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Medication Update: October 2006

Medication Update is a bi-monthly newsletter of the Pharmacy and Therapeutics Committee for physicians, pharmacists and nurses.

New Formulary Drugs

Cefepime (Maxipime®) injection

This third/fourth generation cephalosporin has been added to the formulary with use restricted to heme/onc service for the treatment of AML patients with fever and neutropenia.

These patients are at risk for alpha hemolytic streptococcus infections because they receive high dose cytarabine as part of their chemotherapy.

Cefepime will provide coverage of alpha hemolytic streptococcus, which can cause high fevers and pulmonary complications including ARDS. Other use will require ID approval.

Hyaluronidase (Amphadase®)

Formerly known as Wydase® and was taken off the market due to manufacturing issues, hyaluronidase is available again for the management of IV extravasation of many drugs including vincristine.

Several intradermal or subcutaneous injections are made at the leading edge of the extravasation site. Hyaluronidase breaks down hyaluronic acid in connective tissue, thus facilitating absorption of irritating drugs.

Lisinopril

This once-daily ACE inhibitor provides dosing convenience over captopril and enalapril, which are the other ACE inhibitors on the formulary.

Available as tablets and compounded oral solutions, it may cause hyperkalemia and dry cough. Dosing information for children <6 years old is limited.

Selenium

Oral forms of selenium (50 mcg, 100 mcg, and 200 mcg tablets) have been added to the formulary. Selenium is an essential cofactor for glutathione peroxidase function.

While 20% of epilepsy patients are deficient (some due to valproic acid use), as many as 90% of ketogenic diet patients need selenium replacement.

Melatonin

Melatonin 1 mg and 5 mg tablets have been approved by the committee with use restricted to patients with a sleep disorder and a diagnosis of: Smith-Magenis Syndrome, mental retardation with/without epileptic seizures, or blindness AND approval by neurodevelopment, neurology, or sleep disorders services.

Losartan (Cozaar®)

Losartan is an angiotensin II-receptor blocker used as antihypertensive therapy and/or antiproteinuric therapy in patients where ACE inhibitors are not tolerated, or in combination with ACE inhibitors where ACE inhibitors alone are not successful.

Angiotensin II-receptor blockers do not affect the response to bradykinin, and are less likely to be associated with non-renin-angiotensin effects. It can cause occasional hyperkalemia but has not been associated with dry cough.

Levofloxacin (Levaquin®)

This quinolone antibiotic is now added to the formulary with use restricted to Heme- Onc and Infectious Disease services.

Compared to ciprofloxacin, levofloxacin has broader gram positive but weaker pseudomonas coverage. It offers a more convenient once daily dosing in patients > 5 years old (patients younger than 5 years of age require twice daily dosing).

Available as an injectable, oral solution and tablet forms. Avoid antacid and iron use within 2 hours of oral administration due to an interaction.

Tramadol (Ultram®)

Tramadol is a centrally acting synthetic analgesic. Its mechanism of action appears to be twofold: binding of parent and active M1 metabolite to mu receptors and weak inhibition of norepinephrine and serotonin reuptake.

Compared to opioids, tramadol has a lower incidence of side effects such as respiratory depression, nausea, vomiting, constipation, and sedation. It may benefit patients with history of peptic ulceration, asthma or opioid dependence and patients who will require longterm pain treatment.

Since tramadol is narcoticlike, abrupt discontinuation may result in withdrawal and should be avoided. It may increase the risk of seizure in patients with epilepsy, history of seizures, or those taking medications that lower the seizure threshold.

Other Formulary Issues

Formulary deletion — Visipaque™ (iodixanol)

Combat Methamphetamine Epidemic Act of 2005

By Heidi Colpitts, pharmacy intern

On Sept. 30, 2006, new rules were enacted regulating the sale of ephedrine, pseudoephedrine, or phenylpropanolamine products to comply with the 2006 extension of the USA PATRIOT Act.

The "Combat Methamphetamine Epidemic Act of 2005" requires that retailers selling nonprescription products containing ephedrine, pseudoephedrine and phenylpropanolamine must keep a logbook of sales and that these scheduled listed chemical products must be kept behind the counter or in a locked cabinet.

Retail pharmacies cannot sell more than 3.6g of drug product per day and are limited to selling 9g or less of these products in a 30 day period.

Children's Hospital Pharmacy has not sold these products over the counter in the past. The Pharmacy will continue to sell ephedrine and pseudoephedrine to CHRMC patients by prescription only.

These products will not be available to patients or employees without a prescription.

Use of Lipid Infusion to Treat Local Anesthetic Toxicity

By Sharon Lu, PharmD, BCPS

Systemic toxicity from local anesthetics has been a significant concern and risk since their discovery. In particular, there have been multiple case reports of cardiac arrhythmias and arrests from long-acting local anesthetics such as bupivacaine.

Cardiotoxicity associated with bupivacaine has been shown to be an extremely difficult condition to treat. While the precise mechanism of the toxicity is unclear, one study revealed that bupivacaine interferes with carnitine-dependent mitochondrial lipid transport1.

Weinberg et al. found that lipid infusion increased the dose of bupivacaine required to produce asystole in rats2. Similar observations were made in dogs where lipid infusions during resuscitation from bupivacaineinduced cardiac arrests improved survival3.

Most recently, the first successful case of using 20% lipid infusion in the resuscitation of bupivacaine-induced cardiac arrest was reported in the July 2006 issue of Anesthesiology.

A 58 year old patient with a history of coronary artery disease presented for an elective shoulder procedure. The patient developed seizures followed by asystole with intervals of ventricular tachycardia after receiving an interscalene block with 100 mg bupivacaine and 300 mg mepivacaine.

Ventricular tachycardia persisted after multiple rounds of drugs and shocks. Intralipids was then suggested and administered. A single sinus beat was observed within seconds, and normal cardiac rhythm and blood pressure returned within 20 seconds. The patient recovered without neurologic sequelae4.

This case report might provide a rational approach in the treatment of severe local anesthetic toxicity. However, substantial research on lipid rescue is still needed, specifically, the optimal dose, rate, and duration of infusion as well as safety data of the high doses.

In lieu of the evidence and potential benefits, lipid rescue should be considered following current advanced life support guidelines in treating local anesthetic toxicity.

The recommended dose for the indication is 1ml/kg over 1 min, may be repeated twice every 3-5 minutes; then start infusion at 0.25 ml/kg/min until haemodynamically stable. Twenty-percent lipid is available in the OR pharmacy, PACU Omnicell, and the main pharmacy for this indication.

It is a common misconception that lipid rescue implies the use of propofol, which is formulated in a 10% lipid emulsion.

Small doses of propofol might be beneficial to control seizures; however, administering a sufficient dose of the lipid vehicle would also deliver a dose of propofol that would be contraindicated during cardiovascular collapse.

References

  1. Weinberg GI, Palmer JW, VadeBoncouer TR et al: Bupivacaine inhibits acylcarnitine exchange in cardiac mitochondria. Anesthesiology 2000; 92:523-8.
  2. Weinberg GI, VadeBoncouer TR, Ramaraju GA et al: Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats. Anesthesiology 1998; 88: 1071-5.
  3. Weinberg GI, Ripper R, Feinstein Dl, et al: Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity. Reg Anesth Pain Med 2003; 28:198-202.
  4. Rosenblatt MA, Abel M, Fischer GW, et al: Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest. Anesthesiology 2006; 105:217-8.

Tigecycline (Tygacil®)* — drug review

By Susan Jacob, PharmD

*Not currently on CHRMC formulary

Tigecycline is a new broad spectrum antibiotic approved for intravenous use in complicated skin and skin structure infections and intra-abdominal infections.

It belongs to a new class of drugs know as glycylcyclines, which are structurally similar to the tetracycline class antibiotics. Tigecycline is a semisynthetic derivative of minocycline.

It acts by binding to the 30S ribosomal subunit, blocking the entry of amino-acyl tRNA into acceptor site. This results in prevention of protein synthesis and inhibits bacterial growth.

Tigecycline is not affected by efflux pumps and ribosomal protection proteins, which are the two major mechanisms by which bacteria gain resistance to tetracylines. Tigecycline is not metabolized extensively.

The primary route of elimination is biliary excretion of unchanged tigecycline and its metabolites. Furthermore, it does not inhibit or induce common cytochrome enzymes.

In clinical trials, tigecycline monotherapy (100 mg IV load, followed by 50 mg IV every 12h) was found to be as effective as combination therapy with vancomycin (1g IV every 12h) and aztreonam (2g IV every 12h) for treatment of complicated skin and skin-structure infections. Duration of therapy was 5-14 days.

Infecting pathogens included S. aureus (including MRSA), E. faecalis (vancomycin susceptible), E. coli, Stretococcus pyogenes and B. fragilis. For the treatment of complicated intra-abdominal infections including appendicitis, cholecystitis, diverticulitis, perforation, abscess and peritonitis, tigecycline (100 mg IV load, followed by 50 mg IV every 12h) was found to be as effective as imipenem-cilastin (500 mg IV every 6h) for 5-14 days.

Commonly isolated pathogens were E.coli, Streptococcus anginosus group, B. fragilis and Klebsiella pneumoniae.

Tigecycline does not have clinically significant activity against P.aeroginosa or Proteus species and it has not been evaluated adequately in infections caused by VRE, A.baumanii or ESBL-producing organisms.

The most common adverse effects are nausea (30%) and vomiting (20%). Being structurally similar to the tetracycline class antibiotics, similar adverse effects such as photosensitivity, pancreatitis, pseudomotor cerebri and anti-anabolic action may be seen.

Tigecycline should not be used during pregnancy or in newborns, infants and children less than 8 years old due to risk of tooth discoloration. The recommended dosage of tigecycline for patients 18 years and older is 100 mg IV initially followed by 50 mg IV every 12 hours.

No dosing adjustment is necessary for renal impairment and it is not removed by haemodialysis. In cases of severe hepatic dysfunction, the maintenance dose should be decreased to 25 mg every 12 hours.

Currently no dosing information is available for children less than 18 years old.

References

  1. Tygacil package insert – Wyeth 2006.
  2. The Medical Letter Vol 47, issue 1217, 2005.
  3. Nathwani D. Tigecycline: clinical evidence and formulary positioning. International Journal of Antimicrobial Agents 2005;25:185-192.

Menactra™ vs. Menomune®

By Kara Olson, PharmD

Menactra™ is a tetravalent meningococcal conjugate vaccine that was recently added to the formulary. Although Menomune® and Menactra™ sound quite similar, both vaccines have distinct characteristics.

Menomune® is a polysaccharide vaccine, which stimulates B-cells without the assistance of T-helper cells.

As a result, it has the following three characteristics:

  1. Immune response in children less than 2 years of age is inconsistent, which is most likely due to an immature immune system.
  2. Repeated doses do not produce a booster response.
  3. Antibodies have reduced functional activity.

Conjugate vaccines, such as Menactra™, increase immunogenicity compared to polysaccharide vaccines because they stimulate both B-cells and T-helper cells.

They therefore improve the immune response in children less than 2 years of age, the booster response, and the functional activity of the antibodies.

However, Menactra has not been studied in children less than 11 years of age, and the need for boosters is unknown.

Below is a table with details regarding Menomune® and Menactra™:

Details Menomune® Menactra®
Synonyms Tetravalent meningococcal polysaccharide vaccine Tetravalent meningococcal conjugate vaccine
T-cell Activation T-cell independent T-cell dependent
Prophylaxis Yes Yes
Estimated duration 3-5 years > 8 years
Revaccination Yes if indicated Unknown whether necessary
FDA approved ages Children >2 years of age Ages 11-55
Route Subcutaneously only Intramuscular only
Administration with other vaccinations DO NOT give concurrently with whole-cell pertussis or whole-cell typhoid vaccines Concomitant administration with tetanus, diphtheria, or typhoid vaccine is acceptable
Contraindications
  • Acute illness
  • Sensitivity to thimersol or vaccine components
  • Sensitivity to diphtheria toxoid or vaccine components
  • Sensitivity to dry natural rubber latex (vial stopper)
  • History of Guillain-Barre Syndrome
Precautions Sensitivity to Latex rubber
  • Recent or acute illness
  • Bleeding disorder
  • Concomitant anticoagulant therapy
Adverse Effects
  • Mild injection site tenderness 36%
  • Moderate injection side tenderness 9%
  • Headache <10%
  • Injection site pain <5%
  • Chills <5%
  • Fever, malaise <5%
  • Injection site pain 30-60%
  • Headache 30-36%
  • Fatigue 25-30%
  • Malaise ~20%
  • Arthralgia 10-20%
  • Severe headache, malaise, or fatigue 1.1%
Note
  • Multi-dose vials contain thimersol
  • Single-dose vials do not contain preservatives.
 Not a combination meningococcal and diphtheria vaccine. It is a diphtheria toxoid conjugate vaccine.

References

  • DRUGDEX® System [Internet database]. Greenwood Village, Colo: Thomson Micromedex. Updated periodically.
  • Centers for Disease Control and Prevention. Meningococcal Vaccines. Accessed August 21, 2006.
  • Food and Drug Administration. FDA patient safety news. (9/06). Accessed September 16, 2006.
  • Menactra [package insert]. Swiftwater, PA: Aventis Pasteur Inc.; 2005 January.
  • Menomune [package insert]. Swiftwater, PA: Aventis Pasteur Inc.; 2003 January.
  • Veal K. Tetravalent meningococcal conjugate vaccine (MCV4) monograph. Children's Hospital and Regional Medical Center Pharmacy and Therapeutics Committee, Seattle, WA: 2006.

Credits

Editors

  • Anny Chan, PharmD
  • Eric Harvey, PharmD, MBA, BCPS

P&T Chairs

  • Janet Englund, MD
  • Eric Harvey, PharmD, MBA, BCPS

Address

Children's Hospital and Regional Medical Center P&T Committee
4800 Sand Point Way NE
PO Box 5371/R-3409
Seattle, WA 98105