NEODOSE

INDICATIONS

• Anticoagulation: Advantages over standard unfractionated heparin:
  • (1) May be given subcutaneously,
  • (2) More predictable pharmacokinetics,
  • (3) Minimal monitoring,
  • (4) Dosing every 12 hours,
  • (5)Less frequent bleeding complications.
  • disadvantage: One disadvantage is the inability to quickly and completely reverse its anticoagulant effects.
• Treatment of Thrombosis: Several retrospective studies have suggested that higher initial doses are required to more quickly achieve therapeutic anti-Xa levels and reduce the number of dosage adjustments. In a retrospective study (n=33), initial doses of 1.8 +/- 0.4 mg/kg in full-term infants (younger than 2 months) and 2.2 +/- 0.5 mg/kg in preterm infants (37 weeks gestation or less) would have been necessary to achieve therapeutic anti-factor Xa levels. In another retrospective study in children (n=192), higher initial doses (1.7 mg/kg every 12 hours for children 3 months of age and younger; 1.2 mg/kg every 12 hours for children greater than 3 months of age) achieved more rapid therapeutic anti-factor Xa levels resulting in fewer venipunctures, without an increase in adverse events, compared with standard doses. Treatment outcomes (resolution or reduction of thrombus) were not different between groups. The authors concluded a higher starting dose of 1.8 mg/kg every 12 hours for infants less than 3 months of age and 1.5 mg/kg every 12 hours for children 3 to 12 months of age may be considered . A third retrospective study (n=150) found that only 41% of patients attained therapeutic anti-Xa levels with initial dosing consistent with current standard treatment guidelines. The following doses were required to achieve a therapeutic anti-Xa level (dose given every 12 hours): less than one month of age, 1.8 mg/kg; one month to 1 year, 1.64 mg/kg. A fourth retrospective study (n=140) also revealed that less than half of the population achieved therapeutic anti-Xa levels following the initial dose with the current standard treatment guidelines. The following higher doses were required to achieve a therapeutic anti-Xa level (dose given every 12 hours): less than 2 months of age, 1.6 mg/kg; 2 months to 1 year, 1.5 mg/kg. In a retrospective study, whole-milligram enoxaparin dosing using insulin syringes (undiluted 100 mg/mL; 1 mg enoxaparin = 0.01 mL = 1 unit) was associated with therapeutic anti-Xa levels and no reported dose measurement errors. The study included neonates, infants and children (n=514); 27% were infants less than 3 months of age (900 to 4700 g in weight). Five children (less than 1%) had a supra-therapeutic initial anti-Xa level without hemorrhagic consequences. No patients needed decimal dosing to attain therapeutic levels.

CONTRAINDICATIONS

• Presence of active major bleeding.
• History of immune-mediated heparin-induced thrombocytopenia within the past 100 days or in the presence of circulating antibodies.
• Known hypersensitivity to enoxaparin, heparin or pork products, or benzyl alcohol (multidose form contains alcohol).

PRECAUTIONS

Major bleeding may occur even with anti-factor Xa levels in the therapeutic range. The overall incidence is approximately 4% in children. Reported complications include major bleeding or hematoma at the administration site, compartment syndrome, intracranial hemorrhage, and gastrointestinal hemorrhage. Bleeding can occur at any site. Use with caution in patients with a bleeding diathesis, uncontrolled arterial hypertension or a history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction and hemorrhage. Epidural hematoma has been reported in pediatric patients who underwent lumbar puncture while receiving enoxaparin. It is recommended that 2 doses of enoxaparin be held prior to spinal invasive procedures and if possible, anti-Xa levels should be obtained prior to high-risk procedures. Risk of epidural or spinal hemorrhage and subsequent hematomas is increased with the use of postoperative indwelling epidural catheters, with concomitant use of additional drugs affecting hemostasis (e.g. NSAIDs), with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity Heparin-induced thrombocytopenia or heparin-induced thrombocytopenia with thrombosis (HITTS) may occur and was reported (with normal platelet count) in one case study in a child. Although HIT is rare with enoxaparin therapy (less than 1%), children are still at risk for developing it; consider risk/benefit and alternative non-heparin treatment options in patients with history of HIT; monitoring required. Thrombocytopenia of any severity may occur; closely monitor, discontinuation may be required. Serious and fatal adverse events including “gasping syndrome” may occur in neonates and low birth weight infants with use of the multiple-dose vials, which contain benzyl alcohol.

ADVERSE EFFECTS

Major and minor bleeds occurred in 4% and 17% of pediatric patients (1 day to 18 years of age (median 3.5 years)) receiving enoxaparin for 146 courses of therapeutic uses and 0% and 6% of 31 pediatric patients (1 week to 17 years of age (median 5.5 years)) receiving prophylactic enoxaparin. Major bleeds were 2 gastrointestinal, 3 (2 of whom were neonates) intracranial bleeds, and 2 thigh hematomas in extremely premature neonates.

BLACK BOX WARNING

Epidural or spinal hematomas, which may result in long-term or permanent paralysis, may occur in patients who are anticoagulated with low molecular weight heparins or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing these hematomas include:

• Use of indwelling epidural catheters
• epidural catheters Concomitant use of other drugs that affect hemostasis, such as non-steroidal antiinflammatory drugs (NSAIDs), platelet inhibitors, and other anticoagulants
• A history of traumatic or repeated epidural or spinal punctures
• A history of spinal deformity or spinal surgery
• Optimal timing between the administration of Lovenox and neuraxial procedures is not known

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuroaxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

ADMINISTRATION

Administer by deep subQ injection. Not for IM administration. Insulin syringes have been used to administered enoxaparin (undiluted 100 mg/mL; 1 mg enoxaparin = 0.01 mL = 1 unit). Administration may be aided by using a small plastic indwelling subcutaneous catheter (Insuflon®, Hypoguard USA). Adverse events related to these catheters are much more frequent in ELBW infants.

MONITORING

• Prothrombin time and aPTT are not adequate for monitoring anticoagulant effects.
• Measure anti-factor Xa concentrations:
  • 4 to 6 hours after a subQ dose – target 0.5 to 1 units/mL.
  • 2 to 6 hours after a subQ dose – target 0.5 to 0.8 units/mL.
• Preterm infants are likely to require several dosage adjustments to achieve the target levels. Obtain anti-factor Xa levels initially, weekly during hospitalization, and then every 3 to 4 weeks in stable patients. After attaining target levels, dosage adjustments will be necessary once or twice a month, perhaps more often in preterm infants and infants with hepatic or renal dysfunction. Anti-factor Xa concentrations vary with the assay method; there is a lack of standardization for methods.
• Obtain CBC (including platelet count), stool occult blood, and liver function tests during therapy. Monitor blood pressure. Monitor patients with renal impairment closely during therapy (dose reduction necessary). Assess for signs of bleeding and thrombosis. Patients undergoing concomitant neuraxial anesthesia or spinal puncture should be monitored frequently for neurological impairment indicating possible spinal or epidural hematoma.