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Indications
FRAGMIN is a low molecular weight heparin (LMWH) indicated for
Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction ( 1.1 )
Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip replacement surgery or medical patients with severely restricted mobility during acute illness ( 1.2 )
Extended treatment of symptomatic venous thromboembolism (VTE) to reduce the recurrence in adult patients with cancer. In these patients, the FRAGMIN therapy begins with the initial VTE treatment and continues for six months ( 1.3 )
Treatment of symptomatic venous thromboembolism (VTE) to reduce the recurrence in pediatric patients from birth (gestational age at least 35 weeks) ( 1.4 )
Limitations of Use FRAGMIN is not indicated for the acute treatment of VTE ( 1.5 )
1.1Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction
FRAGMIN Injection is indicated for the prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin therapy [see Clinical Studies (14.1) ] .
1.2Prophylaxis of Deep Vein Thrombosis
FRAGMIN is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE):
In patients undergoing hip replacement surgery [see Clinical Studies (14.2) ] ;
In patients undergoing abdominal surgery who are at risk for thromboembolic complications [see Clinical Studies (14.3) ] ;
In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness [see Clinical Studies (14.4) ] .
1.3Extended Treatment of Symptomatic Venous Thromboembolism (VTE) in Adult Patients with Cancer
FRAGMIN is indicated for the extended treatment of symptomatic venous thromboembolism (VTE) (proximal DVT and/or PE), to reduce the recurrence of VTE in adult patients with cancer. In these patients, the FRAGMIN therapy begins with the initial VTE treatment and continues for six months [see Clinical Studies (14.5) ] .
1.4Treatment of Symptomatic Venous Thromboembolism (VTE) in Pediatric Patients
FRAGMIN is indicated for the treatment of symptomatic venous thromboembolism (VTE) to reduce the recurrence of VTE in pediatric patients from birth (gestational age at least 35 weeks) .
1.5Limitations of Use
FRAGMIN is not indicated for the acute treatment of VTE.
Contraindications
FRAGMIN is contraindicated in:
Patients with active major bleeding.
Patients with a history of heparin induced thrombocytopenia or heparin induced thrombocytopenia with thrombosis.
Patients with prior hypersensitivity to dalteparin sodium (e.g., pruritis, rash, anaphylactic reactions) [see Adverse Reactions (6.1) ] .
Patients undergoing Epidural/Neuraxial anesthesia, do not administer FRAGMIN [see Boxed Warning and Warnings and Precautions (5.1) ] ; o As a treatment for unstable angina and non-Q-wave MI. o For prolonged VTE prophylaxis.
Patients with prior hypersensitivity to heparin or pork products.
Active major bleeding ( 4 )
History of heparin induced thrombocytopenia or heparin induced thrombocytopenia with thrombosis ( 4 )
Hypersensitivity to dalteparin sodium ( 4 , 6.1 )
In patients undergoing Epidural/Neuraxial anesthesia, do not administer FRAGMIN ( 5.1 ) o As a treatment for unstable angina and non-Q-wave MI o For prolonged VTE prophylaxis ( 4 )
Hypersensitivity to heparin or pork products ( 4 )
Warnings and precautions
Hemorrhage: Use caution in conditions with increased risk of hemorrhage ( 5.1 )
Thrombocytopenia: Monitor thrombocytopenia of any degree closely ( 5.2 )
Benzyl Alcohol Preservative: Do not use multiple-dose formulations in neonates and infants as they contain benzyl alcohol ( 5.3 )
5.1 Risk of Hemorrhage including Spinal/Epidural Hematomas 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 , Adverse Reactions (6.2) , and Drug Interactions (7) ] .
To reduce the potential risk of bleeding associated with the concurrent use of FRAGMIN and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of FRAGMIN [see Clinical Pharmacology (12.3) ]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of FRAGMIN 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 thromboprophylaxis dose (2,500 units) should be administered 6 hours to 8 hours postoperatively. The second postoperative dose (2,500 units or 5,000 units) should occur no sooner than 24 hours after the first dose.
Placement or removal of a catheter should be delayed for at least 12 hours after administration of 2,500 units once daily of FRAGMIN, at least 15 hours after the administration of 5,000 units once daily of FRAGMIN, and at least 24 hours after the administration of higher doses (200 units/kg once daily, 120 units/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 4 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 <30 mL/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 (2,500 units or 5,000 units once daily) and at least 48 hours for the higher dose (200 units/kg once daily, 120 units/kg twice daily) [see Clinical Pharmacology (12.3) ].
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.
5.2Thrombocytopenia
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 (4) ] . Closely monitor thrombocytopenia of any degree. In FRAGMIN clinical trials supporting non-cancer indications, platelet counts of <50,000/mm 3 occurred in <1% of patients.
In the clinical trial of adult patients with cancer and acute symptomatic VTE treated for up to 6 months in the FRAGMIN treatment arm, platelet counts of <100,000/mm 3 occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/mm 3 . 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 Oral Anti-Coagulant (OAC) arm.
FRAGMIN dose was decreased or interrupted in patients whose platelet counts fell below 100,000/mm 3 . In the clinical trial of pediatric patients with or without cancer with acute symptomatic VTE treated for up to 3 months with FRAGMIN, platelet counts of <100,000/mm 3 occurred in 37% of patients, including 21% who also had platelet counts less than 50,000/mm 3 . In the same clinical trial, thrombocytopenia was reported as an adverse reaction in 21% of patients.
FRAGMIN dose was interrupted in patients whose platelet counts fell below 50,000/mm 3 .
5.3 Risk of Serious Adverse Reactions in Neonates and Infants due to Benzyl Alcohol Preservative Use preservative-free FRAGMIN in neonates and infants. Serious and fatal adverse reactions including "gasping syndrome" can occur in neonates and low-birth weight infants treated with medications that contain the preservative benzyl alcohol. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations.
When prescribing FRAGMIN in infants, consider the combined daily metabolic load of benzyl alcohol from all sources including FRAGMIN multiple-dose vial (contains 14 mg of benzyl alcohol per mL) and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations (8.4) ]. 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 (8.1) ].
5.4Laboratory 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.
Monitor anti-Xa level periodically in pediatric patients. Anti-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.
Interactions
The use of FRAGMIN in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents may increase the risk of bleeding [see Warnings and Precautions (5) ] . The use of FRAGMIN in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents may increase the risk of bleeding ( 7 )
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
Available data from published literature and postmarketing reports have not reported a clear association with FRAGMIN and adverse developmental outcomes. There are risks to the mother associated with untreated VTE in pregnancy, and a potential for adverse effects on the preterm infant when FRAGMIN is used in pregnancy (see Clinical Considerations ) . In animal reproduction studies, there was no evidence of embryo-fetal toxicity or teratogenicity when dalteparin sodium was administered to pregnant rats and rabbits during organogenesis at doses 2 to 4 times (rats) and 4 times (rabbits) the human dose of 100 units/kg dalteparin based on the body surface area (see Data ) .
Because animal reproduction studies are not always predictive of human response, FRAGMIN should be used during pregnancy only if clearly needed. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data describe that women with a previous history of VTE in pregnancy are at higher risk for recurrence during subsequent pregnancies compared to those with no risk factor for VTE (4.5% versus 2.7% respectively, relative risk 1.7, 95% CI: 1.0–2.8). Fetal/Neonatal Adverse Reactions Cases of "gasping syndrome" have occurred in premature infants when large amounts of benzyl alcohol have been administered (99 mg/kg/day to 404 mg/kg/day).
The 3.8 mL multiple-dose vials of FRAGMIN contain 14 mg/mL of benzyl alcohol [see Warnings and Precautions (5.3) ] . Data Animal Data In reproductive and developmental toxicity studies, pregnant rats and rabbits received dalteparin sodium during organogenesis at intravenous doses up to 2,400 units/kg (14,160 units/m 2 ) (rats) and 4,800 units/kg (40,800 units/m 2 ) (rabbits). These exposures were 2 to 4 times (rats) and 4 times (rabbits) the human dose of 100 units/kg dalteparin based on the body surface area.
These studies revealed no evidence of teratogenicity or embryo-fetal toxicity.
Adverse reactions
The following clinically significant adverse reactions are described in more detail in other sections of the prescribing information .
Risk of Hemorrhage including Spinal/Epidural Hematomas [see Warnings and Precautions (5.1) ]
Thrombocytopenia [see Warnings and Precautions (5.2) ]
Benzyl Alcohol Preservative Risk to Premature Infants [see Warnings and Precautions (5.3) ] Most common adverse reactions (>1%) are: bleeding (including hemorrhage), thrombocytopenia (Type I), hematoma at the injection site, pain at the injection site, transient elevation of transaminases ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not accurately reflect the rates observed in practice. Hemorrhage The most commonly reported adverse reactions are hematoma at the injection site and hemorrhagic complications. The risk for bleeding varies with the indication and may increase with higher doses.
Unstable Angina and Non-Q-Wave Myocardial Infarction Table 7 summarizes major bleeding reactions that occurred with FRAGMIN, heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial infarction. Table 7 Major Bleeding Reactions in Unstable Angina and Non-Q-Wave Myocardial Infarction Indication Dosing Regimen Unstable Angina and Non-Q-Wave MI FRAGMIN 120 units/kg/12 hours subcutaneous Treatment was administered for 5 days to 8 days. n (%) Heparin Heparin intravenous infusion for at least 48 hours, APTT 1.5 to 2 times control, then 12,500 units subcutaneously every 12 hours for 5 days to 8 days. intravenous and subcutaneous n (%) Placebo every 12 hours subcutaneous n (%) Major Bleeding Reactions Aspirin (75 mg to 165 mg per day) and beta blocker therapies were administered concurrently. , Bleeding reactions were considered major if: 1) accompanied by a decrease in hemoglobin of ≥2 g/dL in connection with clinical symptoms; 2) a transfusion was required; 3) bleeding led to interruption of treatment or death; or 4) intracranial bleeding. 15/1497 (1.0) 7/731 (1.0) 4/760 (0.5) Hip Replacement Surgery Table 8 summarizes: 1) all major bleeding reactions and, 2) other bleeding reactions possibly or probably related to treatment with FRAGMIN (preoperative dosing regimen), warfarin sodium, or heparin in two hip replacement surgery clinical trials.
Table 8 Bleeding Reactions Following Hip Replacement Surgery Indication FRAGMIN vs Warfarin Sodium FRAGMIN vs Heparin Dosing Regimen Dosing Regimen Hip Replacement Surgery FRAGMIN Includes three treated patients who did not undergo a surgical procedure. 5,000 units once daily subcutaneous Warfarin Sodium Warfarin sodium dosage was adjusted to maintain a prothrombin time index of 1.4 to 1.5, corresponding to an International Normalized Ratio (INR) of approximately 2.5. oral FRAGMIN Includes two treated patients who did not undergo a surgical procedure. 5,000 units once daily subcutaneous Heparin 5,000 units three times a day subcutaneous n (%) n (%) n (%) n (%) Major Bleeding Reactions A bleeding event was considered major if: 1) hemorrhage caused a significant clinical event, 2) it was associated with a hemoglobin decrease of ≥2 g/dL or transfusion of 2 or more units of blood products, 3) it resulted in reoperation due to bleeding, or 4) it involved retroperitoneal or intracranial hemorrhage. 7/274 (2.6) 1/279 (0.4) 0 3/69 (4.3) Other Bleeding Reactions Occurred at a rate of at least 2% in the group treated with FRAGMIN 5,000 units once daily.
Hematuria 8/274 (2.9) 5/279 (1.8) 0 0 Wound Hematoma 6/274 (2.2) 0 0 0 Injection Site Hematoma 3/274 (1.1) NA 2/69 (2.9) 7/69 (10.1) Six of the patients treated with FRAGMIN experienced seven major bleeding reactions. Two of the reactions were wound hematoma (one requiring reoperation), three were bleeding from the operative site, one was intraoperative bleeding due to vessel damage, and one was gastrointestinal bleeding.
In the third hip replacement surgery clinical trial, the incidence of major bleeding reactions was similar in all three treatment groups: 3.6% (18/496) for patients who started FRAGMIN before surgery; 2.5% (12/487) for patients who started FRAGMIN after surgery; and 3.1% (15/489) for patients treated with warfarin sodium. Abdominal Surgery Table 9 summarizes bleeding reactions that occurred in clinical trials which studied FRAGMIN 2,500 units and 5,000 units administered once daily to abdominal surgery patients.
Table 9 Bleeding Reactions Following Abdominal Surgery Indication FRAGMIN vs Placebo FRAGMIN vs FRAGMIN Dosing Regimen Dosing Regimen Abdominal Surgery FRAGMIN 2,500 units once daily subcutaneous n (%) Placebo once daily subcutaneous n (%) FRAGMIN 2,500 units once daily subcutaneous n (%) FRAGMIN 5,000 units once daily subcutaneous n (%) Postoperative Transfusions 14/182 (7.7) 13/182 (7.1) 89/1,025 (8.7) 125/1,033 (12.1) Wound Hematoma 2/79 (2.5) 2/77 (2.6) 1/1,030 (0.1) 4/1,039 (0.4) Reoperation Due to Bleeding 1/79 (1.3) 1/78 (1.3) 2/1,030 (0.2) 13/1,038 (1.3) Injection Site Hematoma 8/172 (4.7) 2/174 (1.1) 36/1,026 (3.5) 57/1,035 (5.5) Table 9 Cont.
Bleeding Reactions Following Abdominal Surgery Indication FRAGMIN vs Heparin Dosing Regimen Abdominal Surgery FRAGMIN 2,500 units once daily subcutaneous n (%) Heparin 5,000 units twice daily subcutaneous n (%) FRAGMIN 5,000 units once daily subcutaneous n (%) Heparin 5,000 units twice daily subcutaneous n (%) Postoperative Transfusions 26/459 (5.7) 36/454 (7.9) 81/508 (15.9) 63/498 (12.7) Wound Hematoma 16/467 (3.4) 18/467 (3.9) 12/508 (2.4) 6/498 (1.2) Reoperation Due to Bleeding 2/392 (0.5) 3/392 (0.8) 4/508 (0.8) 2/498 (0.4) Injection Site Hematoma 1/466 (0.2) 5/464 (1.1) 36/506 (7.1) 47/493 (9.5) In a trial comparing FRAGMIN 5,000 units once daily to FRAGMIN 2,500 units once daily in patients undergoing surgery for malignancy, the incidence of bleeding reactions was 4.6% and 3.6%, respectively (n.s.).
In a trial comparing FRAGMIN 5,000 units once daily to heparin 5,000 units twice daily, in the malignancy subgroup the incidence of bleeding reactions was 3.2% and 2.7%, respectively for FRAGMIN and Heparin (n.s.). Medical Patients with Severely Restricted Mobility During Acute Illness Table 10 summarizes major bleeding reactions that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness.
Table 10 Bleeding Reactions in Medical Patients with Severely Restricted Mobility During Acute Illness Indication Dosing Regimen Medical Patients with Severely Restricted Mobility FRAGMIN 5,000 units once daily subcutaneous n (%) Placebo once daily subcutaneous n (%) Major Bleeding Reactions A bleeding event was considered major if: 1) it was accompanied by a decrease in hemoglobin of ≥2 g/dL in connection with clinical symptoms; 2) intraocular, spinal/epidural, intracranial, or retroperitoneal bleeding; 3) required transfusion of ≥2 units of blood products; 4) required significant medical or surgical intervention; or 5) led to death. at Day 14 8/1,848 (0.4) 0/1,833 (0) Major Bleeding Reactions at Day 21 9/1,848 (0.5) 3/1,833 (0.2) Three of the major bleeding reactions that occurred by Day 21 were fatal, all due to gastrointestinal hemorrhage (two patients in the group treated with FRAGMIN and one in the group receiving placebo).
Adult Patients with Cancer and Acute Symptomatic VTE Table 11 summarizes the number of patients with bleeding reactions that occurred in the clinical trial of adult patients with cancer and acute symptomatic VTE. A bleeding event was considered major if it: 1) was accompanied by a decrease in hemoglobin of ≥2 g/dL in connection with clinical symptoms; 2) occurred at a critical site (intraocular
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Composition
Active ingredients
DALTEPARIN SODIUM 7,500IU/0.3ML (25,000IU/ML)
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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