Iprivask (Page 3 of 5)

6.2 Post Marketing Experience

In addition to adverse events reported from clinical trials the following adverse events have been identified during post approval use of Iprivask. These events were reported voluntarily from a population of unknown size and the frequency of occurrence cannot be determined precisely: reports of major hemorrhages [ see Warnings and Precautions (5.2) ], some of which were fatal, and anaphylactic/anaphylactoid reactions [ see Warnings and Precautions (5.4) ].

7 DRUG INTERACTIONS

7.1 Drugs that Increase Bleeding Risk

Discontinue any agent which may enhance the risk of hemorrhage prior to initiation of Iprivask therapy. These agents include medications such as Dextran 40, systemic glucocorticoids, thrombolytics, and anticoagulants. If co-administration cannot be avoided, close clinical and laboratory monitoring should be conducted. During prophylaxis of venous thromboembolism, concomitant treatment with heparins (unfractionated and low-molecular weight heparins) or dextrans is not recommended. The effects of desirudin and unfractionated heparins on prolongation of aPTT are additive.

As with other anticoagulants, desirudin should be used with caution in conjunction with drugs which affect platelet function. These medications include systemic salicylates, NSAIDS including ketorolac, acetylsalicylic acid, ticlopidine, dipyridamole, sulfinpyrazone, clopidogrel, abciximab and other glycoprotein IIb/IIIa antagonists [see Warnings and Precautions (5.2)] .

7.2 Coadministration with Warfarin

The concomitant administration of warfarin did not significantly affect the pharmacokinetic effects of desirudin. When warfarin and desirudin were coadministered, greater inhibition of hemostasis measured by activated partial thromboplastin time (aPTT), prothrombin time (PT), and international normalized ratio (INR) was observed [ see Dosage and Administration (2.4) ] .

8 USE IN SPECIFIC POPULATIONS

8.6 Renal Impairment

Iprivask is primarily eliminated and metabolized by the kidney. Patients with moderate and severe renal impairment had significant increases in exposure and aPPT prolongation compared to individuals with normal renal function [ see Clinical Pharmacology (12.3) ] . Reduce dose and monitor daily aPTT and serum creatinine in patients with renal impairment [ see Dosage and Administration (2.2) and Warnings and Precautions (5.6) ] .

8.7 Hepatic Impairment

No information is available about the use of desirudin in patients with hepatic impairment. Although Iprivask is not significantly metabolized by the liver, hepatic impairment or serious liver injury (e.g., liver cirrhosis) may alter the anticoagulant effect of Iprivask due to coagulation defects secondary to reduced generation of vitamin K-dependent coagulation factors. Iprivask bleeding risk may be increased.

8.1 Pregnancy

Pregnancy Category C.

Risk Summary

There are no adequate and well controlled studies in pregnant women. Iprivask should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Iprivask was teratogenic in rats and rabbits when given in doses 0.3 to 4 times the human dose.

Animal Data

Teratology studies have been performed in rats at subcutaneous doses in a range of 1 to 15 mg/kg/day (about 0.3 to 4 times the recommended human dose based on body surface area) and in rabbits at intravenous doses in a range of 0.6 to 6 mg/kg/day (about 0.3 to 3 times the recommended human dose based on body surface area) and have revealed desirudin to be teratogenic. Observed teratogenic findings included: omphalocele, asymmetric and fused sternebrae, edema, and shortened hind limbs in rats; and spina bifida, malrotated hind limb, hydrocephaly, and gastroschisis in rabbits.

8.3 Nursing Mothers

It is not known whether desirudin 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 Iprivask, 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.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

In three clinical studies of Iprivask, the percentage of patients greater than 65 years of age treated with 15 mg of Iprivask subcutaneously every 12 hours was 58.5%, while 20.8% were 75 years of age or older. Elderly patients treated with Iprivask had a reduction in the incidence of VTE similar to that observed in the younger patients.

Regarding safety, in the clinical studies the incidence of hemorrhage (major or otherwise) in patients 65 years of age or older was similar to that in patients less than 65 years of age. In addition, the elderly had a similar incidence of total, treatment-related, or serious adverse events compared to those patients less than 65 years of age. Serious adverse events occurred more frequently in patients 75 years of age or older as compared to those less than 65 years of age [ see Clinical Pharmacology (12.3) and Dosage and Administration (2.2) ] .

8.6 Renal Impairment

Iprivask is primarily eliminated and metabolized by the kidney. Patients with moderate and severe renal impairment had significant increases in exposure and aPPT prolongation compared to individuals with normal renal function [ see Clinical Pharmacology (12.3) ] . Reduce dose and monitor daily aPTT and serum creatinine in patients with renal impairment [ see Dosage and Administration (2.2) and Warnings and Precautions (5.6) ] .

8.7 Hepatic Impairment

No information is available about the use of desirudin in patients with hepatic impairment. Although Iprivask is not significantly metabolized by the liver, hepatic impairment or serious liver injury (e.g., liver cirrhosis) may alter the anticoagulant effect of Iprivask due to coagulation defects secondary to reduced generation of vitamin K-dependent coagulation factors. Iprivask bleeding risk may be increased.

10 OVERDOSAGE

In case of overdose, most likely reflected in hemorrhagic complications or suggested by excessively high aPTT values, Iprivask therapy should be discontinued. Emergency procedures should be instituted as appropriate (for example, determination of aPTT and other coagulation levels, hemoglobin, the use of blood transfusion or plasma expanders).

No specific antidote for Iprivask is available; however, the anticoagulant effect of desirudin may be partially reversible using thrombin-rich plasma concentrates while aPTT levels can be reduced by the intravenous administration of 0.3 μg/kg DDAVP (desmopressin). The clinical effectiveness of DDAVP in treating bleeding due to desirudin overdose has not been studied. In an open, pilot, dose-ascending study to assess safety, the highest dose of desirudin (40 mg every 12 hours) caused excessive hemorrhage.

11 DESCRIPTION

Iprivask ® (desirudin for injection) is a direct inhibitor of human thrombin. It has a protein structure that is similar to that of hirudin, the naturally occurring anticoagulant present in the peripharyngeal glands in the medicinal leech, Hirudo medicinalis. Hirudin is a single polypeptide chain of 65 amino acids residues and contains three disulfide bridges. Desirudin has a chemical formula of C 287 H 440 N 80 O 110 S 6 with a molecular weight of 6963.52. Desirudin, which is expressed in yeast (Saccharomyces cerevisiae, strain TR 1456) by recombinant DNA technology differs from the natural hirudin by lack of a sulfate group on Tyr-63. The biological activity of desirudin is determined through a chromogenic assay which measures the ability of desirudin to inhibit the hydrolysis of a chromogenic peptidic substrate by thrombin in comparison to a desirudin standard. One vial of desirudin contains 15.75 mg desirudin corresponding to approximately 315,000 antithrombin units (ATU) or 20,000 ATU per milligram of desirudin with reference to the WHO International Standard (prepared 1991) for alphathrombin.

Iprivask 15 mg is supplied as a sterile, white, freeze dried powder for injection. Each vial contains 15.75 mg desirudin and the following inactive ingredients: 1.31 mg anhydrous magnesium chloride USP, sodium hydroxide for injection USP. Each prefilled syringe of diluent for Iprivask contains 0.6 mL sterile Mannitol USP (3%) in Water for Injection and is preservative free. The reconstituted solution has a pH of 7.4.

STRUCTURAL FORMULA

Description: structural formula
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