for VTE is no longer present and at least 3 months of treatment have lapsed. In those patients with ongoing risk factors, treatment or prophylactic doses of dalteparin can be used. LMWH can be used in place of a VKA if VKA therapy is too difficult. In neonates with a VTE, LMWH should be used for 10 days to 3 months, and treatment with a vitamin K antagonist or LMWH can be reinstituted if extension of the thrombus occurs after dalteparin discontinuation. In general, it is recommended that central venous lines (CVL) or umbilical vein catheters (UVC) that are in situ be removed as greater than 80% of VTE in young children and infants are secondary to the placement of CVLs; anticoagulation therapy should be given for 3 to 5 days prior to the removal of the CVL. If the CVL or UVC is still in place at the end of anticoagulation therapy, it is recommended that prophylactic doses of dalteparin be instituted until the line can be removed.

    For the treatment of DVT† or PE† in pregnant females.
    Subcutaneous dosage
    Pregnant females

    100 International Units/kg/dose subcutaneously every 12 hours or 200 International Units/kg/dose subcutaneously once daily throughout pregnancy are recommended by the ACCP guidelines; however, twice daily dosing is preferred during pregnancy as the half-life of dalteparin is shorter during pregnancy. Increase the dose to reflect increases in weight or monitor anti-Xa concentrations and adjust the dose accordingly (goal anti-Xa concentration is 0.5 to 1.2 International Units/mL). Some data indicate that once a therapeutic anti-Xa concentration is achieved, dose modifications are not common, and monitoring may not be necessary. Discontinue dalteparin 24 hours prior to elective induction of labor. An anticoagulant should be administered for at least 6 weeks postpartum.

    For the treatment of symptomatic VTE in pediatric patients.
    Subcutaneous dosage
    Children and Adolescents 8 to 16 years

    100 International Units/kg/dose subcutaneously twice daily. Adjust the dosage in 25 International Units/kg increments to achieve a target anti-Xa concentration between 0.5 to 1 International Units/mL. In patients who experience a platelet count between 50,000 and 100,000/mm3, reduce the daily dose by 50% until the platelet count recovers to 100,000/mm3 or more. If the platelet count falls below 50,000/mm3, discontinue therapy until the platelet count recovers to above 50,000/mm3.

    Children 2 to 7 years

    125 International Units/kg/dose subcutaneously twice daily. Adjust the dosage in 25 International Units/kg increments to achieve a target anti-Xa concentration between 0.5 to 1 International Units/mL. In patients who experience a platelet count between 50,000 and 100,000/mm3, reduce the daily dose by 50% until the platelet count recovers to 100,000/mm3 or more. If the platelet count falls below 50,000/mm3, discontinue therapy until the platelet count recovers to above 50,000/mm3.

    Infants and Children 1 to 23 months

    150 International Units/kg/dose subcutaneously twice daily. Adjust the dosage in 25 International Units/kg increments to achieve a target anti-Xa concentration between 0.5 to 1 International Units/mL. In patients who experience a platelet count between 50,000 and 100,000/mm3, reduce the daily dose by 50% until the platelet count recovers to 100,000/mm3 or more. If the platelet count falls below 50,000/mm3, discontinue therapy until the platelet count recovers to above 50,000/mm3.

    For thrombosis prophylaxis.
    NOTE: Mechanical methods of prophylaxis should be used in patients who are at high risk of bleeding or as an adjunct to anticoagulant-based prophylaxis.
    For venous thromboembolism (VTE) prophylaxis, deep venous thrombosis (DVT) prophylaxis, or pulmonary embolism prophylaxis.
    Subcutaneous dosage
    Adults undergoing abdominal surgery with a risk of thromboembolic complications or adults undergoing general 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)

    3,400 antifactor Xa International Units or less subcutaneously once daily. 2,500 International Units is the dose most studied during 'low-dose' DVT/PE prophylaxis studies. Higher doses are associated with an increased risk of bleeding, which may outweigh the benefit in this at moderate-risk population. Previous guidelines have suggested 2,500 International Units subcutaneously once daily starting 1 to 2 hours prior to surgery, then once daily for 5 to 10 days postoperatively.

    Adults undergoing abdominal surgery or general surgery† with a high risk of thromboembolism (e.g., malignancy, 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)

    More than 3,400 antifactor Xa International Units subcutaneously once daily. Previous guidelines have suggested 5,000 International subcutaneously 8 to 12 hours before surgery followed by once daily for 5 to 10 days postoperatively. Alternatively, in patients with malignancy, 2,500 International Units subcutaneously can be given 1 to 2 hours before surgery and repeated in 12 hours. Thereafter, 5,000 International Units should be given once daily for 5 to 10 days postoperatively. In cancer surgery patients, treatment for 2 to 3 weeks after surgery reduces the risk of symptomatic DVT. In all higher-risk general surgery patients, the use of mechanical prophylaxis with elastic stockings (ES) or intermittent pneumatic compression (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 hip replacement surgery or hip-fracture surgery†

    5,000 International Units subcutaneously the evening before surgery (10 to 14 hours preoperatively), then give 5,000 International Units subcutaneously once daily starting at least 4 to 8 hours after surgery. Allow approximately 24 hours between doses. Per the ACCP guidelines, LMWH is the preferred agent for antithrombotic prophylaxis for patients undergoing total hip replacement surgery or hip fracture surgery. Treatment should start 12 hours or more preoperatively or 12 hours or more postoperatively rather than within 4 hours or less before or after surgery (Grade 1B Recommendation). Alternative dosing is 2,500 International Units subcutaneously within 2 hours of surgery and 2,500 International Units 4 to 8 hours after surgery, then 5,000 International Units once daily (at least 6 hours after last dose). Continue treatment for a minimum of 10 to 14 days after surgery (Grade 1B Recommendation); up to 35 days is recommended (Grade 2B Recommendation). The use of an intermittent pneumatic compression device (IPCD) during the hospital stay is encouraged (Grade 2C Recommendation).

    General medical adult patients with risk factors for DVT due to restrictive mobility during acute illness (e.g., moderate to severe congestive heart failure, severe lung disease, or patients who are confined to bed and have 1 or more of the following risk factors: active cancer, history of VTE, sepsis, acute neurological disease, and/or inflammatory bowel disease)

    5,000 International Units subcutaneously once daily for 12 to 14 days. The risk of proximal DVT and symptomatic VTE was decreased in patients receiving dalteparin vs. placebo (2.77% vs. 5%, respectively, p = 0.0015).

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

    3,400 antifactor Xa International Units or less subcutaneously once daily. Prophylaxis should be continued until hospital discharge. Previous guidelines have suggested dalteparin 2,500 International Units subcutaneously 1 to 2 hours prior to surgery then once daily.

    Female Adults undergoing extensive gynecologic surgery for malignancy†

    More than 3,400 antifactor Xa International Units subcutaneously once daily. For most patients, prophylaxis should be continued until hospital discharge; however, in patients that are considered to be at high risk (i.e., older than 60 years of age or a history of VTE), prophylaxis should continue through hospitalization and for 2 to 4 weeks after discharge. Previous guidelines have suggested dalteparin 5,000 International Units subcutaneously 8 to 12 hours before surgery then once daily.

    Adults undergoing laparoscopic surgery†

    2,500 International Units or 5,000 International Units subcutaneously once daily is recommended in patients with additional risk factors for VTE.

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

    The ACCP guidelines recommend prophylaxis for all patients. Previous guidelines have recommended that patients at moderate risk for VTE receive 2,500 International Units subcutaneously 1 to 2 hours prior to surgery then once daily. For patients at highest risk, 5,000 International Units subcutaneously 8 to 12 hours before surgery then once daily in combination with elastic stockings (ES) and with or without intermittent pneumatic compression (IPC) is recommended. The optimal duration of prophylaxis is not known.

    Adults undergoing neurosurgery†

    2,500 International Units or 5,000 International Units subcutaneously once daily with the initial dose given 24 hours postoperatively is recommended, provided hemostasis is established and contraindications to LMWH do not exist. The use of dalteparin must be balanced with the clinically important risk of intracranial bleeding; some clinicians obtain a CT scan prior to initiating LMWH to rule out an intracranial bleed. LMWH may be offered in combination with elastic stockings or intermittent pneumatic compression for patients at high-risk and may be more effective than either modality alone.

    Adults with acute spinal cord injury†

    5,000 International Units subcutaneously once daily, provided hemostasis has been established and no contraindications to LMWH use exist. Continue the LMWH throughout hospitalization and the rehabilitation phase.

    Adults with acute ischemic stroke and impaired mobility†

    2,500 International Units subcutaneously once daily, if not contraindicated. For patients with contraindications to anticoagulant therapy, the ACCP recommends intermittent pneumatic compression devices or elastic stockings.

    Infants†, Children, and Adolescents

    92 International Units/kg subcutaneously once daily; doses should be adjusted to maintain an anti-factor Xa level of 0.1 to 0.3 International Units/mL. Following an initial 3-month therapy for the first central venous catheter-related DVT, prophylactic doses of LMWH are recommended until the catheter is removed.

    For deep venous thrombosis (DVT) prophylaxis in pregnant females.
    NOTE: In all pregnant women with a history of DVT, the use of graduated elastic compression stockings is recommended both antenatally and postpartum.
    Subcutaneous dosage
    Pregnant females with an episode of idiopathic DVT; no current long-term anticoagulation

    5,000 International Units subcutaneously once daily is recommended; anticoagulation should be continued postpartum. Maintain antifactor Xa level of 0.2 to 0.6 International Units/mL.

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

    5,000 International Units subcutaneously once daily or surveillance is recommended; anticoagulation should be given postpartum. Maintain antifactor Xa level of 0.2 to 0.6 International Units/mL. In antithrombin-deficient women, compound heterozygotes for prothrombin G20210A and factor V Leiden and homozygotes for these conditions, 5,000 International Units subcutaneously once daily is recommended.

    Pregnant females with a single episode of DVT and thrombophilia (confirmed laboratory abnormality) or a strong family history of thrombosis; no current long-term anticoagulation

    5,000 International Units subcutaneously once daily or every 12 hours is recommended; anticoagulation should be continued postpartum. In women that are antithrombin-deficient, compound heterozygotes for prothrombin G20210A and factor V Leiden and homozygotes for these conditions, 5,000 International Units subcutaneously every 12 hours is recommended.

    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)

    200 International Units/kg subcutaneously once daily or 100 International Units/kg subcutaneously every 12 hours with resumption of long-term anticoagulation postpartum is recommended. In general, twice daily dosing of LMWH is preferred as the half-life of LMWH is decreased in pregnant patients.

    For thrombosis prophylaxis in pregnant patients with prosthetic heart valves†.
    Subcutaneous dosage
    Pregnant females

    100 International Units/kg subcutaneously twice daily with antifactor Xa concentrations monitored and maintained at 1 to 1.2 International Units/mL 4 hours after dose administration. Dalteparin can be administered either throughout pregnancy or, from weeks 6 to 12, followed by warfarin (INR 2.5 to 3.5) until the middle of the third trimester with dalteparin then given for the remainder of the pregnancy. Prospective, randomized, controlled trials have not been completed in this population, and treatment failures with the use of LMWH have been reported. Patients should be treated and monitored aggressively with dose adjustments throughout pregnancy reflective of changes in the patient's weight or as indicated by antifactor Xa concentrations. In women who are at especially high risk, the addition of aspirin 75 to 162 mg/day PO is recommended. The 2006 ACC/AHA guidelines recommend similar courses of action; however, the goal antifactor Xa concentration is 0.7 to 1.2 International Units/mL 4 hours after dose administration.

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

    As an alternative to heparin for continuation of anticoagulation beyond 48 hours of an acute MI, 2,500 International Units subcutaneously once daily for up to 3 months. All acute MI Patients should receive at least LMWH or low-dose heparin until the patient is ambulatory for prevention of DVT.

    For coronary artery thrombosis prophylaxis and the prevention of ischemic complications in patients with acute coronary syndrome (ACS).
    For patients with ST-segment elevation myocardial infarction (STEMI)† or Q-wave acute myocardial infarction (AMI)†.
    NOTE: Studies comparing dalteparin with UFH in patients with STEMI also receiving a fibrinolytic have been completed; however, further study is needed before dalteparin can be routinely recommended for this indication.
    Subcutaneous dosage
    Adults

    The Fragmin in Acute Myocardial Infarction (FRAMI) study compared dalteparin 150 units/kg/day subcutaneously with placebo in 776 patients (more than 90% received thrombolytic therapy and aspirin prior to dalteparin). Treatment with dalteparin reduced mural thrombosis formation in patients with acute anterior myocardial infarction (RR = 0.63) with an increased risk of bleeding. Dalteparin therapy was associated with increases in both major (2.9% vs. 0.3%) and minor bleeding (14.8% vs. 1.8%), possibly due to the use of thrombolytic therapy or increased doses used. Other studies have used 120 units/kg subcutaneously every 12 hours in patients receiving streptokinase or alteplase; however, superior efficacy of dalteparin over UFH has not been demonstrated, while an increase in bleeding has been associated with the use of dalteparin.

    Geriatric

    See adult dosage. The manufacturer advises careful attention to the dosing interval of dalteparin, especially if of low body weight (less than 45 kg) or if renally impaired.

    For patients with unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), or non-Q-wave myocardial infarction, including those patients undergoing percutaneous coronary intervention (PCI)†.
    NOTE: The terminology used to classify patients presenting with acute chest pain has changed in recent years. Patients presenting with acute chest pain are classified as having ACS with or without ST segment elevation. The terms ST segment elevation MI (STEMI), non-ST-segment elevation MI (NSTEMI), and unstable angina (UA) are used to further differentiate patients with ACS and are consistent with the terminology used in the 2002 ACC/AHA guidelines for the management of patients with UA and NSTEMI. For the purposes of treatment, NSTEMI and UA are distinguishable and often referred to as non-ST segment elevation ACS (NSTE ACS). For the purposes of patient management and treatment, Q-wave MI and non-Q-wave MI are no longer used to classify patients with acute chest pain. It should be noted that the majority of patients with STEMI do have Q-wave MIs; likewise, the majority of patients with NSTEMI do have non-Q-wave MIs.
    Subcutaneous dosage
    Adults

    120 units/kg (Max: 10,000 units) subcutaneously every 12 hours for 5 to 8 days is recommended. Concurrent aspirin therapy should be given except where contraindicated. Treatment guidelines recommend the use of LMWH, in combination with aspirin, over unfractionated heparin, including in those patients that receive an upstream GPIIb/IIIa inhibitor as initial therapy for ACS. In patients that receive LMWH as the upstream anticoagulant, it is recommended that the LMWH be continued during PCI. In patients with NSTE ACS, the evidence supports an aggressive and early invasive strategy (e.g., PCI); extended treatment with dalteparin may provide additional benefit in patients managed medically. In the FRISC II study, dalteparin twice daily for 3 months was compared to placebo in patients with unstable angina. A significant decrease in death or MI was observed at 30 days, but a statistically significant decrease was not seen at 3 months. Patients who underwent revascularization had no benefit from long-term dalteparin. Additionally, in those patients where invasive strategies are planned but delayed, the continued use of LMWH until the procedure is performed is recommended.

    Geriatric

    See adult dosage. The manufacturer advises careful attention to the dosing interval of dalteparin, especially if of low body weight (less than 45 kg) or if renally impaired.

    For the treatment of cerebral thromboembolism† (e.g., cerebral venous sinus thrombosis).
    Subcutaneous dosage
    Adults

    The ACCP guidelines recommend treatment with LMWH during the acute phase, even in the presence of hemorrhagic infarction. Then, treat with a vitamin K antagonists for 3 to 6 months. A specific dose for dalteparin has not been suggested.

    Infants, Children, and Adolescents

    The ACCP guidelines recommend treatment with LMWH initially, followed by warfarin or continued treatment with LMWH for 3 months, even if a localized hemorrhagic infarct is present. In neonates, only treat if there is no large ischemic infarct or an intracranial hemorrhage. A specific dose for dalteparin has not been suggested, although treatment doses of enoxaparin (i.e., 1 mg/kg subcutaenously every 12 hours for infants aged 2 months or older or 1.5 mg/kg subcutaneously every 12 hours for infants younger than 2 months) have been used successfully.

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

    5,000 International Units subcutaneously once daily antepartum with aspirin. Maintain anti-Xa concentration of 0.2 to 0.6 International Units/mL.

    In pregnant women with congenital thrombophilic defects and recurrent miscarriages, a miscarriage during or after the second trimester, severe or recurrent preeclampsia, or abruption.
    Subcutaneous dosage
    Adult females

    5,000 International Units subcutaneously once daily plus antepartum, low-dose aspirin therapy is recommended. Maintain anti-Xa concentration of 0.2 to 0.6 International Units/mL. Give anticoagulants postpartum.

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

    200 International Units/kg/dose subcutaneously once daily or 100 International Units/kg/dose subcutaneously every 12 hours is recommended. In general, twice daily dosing of LMWH is preferred as the half-life of LMWH is decreased in pregnant patients. Resume long-term oral anticoagulation therapy postpartum.

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

    5,000 International Units subcutaneously once daily is recommended. Low-dose aspirin may be used in combination with dalteparin. Maintain anti-Xa concentration of 0.2 to 0.6 International Units/mL.

    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 International Units subcutaneously once daily may be sufficient. 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
    Adults

    100 International Units/kg/dose subcutaneously twice daily or 200 International Units/kg/dose subcutaneously once daily. Alternatively, 5,000 International Units subcutaneously once daily (low-dose prophylactic regimen) has been used. Stop warfarin approximately 5 days prior to procedure and initiate LMWH 24 hours or more after the first missed dose of warfarin. Guidelines recommend starting LMWH 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. Administer the last dose of LMWH approximately 24 hours before procedure, potentially longer in those with renal dysfunction. If necessary, residual anticoagulation can be assessed by checking anti-Xa concentrations. 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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Dalteparin has a narrow therapeutic index, specific for the patient population and indication. The maximum dosage is individualized based on anti-Xa concentrations and assessment of efficacy and safety parameters.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No specific dosage guidelines are available; however, it appears no dosage adjustments are required in patients with hepatic impairment.

    Renal Impairment

    CrCl less than 30 mL/minute: FDA-approved labeling recommends monitoring anti-Xa concentrations to determine the appropriate dose in adult cancer patients with severely impaired renal function. Some experts recommend switching to an alternative anticoagulant with lower renal clearance.

    ADMINISTRATION

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Subcutaneous Administration

    Injection
    If using a FIXED-DOSE prefilled syringe, to ensure the administration of the proper dose, DO NOT expel the air bubble prior to injecting the dose.
    If using a GRADUATED SYRINGE assembly, hold the syringe assembly by the open sides of the device. Remove the needle shield. With the needle pointing up, prepare the syringe by expelling the air bubble and then continuing to push the plunger to the desired dose or volume, discarding the extra solution in an appropriate manner.
    Patients should be sitting or lying down and dalteparin should be administered by deep subcutaneous injection. Dalteparin may be injected in a U-shape area around the navel, the upper outer side of the thigh or the upper outer quadrangle of the buttock. When the area around the navel or the thigh is used, using the thumb and forefinger, lift up a fold of skin while giving the injection. The entire length of the needle should be inserted at a 45 to 90 degree angle.
    The injection site should be rotated daily.
     
    Preparation and stability of dalteparin 2,500 International Units/mL dilution†
    NOTE: The cited stability study did not test microbiologic properties, and the diluted dalteparin was removed from the glass vial and stored in tuberculin syringes.
    Prepare in a sterile environment, using aseptic technique.
    Combine 0.5 mL dalteparin 25,000 International Units/mL and 4.5 mL preservative-free 0.9% Sodium Chloride for Injection in a sterile glass vial and mix well.
    Storage: The dilution may be stored for up to 4 weeks in capped tuberculin syringes under refrigeration (4 degrees C) without significant loss of anti-Xa activity.

    STORAGE

    Fragmin:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Heparin hypersensitivity, porcine protein hypersensitivity

    Dalteparin is contraindicated in patients with porcine protein hypersensitivity, dalteparin hypersensitivity, or heparin hypersensitivity.

    Heparin-induced thrombocytopenia (HIT), thrombocytopenia

    Dalteparin is contraindicated in patients with a history of heparin-induced thrombocytopenia (HIT) or heparin-induced thrombocytopenia with thrombosis (HITT). Closely monitor for thrombocytopenia of any degree. Although low molecular weight heparins are less likely to trigger formation of HIT antibodies than unfractionated heparin (UFH), LMWHs are just as effective as UFH at triggering platelet activation by HIT antibodies (i.e., LMWHs have essentially 100% in vitro cross-reactivity).

    Anticoagulant therapy, renal disease, renal failure, renal impairment

    The manufacturer advises caution for the use of dalteparin in patients with severe renal disease or renal impairment. Patients with renal disease have a higher risk of hemorrhage during anticoagulant therapy. Dalteparin is eliminated renally; the half-life is prolonged to about 5.7 hours in renal failure patients receiving hemodialysis. Monitor anti-factor Xa serum concentrations to guide dosage adjustment in patients with cancer and a CrCl < 30 mL/minute who are receiving dalteparin for the extended treatment of acute, symptomatic venous thromboembolism; monitoring of anti-factor Xa serum concentrations in other patients with renal impairment may be advisable.

    Bleeding, coagulopathy, diabetic retinopathy, endocarditis, epidural anesthesia, GI bleeding, hemophilia, hepatic disease, hypertension, lumbar puncture, peptic ulcer disease, scoliosis, spinal anesthesia, stroke, surgery

    Dalteparin is contraindicated in patients with active major bleeding. Use dalteparin with extreme caution in patients who have an increased risk of hemorrhage, including those with severe uncontrolled hypertension, bacterial endocarditis, congenital or acquired coagulopathy, such as hemophilia, active peptic ulcer disease, angiodysplastic GI disease, hemorrhagic stroke, or those with recent brain, spinal, or ophthalmological surgery. Dalteparin may increase the risk of bleeding in patients with platelet defects, severe renal or hepatic disease, hypertensive or diabetic retinopathy, and recent GI bleeding. Do not use dalteparin as treatment for unstable angina and non-Q-wave myocardial infarct or for prolonged venous thromboembolism prophylaxis in patients undergoing spinal anesthesia or epidural anesthesia. Spinal or epidural hemorrhage and subsequent hematomas can occur with the use of LMWH and neuraxial (spinal/epidural) anesthesia or spinal puncture. Risk is higher with the use of postoperative indwelling catheters, the concomitant use of additional drugs affecting hemostasis (e.g., NSAIDs, platelet inhibitors, other anticoagulants), with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity (e.g., scoliosis). Placement or removal of an epidural catheter or lumbar puncture is best performed when dalteparin's anticoagulant effect is low; however, optimal timing between administration of dalteparin and neuraxial procedures is not known. For patients receiving preoperative thromboprophylaxis, the first postoperative thromboprophylaxis dose should be given 6 to 8 hours postoperatively. Give the second postoperative dose not sooner than 24 hours after the first dose. Delay catheter placement or removal for at least 12 hours after administration of 2,500 International Units once daily, at least 15 hours after administration of 5,000 International Units once daily, and at least 24 hours after administration of higher doses (200 International Units/kg once daily or 120 International Units/kg twice daily). These delays are not a guarantee that neuraxial hematoma will be avoided. Although a specific recommendation for timing of a subsequent dalteparin dose after catheter removal cannot be made, consider delaying this next dose for at least 4 hours. For those with a CrCl less than 30 mL/minute, consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed doses (2,500 or 5,000 International Units/day) and at least 48 hours for the higher doses (200 International Units/kg once daily or 120 International Units/kg twice daily). If it is decided to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor the patient frequently for signs and symptoms of neurological impairment (e.g., midline back pain, sensory and motor deficits, bowel or bladder dysfunction). If spinal hematoma is suspected, initiate urgent diagnosis and treatment.

    Intramuscular injections

    Intramuscular injections should not be administered to patients receiving dalteparin. IM injections may cause bleeding, bruising, or hematoma formation in patients who are anticoagulated.

    Geriatric

    No overall differences in efficacy have been identified between older and younger patients during clinical trials of dalteparin. Geriatric patients generally have a higher risk of bleeding associated with anticoagulants. Post-marketing experience has not revealed any differences in the safety profile of dalteparin in elderly patients. The manufacturer advises careful attention to the dosing interval of dalteparin, and concomitant medications (e.g., platelet inhibitors) in elderly patients, especially patients with low body weight (< 45 kg) and/or reduced renal function.

    Prosthetic heart valves

    LMWHs, such as dalteparin, have not been adequately studied for thromboprophylaxis in patients with prosthetic heart valves, including pregnant women, and have not been adequately studied for long-term use in this patient population. Isolated cases of prosthetic heart valve thrombosis have been reported in patients with mechanical prosthetic heart valves who have received LMWHs for thromboprophylaxis. Some of these cases were pregnant women in whom thrombosis led to maternal and fetal deaths. Insufficient data, the underlying disease, and the possibility of inadequate anticoagulation complicate the evaluation of these cases. Regardless, the ACCP recommends the use of LMWHs for thromboprophylaxis in patients with prosthetic heart valves after prosthetic valve insertion or when vitamin K antagonists must be discontinued.

    Infants, neonates

    Whenever possible, administer benzyl alcohol-free formulations (prefilled syringes) of dalteparin in pediatric patients. Serious and fatal adverse reactions including "gasping syndrome" can occur in neonates and low-birth-weight infants treated with medications that contain benzyl alcohol as a preservative. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When prescribing dalteparin in infants, consider the combined daily dose of benzyl alcohol from all sources; multidose vials of dalteparin contain benzyl alcohol (14 mg/mL) as a preservative.

    Thrombolytic therapy

    Dalteparin should be used with caution in patients receiving other anticoagulant therapy (e.g., warfarin), thrombolytic therapy (e.g., alteplase, reteplase, streptokinase), and/or platelet inhibitors (e.g., aspirin, ticlopidine) due to the potential increased risk of bleeding.

    Dental disease, dental work

    Patients who are anticoagulated with dalteparin are at increased the risk of bleeding during dental procedures. Patient should inform health care providers of anticoagulant therapy prior to having dental work performed. Patients, especially those with dental disease, should be instructed in proper oral hygiene, including caution in use of regular toothbrushes, dental floss, and toothpicks.

    Pregnancy

    Use dalteparin during pregnancy only if clearly needed. If anticoagulation is needed during pregnancy, use preservative-free formulations; the multidose vial of dalteparin contains benzyl alcohol. Data from published literature and postmarketing reports have not reported a clear association between dalteparin and adverse developmental outcomes. In animal reproduction studies, there was no evidence of teratogenicity or embryo-fetal toxicity when dalteparin was administered at doses 2 to 4 times the human dose of 100 International Units/kg based on body surface area. Women with a history of venous thromboembolism in pregnancy are at a higher risk for recurrence during subsequent pregnancies than those with no risk factors. Low molecular heparin (LMWH) requirements may change as pregnancy progresses due to LMWH volume of distribution alterations and glomerular filtration rate increases in the second trimester.

    Breast-feeding

    Limited data indicate dalteparin is present in human milk. Small amounts of anti-Xa activity in breast milk were detected in 11 of 15 lactating women receiving prophylactic doses of dalteparin immediately postpartum. This study evaluated colostrum or transitional milk from a single time point during the 24-hour dosing interval; therefore, the clinical relevance of this data is unclear in regards to passage of dalteparin into mature milk and the quantification of drug exposure to the infant over the full dosing period. No adverse effects on breast-fed infants have been reported. There are no data on the effects of dalteparin on milk production. Oral absorption of dalteparin is expected to be low; however, the clinical implications of this small amount of anticoagulant activity on breast-fed infants are not known. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for dalteparin and any adverse effects on the breast-fed infant from dalteparin or the underlying maternal condition.

    ADVERSE REACTIONS

    Severe

    GI bleeding / Delayed / 0.3-0.3
    spinal hematoma / Delayed / Incidence not known
    intracranial bleeding / Delayed / Incidence not known
    retroperitoneal bleeding / Delayed / Incidence not known
    skin necrosis / Early / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    thrombosis / Delayed / Incidence not known
    disseminated intravascular coagulation (DIC) / Delayed / Incidence not known

    Moderate

    bleeding / Early / 0-13.6
    thrombocytopenia / Delayed / 0-13.6
    elevated hepatic enzymes / Delayed / 4.2-9.5
    hematoma / Early / 0-7.1
    subdural hematoma / Early / Incidence not known
    hematuria / Delayed / Incidence not known
    bullous rash / Early / Incidence not known
    osteoporosis / Delayed / Incidence not known

    Mild

    rash / Early / Incidence not known
    injection site reaction / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    maculopapular rash / Early / Incidence not known
    fever / Early / Incidence not known
    alopecia / Delayed / Incidence not known

    DRUG INTERACTIONS

    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.
    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.
    Alteplase: (Moderate) An additive risk of bleeding may be seen in patients receiving dalteparin in combination with other agents known to increase the risk of bleeding such thrombolytic agents. Monitor clinical and laboratory response closely during concurrent use.
    Altretamine: (Moderate) Due to the thrombocytopenic effects of altretamine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    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.
    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 low molecular weight heparins (LMWHs) concomitantly. The anticoagulant effect of LMWHs 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 LMWH 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.
    Antithymocyte Globulin: (Moderate) Drugs that can cause thrombocytopenia, such as antithymocyte globulin, may lead to an increased risk of bleeding when given concurrently with anticoagulants.
    Apixaban: (Major) Monitor patients closely and promptly evaluate any signs or symptoms of bleeding if apixaban and other anticoagulants are used concomitantly. If switching from apixaban to another anticoagulant, discontinue apixaban and start the other anticoagulant at the usual time of the next dose of apixaban. If switching from another anticoagulant to apixaban, discontinue the other anticoagulant and start apixaban at the usual time of the next dose of the other anticoagulant. Coadministration of apixaban and other anticoagulants may increase the risk of bleeding.
    Argatroban: (Major) An additive risk of bleeding may be seen in patients receiving dalteparin in combination with other anticoagulants. If coadministration of 2 or more anticoagulants is necessary, patients should be closely monitored for evidence of bleeding.
    Arsenic Trioxide: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    Aspirin, ASA; 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.
    Betrixaban: (Major) Avoid concurrent use of betrixaban with dalteparin 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.
    Bivalirudin: (Major) An additive risk of bleeding may be seen in patients receiving dalteparin in combination with other anticoagulants. If coadministration of 2 or more anticoagulants is necessary, patients should be closely monitored for evidence of bleeding.
    Caplacizumab: (Moderate) Assess and monitor closely for bleeding with concomitant use of caplacizumab and anticoagulants. Concomitant use of caplacizumab with any anticoagulant may increase the risk of bleeding. Interrupt caplacizumab use if clinically significant bleeding occurs.
    Carbenicillin: (Moderate) Some penicillins (e.g., carbenicillin) can inhibit platelet aggregation, which may increase the risk of bleeding with any anticoagulants. Clinically important bleeding of this type 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.
    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.
    Chlorambucil: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Cilostazol: (Moderate) The safety of cilostazol has not been established with concomitant administration of anticoagulants. Because cilostazol is a platelet aggregation inhibitor, concomitant administration with similar acting drugs could theoretically result in an increased risk of bleeding due to additive pharmacodynamic effects, and combinations of these agents should be approached with caution. Patients on anticoagulants should be monitored for changes in response to anticoagulation therapy if cilostazol is administered concurrently.
    Clofarabine: (Moderate) Due to the thrombocytopenic effects of clofarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Clopidogrel: (Moderate) Because clopidogrel inhibits platelet aggregation, a potential additive risk for bleeding exists if clopidogrel is given in combination with other agents that affect hemostasis such as anticoagulants.
    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.
    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) Based on the pharmacology of dabigatran, other oral anticoagulants and thrombolytic agents could cause additive risk of bleeding when given concurrently with dabigatran.
    Danaparoid: (Severe) An additive risk of bleeding may be seen in patients receiving other anticoagulants (e.g., heparin, warfarin) in combination with danaparoid. Monitoring of anticoagulant therapy by prothrombin time and Thrombotest is unreliable within 5 hours after danaparoid administration.
    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.
    Decitabine: (Moderate) Due to the thrombocytopenic effects of antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    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: (Severe) 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.
    Denileukin Diftitox: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Desirudin: (Moderate) Any agent which may enhance the risk of hemorrhage should generally be discontinued before initiating desirudin therapy, including anticoagulants. If coadministration cannot be avoided, close clinical and laboratory monitoring should be conducted.
    Dextran: (Moderate) Because of the potential effects of certain dextran formulations on bleeding time, use with caution in patients on anticoagulants concurrently.
    Diclofenac: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diclofenac; Misoprostol: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diflunisal: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diphenhydramine; Ibuprofen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Diphenhydramine; Naproxen: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Dipyridamole: (Moderate) Because dipyridamole is a platelet inhibitor, there is a potential additive risk for bleeding if dipyridamole is given in combination with other agents that affect hemostasis.
    Drotrecogin Alfa: (Major) Treatment with drotrecogin alfa should be carefully considered in patients who are receiving or have received any anticoagulants. There is an additive risk of beeding.
    Edoxaban: (Major) Avoid concurrent use of edoxaban with low molecular weight heparins 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 other anticoagulants in combination with enoxaparin. Monitor clinical and laboratory response closely when enoxaparin is coadministered with drugs known to increase the risk 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.
    Esomeprazole; 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.
    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.
    Estramustine: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    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.
    Famotidine; 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.
    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.
    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.
    Floxuridine: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Fluorouracil, 5-FU: (Major) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    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.
    Folate analogs: (Moderate) Due to the thrombocytopenic effects of folate analogs, when used as antineoplastic agents, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Fondaparinux: (Major) Discontinue dalteparin 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: (Major) Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants. Ginkgo, Ginkgo biloba is reported to inhibit platelet aggregation and several case reports describe bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Since ginkgo produces clinically-significant antiplatelet effects, it should be used cautiously in patients drugs that inhibit platelet aggregation or pose a risk for bleeding, such as anticoagulants (e.g., warfarin), aspirin, ASA or other platelet inhibitors, or thrombolytic agents. A patient who had been taking aspirin 325 mg/day PO for 3 years following coronary-artery bypass surgery, developed spontaneous bleeding into his eye after taking a standardized extract of Ginkgo biloba (Ginkoba commercial product) 40 mg PO twice daily for one week. The patient stopped taking the ginkgo but continued taking the aspirin with no recurrence of bleeding over a 3-month period. Other clinical data exist that describe spontaneous subdural hematomas associated with chronic ginkgo biloba ingestion.
    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.
    Heparin: (Major) An additive risk of bleeding may be seen in patients receiving other anticoagulants (e.g., heparin) in combination with dalteparin.
    Hydrochlorothiazide, HCTZ; Spironolactone: (Moderate) Coadministration of spironolactone with heparin or low-molecular weight heparins (LMWHs) increases the risk of developing severe hyperkalemia, especially in the presence of renal impairment (renal disease, elderly patients). Use together with caution and monitor serum potassium concentrations.
    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.
    Hydroxyurea: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents and anticoagulants concomitantly.
    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 dalteparin 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; 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.
    Imatinib: (Major) Due to the thrombocytopenic effects of imatinib an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants. Monitor closely for bleeding.
    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.
    Interferon Alfa-2a: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-2b: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-2b; Ribavirin: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfacon-1: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Interferon Alfa-n3: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    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.
    Lansoprazole; 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.
    Lepirudin: (Major) An additive risk of bleeding may be seen in patients receiving dalteparin in combination with other anticoagulants. If coadministration of 2 or more anticoagulants is necessary, patients should be closely monitored for evidence of bleeding.
    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.
    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.
    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: (Major) When mifepristone is used for the termination of pregnancy, concurrent use of anticoagulants is contraindicated due to the increased risk of serious bleeding. Consider an alternative to mifepristone in these circumstances. When mifepristone is used chronically for other conditions, such as Cushing's disease, an interaction with low-molecular weight heparins is not expected; however, follow usual cautions and monitor as per standard of care.
    Miltefosine: (Moderate) Caution is advised when administering miltefosine with anticoagulants, as use of these drugs together may increase risk for bleeding. Miltefosine, when administered for the treatment of visceral leishmaniasis, has been associated with thrombocytopenia; monitor platelet counts in patients receiving treatment for this indication. In addition, monitor closely for increased bleeding if use in combination with an anticoagulant.
    Mycophenolate: (Moderate) Mycophenolate may causes thrombocytopenia and increase the risk for bleeding. Agents which may lead to an increased incidence of bleeding in patients with thrombocytopenia include anticoagulants.
    Nabumetone: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Nandrolone Decanoate: (Moderate) Androgens can enhance the effects of anticoagulants. Dosage of the anticoagulant may have to be decreased in order to maintain prothrombin time at the desired therapeutic level. When anabolic steroid or androgen therapy is started or stopped in patients on anticoagulant therapy, close monitoring is required. Additionally, nandrolone decanoate may generate a pharmacodynamic interaction with warfarin by independently affecting the activity of circulating coagulation proteins. Androgens reduce the amount or activity of circulating coagulant proteins thereby enhancing the anticoagulant effect of warfarin.
    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; 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.
    Naproxen; Sumatriptan: (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.
    Natural Antineoplastics: (Moderate) Due to the risk of bleeding with natural antineoplastics, patients should receive other agents that may increase the risk of bleeding, such as anticoagulants.
    Nelarabine: (Moderate) Due to the thrombocytopenic effects of nelarabine, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    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.
    Nonsteroidal antiinflammatory drugs: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Obinutuzumab: (Moderate) Fatal hemorrhagic events have been reported in patients treated with obinutuzumab; all events occured during cycle 1. Monitor all patients for thrombocytopenia and bleeding, and consider withholding concomitant medications which may increase bleeding risk (i.e., anticoagulants, platelet inhibitors), especially during the first cycle.
    Omacetaxine: (Major) Avoid the concomitant use of omacetaxine and anticoagulants when the platelet count is less than 50,000 cells/microliter due to an increased risk of bleeding.
    Orlistat: (Moderate) Patients on chronic stable doses of anticoagulants, like dalteparin, should be monitored closely for changes in coagulation parameters when orlistat is prescribed. Reports of decreased prothrombin, increased INR, and unbalanced anticoagulant treatment resulting in change of hemostatic parameters have been reported in patients treated concomitantly with orlistat and anticoagulants.
    Oxandrolone: (Moderate) An increased effect of anticoagulants may occur with oxandrolone; the anticoagulant dosage may need adjustment downward with oxandrolone initiation or adjustment upward with oxandrolone discontinuation to maintain the desired clinical effect. Oxandrolone suppresses clotting factors II, V, VII, and X, which results in an increased prothrombin time. An increase in plasminogen-activator activity, and serum concentrations of plasminogen, protein C, and antithrombin III have occurred with several 17-alpha-alkylated androgens. For example, concurrent use of oxandrolone and warfarin may result in unexpectedly large increases in the INR or prothrombin time (PT). A multidose study of oxandrolone (5 or 10 mg PO twice daily) in 15 healthy individuals concurrently treated with warfarin resulted in significant increases in warfarin half-life and AUC; a 5.5-fold decrease in the mean warfarin dosage from 6.13 mg/day to 1.13 mg/day (approximately 80 to 85% dose reduction) was necessary to maintain a target INR of 1.5. According to the manufacturer, if oxandrolone therapy is initiated in a patient already receiving warfarin, the dose of warfarin may need to be decreased significantly to reduce the potential for excessive INR elevations and associated risk of serious bleeding events. The patient should be closely monitored with frequent evaluation of the INR and clinical parameter, and the dosage of warfarin should be adjusted as necessary until a stable target INR is achieved. Careful monitoring of the INR and necessary adjustment of the warfarin dosage are also recommended when the androgen therapy is changed or discontinued.
    Oxaprozin: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    Palifermin: (Moderate) The co-administration of palifermin and unfractionated heparin may result in a 4 to 5-fold increase in palifermin exposure; however, this interaction does not appear to affect the pharmacodynamics of either drug. If heparin is used to maintain an IV line, rinse the line with saline prior to and after palifermin administration. The palifermin AUC value was increased by 5-fold and the mean clearance was decreased by 80% after a single 60 mcg/kg dose of palifermin was administered with therapeutic levels of unfractionated heparin compared with no heparin in 27 healthy subjects. The activated partial thromboplastin time (aPTT) was not affected by this interaction. The palifermin AUC value was increased by 425% and the palifermin clearance, volume of distribution, and half-life was decreased by 76.5%, 73.1%, and 38.8%, respectively, following the administration of palifermin 40 mcg/kg/day for 3 days in combination with therapeutic levels of unfractionated heparin compared with no heparin in 31 healthy subjects. Palifermin administration results in a dose-dependent epithelial cell proliferation that may be assessed by Ki67 immunohistochemical staining. In this study, the pharmacokinetics of palifermin did not affect Ki67 expression in buccal biopsies. The co-administration of palifermin and low-molecular weight heparins (LMWHs), such as enoxaparin and dalteparin, is expected to have a similar interaction.
    Pentosan: (Major) Pentosan is a weak anticoagulant. Pentosan has 1/15 the anticoagulant activity of heparin. An additive risk of bleeding may be seen in patients receiving other anticoagulants in combination with pentosan.
    Phentermine; Topiramate: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    Piperacillin: (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.
    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.
    Reteplase, r-PA: (Moderate) An additive risk of bleeding may be seen in patients receiving dalteparin in combination with other agents known to increase the risk of bleeding such thrombolytic agents. Monitor clinical and laboratory response closely during concurrent use.
    Rivaroxaban: (Major) Due to the increased bleeding risk, avoid concurrent use of rivaroxaban with dalteparin; the safety of concomitant use has not been studied. If dalteparin is used during therapeutic transition periods, closely observe patients and promptly evaluate any signs or symptoms of blood loss.
    Rofecoxib: (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.
    Salicylates: (Moderate) An additive risk of bleeding may be seen in patients receiving a low molecular weight heparin in combination with other agents known to increase the risk of bleeding such as salicylates. Monitor clinical and laboratory response closely during concurrent use.
    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 low molecular weight heparins. 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 dalteparin. Case reports and epidemiological studies have demonstrated an association between use of drugs that interfere with serotonin reuptake and gastrointestinal bleeding.
    Sodium Hyaluronate, Hyaluronic Acid: (Moderate) Increased bruising or bleeding at the injection site may occur when using hyaluronate sodium with anticoagulants, including low-molecular weight heparins (LMWHs), especially if used within the 3 weeks prior to the procedure.
    Sodium Iodide: (Moderate) Anticoagulants may alter sodium iodide I-131 pharmacokinetics and dynamics for up to 1 week after administrations.
    Spironolactone: (Moderate) Coadministration of spironolactone with heparin or low-molecular weight heparins (LMWHs) increases the risk of developing severe hyperkalemia, especially in the presence of renal impairment (renal disease, elderly patients). Use together with caution and monitor serum potassium concentrations.
    Streptokinase: (Moderate) An additive risk of bleeding may be seen in patients receiving dalteparin in combination with other agents known to increase the risk of bleeding such thrombolytic agents. Monitor clinical and laboratory response closely during concurrent use.
    Sulfinpyrazone: (Major) Sulfinpyrazone should be avoided when possible with concurrent anticoagulants, thrombin inhibitors, and thrombolytic agents due to potential for increased bleeding risk. Alternative uricosuric agents may be considered. Sulfinpyrazone is a platelet inhibitor and exhibits antithrombotic actions in addition to its uricosuric effects. Additive hematological effects are possible as a result of the platelet inhibitory effects of sulfinpyrazone; the sulfide metabolite of sulfinpyrazone appears responsible for this effect. Sulfinpyrazone is also known to markedly potentiate the effect of warfarin. Sulfinpyrazone may inhibit CYP2C9, leading to a decrease in the clearance of S-warfarin. If concurrent therapy is warranted, significant initial dosage reductions (e.g., 50%) of warfarin may be necessary, with further dosage adjusted based on INR values. The INR should be closely monitored during concurrent therapy with warfarin, particularly during the initiation or termination phases of sulfinpyrazone treatment.
    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.
    Telavancin: (Moderate) Telavancin has no effect on coagulation or platelet aggregation; however, caution is advised when administering telavancin concurrently with anticoagulants as telavancin may interfere with laboratory tests used in monitoring these medications. The coagulation tests affected by telavancin include prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), activated clotting time, and coagulation based factor Xa tests. When measured shortly after completion of a telavancin infusion, the results of these tests are increased; however, the effects of telavancin on these tests dissipate over time as plasma concentrations of telavancin decrease. Therefore, when administering telavancin in conjunction with anticoagulants ensure that blood samples for these coagulation tests are collected as close as possible to the patient's next telavancin dose.
    Tenecteplase: (Moderate) An additive risk of bleeding may be seen in patients receiving dalteparin in combination with other agents known to increase the risk of bleeding such thrombolytic agents. Monitor clinical and laboratory response closely during concurrent use.
    Thrombolytic Agents: (Moderate) An additive risk of bleeding may be seen in patients receiving dalteparin in combination with other agents known to increase the risk of bleeding such thrombolytic agents. Monitor clinical and laboratory response closely during concurrent use.
    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 warfarin, heparin, or low-molecular weight heparins (LMWHs). 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.
    Ticarcillin: (Moderate) Some penicillins (e.g., ticarcillin) 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.
    Ticarcillin; Clavulanic Acid: (Moderate) Some penicillins (e.g., ticarcillin) 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.
    Ticlopidine: (Moderate) Because ticlopidine inhibits platelet aggregation, a potential additive risk for bleeding exists if ticlopidine is given in combination with other agents that affect hemostasis such as anticoagulants. Per the manufacturer of ticlopidine, if a patient is switched from an anticoagulant or a thrombolytic agent to ticlopidine, the former drug should be discontinued prior to the administration of ticlopidine.
    Tinzaparin: (Major) An additive risk of bleeding may be seen in patients receiving other anticoagulants in combination with dalteparin.
    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, may be associated with an increased risk of bleeding.
    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.
    Topiramate: (Moderate) Concurrent use of topiramate and anticoagulants (e.g., warfarin, enoxaparin, dabigatran) may increase the risk of bleeding. In a pooled analysis of placebo-controlled trials, bleeding was more frequently reported in patients receiving topiramate (4.5%) compared to placebo (2-3%). In those with severe bleeding events, patients were often taking drugs that cause thrombocytopenia or affect platelet function or coagulation.
    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.
    Tretinoin, ATRA: (Moderate) An additive risk of bleeding may be seen in thrombocytopenic patients receiving antineoplastic agents in combination with anticoagulants.
    Urokinase: (Moderate) An additive risk of bleeding may be seen in patients receiving dalteparin in combination with other agents known to increase the risk of bleeding such thrombolytic agents. Monitor clinical and laboratory response closely during concurrent use.
    Valdecoxib: (Moderate) An additive risk of bleeding may be seen in patients receiving anticoagulants in combination with other agents known to increase the risk of bleeding such as nonsteroidal antiinflammatory drugs (NSAIDs). Monitor clinical and laboratory response closely during concurrent use.
    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.
    Vorinostat: (Moderate) Concomitant use of vorinostat with anticoagulants may result in an additive risk of bleeding due to vorinostat-induced thrombocytopenia; monitor patients closely.
    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 (e.g., heparin, warfarin) in combination with dalteparin.

    PREGNANCY AND LACTATION

    Pregnancy

    Use dalteparin during pregnancy only if clearly needed. If anticoagulation is needed during pregnancy, use preservative-free formulations; the multidose vial of dalteparin contains benzyl alcohol. Data from published literature and postmarketing reports have not reported a clear association between dalteparin and adverse developmental outcomes. In animal reproduction studies, there was no evidence of teratogenicity or embryo-fetal toxicity when dalteparin was administered at doses 2 to 4 times the human dose of 100 International Units/kg based on body surface area. Women with a history of venous thromboembolism in pregnancy are at a higher risk for recurrence during subsequent pregnancies than those with no risk factors. Low molecular heparin (LMWH) requirements may change as pregnancy progresses due to LMWH volume of distribution alterations and glomerular filtration rate increases in the second trimester.

    Limited data indicate dalteparin is present in human milk. Small amounts of anti-Xa activity in breast milk were detected in 11 of 15 lactating women receiving prophylactic doses of dalteparin immediately postpartum. This study evaluated colostrum or transitional milk from a single time point during the 24-hour dosing interval; therefore, the clinical relevance of this data is unclear in regards to passage of dalteparin into mature milk and the quantification of drug exposure to the infant over the full dosing period. No adverse effects on breast-fed infants have been reported. There are no data on the effects of dalteparin on milk production. Oral absorption of dalteparin is expected to be low; however, the clinical implications of this small amount of anticoagulant activity on breast-fed infants are not known. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for dalteparin and any adverse effects on the breast-fed infant from dalteparin or the underlying maternal condition.

    MECHANISM OF ACTION

    Dalteparin exerts its antithrombotic activity by binding to and accelerating the activity of antithrombin III (AT III). The interaction with antithrombin is mediated by a unique pentasaccharide sequence distributed along the heparin chains. Only 15% to 25% of the chains of dalteparin contain this pentasaccharide sequence, compared with about one-third of the chains of unfractionated heparin (UFH). By activating antithrombin, coagulation factor Xa and factor IIa (thrombin) are inhibited. Dalteparin and other LMWHs are more selective inhibitors of factor Xa than UFH. Although any pentasaccharide chain can inhibit factor Xa, only those at least 18 saccharide units long can inactivate thrombin, since a long chain is required to form a ternary complex between heparin, antithrombin, and thrombin. Although most of the chains of UFH are at least 18 saccharide units long, less than 50% of those of dalteparin and other LMWHs are of adequate length to bind both antithrombin and thrombin (factor IIa). Therefore, the anti-factor Xa:antifactor IIa inhibitory ratio of dalteparin is 2.7:1, compared to 1:1 for UFH. Ultimately, thrombin inhibition prevents the formation of fibrin clots. At recommended doses, dalteparin does not significantly affect platelet activity, prothrombin time (PT), or activated partial thromboplastin time (aPTT).

    PHARMACOKINETICS

    Dalteparin is administered subcutaneously. Vd for dalteparin anti-Xa activity is 40 to 60 mL/kg. The primary route of elimination for dalteparin appears to be renal and is dose-independent, unlike heparin, which has several saturable mechanisms of elimination. Plasma elimination half-life of dalteparin based on factor Xa activity is approximately 3 to 5 hours.
     
    Affected cytochrome P450 isoenzymes and drugs transporters: none

    Subcutaneous Route

    The absolute bioavailability of dalteparin is about 87% after subcutaneous administration. A mean Cmax of 0.19, 0.41, and 0.82 International Units/mL, respectively, after single subcutaneous doses of 2,500, 5,000, and 10,000 International Units were attained in about 4 hours during pharmacokinetic trials. Increasing the dose from 2,500 to 10,000 International Units resulted in an overall increase in anti-Xa AUC that was greater than proportional by about one-third.