Fragmin

Black Box Warnings

Epidural or spinal hematomas may occur in patients anticoagulated with LMWH or heparinoids who receive neuraxial (epidural/spinal) anesthesia or spinal puncture

These hematomas may result in long-term or permanent paralysis

Patients should be frequently monitored for signs and symptoms of neurologic impairment; if neurological compromise noted, urgent treatment necessary

Optimal timing between the administration of dalteparin and neuraxial procedures is not known

Physicians should consider the benefits versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis

Factors increasing risk of epidural or spinal hematomas

• Indwelling epidural catheters
• Concomitant use of other drugs that affect hemostasis (eg, NSAIDs, platelet inhibitors, other anticoagulants)
• History of traumatic or repeated epidural or spinal punctures
• History of spinal deformity or spinal surgery

Contraindications

Hypersensitivity to dalteparin, heparin or pork products

Active major bleeding, thrombocytopenia associated with antiplatelet antibodies

History of heparin induced thrombocytopenia or heparin induced thrombocytopenia with thrombosis

As a treatment for unstable angina and non-Q-wave MI, in patients undergoing epidural/neuraxial anesthesia

For prolonged VTE prophylaxis, in patients undergoing epidural/neuraxial anesthesia

Patients that have undergone epidural neuraxial anesthesia

Cautions

Risk of epidural/spinal hematoma if used in patients getting epidural/spinal anesthesia which may result in paralysis

Use caution in conditions with increased risk of hemorrhage, hemorrhagic diathesis, severe uncontrolled HTN, severe hepatic/renal impairment, retinopathy, thrombocytopenia, bacterial endocarditis, GI ulcer, hemorrhagic stroke, recent brain, spinal or ophthalmologic surgery

Periodic blood counts recommended

History of heparin-induced thrombocytopenia

Do not give IM

Can't be used interchangeably with other LMW heparins

Multidose vials contain benzyl alcohol as preservative (associated with potentially fatal "Gasping Syndrome" in preemies); when prescribing dalteparin multiple-dose vials in infants, consider combined daily metabolic load of benzyl alcohol from all sources including multiple-dose vials (dalteparin contains 14 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol; minimum amount of benzyl alcohol at which serious adverse reactions may occur not known

Therapy may enhance risk of bleeding in patients with thrombocytopenia or platelet defects; severe liver or kidney insufficiency, hypertensive or diabetic retinopathy, and recent gastrointestinal bleeding; bleeding can occur at any site during therapy; monitor thrombocytopenia of any degree closely

If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae

For patients with creatinine clearance <30mL/min, elimination of dalteparin may be prolonged; consider doubling the timing of removal of a catheter, at least 24 hr for lower prescribed dose of dalteparin (2500 IU or 5000 IU once daily) and at least 48 hr for higher dose (200 IU/kg once daily, 120 IU/kg twice daily)

Although specific recommendation for timing of a subsequent dose after catheter removal is unknown, consider delaying this next dose for at least four hours, based on a benefit-risk assessment considering both the risk for thrombosis and the risk for bleeding in the context of the procedure and patient risk factors

Avoid taking aspirin unless your doctor recommends it as part of your treatment. Aspirin can increase your risk of bleeding.

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with dalteparin, especially other medicines used to treat or prevent blood clots, such as:

• abciximab, anagrelide, cilostazol, clopidogrel, dipyridamole, eptifibatide, ticlopidine, tirofiban;
• alteplase, reteplase, tenecteplase, urokinase;
• apixaban, argatroban, bivalirudin, dabigatran, desirudin, enoxaparin, fondaparinux, lepirudin, rivaroxaban, tinzaparin; or
• heparin.

This list is not complete. Other drugs may interact with dalteparin, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Fragmin is a prescription medication used to treat and prevent blood clots from developing in patients with several different medical conditions. Fragmin is also used to prevent further blood clots from developing in cancer patients who have already had a blood clot.

Fragmin belongs to a group of drugs called low molecular weight heparins or "blood thinners". These work by blocking the effects of enzymes involved in making blood clots. 

This medication comes in an injectable form to be given under the skin (subcutaneously) and is typically injected once or twice daily for a duration that is dependent on several medical factors. If Fragmin is to prevent blood clots from developing after surgery, Fragmin will be injected under the skin (subcutaneously) before surgery. 

Common side effects of Fragmin include bleeding, pain at the injection site, and upset stomach.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Fragmin falls into category B. Studies in animals have failed to demonstrate a risk to the unborn baby, and there are no well-controlled studies in pregnant women. Fragmin should be used only be used during pregnancy only if clearly needed. 

Your doctor or pharmacist can provide more information about dalteparin.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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Dalteparin is an anticoagulant that helps prevent the formation of blood clots.

Dalteparin is used together with aspirin to prevent blood vessel complications in people with certain types of angina (chest pain) or heart attack.

Dalteparin is also used to prevent a type of blood clot called deep vein thrombosis (DVT), which can lead to blood clots in the lungs (pulmonary embolism). A DVT can occur after certain types of surgery, or in people who are bed-ridden due to a prolonged illness.

Dalteparin is also used long-term to treat a type of blood clot called venous thromboembolism (VTE) in people with cancer.

Dalteparin may also be used for purposes not listed in this medication guide.

You should not use this medicine if you have active bleeding, or a low level of platelets in your blood after testing positive for a certain antibody while using dalteparin.

Dalteparin can cause a very serious blood clot around your spinal cord if you undergo a spinal tap or receive spinal anesthesia (epidural), especially if you have a genetic spinal defect, a history of spinal surgery or repeated spinal taps, or if you are using other drugs that can affect blood clotting, including blood thinners or NSAIDs (ibuprofen, Advil, Aleve, and others). This type of blood clot can lead to long-term or permanent paralysis.

Get emergency medical help if you have symptoms of a spinal cord blood clot such as back pain, numbness or muscle weakness in your lower body, or loss of bladder or bowel control.

You should not use this medicine if you are allergic to dalteparin, heparin, or pork products, or if you have:

• active or uncontrolled bleeding; or

• a history of blood clot or low levels of platelets in your blood while using heparin.

Dalteparin may cause you to bleed more easily, especially if you have:

• a bleeding disorder that is inherited or caused by disease;

• hemorrhagic stroke;

• an infection of the lining of your heart (also called bacterial endocarditis);

• uncontrolled high blood pressure;

• stomach or intestinal bleeding or ulcer; or

• recent brain, spine, or eye surgery.

Dalteparin can cause a very serious blood clot around your spinal cord if you undergo a spinal tap or receive spinal anesthesia (epidural). This type of blood clot could cause long-term or permanent paralysis, and may be more likely to occur if:

• you have a genetic spinal defect;

• you have a spinal cord injury;

• you have a spinal catheter in place or if a catheter has been recently removed;

• you have a history of spinal surgery or repeated spinal taps;

• you have recently had a spinal tap or epidural anesthesia;

• you take an NSAID (nonsteroidal anti-inflammatory drug)--ibuprofen (Advil, Motrin), naproxen (Aleve), diclofenac, indomethacin, meloxicam, and others; or

• you take a blood thinner (warfarin, Coumadin) or other medicines to treat or prevent blood clots.

To make sure dalteparin is safe for you, tell your doctor if you have ever had:

• eye problems caused by diabetes or high blood pressure;

• severe liver or kidney disease;

• recent stomach bleeding;

• low levels of platelets in your blood; or

• if you have recently had a spinal tap or epidural anesthesia.

It is not known whether this medicine will harm an unborn baby. However, some forms of dalteparin contain a preservative that may be harmful to a newborn. Tell your doctor if you are pregnant or plan to become pregnant during treatment.

Dalteparin can pass into breast milk, but effects on the nursing baby are not known. Tell your doctor if you are breast-feeding.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

When used for DVT or blood vessel complications, dalteparin is usually given every day until your bleeding condition improves. When used for VTE, dalteparin is often used for several months.

Dalteparin is injected under the skin. You may be shown how to use injections at home. Do not give yourself this medicine if you do not understand how to use the injection and properly dispose of used needles and syringes.

Do not mix dalteparin with other medications in the same syringe unless your doctor tells you to.

Prepare your dose in a syringe only when you are ready to give yourself an injection. Do not use dalteparin if it has changed colors or has particles in it. Call your pharmacist for new medication.

You should be sitting or lying down during the injection. Do not inject dalteparin into a muscle.

Use a different place on your stomach each time you give the injection. Your care provider will show you the best places on your body to inject the medication. Do not inject into the same place two times in a row.

If you use a single-dose prefilled syringe, follow the injection instructions closely. Single-dose syringes come in two different types and the directions for use are not the same for each type.

Use a disposable needle only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

Tell any doctor who treats you that you are using dalteparin. If you need surgery or dental work, tell the surgeon or dentist ahead of time that you are using this medication. If you need anesthesia for a medical procedure or surgery, you may need to stop using dalteparin for a short time.

While using dalteparin, your blood and your stool (bowel movement) may need to be tested often. Your nerve and muscle function may also need to be tested.

Store dalteparin vials (bottles) at room temperature away from moisture and heat. Once you have used a vial for the first time, the medicine will keep at room temperature for up to 2 weeks. Throw away the vial after 2 weeks have passed since you first punctured the vial, even if there is still medicine left inside.

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.

Avoid taking aspirin unless your doctor recommends it as part of your treatment. Aspirin can increase your risk of bleeding.

Avoid activities that may increase your risk of bleeding or injury. Use extra care to prevent bleeding while shaving or brushing your teeth.

Unstable Angina and Non-ST-Segment Elevation MI (NSTEMI)

Used to reduce the risk of acute cardiac ischemic events (death, MI) in patients with unstable angina or NSTEMI.1 49 51 52 53 54 66 103 104 991 Used concurrently with aspirin and/or other standard therapy (e.g., nitrates, β-adrenergic blockers, clopidogrel, platelet glycoprotein [GP] IIb/IIIa-receptor inhibitors).1 49 51 52 53 54 66 103 104 991

Initiate anticoagulant therapy as soon as possible after hospital admission.991

In patients undergoing an invasive management strategy, the American College of Cardiology (ACC), the American Heart Association (AHA), and the American College of Cardiology Foundation (ACCF) recommend use of an LMWH, heparin (referring throughout this monograph to unfractionated heparin), bivalirudin, or fondaparinux for anticoagulant therapy.991

In patients undergoing a conservative management strategy, recommended anticoagulants include an LMWH, heparin, or fondaparinux; fondaparinux is preferred in patients with an increased risk of bleeding.991

ACC/AHA/ACCF state that limited data are available for the use of dalteparin compared with enoxaparin in patients with unstable angina or NSTEMI.991

Thromboprophylaxis in Hip-Replacement, Knee-Replacement, or Hip-Fracture Surgery

Prevention of postoperative DVT, which may lead to PE, in patients undergoing hip-replacement surgery.1 60 63 64 1003

LMWHs also have been used for prophylaxis of DVT and/or PE in patients undergoing total knee-replacement† and hip-fracture surgery†.1003

ACCP recommends routine thromboprophylaxis with a pharmacologic (e.g., LMWH) and/or mechanical method in all patients undergoing major orthopedic surgery because of high risk of postoperative venous thromboembolism; continue thromboprophylaxis for at least 10–14 days, and possibly for up to 35 days after surgery.1003

Several antithrombotic agents (e.g., LMWHs, fondaparinux, low-dose heparin, warfarin, aspirin) are recommended by ACCP for pharmacologic prophylaxis during major orthopedic surgery.1003 When selecting an appropriate thromboprophylaxis regimen, consider factors such as relative efficacy, safety, logistics, and compliance.1003

Thromboprophylaxis in General/Abdominal Surgery

Prevention of postoperative DVT, which may lead to PE, in patients undergoing general/abdominal surgery who are at risk for thromboembolic complications.1 3 6 7 8 9 10 19 20 21 22 1002

ACCP recommends pharmacologic (e.g., LMWHs) and/or nonpharmacologic/mechanical (e.g., intermittent pneumatic compression) methods of thromboprophylaxis in patients undergoing general surgery, including abdominal, GI, gynecologic, and urologic surgery, according to the patient’s risk of thromboembolism and bleeding.1002 In general, pharmacologic prophylaxis is recommended in patients with high (and possibly moderate) risk of venous thromboembolism who do not have a high risk of bleeding, while mechanical methods are suggested in patients who require thromboprophylaxis but have a high risk of bleeding.1002

If pharmacologic prophylaxis is used in patients undergoing general surgery, ACCP states that an LMWH or low-dose heparin is preferred.1002

Because risk of venous thromboembolism is particularly high in patients undergoing abdominal or pelvic surgery for cancer, extended (4 weeks) prophylaxis with an LMWH is recommended in such patients.1002

ACCP states that the recommendations for use of antithrombotic agents in general surgery patients can be applied to patients undergoing bariatric, vascular, and plastic/reconstructive surgery.1002

Medical Conditions Predisposing to Thromboembolism

Prevention of DVT, which may lead to PE, in patients with severely restricted mobility during acute illness.1 125 1001

In general, pharmacologic thromboprophylaxis recommended only in patients considered to be at high risk of venous thromboembolism.1001

ACCP recommends anticoagulant prophylaxis (e.g., LMWH) in acutely ill, hospitalized medical patients at increased risk of thrombosis who are not actively bleeding and do not have an increased risk of bleeding.1001 Continued thromboprophylaxis suggested for 6–21 days until full mobility is restored or until hospital discharge, whichever comes first.1001

Use of LMWHs also suggested by ACCP for pharmacologic thromboprophylaxis in critically ill patients (e.g., those in an intensive care unit [ICU]) who are not actively bleeding and do not have risk factors for bleeding.1001

Risk of venous thromboembolism particularly high in patients with cancer.1001 Use of LMWH prophylaxis suggested by ACCP in cancer outpatients with solid tumors who have additional risk factors for thromboembolism provided risk of bleeding is low.1001

Thromboprophylaxis in Cardiac Surgery

Mechanical methods of prophylaxis generally recommended in patients undergoing cardiac surgery; however, ACCP states that an LMWH may be considered for thromboprophylaxis in cardiac surgery† patients with a complicated postoperative course.1002

Thromboprophylaxis in Thoracic Surgery

Pharmacologic thromboprophylaxis (e.g., LMWH) recommended by ACCP in patients undergoing thoracic surgery† who are at high risk of venous thromboembolism, provided risk of bleeding is low.1002

Thromboprophylaxis in Neurosurgery

LMWHs have been used for prevention of venous thromboembolism in patients undergoing craniotomy†; however, benefits of such prophylaxis may be outweighed by possible increased risk of intracranial hemorrhage.1002 ACCP states that LMWH prophylaxis may be considered in patients at very high risk of thromboembolism (e.g., those undergoing craniotomy for malignant disease) once adequate hemostasis established and risk of bleeding decreases.1002

Thromboprophylaxis with LMWHs also may be considered in high-risk patients undergoing spinal surgery† (e.g., those with malignancy or those undergoing surgery with a combined anterior-posterior approach) once adequate hemostasis established and risk of bleeding decreases.1002

Thromboprophylaxis in Trauma

LMWHs may be used for thromboprophylaxis in patients with major trauma†.1002 For major trauma patients at high risk of venous thromboembolism, including those with acute spinal cord injury, traumatic brain injury, or spinal surgery for trauma, ACCP suggests use of both a pharmacologic and mechanical method of prophylaxis unless contraindications exist.1002

Extended Treatment of Acute Venous Thromboembolism in Cancer Patients

Used for extended (6 months' duration) treatment of symptomatic DVT and/or PE in patients with cancer to reduce recurrence (secondary prevention) of venous thromboembolism.1 Manufacturer states that safety and efficacy of treatment durations >6 months not established.1

Acute Venous Thromboembolism

Manufacturer states that dalteparin not indicated for the acute treatment of venous thromboembolism;†1 however, has been recommended by ACCP as an appropriate option for initial treatment of acute proximal DVT and/or PE.1005

LMWHs or fondaparinux generally preferred over heparin for initial treatment of acute venous thromboembolism; however, heparin may be preferred in patients with renal impairment.1005 IV heparin also may be preferred over LMWHs in patients with PE in whom thrombolytic therapy is being considered or if there is concern about adequate sub-Q absorption.1005

For long-term anticoagulant therapy, warfarin generally preferred in patients without cancer; however, ACCP suggests use of an LMWH in patients with cancer because of a possible reduced response to warfarin.1005

Continue anticoagulant therapy for ≥3 months and possibly longer depending on individual clinical situation.1005

Venous Thromboembolism in Pediatric Patients

An LMWH has been used for treatment and secondary prevention of venous thromboembolism in pediatric patients†; venous thromboembolism usually occurs secondary to an identifiable risk factor (e.g., presence of central venous access device in such patients).1013

Recommendations regarding use of antithrombotic therapy in children generally based on extrapolation from adult guidelines.1013

ACCP recommends an LMWH or heparin for both initial and ongoing treatment of venous thromboembolism in children.1013 Potential advantages of an LMWH over heparin include reduced need for monitoring, lack of drug or dietary interactions, reduced risk of heparin-induced thrombocytopenia (HIT), and possible reduced risk of osteoporosis.1013

In children with central venous catheter-related thromboembolism, ACCP recommends removal of catheter if no longer functioning or required; at least 3–5 days of therapeutic anticoagulation is suggested prior to removal.1013 If such catheters must remain in place, ACCP suggests anticoagulant therapy until catheter is removed.1013

Acute ST-Segment Elevation MI (STEMI)

LMWHs are used in combination with thrombolytic therapy and/or antiplatelet agents (e.g., aspirin, a P2Y12 receptor antagonist, GP IIb/IIIa-receptor inhibitor) during and after successful coronary artery reperfusion for the prevention of ischemic complications (e.g., death, reinfarction, stroke) in patients with acute STEMI†.145

Some experts state use of an LMWH also may be reasonable in patients with STEMI who are not receiving thrombolytic therapy, provided no contraindications to anticoagulation exist.145

Adjunctive use of an LMWH in patients with STEMI associated with improvement in short-term clinical outcomes (e.g., death, reinfarction, recurrent ischemia) with generally similar rates of bleeding complications compared with adjunctive heparin or placebo.145 147 148 149 150 151

LMWHs may be preferred over heparin in patients who have preserved renal function (Scr ≤2.5 mg/dL in men or ≤2 mg/dL in women).145

Also used for prevention of systemic embolism following STEMI in high-risk patients (e.g., patients with large or anterior MI, atrial fibrillation, previous embolus, documented left ventricular thrombus, cardiogenic shock).145

Not recommended in place of heparin as adjunctive therapy for patients with STEMI >75 years of age or who have renal dysfunction (Scr >2.5 mg/dL in men or >2 mg/dL in women).145

Treatment of Superficial Vein Thrombosis

LMWHs also have been used for spontaneous superficial vein thrombosis (superficial thrombophlebitis)†; ACCP suggests use of prophylactic dosages for 45 days in patients with superficial vein thrombosis of ≥5 cm in length.1005

Treatment of Renal Vein Thrombosis

Although use of anticoagulant therapy for renal vein thrombosis† (the most common cause of spontaneous venous thromboembolism in neonates) is controversial, LMWHs are suggested by ACCP as a possible treatment option.1013

Thromboprophylaxis in Acute Ischemic Stroke

Heparin anticoagulants (i.e., LMWHs or heparin) have been used for thromboprophylaxis in selected patients with acute ischemic stroke†; those with additional risk factors for venous thromboembolism are more likely to benefit from such prophylaxis.1009 1017

ACCP suggests thromboprophylaxis with an LMWH, sub-Q heparin, or intermittent pneumatic compression in patients with acute ischemic stroke† and restricted mobility; LMWH is preferred over heparin.1009

Prophylactic-dose heparin (heparin or an LMWH) usually initiated within 48 hours of onset of stroke and is continued throughout hospital stay until patient regains mobility; do not administer within the first 24 hours after thrombolytic therapy.1009

LMWHs also recommended by ACCP as an option for initial management of acute arterial ischemic stroke in children† until dissection and embolic causes have been excluded.1013 If arterial ischemic stroke is associated with dissection or a cardioembolic origin, continued anticoagulant therapy suggested.1013

In children with acute arterial ischemic stroke secondary to non-Moyamoya vasculopathy†, ACCP recommends ongoing antithrombotic therapy (e.g., with an LMWH) for 3 months.1013

LMWHs may be considered in neonates with a first episode of arterial ischemic stroke† associated with a documented cardioembolic source.1013

Thromboembolism During Pregnancy

Used during pregnancy for prevention and treatment of venous thromboembolism† and for prevention and treatment of systemic embolism associated with mechanical heart valves†.138 996 1012 (See Prevention and Treatment of Thromboembolism During Pregnancy under Dosage and Administration.)

Also has been used in combination with low-dose aspirin for prevention of recurrent pregnancy loss in women with antiphospholipid antibody (APLA) syndrome†.1012

LMWHs (rather than heparin or warfarin) are recommended by ACCP for prevention and treatment of thromboembolism during pregnancy.1012

In pregnant women with an acute venous thromboembolic event†, ACCP recommends an LMWH for initial treatment and secondary prevention throughout the remainder of the pregnancy.1012 To prevent recurrence, postpartum anticoagulation (for ≥6 weeks and for a total duration of ≥3 months) is suggested.1012

In general, thromboprophylaxis (e.g., with an LMWH) is suggested during the antepartum period only in pregnant women who have a history of thromboembolism† and are considered to be at moderate to high risk of recurrent events (e.g., those with a single episode of unprovoked venous thromboembolism, pregnancy- or estrogen-related venous thromboembolism, history of multiple unprovoked events).1012

Postpartum thromboprophylaxis† for 6 weeks suggested in all pregnant women with a prior venous thromboembolic event; an LMWH (in prophylactic or intermediate dosages) or warfarin (INR 2–3) may be used for such prophylaxis.1012

ACCP suggests antepartum and postpartum prophylaxis with an LMWH in some pregnant women with high-risk hereditary thrombophilias† (e.g., homozygous genetic mutations for factor V Leiden or prothrombin G20210A) who have not experienced a prior venous thromboembolic event, but have a family history of thromboembolism.1012

Discontinue LMWH therapy ≥24 hours prior to induction of labor or cesarean section (or expected time of neuraxial anesthesia) to avoid an unwanted anticoagulant effect on fetus.1012

Cardioversion of Atrial Fibrillation/Flutter

LMWHs have been used for prevention of stroke and systemic embolism in patients with atrial fibrillation or atrial/flutter undergoing electrical or pharmacologic cardioversion†.999 1007

As an alternative to prolonged anticoagulation (e.g., usually with warfarin) prior to cardioversion in patients with atrial fibrillation lasting >48 hours or of unknown duration, an LMWH (in therapeutic dosages) may be used at the time of transesophageal echocardiography (TEE), followed by cardioversion within 24 hours if no thrombus is detected.999 1007

In patients with atrial fibrillation of short duration (e.g., ≤48 hours), an LMWH (in therapeutic dosages) may be used at presentation, followed by immediate cardioversion.1007

In patients with hemodynamic instability who require urgent cardioversion, ACCP suggests administration of a parenteral anticoagulant (in therapeutic dosages) prior to cardioversion if possible; however, such anticoagulant therapy must not delay any emergency intervention.999 1007

After successful cardioversion to sinus rhythm, all patients should receive therapeutic anticoagulation for ≥4 weeks.999 1007

Thromboprophylaxis in Patients with Prosthetic Heart Valves

Used during conversion to maintenance therapy with warfarin to reduce the incidence of thromboembolism in patients with prosthetic mechanical heart valves†.1008

ACCP suggests bridging anticoagulation (an LMWH in either prophylactic or therapeutic dosages or IV heparin in prophylactic dosages) during the early postoperative period after insertion of a mechanical heart valve in patients without bleeding risk, until an adequate response to warfarin is obtained.1008

Also may be used for bridging anticoagulation in patients with a mechanical heart valve in whom therapy with warfarin must be temporarily discontinued (e.g., those undergoing major surgery).1004

Has been used for thromboprophylaxis in pregnant women with prosthetic mechanical heart valves†.138 1012 (See Thromboembolism During Pregnancy under Uses.)

Treatment of Cerebral Venous Sinus Thrombosis

May be used for the treatment of acute cerebral venous sinus (sinovenous) thrombosis† in adults.1009 1017 Once patient stabilized, may convert to coumarin anticoagulant therapy.138 1009 1017

Reasonable to use full-dose LMWH rather than heparin for treatment of acute cerebral venous sinus thrombosis during pregnancy.1017 Prophylaxis with an LMWH during pregnancy and the postpartum period is reasonable in women with history of cerebral venous sinus thrombosis.1017

Recommended by ACCP as an option for initial and follow-up anticoagulation in children with cerebral venous sinus thrombosis† without substantial intracranial hemorrhage.1013 Also has been suggested for use in children with substantial intracranial hemorrhage.1013

LMWHs also suggested by ACCP as a treatment option for neonates with cerebral sinovenous thrombosis†.1013

Perioperative Antithrombotic Prophylaxis

ACCP suggests use of an LMWH or IV heparin during temporary interruption of warfarin therapy (bridging anticoagulation†) in selected patients with venous thromboembolism, atrial fibrillation, or mechanical prosthetic heart valves undergoing surgery or other invasive procedures; use and type of bridging anticoagulation depend on patients' risk of developing thromboembolism without warfarin therapy.1004

In general, bridging anticoagulation is suggested in such patients who are considered to be at particularly high risk of venous thromboembolism without oral anticoagulant therapy.1004

In the U.S.

• Fragmin

Available Dosage Forms:

• Solution
• Injectable

Therapeutic Class: Anticoagulant

Pharmacologic Class: Low Molecular Weight Heparin

2,500 IU / 0.2 mL single-dose prefilled syringe

5,000 IU / 0.2 mL single-dose prefilled syringe

7,500 IU / 0.3 mL single-dose prefilled syringe

10,000 IU / mL single-dose graduated syringe

12,500 IU / 0.5 mL single-dose prefilled syringe

15,000 IU / 0.6 mL single-dose prefilled syringe

18,000 IU / 0.72 mL single-dose prefilled syringe

95,000 IU / 3.8 mL multiple-dose vial (25,000 IU / mL)

Carcinogenesis, Mutagenesis, Impairment of Fertility

Dalteparin sodium has not been tested for its carcinogenic potential in long-term animal studies. It was not mutagenic in the in vitro Ames Test, mouse lymphoma cell forward mutation test and human lymphocyte chromosomal aberration test and in the in vivo mouse micronucleus test. Dalteparin sodium at subcutaneous doses up to 1,200 IU/kg (7,080 IU/m2) did not affect the fertility or reproductive performance of male and female rats.

Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction

In a double-blind, randomized, placebo-controlled clinical trial, patients who recently experienced unstable angina with EKG changes or non-Q-wave myocardial infarction (MI) were randomized to Fragmin Injection 120 IU/kg or placebo every 12 hours subcutaneously. In this trial, unstable angina was defined to include only angina with EKG changes. All patients, except when contraindicated, were treated concurrently with aspirin (75 mg once daily) and beta blockers. Treatment was initiated within 72 hours of the event (the majority of patients received treatment within 24 hours) and continued for 5 to 8 days. A total of 1506 patients were enrolled and treated; 746 received Fragmin and 760 received placebo. The mean age of the study population was 68 years (range 40 to 90 years) and the majority of patients were white (99.7%) and male (63.9%). The combined incidence of the endpoint of death or myocardial infarction was lower for Fragmin compared with placebo at 6 days after initiation of therapy. These results were observed in an analysis of all-randomized and all-treated patients. The combined incidence of death, MI, need for intravenous heparin or intravenous. nitroglycerin, and revascularization was also lower for Fragmin than for placebo (see Table 10).

In a second randomized, controlled trial designed to evaluate long-term treatment with Fragmin (days 6 to 45), data were also collected comparing 1-week (5 to 8 days) treatment of Fragmin 120 IU/kg every 12 hours subcutaneously with heparin at an APTT-adjusted dosage. All patients, except when contraindicated, were treated concurrently with aspirin (100 to 165 mg per day). Of the 1,499 patients enrolled, 1,482 patients were treated; 751 received Fragmin and 731 received heparin. The mean age of the study population was 64 years (range 25 to 92 years) and the majority of patients were white (96.0%) and male (64.2%). The incidence of the combined endpoint of death, myocardial infarction, or recurrent angina during this 1-week treatment period (5 to 8 days) was 9.3% for Fragmin and 7.6% for heparin (p=0.323).

Prophylaxis of Deep Vein Thrombosis in Patients Following Hip Replacement Surgery

In an open-label randomized study, Fragmin 5,000 IU administered once daily subcutaneously was compared with warfarin sodium, administered orally, in patients undergoing hip replacement surgery. Treatment with Fragmin was initiated with a 2,500 IU dose subcutaneously within 2 hours before surgery, followed by a 2,500 IU dose subcutaneously the evening of the day of surgery. Then, a dosing regimen of Fragmin 5,000 IU subcutaneously once daily was initiated on the first postoperative day. The first dose of warfarin sodium was given the evening before surgery, then continued daily at a dose adjusted for INR 2 to 3. Treatment in both groups was then continued for 5 to 9 days postoperatively. Of the 580 patients enrolled, 553 were treated and 550 underwent surgery. Of those who underwent surgery, 271 received Fragmin and 279 received warfarin sodium. The mean age of the study population was 63 years (range 20 to 92 years) and the majority of patients were white (91.1%) and female (52.9%). The incidence of deep vein thrombosis (DVT), as determined by evaluable venography, was significantly lower for the group treated with Fragmin compared with patients treated with warfarin sodium (see Table 11).

In a second single-center, double-blind study of patients undergoing hip replacement surgery, Fragmin 5,000 IU once daily subcutaneously starting the evening before surgery, was compared with heparin 5,000 U subcutaneously three times a day, starting the morning of surgery. Treatment in both groups was continued for up to 9 days postoperatively. Of the 140 patients enrolled, 139 were treated and 136 underwent surgery. Of those who underwent surgery, 67 received Fragmin and 69 received heparin. The mean age of the study population was 69 years (range 42 to 87 years) and the majority of patients were female (58.8%). In the intent-to-treat analysis, the incidence of proximal DVT was significantly lower for patients treated with Fragmin compared with patients treated with heparin (6/67 vs 18/69; p=0.012). The incidence of pulmonary embolism detected by lung scan was also significantly lower in the group treated with Fragmin (9/67 vs 19/69; p=0.032).

A third multi-center, double-blind, randomized study evaluated a postoperative dosing regimen of Fragmin for thromboprophylaxis following total hip replacement surgery. Patients received either Fragmin or warfarin sodium, randomized into one of three treatment groups. One group of patients received the first dose of Fragmin 2,500 IU subcutaneous within 2 hours before surgery, followed by another dose of Fragmin 2,500 IU subcutaneous at least 4 hours (6.6 ± 2.3 hr) after surgery. Another group received the first dose of Fragmin 2,500 IU subcutaneous at least 4 hours (6.6 ± 2.4 hr) after surgery. Then, both of these groups began a dosing regimen of Fragmin 5,000 IU once daily subcutaneous on postoperative day 1. The third group of patients received warfarin sodium the evening of the day of surgery, then continued daily at a dose adjusted to maintain INR 2 to 3. Treatment for all groups was continued for 4 to 8 days postoperatively, after which time all patients underwent bilateral venography.

In the total enrolled study population of 1,501 patients, 1472 patients were treated; 496 received Fragmin (first dose before surgery), 487 received Fragmin (first dose after surgery) and 489 received warfarin sodium. The mean age of the study population was 63 years (range 18 to 91 years) and the majority of patients were white (94.4%) and female (51.8%).

Administration of the first dose of Fragmin after surgery was as effective in reducing the incidence of thromboembolic reactions as administration of the first dose of Fragmin before surgery (44/336 vs 37/338; p=0.448). Both dosing regimens of Fragmin were more effective than warfarin sodium in reducing the incidence of thromboembolic reactions following hip replacement surgery.

Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery in Patients at Risk for Thromboembolic Complications

Abdominal surgery patients at risk include those who are over 40 years of age, obese, undergoing surgery under general anesthesia lasting longer than 30 minutes, or who have additional risk factors such as malignancy or a history of deep vein thrombosis or pulmonary embolism.

Fragmin administered once daily subcutaneously beginning prior to surgery and continued for 5 to 10 days after surgery, reduced the risk of DVT in patients at risk for thromboembolic complications in two double-blind, randomized, controlled clinical trials performed in patients undergoing major abdominal surgery. In the first study, a total of 204 patients were enrolled and treated; 102 received Fragmin and 102 received placebo. The mean age of the study population was 64 years (range 40 to 98 years) and the majority of patients were female (54.9%). In the second study, a total of 391 patients were enrolled and treated; 195 received Fragmin and 196 received heparin. The mean age of the study population was 59 years (range 30 to 88 years) and the majority of patients were female (51.9%). Fragmin 2,500 IU was superior to placebo and similar to heparin in reducing the risk of DVT (see Tables 12 and 13).

In a third double-blind, randomized study performed in patients undergoing major abdominal surgery with malignancy, Fragmin 5,000 IU subcutaneous once daily was compared with Fragmin 2,500 IU subcutaneous once daily. Treatment was continued for 6 to 8 days. A total of 1,375 patients were enrolled and treated; 679 received Fragmin 5,000 IU and 696 received 2,500 IU. The mean age of the combined groups was 71 years (range 40 to 95 years). The majority of patients were female (51.0%). Fragmin 5,000 IU once daily was more effective than Fragmin 2,500 IU once daily in reducing the risk of DVT in patients undergoing abdominal surgery with malignancy (see Table 14).

Prophylaxis of Deep Vein Thrombosis in Medical Patients at Risk for Thromboembolic Complications Due to Severely Restricted Mobility During Acute Illness

In a double-blind, multi-center, randomized, placebo-controlled clinical trial, general medical patients with severely restricted mobility who were at risk of venous thromboembolism were randomized to receive either Fragmin 5,000 IU or placebo subcutaneously once daily during Days 1 to 14 of the study. These patients had an acute medical condition requiring a projected hospital stay of at least 4 days, and were confined to bed during waking hours. The study included patients with congestive heart failure (NYHA Class III or IV), acute respiratory failure not requiring ventilatory support, and the following acute conditions with at least one risk factor occurring in > 1% of treated patients: acute infection (excluding septic shock), acute rheumatic disorder, acute lumbar or sciatic pain, vertebral compression, or acute arthritis of the lower extremities. Risk factors include > 75 years of age, cancer, previous DVT/PE, obesity and chronic venous insufficiency. A total of 3,681 patients were enrolled and treated: 1,848 received Fragmin and 1,833 received placebo. The mean age of the study population was 69 years (range 26 to 99 years), 92.1% were white and 51.9% were female. The primary efficacy endpoint was evaluated at Day 21 and was defined as at least one of the following within Days 1 to 21 of the study: asymptomatic DVT (diagnosed by compression ultrasound), a confirmed symptomatic DVT, a confirmed pulmonary embolism or sudden death. The follow-up extended through Day 90.

When given at a dose of 5,000 IU once a day subcutaneously, Fragmin significantly reduced the incidence of thromboembolic reactions including verified DVT by Day 21 (see Table 15). The prophylactic effect was sustained through Day 90.

Patients with Cancer and Acute Symptomatic Venous Thromboembolism

In a prospective, multi-center, open-label, clinical trial, 676 patients with cancer and newly diagnosed, objectively confirmed acute deep vein thrombosis (DVT) and/or pulmonary embolism (PE) were studied. Patients were randomized to either Fragmin 200 IU/kg subcutaneous (max 18,000 IU subcutaneous daily for one month) then 150 IU/kg subcutaneous (max 18,000 IU subcutaneous daily for five months (Fragmin arm) or Fragmin 200 IU/kg subcutaneous (max 18,000 IU subcutaneous daily for five to seven days and oral anticoagulant for six months (OAC arm). In the OAC arm, oral anticoagulation was adjusted to maintain an INR of 2 to 3. Patients were evaluated for recurrence of symptomatic venous thromboembolism (VTE) every two weeks for six months.

The median age of patients was 64 years (range: 22 to 89 years); 51.5% of patients were females; 95.3% of patients were Caucasians. Types of tumors were: gastrointestinal tract (23.7%), genito-urinary (21.5%), breast (16%), lung (13.3%), hematological tumors (10.4%) and other tumors (15.1%).

A total of 27 (8.0%) and 53 (15.7%) patients in the Fragmin and OAC arms, respectively, experienced at least one episode of an objectively confirmed, symptomatic DVT and/or PE during the 6-month study period. Most of the difference occurred during the first month of treatment (see Table 16). The benefit was maintained over the 6-month study period.

In the intent-to-treat population that included all randomized patients, the primary comparison of the cumulative probability of the first VTE recurrence over the 6-month study period was statistically significant (p < 0.01) in favor of the Fragmin arm, with most of the treatment difference evident in the first month.

Store at 20°C to 25°C (68°F to 77°F);
excursion permitted between
15°C to 30°C (59°F to 86°F) [see USP
Controlled Room Temperature].

DOSAGE AND USE: See accompanying
prescribing information.

Distributed by Pfizer Labs
Division of Pfizer Inc
New York, NY 10017

1 mL Single-dose graduated syringe
NDC 0069-0217-01

Fragmin® (dalteparin sodium) Injection

10,000 IU per mL

For subcutaneous injection.
Rx only

10005278-02

To Open Pull Tab

NDC 0069-0223-02
Contains 10 of NDC 0069-0223-01

10 x 0.6 mL Single-dose prefilled syringes,
preassembled with needle guards

Fragmin®

(dalteparin sodium) Injection

15,000 IU per 0.6 mL*

For subcutaneous injection
Sterile

Pfizer Injectables
Rx only

More Common Side Effects

The more common side effects of Fragmin can include:

• a swelling filled with blood at the injection site

• increased bruising or bleeding

• longer bleeding from cuts or scrapes

If these effects are mild, they may go away within a few days or a couple of weeks. If they’re more severe or don’t go away, talk to your doctor or pharmacist.