……………For Your Drug Information ………….

OSF Saint Francis Medical Center Peoria, IL

Xelodaâ (capecitabine) – Formulary item: New Black Box Warning. There is a clinically significant Xeloda-warfarin drug interaction. Patients stabilized on anticoagulant therapy had significantly increased PT and INR after the introduction of Xelodaâ . Patients started on Xelodaâ should have their PT/INR monitored frequently to adjust warfarin dose as necessary. (November FDA Medwatch)

Remicadeâ (infliximab) – Formulary item: New Black Box Warning. Including tuberculosis, opportunisitic infections such as histoplasmosis, listeriosis, and pneumocystis have been reported in post-marketing surveillance. Also, in patients already diagnosed with CHF, phase 2 trials are showing an increase in mortality and hospitalization for worsening congestive heart failure. This risk is greater at higher doses of Remicadeâ . (October FDA Medwatch)

Tikosynâ (dofetilide) – Formulary item: New Warning. Dofetilide is contraindicated in use with hydrochlorothiazide alone or in combination with triamterene. Both agents combined can cause QTc prolongation and ventricular arrythmia.

Serzone (nefazodone) – The FDA has notified Bristol-Myers Squibb to add a black box warning to its label for Serzone. They wanted to add a statements to warn clinicians of cases of life-threatening liver failure in patients receiving this drug. FDA estimated that the reported rate in this country is 1 case / 250,000 to 300,000 patients using the drug for 1 year. (source: Reuters Health 12/10/01).

Varicella and MMR vaccines – CDC recommends that these 2 vaccines should be given either simultaneously or wait at least 30 days if vaccines are given separately. It was noted that if one vaccine was given within 30 days after the other, the antibody titer do not get as high as needed for immunity.

by Margaret Heger, Pharm.D.

Gatifloxacin (Tequinâ ) is a member of the fluoroquinolone class of antibiotics. This particular fluoroquinolone inhibits two different components of the cell division cycle, DNA gyrase and topoisomerase IV. DNA gyrase is responsible for unwinding cellular DNA for repair, transcription, and replication. Topoisomerase IV is responsible for cell division. It is proposed that gatifloxacin’s affinity for topoisomerase IV increases it’s activity against gram positive organisms and decreases the amount of gram positive resistance to the drug. Levofloxacin is more specific for DNA gyrase.

Gatifloxacin is 96% absorbed as an oral dose. The oral dosage form should be given at least four hours before the administration of iron, calcium, magnesium, or Videx â (didanosine). Gatifloxacin can be given without regard to meals.

Over 99% of the drug is renally eliminated. The dosage is renal impairment is recommended as follows:

There are no recommendations for dosage adjustments based on age or hepatic function. The average half life is 7-14 hours.

Gatifloxacin is indicated for the treatment of bronchitis, community acquired pneumonia, sinusitis, uncomplicated urinary tract infections, pyelonephritis, and gonorrhea. Culture and sensitivity reports are similar to that of levofloxacin.

Common adverse effects include nausea, diarrhea, headache, and dizziness. There is some concern with QTc prolongation with all fluoroquinolines. Decreased expression of potassium channels because of gene inhibition has caused the problem with grepafloxacin, sparfloxacin, and moxifloxacin. Studies have shown that gatifloxacin has negligible effects on the genes responsible, even at higher concentration than would be found with therapeutic levels. Gatifloxacin can increase concentrations of warfarin and digoxin; levels should be monitored accordingly.

Gatifloxacin is the new preferred fluoroquinolone on formulary at SFMC for adult use.

By Margaret Heger, Pharm.D.

Darbepoetin alfa is a "novel erthropoiesis stimulating protein" (NESP) with the same mechanism of action of epoetin alfa (EpogenÒ ). Darbepoetin alfa was created to increase the half-life of the molecule by increasing the amount of sialic acid carbohydrate on the molecule. Identical to natural erythropoetin, darbepoetin interacts with progenitor stem cells to increase red cell production.

After IV administration, darbepoetin alfa has a half-life of approximately 21 hours. Subcutaneous administration results in an increased half-life of 49 hours.

Initial dosing of darbepoetin alfa is based on weight, 0.45 mcg/kg given IV or SQ once weekly. Hemoglobin monitoring is recommended once a week for four weeks. If there is an increase in hemoglobin 1g/dL or greater in a two week period, the dose should be decreased 25%. If the hemoglobin continues to increase, doses should be withheld until the hemoglobin begins to drop, and then dosing should be restarted with an additional 25% reduction in dose. If the hemoglobin does not increase greater than 1g/dL in a four week period, the dose may be increased by 25%. The dose of darbepoetin alfa should not be increased more often than once every four weeks.

Conversion of epoetin alfa to darbepoetin alfa:

Patients receiving epoetin alfa three times per week should receive darbepoetin once weekly.

Patients receiving epoetin alfa once per week should receive darbepoetin alfa every two weeks.

Maintenance dosing should be adjusted to meet desired hemoglobin levels. The target hemoglobin for darbepoetin alfa is 12g/dL.

Adverse reactions to darbepoetin alfa are very similar to epoetin alfa. Reactions requiring adjustments in dose were hypertension, hypotension, chest pain, fever, myalgia, and nausea. The most common reactions were infection, hypertension, hypotension, myalgia, headache, and diarrhea.

Darbepoetin alfa should not be shaken, as turbulence can denature the protein. It should not be diluted and is not compatible with any other running solution.

By Ruth Avelino, Pharm.D.

Drotrecogin alpha (XigrisÒ ) is a recombinant form of human activated Protein C. It is indicated for the reduction of mortality in adult patients with severe sepsis ( sepsis associated with acute organ dysfunction). The exact mechanism on how it can increase survival in patients with severe sepsis is unknown, but it might be related to both its antithrombotic and anti-inflammatory effects. It exerts antithrombotic effects through inhibition of Factors Va, VIIIa , plasminogen activator inhibitor (PAI-1) and limiting a fibrinolysis inhibitor usually activated by thrombin. It also exerts an anti-inflammatory effect by inhibiting tumor necrosis factor production thus limiting the inflammatory responses within the microvascular endothelium.

Adult patients with severe sepsis = 24mcg/kg/hr infused over 96 hours and should be started within 48hrs after the onset of first sepsis induced organ dysfunction.

Dose adjustment is not needed based on age, gender, renal or hepatic dysfunction. Safety and efficacy in the pediatric population have not been studied therefore no dosage recommendation available. However, pharmacokinetics studies based on 24mcg/kg/hr on this population appears similar to adults.

Should an invasive surgery or procedure be needed, XigrisÒ should be discontinued 2hrs prior to procedure. XigrisÒ can be restarted 12hrs after major invasive surgery or procedure OR immediately after uncomplicated less invasive procedures.

See IV guideline for dosage preparation – Do not use pneumatic tube for delivery; Should use a dedicated line.

XigrisÒ , as well as endogenous activated protein C, are inactivated by endogenous plasma protease inhibitors. Steady state concentration were noted after 2 hours of infusion and XigrisÒ serum concentration falls to undetectable levels 2hrs after stopping the infusion.

Small differences in plasma clearance was detected with regard to age, gender, hepatic and renal dysfunction among adult patients with severe sepsis.

Bleeding is the most common side-effect seen in the PROWESS study (25% for the XigrisÒ treated patients vs 18% for the placebo group). A majority were ecchymoses and GI tract bleeding. Approximately 2.4% in the XigrisÒ group and 1% in the placebo group experienced serious bleeding events.

These bleeding events were noted during the 96hr infusion period.

Active internal bleeding

Recent (within 3 mos) hemorrhagic stroke

Recent (within 2 mos) intracranial, intraspinal surgery, or severe head trauma

Trauma with an increased risk of life-threatening bleeding

Presence of an epidural catheter

Intracranial neoplasm or mass lesion or evidence of cerebral herniation

Patients with known hypersensitivity to drotrecogin alpha (activated) or any of its component

Patients with the following factors may have an increased risk of bleeding and should be carefully monitored or assessed:

Concurrent heparin therapy ( ³ 15 units/kg/hr) ; Platelets < 30,000 x 10⁶ /L, even if platelet count is increase after transfusions; INR > 3 ; Recent (within 6 wks) of GI bleed; Recent (within 3days) of thrombolytic therapy; Recent ( within 7 days) of oral anticoagulants or g2b/3a inhibitors; recent administration (within 7days) of aspirin >650mg /day or other platelet inhibitors; recent ( within 3 mos) ischemic stroke; intracranial arteriovenous malformation or aneurysm; known bleeding diathesis; chronic severe hepatic disease … and any other condition which bleeding constitutes a significant hazard or difficult to manage because of its location.

Drug interaction: Not studied; Caution with drugs that affect hemostasis.

1. No antidote available for overdose cases or bleeding. Discontinue drug.
2. Bolus doses, dose escalation or dose adjustments based on clinical or laboratory parameters are NOT recommended due to lack of data (both safety and efficacy). Any dose interruptions should be restarted , if needed, at same rate of 24mcg/kg/hr.
3. XigrisÒ variably affect PTT but not PT. Therefore, INR or PT measurements more reliably measures the patient’s own coagulation status.

Added on December P &T meeting.

Is it safe for Lovenox to be given to a patient that already has the epidural catheter in place?

1. Delay LMWH therapy for 24hrs post-op if there is presence of blood during needle and catheter placement (especially traumatic needle and catheter placement).
2. In patients receiving pre-op LMWH, catheter needle placement should occur at least 10-12 hrs after LMWH dose; delay for 24hrs if patients receive higher doses (1mg/kg bid)
3. Avoid concurrent use of indwelling catheters and LMWH. Remove indwelling catheters before initiating LMWH. If epidural anesthesia is to be continued for greater that 24hrs, use an alternate method or delay LMWH use while patient has the catheter in place.
4. First LMWH dose should not be administered sooner than 2hrs after indwelling catheter removal.

(Source: Aventis personal letter/communications – see enoxaparin file)

Cross Sensitivities between Narotics, NSAIDS, Cephalosporins and PCNS: -

(Source: Drug consults –Drugdex; JAMA 1997; 278(22):1895-1906; Emergency Medicine Practice April 2000; 2(4) – see Disease file – Hypersensitivity reactions – for hard copy of above)