……………For Your Drug Information ………….

1). Adalimumab (HumiraÒ ): A monoclonal antibody that binds to human tumor necrosis factor alpha (TNF-a ) for the treatment of rheumatoid arthritis. HumiraÒ is the second TNF blocker to be approved by the FDA. The first was etanercept (EnbrelÒ ). TNF mediates both immune and inflammatory responses in the body. Patients with rheumatoid arthritis have excessive amounts of TNF in their synovial fluid, causing inflammation and joint damage. TNF blockers have been shown to be effective in controlling rheumatoid arthritis symptoms as well as inhibiting joint destruction in patients with moderate to severe rheumatoid arthritis. The usual dose of HumiraÒ is 40mg given as a subcutaneous injection once every other week. In contrast, EnbrelÒ must be injected subcutaneously twice weekly. HumiraÒ can be used alone or in combination with other disease-modifying anti-rheumatic drugs (DMARDS) like methotrexate. The most common side effects are injection site reactions, upper respiratory infections, rhinitis, and sinusitis and incidence was similar to placebo. The most serious side effects are the chance of serious, sometimes fatal infections (TB, sepsis), neurologic effects, and malignancies of the lymph system.

2.) Erletriptan (Relpaxâ ) is another serotonin 1D (5-HT_1D) agonist recently approved for the treatment of acute migraine attacks. It has a faster onset compared to oral sumitriptan, but is comparable to the newer agents zolmitriptan and rizatriptan.

3). Pediarix^®: GlaxoSmithKline received a letter of approval from the FDA in December 2002 and plans to begin marketing the product in early 2003. Pediarix® is a five-in-one combination vaccine which contains protection against diphtheria, tetanus, pertusis, hepatitis B, and polio. Pediarix® will be used as the three dose primary series in infants born to HBs-AG negative mothers, who are at least 6 weeks old. The dose will be contained in 0.5 ml of solution. GSK plans to market Pediarix® at a price that will be comparable to the cost of the 5 individual vaccines. NOTE: The package insert states that this product is associated with a higher incidence of fever when compared to the separately administered vaccines.

4). Alefacept (Ameviveâ ) is the first biologic agent approved to treat adults with moderate to sever plaque psoriasis. Alefacept binds to the CD2 receptor on T-lymphocytes, inhibiting T-cell activation/proliferation. Adverse effects include flu-like symptoms, infection, dizziness, pruritus, nausea, and transient decreases in lymphocyte counts. It is currently under investigation for scleroderma and rheumatoid arthritis.

In a recent article by Lau et al¹, platelet aggregation was measured in 44 patients undergoing stent implantation. They were treated with either clopidogrel (Plavix) alone or clopidogrel (Plavix) + atorvastatin (Lipitor) or pravastatin (Pravachol). The objective was to determine if clopidogrel’s platelet aggregation inhibition effect is reduced by the addition of a competitive CYP3A4 inhibitor (i.e. atorvastatin). The theory is that since clopidogrel is a pro-drug requiring activation by the CYP3A4 enzyme, competitive inhibition will prevent the activation of clopidogrel. They also looked at 27 volunteers treated with clopidogrel and either (erythromycin or troleandomycin) or rifampin.

The investigators observed that atorvastatin, erythromycin, and troleandomycin all attenuated the platelet aggregation inhibition of clopidogrel. The effects of atorvastatin were dose dependent. Rifampin enhanced the therapeutic effects of clopidogrel. Platelet aggregation inhibition remained unchanged for those patients who also took pravastatin.

The clinical impact of these drug interaction observations remains unknown. Complications after coronary stenting remain low due to the technical improvements in the devices used and with the advent of dual anti-platelet therapy (glycoprotein II_bIII_a inhibitor + aspirin/clopidogrel). It would be difficult to detect a clinical difference solely due to a CYP 3A4 drug interaction. However, hydrophilic anti-lipemic agents, such as pravastatin, may be better alternatives for those patients requiring PTCA therapy and clopidogrel.

1. Lau WC, Waskell LA, Watkins PB, et al. Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation. Circulation. 2003;107:32-37.

Per personal communication with Roche Laboratories, an in house study was conducted to test the stability of valgancyclovir in an acidic solution. Commercially available tablets were crushed and dissolved in a cherry syrup base (acidic pH) at a final concentration of 90 mg/ml. The product maintained 90% potency at refrigerated temperatures (2 – 8 º) for 125 days (when Sodium Benzoate was used as a preservative). Recommend that we make in above tested concentration (90 mg/ml), using cherry syrup and give a 7 day expiration with REFRIGERATE sticker. Valgancyclovir is mutagenic and listed as Pregnancy Category C. Would recommend compounding in the vertical flow hood to insure the person preparing the solution take maximum safety precautions.

Personal communication with Roche Medical Information 12/20/02. RRA

Micomedex Drug Evaluation for Valgancyclovir. 1974-2002. Vol. 114

Patient receive intravenous immune globulins for a variety of conditions such as primary immune deficiency, idiopathic thrombocytopenia purpura, Kawasaki disease, AIDS or transplant patients, and chronic lymphocytic leukemia. The amount of IgA that an IVIG product contains is a question that is occasionally asked. Patients who have an IgA deficiency may have IgA antibodies that may predispose them to a severe allergic reaction during the administration of IVIG with higher amounts of IgA. Patients with the IgA deficiency should receive a product with the lowest amount of IgA to minimize infusion related reactions. Gammagard® (Baxter-Hyland) is often used for this patient population and contains only a range of < 1 to 1.2 mcg/ml. Carimune® (ZLB Bioplasma Inc.) contains about 720 –890 mcg/ml of IgA and should NOT be used in this patient population. Carimune® is the same product as what was previously marketed as Sandoglobulin®. IgA content of various IVIG products can be found in the following

3). Rectal Drug Administration of Vancomycin for Clostridium difficile colitis

Clostridium difficile is a gram-positive, spore-forming, anaerobic bacillus that is widely distributed in nature. However, it is not a typical component of the colonic microflora. It is a nosocomial pathogen whose spread can be reduced within an institution by following proper infection-control procedures. Pathogenesis of Clostridium difficile induced colitis requires four essential features: readily available source of C. difficile, loss of the normal bowel microflora, production of toxins, and individual risk factors (advanced age, immunosuppressant disease states, concomitant or previous antimicrobial/ anti-neoplastic therapy, nasogastric intubation, prolonged hospitalization, residence in a intensive care unit, recent surgery). ¹

The first step in treatment of C. difficile colitis is discontinuation of the offending antimicrobial whenever possible. If symptomatic improvement occurs within 48-72 hours after antimicrobial withdrawal, treatment of C. difficile is often unnecessary. Patients who present with symptoms of severe C. difficile (high fever, leukocytosis, and severe abdominal pain) or patients who cannot be withdrawn from the inciting antimicrobials should be treated. Numerous position statements support the use of oral metronidazole as the preferred antimicrobial to treat C. difficile induced colitis. Although historically, oral vancomycin was the gold standard of therapy, both show equal efficacy for treatment. When patients cannot tolerate oral regimens, IV metronidazole is an acceptable alternative. IV vancomycin does not reach the colon for effective treatment and should not be used. ^2-3

There are special circumstances when alternatives to oral therapy are needed to treat C. difficile induced colitis. Patients with severe ileus, alterations in small/large bowl anatomy which prevent oral administration of drugs or patients with C. difficile sepsis failing previous treatment may be candidates for rectal administration of vancomycin. There are a few case-reports summarizing a variety of dosing and administration attempts.

• 500mg vancomycin in 1000ml NS q 8 hours, as a retention enema⁴
• 1gram vancomycin in 1000ml NS q 6 hours, as a retention enema⁵
• 2000mg vancomycin instilled intracolonically during colonoscopy, followed by 100mg in 100ml via colonic catheter q6hours combined with an additional 100mg after every watery stool⁶
• 1gram vancomycin in 500ml NS q 4 hours, as a retention enema⁷
• 500mg vancomycin in 500ml NS bid, as a retention enema⁸

Volumes and doses varied in the case reports due to the severity of the dilated colonic loops observed on colonoscopy, the clinical status of the patient, as well as the immune status of the patient.

Rectal administration of vancomycin for C. difficile colitis is not routine treatment of the infection. It is more the art than the evidence of medicine. The exact approach will need to be decided between the physician and the pharmacist on a case-to-case basis.

1. Reinke CM, Messick CR. Update on clostridium difficile-induced colitis, part 1. Am J Hosp Pharm 1994; 51:1771-81.
2. Kyne, L, Kelly CP. Recurrent clostridium difficile diarrhoea. Gut. 2001; 49(1): 152-153.
3. Reinke CM, Messick CR. Update on clostridium difficile-induced colitis, part 2. Am J Hosp Pharm. 1994; 51:1892-901.
4. Silva J Jr. Update on pseudomembranous colitis. West J Med 1989; 151:644-8.
5. Goodpasture HC, Dolan PJ, Jacobs ER, et al. Pseudomembranous colitis and antibiotics. Kans Med 1986; 87(5): 133, 146.
6. Pasic M, Res J, Carrel T, et al. Intracolonic vancomycin for pseudomembranous colitis. NEJM 1993; 329(8); 583.
7. Nathanson DR, Sheahan M, Chao L, et al. Intracolonic use of vancomycin for treatment of clostridium difficile colitis in a patient with a diverted colon: report of a case and review of the literature. Dis Colon Rectum 2001; 44:1871-1872.
8. Apisarnthanarak A, Khoury H, Reinus W, et al. Severe clostridium difficile colitis: the role of intracolonic vancomycin? Am J Med 2002; 112(4): 328-329.

4). IV streptomycin dosing in patient with high level gentamicin resistant enterococcus faecalis:

Penicillin in combination with synergistic-gentamicin is the standard of care for management of enterococcus endocarditis. However, recent reports indicate an increase in high-level gentamicin resistance. As a result, synergy between the gentamicin and the cell-wall synthesis inhibitor (i.e. penicillin) cannot be achieved.

Although historically enterococcus had a high-level resistance to streptomycin, the drug was re-introduced into the market for treatment of high-level, gentamicin resistant E. faecalis and multi-drug resistant M. tuberculosis. Streptomycin is typically used as an intramuscular injection for management of both types of infections. However, the intramuscular injection is very painful and can present a problem for those patients who also require anticoagulation during their treatment course.

When streptomycin first came to market, it was used as an intravenous infusion. Administration by this route declined over time due to the severe infusion related reactions (flushing, headache, and nausea). In addition, streptomycin is associated with ototoxicity more so than nephrotoxicity, in comparison with the other aminoglycosides. Ototoxicity is not reversible. Since nephrotoxicity is potentially reversible, the new aminoglycosides became favored.

However, when patients have contraindications to intramuscular drug administration and have cultures and sensitivities that indicate streptomycin is the drug of choice, the intravenous route may still be considered.^1-2

Streptomycin is dosed at 7.5mg/kg every 12 hours as an intravenous infusion over one hour. Most intravenous doses should not exceed 500mg per dose because the risk of ototoxicity increases with higher doses administered intravenously.^1-2 All doses should be diluted in 100 milliliters of normal saline. Streptomycin has similar pharmacokinetic parameters to amikacin. Goal peaks for endocarditis management are between 25 and 35mcg/mL; goal troughs, less than 5mcg/mL.³ The difference between streptomycin and more familiar aminoglycosides lies in when to draw the peak. Intravenous streptomycin has a larger distribution time and the peak should be drawn 2 hours after the start of the infusion. Troughs are drawn routinely, at 30 minutes prior to the start of the next dose.³ Streptomycin levels are not performed at OSF-St. Francis. They are sent out to a regional laboratory and can take 48 to 72 hours to return. Dose adjustments are then made using the traditional dosing pharmacokinetic equations.

Infusion reactions are still a problem. The product has been "purified" since its original 1940’s release, so the reactions are less and less documented. If flushing, headache, circumoral numbness, tingling and nausea do occur throughout the infusion, it is appropriate to extend the infusion time to 2 hours. Ototoxicity is the primary adverse effect associated with streptomycin. Based on the original 1940’s data, patients would typically not experience both nephrotoxicity and ototoxicity.² Therefore, peak monitoring is of primary importance. Risk factors for the development of streptomycin-induced ototoxicity include: advanced age, too high of peaks, and concomitant administration of other ototoxic drugs (i.e. high dose loop diuretics).

Intravenous streptomycin should only be considered for those patients who require long-term antibiotic therapy and/or have contraindications to intramuscular drug administration.

Augmentin ES 600mg/5ml is a product that is approved for otitis media caused by drug-resistant Streptococcus pneumoniae. The product delivers 90mg/kg/day amoxicillin and 6.4mg/kg/day of clavulanate given in two divided doses every 12 hours. The Augmentin ES suspension is pending P&T approval in March. All orders for augmentin (usual dose: 45mg/kg/day to 90mg/kg/day) will be dispensed using the ES suspension. Until the switch occurs, please use both Augmentin 400mg/5ml AND amoxicillin 250mg/5ml when high dose amoxicillin is desired to keep the clavulanate component at 6.4mg/kg/day to prevent diarrhea.

Augmentin XR is an extended release product for adults (over 40kg) to treat sinusitis and community acquired pneumonia. XR tablets are not interchangeable with regular augmentin, since it contains both immediate release and extended release preparations of amoxicillin. (Normal dose is 2 tabs q12h = 4000mg amoxicillin/day)

1. The medical letter 2003;45(1148):5-6.
2. Bottenfield et al. Safety and tolerability of a new formulation of amoxicillin/clavulanate in the empiric treatment of pediatric acute otitis media caused by drug-resistant Streptococcus pneumoniae. Pediatr Infect Dis J 1998;17:963-968.

6). RSV & Surfactant use?

Respiratory syncytial virus (RSV) decreases levels of endogenous lung surfactant in RSV infected infants¹. There are two small trials that have shown improved lung function and possible decrease in ICU stay on mechanical ventilation by giving surfactant to infected infants^2,3. The likely candidates would be infants less than 6 months, with a history of prematurity who are failing conventional ventilator management. Dosing of surfactant has been given at full neonatal respiratory distress syndrome (NRDS) dosing to 25-50% of the NRSD dosing at similar efficacy. Further evaluation of surfactant therapy for RSV induced respiratory failure is needed to determine cost-effectiveness and dosing before we can recommend this in daily practice.

1. Kerr et al. Surfactant protein levels in severe respiratory syncytial virus infections. Am J Respir Crit Care Med 1999;159:115-18.
2. Tibby et al. Exogenous surfactant supplementation in infants with respiratory syncytial virus bronchiolitis. Respir Crit Care Med 2000;162:1251-56.
3. Luchetti et al. Multicentered, randomized, controlled study of porcine surfactant in severe respiratory syncytial virus-induced respiratory failure. Pediatr Crit Care Med 2002;3:261-68.

7). Vaccine schedules:

Pediarix is here! (See new FDA approvals this issue) 5 in 1 protection against disease means one less IM injection for infants at the 2, 4, and 6-month checkups: DTaP/HepB/IPV 0.5ml IM, Hib 0.5ml IM, Prevnar 0.5ml IM. It is okay to finish the series with the Pediarix vaccine per manufacturer. HOWEVER: please note that in infants less than 2kg at 2 months of age, Hepatitis B vaccine is not reliable at producing adequate immunogenicity. Bottom line: vaccines should be given at 2 months in children under 2kg with the standard: DTaP 0.5ml IM, IPV 0.5ml SC, Hib 0.5ml IM, and Prevnar 0.5ml IM.

-By Sandra Salverson, PharmD

Traditional anticoagulation strategies prevent thrombin generation through the inhibition of clotting enzymes. Newer strategies have focused on inhibition of thrombin in hopes of a more predictable anticoagulant response. Direct-acting thrombin inhibitors, such as hirudin and its analogues, have several theoretical advantages over heparin. Thrombin inhibitors that act directly do not require a cofactor such as antithrombin III; are active against clot-bound thrombin; and have no known natural inhibitors, such as platelet factor 4. However, due to their high cost, they remain as second line parenteral anticoagulation therapy.

Heparin induced thrombocytopenia (HIT) is a fairly common (3% to 5%) but under recognized complication of heparin administration. Approximately 36% to 50% of HIT patients develop heparin-induced thrombocytopenia with thrombosis (HITT), the major life and limb threatening complication of HIT. While immediate discontinuation of heparin is the essential foundation of HIT management, the use of the direct thrombin inhibitors, lepirudin and argatroban has been shown to significantly improve clinical outcomes and platelet counts in HIT(T) patients. Low molecular weight heparins (LMWHs) however, should not be used in patients with suspected or confirmed HIT because of the high likelihood for cross-reactivity (80-100%) of the HIT-IgG for LMWHs.

Pharmacology^1-3: Direct thrombin inhibitors inactivate both circulating thrombin and clot bound thrombin irreversibly, independent of the action of circulating antithrombin. Lepirudin is a bivalent inhibitor that binds to thrombin both at exosite 1 and the active site. Argatroban, a low-molecular-weight inhibitor, only binds the active site of thrombin. Bivalent inhibitors are more selective for thrombin than the low-molecular-weight inhibitors.

Adverse Effects^4-5: The primary adverse effect associated with the direct thrombin inhibitors is bleeding. Non-hemorrhagic adverse events observed include dyspnea, hypotension, fever, allergic reactions, and injection site reactions.

The direct thrombin inhibitors are not cross-reactive with heparin in terms of an antibody mediated thrombocytopenia. Thrombocytopenia has not been documented with any of the agents. Anti-hirudin antibodies may develop in 40% of heparin-induced-thrombocytopenia patients treated with lepirudin. These antibodies may increase the anticoagulant effect of lepirudin due to the decrease in renal clearance of the lepirudin-antilepirudin complexes. Despite this immunological response, no decrease in lepirudin activity has been demonstrated.

Drug Interactions^4-5: The direct thrombin inhibitors are not metabolized by the cytochrome P450 system, suggesting the absence of interactions with drugs metabolized by that route. Potential pharmacodynamic interactions exist between the direct thrombin inhibitors and other anti-platelet or anticoagulants. Increased bleeding is documented to occur when used in conjunction with thrombolytics.

Drug Interactions^4-5: The direct thrombin inhibitors are not metabolized by the cytochrome P450 system, suggesting the absence of interactions with drugs metabolized by that route. Potential pharmacodynamic interactions exist between the direct thrombin inhibitors and other anti-platelet or anticoagulants. Increased bleeding is documented to occur when used in conjunction with thrombolytics.

Monitoring Parameters: The pharmacodynamic effects of the direct thrombin inhibitors are assessed by an increase in aPTT. For routine anticoagulation aPTT values of 1.5 - 2.5x control/baseline are considered therapeutic. ACT valued > 300 are considered therapeutic for patients undergoing PTCA.

1. Weitz JI, Hirsh J. New anticoagulant drugs. Chest 2001; 119:95S-107S.
2. Hirsh J. New anticoagulants. Am Heart J 2001; 142:S3-8.
3. Bates SM, Weitz JI. The mechanism of action of thrombin inhibitors. J Inv Cardiol 2000; 12 (Suppl F): 27F-32F.
4. Argatroban Clinical Overview. GlaxoSmithKline. March 2001.
5. Refludan Prescribing Information. Hoechst Marion Roussel. October 1998.

Acetaminophen Peds

Angiomax Peds Study

CAPS (Cathflo) Study

Xigris Pediatric Study (RESOLVE trial) *

AT3 ECMO Study

ARTIST Stroke study Exclaim Study

Apollo Study ED- albuterol/levoalbuterol study

Baxter r-AHF-PFM Study Fenoldopam - Radiology

Synergy Study

CancerVax Melanoma Study* ONO- stroke study

Daptomycin VRE Study Prevent (Drug/Device) Study**