Medication Update: August 2006
Medication Update is a bi-monthly newsletter of the Pharmacy and Therapeutics Committee for physicians, pharmacists and nurses.
- New drugs
- Other formulary issues
- Narcotic and Benzodiazepine Weaning Protocol in ICU
- Interactions between Medications and Enteral Feeds
- Intramuscular Penicillin Products Can be Confusing!
- Vancomycin Dosing and Monitoring Revisited
New Formulary Drugs
Budesonide oral (Entocort® EC)
This corticosteroid has been added to the formulary for the topical treatment of graft-versus-host disease in the lower gastrointestinal tract. Budesonide oral is a capsule that contains granules in an ethylcellulose matrix.
The granules are coated with a methacrylic acid polymer that dissolves at a pH > 5.5 (duodenal pH) in order to protect from dissolution in the stomach. The ethylcellulose matrix controls the release of drug in a time-dependent manner (until the drug reaches the ileum and ascending colon).
Clinical effect is mainly due to direct local effect and oral availability is ~10% (large first pass effect). Capsules should be swallowed whole; chewing, crushing, breaking or opening the capsules are not recommended for administration.
Tacrolimus ointment 0.03% and 0.1% (Protopic®)
Indicated for the treatment of cutaneous graft-versus-host disease in patients who have received a stem cell transplant, tacrolimus ointment is available in 2 strengths.
Children 2-15 years of age should use the lower 0.03% strength. Consider monitoring blood levels if > 25% of body surface area is covered.
Use in patients less than two years of age will be restricted to BMT Service.
Micafungin injectable (Mycamine®)
After caspofungin, this is the second echinocandin antifungal to be approved by P&T. Its indications of use include treatment of patients with esophageal candidiasis; prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplant and treatment of invasive aspergillosis or disseminated candidiasis (the last two are unlabeled uses).
Significant savings in drug cost are expected if micafungin is used instead of caspofungin. In contrast to caspofungin that is compatible with only saline and may decrease tacrolimus levels, micafungin is compatible with either saline or dextrose, and has no interaction with tacrolimus.
| Population | Recommendation |
|---|---|
| Completed childhood DTP/DTaP series, not received Td or Tdap booster | Single dose at age 11-18y (age 11-12 y preferred) |
| Completed childhood DTP/DTaP series, previously received Td or Tdap booster | Single dose after an interval of at least 5 years following Td or Tdap booster |
NOTE: Watch out for DTaP and Tdap mix up since they may look and sound alike! Tdap is not indicated for children younger than 10 years of age. It contains reduced amounts of diphtheria toxoid and some pertussis antigens compared to DTaP, and its efficacy in younger children has not been established. Pediatric DTaP contains increased amounts of diphtheria toxoid and may cause more adverse reactions if given to older persons.
Other Formulary Issues
Zosyn Use in PICU
The committee approved the use of zosyn as empiric therapy of presumed hospital-associated sepsis in symptomatic patients in the PICU without the need for ID approval.
Vancomycin Lock Therapy
The concentration of vancomycin is now lowered from 5 mg/mL to 100 mcg/mL in order to avoid precipitation with heparin.
This therapy is used in conjunction with systemic antibiotic therapy for the treatment of uncomplicated, difficult-to-treat infections with coagulase-negative Staphylococcus in surgically-implanted, central venous catheters where catheter removal is not practical.
Narcotic and Benzodiazepine Weaning Protocol in ICU
Morphine and lorazepam drips are frequently utilized for sedation in the ICU. Despite their effectiveness, tolerance and dependence to opioids and benzodiazepines develop when used over an extended period of time.
Weaning of these medications is therefore recommended in order to avoid withdrawal symptoms. Upon reviewing the literature, numerous studies offer recommendations on weaning narcotics and benzodiazepines. Since there seems to be no clear standard of care for weaning, a protocol was developed at CHRMC to assess the optimal weaning approach to use in our patients.
This protocol has been implemented for ICU patients and we plan to extend it to the entire hospital. It provides guidelines for weaning the opioids and benzodiazepines for patients maintained on continuous drips and also for converting patients from IV to oral formulations. Weaning is not necessary for patients on an opioid or benzodiazepine drip for < 5 days.
In patients who have been on a drip for 5-14 days, the opioid or benzodiazepine should be decreased every day by 20% of the original dose. If the medication has been given for >14 days, the patients should be weaned by 10% of the original dose every day.
Withdrawal scores should be assessed every 4 hours or every 2 hours if patient has a withdrawal score >10. Conversion to oral agents is recommended when possible, but only if the patient is on < 100 mcg/kg/hr of either morphine or lorazepam.
Intravenous morphine is converted to oral morphine by a 1:2 conversion and then the total dose divided every 6 hours. For lorazepam, a 1:1 conversion is used and then the total dose is divided every 6 hours.
The protocol is located in the ICU policy and procedures under Weaning from Opioids and Benzodiazepines (link only available from Children's network).
The pharmacy department is available for assisting with weaning and converting medications to oral agents. Feel free to contact us if you have any questions.
Interactions between Medications and Enteral Feeds
Use of the enteral route is a common way to administer both medications and nutritional support. However, problems arise due to interactions between enteral feeds and medications.
In order to better manage patients who receive both enteral feeds and medications, the most common interactions will be reviewed. The anatomic location of the enteral tube as well as the bore size of the tube should be considered when administering medications and feeds.
The majority of tubes will deliver their contents either to the stomach or the small intestine. The small intestine is the site of absorption for most medications, but is not an appropriate place to administer medications such as antacids which are intended to work within the stomach.
Occasionally, the tube may be advanced past the site of optimal absorption leading to decreased drug and nutrient absorption. The feeding tube size can also be problematic when administering medications. Jejunal and duodenal tubes tend to have a smaller bore and can clog easily.
Possible routes for feeding — reprinted from Gastroenterology, 108(4), DF Kirby, MH DeLegge and CR Fleming, American Gastroenterological Association technical Review on Tube Feeding For Enteral Nutrition, 1282-1301, © (1995), with permission from the American Gastroenterological Association.
Many liquid medications may be too viscous to pass easily through these tubes. The thinnest available preparation of a medication should be used preferentially.
Drugs may also form complexes with the protein in nutritional formulas which can obstruct the tube.
If possible, it is best to stop the feeds during medication administration and flush the feeding tube before and after each dose is given.
The bioavailability of a drug can be affected by the site of administration as well as physical interactions with the formula.
Certain drugs need stomach acid in order to be properly absorbed, including iron preparations and the azole antifungals.
When these drugs are administered through J or D tubes, absorption can be enhanced by adding an acidic compound such as ascorbic acid.
Divalent cations such as calcium, magnesium, and aluminum that are present in enteral feeds may chelate a drug and render it ineffective. The absorption of fluoroquinolones is reduced by up to 70 percent when administered with enteral feeds.
Co-administration of feeds and medications can also lead to electrolyte disturbancescalcium can bind to dietary phosphorous resulting in clinical hypophosphatemia. Medications with a narrow therapeutic index should be monitored more carefully when administered with enteral feeds.
A well known interaction exists between phenytoin and enteral nutrition. Casein protein found in enteral formulas binds to phenytoin and prevents its absorption. This leads to decreased phenytoin levels and an increased seizure risk.
In order to optimize nutrition, the phenytoin may be administered twice a day while holding the feeds for one hour before and after administration. Another antiepileptic drug, carbamazepine, may adsorb to the feeding tube which decreases its absorption.
Any change in the absorption properties of a drug can decrease the efficacy or increase the risk of toxicity. Medication therapy during enteral feeding can be affected by several factors.
When administering medications through a feeding tube it is important to consider the tube placement and size, as well as any physical or chemical interactions between the formula and the medication.
Awareness of these potential problems can help streamline nutrition support and medication administration and prevent complications.
References
- Brown RO, Dickerson RN. Drug-Nutrient Interactions. American Journal of Managed Care 1999; 5(3): 345-352.
- Lourenco R. Enteral feeding: Drug/nutrient interaction. Clinical Nutrition 2001;20(2): 187-193.
- Magnuson BL, Clifford TM, et al. Enteral Nutrition and Drug Administration, Interactions, and Complications. Nutrition in Clinical Practice 2005;20: 618-624.
Intramuscular Penicillin Products Can be Confusing!
By Anny Chan, PharmD
Penicillin G benzathine and penicillin G procaine are long-acting, repository formulations of penicillin G. They are given as single IM injection or as once or twice weekly injection for multiple weeks.
When compared to IV penicillin, they produce low but sustained serum concentrations. These formulations have limited indications for usage: treatment of only moderately serious infections caused by bacteria susceptible to low penicillin concentrations (such as N. gonorrhoeae, S. pyogenes, S. pneumoniae), for prophylaxis against such infections, or as follow-up therapy after IV penicillin.
Penicillin G procaine contains an equimolecular portion of penicillin G and procaine. Its level peaks within about 4 hours, and declines gradually over a period of 15-20 hours. Penicillin IM injections can cause pain and sterile abscess partly due to the volume of each injection.
Due to procaine's anesthetic effect, IM penicillin G procaine reportedly causes significantly less discomfort than other preparations. On the other hand, penicillin G benzathine is absorbed very slowly, produces much lower but more prolonged serum levels, which can last for 1-4 weeks depending on the dose.
Larger doses of penicillin G benzathine do not produce higher levels but maintain a longer period of therapeutic level.
Bicillin® C-R and L-A
Bicillin® C-R is a combination product that contains both penicillin G procaine and penicillin G benzathine.
It has a pharmacokinetic profile that consists of higher initial concentrations (due to the procaine salt) and more prolonged concentrations (due to the benzathine salt) when compared to either drug alone.
However, Bicillin® C-R is not appropriate for the treatment of venereal diseases, including syphilis, gonorrhea, yaws, bejel, and pinta.
Bicillin C-R has only half the recommended dose of penicillin G benzathine and is therefore deemed sub-therapeutic treatment for syphilis.
Penicillin G benzathine should be used for syphilis treatment as sustained therapeutic levels are essential to target the slow growth of Treponema pallidum. In 1999, MMWR reported the inadvertent use of Bicillin® C-R in the treatment of syphilis.
The package and label of all these penicillin IM products are very similar, which was thought to be the cause of confusion in the incidence.
Care should be taken to NOT give IM penicillin products intravenously, as inadvertent IV administration has caused thrombosis, severe neurovascular damage, cardiac arrest, and death.
| Generic name | US Brand name | Route | Appearance |
|---|---|---|---|
| Penicillin G Benzathine | Bicillin® L-A | IM only | Suspension / opaque |
| Penicillin G Benzathine / Penicillin G Procaine combination | Bicillin® C-R | IM only | Suspension / opaque |
| Penicillin G Potassium | Pifzerpen® | IM or IV | Clear |
| Penicillin V Potassium | Pen.Vee® K; V-Cillin K®; Veetids® | Oral | Suspension |
References
- Bass JW. A review of the rationale and advantages of various mixtures of benzathine penicillin G. (Group A Streptococcal Infections: Proceedings of a conference held January 20-22, 1995, in Tampa, Florida). American Academy of Pediatrics 1996;97(6):960(4).
- Bycroft TC, O'Connor T, Hoff C, et al. When choosing injectable penicillin for the treatement of group A beta-hemolytic streptococcal pharyngitis, there is a less painful choice. Pediatric emergency care 2000;16(6):398-400. Institute for safe medication practices. Bicillin C-R-not for syphilis! ISMP medication safety alert! newsletters 2004;9(6).
- CDC. Inadvertent use of Bicillin® C-R for treatment of syphilis – Maryland, 1998. MMWR 1999;48(35):777-779. -Drug Facts and Comparison 2006.
- Package insert Bicillin® C-R. Monarch Pharmaceuticals June 2004.
- Package insert Bicillin® L-A. Monarch Pharmaceuticals June 2004.
Vancomycin Dosing and Monitoring Revisited
By Jonah Christian, PharmD
CHRMC guidelines for vancomycin dosing and monitoring have recently changed. Consider using the vancomycin order set to best follow these new guidelines.
Monitoring
Vancomycin troughs should target 10-15 mg/L for most infections. The trough should be obtained before the fifth dose if duration of therapy is > 3 days.
No prospective, randomized, controlled trial has made a statistically sound relationship between serum concentration and clinical response.
Retrospective, observational and microbiologic data have correlated vancomycin serum concentration and Staphylococcal minimum inhibitory concentrations with clinical outcome. (1-2)
Respiratory Infections
The American Thoracic Society recommends a 15 mg/L trough for adult MRSA pneumonia. (3) Vancomycin concentrations are 4- to 8-fold lower in pleural tissue and epithelial lining fluid relative to serum.
A trough of 15-20 mg/L will diffuse the drug to pulmonary tissue and adequately exceed staphylococcal MIC by two to four folds. (4-6)
Toxicity
Since less toxic formulations of vancomycin became widely used about 15 years ago, the toxicity of vancomycin has been called into question. In a 2003 retrospective study, ototoxicity occurred in 11 of 130 infants who received both vancomycin and a hearing screen.
Of these, vancomycin concentrations were out of range in two. Of these two, one patient also received gentamicin and the other had septic meningitis. (7) A 1999 study reviewed nephrotoxicity patterns in 69 infants receiving vancomycin.
Serum creatinine doubled in six patients, but of these, it did not exceed 0.5 mg/dL in three. All six patients received furosemide, indomethacin or gentamicin concurrently. (8)
Empiric Dosing
Empiric dosing for children weighing 5-40 kg should use 15 mg/kg every 6 hours. We reviewed 128 CHRMC patients who used vancomycin 15 mg/kg every 8 hours and found 91% of patients in this weight group had an initial trough <10 mg/L. Compared to children >40 kg, this group also had a shorter half life. (9)
| Age group | Vancomycin dosing |
|---|---|
| INFANTS < 5 kg | 15 mg/kg Q 8 hrs |
| CHILDREN 5 — 40 kg | 15 mg/kg Q 6 hrs |
| CHILDREN 40 — 66 kg | 15 mg/kg Q 8 hrs |
| PEDIATRIC PATIENTS < 18 yrs but > 66 kg | 1000 mg Q 8 hrs |
| PATIENTS > 18 yrs | 1000 mg Q 12 hrs |
| Patients with CNS INFECTION OR PNEUMONIA | 15 mg/kg Q 6 hrs |
References
- Zimmermann AE, Katona BG, Plaisance KI. Association of vancomycin serum concentrations with outcomes in patients with gram-positive bacteremia. Pharmacotherapy 1995;15(1):85-91.
- Sakoulas G, Moise-Broder PA, Schentag J, et al. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol 2004;42(6):2398-402.
- American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171(4):388-416.
- Cruciani M, Gatti G, Lazzarini L, et al. Penetration of vancomycin into human lung tissue. J Antimicrob Chemother 1996;38(5):865-9.
- Lamer C, de Beco V, Soler P, et al. Analysis of vancomycin entry into pulmonary lining fluid by bronchoalveolar lavage in critically ill patients. Antimicrob Agents Chemother 1993;37(2):281-6.
- Georges H, Leroy O, Alfandari S, et al. Pulmonary disposition of vancomycin in critically ill patients. Eur J Clin Microbiol Infect Dis 1997;16(5):385-8.
- de Hoog M, van Zanten BA, Hop WC, et al. Newborn hearing screening: tobramycin and vancomycin are not risk factors for hearing loss. J Pediatr 2003;142(1):41-6.
- Bhatt-Mehta V, Schumacher RE, Faix RG, Leady M, Brenner T. Lack of vancomycin-associated nephrotoxicity in newborn infants: a case-control study. Pediatrics. 1999 Apr;103(4):e48.
- Internal data available upon request.
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