Refludan Side Effects, and Drug Interactions - Lepirudin

Refludan Side Effects, and Drug Interactions - Lepirudin

SIDE EFFECTS

The following safety information is based on all 198patients treated with REFLUDAN in the HAT-1 and HAT-2 studies. The safety profile of 113REFLUDAN patients from these studies who presented with TECs at baseline is compared to 91such patients in the historical control.

The following safety information is based on a total of 2302 individuals who were treated with REFLUDAN in clinical pharmacology studies (n=323) or for clinical indications other than HIT (n=1979).

Intracranial Bleeding. Intracranial bleeding was the most serious adverse reaction found in populations other than HIT patients. It occurred in patients with acute myocardial infarction who were started on both REFLUDAN and thrombolytic therapy with rt-PA or streptokinase. The overall frequency of this potentially life-threatening complication among patients receiving both REFLUDAN and thrombolytic therapy was 0.6% (7 out of 1134 patients). Although no intracranial bleeding was observed in 1168 subjects or patients who did not receive concomitant thrombolysis, there have been post marketing reports of intracranial bleeding with REFLUDAN in the absence of concomitant thrombolytic therapy (see ADVERSE REACTIONS – Adverse Events from Post Marketing Reports and WARNINGS). Allergic Reactions.(See PRECAUTIONS.) Allergic reactions or suspected allergic reactions in populations other than HIT patients include (in descending order of frequency*):

• Airway reactions (cough, bronchospasm, stridor, dyspnea): common

• Unspecified allergic reactions: uncommon

• Skin reactions (pruritus, urticaria, rash, flushes, chills): uncommon

• General reactions (anaphylactoid or anaphylactic reactions): uncommon

• Edema (facial edema, tongue edema, larynx edema, angioedema): rare

* The CIOMS (Council for International Organization of Medical Sciences) III standard categories are used for classification of frequencies:

very common____________________________10% or more

common (frequent)________________________1 to <10%

uncommon (infrequent)____________________0.1 to <1%

rare____________________________________0.01 to <0.1%

very rare________________________________0.01% or less

About 53% (n = 46) of all allergic reactions or suspected allergic reactions occurred in patients who concomitantly received thrombolytic therapy (eg, streptokinase) for acute myocardial infarction and/or contrast media for coronary angiography.

Serious anaphylactic reactions that have resulted in shock or death have been reported. (See PRECAUTIONS.)

Intracranial bleeding has been reported in patients treated with REFLUDAN with or without concomitant thrombolytic therapy. (See WARNINGS.) Although no intracranial bleeding was observed in Clinical Trials in those patients who did not receive concomitant thrombolytic therapy (see Adverse Events Reported in Clinical Trials in HIT Patients and Adverse Events Reported in Clinical Trials in Other Populations below), there have been post marketing reports of intracranial bleeding in patients who received REFLUDAN without concomitant thrombolytic therapy.

Concomitant treatment with thrombolytics (eg, rt-PA or streptokinase) may:

• increase the risk of bleeding complications

• considerably enhance the effect of REFLUDAN on aPTT prolongation

(See also WARNINGS: Hemorrhagic Events, ADVERSE REACTIONS: Adverse Events Reported in Other Populations; Intracranial Bleeding and DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Concomitant Use With Thrombolytic Therapy).

Concomitant treatment with coumarin derivatives (vitamin K antagonists) and drugs that affect platelet function may also increase the risk of bleeding (see also DOSAGE AND ADMINISTRATION: Monitoring and Adjusting Therapy; Use in Patients Scheduled for a Switch to Oral Anticoagulation).

General Toxicity. Lepirudin caused bleeding in animal toxicity studies. Antibodies against hirudin which appeared in several monkeys ± 17 treated with lepirudin resulted in a prolongation of the terminal half-life and an increase of AUC plasma values of lepirudin.

Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies to evaluate the potential for carcinogenesis have not been performed with lepirudin. Lepirudin was not genotoxic in the Ames test, the Chinese hamster cell (V79/HGPRT) forward mutation test, the A549 human cell line unscheduled DNA synthesis (UDS) test, the Chinese hamster V79 cell chromosome aberration test, or the mouse micronucleus test. An effect on fertility and reproductive performance of male and female rats was not seen with lepirudin at intravenous doses up to 30 mg/kg/day (180 mg/m²/day, 1.2 times the recommended maximum human total daily dose based on body surface area of 1.45m²for a 50 kg subject).

Teratogenic Effects: Category B. Teratology studies with lepirudin performed in pregnant rats at intravenous doses up to 30 mg/kg/day (180 mg/m²/day, 1.2 times the recommended maximum human total daily dose based on body surface area) and in pregnant rabbits at intravenous doses up to 30 mg/kg/day (360 mg/m²/day, 2.4 times the recommended maximum human total daily dose based on body surface area) have revealed no evidence of harm to the fetus due to lepirudin. 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.

Lepirudin (1 mg/kg) by intravenous administration crosses the placental barrier in pregnant rats. It is not known whether the drug crosses the placental barrier in humans.

Following intravenous administration of lepirudin at 30mg/kg/day (180mg/m²/day, 1.2times the recommended maximum human total daily dose based on body surface area) during organogenesis and perinatal-postnatal periods, pregnant rats showed an increased maternal mortality due to undetermined causes.

It is not known whether REFLUDAN is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from REFLUDAN, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in pediatric patients have not been established. In the HAT-2 study, two children, an 11-year-old girl and a 12-year-old boy, were treated with REFLUDAN. Both children presented with TECs at baseline. REFLUDAN doses given ranged from 0.15 mg/kg/h to 0.22 mg/kg/h for the girl, and from 0.1 mg/kg/h (in conjunction with urokinase) to 0.7 mg/kg/h for the boy. Treatment with REFLUDAN was completed after 8and 58days, respectively, without serious adverse events (Schiffmann1997).