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FRAGMIN(dalteparin sodium injection) for Subcutaneous

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use FRAGMIN® safely and effectively. See full prescribing information for FRAGMIN.
FRAGMIN (dalteparin sodium injection) for Subcutaneous Use Only
Initial U.S. Approval: 1994
WARNING: SPINAL/EPIDURAL HEMATOMA
See full prescribing information for complete boxed warning.
Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:

Use of indwelling epidural catheters
Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants.
A history of traumatic or repeated epidural or spinal punctures
A history of spinal deformity or spinal surgery
Optimal timing between the administration of FRAGMIN and neuraxial procedures is not known.

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions (5.1) and Drug Interactions (7)].
RECENT MAJOR CHANGES

Boxed Warning 1/2015

Risk of Hemorrhage including Spinal / Epidural Hematoma (5.1) 1/2015

INDICATIONS AND USAGE

FRAGMIN is a low molecular weight heparin [LMWH] indicated for

Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction (1.1)
Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip replacement surgery or medical patients with severely restricted mobility during acute illness (1.2)
Extended treatment of symptomatic venous thromboembolism (VTE) to reduce the recurrence in patients with cancer. In these patients, the FRAGMIN therapy begins with the initial VTE treatment and continues for six months (1.3)

Limitations of Use
FRAGMIN is not indicated for the acute treatment of VTE.

DOSAGE AND ADMINISTRATION

Indication	Dosing Regimen
Unstable angina and non-Q-wave MI	120 IU/kg subcutaneous every 12 hours (with aspirin) (2.1)
DVT prophylaxis in abdominal surgery	2500 IU subcutaneous once daily or 5000 IU subcutaneous once daily or 2500 IU subcutaneous followed by 2500 IU subcutaneous 12 hours later and then 5000 IU subcutaneous once daily (2.1)
DVT prophylaxis in hip replacement surgery	Postoperative start - 2500 IU subcutaneous 4 to 8 hours after surgery, then 5000 IU subcutaneous once daily or Preoperative start - day of surgery 2500 IU subcutaneous 2 hours before surgery followed by 2500 IU subcutaneous 4 to 8 hours after surgery, then 5000 IU subcutaneous once daily (2.1) Preoperative start - Evening Before Surgery 5000 IU subcutaneous followed by 5000 IU subcutaneous 4 to 8 hours after surgery (2.1)
DVT prophylaxis in medical patients	5000 IU subcutaneous once daily (2.1)
Extended treatment of VTE in patients with cancer	Month 1 - 200 IU/kg subcutaneous once daily (2.1) Months 2 - 6 150 IU/kg subcutaneous once daily (2.1)

Do not use as intramuscular injection. FRAGMIN should not be mixed with other injections or infusions. (2)

DOSAGE FORMS AND STRENGTHS

Single-dose prefilled syringe: 2,500 IU/ 0.2 mL, 5,000 IU/ 0.2 mL. 7500 IU/ 0.3 mL, 10,000 IU/ 0.4 mL, 12,500 IU/ 0.5 mL, 15,000 IU/ 0.6 mL, 18,000 IU/ 0.72 mL (3)
Single-dose graduated syringe: 10,000 IU/ 1 mL (3)
Multiple dose vial: 95,000 IU/ 9.5 mL, 95,000/ 3.8 mL (3)

CONTRAINDICATIONS

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 [see Boxed Warning, (4)];
- As a treatment for unstable angina and non-Q-wave MI
- For prolonged VTE prophylaxis (4)
Hypersensitivity to heparin or pork products (4)

WARNINGS AND PRECAUTIONS

Use caution in conditions with increased risk of hemorrhage (5.1)
Monitor thrombocytopenia of any degree closely (5.2)
Multiple-dose formulations contain benzyl alcohol (5.3)
Periodic blood counts recommended (5.4)

ADVERSE REACTIONS

Most common adverse reaction is hematoma at the injection site. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Eisai at (1-888-274-2378) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Use FRAGMIN with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents (7)

USE IN SPECIFIC POPULATIONS

Safety and effectiveness in pediatric patients have not been established. (8.4)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 1/2015

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SPINAL/EPIDURAL HEMATOMAS

1 INDICATIONS AND USAGE

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

1.2 Prophylaxis of Deep Vein Thrombosis

1.3 Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer

2 DOSAGE AND ADMINISTRATION

2.1 Adult Dosage

2.2 Dose Reductions for Thrombocytopenia in Patients with Cancer and Acute Symptomatic VTE

2.3 Dose Reductions for Renal Insufficiency in Extended Treatment of Acute Symptomatic Venous Thromboembolism in Patients with Cancer

2.4 Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Risk of Hemorrhage including Spinal / Epidural Hematoma

5.2 Thrombocytopenia

5.3 Benzyl Alcohol

5.4 Laboratory Tests

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Post-Marketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

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

14.2 Prophylaxis of Deep Vein Thrombosis in Patients Following Hip Replacement Surgery

14.3 Prophylaxis of Deep Vein Thrombosis Following Abdominal Surgery in Patients at Risk for Thromboembolic Complications

14.4 Prophylaxis of Deep Vein Thrombosis in Medical Patients at Risk for Thromboembolic Complications Due to Severely Restricted Mobility During Acute Illness

14.5 Patients with Cancer and Acute Symptomatic Venous Thromboembolism

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*: Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

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

FRAGMIN® Injection is indicated for the prophylaxis of ischemic complications in unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin therapy [see Clinical Studies (14.1)].

1.2 Prophylaxis of Deep Vein Thrombosis

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 [see Clinical Studies (14.2)];
In patients undergoing abdominal surgery who are at risk for thromboembolic complications [see Clinical Studies (14.3)];
In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness [see Clinical Studies (14.4)].

1.3 Extended Treatment of Symptomatic Venous Thromboembolism in Patients with Cancer

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. In these patients, the FRAGMIN therapy begins with the initial VTE treatment and continues for six months [see Clinical Studies (14.5)].

Limitations of Use
FRAGMIN is not indicated for the acute treatment of VTE.

2 DOSAGE AND ADMINISTRATION

FRAGMIN is administered by subcutaneous injection. It must not be administered by intramuscular injection.

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

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. [see Warnings and Precautions (5)].

2.1 Adult Dosage

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 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.