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LOW MOLECULAR WEIGHT HEPARINS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Low molecular weight heparins (LMWH) are fragments of heparin with anticoagulant activity and are isolated from standard heparin by gel filtration chromatography or differential precipitation with ethanol.

Specific Substances

    A) DALTEPARIN
    1) Dalteparin sodium
    2) Dalteparina
    3) Dalteparinnatrium
    4) Dalteparino
    5) Dalteparinum
    6) Kabi-2165
    7) Tedelparin sodium
    8) CAS 9041-08-1
    DANAPAROID
    1) Danaparoid sodium
    2) Danaparoide
    3) Danaparoidum
    4) Lomoparan
    5) Org-10172
    6) CAS 83513-48-8
    ENOXAPARIN
    1) Enoxaparin sodium
    2) Enoxaparina
    3) Enoxaparinnatrium
    4) Enoxaparinum
    5) PK-10169
    6) RP-54563
    7) CAS 9005-49-6
    NADROPARIN
    1) Nadroparin calcium
    2) CY-216
    PARNAPARIN
    1) Parnaparin sodium
    2) OP-21-23
    3) CAS 91449-79-5
    TINZAPARIN
    1) Tinzaparin sodium
    2) Tinzaparina
    3) Tinzaparine
    4) Tinzaparinnatrium
    5) Tinzaparino
    6) Tinzaparinum
    7) CAS 9041-08-1

Available Forms Sources

    A) FORMS
    1) Dalteparin is available in the United States as single-dose prefilled syringes (2,500 International Units (IU)/0.2 mL, 5000 IU/0.2 mL, 7500 IU/0.3 mL, 10,000 IU/0.4 mL, 12,500 IU/0.5 mL, 15,000 IU/0.6 mL, 18,000 IU/0.72 mL), single-dose graduated syringes (10,000 IU/1 mL), and multiple dose vials (95,000 IU/9.5 mL, 95,000/3.8 mL) (Prod Info FRAGMIN(R) subcutaneous injection, 2010).
    2) Enoxaparin is available in the United States as prefilled syringes (30 mg/0.3 mL, 40 mg/0.4 mL), graduated prefilled syringes (60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/1 mL), multiple-dose vials (300 mg/3 mL), and graduated prefilled syringes (120 mg/0.8 mL, 150 mg/1 mL) (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    3) Tinzaparin is available in the United States as multiple dose 2 mL vials (20,000 Anti-Xa International Units/mL) (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    4) Danaparoid was withdrawn from the United States market in 2002, but it remains approved and available for treatment and prevention of heparin-induced thrombocytopenia with thrombosis in Canada, Europe, New Zealand, Australia, Japan, and Israel (Warkentin et al, 2008).
    5) Ardeparin, nadroparin, and parnaparin are not available in the United States.
    B) USES
    1) Dalteparin is used for the following indications: extended treatment of symptomatic venous thromboembolism (VTE), including proximal deep vein thrombosis and pulmonary embolism, to reduce the recurrence of VTE in cancer patients; prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction; prophylaxis of deep venous thrombosis in patients undergoing total hip arthroplasty or abdominal surgery, or in patients at risk for thromboembolism due to severely restricted mobility during acute illness (Prod Info FRAGMIN(R) subcutaneous injection, 2010).
    2) Enoxaparin is used for the following indications: prophylaxis of deep venous thrombosis (DVT) in abdominal surgery, hip replacement surgery, or medical patients with severely restricted mobility during acute illness; treatment of acute DVT with or without pulmonary embolism; prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction; treatment of acute ST-segment elevation myocardial infarction managed medically or with subsequent percutaneous coronary intervention (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009)
    3) Tinzaparin is used for the following indications: treatment of acute symptomatic deep vein thrombosis (DVT) with or without pulmonary embolism when administered with warfarin (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Low molecular weight heparins (LMWHs) (dalteparin, enoxaparin, and tinzaparin) are anticoagulant agents commonly used for prophylaxis and treatment of DVT and pulmonary embolism. Dalteparin and enoxaparin may also be used for the prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction (MI), in patients at risk for thromboembolism due to severely restricted mobility during acute illness, and in patients undergoing treatment of acute ST-segment elevation MI.
    B) PHARMACOLOGY: LMWHs are anticoagulant agents with anti-Factor Xa and anti-thrombin (anti-Factor IIa) activities. They inhibit thrombin formation and thrombus development. They are prepared from unfractionated heparin by chemical or enzymatic depolymerization. LMWHs have lower molecular weight (range, 2000 to 9000; mean, 4000 to 5000) with reduced binding to proteins and cells. Overall, compared with heparin, LMWHs have lower anti-IIa activity relative to anti-Xa activity and a more predictable anticoagulant response. They are cleared through renal mechanism and have a greater bioavailability and longer plasma half-life. LMWHs are not clinically interchangeable, as LMWHs have different pharmacokinetic properties and anticoagulant profiles.
    C) TOXICOLOGY: Excessive anticoagulant effect can cause bleeding complications.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) The main complication of LMWH therapy is bleeding. The following adverse effects have also been reported: nausea, peripheral edema, pruritus, eczema-like plaques, rash, skin necrosis, pain and hematomas at the injection site, hyperkalemia and secondary hypoaldosteronism, anemia, increased liver enzymes, acute allergic reaction, fever, and fever. Heparin-induced thrombocytopenia (HIT) may develop in patients receiving LMWHs, but the frequency of HIT is 3-fold lower with LMWHs than with heparin.
    F) WITH POISONING/EXPOSURE
    1) TOXICITY: Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. The main complication of overdose is bleeding. Patients may experience epistaxis, hematuria, tarry stool, easy bruising, or petechial formation, followed by frank bleeding.
    0.2.3) VITAL SIGNS
    A) WITH THERAPEUTIC USE
    1) Fever has been reported in patients receiving dalteparin.
    0.2.20) REPRODUCTIVE
    A) Dalteparin, enoxaparin, and tinzaparin are classified as FDA pregnancy category B. Although heparin and low-molecular-weight heparins (LMWHs) do not cross the placenta and are currently the anticoagulants of choice for pregnant patients at risk or requiring treatment for venous thrombosis, maternal and neonatal hemorrhage may occur. Manufacturer product labeling for enoxaparin reports both teratogenic and nonteratogenic effects in pregnant women, although such effects have not been clearly attributed to enoxaparin. The manufacturers recommend the use of LMWHs during pregnancy only if clearly needed.
    0.2.21) CARCINOGENICITY
    A) At the time of this review, the manufacturers do not report any carcinogenic potential for dalteparin, enoxaparin, or tinzaparin in humans.

Laboratory Monitoring

    A) Monitor for evidence of bleeding (eg, venous access sites, urinary, gastrointestinal, vaginal).
    B) Monitor CBC with platelet count, vital signs, and hepatic enzymes in symptomatic patients.
    C) Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are not sensitive measures of activity at therapeutic doses of LMWH, and routine coagulation monitoring is not required. However, aPTT and standard anti-Xa monitoring may be useful to follow the degree of anti-IIA and anti-Xa neutralization by protamine in patients with severe bleeding.
    D) Monitor for signs and symptoms of heparin-induced thrombocytopenia and thrombosis (HITT), including deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, or gangrene of the extremities.

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor for clinical evidence of bleeding.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat patients with severe bleeding with protamine sulfate. Blood transfusions or plasma may be indicated in addition to protamine sulfate. In patients with strongly suspected or confirmed heparin-induced thrombocytopenia (HIT), with or without thrombosis, discontinue LMWH agent and start an alternative, nonheparin anticoagulant (lepirudin, argatroban). An anaphylactoid or anaphylactic reaction may require aggressive airway management and support.
    C) DECONTAMINATION
    1) Decontamination is not indicated; LMWHs are only available parenterally.
    D) AIRWAY MANAGEMENT
    1) Assess airway; endotracheal intubation may be required in patients with intracranial bleeding, severe hemoptysis, or acute allergic reaction.
    E) ANTIDOTE
    1) PROTAMINE: Following an inadvertent LMWH exposure, protamine is indicated to treat severe cases of hemorrhage. Protamine is able to partially neutralize the anticoagulant activity, but some residual anti factor Xa activity will remain. Approximately 60% (maximum) of anti-factor Xa is completely neutralized with protamine administration. The following doses are suggested for severe bleeding or large overdoses of selected LMWH(s): ADULTS: DALTEPARIN AND TINZAPARIN: Administer 1 mg protamine for every 100 anti-Xa International Units of dalteparin or tinzaparin given; administer protamine by slow IV injection. A second infusion of 0.5 mg protamine per 100 anti-Xa International Units of dalteparin or tinzaparin may be necessary if the aPTT concentration remains prolonged 2 to 4 hours after the first infusion. ENOXAPARIN: Administer protamine by slow IV injection (1% solution) to equal the dose of enoxaparin injected: 1 mg protamine to neutralize 1 mg enoxaparin, if enoxaparin was given within the past 8 hours. An infusion of 0.5 mg protamine per 1 mg of enoxaparin may be given if it has been greater than 8 hours since the initial dose of protamine or it is necessary to give a second dose of protamine. If it has been 12 hours or greater since the last dose of enoxaparin, protamine may NOT be necessary. PEDIATRICS: The safety and effectiveness of protamine sulfate has not been established in pediatric patients.
    F) HEPARIN-INDUCED THROMBOCYTOPENIA
    1) In patients with strongly suspected or confirmed heparin-induced thrombocytopenia (HIT), with or without thrombosis, discontinue LMWH therapy and start an alternative, nonheparin anticoagulant (lepirudin, argatroban). LEPIRUDIN: ADULTS: 0.4 mg/kg (maximum 44 mg) IV bolus, at a concentration of 5 mg/mL, is administered slowly (eg, over 15 to 20 seconds) followed by a continuous infusion of lepirudin at a rate of 0.15 mg/kg/hr (maximum initial infusion dose of 16.5 mg/hr) for 2 to 10 days or longer if clinically needed. According to the American College of Chest Physicians (ACCP) guidelines, the initial lepirudin IV infusion should not exceed 0.1 mg/kg/hour (mg/kg/hr). Initial bolus dose is recommended either to be omitted or, in case of perceived life- or limb-threatening thrombosis, be given at 0.2 mg/kg. ARGATROBAN: The recommended initial dose is 2 mcg/kg/min administered as a continuous infusion. Dose can be adjusted as clinically indicated, not exceeding 10 mcg/kg/min, until the steady-state aPTT is 1.5 to 3 times the initial baseline value (not to exceed an aPTT of 100 seconds). CHILDREN: initial, 0.75 mcg/kg/min continuous IV infusion; adjust in increments of 0.1 to 0.25 mcg/kg/min to achieve aPTT of 1.5 to 3 times the initial baseline value (not to exceed 100 seconds). In the absence of any prospective comparative clinical trials, the choice between lepirudin and argatroban usually is based on their different elimination mechanisms. Lepirudin is cleared by the kidneys, so it is preferred in patients with liver disease. Argatroban is cleared by the liver, so it is preferred in patients with renal insufficiency. Other agents such as bivalirudin, danaparoid (not available in the United States), and fondaparinux have also been used in patients with HIT.
    G) ACUTE ALLERGIC REACTION
    1) MILD to MODERATE effects: Monitor airway. Administer antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE Effects: Administer oxygen, aggressive airway management may be necessary. Administer antihistamines, epinephrine, corticosteroids as needed. Treatment includes IV fluids and ECG monitoring.
    H) ENHANCED ELIMINATION
    1) Hemodialysis and hemoperfusion are UNLIKELY to be of value because of the large volume of distribution of LMWHs.
    I) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: All patients with LMWH overdose should be evaluated and monitored until symptoms resolve. Patients can be discharged when laboratory values are stable with no evidence of bleeding.
    2) ADMISSION CRITERIA: Patients with severe symptoms (eg, anaphylaxis, hemorrhage) should be admitted to an intensive care setting.
    J) PITFALLS
    1) When managing a suspected LMWH overdose, the possibility of multi-drug involvement should be considered.
    K) PHARMACOKINETICS
    1) DALTEPARIN: Tmax, subQ: approximately 4 hours. Bioavailability: measured as anti-Factor Xa activity, 87 +/- 6%. Vd: 40 to 60 mL/kg. Elimination half-life: 3 to 5 hours. ENOXAPARIN: Tmax, subQ: 3 to 5 hours. Vd: 4.3 L. Metabolized in the liver by desulfation and/or depolymerization. Excretion of enoxaparin is 40% in the kidneys with 10% unchanged. Elimination half-life: 3 to 6 hours; 7 hours with repeated dosing. TINZAPARIN: Tmax, subQ: 4.4 to 4.6 hours. Bioavailability: 86.7%. Vd: 3.1 to 5 L. Elimination half-life: approximately 3 to 4 hours based on anti-Xa activity.
    L) DIFFERENTIAL DIAGNOSIS
    1) Bleeding diathesis: Disseminated intravascular coagulation, Vitamin K deficiency, rattlesnake envenomation, congenital bleeding disorders (hemophilia, von Willebrand’s disease), or coumadin overdose. Thrombocytopenia: Caused by other drugs, vitamin B12 or folic acid deficiency, hereditary syndromes, leukemia. Thromboembolic events: Includes other agents (e.g. oral contraceptives) or disorders such as a history of deep vein thrombosis, superficial thrombophlebitis, trauma, soft tissue injury, immobility, or cellulitis.

Range Of Toxicity

    A) TOXICITY: Varies with agent. A minimum toxic dose has not been established. DALTEPARIN: A 39-year-old woman experienced only ecchymosis at the injection site after injecting herself 360,000 Units of dalteparin subQ (approximately 4000 Units/kg). A 40-year-old man presented on 5 different occasions with massive, self-induced overdoses of dalteparin (range, 72,000 to 720,000 International Units). There were no bleeding complications in 3 of the 5 episodes. Mild to moderate bleeding developed in 2 episodes. ENOXAPARIN: A 34-year-old woman injected herself with 1600 mg of enoxaparin (20 syringes of 80 mg) and developed retroperitoneal bleeding requiring transfusion. She recovered following supportive therapy, including protamine and rFVIIa therapies. A neonate received 40 mg of enoxaparin instead of 4 mg, and was treated successfully with protamine.
    B) THERAPEUTIC DOSES: DALTEPARIN: ADULTS: Varies by indication; up to 200 international units/kg subQ every 24 hours; total daily dose should not exceed 18,000 international units. ENOXAPARIN: Varies by indication; the following dosing has been used for myocardial infarction: Initially, single IV bolus dose of 30 mg plus 1 mg/kg subQ; maintenance, 1 mg/kg subQ every 12 hours for minimum of 8 days; MAXIMUM DOSE: 100 mg for the first 2 doses only. TINZAPARIN: 175 anti-Xa international units/kg subQ once daily for 6 days; 100 international units antifactor Xa activity is equivalent to 1 mg. CHILDREN: Safety and efficacy have not been established in pediatric patients.

Clinical Effects

Summary Of Exposure

    A) USES: Low molecular weight heparins (LMWHs) (dalteparin, enoxaparin, and tinzaparin) are anticoagulant agents commonly used for prophylaxis and treatment of DVT and pulmonary embolism. Dalteparin and enoxaparin may also be used for the prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction (MI), in patients at risk for thromboembolism due to severely restricted mobility during acute illness, and in patients undergoing treatment of acute ST-segment elevation MI.
    B) PHARMACOLOGY: LMWHs are anticoagulant agents with anti-Factor Xa and anti-thrombin (anti-Factor IIa) activities. They inhibit thrombin formation and thrombus development. They are prepared from unfractionated heparin by chemical or enzymatic depolymerization. LMWHs have lower molecular weight (range, 2000 to 9000; mean, 4000 to 5000) with reduced binding to proteins and cells. Overall, compared with heparin, LMWHs have lower anti-IIa activity relative to anti-Xa activity and a more predictable anticoagulant response. They are cleared through renal mechanism and have a greater bioavailability and longer plasma half-life. LMWHs are not clinically interchangeable, as LMWHs have different pharmacokinetic properties and anticoagulant profiles.
    C) TOXICOLOGY: Excessive anticoagulant effect can cause bleeding complications.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH THERAPEUTIC USE
    1) The main complication of LMWH therapy is bleeding. The following adverse effects have also been reported: nausea, peripheral edema, pruritus, eczema-like plaques, rash, skin necrosis, pain and hematomas at the injection site, hyperkalemia and secondary hypoaldosteronism, anemia, increased liver enzymes, acute allergic reaction, fever, and fever. Heparin-induced thrombocytopenia (HIT) may develop in patients receiving LMWHs, but the frequency of HIT is 3-fold lower with LMWHs than with heparin.
    F) WITH POISONING/EXPOSURE
    1) TOXICITY: Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. The main complication of overdose is bleeding. Patients may experience epistaxis, hematuria, tarry stool, easy bruising, or petechial formation, followed by frank bleeding.

Vital Signs

    3.3.1) SUMMARY
    A) WITH THERAPEUTIC USE
    1) Fever has been reported in patients receiving dalteparin.
    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) FEVER
    a) ENOXAPARIN: Fever was reported in 8% of patients (n=288) receiving enoxaparin 40 mg subQ once daily during the perioperative period (initiated up to 12 hours before knee or hip replacement surgery) (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) ENOXAPARIN: Peripheral edema was reported in 6% of patients (n=288) receiving enoxaparin 40 mg subQ once daily during the perioperative period (initiated up to 12 hours before knee or hip replacement surgery) (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) ENOXAPARIN: Nausea was reported in 3% of patients who received enoxaparin 30 mg subQ every 12 hours (n=1080) compared with 2% of patients who received heparin 15,000 units/day subQ (n=766) and 2% of patients who received placebo (n=115) (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) INCREASED LIVER ENZYMES
    1) WITH THERAPEUTIC USE
    a) ENOXAPARIN
    1) In clinical trials, asymptomatic elevations of liver enzymes (AST and ALT) greater than 3 times the upper limit of normal developed in up to 6.1% and 5.9% of enoxaparin-treated patients, respectively. These increases were reversible and rarely associated with increases in bilirubin (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    2) Elevated serum liver enzyme concentrations were reported in 2 patients 4 to 5 days after beginning low-molecular weight heparin therapy (enoxaparin and nadroparin). A liver biopsy in one patient showed ballooning degeneration with scattered foci of spotty necrosis. The serum liver enzyme concentrations of both patients gradually normalized following discontinuation of LMWH therapy (Hui et al, 2001).
    b) TINZAPARIN
    1) In clinical trials, asymptomatic elevations of liver enzymes (AST and ALT) greater than 3 times the upper limit of normal developed in up to 8.8% and 13% of tinzaparin-treated patients, respectively. These increases were reversible and rarely associated with increases in bilirubin (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    2) Reversible elevations of liver enzymes have also been reported in surgical patients receiving tinzaparin prophylaxis (Christiansen et al, 1991; Christiansen et al, 1991a; Friedel & Balfour, 1994).
    3) In one study involving patients undergoing total hip replacement, alkaline phosphatase and AST values were above normal in 17% and 35% of patients (n=103), respectively, during administration of tinzaparin 50 anti-Xa international units/kg once daily. In the placebo group (n=100), rises in alkaline phosphatase were seen in 6% of patients, with increases in AST occurring in 13% (Christiansen et al, 1991).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) ANEMIA
    1) WITH THERAPEUTIC USE
    a) ENOXAPARIN: Anemia was reported in 16% of patients (n=288) receiving enoxaparin 40 mg subQ once daily during the perioperative period (initiated up to 12 hours before knee or hip replacement surgery) (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    B) BLEEDING
    1) WITH THERAPEUTIC USE
    a) DALTEPARIN
    1) In clinical trials, bleeding developed in 4.6% of patients receiving dalteparin 5000 IU once daily. Patients treated with dalteparin 2500 International Units (IU) per day following abdominal surgery experienced a lower incidence of bleeding events compared with those treated with heparin 5000 units twice a day. However, more patients who received dalteparin 5000 IU daily needed postoperative transfusions (dalteparin, 15.9% of patients compared with heparin 12.7%), experienced wound hematoma (dalteparin, 2.4%; heparin 1.2%), and required reoperation due to bleeding (dalteparin, 0.8%; heparin 0.4%). However, there were more injection site hematomas (9.5% compared with 7.1%) in the heparin-treated group than in the dalteparin group (Prod Info FRAGMIN(R) subcutaneous injection, 2010).
    2) CASE REPORT: Fetal subdural hemorrhage occurred in association with maternal exposure to dalteparin 200 international units/kg/day (beginning in week 12 of gestation) for the treatment of DVT. At 30 weeks of gestation, the 47-year-old primipara woman experienced vaginal bleeding and contractions and received treatment with steroids for fetal lung maturation. Due to decidual bleeding and a pathological fetal cardiotocogram, cesarean delivery was performed at 32 weeks gestation. Bilateral subdural calcified hematomas were found on postnatal CT scan, which corresponded to the high-echodensity lesions detected on prenatal fetal cranial ultrasound. The preterm male had anemia at birth (hematocrit 35%), but no signs of infection and the placenta was normal. The coagulation profile revealed abnormal INR, fibrinogen concentration, factor XIII and platelet count. Due to persistent subdural bleeding, the neonate received packed-red-blood cell transfusions daily and repeated fresh frozen plasma and factor XIII concentrate. On day 6, a subdural drain was placed in the right-side convexity hematoma and was removed 2 days later. Between days 5 to 12, platelet counts, INR, fibrinogen and factor XIII values normalized. Maternal trauma during pregnancy, evidence of intrauterine infection, hepatic disease or cerebral vascular formation were ruled out as possible causes, and family studies excluded a congenital factor XIII deficiency. By age of 10 weeks, no further subdural hemorrhage was observed and the boy was discharged with left-sided hemiparesis and predominantly right-sided sensorineural hearing loss (Bauder et al, 2009).
    b) ENOXAPARIN
    1) In clinical trials, hemorrhage was reported in up to 13% of patients (n=1228) receiving enoxaparin 40 mg/day subQ (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    2) A 34-year-old woman (heterozygous for the factor V Leiden mutation) who was using enoxaparin (1 mg/kg [80 mg] every 12 hours) injected herself with 1600 mg of enoxaparin (20 syringes of 80 mg). An initial laboratory result revealed an antifactor Xa activity concentration of 8.3 International Units/mL (therapeutic range: 0.5 to 1.1 IU/mL for twice daily dosing, 1 to 2 IU/mL for once daily dosing), partial thromboplastin time (PTT) of 98 s (23 to 38 s), hemoglobin of 12.6 g/dL (12 to 16 g/dL), and hematocrit of 38.1% (35% to 45%). She didn't have any clinical evidence of bleeding. Six hours after admission, her PTT increased to 169 s. At this time, a drop in her hematocrit (28.8%) was noted and she received 2 units of packed red blood cells about 15 hours after admission and 2 additional units of transfusion 3 hours later. A CT scan of the abdomen and pelvis revealed bilateral retroperitoneal hematomas. Because of active bleeding, she received protamine sulfate 50 mg IV 25 hours after admission and 3 doses of rFVIIa (45 mcg/kg) at 24, 26, and 28 hours after admission. Following further supportive care, she gradually recovered by day 5 (Byrne & Zumberg, 2012).
    3) Bleeding events were more common in patients older than 75 years, irrespective of renal function, when treated with enoxaparin compared with unfractionated heparin (UFH) for acute myocardial infarction (13 vs 8; p=0.007) in a retrospective study. Among 113 patients (52.2% male) older than 75 years, 36 subjects received enoxaparin 1 mg/kg every 12 hours while the remaining patients received UFH 1000 international units/hour for at least 5 days. Among patients who also had severe renal insufficiency (creatinine clearance less than 30 mL/min; n=11), 3 bleeding events occurred in the enoxaparin group compared with 1 event in the UFH group (p=0.024). Regardless of the presence of severe renal insufficiency or type of therapy, 352 patients from other age groups (66 to 75 years or 65 years and younger) did not experience an increased bleeding risk with enoxaparin (Despotovic et al, 2007).
    4) Spinal epidural hematoma has been associated with the combination of epidural anesthesia and the use of heparin or low-molecular weight heparin (enoxaparin) (Dickman et al, 1990; Hynson et al, 1996).
    5) Major bleeding complications occurred at a rate of 69% (9 of 13) in kidney (n=10) and kidney/pancreas (n=3) transplant patients who received enoxaparin and aspirin within 10 days of transplantation. Dosing of subQ enoxaparin was 1 mg/kg (70 mg) twice daily (n=2) or 30 mg twice daily (n=11). All received aspirin 81 mg once daily. Immunosuppressant agents were tacrolimus, mycophenolate mofetil, and prednisone. Six patients received enoxaparin within 1 day of transplantation and the bleeding event occurred within the first 6 days of receipt of enoxaparin. Six of 9 patients with major bleeding events had elevated serum creatinine concentrations. Bleeding complications required blood transfusions in 9 patients and re-exploratory surgery in 6 patients. Subsequent to the study, the authors discontinued giving enoxaparin with aspirin to their renal transplant patients (Shullo et al, 2002).
    6) CASE REPORT: COMPARTMENT SYNDROME: A 62-year-old man with a past medical history consisting of diabetes, hypertension, and recent DVT of the left leg, presented with left thigh swelling and pain. The patient claimed the pain began shortly after injecting insulin into his left thigh. He had also been receiving enoxaparin injections for 3 months. Ultrasound revealed a collection of fluid, and needle aspiration resulted in removal of 300 mL of blood from the thigh. This resulted in pain relief and softening of the thigh tissue, although the pocket of fluid reaccumulated within 1 hour. CT scan showed a left thigh hematoma with active extravasation. Angiogram was performed, showing active bleeding from the left profunda artery in multiple sites. The artery was embolized, and the patient received an anterolateral fasciotomy for compartment syndrome. The authors believe this patient had several known risk factors for LMWH-induced spontaneous bleeds, including advanced age and renal impairment (CrCl = 64 mL/min), which contributed to the thigh hematoma formation (Limberg et al, 2008).
    c) TINZAPARIN
    1) In clinical trials, major bleeding developed in 0.8% of patients (n=519) receiving tinzaparin and 2.7% of patients (n=524) receiving heparin for the treatment of acute DVT with or without pulmonary embolism (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    2) In surgical patients receiving thromboembolism prophylaxis with subQ tinzaparin, the overall incidence of bleeding complications has been similar to that observed with subQ unfractionated heparin and dextran 70, but greater than with warfarin. The incidence of severe bleeding with tinzaparin in these trials ranged from 2.8% to 4% (Friedel & Balfour, 1994; Hull et al, 1993; Liezorovicz et al, 1991).
    2) WITH POISONING/EXPOSURE
    a) Hemorrhagic complications may occur following accidental overdose. Patients may experience epistaxis, hematuria, tarry stool, easy bruising, or petechial formation, followed by frank bleeding (Prod Info FRAGMIN(R) subcutaneous injection, 2010; Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009; Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    b) DALTEPARIN: CASE REPORT: A 40-year-old man with a history of a deep venous thrombosis and an episode of pulmonary embolism presented on 5 different occasions with massive, self-induced overdoses of dalteparin (dose range, 72,000 to 720,000 International Units) within 2 years. There were no bleeding complications in 3 of the 5 episodes. In episode 3 (dalteparin dose, 450,000 to 540,000 International Units), he developed large subcutaneous hematomas on the scalp and torso caused by a fall before admission, gingival bleeding, and a self-reported hematemesis. He had only mild bleeding after episode 5 (dalteparin dose, 720,000 International Units). Laboratory results revealed aPTT peaks ranging from 51 to greater than 300 seconds. Duration of aPTT abnormality ranged from greater than 16 hours to greater than 40 hours. He received protamine (bolus range, 50 to 200 mg; continuous infusion of 10 mg/hr, total of 200 mg after episode 2 and 360 mg after episode 3) after 4 of the 5 episodes. Tranexamic acid was administered in 3 occasions. He recovered following supportive care after each episode (Odeberg et al, 2012).
    c) TINZAPARIN
    1) In clinical trials, a bleeding complication developed in approximately 16% of patients known to have received an overdose (described as one or more doses greater than 200 International Units (IU)/kg for the treatment of DVT or greater than 100 IU/kg for the prevention of DVT) (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    2) CASE REPORT: A 33-year-old woman, who was using tinzaparin for recurrent pulmonary emboli, presented with multiple self-inflicted lacerations in her antecubital fossa and left forearm after drinking ethanol, smoking marijuana, and using a large amount of tinzaparin in a suicide attempt. Laboratory results revealed an initial hemoglobin of 148 g/L, PTT greater than 200 seconds, serum ethanol of 53 mmol/L, and urine drug screen of abuse positive for cannabis metabolite. Her lacerations were sutured and about 5 hours after receiving protamine 25 mg IV, her PTT was 116 seconds. A day after presentation, her bleeding was well controlled, and laboratory results revealed a hemoglobin of 99 g/L and a PTT of 40 seconds (Haws & Chuang, 2015).
    C) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) LMWHs typically produce less thrombocytopenia than unfractionated heparin when given for prophylaxis (Weitz, 1997a).
    b) Heparin-induced thrombocytopenia (HIT) is an acquired hypercoagulability syndrome caused by the antibody-mediated adverse effect of heparin, characterized by thrombocytopenia and a high risk for venous or arterial thrombosis (Warkentin et al, 2008). It occurs in 2 distinctive types, HIT type I and HIT type II. Type I HIT is a minor decrease in platelet count attributed to the direct interaction between heparin and circulating platelets (Brieger et al, 1998). Type II HIT is a syndrome of antibody-mediated thrombocytopenia associated with thrombosis, and is the less common but more clinically severe form (Menajovsky, 2005).
    1) Type II HIT occurs in 1% to 3% of patients exposed to unfractionated heparin (UFH) and in 0% to 0.8% of those receiving LMWHs (Menajovsky, 2005).
    c) HIT, unlike other acquired hypercoagulation syndromes (eg, antiphospholipid antibody syndrome), is transient. The platelet counts return to normal levels within days or weeks, and the detectable pathogenic HIT antibodies disappear within a few weeks or months. Among patients with isolated HIT who are managed by simple discontinuation of heparin, the risk of symptomatic thrombosis is between 25% and 50%, including an overall fatal thrombosis risk of about 5% (Warkentin et al, 2008).
    d) DALTEPARIN
    1) In clinical trials, platelet counts less than 100,000/mm(3) occurred in 13.6% of patients with cancer and acute symptomatic venous thromboembolism treated for up to 6 months with dalteparin. This includes 6.5% of patients who also had platelet counts less than 50,000/mm(3). Thrombocytopenia was reported in 10.9% of patients in the dalteparin arm and in 8.1% of patients in the oral anticoagulant arm in the same clinical trial (Prod Info FRAGMIN(R) subcutaneous injection, 2010).
    2) In vitro studies using serum of patients with heparin-associated thrombocytopenia (HAT) have demonstrated cross-reactivity (platelet activation) with dalteparin (Greinacher et al, 1992).
    e) ENOXAPARIN
    1) In clinical trials, moderate thrombocytopenia (platelet count between 50,000 to 100,000 per mm(3)) developed in 1.3% of patients receiving enoxaparin, 1.2% of patients receiving heparin, and 0.7% of patients in the placebo group. Thrombocytopenia with platelet counts less than 50,000 per mm(3) developed in 0.1% of patients in the enoxaparin group, 0.2% of patients in heparin group, and 0.4% of patients in the placebo group (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    2) In postmarketing surveillance, thrombocytopenia with thrombosis has been reported with enoxaparin therapy (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    3) Heparin-induced thrombocytopenia (HIT) was reported in 9 of 332 patients (2.7%) who received unfractionated heparin 7500 units subQ 2 times daily and in none of 333 patients who received enoxaparin 30 mg subQ 2 times daily (p=0.0018) for prevention of thrombosis after elective hip surgery. HIT was defined as a platelet count below 150,000 mm(3) after 5 days of treatment plus a positive test for heparin-dependent IgG antibodies. HIT was found to be a risk factor for the development of venous thromboembolism. In a subgroup of 387 patients, heparin-dependent IgG antibodies were found in 7.8% of the patients receiving unfractionated heparin and 2.2% of those receiving enoxaparin (p=0.02) (Warkentin et al, 1995).
    f) TINZAPARIN
    1) In clinical trials, thrombocytopenia developed in 1% of patients receiving tinzaparin (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    2) In one study, thrombocytopenia (less than 15 x 10(9)/L) was observed in 2.8% of patients during tinzaparin treatment of established DVT (Friedel & Balfour, 1994).
    3) Organ infarction with secondary organ dysfunction or limb ischemia, and death have been reported in some patients with thrombocytopenia with disseminated thrombosis (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    D) THROMBOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) ENOXAPARIN: A 67-year-old woman developed a rise in her platelet count after 4 weeks of enoxaparin therapy to treat a bilateral pulmonary thrombus. Enoxaparin therapy was discontinued, and within 1 week, the patient's platelet count had nearly returned to baseline values (Rizzieri et al, 1996).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN FINDING
    1) WITH THERAPEUTIC USE
    a) DALTEPARIN
    1) Pruritus has rarely occurred with dalteparin (Prod Info FRAGMIN(R) subcutaneous injection, 2010; Suzuki et al, 1990; Ockelford et al, 1989).
    b) ENOXAPARIN
    1) Eczema-like plaques have been reported following enoxaparin administration in several cases. Discontinuation of enoxaparin and treatment with topical corticosteroids usually resolved the eruption (White et al, 2006; Valdes et al, 1998).
    2) CASE REPORT: Immediate itchy erythematous patches appeared on a 65-year-old woman after subQ injections of enoxaparin sodium on the abdominal wall. Biopsy of the lesions showed spongiotic dermatitis (suggesting a delayed hypersensitivity mechanism). Skin prick tests with commercial preparations of enoxaparin, nadroparin, and calcium heparin along with the European standard series yielded negative results, and again a month after the reaction. Patient refused a challenge test with another heparin (Cabanas et al, 1998).
    3) CASE REPORT: A 73-year-old woman developed pruritic, erythematous plaques at the sites of previous injections 13 days after beginning prophylactic enoxaparin therapy (40 mg subQ once daily). The authors concluded that the plaques represented a delayed hypersensitivity skin reaction to enoxaparin. She recovered after treatment with antihistamines and topical corticosteroids (Mendez et al, 1996).
    c) TINZAPARIN
    1) Bullous eruption, erythematous rash, maculopapular rash, and skin necrosis have been reported with tinzaparin therapy (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    B) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) DALTEPARIN
    1) In clinical trials, pain at the injection site was reported in 4.5% to 12% of patients treated with dalteparin 5000 international units (IU) once daily (Prod Info FRAGMIN(R) subcutaneous injection, 2010).
    2) Hematomas at the injection site have occurred in up to 35% of abdominal surgery patients receiving subQ dalteparin for thrombosis prophylaxis in various studies (Bergqvist et al, 1986; Sandset et al, 1990; Bergqvist et al, 1990).
    b) ENOXAPARIN
    1) Pain and local reactions at the injection site including nodules, inflammation, and oozing have been reported with enoxaparin therapy during postmarketing surveillance period (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    2) Among patients undergoing DVT treatment with or without pulmonary embolism, injection site hemorrhage was reported in 5% of patients who received enoxaparin 1.5 mg/kg/day subQ (n=298) and 3% of patients who received enoxaparin 1 mg/kg subQ every 12 hours (n=559) compared with less than 1% of patients who received heparin (n=544) (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    c) TINZAPARIN
    1) Injection-site hematoma is the most frequent adverse effect of subQ tinzaparin administration, and is reported in 16% of patients treated with tinzaparin (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    2) CASE REPORT: An extremely low birth weight neonate developed a large hematoma in the left thigh after receiving tinzaparin (275 International Units/kg/day SubQ) for 13 days through an indwelling catheter to treat a small atrial thrombus. Laboratory results revealed a hemoglobin level that had dropped from 14.6 g/dL to 10.7 g/dL within a few days. Following protamine (1 mg) therapy, the infant recovered completely (van Elteren et al, 2010).
    C) SKIN NECROSIS
    1) WITH THERAPEUTIC USE
    a) DALTEPARIN
    1) CASE REPORT: Skin necrosis developed in a 61-year-old woman with metastatic lung carcinoma receiving dalteparin for bilateral DVT and pulmonary emboli. The woman presented with fatigue, leg pain, dyspnea, and fever. Physical examination revealed hepatomegaly, lower leg swelling, and erythema. Bilateral DVT was confirmed via sonography. Laboratory results included elevated liver enzymes, white blood cell count 14.7 x 10(9) per liter (/L), and platelet count 160 x 10(9)/L. Chest tomography revealed an apical lung mass and bilateral pulmonary emboli. Liver biopsy confirmed the diagnosis of adenocarcinoma with lung primary. Unfractionated heparin was initiated during hospitalization and switched to dalteparin, 100 international units per kilogram (IU/kg) every 12 hours, upon discharge. The patient returned to the hospital 24 hours later with 3 necrotic skin lesions at the dalteparin injection sites. Dalteparin was stopped and lepirudin was initiated. Lab values were positive for heparin-induced thrombocytopenia antibody, reduced protein C, elevated anticardiolipin IgM antibody, and platelet count within normal limits. The patient's anticoagulation therapy continued with fondaparinux and later lepirudin. The patient experienced no additional skin or thrombotic complications (Moore et al, 2007).
    b) ENOXAPARIN
    1) In postmarketing surveillance, skin necrosis (occurring at either the injection site or distant from the injection site) has been reported with enoxaparin therapy (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    2) CASE REPORT: Cutaneous necrosis and fat necrosis occurred in a 79-year-old woman being treated with enoxaparin (20 mg/day subQ) for thrombosis prophylaxis following hip fracture. On day 12, the patient was febrile and had an area of inflammation across her lower abdomen. Despite 4 days of oral antibiotics, her abdomen and rash became increasingly uncomfortable. There was a tender indurated band of erythema and purple discoloration measuring approximately 50 x 15 cm across the central abdominal wall; the inflamed area surrounded small patches of devitalized skin. Enoxaparin was stopped, and intravenous antibiotics started. The patient underwent surgical debridement in which necrotic areas of skin and fat were excised. The excised tissue yielded Enterococcus gallinarum using enrichment culture. Intravenous amoxicillin was introduced, her abdominal wounds healed, and the patient was discharged on postoperative day 14 (Davies et al, 2001).
    3) CASE REPORT: A 43-year-old woman developed skin necrosis after receiving enoxaparin. She also had heparin-mediated antibodies and thrombocytopenia. The indurated, erythematous, necrotic lesion occurred at the site of enoxaparin injection. After switching the anticoagulation therapy to warfarin, the patient's platelet count returned to normal. Enoxaparin was given for thrombi in the left internal jugular, axillary, brachial, and basilic veins. Heparin had been previously given to the patient and was discontinued when thrombocytopenia developed (Tonn et al, 1997).
    c) TINZAPARIN
    1) Severe skin necrosis occurred in a 66-year-old woman after treatment with tinzaparin for suspected DVT. Tinzaparin 5000 international units (IU) was administered subQ into the periumbilical abdominal wall on 3 consecutive days. Four days after discharge, the patient developed painful areas of induration and erythema at the injection site and on her hips, buttocks, left thigh, and lower leg. Her platelet count fell to 149 x 10(9)/L, but clotting studies were normal. The dermal lesions enlarged to involve approximately 6% of total body surface area, then became necrotic. The patient recovered with surgical treatment, including debridement and skin grafts. Four years earlier, the patient had been treated uneventfully with IV unfractionated heparin for a possible pulmonary embolism (Drew et al, 1999).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) ENOXAPARIN
    1) In postmarketing surveillance, systemic allergic reactions, including pruritus, urticaria, and anaphylactic/anaphylactoid reactions, have been reported with enoxaparin therapy (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    b) TINZAPARIN
    1) Anaphylactic/anaphylactoid reaction may develop with tinzaparin therapy (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    B) LOCALIZED CUTANEOUS VASCULITIS
    1) WITH THERAPEUTIC USE
    a) ENOXAPARIN: In postmarketing surveillance, rare cases of hypersensitivity cutaneous vasculitis have been reported with enoxaparin therapy (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    C) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) ENOXAPARIN
    1) In postmarketing surveillance, systemic allergic reactions, including pruritus, urticaria, and anaphylactic/anaphylactoid reactions, have been reported with enoxaparin therapy (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    2) Widespread urticaria and angioedema were reported in association with the use of enoxaparin in one patient. These effects occurred 3 days after enoxaparin administration was initiated. Enoxaparin was continued for 3 more days with worsening effects, despite the use of antihistamines and prednisone. Rapid resolution of symptoms occurred after discontinuation of enoxaparin, and rechallenge was not attempted (Odeh & Oliven, 1992).

Reproductive

    3.20.1) SUMMARY
    A) Dalteparin, enoxaparin, and tinzaparin are classified as FDA pregnancy category B. Although heparin and low-molecular-weight heparins (LMWHs) do not cross the placenta and are currently the anticoagulants of choice for pregnant patients at risk or requiring treatment for venous thrombosis, maternal and neonatal hemorrhage may occur. Manufacturer product labeling for enoxaparin reports both teratogenic and nonteratogenic effects in pregnant women, although such effects have not been clearly attributed to enoxaparin. The manufacturers recommend the use of LMWHs during pregnancy only if clearly needed.
    3.20.2) TERATOGENICITY
    A) GASPING SYNDROME
    1) Serious and fatal adverse reactions, including gasping syndrome, may occur in neonates and low-birth weight infants who are exposed to medications containing the preservative, benzyl alcohol. CNS depression, metabolic acidosis, and gasping respirations are some of the manifestations of gasping syndrome. When large amounts of benzyl alcohol (99 to 404 mg/kg/day) were administered, premature infants experienced gasping syndrome and other adverse reactions, including gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. The minimum amount of benzyl alcohol at which serious adverse reactions, such as gasping syndrome, may occur is not known. Because benzyl alcohol may cross the placenta, in utero exposure to dalteparin sodium from multi-dose vials, which contain 14 mg benzyl alcohol per mL, may put the neonate at risk for gasping syndrome and other serious adverse reactions (Prod Info FRAGMIN(R) subcutaneous injection, 2016).
    B) LACK OF EFFECT
    1) DALTEPARIN
    a) Thromboprophylaxis with adjusted, therapeutic doses of dalteparin (12,500 to 15,000 International Units/24 hr) in pregnant women with mechanical heart valve prosthesis was not associated with fetal complications. In a retrospective case series, 12 women with mechanical heart valves receiving therapeutic doses of subcutaneous dalteparin were identified; 9 were started on therapeutic doses of dalteparin (12,500 to 15,000 International Units/24 hr) in weeks 5 to 7 of their pregnancies, 1 was started in week 9, and 2 women were initially started on sub-therapeutic doses for 20 (dalteparin 7500 International Units/24 hr) and 27 days (5000 International Units/24 hr) prior to increasing to therapeutic doses. Six women were administered aspirin concomitantly, including the 2 women started on sub-therapeutic doses of dalteparin. Dalteparin doses ranged from 10,000 to 20,000 International Units/24 hr with a median daily dose of 257 International Units (range, 211 to 328 International Units/kg/24 hr). Median peak anti-Xa activity during pregnancy ranged from 0.54 to 0.92 anti-Xa Units/mL. With the exception of one newborn diagnosed with patent ductus arteriosus, all 13 babies were healthy (Abildgaard et al, 2009).
    b) A 26-year-old woman was successfully treated for left iliac thrombosis and small pulmonary emboli with dalteparin 5000 anti-Xa Units subcutaneously daily beginning in week 18 of pregnancy. Anti-Xa activity in plasma did not exceed 0.3 Units/mL and the patient delivered a healthy female child (2.66 kg, 48 cm) via caesarean section in week 37. Testing done immediately post partum revealed an anti-Xa activity of 0.3 Units/mL in the mother's venous blood, with none detectable in the umbilical cord venous blood (Kelbel et al, 1994).
    2) ENOXAPARIN
    a) In a retrospective study of maternal enoxaparin use during pregnancy, there were 624 pregnancies that resulted in 693 live births. The rate at which major congenital anomalies in live births occurred (2.5%) was similar to background rates (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    b) In a review of 41 pregnancies, enoxaparin treatment was safe and effective. A total of 34 women were treated with enoxaparin for acute thromboembolic events, history of thromboembolic event, antiphospholipid syndrome, and active lupus disease. The majority of women received a single daily enoxaparin dose of 40 mg administered subcutaneously. No bleeding disorders occurred during therapy, despite continued therapy during surgical procedures including cesarean deliveries. Nine patients received epidural anesthesia with no noted complications (Dulitzki et al, 1996).
    3) TINZAPARIN
    a) In an international, multicenter, retrospective study, VTE treatment or prophylaxis with tinzaparin during pregnancy did not increase the risk of maternal or fetal hemorrhage or death compared with other low-molecular-weight heparins. In 1267 pregnancies (1120 women; 1303 fetuses), tinzaparin was administered at doses up to 23,100 international units/day for a median duration of 72 days (treatment) or 183 days (prophylaxis). Overall, 70.2% of the deliveries were vaginal and 29.8% were caesarean sections, with no hematomas reported among women who received neuraxial anaesthesia (39.3%). Maternal blood loss during delivery was reported at 500 mL or less (86.9%), greater than 500 to 1000 mL or less (11%), greater than 1000 to 1500 mL or less (0.9%), and greater than 1500 mL (1.1%). Six neonatal deaths were reported, 5 at less than 27 weeks and 1 Ebstein anomaly, although none were attributed to tinzaparin. There were no maternal deaths or neonatal hemorrhages reported. Any bleeding events attributed to tinzaparin were reported in 9.9% of patients, with 1.3% of the cases requiring medical intervention. Adverse events related to tinzaparin were similar to those found in studies of other low-molecular-weight heparins (Nelson-Piercy et al, 2011).
    b) In an open-label, prospective pregnancy dose finding study involving tinzaparin treatment in 54 women who were pregnant or were planning to become pregnant, results included 55 pregnancies with 50 live births and no neonatal adverse events related to the drug. The women were treated for either venous thromboembolism or thromboprophylaxis, at doses ranging from 50 to 175 anti-Xa International Units/kg per dose, with a duration of exposure of 3 to 463 days. Dosing was initiated as early as prior to conception and as late as 32 weeks gestation. Besides the 50 live births among the 55 pregnancy outcomes, there were 3 first trimester miscarriages and 2 intrauterine deaths (at weeks 17 and 30). Fetal distress was present in approximately 6% of the pregnancies (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009; Smith et al, 2004).
    C) ANIMAL STUDIES
    1) DALTEPARIN
    a) RATS, RABBITS: Reproductive studies with dalteparin sodium at IV doses 2 to 4 times the recommended human dose (RHD) in pregnant rats and 4 times the RHD in pregnant rabbits did not produce any evidence of fetal harm (Prod Info FRAGMIN(R) subcutaneous injection, 2016).
    2) ENOXAPARIN
    a) RATS, RABBITS: There was no evidence of teratogenicity when rats and rabbits were given subQ enoxaparin doses up to 15 times the recommended human dose with 2 mg/kg as the maximum recommended daily dose (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    3) TINZAPARIN
    a) RATS, RABBITS: No evidence of harm to the fetus was noted when rats and rabbits were given subQ tinzaparin doses up to 1800 and 1900 International Units/kg/day (about 2 times and about 4 times the maximum recommended human dose based on body surface area), respectively (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Dalteparin is classified as FDA pregnancy category B (Prod Info FRAGMIN(R) subcutaneous injection, 2016).
    2) Enoxaparin is classified as FDA pregnancy category B (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    3) Tinzaparin is classified as FDA pregnancy category B (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    4) Heparin and low-molecular-weight heparins (LMWHs) are currently the anticoagulants of choice for pregnant patients at risk or requiring treatment for venous thrombosis (Ginsberg et al, 2001); however, these agents should be used during pregnancy only if clearly needed (Prod Info ARIXTRA(R) subcutaneous injection, 2010; Prod Info INNOHEP(R) solution for subcutaneous injection, 2009; Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    5) In pregnant patients with mechanical heart valves, heparin or LMWH may inadequately prevent thromboembolism (Hung & Rahimtoola, 2003; Mahesh et al, 2002). For these pregnant women with mechanical heart valves, the recommendations of the American College of Chest Physicians clinical guidelines are as follows. If maternal thromboembolic complications and fetal risk are of equal concern, then the recommendation is to either use 1) adjusted-dose twice-daily low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) throughout pregnancy; or 2) adjusted-dose twice-daily LMWH or UFH until week 13, then substitute a vitamin K antagonist, such as warfarin, at that time, and re-initiate LMWH or UFH close to the time of delivery. If high maternal risk is of greater concern (eg, older-generation valve in the mitral position or a history of thromboembolism) and there are concerns about the efficacy and safety of LMWH or UFH, the recommendation is to administer a vitamin K antagonist, such as warfarin, throughout pregnancy, and replace with adjusted-dose twice-daily LMWH or UFH close to the time of delivery (Bates et al, 2008).
    B) BLEEDING COMPLICATIONS
    1) LOW MOLECULAR WEIGHT HEPARINS
    a) In a retrospective community-based study, bleeding complications during delivery in pregnant women treated with prophylactic low molecular-weight heparin (LMWH) (dalteparin 5000 International Units daily, n=33; enoxaparin 40 mg daily, n=1) were compared with 1697 non-heparin treated pregnant women. The results demonstrated that LMWH resulted in significantly more blood loss during delivery and more postpartum anemia. LMWH therapy was associated with significantly more mean loss of blood during delivery (473 mL) and a longer mean time of hospitalization (4.5 days) compared with the control group (365 mL and 2.8 days, respectively; p less than or equal to 0.02) (Lindqvist & Dahlback, 2000).
    2) DALTEPARIN
    a) CASE REPORT: Fetal subdural hemorrhage occurred in association with maternal exposure to dalteparin 200 international units/kg/day (beginning in week 12 of gestation) for the treatment of deep vein thrombosis. At 30 weeks of gestation, the 47-year-old primipara woman experienced vaginal bleeding and contractions and received treatment with steroids for fetal lung maturation. Due to decidual bleeding and a pathological fetal cardiotocogram, cesarean delivery was performed at 32 0/7 weeks gestation. Bilateral subdural calcified hematomas were found on postnatal CT scan, which corresponded to the high-echodensity lesions detected on prenatal fetal cranial ultrasound. The preterm male had anemia at birth (hematocrit 35%), but there were no signs of infection and the placenta was normal. The coagulation profile revealed abnormal INR, fibrinogen concentration, factor XIII and platelet count. Due to persistent subdural bleeding, the neonate received packed-red-blood cell transfusions daily and repeated fresh frozen plasma and concentrate of factor XIII. On day 6, a subdural drain was placed in the right-side convexity hematoma and was removed 2 days later. Between days 5 to 12, platelet counts, INR, fibrinogen and factor XIII values normalized. Maternal trauma during pregnancy, evidence of intrauterine infection, hepatic disease or cerebral vascular formation were ruled out as possible causes, and family studies excluded a congenital factor XIII deficiency. By age of 10 weeks, no further subdural hemorrhage was observed and the boy was discharged with left-sided hemiparesis and predominantly right-sided sensorineural hearing loss (Bauder et al, 2009).
    3) ENOXAPARIN
    a) In a retrospective study of maternal enoxaparin use during pregnancy, there were 624 pregnancies that resulted in 693 live births. In 63 women, there were 72 hemorrhagic events, 11 of which were serious. There were also 14 cases of neonatal hemorrhage (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    C) MISCARRIAGES
    1) ENOXAPARIN: In a study in which enoxaparin was used to treat 61 pregnant women (69 pregnancies), there were five miscarriages early in pregnancy, four fetal losses in the second trimester, and seven infants delivered preterm (Nelson-Piercy et al, 1997). The authors question whether these adverse outcomes were due to enoxaparin or to the antiphospholipid syndrome which necessitated treatment with the drug.
    2) DALTEPARIN: Dalteparin use during pregnancy resulted in no thrombotic events, 3 self-limited incidences of minor bleeding, 1 placental abruption, 3 miscarriages, and 1 intrauterine death in one small study. Eight of the women had previously experienced first trimester fetal losses, 7 had second trimester fetal deaths, and 2 had a history of stillbirths. Four of the 27 pregnancies did not result in a live birth. Subcutaneous dalteparin 5000 Units daily was begun at the time of a positive pregnancy test in 27 pregnancies among 25 non-obese women at a high risk for a thrombotic event. After 16 to 20 weeks, the dalteparin dose was increased to 5000 units twice daily. The drug was discontinued for labor, then restarted on the third postpartum day for 6 additional weeks unless warfarin was restarted. Two women who had cerebral antiphospholipid syndrome began dalteparin 5000 units twice daily during weeks 5 to 7 of gestation. Twenty-two patients were on concomitant low-dose (75 mg) aspirin therapy in this study. None of these women had anti-FXa levels monitored during drug administration. However, these patients were identified as regular attendees at a specialist thrombophilia clinic, which elevates the level of expertise in managing such pregnancies. The authors also emphasized the importance of appropriate intermediate twice-daily dosing (Hunt et al, 2003).
    D) THROMBOPROPHYLAXIS FAILURE
    1) There may be a higher risk for thromboembolism in pregnant women with mechanical prosthetic heart valves. There are postmarketing reports of both successful use and thromboprophylaxis failure in pregnant women with prosthetic heart valves who received enoxaparin; these latter events have resulted in maternal and fetal death or surgical interventions (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009; Mahesh et al, 2002a; Rowan et al, 2001).
    2) Based on published case reports and their own investigation, the likelihood of a thromboembolic event was estimated to be 1 event in 66 months of LMWH use; 1 event in 20 months of unfractionated heparin use; and 1 complication in 294 months of warfarin exposure. This latter study investigated the frequency of events and successful pregnancy outcome in women who either used LMWH throughout a pregnancy or to use LMWH in early and late pregnancy with warfarin use in the second trimester. Of 14 pregnancies, there were 9 live healthy births, 2 miscarriages and 1 medical termination in patients on enoxaparin; there were no reports of hemorrhagic complications, enoxaparin-induced thrombocytopenia or osteoporotic fractures (Rowan et al, 2001).
    E) LACK OF EFFECT
    1) DALTEPARIN
    a) Dalteparin did not cross the placenta when given subcutaneously in single doses of 5000 anti-Xa Units or less during the second or third trimester of pregnancy in one study (Forestier et al, 1992).
    2) LOW MOLECULAR WEIGHT HEPARIN
    a) In a case-control study, rates of bleeding complications, including postpartum hemorrhage (PPH) or RBC transfusions, were not increased in patients treated either prophylactically or therapeutically with low molecular weight heparin (n=49) compared with controls (controls to cases ratio, 2:1) matched for delivery route (cesarean vs vaginal). With the exception of 1 patient who received twice daily dalteparin for a prosthetic mitral valve, cases received twice daily enoxaparin and delivered a total of 55 infants. Prepregnancy obesity occurred in a higher number of cases than controls (odds ratio (OR), 3.91; 95% confidence interval (CI), 1.7 to 9.09). The rate of PPH (primary endpoint) was defined as an estimated blood loss (EBL) of more than 500 cm(3) for a vaginal delivery and more 1000 cm(3) for a cesarean delivery, or a return to the operating room for postpartum bleeding complications within 14 days of delivery. The rates of PPH were 11% (n=6/55) and 8.2% (n=9/110) for cases and controls, respectively (OR, 1.37; 95% CI, 0.16 to 11.5). Postpartum RBC transfusions occurred in 5.4% and 3.6% of cases and controls, respectively (OR, 1.5; 95% CI, 0.3 to 7.48). The EBL was similar between cases and controls for vaginal (296 vs 307 cm(3); p=0.62) or cesarean delivery (688 vs 765 cm(3); p=0.34). Notably, the study was not adequately powered to detect differences in either PPH or RBC transfusions. Cases were more likely to have a labor induction (45% vs 26%; p=0.01) and gestational age was lower in cases versus controls (37.4 vs 38.3 weeks; p=0.03). There were no fetal demises or complications from regional anesthesia in either group. Birth weights and length of neonatal hospital stay were similar between the cases and controls, rates of neonatal mortality were not statistically different between cases (3.6%) and controls (0.9%; p=0.26) (Kominiarek et al, 2007).
    3) TINZAPARIN
    a) Based on human data, tinzaparin does not cross the placenta and shows no evidence of fetotoxicity (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    b) In an open-label, prospective pregnancy dose-finding study involving tinzaparin treatment in 54 women who were pregnant or were planning to become pregnant, results included 55 pregnancies with 50 live births and no neonatal adverse events related to the drug. The women were treated for either venous thromboembolism or thromboprophylaxis, at doses ranging from 50 to 175 anti-Xa International Units/kg per dose, with a duration of exposure of 3 to 463 days. Dosing was initiated as early as prior to conception and as late as 32 weeks gestation. Besides the 50 live births among the 55 pregnancy outcomes, there were 3 first trimester miscarriages and 2 intrauterine deaths (at weeks 17 and 30). Fetal distress was present in approximately 6% of the pregnancies (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    F) ANIMAL STUDIES
    1) ENOXAPARIN
    a) RATS, RABBITS: There was no evidence of fetotoxicity when rats and rabbits were given subQ enoxaparin doses up to 15 times the recommended human dose with 2 mg/kg as the maximum recommended daily dose (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    2) TINZAPARIN
    a) Based on animal data, tinzaparin does not cross the placenta and shows no evidence of fetotoxicity (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) At the time of this review, no data were available to assess the potential effects of exposure to dalteparin, enoxaparin, and tinzaparin during lactation in humans (Prod Info ARIXTRA(R) subcutaneous injection, 2010; Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009; Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    B) LACK OF EFFECT
    1) DALTEPARIN
    a) One study concluded that it would be unlikely that any clinically relevant effect would be seen in nursing infants of lactating mothers who were treated with subcutaneous dalteparin 2500 International Units once daily after cesarean section. Samples of maternal plasma and breast milk were collected on days 4 to 8 after cesarean delivery (3 to 4 hours after dalteparin injection) from 15 mothers (mean sample collection day 5.3 after cesarean). Plasma anti-Xa activity ranged from 0.074 to 0.308 International Units/mL of plasma. Breast milk anti-Xa activity ranged from less than 0.005 to 0.037 International Units/mL of milk. The milk:plasma ratio was equal to less than 0.025 to 0.224. The investigators noted that excretion of dalteparin into breast milk was observed in at least 11 of the 15 subjects. It was calculated that a newborn might consume 250 mL breast milk on day 5 of life, resulting in maximum oral exposure not exceeding 9 International Units/24 hours (equivalent to 5.4% of the maternal dose per kg of body weight) (Richter et al, 2001).
    C) ANIMAL STUDIES
    1) TINZAPARIN
    a) RATS: Animal studies have shown that tinzaparin is excreted into the milk of lactating rats at very low levels (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) DALTEPARIN
    a) RATS, RABBITS: Reproductive studies with dalteparin sodium at IV doses 2 to 4 times the recommended human dose (RHD) in pregnant rats and 4 times the RHD in pregnant rabbits did not produce any evidence of impaired fertility (Prod Info FRAGMIN(R) subcutaneous injection, 2016).
    2) ENOXAPARIN
    a) RATS: There was no effect on fertility or reproductive performance when male and female rats were given subQ enoxaparin at daily doses up to 20 mg/kg or 141 mg/m(2). In clinical trials, the maximum human daily dose was 2 mg/kg or 78 mg/m(2) (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    3) TINZAPARIN
    a) RATS, RABBITS: No evidence of impaired fertility was noted when rats and rabbits were given subQ tinzaparin doses up to 1800 and 1900 International Units/kg/day (about 2 times and about 4 times the maximum recommended human dose based on body surface area), respectively (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) At the time of this review, the manufacturers do not report any carcinogenic potential for dalteparin, enoxaparin, or tinzaparin in humans.
    3.21.4) ANIMAL STUDIES
    A) LACK OF INFORMATION
    1) At the time of this review, the manufacturers do not report any carcinogenic potential for dalteparin, enoxaparin, or tinzaparin in animals (Prod Info FRAGMIN(R) subcutaneous injection, 2010; Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009; Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).

Genotoxicity

    A) DALTEPARIN SODIUM
    1) There was no evidence of mutagenicity in the following tests: in vitro Ames Test, in vitro mouse lymphoma cell forward mutation test, in vitro human lymphocyte chromosomal aberration test, and in vivo mouse micronucleus test (Prod Info FRAGMIN(R) subcutaneous injection, 2010).
    B) ENOXAPARIN SODIUM
    1) There was no evidence of mutagenicity in the following tests: in vitro Ames Test; in vitro mouse lymphoma cell forward mutation test, in vitro human lymphocyte chromosomal aberration test, and in vivo rat bone marrow chromosomal aberration test (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    C) TINZAPARIN SODIUM
    1) There was no evidence of genotoxicity in the following tests: in vitro Ames test, in vitro Chinese hamster ovary cell forward gene mutation test, in vitro human lymphocyte chromosomal aberration assay, and in vivo mouse micronucleus assay (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor for evidence of bleeding (eg, venous access sites, urinary, gastrointestinal, vaginal).
    B) Monitor CBC with platelet count, vital signs, and hepatic enzymes in symptomatic patients.
    C) Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are not sensitive measures of activity at therapeutic doses of LMWH, and routine coagulation monitoring is not required. However, aPTT and standard anti-Xa monitoring may be useful to follow the degree of anti-IIA and anti-Xa neutralization by protamine in patients with severe bleeding.
    D) Monitor for signs and symptoms of heparin-induced thrombocytopenia and thrombosis (HITT), including deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, or gangrene of the extremities.
    4.1.2) SERUM/BLOOD
    A) Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are not sensitive measures of activity and routine coagulation monitoring is not required (Prod Info FRAGMIN(R) subcutaneous injection, 2010; Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009; Prod Info INNOHEP(R) solution for subcutaneous injection, 2009; Hirsh et al, 2008). However, aPTT and standard anti-Xa monitoring may be useful to follow the degree of anti-IIA and anti-Xa neutralization by protamine in patients with severe bleeding (Hasan et al, 2010). One study recommended that anti-factor Xa activity be measured 5 to 15 minutes after protamine administration (Bjornaas et al, 2010).
    B) CASE REPORTS - MONITORING
    1) DALTEPARIN
    a) A 39-year-old woman experienced only ecchymosis at the injection site after injecting herself 360,000 Units of dalteparin subQ (approximately 4000 Units/kg). Approximately 10 hours after the dalteparin use, the anticoagulant response reached a peak (aPTT greater than 240 seconds; PT = 24.1 seconds; anti-Xa activity = 9 units/mL; anti-IIa activity = 6 Units/mL). Approximately 50 hours after exposure, the aPTT and anti-IIa activity (less than 0.1 Units/mL; lower limit of detection) normalized. Anti-Xa activity returned to less than 0.1 Units/mL approximately 80 hours after exposure. She was discharged 4 days later without further sequelae. The authors suggested that: 1) aPTT monitoring may be useful to follow the degree of anti-IIA neutralization by protamine during the initial 24 to 36 hours; 2) Standard anti-Xa monitoring may be useful to follow the degree of anti-Xa neutralization by protamine for 48 to 60 hours (Hasan et al, 2010).
    b) In a suicide attempt, a 42-year-old woman (heterozygous for factor V Leiden mutation) injected herself with 17 doses of 12,500 International Units of dalteparin (212,500 IU in total), and ingested 625 mg of promethazine, and unknown amounts of citalopram, lamotrigine, and salicylate. At admission, the APTT was greater than 180 s (normal range 27 to 40 s) and her anti-Xa activity was 4.4 (therapeutic range, 0.5 to 1 Units/mL). She received 500 mg of IV protamine sulfate over 100 minutes. Five hours later, her APTT and anti-Xa activity decreased to 53 s and 1.9, respectively. One again, her APTT increased to greater than 180 s 12 hours later. She was treated with 500 mg of IV protamine which normalized her APTT. No signs of bleeding were observed. She was discharged after 72 hours of observation (Bjornaas et al, 2010).
    c) Three episodes of LMWH overdose in 2 patients were successfully managed with only observation and biomarker monitoring.
    1) A 35-year-old woman presented to an ED after self-injection of 72,000 Units of dalteparin. Laboratory analysis revealed a normal INR, a prolonged APTT (greater than 200 seconds), and an anti-Xa activity of 5.72 Units/mL (therapeutic range, 0.6 to 1.2). All values normalized approximately 26 hours postinjection. She did not experience any bleeding. She presented again 20 days later after self-injection of 72,000 Units of dalteparin. No bleeding were observed at this time. She was discharged without any treatment (Monte et al, 2010).
    2) A 29-year-old man who was taking enoxaparin and warfarin presented 2 hours after the injection of four 120-mg enoxaparin syringes (480 mg total). Laboratory analysis revealed a supratherapeutic INR of 5 (peaked at 6.2 14 hours postinjection) and an anti-Xa activity of 1.9 Units/mL (2 hours postinjection) and 1.4 Units/mL (14 hours postinjection). No signs of bleeding were observed (Monte et al, 2010).
    2) ENOXAPARIN
    a) A neonate received 40 mg of enoxaparin instead of 4 mg, and was treated successfully with protamine (total dose, 35 mg). Thrombin clotting time (TCT; a surrogate marker of anti-IIa activity reversal) was used to monitor the efficacy of enoxaparin reversal by protamine. Shorter TCTs indicate more thrombin activity and greater reversal of the LMWH action (Wiernikowski et al, 2007).
    b) A 34-year-old woman (heterozygous for the factor V Leiden mutation) who was using enoxaparin (1 mg/kg [80 mg] every 12 hours) injected herself with 1600 mg of enoxaparin (20 syringes of 80 mg). An initial laboratory result revealed an antifactor Xa activity concentration of 8.3 International Units/mL (therapeutic range: 0.5 to 1.1 IU/mL for twice daily dosing, 1 to 2 IU/mL for once daily dosing), partial thromboplastin time (PTT) of 98 s (23 to 38 s), hemoglobin of 12.6 g/dL (12 to 16 g/dL), and hematocrit of 38.1% (35% to 45%). She didn't have any clinical evidence of bleeding. Six hours after admission, her PTT increased to 169 s. At this time, a drop in her hematocrit (28.8%) was noted and she received 2 units of packed red blood cells about 15 hours after admission and 2 additional units of transfusion 3 hours later. A CT scan of the abdomen and pelvis revealed bilateral retroperitoneal hematomas. Because of active bleeding, she received protamine sulfate 50 mg IV 25 hours after admission and 3 doses of rFVIIa (45 mcg/kg) at 24, 26, and 28 hours after admission. Following further supportive care, she gradually recovered by day 5 (Byrne & Zumberg, 2012).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with severe symptoms (eg, anaphylaxis, hemorrhage) should be admitted to an intensive care setting.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) All patients with LMWH overdose should be evaluated and monitored until symptoms resolve. Patients can be discharged when laboratory values are stable with no evidence of bleeding.

Monitoring

    A) Monitor for evidence of bleeding (eg, venous access sites, urinary, gastrointestinal, vaginal).
    B) Monitor CBC with platelet count, vital signs, and hepatic enzymes in symptomatic patients.
    C) Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are not sensitive measures of activity at therapeutic doses of LMWH, and routine coagulation monitoring is not required. However, aPTT and standard anti-Xa monitoring may be useful to follow the degree of anti-IIA and anti-Xa neutralization by protamine in patients with severe bleeding.
    D) Monitor for signs and symptoms of heparin-induced thrombocytopenia and thrombosis (HITT), including deep vein thrombosis, pulmonary embolism, cerebral vein thrombosis, limb ischemia, stroke, myocardial infarction, mesenteric thrombosis, renal arterial thrombosis, skin necrosis, or gangrene of the extremities.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination is not indicated; LMWHs are only available parenterally.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Refer to the PARENTERAL EXPOSURE section of treatment recommendations.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis and hemoperfusion are UNLIKELY to be of value because of the large volume of distribution of LMWHs.
    B) EXCHANGE TRANSFUSION
    1) Plasma exchange was successful in 4 patients with heparin-induced thrombocytopenia (Bouvier et al, 1988).

Range Of Toxicity

Summary

    A) TOXICITY: Varies with agent. A minimum toxic dose has not been established. DALTEPARIN: A 39-year-old woman experienced only ecchymosis at the injection site after injecting herself 360,000 Units of dalteparin subQ (approximately 4000 Units/kg). A 40-year-old man presented on 5 different occasions with massive, self-induced overdoses of dalteparin (range, 72,000 to 720,000 International Units). There were no bleeding complications in 3 of the 5 episodes. Mild to moderate bleeding developed in 2 episodes. ENOXAPARIN: A 34-year-old woman injected herself with 1600 mg of enoxaparin (20 syringes of 80 mg) and developed retroperitoneal bleeding requiring transfusion. She recovered following supportive therapy, including protamine and rFVIIa therapies. A neonate received 40 mg of enoxaparin instead of 4 mg, and was treated successfully with protamine.
    B) THERAPEUTIC DOSES: DALTEPARIN: ADULTS: Varies by indication; up to 200 international units/kg subQ every 24 hours; total daily dose should not exceed 18,000 international units. ENOXAPARIN: Varies by indication; the following dosing has been used for myocardial infarction: Initially, single IV bolus dose of 30 mg plus 1 mg/kg subQ; maintenance, 1 mg/kg subQ every 12 hours for minimum of 8 days; MAXIMUM DOSE: 100 mg for the first 2 doses only. TINZAPARIN: 175 anti-Xa international units/kg subQ once daily for 6 days; 100 international units antifactor Xa activity is equivalent to 1 mg. CHILDREN: Safety and efficacy have not been established in pediatric patients.

Therapeutic Dose

    7.2.1) ADULT
    A) DALTEPARIN
    1) DVT PROPHYLAXIS, POSTOPERATIVE OR RESTRICTED MOBILITY: 2500 to 5000 international units subQ/24 hours for up to 14 days based on indication (Prod Info FRAGMIN(R) subcutaneous injection, 2010).
    2) MYOCARDIAL ISCHEMIA PROPHYLAXIS: 120 international units/kg subQ every 12 hours for 5 to 8 days; dose should not exceed 10,000 international units (Prod Info FRAGMIN(R) subcutaneous injection, 2010).
    3) VENOUS THROMBOEMBOLISM: first 30 days, 200 international units/kg subQ every 24 hours; months 2 through 6, 150 international units/kg subQ every 24 hours; total daily dose should not exceed 18,000 international units (Prod Info FRAGMIN(R) subcutaneous injection, 2010).
    B) ENOXAPARIN
    1) DVT PROPHYLAXIS, POSTOPERATIVE OR RESTRICTED MOBILITY: 30 mg subQ every 12 hours or 40 mg subQ every 24 hours for up to 14 days based on indication; continue additional 3 weeks for extended prophylaxis in hip surgery (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    2) DVT WITH/WITHOUT PULMONARY EMBOLISM: 1 mg/kg subQ every 12 hours or 1.5 mg/kg every 24 hours for a minimum of 5 days and up to 17 days (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    3) MYOCARDIAL INFARCTION: Initially, single IV bolus dose of 30 mg plus 1 mg/kg subQ; maintenance, 1 mg/kg subQ every 12 hours for minimum of 8 days; MAXIMUM DOSE: 100 mg for the first 2 doses only (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    4) MYOCARDIAL ISCHEMIA PROPHYLAXIS: 1 mg/kg subQ every 12 hours for 2 to 8 days (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009).
    C) TINZAPARIN
    1) DVT WITH/WITHOUT PULMONARY EMBOLISM: 175 anti-Xa international units/kg subQ once daily for 6 days; 100 international units antifactor Xa activity is equivalent to 1 mg (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    7.2.2) PEDIATRIC
    A) DALTEPARIN
    1) Safety and efficacy have not been established in pediatric patients (Prod Info FRAGMIN(R) subcutaneous injection, 2010).
    B) ENOXAPARIN
    1) TREATMENT OF THROMBOSIS
    a) LESS THAN 2 MONTHS OF AGE: initial, 1.5 mg/kg subQ every 12 hours (Moharir et al, 2010; Monagle et al, 2008; Roach et al, 2008; Merkel et al, 2006; Dix et al, 2000; deVeber et al, 1998).
    b) 2 MONTHS OF AGE AND OLDER: initial, 1 mg/kg subQ every 12 hours (Moharir et al, 2010; Monagle et al, 2008; Roach et al, 2008; Merkel et al, 2006; Dix et al, 2000; deVeber et al, 1998; Massicotte et al, 1996)
    c) Adjust dosage to maintain anti-factor Xa level between 0.5 and 1 unit/mL. It will usually take several days to attain levels in the target range (Bauman et al, 2009; Monagle et al, 2008; Roach et al, 2008; Dix et al, 2000). A suggested dosage adjustment is 0.125 mg/kg/dose until therapeutic anti-Xa level is achieved (Manco-Johnson, 2006).
    2) PROPHYLAXIS OF THROMBOSIS
    a) LESS THAN 2 MONTHS OF AGE: 0.75 mg/kg subQ every 12 hours (Jackson & Morgan, 2008; Monagle et al, 2008; Roach et al, 2008; Dix et al, 2000)
    b) 2 MONTHS OF AGE AND OLDER: 0.5 mg/kg subQ every 12 hours. Maximum: 20 mg/dose (Jackson & Morgan, 2008; Monagle et al, 2008; Roach et al, 2008; Dix et al, 2000)
    c) ADOLESCENTS (GREATER THAN 40 KG): Consider 40 mg subQ once daily (Jackson & Morgan, 2008)
    d) Adjust dosage to maintain anti-factor Xa level between 0.1 and 0.4 unit/mL (Jackson & Morgan, 2008; O'Brien et al, 2007; Dix et al, 2000).
    C) TINZAPARIN
    1) Safety and efficacy have not been established in pediatric patients (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).

Maximum Tolerated Exposure

    A) DALTEPARIN: A 39-year-old woman experienced only ecchymosis at the injection site after injecting herself 360,000 Units of dalteparin subQ (approximately 4000 Units/kg). Approximately 10 hours after the dalteparin use, the anticoagulant response reached a peak (aPTT greater than 240 seconds; PT = 24.1 seconds; anti-Xa activity = 9 units/mL; anti-IIa activity = 6 Units/mL). Approximately 50 hours after exposure, the aPTT and anti-IIa activity (less than 0.1 Units/mL; lower limit of detection) normalized. Anti-Xa activity returned to less than 0.1 Units/mL approximately 80 hours after exposure. She was discharged 4 days later without further sequelae (Hasan et al, 2010).
    B) DALTEPARIN: In a suicide attempt, a 42-year-old woman (heterozygous for factor V Leiden mutation) injected herself with 17 doses of 12,500 International Units of dalteparin (212,500 IU in total), and ingested 625 mg of promethazine, and unknown amounts of citalopram, lamotrigine, and salicylate. At admission, the APTT was greater than 180 s (normal range 27 to 40 s) and her anti-Xa activity was 4.4 (therapeutic range, 0.5 to 1 Units/mL). She received 500 mg of IV protamine sulfate over 100 minutes. Five hours later, her APTT and anti-Xa activity decreased to 53 s and 1.9, respectively. One again, her APTT increased to greater than 180 s 12 hours later. She was treated with 500 mg of IV protamine which normalized her APTT. No signs of bleeding were observed. She was discharged after 72 hours of observation (Bjornaas et al, 2010).
    C) DALTEPARIN: Three episodes of LMWH overdose in 2 patients were successfully managed with only observation and biomarker monitoring.
    1) A 35-year-old woman presented to an ED after self-injection of 72,000 Units of dalteparin. Laboratory analysis revealed a normal INR, a prolonged APTT (greater than 200 seconds), and an anti-Xa activity of 5.72 Units/mL (therapeutic range, 0.6 to 1.2). All values normalized approximately 26 hours postinjection. She did not experience any bleeding. She presented again 20 days later after self-injection of 72,000 Units of dalteparin. No bleeding were observed at this time. She was discharged without any treatment (Monte et al, 2010).
    2) A 29-year-old man who was taking enoxaparin and warfarin presented 2 hours after the injection of four 120-mg enoxaparin syringes (480 mg total). Laboratory analysis revealed a supratherapeutic INR of 5 (peaked at 6.2 14 hours postinjection) and an anti-Xa activity of 1.9 Units/mL (2 hours postinjection) and 1.4 Units/mL (14 hours postinjection). No signs of bleeding were observed (Monte et al, 2010).
    D) DALTEPARIN: CASE REPORT: A 40-year-old man with a history of a deep venous thrombosis and an episode of pulmonary embolism presented on 5 different occasions with massive, self-induced overdoses of dalteparin (dose range, 72,000 to 720,000 International Units) within 2 years. There were no bleeding complications in 3 of the 5 episodes. In episode 3 (dalteparin dose, 450,000 to 540,000 International Units), he developed large subcutaneous hematomas on the scalp and torso caused by a fall before admission, gingival bleeding, and a self-reported hematemesis. He had only mild bleeding after episode 5 (dalteparin dose, 720,000 International Units). Laboratory results revealed aPTT peaks ranging from 51 to greater than 300 seconds. Duration of aPTT abnormality ranged from greater than 16 hours to greater than 40 hours. He received protamine (bolus range, 50 to 200 mg; continuous infusion of 10 mg/hr, total of 200 mg after episode 2 and 360 mg after episode 3) after 4 of the 5 episodes. Tranexamic acid was administered in 3 occasions. He recovered following supportive care after each episode (Odeberg et al, 2012).
    E) ENOXAPARIN: A neonate received 40 mg of enoxaparin instead of 4 mg, and was treated successfully with protamine (total dose, 35 mg) (Wiernikowski et al, 2007).
    F) A 34-year-old woman injected herself with 1600 mg of enoxaparin (20 syringes of 80 mg) and developed retroperitoneal bleeding requiring transfusion. She recovered following supportive therapy, including protamine and rFVIIa therapies (Byrne & Zumberg, 2012).
    G) TINZAPARIN: In clinical trials, a bleeding complication developed in approximately 16% of patients known to have received an overdose (described as one or more doses greater than 200 International Units (IU)/kg for the treatment of deep venous thrombosis (DVT) or greater than 100 IU/kg for the prevention of DVT) (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    H) TINZAPARIN: An extremely low birth weight neonate developed a large hematoma in the left thigh after receiving tinzaparin (275 International Units/kg/day SubQ) for 13 days through an indwelling catheter to treat a small atrial thrombus. Laboratory results revealed a hemoglobin level that had dropped from 14.6 g/dL to 10.7 g/dL within a few days. Following protamine (1 mg) therapy, the infant recovered completely (van Elteren et al, 2010).
    I) TINZAPARIN: A 24-year-old man with a history of antiphospholipid antibody syndrome and recurrent deep vein thrombosis, presented an hour after the self-injection of 240,000 units of tinzaparin. Laboratory results, an hour after presentation, revealed a hemoglobin of 121 g/L, PT of 1.9, PTT of greater than 200 msec, and serum creatinine of 129 mmol/L (similar to his baseline). His heparin assays at 7 hours, 24 hours, and 48 hours post-overdose were greater than 2 Units/mL (target level 4 hours post-injection is 0.85 Units/mL), greater than 2 Units/mL, and 0.34 Units/mL, respectively. His PTT was greater than 200 msec 24 hours and decreased to 102 msec at 48 hours. His peak PT was 2.4 about 5 hours post-overdose and decreased to 1.4 by 48 hours. At 3 days, his hemoglobin was at a nadir of 91 g/L. He did not experience any significant bleeding and was discharged 3 days later (Haws & Chuang, 2015).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Dalteparin, enoxaparin, and tinzaparin are anticoagulant agents with anti-Factor Xa and anti-thrombin (anti-Factor IIa) activities. They inhibit thrombin formation and thrombus development (Prod Info FRAGMIN(R) subcutaneous injection, 2010; Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009; Prod Info INNOHEP(R) solution for subcutaneous injection, 2009).
    B) LMWHs are prepared from unfractionated heparin by chemical or enzymatic depolymerization. LMWHs have lower molecular weight (range, 2000 to 9000; mean, 4000 to 5000) with reduced binding to proteins and cells. Overall, compared with heparin, LMWHs have lower anti-IIa activity relative to anti-Xa activity and a more predictable anticoagulant response (no coagulation monitoring with minimal effect on aPTT). They are cleared through renal mechanism and have a greater bioavailability and longer plasma half-life. LMWHs are not clinically interchangeable as LMWHs have different pharmacokinetic properties and anticoagulant profiles (Hirsh et al, 2008).

Physicochemical

Physical Characteristics

    A) ENOXAPARIN SODIUM has a specific activity of anti-Factor Xa of 100 international units/mg (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009) and anti-Factor IIa of 20 to 40 international units/mg (Buckley & Sorkin, 1992; Frydman et al, 1988).

Ph

    A) DALTEPARIN SODIUM: 5 to 7.5 (Prod Info FRAGMIN(R) subcutaneous injection, 2010)
    B) ENOXAPARIN SODIUM: 5.5 to 7.5 (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009)
    C) TINZAPARIN: 5 to 7.5 (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009)

Molecular Weight

    A) DALTEPARIN: 5000 daltons (average); about 90% of the material is between 2000 and 9000 daltons (Prod Info FRAGMIN(R) subcutaneous injection, 2010)
    B) ENOXAPARIN SODIUM: 4500 daltons (average); about 68% or more of the material is between 2000 and 8000 daltons (Prod Info LOVENOX(R) solution for subcutaneous and intravenous injection, 2009)
    C) TINZAPARIN SODIUM: 5500 to 7500 daltons (average) (Prod Info INNOHEP(R) solution for subcutaneous injection, 2009)

References

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