APRIL                                                                                           2002

FORMULARY ADDITIONS

Fondaparinux Sodium

Arixtra®

2.5 mg/0.5 mL syringe

Restricted to Orthopedics

            Fondaparinux, also known as fondaparin, is an anti-factor Xa anticoagulant that is similar to low-molecular weight heparin in action.  The fondaparin molecule is a copy of the antithrombin III binding area of heparin.  Once bound to antithrombin III, a complex is formed that inhibits the activity of factor Xa and decreases thrombin generation without affecting circulating thrombin. The lack of impact on circulating thrombin levels occurs because the molecular size of fondaparinux is smaller than heparin so it selectively binds to factor Xa but not to the thrombin molecule.   A comparison of the FDA approved indications for fondaparin and other low molecular weight heparins is provided in Table 1.

Table 1. Comparative indications for low molecular weight heparins on formulary

            Fondaparinux is contraindicated in patients allergic to the drug or any component of its formulation. It is also contraindicated in patients with severe renal impairment (CrCl < 30 mL/min) as these patients are at increased risk of accumulation and increased risk of bleeding episodes. Fondaparinux is also contraindicated in patients weighing less than 50 kg. In clinical trials, major bleeding events were doubled in patients weighing less than 50 kg.  The use of this agent is also contraindicated in patients with active major bleeding, bacterial endocarditis, and in patients wit thrombocytopenia associated with a positive in vitro test for antiplatelet antibody in the presence of fondaparinux sodium.

            This drug is not indicated for intramuscular injection and can not be used interchangeably (unit for unit) with other low molecular weight heparins.       Fondaparinux has been well-tolerated in clinical trials.  Like other low-molecular weight heparins and heparoids, major and minor bleeding is a dose-related risk with fondaparinux therapy. Like other LMW heparins, this drug should be used with extreme caution in conditions of increased risk of hemorrhage. Thrombocytopenia has occurred a rate of 2.9% in clinical trials.

            Fondaparinux pharmacokinetics are not altered by concomitant aspirin or warfarin administration.  Concurrent therapy with aspirin may enhance the antithrombotic effects of each agent or increase the risk of bleeding.  Fondaparinux has no impact on the effect of warfarin on INR.

DOSAGE AND ADMINISTRATION: The recommended dose of fondaparinux after surgery is 2.5 mg administered once daily subcutaneously. After hemostasis has been established, the initial dose should be given 6 to 8 hours after surgery. Administration before 6 hours after surgery has been associated with increased risk of bleeding. The usual duration of administration is 5 to 9 days and up to 11 days has been tolerated.

Nesiritide

Natrecor®

1.5 mg single-use vials, sterile lyophilized powder

Restricted to Cardiology Consult

          Nesiritide is a human B-type natriuretic peptide that is indicated for the intravenous treatment of acutely decompensated congestive heart failure in patients with dyspnea at rest or with minimal activity.  Hemodynamic effects of nesiritide, including venous and arterial vasodilation, result in decreased preload and afterload and decreases pulmonary capillary wedge pressure, mean right atrial pressure, pulmonary pressures, and systemic vascular resistance.  Although nesiritide does not exhibit direct inotropic effects, cardiac index is also increased secondary to afterload reduction.  These effects are sustained through 48 hours. Nesiritide had a mild diuretic effect and causes increased sodium excretion.

Nesiritide should not be used in patients with systolic blood pressure < 90 mm Hg or in those in cardiogenic shock.  Administration to patients with low cardiac filling pressures should be avoided.  Nesiritide is not recommended for patients with significant valvular stenosis, restrictive or obstructive cardiomyopathy, constrictive pericarditis, pericardial tamponade, or other conditions in which cardiac output is dependent on venous return. 

Serum creatinine was increased over baseline when compared to standard therapies when administered at doses greater than 0.01 mcg/kg/min.  Dose-dependent hypotension may occur with nesiritide; monitor blood pressure closely. Nesiritide should be discontinued or the dose reduced in patients who develop hypotension.

Adverse reactions occurring with at least 3% frequency include hypotension, ventricular tachycardia and extrasystoles, headache, and nausea.  In studies comparing the occurrence of ventricular arrhythmias of dobutamine and nesiritide, ventricular arrhythmias, including sustained and nonsustained ventricular tachycardia, occurred more often with dobutamine than nesiritide.  Concomitant oral ACE inhibitor-therapy resulted in an increased frequency of hypotension compared to therapy without oral ACE inhibitors.  Nesiritide has not been administered with nitroglycerin, nitroprusside, milrinone, or intravenous ACE inhibitors, effects are unknown. 

INCOMPATABILITIES:  Nesiritide is physically incompatible with heparin, furosemide, insulin, bumetanide, ethacrynate sodium, enalaprilat, and hydralazine.

DOSAGE AND ADMINISTRATION: Nesiritide should only be administered in a setting where blood pressure can be closely monitored.  The recommended dose of nesiritide is an IV bolus of 2 mcg/kg followed by a continuous infusion at 0.01 mcg/kg/min.  In clinical trials, nesiritide was increased by 0.005 mcg/kg/min at no more than every three hours, up to a maximum of 0.03 mcg/kg/min.  There is limited experience with nesiritide administration beyond 48 hours and is therefore not recommended.

Papain-Urea-Chlorophyllin Copper Complex Sodium Debriding Ointment

Panafil®

30 g tube, 1 pound jar

Panafil is a debriding ointment indicated for several different types of wounds (see Table 2).  Panafil is similar to another debriding agent currently on the formulary, Accuzyme, except Panafil contains one additional ingredient, chlorophyllin copper complex. The addition of the chlorophyllin copper complex adds healing action to the cleansing and debriding action of the papain-urea combination. Chlorophyllin also inhibits the hemagglutinating and inflammatory properties of protein degradation products in the wound.

Table 2: Indications for Papain/Urea Combination Products

A transient burning sensation may be experienced by a small percentage of patients upon applying the ointment.  Occasionally, the profuse exudate from enzymatic digestion may irritate the skin.  In such cases, more frequent dressing changes will alleviate discomfort until exudate decreases.  This product is contraindicated in patients who have shown sensitivity to papain or any other components of this preparation.

Avoid cleansing the wound with hydrogen peroxide solution as it may inactivate the papain.  Papain may also be inactivated by the salts of heavy metals such as lead, mercury, and silver.  Contact with medications containing these metals should be avoided.  Terramycin, aureomycin, and chloromycetin may inhibit protein degradation.

DOSAGE AND ADMINISTRATION: Cleanse wounds with saline, AllClenz Wound Cleanser or Curasol Wound Cleanser.  Apply Panafil directly to the wound, cover with appropriate dressing and secure into place.  Daily or twice daily applications are preferred.  Irrigate the wound at each dressing change to remove any accumulation of liquefied necrotic material.

Ertapenem Sodium

Invanz^®

1 Gram IM/IV

Restricted to Complicated Intra-abdominal Infections and Diabetic Foot Ulcers

INVANZ (ertapenem for injection) is a carbapenem antibiotic that is structurally related to beta-lactam antibiotics. INVANZ is indicated for various types of infections but will be restricted at KU Med for the treatment of severe, complicated intra-abdominal infections and diabetic foot ulcers.

INVANZ is contraindicated in patients with known hypersensitivity to any component of this product or to other drugs in the same class or in patients who have demonstrated anaphylactic reactions to penicillin or other beta-lactams.  Before initiating therapy with INVANZ, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams, and other allergens. 

Due to the use of lidocaine HCl as a diluent, intramuscular administration of INVANZ is contraindicated in patients hypersensitive to local anesthetics of the amide type. Caution should be taken when administering INVANZ intramuscularly to avoid inadvertent injection into a blood vessel.

Pseudomembranous colitis has been reported with nearly all antibacterial agents, including ertapenem, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

During clinical investigations, seizures occurred in 0.5% of patients. Seizures occurred most commonly in patients with CNS disorders (e.g., brain lesions or history of seizures) and/or compromised renal function. Close adherence to the recommended dosage regimen is urged, especially in patients with predisposing factors.  Dose adjustment is recommended in patients with reduced renal function.

The most common drug-related adverse experiences in patients treated with INVANZ, were diarrhea (5.5%), infused vein complication (3.7%), nausea (3.1%), headache (2.2%), vaginitis in females (2.1%), phlebitis/thrombophlebitis (1.3%), and vomiting (1.1%).  Consult the full INVANZ prescribing information for a complete list of adverse reactions observed in clinical studies.

In clinical studies, ertapenem was discontinued due to laboratory changes in 0.3% of patients. Drug-related laboratory changes reported in > 1.0% of patients were increases in ALT (6.0%), AST (5.2%), alkaline phosphatase (3.4%), platelet counts (2.8%), and eosinophils (1.1%).  Additional laboratory changes that occurred in > 0.1% but < 1.0% of patients included increases in BUN, direct and indirect serum bilirubin, serum sodium, monocytes, PTT, urine epithelial cells and decreases in serum bicarbonate.

DRUG INTERACTIONS: No specific clinical drug interaction studies have been conducted other than with probenecid.  When used concomitantly with probenecid, the renal clearance of ertapenem is reduced.  Ertapenem has not been found to inhibit P-glycoprotein-mediated transport of digoxin or vinblastine or to be a substrate for P-glycoprotein-mediated transport. Ertapenem also does not inhibit metabolism mediated by any of the cytochrome P450 (CYP) isoforms.

DOSAGE AND ADMINISTRATION

The usual adult dose of INVANZ is 1 gram once daily given by IV infusion for up to 14 days or by IM injection for up to 7 days. When administered IV, INVANZ should be infused over a period of 30 minutes. Do not mix or co-infuse INVANZ with any other medications.  Do not use diluents containing dextrose.

* Defined as creatinine clearance >90 mL/min/1.73 m2

† Due to the designated pathogens

Renal Insufficiency: In patients whose creatinine clearance is > 30 mL/min, no dose adjustment is necessary. When the creatinine clearance is < 30 mL/min or in end-stage renal disease (creatinine clearance < 10 mL/min) the dose should be reduced to 500 mg daily.  When patients on hemodialysis are given the recommended daily dose of 500 mg of INVANZ within 6 hours prior to hemodialysis, a supplementary dose of 150 mg is recommended following the hemodialysis session. If INVANZ is given at least 6 hours prior to hemodialysis, no supplementary dose is needed. There is no data in patients undergoing peritoneal dialysis or hemofiltration.

Patients with Hepatic Insufficiency: No dose adjustment recommendations can be made in patients with impaired hepatic function.

PREPARATION OF SOLUTION:

For Intravenous administration:

Do not mix or co-infuse INVANZ with other medications.  Do not use diluents containing dextrose.  INVANZ must be reconstituted and diluted prior to administration.

1.     Reconstitute the 1-gm vial with 10 mL of Water for Injection, 0.9% Sodium Chloride Injection, or Bacteriostatic Water for Injection.

2.  Shake well to dissolve and immediately transfer contents of the reconstituted vial to 50 ml of 0.9% Sodium Chloride Injection.

3.  Complete the infusion within 6 hours of reconstitution.

For intramuscular administration:

INVANZ must be reconstituted prior to administration.

1.   Reconstitute the 1-gm vial with 3.2 mL of 1.0% lidocaine HCl injection. Shake vial thoroughly to form solution.

2.   Immediately withdraw the contents of the vial and administer by deep IM injection into a large muscle mass (such as the gluteal muscles or lateral part of the thigh).

3.   The reconstituted IM solution should be used within 1 hour after preparation. The reconstituted intramuscular solution should never be administered intravenously.

Prepared by Jenny Meyer, Pharm.D.

Drug Information Resident (4/2/02)