Important FDA Public Health Advisory

Here is an important FDA Public Health Advisory:

Dolophine (Methadone Hydrochloride) - Reports of Death, Narcotic Overdose, and Cardiac Arrhythmias
MedWatch - The FDA Safety Information and Adverse Event Reporting Program

FDA notified healthcare professionals of reports of death and life-threatening adverse events such as respiratory depression and cardiac arrhythmias in patients receiving methadone. These adverse events are the possible result of unintentional methadone overdoses, drug interactions, and methadone's cardiac toxicities (QT prolongation and Torsades de Pointes).

The reports underscore the importance of knowing methadone's toxicities and unique pharmacologic properties, including dosing and monitoring recommendations.

FDA has reviewed reports of death and life-threatening adverse events such as respiratory depression and cardiac arrhythmias in patients receiving methadone. These adverse events are the possible result of unintentional methadone overdoses, drug interactions, and methadone’s cardiac toxicities (QT prolongation and Torsades de Pointes). Physicians prescribing methadone should be familiar with methadone’s toxicities and unique pharmacologic properties. Methadone’s elimination half-life (8-59 hours) is longer than its duration of analgesic action (4-8 hours). Methadone doses for pain should be carefully selected and slowly titrated to analgesic effect even in patients who are opioid-tolerant. Physicians should closely monitor patients when converting them from other opioids and changing the methadone dose, and thoroughly instruct patients how to take methadone. Healthcare professionals should tell patients to take no more methadone than has been prescribed without first talking to their physician.

This information reflects FDA’s current analysis of data available to FDA concerning this drug. FDA intends to update this sheet when additional information or analyses become available.

Read the complete MedWatch 2006 Safety summary, including links to the FDA Healthcare Professional Sheet, Patient Information Sheet, and new prescribing information for Dolophine regarding this issue at this link.
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Excerpt from the FDA Healthcare Professional Sheet [November 27, 2006 - Healthcare Professional Sheet - FDA]

Considerations

Methadone is an effective analgesic and may provide pain relief when other analgesics are ineffective. However, methadone can cause significant toxicities. We are highlighting important safety information from the new label about using methadone for pain. See the methadone label (Dolophine) for more details.

Methadone’s elimination half-life (8-59 hours) is longer than its duration of analgesic action (4-8 hours). Methadone’s peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects. During treatment initiation, methadone’s full analgesic effect is usually not attained until 3-5 days of dosing. Initiation and titration to analgesic effect and dose adjustments should be done cautiously and in consideration of these properties. In chronic use, methadone may be retained in the liver and then slowly released, prolonging the duration of action despite low plasma concentrations.

Cross-tolerance between methadone and other opioids is incomplete. This incomplete cross-tolerance makes the conversion of patients on other opioids to methadone complex and does not eliminate the possibility of methadone overdose, even in patients tolerant to other opioids. Deaths have been reported during conversion from chronic, high-dose treatment with other opioid agonists to methadone. It is critical to understand the pharmacokinetics of methadone when converting patients from other opioids to methadone. Particular vigilance is necessary during treatment initiation, during conversion from one opioid to another, and during dose adjustments.

Methadone can cause serious cardiac conduction effects, including QT interval prolongation and Torsades de Pointes.

There are pharmacokinetic and pharmacodynamic drug interactions between methadone and many other drugs. Drugs administered concomitantly with methadone should be evaluated for interaction potential.

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