……………For Your Drug Information ………….

Zetia® (ezetimibe) – a selective inhibitor of intestinal absorption of cholesterol and related phytosterols, was approved by the FDA for treatment of high cholesterol. Schering-Plough Corp. and Merck and Co. Inc manufacture the drug. Zetia® is dosed as 10 mg once daily. This drug can be used as monotherapy or in combination with a statin. Although this drug is generally well tolerated, viral infections, headache, and infrequent gastrointestinal symptoms can occur.

Pegasys® (peginterferon alfa-2a) was approved in November 2002 by the FDA. The drug is manufactured by Hoffmann-La Roche and is dosed as 180 mcg SQ once weekly for 48 weeks. The drug is approved for stand alone therapy for hepatitis C. The most common side effects include flu-like symptoms (myalgias, headache, nausea, pyrexia), abdominal pain, and depression.

Teriparatide a synthetic form of parathyroid hormone (PTH). It activates bone building cells (Osteoblasts) to stimulate new bone growth and improve bone density in patients with severe osteoporosis. It is supplied as prefilled penlet syringe to be used subcutaneously. Recommended dosage is 20mcg SQ QD for up to 24 months. Higher doses may be needed in males (maximum recommended dose of 40mcg daily). The drug is manufactured by Eli Lilly.

This is the first non-controlled substance available for treatment of ADHD in children, adolescents, and adults. Atomoxetine is a selective norepinephrine re-uptake inhibitor. The capsules are available in 10, 18, 25, 40, and 60mg strengths and manufactured by Eli Lilly. In adolescents and children less than 70kg, the dose should be started at 0.5mg/kg/day and increased to 1.2mg/kg/day as tolerated. Those over 70kg should be started at 40mg daily and then increased to 80mg daily as tolerated. The maximum dose in children and adults is 100mg/daily.

Eplerenone , a selective aldosterone receptor antagonist, approved for use in patients with essential hypertension. The recommended starting dose is 50mg po qd with full therapeutic effects seen in 4 weeks. Doses could be adjusted up to 100mg per day (given as 50mg po bid). Doses higher than that have not shown any advantages over 100mg/day dose. Adverse effect profile similar to spironolactone. Drug interaction profile is similar to spironolactone in addition to CYP3A4 inhibitors and inducers. If given with a weak CYP3A4 inhibitor (i.e fluconazole, erythromycin etc.) starting dose should be 25mg po qd. Strong CYP3A4 inhibitors and K-supplements and K-sparing diuretics are contraindications for this drug. EPHESUS trial looked at this drug’s use in systolic heart failure complicating acute MI with seemingly favorable results.

2). Zoloft® and Orap® contraindicated in use together – a dose of Zoloft® increased the concentration of pimozide 40% in the body. The mechanism of action for the interaction has not been determined but there may be a potential for effects on the QT interval – the FDA requested that the this contraindication be added to the labeling information for Zoloft®.

Triostat is an injectable, synthetic version of T₃, the active form of natural thyroid hormone. Nearly 80% of circulating T₃ is the result of peripheral conversion of T₄ to T₃ by the membrane bound enzyme iodothyronine 5'-deiodinase. The remaining 20% of T₃ is secreted by the pituitary gland. Thyroid hormone plays a role in regulating metabolism as well as influencing the cardiovascular system by increasing heart rate, ventricular contractility, and decreasing peripheral vascular resistance. Circulating levels of T₃ decrease during times of stress and illness, including cardiopulmonary bypass, presumably due to decreased/inhibited activity of iodothyronine 5'-deiodinase.¹ These decreased levels have been associated with increased morbidity in the postoperative period following cardiac surgery, possible secondary to hemodynamic dysfunction. These alterations in T₃ levels may be of special significance in neonatal and pediatric patients, as levels of T₃ have decreased up to 69% when compared with preoperative levels.² These low levels have been correlated with a need for diuretics, mechanical ventilation, and vasopressor and inotropic support postoperatively. A few pediatric case studies have been published showing that the use of a postoperative T₃ infusion can improve postoperative morbidity and shorten recovery time.³ Patients in the case reports received T₃ infusions at a rate of 0.05-0.15 mcg/kg/hour. An outside institution is using a 0.04 mcg/kg loading dose followed by a 0.016 mcg/kg/hour maintenance infusion x 7 days.

Currently, Jones Pharmacia, the manufacturer of Triostat®, has no guidelines or stability information regarding the preparation of a parenteral infusion. However, Smith-Kline Beecham tested the stability of a parenteral preparation and found that a 0.04mcg/ml concentration preparation was stable at room temperature or under refrigeration for 48 hours (unpublished results). The solution did not need to be protected from light, but needs to be made in D₅W. As no other compatibility/stability data exists, the infusion needs to run in a dedicated line. Preparation instructions can be found in the IV Guidelines book.

1. Klemperer JD, Klein I, Gomez M, Helm RE, Ojamaa K, Thomas SJ, Isom OW, Krieger K. Thyroid homone treatment after coronary-artery bypass surgery. N Eng J Med 1995; 333:1522-1527.

2. Bettendorf M, Schmidt KG, Tiefenbasher U, Grulich-Henn J, Heinrich UE, Scheonberg DK. Transient secondary hypothyroidism in children after cardiac surgery. Pediatr Res 1997; 41:375-379.
3. Chowdhury D, Parnell VA, Ojamaa K, Boxer R, Cooper R, Klein I. Usefulness of triiodothyronine (T₃) treatment after surgery for complex congenital heart disease in infants and children. Am J Cardiol 1999; 84:1107-1109.

2). CDC guidelines for vaccine use in patients who have had or are going to have a spleenectomy: (by Ann Corkery)

Ideally, if the surgery is an elective procedure, the required vaccines would be given 2 weeks prior to surgery. Patients without a spleen have a difficult time clearing encapsulated bacteria from the body. Vaccination against infections from encapsulated bacteria becomes necessary if spleenectomy is performed. The CDC definitely recommends pneumococcal, and menningicoccal vaccines. Theoretically, there is an increase in the risk for infection by Haemophilus Influenza, so the Haemophilus B conjugated vaccine should also be considered.

MMWR 4/9/93 Recommendations of the AdvisoryCommittee on Immunization Practices (ACIP):Use of Vaccines and Immune Globulins in Persons with Altered Immunocompetence

3). Aminoglycoside of choice for infective endocarditis and levels to target: (by Ann Corkery)

Gentamicin (or streptomycin) act synergistically when used in combination with a cell-wall synthesis inhibitor such as penicillin (or vancomycin). Tobramycin or amikacin does not act synergistically and should not be used in the place of gentamicin. Synergistic killing requires the simultaneous presence of an agent active in the cell wall and the aminoglycoside. Streptococcus (viridans, bovis, and others), enterococcus (faecalis, faecium and VRE), and staphylococcus (MSSA or MRSA) are the most common pathogens found in infective endocarditis. The addition of gentamicin to the regimen is dependent on the location (eg. Native or prosthetic valve), results of cultures (eg. culture positive or culture negative), the organism involved and that organisms MIC to penicillin or vancomycin. If gentamicin is added to the cell wall synthesis inhibitor, generally most patients will do well on 1 mg/kg every 8 hours. High peak levels of gentamicin are not required for the synergistic killing effects. Peak gentamicin levels of 3-5 mcg/ml, with a trough less than 2 mcg/ml can often be obtained with the above recommended dosing regimen and should be adequate for the treatment of most cases of bacterial endocarditis.

Pelletier, L. Infective Endocarditis eMedicine Journal, January 2 2002, Vol 3(1)

Gilbert, DN. Moellering, RC. Sande, MA. The Sanford Guide to Antimicrobial Therapy. 2002. Pg. 18-20.

4). Drug allergy and cross-reactivity (by Sandra Salverson)

Numerous predictable drug misadventures get documented as a drug allergy. This can often make it difficult for health-care practitioners to create the most appropriate drug therapy. In addition, poor documentation of the actual adverse reaction makes it equally difficult to discern whether a true allergic reaction or an expected adverse event occurred. True drug allergy requires the activation of immune-globulins. There are four types of true drug allergies summarized in the table below.¹

All allergic reactions have no correlation with the known pharmacologic properties of the agent involved. All allergic responses require an induction period upon primary exposure. Subsequent exposures will result in an immediate reaction. The incidence of true allergy is small in the general population.

There has been much debate about the real incidence of cross-reactivity between the beta-lactams, carbapenems, and cephalosporins. In the literature, incidence of penicillin-cephalosporin cross-reactivity ranges from 1% - 10%. (Lower percentages appear in the more current literature). One reason for the "decrease" in incidence is early cephalosporin compounds actually contained trace amounts of penicillin. The beta-lactam ring and its side chain cause penicillin allergy. Side chains cause cephalosporin allergy. The second reason for the "decrease" in incidence is that earlier cephalosporins (cephalothin, cephaloridine, and cefamandole) all have similar side chains to the penicillin molecule. Other beta-lactam compounds with similar side-chains that predict higher risk of cross-allergenicity include: cephalexin and ampicillin, cefadroxil and amoxicillin, and ceftazidime and aztreonam. Cross-reactivity between penicillin and carbapenems is also high. A skin test study showed 47% of patients with penicillin allergy also reacted to imipenem/cilistatin. A retrospective study in bone-marrow-transplant patients indicated 33% documented cross-reactivity.

A "sulfa" allergy does not equal an allergy to sulfur, inorganic sulfate, or sulfite compounds. Sulfa allergy usually refers to a reaction to an aromatic sulfonamide compound such as, sulfamethoxazole, sulfadizine, sulfafurazole, or sulfisoxazole. It is hypothesized that their hydroxylamine metabolite is the trigger for immune responses. Non-aromatic sulfonamides yield a different metabolite. Hence, compounds like the thiazides, loop diuretics, glipizide, glimepiride, celecoxib, sumatriptan are less likely to have a cross-reactive reaction. Sulfones are structurally similar to the sulfonamides, however, like the non-anti-infective compounds they do not share the same metabolic results as the anti-infective sulfonamides. They are also less likely to have a risk of cross-reactivity. However, if the reaction is severe, the physician should be informed of the potential allergy possibility. Combinations of drug compounds and sulfuric acid make sulfate salts (potassium sulfate, and quinidine sulfate). These compounds are structurally different from sulfonamides and should pose no risk of cross-allergenicity. Sulfites are incorporated into many compounds to serve as a preservative. While numerouse allergic reactions have been reported, there is no cross-reactivity with a sulfa allergy.

The "sulfa" portion of any of these compounds does not cause Steven’s Johnson Syndrome and toxic epidermal necrolysis. It is rather the aromatic amine portion of sulfamethoxazole, sulfadiazine, sulfafurazole, or sulfisoxazole. Non-sulfa aryl amines also have this predisposition (procainamide, dapsone, and acebutolol). It is always important to clarify the type of reaction prior to recommending alternatives.

Many documented "allergies" to NSAIDs are truly drug induced bronchospasm. This reaction is not an antigen-antibody reaction, but rather the inhibition of the COX enzymes within the respiratory cells. The higher the affinity and potency for COX-1, the higher the likelihood of the compound inducing asthma. If the agent has a higher affinity and potency for COX-2, patients seem to tolerate them better. A small study also found patients with a history of anaphylaxis to one NSAID, who were challenged with a different NSAID chemically unrelated structure had no incidence of cross-reactivity.

Angiomax Peds Study

CAPS (Cathflo) Study

Xigris Pediatric Study (RESOLVE trial) *

AT3 ECMO Study

ARTIST Stroke study Exclaim Study

Apollo Study Fenoldopam - Radiology

Baxter r-AHF-PFM Study Fusion I (natrecor) Study

CancerVax Melanoma Study* Synergy Study

DTI – 0009 Study Prevent (Drug/Device) Study

Daptomycin VRE Study

Dr. Wang’s heparin/reopro Stroke Study

ISO Study (UICOMP opoid study