Fragmin Information
Fragmin (Dalteparin)
Fragmin (Dalteparin) Spinal/epidural Hematomas
When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis.
The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting hemostasis such as non steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture.
Patients should be frequently monitored for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.
The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis (also see and ).
Fragmin (Dalteparin) Description
Fragmin (Dalteparin) Injection (dalteparin sodium injection) is a sterile, low molecular weight heparin. It is available in single-dose, prefilled syringes preassembled with a needle guard device, and multiple-dose vials. With reference to the W.H.O. First International Low Molecular Weight Heparin Reference Standard, each syringe contains either 2500, 5000, 7500, 10,000, 12,500, 15,000 or 18,000 anti-Factor Xa international units (IU), equivalent to 16, 32, 48, 64, 80, 96 or 115.2 mg dalteparin sodium, respectively. Each multiple-dose vial contains either 10,000 or 25,000 anti-Factor Xa IU per 1 mL (equivalent to 64 or 160 mg dalteparin sodium, respectively), for a total of 95,000 anti-Factor Xa IU per vial.
Each prefilled syringe also contains Water for Injection and sodium chloride, when required, to maintain physiologic ionic strength. The prefilled syringes are preservative-free. Each multiple-dose vial also contains Water for Injection and 14 mg of benzyl alcohol per mL as a preservative. The pH of both formulations is 5.0 to 7.5.
Dalteparin sodium is produced through controlled nitrous acid depolymerization of sodium heparin from porcine intestinal mucosa followed by a chromatographic purification process. It is composed of strongly acidic sulphated polysaccharide chains (oligosaccharide, containing 2,5-anhydro-D-mannitol residues as end groups) with an average molecular weight of 5000 and about 90% of the material within the range 2000–9000. The molecular weight distribution is:
Fragmin (Dalteparin) Clinical Pharmacology
Dalteparin is a low molecular weight heparin with antithrombotic properties. It acts by enhancing the inhibition of Factor Xa and thrombin by antithrombin. In man, dalteparin potentiates preferentially the inhibition of coagulation Factor Xa, while only slightly affecting the activated partial thromboplastin time (APTT).
Mean peak levels of plasma anti-Factor Xa activity following single s.c. doses of 2500, 5000 and 10,000 IU were 0.19 ± 0.04, 0.41 ± 0.07 and 0.82 ± 0.10 IU/mL, respectively, and were attained in about 4 hours in most subjects. Absolute bioavailability in healthy volunteers, measured as the anti-Factor Xa activity, was 87 ± 6%. Increasing the dose from 2500 to 10,000 IU resulted in an overall increase in anti-Factor Xa AUC that was greater than proportional by about one-third.
Peak anti-Factor Xa activity increased more or less linearly with dose over the same dose range. There appeared to be no appreciable accumulation of anti-Factor Xa activity with twice-daily dosing of 100 IU/kg s.c. for up to 7 days.
The volume of distribution for dalteparin anti-Factor Xa activity was 40 to 60 mL/kg. The mean plasma clearances of dalteparin anti-Factor Xa activity in normal volunteers following single intravenous bolus doses of 30 and 120 anti-Factor Xa IU/kg were 24.6 ± 5.4 and 15.6 ± 2.4 mL/hr/kg, respectively. The corresponding mean disposition half-lives are 1.47 ± 0.3 and 2.5 ± 0.3 hours.
Following intravenous doses of 40 and 60 IU/kg, mean terminal half-lives were 2.1 ± 0.3 and 2.3 ± 0.4 hours, respectively. Longer apparent terminal half-lives (3 to 5 hours) are observed following s.c. dosing, possibly due to delayed absorption. In patients with chronic renal insufficiency requiring hemodialysis, the mean terminal half-life of anti-Factor Xa activity following a single intravenous dose of 5000 IU Fragmin (Dalteparin) was 5.7 ± 2.0 hours, i.e. considerably longer than values observed in healthy volunteers, therefore, greater accumulation can be expected in these patients.
Fragmin (Dalteparin) Clinical Trials
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 (Dalteparin) Injection 120 IU/kg every 12 hours subcutaneously (s.c.) or placebo every 12 hours s.c. 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 (Dalteparin) 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 double endpoint of death or myocardial infarction was lower for Fragmin (Dalteparin) 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 (i.v.) heparin or i.v. nitroglycerin, and revascularization was also lower for Fragmin (Dalteparin) than for placebo (see ).
In a second randomized, controlled trial designed to evaluate long-term treatment with Fragmin (Dalteparin) (days 6 to 45), data were also collected comparing 1-week (5 to 8 days) treatment of Fragmin (Dalteparin) 120 IU/kg every 12 hours s.c. 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 total enrolled study population of 1499 patients, 1482 patients were treated; 751 received Fragmin (Dalteparin) 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 triple endpoint of death, myocardial infarction, or recurrent angina during this 1-week treatment period (5 to 8 days) was 9.3% for Fragmin (Dalteparin) and 7.6% for heparin (p=0.323).
In an open-label randomized study, Fragmin (Dalteparin) 5000 IU administered once daily s.c. was compared with warfarin sodium, administered orally, in patients undergoing hip replacement surgery. Treatment with Fragmin (Dalteparin) was initiated with a 2500 IU dose s.c. within 2 hours before surgery, followed by a 2500 IU dose s.c. the evening of the day of surgery. Then, a dosing regimen of Fragmin (Dalteparin) 5000 IU s.c. 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 total enrolled study population of 580 patients, 553 were treated and 550 underwent surgery. Of those who underwent surgery, 271 received Fragmin (Dalteparin) 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), any vein, as determined by evaluable venography, was significantly lower for the group treated with Fragmin (Dalteparin) compared with patients treated with warfarin sodium (28/192 vs 49/190; p=0.006) (see ).
In a second single-center, double-blind study of patients undergoing hip replacement surgery, Fragmin (Dalteparin) 5000 IU once daily s.c. starting the evening before surgery, was compared with heparin 5000 U s.c. three times a day, starting the morning of surgery. Treatment in both groups was continued for up to 9 days postoperatively. Of the total enrolled study population of 140 patients, 139 were treated and 136 underwent surgery. Of those who underwent surgery, 67 received Fragmin (Dalteparin) 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 (Dalteparin) compared with patients treated with heparin (6/67 vs 18/69; p=0.012). Further, the incidence of pulmonary embolism detected by lung scan was also significantly lower in the group treated with Fragmin (Dalteparin) (9/67 vs 19/69; p=0.032).
A third multi-center, double-blind, randomized study evaluated a postoperative dosing regimen of Fragmin (Dalteparin) for thromboprophylaxis following total hip replacement surgery. Patients received either Fragmin (Dalteparin) or warfarin sodium, randomized into one of three treatment groups. One group of patients received the first dose of Fragmin (Dalteparin) 2500 IU s.c. within 2 hours before surgery, followed by another dose of Fragmin (Dalteparin) 2500 IU s.c. at least 4 hours (6.6 ± 2.3 hr) after surgery. Another group received the first dose of Fragmin (Dalteparin) 2500 IU s.c. at least 4 hours (6.6 ± 2.4 hr) after surgery. Then, of these groups began a dosing regimen of Fragmin (Dalteparin) 5000 IU once daily s.c. 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 for 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 1501 patients, 1472 patients were treated; 496 received Fragmin (Dalteparin) (first dose before surgery), 487 received Fragmin (Dalteparin) (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 (Dalteparin) after surgery was as effective in reducing the incidence of thromboembolic events as administration of the first dose of Fragmin (Dalteparin) before surgery (44/336 vs 37/338; p=0.448). Both dosing regimens of Fragmin (Dalteparin) were more effective than warfarin sodium in reducing the incidence of thromboembolic events following hip replacement surgery.
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 (Dalteparin) administered once daily s.c. beginning prior to surgery and continuing for 5 to 10 days after surgery, was shown to reduce 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 (Dalteparin) 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 (Dalteparin) 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%). As summarized in the following tables, Fragmin (Dalteparin) 2500 IU was superior to placebo and similar to heparin in reducing the risk of DVT (see and ).
In a third double-blind, randomized study performed in patients undergoing major abdominal surgery with malignancy, Fragmin (Dalteparin) 5000 IU once daily was compared with Fragmin (Dalteparin) 2500 IU once daily. Treatment was continued for 6 to 8 days. A total of 1375 patients were enrolled and treated; 679 received Fragmin (Dalteparin) 5000 IU and 696 received 2500 IU. The mean age of the combined groups was 71 years (range 40 to 95 years). The majority of patients were female (51.0%). The study showed that Fragmin (Dalteparin) 5000 IU once daily was more effective than Fragmin (Dalteparin) 2500 IU once daily in reducing the risk of DVT in patients undergoing abdominal surgery with malignancy (see ).
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 (Dalteparin) 5000 IU or placebo s.c. once daily during Days 1 to 14 of the study. The primary endpoint was evaluated at Day 21, and the follow-up period was up to Day 90. 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 3681 patients were enrolled and treated: 1848 received Fragmin (Dalteparin) and 1833 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 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.
When given at a dose of 5000 IU once a day s.c., Fragmin (Dalteparin) significantly reduced the incidence of thromboembolic events including verified DVT by Day 21 (see ). The prophylactic effect was sustained through Day 90.
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 (Dalteparin) 200 IU/kg (max 18,000 IU/ s.c. daily for one month) then 150 IU/kg (max 18,000 IU s.c. daily for five months (Fragmin (Dalteparin) arm) or Fragmin (Dalteparin) 200 IU/kg (max 18,000 IU s.c. 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%). Venous thrombotic events were adjudicated by a blinded central committee.
A total of 27 (8.0%) and 53 (15.7%) patients in the Fragmin (Dalteparin) 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 ). 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=0.0017) in favor of the Fragmin (Dalteparin) arm, with most of the treatment difference evident in the first month.
Fragmin (Dalteparin) Indications And Usage
Fragmin (Dalteparin) Injection is indicated for the prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin therapy (as described in ).
Fragmin (Dalteparin) is also indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE):
Fragmin (Dalteparin) is also indicated for the extended treatment of symptomatic venous thromboembolism (VTE) (proximal DVT and/or PE), to reduce the recurrence of VTE in patients with cancer.
Fragmin (Dalteparin) Contraindications
Fragmin (Dalteparin) Injection is contraindicated in patients with known hypersensitivity to the drug, active major bleeding, or thrombocytopenia associated with positive tests for antiplatelet antibody in the presence of Fragmin (Dalteparin) .
Patients undergoing regional anesthesia should not receive Fragmin (Dalteparin) for unstable angina or non-Q-wave myocardial infarction, and patients with cancer undergoing regional anesthesia should not receive Fragmin (Dalteparin) for extended treatment of symptomatic VTE, due to an increased risk of bleeding associated with the dosage of Fragmin (Dalteparin) recommended for these indications.
Patients with known hypersensitivity to heparin or pork products should not be treated with Fragmin (Dalteparin) .
Fragmin (Dalteparin) Warnings
Fragmin (Dalteparin) Injection is not intended for intramuscular administration.
Fragmin (Dalteparin) cannot be used interchangeably (unit for unit) with unfractionated heparin or other low molecular weight heparins.
Fragmin (Dalteparin) Precautions
Fragmin (Dalteparin) Injection should not be mixed with other injections or infusions unless specific compatibility data are available that support such mixing.
Fragmin (Dalteparin) should be used with caution in patients with bleeding diathesis, thrombocytopenia or platelet defects; severe liver or kidney insufficiency, hypertensive or diabetic retinopathy, and recent gastrointestinal bleeding.
If a thromboembolic event should occur despite dalteparin prophylaxis, Fragmin (Dalteparin) should be discontinued and appropriate therapy initiated.
Periodic routine complete blood counts, including platelet count, blood chemistry, and stool occult blood tests are recommended during the course of treatment with Fragmin (Dalteparin) . No special monitoring of blood clotting times (i.e., APTT) is needed.
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 (Dalteparin) activity and, therefore, unsuitable for monitoring the anticoagulant effect of Fragmin (Dalteparin) .
Anti-Factor Xa may be used to monitor the anticoagulant effect of Fragmin (Dalteparin) , such as in patients with severe renal impairment or if abnormal coagulation parameters or bleeding should occur during Fragmin (Dalteparin) therapy.
Fragmin (Dalteparin) Adverse Reactions
The incidence of hemorrhagic complications during treatment with Fragmin (Dalteparin) Injection has been low. The most commonly reported side effect is hematoma at the injection site. The incidence of bleeding may increase with higher doses; however, in abdominal surgery patients with malignancy, no significant increase in bleeding was observed when comparing Fragmin (Dalteparin) 5000 IU to either Fragmin (Dalteparin) 2500 IU or low dose heparin.
In a trial comparing Fragmin (Dalteparin) 5000 IU once daily to Fragmin (Dalteparin) 2500 IU once daily in patients undergoing surgery for malignancy, the incidence of bleeding events was 4.6% and 3.6%, respectively (n.s.). In a trial comparing Fragmin (Dalteparin) 5000 IU once daily to heparin 5000 U twice daily, the incidence of bleeding events was 3.2% and 2.7%, respectively (n.s.) in the malignancy subgroup.
Table 9 summarizes: 1) all major bleeding events and, 2) other bleeding events possibly or probably related to treatment with Fragmin (Dalteparin) (preoperative dosing regimen), warfarin sodium, or heparin in two hip replacement surgery clinical trials.
Six of the patients treated with Fragmin (Dalteparin) experienced seven major bleeding events. Two of the events 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. None of the patients experienced retroperitoneal or intracranial hemorrhage nor died of bleeding complications.
In the third hip replacement surgery clinical trial, the incidence of major bleeding events was similar in all three treatment groups: 3.6% (18/496) for patients who started Fragmin (Dalteparin) before surgery; 2.5% (12/487) for patients who started Fragmin (Dalteparin) after surgery; and 3.1% (15/489) for patients treated with warfarin sodium.
Table 11 summarizes major bleeding events that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness.
Three of the major bleeding events that occurred by Day 21 were fatal, all due to gastrointestinal hemorrhage (two patients in the group treated with Fragmin (Dalteparin) and one in the group receiving placebo). Two deaths occurred after Day 21: one patient in the placebo group died from a subarachnoid hemorrhage that started on Day 55, and one patient died on day 71 (two months after receiving the last dose of Fragmin (Dalteparin) ) from a subdural hematoma.
Table 12 summarizes the number of patients with bleeding events that occurred in the clinical trial of patients with cancer and acute symptomatic venous thromboembolism. A bleeding eventwas 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 (Dalteparin) arm and 62 (18.5%) patients in the OAC arm experienced any bleeding event. One bleeding event (hemoptysis in a patient in the Fragmin (Dalteparin) arm at Day 71) was fatal.
See .
Fragmin (Dalteparin) Dosage And Administration
In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of Fragmin (Dalteparin) Injection is 120 IU/kg of body weight, but not more than 10,000 IU, subcutaneously (s.c.) every 12 hours with concurrent oral aspirin (75 to 165 mg once daily) therapy. Treatment should be continued until the patient is clinically stabilized. The usual duration of administration is 5 to 8 days. Concurrent aspirin therapy is recommended except when contraindicated.
Table 13 lists the volume of Fragmin (Dalteparin) , based on the 9.5 mL multiple-dose vial (10,000 IU/mL), to be administered for a range of patient weights.
In patients undergoing abdominal surgery with a risk of thromboembolic complications, the recommended dose of Fragmin (Dalteparin) is 2500 IU administered by s.c. injection once daily, starting 1 to 2 hours prior to surgery and repeated once daily postoperatively. The usual duration of administration is 5 to 10 days.
In patients undergoing abdominal surgery associated with a high risk of thromboembolic complications, such as malignant disorder, the recommended dose of Fragmin (Dalteparin) is 5000 IU s.c. the evening before surgery, then once daily postoperatively. The usual duration of administration is 5 to 10 days. Alternatively, in patients with malignancy, 2500 IU of Fragmin (Dalteparin) can be administered s.c. 1 to 2 hours before surgery followed by 2500 IU s.c. 12 hours later, and then 5000 IU once daily postoperatively. The usual duration of administration is 5 to 10 days.
Dosage adjustment and routine monitoring of coagulation parameters are not required if the dosage and administration recommendations specified above are followed.
Fragmin (Dalteparin) is administered by subcutaneous injection. It must not be administered by intramuscular injection.
Subcutaneous injection technique: Patients should be sitting or lying down and Fragmin (Dalteparin) administered by deep s.c. injection. Fragmin (Dalteparin) may be injected in a U-shape area around the navel, the upper outer side of the thigh or the upper outer quadrangle of the buttock. The injection site should be varied daily. When the area around the navel or the thigh is used, using the thumb and forefinger, you lift up a fold of skin while giving the injection. The entire length of the needle should be inserted at a 45 to 90 degree angle.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
After first penetration of the rubber stopper, store the multiple-dose vials at room temperature for up to 2 weeks. Discard any unused solution after 2 weeks.
Fragmin (Dalteparin) How Supplied
Fragmin (Dalteparin) Injection is available in the following strengths and package sizes:
Fragmin (Dalteparin) is a registered trademark of Pfizer Health AB and is licensed to Eisai Inc.
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Fragmin (Dalteparin)
