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Medication Update: August 2007

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

New Formulary Drugs

Rotavirus vaccine (Rotateq®)

Rotateq vaccine is a live vaccine given to prevent viral gastroenteritis. It is given in a 3 dose series. Rotavirus vaccine is not intended to treat rotavirus. The vaccine was added to the formulary with restriction to healthy patients 2 month and older. It is not to be used in premature infants <46 weeks gestational age or in immunosuppressed patients.

Treprostinil (Remodulin®) injection

Treprostinil is a prostacyclin analog with vasodilatory effects that is indicated for use as a subcutaneous or intravenous infusion for the treatment of pulmonary arterial hypertension. It is also indicated to diminish the rate of clinical deterioration in patients requiring transition from epoprostenol. The use of this drug is restricted to use by cardiology and ICU attendings and ICU fellows.

Other Formulary Issues

Formula Changes

Deletions:

Potassium gluconate will be deleted due to manufacturer discontinuation Diatrizoate was removed from formulary because it is no longer used by radiology.

Formulary monograph updates:

  • Micafungin will include the addition of a recommendation of 200 mg maximum dosing for children 2-8 years of age. This is higher than the usual maximum dose because it is eliminated quicker in this age group.
  • Valganciclovir monograph with now include a detailed table of dosing regimens.
  • Vancomycin will include an increase dosing recommendation for use in patients with central nervous system infections or pneumonia weighing 5-40 kg of 23 mg/kg/dose and 40-66 kg of 15 mg/kg/dose every six hours.

Passing of the torch

After 6 years of working on the newsletter Anny Chan, PharmD. will pass the torch to the new editor Renee Freitag, PharmD. Fortunately, Anny will still be working here at Children’s. We appreciate all her years of dedication to this endeavor and are glad she is still here to give us great advice and input. Thank you Anny!!

Ceftriaxone alert

  • Ceftriaxone is now contraindicated for patients <30 days old.
  • This change comes from 5 case reports in newborns in which precipitates of calcium and ceftriaxone were found.

Drug Interactions

By Becky Dant, PharmD.

The overwhelming number of drug interactions can make it difficult to design medication regimens for our patients. Published reports of drug interactions in humans, animals, and in vitro tests do not always consider the clinical significance of the interaction. One of the most common mechanisms of drug interactions is through the CYP450 enzyme system. In order to better understand these drug interactions and their clinical significance, CYP450 interactions will be reviewed.

CYP450 interactions occur when the hepatic enzyme system is induced or inhibited. When an enzyme system is induced it will increase the metabolism of the object drug by either increased activity of the existing enzymes and/or synthesis of additional enzymes. Induction leads to decreased concentrations of the object drug and decreased effectiveness. The onset of induction depends on the half-life of the precipitant drug. A drug with a short half-life, such as rifampin, will stimulate induction quite rapidly and have a shorter duration of induction once therapy is discontinued. Inducers that have long half-lives, such as phenobarbital, may cause a delay in onset of induction and increased metabolism will persist for days to weeks after the precipitant drug is discontinued. Conversely, when the enzyme system is inhibited it can lead to increased blood levels of the target drug and serious side effects. Inhibition occurs as soon as the drug reaches sufficient concentrations in the liver, usually within hours. In contrast to induction, inhibition generally abates quickly.

The following points can help predict if an interaction will be clinically significant.

  • Medications with narrow therapeutic indices, such as digoxin or warfarin, could result in more serious adverse effects if their blood levels are altered.
  • Pharmacokinetic parameters that are changed by more than 30 percent in drugs with wide therapeutic indices. A change in half-life or elimination rate of less than 30 percent can be caused by patient variability alone, and may not result in clinically significant effects.
  • The drug interaction is documented in humans. Tests performed in vitro and on animals do not always reflect how the drug will behave in a human.
  • There are two drug interaction programs available at Children’s: Lexi-Interact and Micromedex Drug-Reax. Both of these programs allow the user to input a patient’s complete medication regimen to evaluate for drug interactions. The programs then list the interactions as well as the mechanism and severity. Also, the pharmacists at Children’s can help sort out which interactions are likely to effect patients and assist in guiding changes to medication regimens. Close monitoring of the patient and supervision of drug therapy can help prevent adverse drug reactions and detect drug interactions at early stages.

References

  1. Hansten P, Horn J. Pharmacokinetic Drug Interaction Mechanisms and Clinical Characteristics. In: Hansten and Horn’s Drug Interactions Analysis and Management. St. Louis, MO: Wolters Kluwer Health; 2000:PM1-PM20.
  2. Hussar DA. Drug Interactions. In: Remington: The Science and Practice of Pharmacy. 20th Ed. Baltimore, MD: Lippincott Williams & Wilkins; 2000:1746-1761.
  3. Brater DC. General principles of drug interactions. Available at: www.uptodate.com.
  4. Lexi-Interact Available through Child
  5. Micromedex Drug-Reax Available through Child

Common CYP450 Isozyme Drug Interactions

Drug 1A2 2C9 2C19 2D6 2E1 3A4
Amiodarone - -
Bactrim -
Barbiturates + + + +
Carbamazepine + + +, S
Cigarette Smoking +
Cimetidine - - -
Codeine S
Diltiazem - -, S
Erythromycin - -, S
Fluconazole + - -
Fluoxetine + - -, S -
Grapefruit Juice -
Isoniazid - - -, S -
Itraconazole -, S
Ketoconazole -, S
Metronidazole -
Paroxetine -, S
Phenytoin S +
Quinidine -
Rifampin + + +
Ritonavir - -, S
Simvastatin S
Theophylline S S
Verapamil S
Warfarin, R-isomer S S S
Warfarin, S-isomer S

+ inducer, - inhibitor, S substrate          Adapted from Hansten & Horn’s Drug Interactions1

Methadone Conversion

By Kristin Veal, PharmD.

Methadone is a synthetic opioid that is used primarily to manage chronic pain. Given its long half-life, it is usually initiated in a conversion from a shorter acting opioid when long-term pain management is desired, or when patients experience inadequate pain relief or intolerable side effects from other opioids. However, choosing an appropriate dose of methadone can be difficult due to the drug’s variable pharmacokinetics, drug interaction potential, and its varying equianalgesic dose ratios with other opioids. This article will review the pharmacokinetics and pharmacodynamics of methadone and provide guidelines for transitioning patients to a safe and efficacious dose of methadone.

Methadone’s excellent oral bioavailability, absence of metabolites, and long half life make it a great choice for chronic pain management. However, its half life is biexponential, with an initial half life of 2-3 hours followed by a terminal half life of 15-60 hours. This produces both a relatively short term analgesic effect and also a tendency to accumulate with repeated dosing, resulting in risk of delayed toxicity, since steady state drug levels may not be reached for a week or longer2,3. Clearance may also differ among individuals; in particular, patients receiving drugs that inhibit or induce CYP450 enzymes may decrease or increase methadone clearance, respectively. Finally, methadone’s bioavailability is highly variable among individuals, ranging from 41% to 99%, complicating IV to PO conversion4.

Methadone can prolong the QT interval and torsades de pointes has been reported in patients receiving high doses of methadone1. Concomitant use of methadone and other medications that can prolong the QT interval should be avoided, or EKG monitoring considered4.

August 2007

Methadone’s analgesic effects result from its agonist activity at both the mu and delta opioid receptors, each of which is involved in pain mediation. This quality may provide some clinical advantage over other opioids, which work only at the mu receptor2. Also unique to methadone is its N-methyl-D-aspartate (NMDA) antagonist activity. NMDA stimulation is associated with neuropathic pain.

Methadone’s NMDA antagonist and/or delta agonist activity may be the reason the equianalgesic ratio is dependent upon the dose of the previous opioid5,6. Two recently published tables illustrate this effect and provide a guideline for converting patients to methadone1,4. One way to apply this data to pediatrics is to convert the oral morphine daily dose to a mg/kg dose. This conversion is illustrated in the third column of each table, and may help in transitioning pediatric patients to methadone. Please note that these tables reflect adult doses and do not take into account drug interactions or the drug’s variable oral bioavailability.

Table 1. Opioid conversion recommended by the National Cancer Institute4

Oral morphine daily dose (mg/day) Initial dose ratio (oral morphine: oral methadone) Oral morphine (pediatrics) mg/kg/day
<30 2:10.6mg/kg/day
30-994:10.6-2mg/kg/day
100-2998:12-6mg/kg/day
300-49912:16-10mg/kg/day
500-99915:110-20mg/kg/day
>100020:1 or greater >20mg/kg/day

Table 2. Opioid conversion recommended in methadone package insert1

Oral morphine daily dose (mg/day) Daily oral methadone dose as percent of daily morphine dose Oral morphine (pediatrics) mg/kg/day
<10020-30%<2mg/kg/day
100-30010-20%2-6mg/kg/day
300-6008-12%6-12mg/kg/day
600-10005-10%12-20mg/kg/day
>1000<5%>20mg/kg/day

Conversion method

Once the appropriate methadone dose is calculated using the ratios above, Mancini recommends converting patients to methadone over a three day period5. Over three days, the original opioid is decreased by onethird of the original dose each day, while the methadone is added in one-third increments of the calculated replacement dose each day. Thus, after three days, the patient would be fully converted to methadone. This approach facilitates evaluation of the effects of the methadone dose on the patients. For instance, some patients may experience pain relief with just two-thirds of the calculated dose of methadone and not require a dose increase on day three. Because signs of overdose should be evident within ten hours of dosing, methadone initiation or dosage increase should occur in the morning, so that the patient can be monitored during the day2.

Conclusion

In conclusion, methadone can be an excellent agent for management of chronic pain. In addition to its powerful analgesic effects, its long half life, excellent oral availability and low cost can improve patient quality of life. When dosed appropriately, methadone can be a safe and efficacious pain medication.

References

  1. http://www.fda.gov/cder/drug/advisory/methadone.htm accessed 4/6/07
  2. Manfredi PL, Borsook D, Chandler SW, Payne R. Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations. Pain 1997; 70:99-101.
  3. Santiago-Palma J et al. Intravenous methadone in the management of chronic cancer pain. Cancer 2001;92:1919- 1925
  4. http://www.cancer.gov/cancertopics/pdq/supportivecare/pain/HealthProfessional accessed 4/6/07.
  5. Mancini I, Lossignol DA, Body JJ. Opioid switch to oral methadone in cancer pain. Curr opin onc 2000; 12:308- 313.
  6. Ripamonti C, Zecca E, Bruera E. An update on the clinical use of methadone for cancer pain. Pain 1997; 70:109-115.

Credits

Editors

  • Renee Freitag, 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