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Fragmin

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Fragmin




Warnings
Precautions

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Risk Of Hemorrhage Including Spinal / Epidural Hematoma

Spinal or epidural hemorrhage and subsequent hematomas can occur with the associated use of low molecular weight heparins or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture. The risk of these events is higher with the use of post-operative indwelling epidural catheters, with the concomitant use of additional drugs affecting hemostasis such as NSAIDs, with traumatic or repeated epidural or spinal puncture, or in patients with a history of spinal surgery or spinal deformity [see BOXED WARNING and ADVERSE REACTIONS and DRUG INTERACTIONS].

To reduce the potential risk of bleeding associated with the concurrent use of dalteparin sodium and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of dalteparin [see CLINICAL PHARMACOLOGY].

Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of dalteparin is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. No additional hemostasis-altering medications should be administered due to the additive effects.

Patients on preoperative FRAGMIN thromboprophylaxis can be assumed to have altered coagulation. The first postoperative FRAGMIN thrombophylaxis dose (2500 IU) should be administered 6 to 8 hrs postoperatively. The second postoperative dose (2500 or 5000 IU) should occur no sooner than 24 hrs after the first dose. Placement or removal of a catheter should be delayed for at least 12 hours after administration of 2500 IU once daily of FRAGMIN, at least 15 hours after the administration of 5000 IU once daily of FRAGMIN, and at least 24 hours after the administration of higher doses (200 IU/kg once daily, 120 IU/kg twice daily) of

FRAGMIN. Anti-Xa levels are still detectable at these time points, and these delays are not a guarantee that neuraxial hematoma will be avoided.

Although a specific recommendation for timing of a subsequent FRAGMIN dose after catheter removal cannot be made, 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. For patients with creatinine clearance < 30mL/minute, additional considerations are necessary because elimination of FRAGMIN may be more prolonged; consider doubling the timing of removal of a catheter, at least 24 hours for the lower prescribed dose of FRAGMIN (2500 IU or 5000 IU once daily) and at least 48 hours for the higher dose (200 IU/kg once daily, 120 IU/kg twice daily) [see CLINICAL PHARMACOLOGY].

Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to report immediately if they experience any of the above signs or symptoms. 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.

Use FRAGMIN with extreme caution in patients who have an increased risk of hemorrhage, such as those with severe uncontrolled hypertension, bacterial endocarditis, congenital or acquired bleeding disorders, active ulceration and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal or ophthalmological surgery. FRAGMIN may enhance the 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 with FRAGMIN.

Thrombocytopenia

Heparin-induced thrombocytopenia can occur with the administration of FRAGMIN. The incidence of this complication is unknown at present. In clinical practice, cases of thrombocytopenia with thrombosis, amputation and death have been observed. [see CONTRAINDICATIONS] Closely monitor thrombocytopenia of any degree.

In FRAGMIN clinical trials supporting non-cancer indications, platelet counts of < 50,000/mm³ occurred in < 1% of patients.

In the clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated for up to 6 months in the FRAGMIN treatment arm, platelet counts of < 100,000/mm³ occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/mm³. In the same clinical trial, thrombocytopenia was reported as an adverse event in 10.9% of patients in the FRAGMIN arm and 8.1% of patients in the OAC arm. FRAGMIN dose was decreased or interrupted in patients whose platelet counts fell below 100,000/mm³.

Benzyl Alcohol Preservative Risk To Premature Infants

Each multiple-dose vial of FRAGMIN contains benzyl alcohol as a preservative. Benzyl alcohol has been reported to be associated with a fatal “Gasping Syndrome” in premature infants. Because benzyl alcohol may cross the placenta, use caution when administering FRAGMIN preserved with benzyl alcohol to pregnant women. If anticoagulation with FRAGMIN is needed during pregnancy, use preservative-free formulations, where possible. [see Use in Specific Populations].

Laboratory Tests

Periodic routine complete blood counts, including platelet count, blood chemistry, and stool occult blood tests are recommended during the course of treatment with FRAGMIN. When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively insensitive measures of FRAGMIN activity and, therefore, unsuitable for monitoring the anticoagulant effect of FRAGMIN. Anti-Factor Xa may be used to monitor the anticoagulant effect of FRAGMIN, such as in patients with severe renal impairment or if abnormal coagulation parameters or bleeding occurs during FRAGMIN therapy.

Nonclinical Toxicology

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 1200 IU/kg (7080 IU/m²) did not affect the fertility or reproductive performance of male and female rats.

Use In Specific Populations

Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies of FRAGMIN use in pregnant women. In reproductive and developmental toxicity studies, pregnant rats and rabbits received dalteparin sodium at intravenous doses up to 2400 IU/kg (14,160 IU/m²) (rats) and 4800 IU/kg (40,800 IU/m²) (rabbits). These exposures were 2 to 4 times (rats) and 4 times (rabbits) the human dose of 100 IU/kg dalteparin based on the body surface area. No evidence of impaired fertility or harm to the fetuses occurred in these studies. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Cases of “Gasping Syndrome” have occurred in premature infants when large amounts of benzyl alcohol have been administered (99–404 mg/kg/day). The 9.5 mL and the 3.8 mL multiple-dose vials of FRAGMIN contain 14 mg/mL of benzyl alcohol [see WARNINGS AND PRECAUTIONS].

Nursing Mothers

Based on limited published data dalteparin is minimally excreted in human milk. One study of 15 lactating women receiving prophylactic doses of dalteparin, in the immediate postpartum period, detected small amounts of anti-Xa activity (range < 0.005 to 0.037 IU/ml) in breast milk that were equivalent to a milk/plasma ratio of < 0.025-0.224. Oral absorption of LMWH is extremely low, but the clinical implications, if any, of this small amount of anticoagulant activity on a nursing infant are unknown. Caution should be exercised when FRAGMIN is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Of the total number of patients in clinical studies of FRAGMIN, 5516 patients were 65 years of age or older and 2237 were 75 or older. No overall differences in effectiveness were observed between these subjects and younger subjects. Some studies suggest that the risk of bleeding increases with age. Postmarketing surveillance and literature reports have not revealed additional differences in the safety of FRAGMIN between elderly and younger patients. Give careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) in geriatric patients, particularly in those with low body weight ( < 45 kg) and those predisposed to decreased renal function [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 2/10/2015
This monograph has been modified to include the generic and brand name in many instances.

Warnings
Precautions
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