Fragmin

Pfizer, Inc.

Fragmindalteparin sodium injection

FULL PRESCRIBING INFORMATION: CONTENTS*

• SPINAL/EPIDURAL HEMATOMAS
• FRAGMIN DESCRIPTION
  • Structural Formula
• CLINICAL PHARMACOLOGY
  • Pharmacodynamics
  • Pharmacokinetics
• CLINICAL TRIALS
  • Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction
  • Prophylaxis of Deep Vein Thrombosis in Patients Following Hip Replacement Surgery
  • Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery in Patients at Risk for Thromboembolic Complications
  • Prophylaxis of Deep Vein Thrombosis in Medical Patients at Risk for Thromboembolic Complications Due to Severely Restricted Mobility During Acute Illness
  • Patients with Cancer and Acute Symptomatic Venous Thromboembolism
• FRAGMIN INDICATIONS AND USAGE
• FRAGMIN CONTRAINDICATIONS
• WARNINGS
  • Hemorrhage
  • Thrombocytopenia
  • Miscellaneous
• PRECAUTIONS
  • General
  • Drug Interactions
  • Laboratory Tests
  • Drug/Laboratory Test Interactions
  • Carcinogenicity, Mutagenesis, Impairment of Fertility
  • Pregnancy
  • Nursing Mothers
  • Pediatric Use
  • Geriatric Use
• FRAGMIN ADVERSE REACTIONS
  • Hemorrhage
  • Unstable Angina and Non-Q-Wave Myocardial Infarction
  • Hip Replacement Surgery
  • Abdominal Surgery
  • Medical Patients with Severely Restricted Mobility During Acute Illness
  • Patients with Cancer and Acute Symptomatic Venous Thromboembolism
  • Thrombocytopenia
  • Other
• OVERDOSAGE
  • Symptoms/Treatment
• FRAGMIN DOSAGE AND ADMINISTRATION
  • Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction
  • Prophylaxis of Venous Thromboembolism Following Hip Replacement Surgery
  • Prophylaxis of Venous Thromboembolism Following Abdominal Surgery
  • Medical Patients with Severely Restricted Mobility During Acute Illness
  • Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer
  • Administration
  • Instructions for using the prefilled single-dose syringes preassembled with needle guard devices
• HOW SUPPLIED

FULL PRESCRIBING INFORMATION

For Subcutaneous Use Only

FRAGMIN DESCRIPTION

FRAGMIN 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:

Structural Formula

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).

Pharmacodynamics

Doses of FRAGMIN Injection of up to 10,000 anti-Factor Xa IU administered subcutaneously as a single dose or two 5000 IU doses 12 hours apart to healthy subjects do not produce a significant change in platelet aggregation, fibrinolysis, or global clotting tests such as prothrombin time (PT), thrombin time (TT) or APTT. Subcutaneous (s.c.) administration of doses of 5000 IU twice daily of FRAGMIN for seven consecutive days to patients undergoing abdominal surgery did not markedly affect APTT, Platelet Factor 4 (PF4), or lipoprotein lipase.

Pharmacokinetics

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 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.

CLINICAL TRIALS

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 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 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 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 than for placebo (see Table 1).

Table 1 Efficacy of FRAGMIN in the Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction

	Dosing Regimen
Indication	FRAGMIN	Placebo
	120 IU/kg/every 12 hr s.c.	every 12 hr s.c.
	n(%)	n(%)
All Treated Unstable Angina and Non-Q-Wave MI Patients	746	760
Primary Endpoints - 6 day timepoint   Death, MI	13/741 (1.8)p-value = 0.001	36/757 (4.8)
Secondary Endpoints - 6 day timepoint   Death, MI, i.v. heparin, i.v. nitroglycerin,     Revascularization	59/739 (8.0)p-value = 0.001	106/756 (14.0)

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 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 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 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 5000 IU administered once daily s.c. was compared with warfarin sodium, administered orally, in patients undergoing hip replacement surgery. Treatment with FRAGMIN 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 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 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 compared with patients treated with warfarin sodium (28/192 vs 49/190; p=0.006) (see Table 2).

In a second single-center, double-blind study of patients undergoing hip replacement surgery, FRAGMIN 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 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). Further, 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 2500 IU s.c. within 2 hours before surgery, followed by another dose of FRAGMIN 2500 IU s.c. at least 4 hours (6.6 ± 2.3 hr) after surgery. Another group received the first dose of FRAGMIN 2500 IU s.c. at least 4 hours (6.6 ± 2.4 hr) after surgery. Then, both of these groups began a dosing regimen of FRAGMIN 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 (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 events 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 events 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 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 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%). As summarized in the following tables, FRAGMIN 2500 IU was superior to placebo and similar to heparin in reducing the risk of DVT (see Tables 3 and 4).

In a third double-blind, randomized study performed in patients undergoing major abdominal surgery with malignancy, FRAGMIN 5000 IU once daily was compared with FRAGMIN 2500 IU once daily. Treatment was continued for 6 to 8 days. A total of 1375 patients were enrolled and treated; 679 received FRAGMIN 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 5000 IU once daily was more effective than FRAGMIN 2500 IU once daily in reducing the risk of DVT in patients undergoing abdominal surgery with malignancy (see Table 5).

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 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 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 significantly reduced the incidence of thromboembolic events including verified DVT by Day 21 (see Table 6). 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 (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 arm) or FRAGMIN 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 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 7). 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 arm, with most of the treatment difference evident in the first month.

FRAGMIN INDICATIONS AND USAGE

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 (as described in CLINICAL TRIALS, Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction).

FRAGMIN is also indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE):

• In patients undergoing hip replacement surgery;
• In patients undergoing abdominal surgery who are at risk for thromboembolic complications;
• In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness.

FRAGMIN 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 CONTRAINDICATIONS

FRAGMIN Injection is contraindicated in patients with known hypersensitivity to the drug, active major bleeding, or thrombocytopenia associated with positive in vitro tests for antiplatelet antibody in the presence of FRAGMIN.

Patients undergoing regional anesthesia should not receive FRAGMIN for unstable angina or non-Q-wave myocardial infarction, and patients with cancer undergoing regional anesthesia should not receive FRAGMIN for extended treatment of symptomatic VTE, due to an increased risk of bleeding associated with the dosage of FRAGMIN recommended for these indications.

Patients with known hypersensitivity to heparin or pork products should not be treated with FRAGMIN.

WARNINGS

FRAGMIN Injection is not intended for intramuscular administration.

FRAGMIN cannot be used interchangeably (unit for unit) with unfractionated heparin or other low molecular weight heparins.

FRAGMIN should be used with extreme caution in patients with history of heparin-induced thrombocytopenia.

Hemorrhage

FRAGMIN, like other anticoagulants, should be used 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.

Spinal or epidural hematomas can occur with the associated use of low molecular weight heparins or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture, which can result in long-term or permanent paralysis. The risk of these events is higher with the use of indwelling epidural catheters or concomitant use of additional drugs affecting hemostasis such as NSAIDs (see boxed WARNING and ADVERSE REACTIONS, Ongoing Safety Surveillance).

As with other anticoagulants, bleeding can occur at any site during therapy with FRAGMIN. An unexpected drop in hematocrit or blood pressure should lead to a search for a bleeding site.

Thrombocytopenia

In FRAGMIN clinical trials supporting non-cancer indications, platelet counts of < 100,000/mm³ and < 50,000/mm³ occurred in < 1% and < 1% of patients, respectively.

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.

Thrombocytopenia of any degree should be monitored closely. Heparin-induced thrombocytopenia can occur with the administration of FRAGMIN. The incidence of this complication is unknown at present. In clinical practice, rare cases of thrombocytopenia with thrombosis have also been observed.

Miscellaneous

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, FRAGMIN preserved with benzyl alcohol should be used with caution in pregnant women and only if clearly needed. If anticoagulation with FRAGMIN is needed during pregnancy, preservative-free formulations should be used, where possible. (see PRECAUTIONS, Pregnancy Category B, Nonteratogenic Effects).

PRECAUTIONS

General

FRAGMIN Injection should not be mixed with other injections or infusions unless specific compatibility data are available that support such mixing.

FRAGMIN 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 should be discontinued and appropriate therapy initiated.

Drug Interactions

FRAGMIN should be used with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents because of increased risk of bleeding (see PRECAUTIONS, Laboratory Tests). Aspirin, unless contraindicated, is recommended in patients treated for unstable angina or non-Q-wave myocardial infarction (see DOSAGE AND ADMINISTRATION).

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. 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 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 should occur during FRAGMIN therapy.

Drug/Laboratory Test Interactions

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.

Carcinogenicity, 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.

Pregnancy

Pregnancy Category B

Teratogenic Effects

Reproduction studies with dalteparin sodium at intravenous doses up to 2400 IU/kg (14,160 IU/m²) in pregnant rats and 4800 IU/kg (40,800 IU/m²) in pregnant rabbits did not produce any evidence of impaired fertility or harm to the fetuses. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nonteratogenic Effects

Cases of "Gasping Syndrome" have occurred 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.

Nursing Mothers

Limited data are available for excretion of dalteparin in human milk. One study in 15 lactating women receiving prophylactic doses of dalteparin detected small amounts of anti-Xa activity in breast milk, equivalent to a milk/plasma ratio of <0.025–0.224. As oral absorption of LMWH is extremely low, the clinical implications, if any, of this small amount of anticoagulant activity on the nursing infant are unknown. Caution should be exercised when Fragmin is administered to nursing women.

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. Careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) is advised, particularly in geriatric patients with low body weight (< 45 kg) and those predisposed to decreased renal function (see also CLINICAL PHARMACOLOGY and General and Drug Interactions subsections of PRECAUTIONS).

FRAGMIN ADVERSE REACTIONS

Hemorrhage

The incidence of hemorrhagic complications during treatment with FRAGMIN 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 5000 IU to either FRAGMIN 2500 IU or low dose heparin.

In a trial comparing FRAGMIN 5000 IU once daily to FRAGMIN 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 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.

Unstable Angina and Non-Q-Wave Myocardial Infarction

Table 8 summarizes major bleeding events that occurred with FRAGMIN, heparin, and placebo in clinical trials of unstable angina and non-Q-wave myocardial infarction.

Hip Replacement Surgery

Table 9 summarizes: 1) all major bleeding events and, 2) other bleeding events possibly or probably related to treatment with FRAGMIN (preoperative dosing regimen), warfarin sodium, or heparin in two hip replacement surgery clinical trials.

Six of the patients treated with FRAGMIN 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 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 10 summarizes bleeding events that occurred in clinical trials which studied FRAGMIN 2500 and 5000 IU administered once daily to abdominal surgery patients.

Medical Patients with Severely Restricted Mobility During Acute Illness

Table 11 summarizes major bleeding events that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness.

Table 11 Bleeding Events in Medical Patients with Severely Restricted Mobility During Acute Illness

Indication	Dosing Regimen
Medical Patients with Severely Restricted Mobility	FRAGMIN 5000 IU once daily s.c. n(%)	Placebo once daily s.c. n(%)
Major Bleeding EventsA 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	8/1848 (0.4)	0/1833 (0)
Major Bleeding EventsA 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 21	9/1848 (0.5)	3/1833 (0.2)

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 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) from a subdural hematoma.

Patients with Cancer and Acute Symptomatic Venous Thromboembolism

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 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.

Thrombocytopenia

See WARNINGS, Thrombocytopenia.

Other

Allergic Reactions

Allergic reactions (i.e., pruritus, rash, fever, injection site reaction, bulleous eruption) have occurred rarely. A few cases of anaphylactoid reactions have been reported.

Local Reactions

Pain at the injection site, the only non-bleeding event determined to be possibly or probably related to treatment with FRAGMIN and reported at a rate of at least 2% in the group treated with FRAGMIN, was reported in 4.5% of patients treated with FRAGMIN 5000 IU once daily vs 11.8% of patients treated with heparin 5000 U 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 5000 IU once daily vs 13% of patients treated with heparin 5000 U three times a day.

Ongoing Safety Surveillance

Since first international market introduction in 1985, there have been more than 15 reports of epidural or spinal hematoma formation with concurrent use of dalteparin sodium 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). Because these events were reported voluntarily from a population of unknown size, estimates of frequency cannot be made.

Post-Marketing Experience

Skin necrosis has occurred rarely. There have been isolated cases of alopecia reported that improved on drug discontinuation.

OVERDOSAGE

Symptoms/Treatment

An excessive dosage of FRAGMIN Injection may lead to hemorrhagic complications. These may generally be stopped by the slow intravenous injection of protamine sulfate (1% solution), at a dose of 1 mg protamine for every 100 anti-Xa IU of FRAGMIN given. A second infusion of 0.5 mg protamine sulfate per 100 anti-Xa IU of FRAGMIN may be administered if the APTT measured 2 to 4 hours after the first infusion remains prolonged. Even with these additional doses of protamine, the APTT may remain more prolonged than would usually be found following administration of conventional heparin. In all cases, the anti-Factor Xa activity is never completely neutralized (maximum about 60 to 75%).

Particular care should be taken 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, it should be given only when resuscitation techniques and treatment of anaphylactic shock are readily available. For additional information, consult the labeling of Protamine Sulfate Injection, USP, products. A single subcutaneous dose of 100,000 IU/kg of FRAGMIN to mice caused a mortality of 8% (1/12) whereas 50,000 IU/kg was a non-lethal dose. The observed sign was hematoma at the site of injection.

FRAGMIN DOSAGE AND ADMINISTRATION

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

In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of FRAGMIN 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, based on the 9.5 mL multiple-dose vial (10,000 IU/mL), to be administered for a range of patient weights.

Prophylaxis of Venous Thromboembolism Following Hip Replacement Surgery

Table 14 presents the dosing options for patients undergoing hip replacement surgery. The usual duration of administration is 5 to 10 days after surgery; up to 14 days of treatment with FRAGMIN have been well tolerated in clinical trials.

Table 14 Dosing Options for Patients Undergoing Hip Replacement Surgery

	Dose of FRAGMIN to be Given Subcutaneously
Timing of First Dose of FRAGMIN	10 to 14 Hours Before Surgery	Within 2 Hours Before Surgery	4 to 8 Hours After SurgeryOr later, if hemostasis has not been achieved.	Postoperative PeriodUp to 14 days of treatment was well tolerated in controlled clinical trials, where the usual duration of treatment was 5 to 10 days postoperatively.
Postoperative Start	---	---	2500 IUAllow a minimum of 6 hours between this dose and the dose to be given on Postoperative Day 1. Adjust the timing of the dose on Postoperative Day 1 accordingly.	5000 IU once daily
Preoperative Start - Day of Surgery	---	2500 IU	2500 IUAllow a minimum of 6 hours between this dose and the dose to be given on Postoperative Day 1. Adjust the timing of the dose on Postoperative Day 1 accordingly.	5000 IU once daily
Preoperative Start - Evening Before SurgeryAllow approximately 24 hours between doses.	5000 IU	---	5000 IU	5000 IU once daily

Prophylaxis of Venous Thromboembolism Following Abdominal Surgery

In patients undergoing abdominal surgery with a risk of thromboembolic complications, the recommended dose of FRAGMIN 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 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 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.

Medical Patients with Severely Restricted Mobility During Acute Illness

In medical patients with severely restricted mobility during acute illness, the recommended dose of FRAGMIN is 5000 IU administered by s.c. injection once daily. In clinical trials, the usual duration of administration was 12 to 14 days.

Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer

In patients with cancer and symptomatic venous thromboembolism, the recommended dosing of FRAGMIN is as follows: for the first 30 days of treatment administer FRAGMIN 200 IU/kg total body weight subcutaneously (s.c.) once daily. The total daily dose should not exceed 18,000 IU. Table 15 lists the dose of FRAGMIN to be administered once daily during the first month for a range of patient weights.

Month 1

Months 2 to 6

Administer FRAGMIN at a dose of approximately 150 IU/kg, s.c. once daily during Months 2 through 6. The total daily dose should not exceed 18,000 IU. Table 16 lists the dose of FRAGMIN to be administered once daily for a range of patient weights during months 2–6.

Safety and efficacy beyond six months have not been evaluated in patients with cancer and acute symptomatic VTE (see WARNINGS, Thrombocytopenia and ADVERSE REACTIONS, Patients with Cancer and Acute Symptomatic VTE).

Dose reductions for thrombocytopenia in patients with cancer and acute symptomatic VTE

In patients receiving FRAGMIN who experience platelet counts between 50,000 and 100,000/mm³, reduce the daily dose of FRAGMIN by 2,500 IU until the platelet count recovers to ≥100,000/mm³. In patients receiving FRAGMIN who experience platelet counts < 50,000/mm³, FRAGMIN should be discontinued until the platelet count recovers above 50,000/mm³.

Dose reductions for renal insufficiency in extended treatment of acute symptomatic venous thromboembolism in patients with cancer

In patients with severely impaired renal function (CrCl < 30 mL/min), monitoring for anti-Xa levels is recommended to determine the appropriate FRAGMIN dose. Target anti-Xa range is 0.5–1.5 IU/mL. When monitoring anti-Xa in these patients, sampling should be performed 4–6 hrs after FRAGMIN dosing and only after the patient has received 3–4 doses.

Administration

FRAGMIN 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 administered by deep s.c. injection. FRAGMIN 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 must 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.

Instructions for using the prefilled single-dose syringes preassembled with needle guard devices

Fixed dose syringes

To ensure delivery of the full dose, do not expel the air bubble from the prefilled syringe before injection. Hold the syringe assembly by the open sides of the device. Remove the needle shield. Insert the needle into the injection area as instructed above. Depress the plunger of the syringe while holding the finger flange until the entire dose has been given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of the plunger and allow syringe to move up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.

Graduated syringes

Hold the syringe assembly by the open sides of the device. Remove the needle shield. With the needle pointing up, prepare the syringe by expelling the air bubble and then continuing to push the plunger to the desired dose or volume, discarding the extra solution in an appropriate manner. Insert the needle into the injection area as instructed above. Depress the plunger of the syringe while holding the finger flange until the entire dose remaining in the syringe has been given. The needle guard will not be activated unless the entire dose has been given. Remove needle from the patient. Let go of the plunger and allow syringe to move up inside the device until the entire needle is guarded. Discard the syringe assembly in approved containers.

HOW SUPPLIED

FRAGMIN Injection is available in the following strengths and package sizes:

Dosage Form	Strength	Package Size	NDC Number
Single-dose prefilled syringeSingle-dose prefilled syringe, affixed with a 27-gauge × 1/2 inch needle and preassembled with UltraSafe Passive™ Needle Guard* devices.	2,500 IU / 0.2 mL	10 Syringes	62856-250-10
	5,000 IU / 0.2 mL	10 Syringes	62856-500-10
	7,500 IU / 0.3 mL	10 Syringes	62856-750-10
	10,000 IU / 0.4mL	10 Syringes	62856-100-10
Single-dose graduated syringeSingle-dose graduated syringe, affixed with a 27-gauge × 1/2 inch needle and preassembled with UltraSafe Passive™ Needle Guard* devices.	10,000 IU / 1 mL	10 Syringes	62856-101-10
Single-dose prefilled syringeSingle-dose prefilled syringe, affixed with a 27-gauge × 1/2 inch needle and preassembled with UltraSafe Passive™ Needle Guard* devices.	12,500 IU / 0.5mL	10 Syringes	62856-125-10
	15,000 IU / 0.6 mL	10 Syringes	62856-150-10
	18,000 IU / 0.72mL	10 Syringes	62856-180-10
Multiple dose vial	95,000 IU / 3.8 mL	3.8 mL vial	62856-251-01
Multiple dose vial	95,000 IU / 9.5 mL	9.5 mL Vial	62856-102-01

Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP] .

Fragmin is a registered trademark of Pfizer Health AB and is licensed to Eisai Inc.

^* UltraSafe Passive™ Needle Guard is a trademark of Safety Syringes, Inc.

Rx only

Manufactured for
Eisai Inc.
Woodcliff Lake, NJ 07677

Manufactured by
Pfizer Inc
New York, NY 10017
Made in Belgium
(multiple-dose vials)

Jointly manufactured by
Pfizer Inc, New York, NY 10017
and Vetter Pharma-Fertigung, GmbH & Co. KG
Ravensburg, Germany
(prefilled syringes)

LAB-0058-9.0
April 2007