Medication Update: July 2007
Medication Update is a bi-monthly newsletter of the Pharmacy and Therapeutics Committee for physicians, pharmacists and nurses.
- New Formulary Drugs
- Other Formulary Issues
- Medication Use Evaluation (MUE) – Melatonin
- Pharmacokinetic Considerations During ECMO
New Formulary Drugs
Arginine oral solution
Sodium benzoate oral solution
These two compounds are both standard chronic management of urea cycle disorders. Arginine is used as a supplement in urea cycle disorders as deficiencies in the cycle render arginine an essential amino acid. Arginine also replenishes urea cycle intermediates to allow for increased waste nitrogen excretion. Benzoate is conjugated to glycine to form hippurate, allowing for an alternative pathway of waste nitrogen excretion. These oral solutions are extemporaneously compounded by CHRMC pharmacy.
Cinacalcet (Sensipar®) oral tablet
Cinacalcet is a calcimimetic that increases the sensitivity of the calcium-sensing receptor on the parathyroid gland. It provides an alternative for the treatment of secondary hyperparathyroidism in patients who are unresponsive to vitamin D analogues. Common side effects include hypocalcemia, nausea, vomiting, diarrhea and myalgia. Dosing for patients <18 years is unclear. Cinacalcet use will be restricted to nephrology service.
Dihydroergotamine (D.H.E. 45®) injection
This agent has been added to the formulary for use as a second-line agent for status migrainosus with approval by the neurology service. It causes direct vasoconstriction of vascular smooth muscle, particularly of the carotid artery bed but also peripheral and cerebral vessels, which reduce the amplitude of pulsation in the cranial arteries; it also has partial agonist or antagonistic activity against tryptaminergic and dopaminergic receptors. Dihydroergotamine cannot be used within 24 hours of sumatriptan, zolmitriptan, or other serotonin agonists since their overlapping effects may prolong vasospastic reactions. Due to its vasoconstrictive property, it also carries the risk of severe cardiovascular adverse reaction. When given as IV injection, the onset of action is almost immediate. It can also be given SQ or IM.
Trypan blue dye
This ophthalmic agent will be used to stain anterior capsule of lens during cataract surgery.
Flurandrenolide (Cordran tape)
This tape contains the topical steroid, flurandrenolide, that is applied for scar management post-operatively.
Pantoprazole (Protonix®) IV and lansoprazole solu-tabs
Due to the discontinuation of lansoprazole IV production, pantoprazole IV has been added to the formulary as the IV proton pump inhibitor (PPI) of choice. Pantoprazole IV has a longer stability (24 hr vs. 12 hr) and dosing is the same as lansoprazole (1 mg/kg/dose, max 40 mg). GI service is in the process of developing explicit criteria for use of IV PPI. Lansoprazole solu-tabs with standard dosing are also added to the formulary and are encouraged to be used in place of the compounded suspension form when possible. Lansoprazole solutabs are not supposed to clog g-tubes as small as 7 French.
Other Formulary Issues
Formula Changes
Deletions: the following agents will be deleted due to manufacturer discontinuation - sulfacetamide ophthalmic ointment; calcium gluconate tablets; trimethobenzamide suppositories.
Addition: Deletion of OKT3 from the formulary has been reversed as continued usage by GI transplant service was identified shortly after the deletion decision.
Formulary restriction change: Cytomegalovirus immune globulin (Cytogam) will be restricted for the treatment of CMV pneumonitis and Infectious Disease approval will be required for all other uses.
Formulary monograph updates: Responding to a recent FDA declaration that quinine cannot be used for leg cramps due to potentially severe toxicity and no clear evidence of benefit, such indication and dosing information are removed.
F.Y.I.
- "Lidoderm" order set is now available for use in CIS. It contains an order to remove the patch after 12 hours in addition to the order for applying the patch.
- The narcotic order set no longer has naloxone for itching or urinary retention. Diphenhydramine and nalbuphine should be used instead. Naloxone is being reserved for treating respiratory depression and should NOT be used for itching or urinary retention.
Medication Use Evaluation (MUE) – Melatonin
In the September 2006 P&T Meeting, melatonin was added to the formulary for treatment of diagnosed sleep disorders (circadian rhythm sleep disorder including delayed onset of sleep, multiple night awakenings and short duration of night sleep) in the following patients with approval by neurodevelopmental, neurology or sleep disorders services: Smith-Magenis Syndrome, mental retardation with or without epileptic seizures, blindness. In patients who experience a beneficial effect, therapy should be cycled off (after an established response) to see if there is a continued need for treatment. If melatonin does not work after a 2-week trial, patients should stop taking it.
Melatonin is a pineal hormone released during the dark hours, and is important in the regulation of the circadian rhythm. There are a few controlled studies of melatonin use in pediatric patients. In the studies the patients had a diagnosis of blindness, mental retardation or Smith-Magenis Syndrome. The dose ranged from 1 to 6mg. A dose was given when the patient was ready to go to sleep. There was no report of adverse drug reactions in the studies.
A follow up MUE for melatonin usage from October, 2006 to March, 2007 was presented to the P&T Committee. This MUE showed:
- Thirteen patient received melatonin during this six month data collection period, reaffirming limited usage.
- All the patients received a melatonin dose within the Children’s formulary dose range (1-6mg).
- All the patients were on the Neurology or Psychiatric services. The data showed the hospital guidelines for melatonin use needed adjustment. The expanded guidelines now include development delay or disability along with mental retardation.
Pharmacokinetic Considerations During ECMO
ECMO (Extra Corporeal Membrane Oxygenation) is cardiopulmonary bypass used in respiratory and cardiac failures. Since its introduction in 1975, ECMO has been used in neonates and older children for many indications including persistent pulmonary hypertension, congenital diaphragmatic hernia and congenital heart defects. Medication therapy is often required for underlying conditions, but little is known about drug therapeutics in this population. This article will review known pharmacokinetic data during ECMO.
Mechanisms by which drug pharmacokinetic is altered during ECMO
- Increased volume of distribution – increased 125% in infants, 25% in adolescents.
- Adsorption into circuit - irreversible binding to oxygenator and tubing polymers (e.g. fentanyl).
- Circuit age - in vitro studies show increased morphine and lorazepam extraction over time.
- Flow rate - dye will pool in circuit when flow is <250ml/min.
- Veno-arterial (VA) vs veno-venous (VV) - lack of pulsatile flow in VA ECMO may compromise renal and hepatic blood flow, changing drug elimination and metabolism. However, gentamicin clearance was the same in both VA and VV ECMO in one case series.
Considerations of specific drug
- Morphine – Data is conflicting but shows high interpatient variability in clearance, increasing five fold after 10 days in one case series. Clearance appears to increase after decannulization which could precipitate withdrawl. Binding may increase to 40% as the circuit ages.
- Lorazepam – Data is limited to in vitro studies. Sedation requirements appear to increase over time due to either adsoption in the circuit or tolerance.
- Fentanyl – In vitro studies show 70% irreversibly bound to circuit. Ten fold higher dosing in a case series.
- Propofol – High circuit binding (around 90%), makes this sedative a poor choice in ECMO.
- Furosemide – Single study was unable to determine optimal dosing regimen. Bumetanide data appears to show shortened duration of action.
- Phenobarbital –Case reports show increased requirements particularly after circuit change. In vitro data is conflicting, which ranges from no effect to 17% of drug lost to circuit.
- Gentamicin – Most studied drug in ECMO. Most authors recommend 2.5-3 mg/kg every 18-24 hours in term neonates.
- Vancomycin – Significant interpatient variability. A dose modeling study developed and validated the guidelines below (Mulla et al 2005). Monitoring of levels is critical in neonates <1 week.
| Serum creatinine(mg/dl) |
Dose (mg/kg) / interval (h) | ||||
|---|---|---|---|---|---|
| 0-1 month | 1 mo - 1 year | 1-3 years | 3-10 years | >10 years | |
| 0.3 | 15/8 | 20/8 | 20/6 | 20/6 | 20/6 |
| 0.6 | 10/12 | 10/8 | 10/8 | 10/6 | 10/6 |
| 1.2 | 10/24 | 15/24 | 10/12 | 15/18 | 10/12 |
| 1.8 | 15/48 | 15/36 | 12.5/24 | 15/24 | 12.5/24 |
| 2.4 | Dose by levels, about q 72 h |
15/48 | 15/36 | 15/36 | 15/36 |
Summary
Significant pharmacokinetic changes occur during ECMO. Close clinical and kinetic monitoring is essential due to wide interpatient variability and lack of data. Pharmacy consultation is encouraged for drug dosing, particularly vancomycin and gentamicin.
References
- Bhatt-Meht V, Annich G. Sedative clearance during extracorporeal membrane oxygenation. Perfusion. 2005;20(6):309-15.
- Bhatt-Meht V, Johanson CE, Schumacher RE. Gentamicin pharmacokinetics in term neonates receiving ECMO. Pharmacotherapy. 1992;12(1):28-32.
- Buck ML. Pharmacokinetic changes during extracorporeal membrane oxygenation: implications for drug therapy of neonates. Clin Pharmacokinet. 2003;42(5):403-17.
- Geiduschek JM, Lynn AM, Bratton SL, et al. Morphine pharmacokinetics during continuous infusion of morphine sulfate for infants receiving extracorporeal membrane oxygenation. Crit Care Med. 1997;25(2):360-4.
- Mulla H, Pooboni S. Population pharmacokinetics of vancomycin in patients receiving extracorporeal membrane oxygenation. Br J Clin Pharmacol. 2005;60(3):265-75.
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, R-3409
4800 Sand Point Way NE
PO Box 5371/R-3409
Seattle, WA 98105