FRAGMIN (dalteparin sodium) Warnings And Precautions

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Serious Warnings and Precautions
The multi-dose vial of FRAGMIN (25,000 IU/mL) contains benzyl alcohol (14 mg/mL) as a preservative. Benzyl alcohol has been associated with a potentially fatal “Gasping Syndrome” in neonates. Because benzyl alcohol may cross the placenta, FRAGMIN preserved with benzyl alcohol should not be used in pregnant women (see Special Populations, Pregnant Women).

The multi-dose vial of FRAGMIN (25,000 IU/mL) which contains benzyl alcohol must not be used in premature or newborn babies.

General

FRAGMIN should NOT be administered intra-muscularly.

FRAGMIN CANNOT BE USED INTERCHANGEABLY (UNIT FOR UNIT) WITH UNFRACTIONATED HEPARIN (UFH) OR OTHER (LMWH) AS THEY DIFFER IN THEIR MANUFACTURING PROCESS, MOLECULAR WEIGHT DISTRIBUTION, ANTI-Xa AND ANTI-IIa ACTIVITIES, UNITS AND DOSAGES. SPECIAL ATTENTION AND COMPLIANCE WITH INSTRUCTIONS FOR USE OF EACH SPECIFIC PRODUCT ARE REQUIRED DURING ANY CHANGE IN TREATMENT.

The needle shield of the prefilled syringes may contain latex (natural rubber) which may potentially cause allergic reactions in individuals with hypersensitivity to latex. 

Cardiovascular

Use in Patients with Prosthetic Heart Valves: Cases of prosthetic valve thrombosis have been reported in these patients who have received LMWHs for thromboprophylaxis. Some of these patients were pregnant women in whom thrombosis led to maternal and/or fetal deaths. Pregnant women are at higher risk of thromboembolism (see WARNINGS AND PRECAUTIONS, Special populations, Pregnant Women).

Use in Unstable Coronary Artery Disease: When thrombolytic treatment is considered appropriate in patients with unstable angina and non-Q-wave myocardial infarction, concomitant use of an anticoagulant such as FRAGMIN may increase the risk of bleeding.

Gastrointestinal

FRAGMIN should be used with caution in patients with a history of gastrointestinal ulceration.

Hematologic

Hemorrhage: Bleeding may occur in conjunction with unfractionated heparin or LMWH use. As with other anticoagulants, FRAGMIN should be used with extreme caution in patients at increased risk of hemorrhage. 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 (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Bleeding, Post-Marketing Adverse Drug Reactions).

Platelets/Thrombocytopenia: Platelet counts should be determined prior to the start of treatment with FRAGMIN and, subsequently, twice weekly for the duration of treatment. Thrombocytopenia of any degree should be monitored closely. Heparin-induced thrombocytopenia can occur with the administration of FRAGMIN. Its incidence is unknown at present.

Caution is recommended when administering FRAGMIN to patients with congenital or drug induced thrombocytopenia or platelet defects.

During FRAGMIN administration, special caution is necessary in rapidly developing thrombocytopenia and severe thrombocytopenia (<100 000/μL). A positive or unknown result obtained from in vitro tests for antiplatelet antibody in the presence of FRAGMIN or other LMWHs and/or heparins would contraindicate FRAGMIN.

Hepatic

FRAGMIN should be used with caution in patients with hepatic insufficiency, as these patients may have potentially higher risk of hemorrhage (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Liver).

Hyperkalemia

Heparin and LMWH can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, raised plasma potassium or taking potassium sparing drugs.Plasma potassium should be measured in patients at risk.

Osteoporosis

Long term treatment with heparin has been associated with a risk of osteoporosis. Although this has not been observed with dalteparin the risk of osteoporosis cannot be excluded (see TOXICOLOGY, Long-term Toxicity, Human Toxicology).

Peri-Operative Considerations

Spinal/Epidural Hematomas:

When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with LMWHs 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 (see CONTRAINDICATIONS and ADVERSE REACTIONS).

When a higher dose (5000 IU s.c.) of FRAGMIN is administered for thromboprophylaxis in conjunction with surgery, no spinal/epidural invasion should be performed for at least 12 hours following the last dose of FRAGMIN and the next dose should be held until at least 12 hours after the anaesthetic procedure. Alternatively, when a lower dose (2500 IU s.c.) of FRAGMIN is administered, the dose can be initiated 1 - 2 hours prior to surgery. FRAGMIN injection should be given after spinal/epidural anaesthesia and only if the anaesthesiologist considers the spinal/epidural puncture as uncomplicated. Indwelling catheters should not be removed or manipulated for at least 10 - 12 hours following the last dose of FRAGMIN.

In patients receiving higher therapeutic dalteparin doses (such as 100IU/kg -120 IU/kg every 12 hours or 200 IU/kg once daily), the interval for the insertion or removal of the epidural or spinal catheter should be a minimum of 24 hours. Extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurologic impairment such as back pain, sensory or motor deficits (numbness and weakness in lower limbs) and bowel or bladder dysfunction.

Use in Knee Surgery: The risk of bleeding in knee surgery patients receiving LMWHs may be greater than in other orthopedic surgical procedures. It should be noted that hemarthrosis is a serious complication of knee surgery. The frequency of bleeding events observed with FRAGMIN in orthopedic surgery patients is derived from clinical trials in hip replacement surgery patients. The physician should weigh the potential risks with the potential benefits to the patient in determining whether to administer a LMWH in this patient population.

Selection of General Surgery Patients: Risk factors associated with postoperative venous thromboembolism following general surgery include history of venous thromboembolism, varicose veins, obesity, heart failure, malignancy, previous long bone fracture of a lower limb, bed rest for more than 5 days prior to surgery, predicted duration of surgery of more than 30 minutes, and age 60 years or above.

Renal

FRAGMIN should be used with caution in patients with renal insufficiency, particularly in patients with severe renal insufficiency (CrCl < 30 mL/min).

These patients should be carefully monitored because the half-life for anti-Xa activity after administration of FRAGMIN may be prolonged in this patient population (see ACTION AND CLINICAL PHARMACOLOGY, and DOSAGE AND ADMINISTRATION, Use in Patients with Renal Impairment). Although anti-Xa monitoring is the most appropriate measure of the pharmacodynamics effects of FRAGMIN, it remains a poor predictor of haemorrhage risk, nonetheless monitoring of anti-factor Xa activity may be considered in patients with severe renal impairment (CrCl < 30 mL/min). Dose reduction should be considered in patients with severe renal impairment.

Meanwhile, data from publications based on one study suggest that in critically ill patients with severe renal insufficiency, thromboprophylaxis with Fragmin at 5,000 IU once daily, does not appear to be associated with an excessive anticoagulant effect due to drug bioaccumulation and is unlikely to contribute to bleeding8, 13 (see ACTION AND CLINICAL PHARMACOLOGY – Special Populations and Conditions, Renal Insufficiency).

A post-hoc subgroup analysis of a randomized open-label controlled study (CLOT study) was performed on patients with cancer and renal impairment who received FRAGMIN for up to 6 months at a dose level of 200 IU/kg daily for Month 1 and 150 IU/kg daily for Month 2-6. The bleeding rates increased as renal function decreased. The bleeding rates were 11.8% (any bleeding) and 4.1% (major bleeding) for patients with normal renal function, and were 15.4% (any bleeding) and 7.7% (major bleeding) for patients with moderate renal impairment (CrCL ≥30 and <60 ml/min). For patients with severe renal impairment (CrCL <30 ml/min), the bleeding rates were 55.6% (any bleeding) and 22.2% (major bleeding).

Special Populations

Pregnant Women:

The multi-dose vial of FRAGMIN (25,000 IU/mL) contains benzyl alcohol (14 mg/mL) as a preservative. Benzyl alcohol has been associated with serious adverse events, including a potentially fatal “Gasping Syndrome” in neonates. Cases of Gasping Syndrome have been reported in neonates when benzyl alcohol has been administered in amounts of 99-404 mg/kg/day. Manifestations of the disease include: metabolic acidosis, respiratory distress, gasping respirations, central nervous system dysfunction, convulsions, intracranial hemorrhages, hypoactivity, hypotonia, cardiovascular collapse and death. Benzyl alcohol containing formulations must not be used in premature or newborn babies. Although normal therapeutic doses of this product ordinarily deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the “gasping syndrome”, the minimum amount of benzyl alcohol at which toxicity may occur is not known. The risk of benzyl alcohol toxicity depends on the quantity administered and the liver and kidneys’ capacity to detoxify the chemical. Premature and low-birth weight infants may be more likely to develop toxicity. Benzyl alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years old. Other formulations without benzyl alcohol are available. Because benzyl alcohol may cross the placenta, FRAGMIN preserved with benzyl alcohol should not be used in pregnant women.

There are also postmarketing reports of prosthetic valve thrombosis in pregnant women with prosthetic heart valves while receiving LMWHs for thromboprophylaxis. These events led to maternal death or surgical interventions.

Pregnant women with prosthetic heart valves appear to be at exceedingly high risk of thromboembolism. An incidence of thromboembolism approaching 30% has been reported in these patients, in some cases even with apparent adequate anticoagulation at treatment doses of LMWHs or unfractionated heparin. Any attempt to anticoagulate such patients should normally only be undertaken by medical practitioners with documented expertise and experience in this clinical area.

Data from one single publication suggest that ante partum thromboprophylaxis is warranted in pregnant women with idiopathic thrombosis or symptomatic thrombophilia4 (see ACTION AND CLINICAL PHARMACOLOGY – Special Populations and Conditions, Pregnant Women)

Caution is recommended when treating patients with an increased risk of haemorrhage, such as perinatal women (see WARNING AND PRECAUTIONS, Hematologic).

Teratogenic Effects: Available data from published literature have not reported a clear association with dalteparin and adverse developmental outcomes. A prospective study “Efficacy of Thromboprophylaxis as an Intervention during Gravidity” (EThIG) involved 810 pregnant women and investigated a pregnancy-specific scheme for risk stratification (low, high, very high risk of VTE) with daily doses of FRAGMIN between 50 and 150 IU/kg body weight (in single cases up to max. 200 IU/kg body weight). Out of 810 pregnant women, 26 had no pregnancy outcome data. Out of 784 pregnancies with known outcomes: the incidence of miscarriage was 4.9%, premature births 15.9%, physical malformations 2.5%, and small for gestational age 11.2%.

Pregnant women receiving anticoagulants, including FRAGMIN, are at increased risk for bleeding. Hemorrhage can occur at any site and may lead to death of mother and/or fetus. Pregnant women receiving FRAGMIN should be carefully monitored. Pregnant women and women of child-bearing potential should be informed of the potential hazard to the fetus and the mother if FRAGMIN is administered during pregnancy.

Nursing Women:

It is not known whether FRAGMIN is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FRAGMIN is administered to nursing women.

Fertility:

Four animal studies were conducted with Heparin fragment Kabi 2165 (dalteparin sodium) in rats and rabbits32. No effects on fertility, copulation or peri- and postnatal development were noted in these studies.

Pediatrics:

There is limited safety and efficacy data on the use of FRAGMIN in pediatric patients (see ADVERSE REACTIONS, Clinical Trial Adverse Reactions (Pediatrics) and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Pediatric population). If FRAGMIN is used in pediatric patients, anti-Xa levels should be monitored (see Monitoring and Laboratory Tests and DOSAGE AND ADMINISTRATION).

Geriatrics:

Elderly patients receiving LMWHs are at increased risk of bleeding. Careful attention to dosing intervals and concomitant medications, especially anti-platelet preparations, is advised. Close monitoring of elderly patients with low body weight (e.g., <45 kg) and those predisposed to decreased renal function is recommended.

Patients with Extreme Body Weight:

Safety and efficacy of LMWHs in high weight (e.g., >120 kg) and low weight (e.g., <46 kg) patients have not been fully determined. Individualized clinical and laboratory monitoring are recommended in these patients.

However, data from one single publication suggest that in the thrombosis treatment setting, a weight-adjusted dose beyond the recommended maximum dose of 18000 International Units/day (the largest patient weighed 190 kg and received a daily dose of 38000 IU) results in mean peak anti-Xa levels that are within the therapeutically acceptable range31 (see ACTION AND CLINICAL PHARMACOLOGY – Special Populations and Conditions, Overweight population)

Monitoring and Laboratory Tests

Monitoring FRAGMIN Activity: Determination of anti-factor Xa levels in plasma is the only method available for monitoring FRAGMIN activity. Routine clotting assays are unsuitable for monitoring its anticoagulant activity. Only at very high plasma FRAGMIN levels is activated partial thromboplastin time (APTT) prolongation observed. Prolongation of APTT during hemodialysis and treatment of acute deep venous thrombosis should only be used as a criterion of overdose. Dose increases aimed at prolonging APTT could cause overdosing and bleeding.

Measurement of peak anti-Xa levels at about 4 hours post-dose should be considered for certain special patient populations at higher risk of bleeding and receiving FRAGMIN, such as the elderly, patients with renal impairment or the extremes of body weight, during pregnancy, or for children. At treatment doses of 100 IU/kg s.c. twice daily, peak anti-Xa levels should generally be maintained at no more than 1.0 IU/mL in these patients.

Due to pharmacokinetic differences in neonates and young infants (≤ 2 years), a larger starting dose (e.g. 150 IU/kg) is required with upward dose adjustments expected (see DOSAGE AND ADMINISTRATION, Dosage, Use in Pediatrics (2 weeks – 18 years). Close monitoring of anti-Xa levels in pediatrics is warranted.

When FRAGMIN is administered subcutaneously, the individual patient’s anti-Xa activity level will not remain within the range that would be expected with unfractionated heparin by continuous i.v. infusion throughout the entire dosing interval (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics). FRAGMIN should be administered as directed (see DOSAGE AND ADMINISTRATION).

With normal prophylactic doses, FRAGMIN does not modify global clotting tests of APTT, prothrombin time (PT) and thrombin clotting time (TT). Therefore, treatment cannot be monitored with these tests.

Liver Function Tests: Since FRAGMIN use may be associated with a rise in hepatic transaminases, this observation should be considered when liver function tests are assessed (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions, Liver).

As with all antithrombotic agents, there is a risk of systemic bleeding with dalteparin sodium administration. Care should be taken with dalteparin sodium use in newly operated patients. After treatment is initiated patients should be carefully monitored for bleeding complications. This may be done by regular physical examination of the patients, close observation of the surgical drain, periodic measurements of hemoglobin, and anti-Xa determinations.