Fragmin Drug Information

• 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 . 6.1 Clinical 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, spinal/epidural, intracranial, retroperitoneal, or pericardial bleeding); 3) required transfusion of ≥2 units of blood products; or 4) led to death. Minor bleeding was classified as clinically overt bleeding that did not meet criteria for major bleeding. At the end of the six-month study, a total of 46 (13.6%) patients in the FRAGMIN arm and 62 (18.5%) patients in the OAC arm experienced any bleeding event. One bleeding event (hemoptysis in a patient in the FRAGMIN arm at Day 71) was fatal. Table 11 Bleeding Reactions (Major and Any) (As treated population) Patients with multiple bleeding episodes within any time interval were counted only once in that interval. However, patients with multiple bleeding episodes that occurred at different time intervals were counted once in each interval in which the event occurred. Study period FRAGMIN 200 units/kg (max. 18,000 units) subcutaneous once daily x 1 month, then 150 units/kg (max. 18,000 units) subcutaneous once daily x 5 months OAC FRAGMIN 200 units/kg (max 18,000 units) subcutaneous once daily x 5 to 7 days and OAC for 6 months (target INR 2 to 3) Number at risk Patients with Major Bleeding n (%) Patients with Any Bleeding n (%) Number at risk Patients with Major Bleeding n (%) Patients with Any Bleeding n (%) Total during study 338 19 (5.6) 46 (13.6) 335 12 (3.6) 62 (18.5) Week 1 338 4 (1.2) 15 (4.4) 335 4 (1.2) 12 (3.6) Weeks 2 to 4 332 9 (2.7) 17 (5.1) 321 1 (0.3) 12 (3.7) Weeks 5 to 28 297 9 (3.0) 26 (8.8) 267 8 (3) 40 (15) Elevations of Serum Transaminases In FRAGMIN clinical trials supporting non-cancer indications, where hepatic transaminases were measured, asymptomatic increases in transaminase levels (SGOT/AST and SGPT/ALT) greater than three times the upper limit of normal of the laboratory reference range were seen in 4.7% and 4.2%, respectively, of patients during treatment with FRAGMIN. In the FRAGMIN clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated with FRAGMIN for up to 6 months, asymptomatic increases in transaminase levels, AST and ALT, greater than three times the upper limit of normal of the laboratory reference range were reported in 8.9% and 9.5% of patients, respectively. The frequencies of Grades 3 and 4 increases in AST and ALT, as classified by the National Cancer Institute, Common Toxicity Criteria (NCI-CTC) Scoring System, were 3% and 3.8%, respectively. Grades 2, 3 & 4 combined have been reported in 12% and 14% of patients, respectively. Other Allergic Reactions: Allergic reactions (i.e., pruritus, rash, fever, injection site reaction, bullous eruption) have occurred. Cases of anaphylactoid reactions have been reported. Local Reactions: Pain at the injection site was reported in 4.5% of patients treated with FRAGMIN 5,000 units once daily vs 11.8% of patients treated with heparin 5,000 units twice daily in the abdominal surgery trials. In the hip replacement trials, pain at injection site was reported in 12% of patients treated with FRAGMIN 5,000 units once daily vs 13% of patients treated with heparin 5,000 units three times a day. Pediatric Patients with Symptomatic VTE The data below reflect exposure to FRAGMIN from two studies in pediatric patients from newborn to less than 18 years of age with or without cancer and symptomatic VTE (n = 50). Patients were started on FRAGMIN using age and weight-based dosing via subcutaneous injection twice daily. Anti-Xa levels were measured prior to the 4 th dose and then periodically to determine whether dose adjustments were required, using 25 units/kg increments, to achieve a target anti-Xa level of 0.5 units/mL to 1.0 units/mL. The median time on treatment with FRAGMIN was 86 days (range 2 days to 170 days). In pediatric patients with symptomatic VTE, the most common (greater than 10%) adverse reactions were injection site bruising (30%), contusion (12%), and epistaxis (10%). Major bleeding was defined as any fatal bleeding, clinically overt bleeding with a decrease in hemoglobin of ≥2g/dL in 24 hours, overt bleeding deemed by the attending physician to be unrelated to the subject's underlying condition and accompanied by blood product administration, overt bleeding that was retroperitoneal, intracranial, intraspinal, intraocular, or intraarticular, or overt bleeding deemed by the attending physician to necessitate permanent discontinuation of trial medication. Major bleeding (intestinal hematoma) occurred in one patient (2%). Discontinuation due to adverse reactions occurred in 12% of patients, most often due to thrombocytopenia (4%). Neonatal Patients No controlled clinical trials have been conducted with FRAGMIN in neonatal patients with VTE; however, data are available from a non‑interventional retrospective medical chart review study of 16 neonates with VTE in the UK who were admitted to hospital between January 2010 and December 2021 and were treated with FRAGMIN. The mean (±SD) duration of dalteparin treatment was 62±30 days. For these 16 neonatal patients, the mean (±SD) daily dose of dalteparin at initiation was 365±196 units/kg (median:309 units/kg). The mean (±SD) daily dose of dalteparin including dose at initiation and dose changes was 575±320 units/kg (median: 450 units/kg). After the initial dose, all patients required one or more dose changes; 15 of 16 patients required dose increases due to anti-Xa level being initially below the target range of 0.5 units/mL to 1 units/mL. The safety profile in neonates was similar to other pediatric patients. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of FRAGMIN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Since first international market introduction in 1985, there have been more than 15 reports of epidural or spinal hematoma formation with concurrent use of FRAGMIN and spinal/epidural anesthesia or spinal puncture. The majority of patients had postoperative indwelling epidural catheters placed for analgesia or received additional drugs affecting hemostasis. In some cases, the hematoma resulted in long-term or permanent paralysis (partial or complete) [see Boxed Warning ] . Musculoskeletal system: Osteoporosis Skin or subcutaneous tissues disorders: Skin necrosis, cases of alopecia reported that improved on drug discontinuation Metabolism and nutrition disorders: Hyperkalemia

The use of FRAGMIN in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents may increase the risk of bleeding . The use of FRAGMIN in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents may increase the risk of bleeding

Pregnancy 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 . 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.

Pediatric Use The safety and effectiveness of FRAGMIN for the treatment of symptomatic venous thromboembolism (VTE) in patients have been established in pediatric patients from birth (gestational age at least 35 weeks) to less than 17 years of age. Use of FRAGMIN for this indication is supported by evidence from well-controlled studies in adults with additional pharmacokinetic, pharmacodynamic, efficacy, and safety data from two separate prospective studies in pediatric patients aged 1 month and older with symptomatic VTE, and a retrospective study in neonatal patients aged birth (gestational age at least 35 weeks) to 1 month with VTE . The frequency, type and severity of adverse reactions observed were generally consistent with those observed in adults. Use preservative-free FRAGMIN in neonates and infants.

Serious adverse reactions including fatal reactions and the “gasping syndrome” occurred in premature neonates and low-birth weight infants in the neonatal intensive care unit who received benzyl alcohol preserved medications. In these cases, benzyl alcohol dosages of 99 mg/kg/day to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 mmol/L to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low-birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol.

When prescribing FRAGMIN multiple-dose vials in infants consider the combined daily metabolic load of benzyl alcohol from all sources including FRAGMIN multiple-dose vials (FRAGMIN 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 . The long-term effects of treatment with FRAGMIN in pediatric patients, including effects on growth and bone metabolism, are unknown.

• 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 )

An excessive dosage of FRAGMIN Injection may lead to hemorrhagic complications. These may generally be stopped by slow intravenous injection of protamine sulfate (1% solution), at a dose of 1 mg protamine for every 100 anti-Xa units of FRAGMIN given. If the APTT measured 2 hours to 4 hours after the first infusion remains prolonged, a second infusion of 0.5 mg protamine sulfate per 100 anti-Xa units of FRAGMIN may be administered.

Even with these additional doses of protamine, the APTT may remain more prolonged than would usually be found following administration of unfractionated heparin. In all cases, the anti-Xa activity is never completely neutralized (maximum about 60% to 75%). Take particular care to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions.

Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, give protamine sulfate only when resuscitation techniques and treatment for anaphylactic shock are readily available. For additional information, consult the labeling of Protamine Sulfate Injection, USP, products.