Revasc

Revasc is indicated for the prophylaxis of deep vein thrombosis, which may lead to pulmonary embolism, in patients undergoing elective hip replacement surgery.

Recommended Dose

All patients should be evaluated for bleeding disorder risk before prophylactic administration of Revasc.

Initial Dosage: In patients undergoing hip replacement surgery, the recommended dose of Revasc is 15 mg every 12 hours administered by subcutaneous injection with the initial dose given up to 5 to 15 minutes prior to surgery, but after induction of regional block anesthesia, if used. Up to 12 days administration (average duration 9 to 12 days) of Revasc has been well tolerated in controlled clinical trials.

Dose Adjustment In Renal Impairment

Clinical Monitoring

Activated partial thromboplastin time (aPTT) should be monitored daily in patients with increased risk of bleeding and/or renal impairment. Serum creatinine should be monitored daily in patients with renal impairment. Adjust Revasc dosage according to creatinine levels.

Peak aPTT should not exceed two times control. Should peak aPTT exceed this level, reduce the dosage of Revasc based on the degree of aPTT abnormality. If necessary, interrupt therapy with desirudin until aPTT falls to less than two times control, at which time treatment with desirudin can be resumed at a reduced dose. Thrombin time (TT) is not a suitable test for routine monitoring of Revasc therapy.

Conversion From Other Anticoagulants

If a patient is switched from oral anticoagulants to Revasc therapy or from Revasc to oral anticoagulants, the anticoagulant activity should continue to be closely monitored with appropriate methods.

Instructions For Administration

Directions on Preparation

Use Revasc before the expiration date given on the carton and container.

• To prepare the reconstituted aqueous solution, 0.5 mL of the mannitol diluent is added under aseptic conditions to the vial containing the sterile powder.
• Remove plastic flip-top cap from Revasc Vial. Remove back cover of Vial Adapter package. Attach Vial Adapter to Vial by using the outer package to handle Adapter. Push Adapter down onto Vial until spike pierces rubber stopper and snaps into place. Discard Vial Adapter package.
• Remove Syringe cap by twisting and pulling gently. Attach Syringe to Adapter on Vial by twisting. Slowly push plunger down to completely transfer solution into Vial. Leaving Syringe connected to Vial, gently swirl. Lyophilized powder in Vial will dissolve within 10 seconds.
• With Syringe still connected to Vial, turn Vial upside down and withdraw entire contents of Vial back into Syringe. Remove Syringe from Vial and hold it with plunger-end down.
• You must use enclosed Eclipse™ needle. Attach Needle to Syringe by twisting. Pull pink lever down and uncap needle. You are ready to inject Revasc. After injection, flip up pink lever to cover needle until it snaps into place. Dispose of the used Syringe in a Sharps^® container.

Revasc should not be mixed with other injections, solvents, or infusions. Revasc is administered by subcutaneous injection. It must not be administered by intramuscular injection.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Subcutaneous Injection Technique:

Patients should be sitting or lying down and Revasc injection administered by deep subcutaneous injection. Administration should be alternated between the left and right anterolateral and left and right posterolateral thigh or abdominal wall. The whole length of the needle should be introduced into a skin fold held between the thumb and forefinger; the skin fold should be held throughout the injection. To minimize bruising, do not rub the injection site after completion of the injection.

Storage After Reconstitution

Once Revasc is reconstituted it may be used for up to 24 hours, when stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F). Protect from light. After 24 hours, discard the solution.

Revasc is contraindicated in patients with known hypersensitivity to natural or recombinant hirudins due to risk of anaphylaxis, and in patients with active bleeding and/or irreversible coagulation disorders due to risk of hemorrhage.

WARNINGS

Included as part of the "PRECAUTIONS" Section

PRECAUTIONS

Spinal/Epidural Hematoma

There is a risk of neuraxial hematoma formation with the concurrent use of desirudin and spinal/epidural anesthesia, which has the potential to result in long term or permanent paralysis. The risk may be greater with the use of post-operative indwelling catheters or the concomitant use of additional drugs affecting hemostasis such as NSAIDs (Non-Steroidal Anti-Inflammatory Drugs), platelet inhibitors or other anticoagulants. The risk may also be increased by traumatic or repeated neuraxial puncture.

To reduce the potential risk of bleeding associated with the concurrent use of desirudin and epidural or spinal anesthesia/analgesia, the pharmacokinetic profile of the drug should be considered when scheduling or using epidural or spinal anesthesia in proximity to desirudin administration. The physician should consider placement of the catheter prior to initiating desirudin and removal of the catheter when the anticoagulant effect of desirudin is low.

Should the physician decide to administer anticoagulation in the context of epidural/spinal anesthesia, extreme vigilance and frequent monitoring must be exercised to detect any signs and symptoms of neurological impairment such as midline back pain, sensory and motor deficits (numbness or weakness in lower limbs), bowel and/or bladder dysfunction. Patients should be instructed to inform their physician immediately if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, urgent diagnosis and treatment including spinal cord decompression should be initiated.

The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

Revasc cannot be used interchangeably with other hirudins as they differ in manufacturing process and specific biological activity (ATUs). Each of these medicines has its own instructions for use.

Hemorrhagic Events

Avoid intramuscular injection of Revasc as bleeding and local hematoma formation can occur.

Revasc increases the risks of hemorrhage in patients with recent major surgery, organ biopsy or puncture of a non-compressible vessel within the last month; a history of hemorrhagic stroke, intracranial or intraocular bleeding including diabetic (hemorrhagic) retinopathy; recent ischemic stroke, severe uncontrolled hypertension, bacterial endocarditis, a known hemostatic disorder (congenital or acquired, e.g. hemophilia, liver disease) or a history of gastrointestinal or pulmonary bleeding within the past 3 months.

Bleeding can occur at any site during therapy with Revasc. An unexplained fall in hematocrit or blood pressure should lead to a search for a bleeding site. In post marketing experience reports of fatal and serious bleeding events have occurred in patients treated with Revasc. Sources of hemorrhage included bleeding from the brain, gastrointestinal tract, spleen, rectum, and vagina.

Avoid use with other drugs that inhibit or modify platelet function or affect blood clotting (e.g., anticoagulants, antiplatelet agents, NSAIDs, SSRIs) as coadministration with Revasc may potentiate bleeding. If these concomitant medications cannot be avoided, patients should be monitored for bleeding.

Increased Risk Of Bleeding With Renal Impairment

Revasc must be used with caution in patients with renal impairment due to an increased risk for bleeding, particularly in those with moderate and severe renal impairment (creatinine clearance ≤60 mL/min). Reduce dose and monitor daily aPTT and serum creatinine in patients with moderate and severe renal impairment.

Antibodies /Re-Exposure

Antibodies have been reported in patients treated with hirudins. Potential for cross-sensitivity to hirudin products cannot be excluded. Irritative skin reactions were observed in 9/322 volunteers exposed to Revasc by subcutaneous injection or intravenous bolus or infusion in single or multiple administrations of the drug. The allergic reaction in volunteers consisted of arthralgia, erythema, pruritus, or uticaria. Allergic events were reported in <2% of patients who were administered desirudin in Phase III clinical trials. Allergic events were reported in 1% of patients receiving unfractionated heparin and 1% of patients receiving enoxaparin. Hirudin-specific IgE evaluations may not be indicative of sensitivity to Revasc as this test was not always positive in the presence of symptoms. Anti-hirudin antibodies have been detected upon re-exposure to desirudin. Fatal anaphylactic reactions have been reported during hirudin therapy.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No long-term studies in animals have been conducted to evaluate the carcinogenic potential of desirudin.

Desirudin was not genotoxic in the Ames test, the Chinese hamster lung cell (V79/HGPRT) forward mutation test or the rat micronucleus test. It was, however, equivocal in its genotoxic effect in Chinese hamster ovarian cell (CCL 61) chromosome aberration tests.

Desirudin at subcutaneous doses up to 10mg/kg/day (about 2.7 times the recommended human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.

Use In Specific Populations

Renal Impairment

Revasc 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. Reduce dose and monitor daily aPTT and serum creatinine in patients with renal impairment.

Hepatic Impairment

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

Pregnancy

Pregnancy Category C.

Risk Summary

There are no adequate and well controlled studies in pregnant women. Revasc should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Revasc 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.

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 Revasc, 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.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

In three clinical studies of Revasc, the percentage of patients greater than 65 years of age treated with 15 mg of Revasc subcutaneously every 12 hours was 58.5%, while 20.8% were 75 years of age or older. Elderly patients treated with Revasc 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.

Renal Impairment

Revasc 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. Reduce dose and monitor daily aPTT and serum creatinine in patients with renal impairment.

Hepatic Impairment

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

The following serious reactions are described further in other sections of the prescribing information:

• Spinal/Epidural Hematoma
• Hemorrhagic Events
• Increased Risk of Bleeding with Renal Impairment
• Antibodies/Re-exposure

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In the Phase II and III clinical studies, desirudin was administered to 2159 patients undergoing elective hip replacement surgery to determine the safety and efficacy of Revasc in preventing VTE in this population. Below is the safety profile of the Revasc 15 mg (q12h) regimen.

Hemorrhagic Events

The following rates of hemorrhagic events have been reported during clinical trials.

Hemorrhage in Patients Undergoing Hip Replacement Surgery

Non-Hemorrhagic Events

Non-hemorrhagic adverse events occurring at ≥2% incidence in patients treated with Revasc 15 mg (q 12h) during elective hip replacement surgery and considered to be remotely, possibly, or probably related to desirudin are provided below.

Adverse Events Occurring at ≥2% in Revasc Treated Patients Undergoing Hip Replacement Surgery^a,b

Related Adverse Events with a Frequency of <2% and >0.2% (in decreasing order of frequency): thrombosis, hypotension, leg edema, fever, decreased hemoglobin, hematuria, dizziness, epistaxis, vomiting, impaired healing, cerebrovascular disorder, leg pain, hematemesis.

Allergic Reactions. In clinical studies, allergic events were reported <2% overall and in 2% of patients who were administered 15 mg desirudin.

Post Marketing Experience

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

In case of overdose, most likely reflected in hemorrhagic complications or suggested by excessively high aPTT values, Revasc 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 Revasc 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.

The pharmacodynamic effect of desirudin on proteolytic activity of thrombin was assessed as an increase in aPTT. A mean peak aPTT prolongation of about 1.38 times baseline value (range 0.58 to 3.41) was observed following subcutaneous b.i.d. injections of 15 mg desirudin. Thrombin time (TT) frequently exceeds 200 seconds even at low plasma concentrations of desirudin, which renders this test unsuitable for routine monitoring of Revasc therapy. At therapeutic serum concentrations, desirudin has no effect on other enzymes of the hemostatic system such as factors IXa, Xa, kallikrein, plasmin, tissue plasminogen activator, or activated protein C. In addition, it does not display any effect on other serine proteases, such as the digestive enzymes trypsin, chymotrypsin, or on complement activation by the classical or alternative pathways.

Properties

Pharmacokinetic parameters were calculated based on plasma concentration data obtained by a nonspecific ELISA method that does not discriminate between native desirudin and its metabolites. It is not known if the metabolites are pharmacologically active.

Absorption

The absorption of desirudin is complete when subcutaneously administered at doses of 0.3 mg/kg or 0.5 mg/kg. Following subcutaneous administration of single doses of 0.1 to 0.75 mg/kg, plasma concentrations of desirudin increased to a maximum level (Cmax) between 1 and 3 hours. Both Cmax and area-under-the-curve (AUC) values are dose proportional.

Mean Desirudin Concentrations and Changes in APTT
After A Single 15 mg Subcutaneous Dose in 12 Healthy Subjects

Distribution

The pharmacokinetic properties of desirudin following intravenous administration are well described by a two-or three-compartment disposition model. Desirudin is distributed in the extracellular space with a volume of distribution at steady state of 0.25 L/kg, independent of the dose. Desirudin binds specifically and directly to thrombin, forming an extremely tight, non-covalent complex with an inhibition constant of approximately 2.6 x 10^-13 M. Thus, free or protein bound desirudin immediately binds circulating thrombin. The pharmacological effect of desirudin is not modified when coadministered with highly protein bound drugs (>99%).

Metabolism

Human and animal data suggest that desirudin is primarily eliminated and metabolized by the kidney. The total urinary excretion of unchanged desirudin amounts to 40 to 50% of the administered dose. Metabolites lacking one or two C-terminal amino acids constitute a minor proportion of the material recovered from urine (< 7%). There is no evidence for the presence of other metabolites. This indicates that desirudin is metabolized by stepwise degradation from the C-terminus probably catalyzed by carboxypeptidase(s) such as carboxypeptidase A, originating from the pancreas. Total clearance of desirudin is approximately 1.5 to 2.7 mL/min/kg following either subcutaneous or intravenous administration and is independent of dose. This clearance value is close to the glomerular filtration rate.

Elimination

The elimination of desirudin from plasma is rapid after intravenous administration, with approximately 90% of the dose disappearing from the plasma within 2 hours of the injection. Plasma concentrations of desirudin then decline with a mean terminal elimination half-life of 2 to 3 hours. After subcutaneous administration, the mean terminal elimination half-life is also approximately 2 hours.