……………For Your Drug Information ………….

10. NovoLogÒ (Insulin aspart) – a rapid-acting human insulin analog. The

maximum glucose-lowering effect occurs between 1 and 3 hours after subcutaneous injection. The duration of action is 3 to 5 hours. This product is very similar to Humalog®, except that NovoLog® has FDA approval for use in the continuous SC infusion pumps used by many IDDM patients.

11. InvanzÒ (Ertapenem) – a carbapenem broad-spectrum antibiotic that is in the same class

as meropenem and imipenem – see drugs in review. NOTE: Invanz® does NOT cover

pseudomonas.

12. EligardÒ (Leuprolide acetate) – formerly known as Leuprogel One-Month Depot, Eligard is a

new 7.5 mg subcutaneous formulation delivered once monthly for the indication of prostate

cancer.

13. EnbrelÒ (Etanercept) – approved on 1998 for rheumatoid arthritis , received new indication

approval for psoriatic arthritis. Doses used for this indication: 25mg SC twice weekly

Serotonergic Agents – Researchers from Massachusetts General Hospital, Boston, report three cases of Call-Fleming syndrome apparently induced by the use of serotonin-enhancing drugs. The syndrome is characterized by the sudden onset of severe headache, focal neurologic deficits, and seizures causing reversible cerebral artery vasoconstriction and ischemic stroke. It is most common in women 20 to 50 years of age. Serotonin-enhancing drugs include antidepressants, antimigraine agents, decongestants, diet pills, St. John’s wort, ecstasy, cocaine, and methamphetamine.

Ertapenem (InvanzÒ ) is a broad spectrum carbapenem antibiotic that falls into the same class as imipenem and meropenem. Like the previous carbapenems, ertapenem inhibits bacterial cell wall synthesis by binding to penicillin binding proteins (PBPs). Ertapenem is indicated for complicated intra-abdominal infections; complicated skin and skin structure infections; community acquired pneumonia; complicated urinary tract infections including pyelonephritis; and acute pelvic infections including postpartum endomyometritis, septic abortion and post surgical gynecologic infections due to the following gram-positive and gram-negative aerobic and anaerobic microorganisms:

Staph. aureas (no MRSA)

Strep. agalactiae

Strep. pneumoniae (penicillin susceptible strains only)

Strep. pyogenes

E. coli

H. influenza (Beta-lactamase negative strains only)

Klebsiella pneumoniae

Bacteroides fragilis

Ertapenem does not exhibit bactericidal activity against the following organisms:

MRSA

Enterococcus spp.

Pseudomonas

Ertapenem is stable against hydrolysis by a variety of beta-lactamases such as penicllinases, cephalosporinases, and extended spectrum beta-lactamases. Ertapenem is unstable against metallo-beta-lactamases.

The dose of ertapenem is 1 gram once a day administered by intravenous infusion for up to 14 days or by intramuscular injection for up to 7 days. When administered intravenously, ertapenem should be infused over a period of 30 minutes. Patients with CrCL less than or equal to 30 mL/min the recommended dose is 0.5 grams every 24 hours.

Ertapenem should not be mixed or co-infused with other medications. Diluents containing dextrose should not be used with ertapenem. For intravenous administration, Water for Injection, 0.9% Sodium Chloride, or Bacteriostatic Water for Injection should be utilized to prepare ertapenem. For intramuscular administration, 1.0% lidocaine HCl should be used to prepare ertapenem.

Ertapenem exhibits non-linear pharmacokinetics due to concentration-dependent plasma protein binding. It is primarily bound to albumin. Protein binding decreases as plasma concentrations increase from 95% bound at plasma concentrations of <100 mcg/mL to 85% bound at plasma concentrations of 300 mcg/mL.

The apparent volume of distribution of ertapenem is 8.2 liters. Ertapenem is primarily eliminated by the kidneys and it has a plasma half–life of 4 hours. It does not appear to undergo hepatic metabolism.

The most common drug-related adverse effects were diarrhea (5.5%), infused vein complication (3.7%), nausea (3.1%), headache (2.2%), vaginitis (2.1%), phlebitis/thrombophlebitis (1.3%), vomiting (1.1%), and seizures (0.5%-most commonly in patients with CNS disorders and/or compromised renal function).

Patients who have demonstrated anaphylactic reactions to beta-lactams.

Patients with known hypersensitivity to imipenem and/or meropenem.

Before initiating therapy with ertapenem, careful inquiry should be made concerning previous hypersensitivity reactions to penicillins, cephalosporins, other beta-lactams, and other allergens. The probability of an adverse reaction increases in individuals with a history of penicillin hypersensitivity who have experienced severe hypersensitivity reactions when treated with other beta-lactams. Safety and effectiveness in pediatric patients have not been established so use in patients under 18 years of age is not recommended.

Probenecid reduces the plasma and renal clearance of ertapenem by 20% and 35%. Probenecid also increases the half-life of ertapenem from 4.0 to 4.8 hours. No other specific drug interaction studies have been conducted.

In the event of an overdose, ertapenem should be discontinued and general supportive treatment given until renal elimination takes place.

Bosentan, an endothelin receptor antagonist, is the first oral agent approved for the treatment of pulmonary arterial hypertension in patients with WHO Class III or IV symptoms. Bosentan significantly improves exercise ability and decreases the rate of clinical worsening in patients with significant limitation of physical activity. The pathophysiology of pulmonary arterial hypertension involves elevated concentrations of endothelin-1, a neurohormone that binds to receptors in the endothelium and vascular smooth muscle. Bosentan acts as a specific and competitive antagonist at endothelin receptors.

Bosentan treatment should be initiated at an oral dose of 62.5 mg twice a day for 4 weeks and then increased to the maintenance dose of 125 mg twice a day. Bosentan comes 62.5 mg and 125 mg tablets

Dose adjustments are not needed in renal impairment and/or geriatric patients. Safety and efficacy in pediatric patients have not been established.

Dose adjustment is needed in patients who develop abnormal aminotransferase levels while on bosentan.

If bosentan is re-introduced it should be at the starting dose; aminotransferase levels should be checked within 3 days and thereafter according to the recommendations above

If liver aminotransferase elevations are accompanied by clinical symptoms of liver injury (such as nausea, vomiting, fever, abdominal pain, jaundice, or unusual lethargy or fatigue) or increases in bilirubin greater than or equal to 2 X ULN, then treatment should be stopped.

Maximum plasma concentrations of bosentan are attained within 3-5 hours and steady state is reached within 3-5 days. The terminal half-life is 5 hours. Bosentan is highly bound (>98%) to plasma proteins, mainly albumin, and has a volume of distribution of 18 liters. Bosentan is eliminated by biliary excretion following metabolism in the liver; less than 3% of the dose is recovered in urine.

The most common adverse drug reactions that occurred more frequently on bosentan than on placebo were headache (16% vs. 13%), flushing (7% vs. 2%), abnormal hepatic function (6% vs. 2%), leg edema (5% vs. 1%), and anemia (3% vs. 1%).

Pregnancy Category X

Concomitant use of bosentan and cyclosporine A. Co-administration results in markedly increased plasma concentrations of bosentan.

Bosentan has the potential to cause liver injury. Bosentan has been shown to cause at least a 3-fold elevation in liver aminotransferase levels accompanied by elevated bilirubin levels. These elevations in aminotransferase levels are dose-dependent. As a result of this potential hepatotoxicity, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly. Bosentan should be avoided in patients with moderate or severe liver impairment and/or elevated aminotransferases greater than 3 times the upper limit normal (ULN).

Hormonal Contraceptives: Since many hormonal contraceptives are metabolized by CYP3A4, there is a possibility of failure of contraception when bosentan is co-administered. Women should not rely on hormonal contraceptives alone when taking bosentan

Ketoconazole: Ketoconazole is a potent inhibitor of CYP3A4 and it increases plasma concentrations of bosentan by approximately 2-fold. No dosage adjustment of bosentan is necessary, but increased effects of bosentan should be considered.

Bosentan causes a dose-related decrease in hemoglobin and hematocrit. Hemoglobin levels should be monitored after 1 and 3 months of treatment and then every 3 months.

As a result of potential hepatotoxicity, serum aminotransferase levels must be measured prior to initiation of treatment and then monthly.

Due to the expected teratogenic effects of bosentan, urine or serum pregnancy tests should be obtained monthly in women of childbearing age. Bosentan should only be initiated in women of child-bearing potential who practice adequate contraception that does not rely solely upon hormonal contraception.

2). Mucomyst®(N-acetylcysteine) solution is administered by mouth for treatment of acetaminophen poisoning. If the patient cannot tolerate the oral preparation, what are the alternatives?

Mucomyst® can be given via a NG tube to patients who unable to retain oral doses of the product. The Mucomyst® 20% solution should be diluted according to the manufacturer’s directions contained in the package insert. NaCl or Sterile water for Injection or

Inhalation are the recommended diluents. The Mucomyst 10% solution may be admini-

stered in the undiluted form.

The Rocky Mountain Poison Center has a protocol for administration of the Mucomyst®

by the IV route. The N-acetylcysteine solution should be diluted to 3-5% in D5W and an

in-line 0.2 micron filter should be employed. The Rocky Mountain Protocol and a journal article from Critical Care Medicine 1998 Vol.26 is in the drug information files under N-acetylcysteine for your reference. A copy of the protocol will also be available in the new IV Guidelines book.

3). A new antidote alternative is available for the treatment of potentially life-threatening digoxin toxicity or overdose called Digifab®.

A new product was approved in August 2001 called DigiFab® from Savage Laboratories

for above indication. This product is very similar to that of Digibind® as far as dosing, and indications. The primary advantage to this new product would be a lower AWP than Digibind® ($400 vs $728 per vial).

4). Patient is on a controlled release product and has to have medication down a feeding tube/NG, need to convert to regular release formulation.

*** Products that have different bioavailability, if converted from tabs to liquids, will require an order from the physician.

5). Linezolid is a reversible, nonselective inhibitor of monoamine oxidase. Do patients taking this medication have to be place on a low tyramine diet?

No such interactions were observed with Meperidine, SSRIs during phase I, II and III clinical trials. However, 3 patients were reported to have signs/symtoms of seratonin syndrome during the postmarketing phase with concurrent use of linezolid and SSRIs. Currently, this should be handled as a precaution and not a contraindication. It would be prudent to make sure that the physician ordering the interacting drug be informed of the possibility.

** As a reminder, the most significant adverse event related to Linezolid, to this date, is still myelosuppression (anemia, thrombocytopenia, leukopenia, and pancytopenia).

6). Quinolone antibiotic interaction with divalent cations (Magnesium, Calcium, Aluminum, Iron, and Zinc).

Possible courses of action:

1. Inform the physician to hold all medications containing cations while the patient is on the antibiotic ( FYI – Tequin does not appear to be affected by Calcium products ) to avoid therapeutic failure.
2. Rewrite the physician order (without having to contact the physician) to clarify the dosing schedule between these products. (i.e Give Tequin in AM at least 2 hours prior to any Iron, Mom etc.. to avoid reduced absorption of Tequin or Cipro or… ). It is important to include the reason why you adjusted the dosing schedule in the order.This would be taken as a sign of good professional etiquette/courtesy , and serve as an educational tool The physician need not be contacted for this because it serves to clarify a "qd" or "q24h" dosing schedule.

7). A note on Protonixâ in pediatric populations…

The following studies have been closed: The following studies are still open/opening:

Cubist Pneumonia study A to Z Study

Argis(Argatroban) Study

Artist Study

AT3 ECMO Study

Baxter r-AHF-PFM Study

CancerVax Melanoma Study

Cardiology- Fenoldopam Study

Carperitide Study

Corlopam Study

Covance(diabetic foot) Study

DTI-0009 study

ISO Study(UICOMP opiod study)

Relax Study

Synergy study

Dr. Wang’s heparin/reopro Stroke Study

Voriconazole Study(compassionate use)

Ruth Avelino

Ann Corkery

Margaret Heger

Azra Hussain

All the pharmacists covering DI for input and ideas.