Fragmin7500 IU/0.3 ml

Established (FDA-Approved) Indications

• Prophylaxis of deep vein thrombosis (DVT): In patients undergoing abdominal surgery who are at risk of thromboembolic complications, in patients undergoing hip replacement surgery, and in medical patients with severely restricted mobility during acute illness.
• Prevention of clot formation in the extracorporeal circuit during hemodialysis or hemofiltration.
• Treatment of unstable angina and non-Q-wave myocardial infarction: Used in conjunction with aspirin to prevent progression to myocardial infarction or death.
• Extended treatment of symptomatic venous thromboembolism (proximal DVT and/or pulmonary embolism): To reduce the recurrence of VTE in patients with cancer.

Guideline-Supported / Off-Label Use

• Fragmin is also used off-label, based on clinical guidelines, for anticoagulation during pregnancy (e.g., treatment or prophylaxis of VTE in pregnant women, where warfarin and direct oral anticoagulants are avoided) and for VTE treatment/prophylaxis in select pediatric patients under specialist supervision.

Fragmin must always be used under medical supervision, with the specific dose and duration individualized to the indication, body weight, and bleeding risk of the patient.

Dalteparin Sodium is a low molecular weight heparin (LMWH) obtained by controlled nitrous acid depolymerization of unfractionated heparin derived from porcine intestinal mucosa, with an average molecular weight of approximately 6000 daltons. It is formulated as a sterile aqueous solution for subcutaneous (and, in specific settings, intravenous) injection.

It is commonly available as single-dose pre-filled syringes/ampoules of various strengths (e.g., 2,500 IU, 5,000 IU, 7,500 IU, 10,000 IU, 12,500 IU, 15,000 IU, 18,000 IU per syringe) and as multi-dose vials (e.g., 10,000 IU/mL), the latter containing benzyl alcohol as a preservative.

Fragmin is a low molecular weight heparin (LMWH) anticoagulant. It works by potentiating the inhibition of activated Factor Xa and, to a lesser extent, thrombin (Factor IIa) in the coagulation cascade, thereby reducing the formation and extension of blood clots.

Compared with unfractionated heparin, Fragmin has a higher ratio of anti-Factor Xa to anti-Factor IIa activity, more predictable pharmacokinetics after subcutaneous injection, and a longer duration of action, which generally allows once- or twice-daily dosing without routine coagulation monitoring in most patients.

Fragmin carries a boxed warning regarding the risk of epidural or spinal hematoma in patients who are receiving neuraxial anesthesia (epidural/spinal anesthesia) or undergoing spinal puncture, which can result in long-term or permanent paralysis; the timing of dosing around such procedures is critical and is specifically defined in the product labeling.

Low Molecular Weight Heparin (LMWH) / Anticoagulant. Fragmin belongs to this class of medicines.

Mechanism of Action

Dalteparin Sodium binds to antithrombin III (AT-III) and accelerates its inhibitory action, predominantly against activated Factor Xa, with lesser inhibition of thrombin (Factor IIa), compared with unfractionated heparin. This interrupts the coagulation cascade and prevents the formation and extension of fibrin clots.

Pharmacokinetics

• Absorption: Bioavailability after subcutaneous injection is approximately 87%; peak anti-Factor Xa activity occurs about 4 hours after subcutaneous dosing.
• Distribution: Limited to the vascular compartment; volume of distribution approximates blood volume.
• Metabolism: Primarily hepatic desulfation and depolymerization.
• Elimination: Mainly renal; the elimination half-life is approximately 3–5 hours after subcutaneous injection and is prolonged in patients with renal impairment.

Fragmin is administered only by subcutaneous injection (never intramuscularly), typically into the abdominal wall, alternating injection sites. For hemodialysis/hemofiltration, it may be given via the extracorporeal circuit as directed by a physician. Do not mix Fragmin with other injections or infusions unless specifically instructed. Patients should not attempt to self-adjust the dose or injection technique without guidance from their physician or nurse.

• Oral anticoagulants (e.g., warfarin) and other anticoagulants: Concurrent use with Fragmin increases the risk of bleeding; careful clinical and laboratory monitoring is needed during any transition therapy.
• Antiplatelet agents (aspirin, clopidogrel, ticlopidine) and NSAIDs: Increase the risk of bleeding when used with Fragmin; aspirin is specifically co-administered for the unstable angina indication under close medical supervision, but the added bleeding risk must be monitored.
• Thrombolytic agents: Concomitant use substantially increases the risk of serious bleeding.
• Other drugs affecting hemostasis (e.g., high-dose systemic glucocorticoids, dextran): May further increase bleeding risk when combined with Fragmin.

Neuraxial anesthesia performed in patients receiving Fragmin together with other drugs affecting hemostasis carries a higher risk of spinal/epidural hematoma; see Precautions and Warnings.

Common

• Bleeding (ranging from minor bruising to serious hemorrhage)
• Injection site reactions: pain, hematoma, erythema, and irritation
• Mild, transient, asymptomatic elevation of liver transaminases

Less Common / Serious

• Thrombocytopenia, including immune-mediated heparin-induced thrombocytopenia (HIT)
• Hypersensitivity reactions (rash, urticaria, rarely anaphylaxis)
• Skin necrosis at the injection site (rare)
• Spinal or epidural hematoma in patients undergoing neuraxial anesthesia or spinal puncture (rare but can cause long-term or permanent paralysis; see Precautions and Warnings)
• Alopecia (rare)
• Osteoporosis with prolonged (months) use (rare)

Patients should seek prompt medical attention for unusual bruising, prolonged bleeding, black or bloody stools, severe headache, or signs of numbness/weakness while on Fragmin.

Pregnancy: Fragmin should be used during pregnancy only if clearly needed and if the potential benefit justifies the potential risk to the fetus; a physician must be consulted. Fragmin does not readily cross the placenta due to its molecular size. There have been reports of prosthetic heart valve thrombosis in pregnant women receiving LMWH anticoagulation for that indication; such use requires intensive monitoring. Multi-dose vials containing benzyl alcohol should be avoided in pregnancy when a preservative-free alternative is available.

Lactation: Limited data suggest that Fragmin is present in breast milk in low amounts with low expected oral bioavailability in the infant; it is generally considered compatible with breastfeeding, but a physician should be consulted before use in nursing mothers, particularly regarding avoidance of benzyl-alcohol-containing multi-dose vials in mothers of neonates.

Boxed Warning: Spinal/Epidural Hematoma

Patients receiving Fragmin who undergo neuraxial anesthesia (epidural or spinal anesthesia) or spinal puncture are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. This risk is increased by the use of indwelling epidural catheters, concomitant use of other drugs affecting hemostasis (e.g., NSAIDs, platelet inhibitors, other anticoagulants), a history of traumatic or repeated epidural/spinal puncture, and a history of spinal deformity or spinal surgery. The timing of Fragmin dosing before and after such procedures is critical and follows specific labeling guidance; patients must be monitored frequently for signs and symptoms of neurological impairment, and urgent treatment is required if these occur.

Other Precautions

• Heparin-induced thrombocytopenia (HIT): Monitor platelet counts during treatment; discontinue Fragmin promptly if HIT is suspected or confirmed.
• Renal impairment: Use with caution; dose adjustment and anti-Factor Xa monitoring are recommended in severe renal impairment (see Dosage and Administration).
• Hepatic impairment: Use with caution due to a theoretically increased bleeding risk; no formal dose adjustment has been established.
• Not for intramuscular use; not interchangeable unit-for-unit with unfractionated heparin or other LMWHs.
• Benzyl alcohol (multi-dose vials): Avoid in neonates and infants due to the risk of a fatal "gasping syndrome."
• Prosthetic heart valves: Increased reports of valve thrombosis with LMWH use for this purpose, particularly in pregnant women; requires close monitoring.
• Elderly patients may have an increased risk of bleeding complications.

Overdose of Fragmin primarily manifests as bleeding, which can range from minor to life-threatening. In case of suspected overdose, seek immediate medical attention or contact emergency services / a poison control center without delay.

Management is generally supportive and includes discontinuation of Fragmin and close monitoring. For serious bleeding, protamine sulfate may partially neutralize the anti-Factor IIa activity of Fragmin (its effect on anti-Factor Xa activity is only partial), and should be administered only under direct medical supervision in a hospital setting.

Store at room temperature (below 30°C), away from light and moisture. Do not freeze. Keep out of reach of children. Discard multi-dose vials according to the labeled in-use period after first opening.

• Renal impairment: Fragmin is renally eliminated; use with caution in moderate impairment and with dose reduction plus anti-Factor Xa monitoring in severe impairment, particularly at treatment (non-prophylactic) doses.
• Hepatic impairment: Use with caution; increased bleeding risk is theoretically possible; no specific dose adjustment is established.
• Elderly: No specific dose adjustment is generally required based on age alone, but elderly patients may have an increased risk of bleeding and should be monitored closely, particularly if renal function is reduced.
• Pediatric patients: Safety and efficacy have not been formally established; used off-label with weight-based dosing in specialized pediatric centers when needed. See Pediatric Uses.
• Pregnancy and lactation: See Pregnancy and Lactation section.
• Body weight extremes (very low or high body weight): May require individualized dose adjustment and closer monitoring for bleeding or reduced efficacy.

Duration of Fragmin therapy depends on the indication: 5–10 days for surgical DVT prophylaxis (up to 35 days for extended hip replacement prophylaxis), 12–14 days for medically ill patients with restricted mobility, 5–8 days for unstable angina/non-Q-wave MI, and up to 6 months (with periodic reassessment of the risk/benefit of continued anticoagulation) for extended treatment of cancer-associated venous thromboembolism.

Anticoagulants; Low Molecular Weight Heparins (LMWH)

Dalteparin Sodium binds antithrombin III and markedly accelerates its inhibition of activated Factor Xa, with a lesser effect on thrombin (Factor IIa), giving it a higher anti-Xa:anti-IIa activity ratio than unfractionated heparin. This interruption of the coagulation cascade prevents new clot formation and limits extension of existing thrombi, without directly dissolving already-formed clots.

B (Legacy FDA pregnancy category, from pre-2015 labeling)

The safety and efficacy of Fragmin have not been formally established in pediatric patients in the FDA-approved labeling. It is used off-label, based on weight-based dosing protocols, for prevention or treatment of venous thromboembolism in children under the supervision of a pediatric hematology/anticoagulation specialist, with close monitoring of anti-Factor Xa levels. Multi-dose vials of Fragmin containing benzyl alcohol must not be used in neonates or infants because benzyl alcohol has been associated with a fatal 'gasping syndrome' in this age group; preservative-free, single-dose formulations should be used instead if therapy is required.