The focus here is on minimizing the potential for cardiac electrical conduction disturbances being caused by LAAM in patients attending opioid agonist treatment (OAT) programs regulated by CSAT.

A.  Patients Already on LAAM:

Twelve-lead ECGs are to be performed on all patients. All ECGs should be reviewed by a physician with expertise in reading ECGs. Followup ECGs can be performed every 12-18 months thereafter unless indicated sooner for clinically suspicious events, increases in dosage, or new medications.
   

LAAM should not be continued in patients with confirmed QTc prolongation greater than 480 msec (milliseconds) without timely cardiologic consultation.

Bazett's correction is used to calculate QTc (QTc msec = QT msec / square root of RR in seconds).

Heart rate must be between 50 and 75 bpm for accurate interpretation. BPM <50 will result in artifactual shortening of QTc;
BPM >75 will result in artifactually prolonged QTc.

If a patient's heart rate is high, some minutes of rest and relaxation may be used to reduce it. Or, consultation with an experienced electrocardiographer might be recommended in patients falling outside the range.

Or, consultation with an experienced electrocardiographer might be recommended in patients falling outside the range.

   
All patients are to have medical histories updated with emphasis on a family history (of long QT syndrome, cardiac conduction defects, arrhythmias, syncopal attacks, seizures, and sudden or unexpected death) and personal history (of long QT syndrome, cardiac conduction defects, arrhythmias, syncopal attacks, seizures, palpitations, dizziness, and light-headedness).
   
Update drug/medication history:
   
  a)
 List all concomitant pharmacologic agents, including prescribed medications, OTC agents, herbal preparations, dietary supplements, illicit substances and alcohol. Results of laboratory tests, including urine toxicology screens, should be taken into consideration when compiling this list, especially for cocaine and amphetamines (which increase risk).
   
  b)
 Patients should be advised to inform the program physician of any additional medications being prescribed, prior to starting them (and to inform any prescribing physician that they are already taking a medication that prolongs the QT interval).
   
  c)
 Of special importance are drugs/medications that may affect cardiac function or metabolically interact with LAAM.

Medications can be checked against those previously reported to prolong QT at www.torsades.org.

LAAM is metabolized to active metabolites by the cytochrome P450 isoform, CYP3A4. Therefore, the addition of drugs that induce this enzyme (such as rifampin, phenobarbital, phenytoin, ritonavir, and St. John's wort) or inhibit this enzyme (such as ketoconazole, itraconazole, erythromycin, amiodarone, cimetidine, saquinavir, and grapefruit juice) could increase the levels of parent drug or its active metabolites in a patient that had previously been at steady-state, and this could potentially precipitate serious arrhythmias, including torsade de pointes.

Caution should be used when prescribing concomitant drugs known to induce hypokalemia or hypomagnesemia as they may precipitate QT prolongation and interact with LAAM. These would include diuretics, laxatives, and supraphysiological use of steroid hormones with mineralocorticoid potential, as well as alcohol intake at a level to cause significant fluid and electrolyte disturbance.
   
The program physician should document the risks/benefits of continuing LAAM therapy in the patient record, following a discussion of such risks and benefits with the patient. Patients with higher risk profiles may be managed more safely without the use of LAAM.
   
   



B. New LAAM Patients:

 A pretreatment 12-lead ECG is to be performed and then followup ECGs. At least one followup ECG should be obtained between twelve days and four weeks after starting treatment and when steady-state dosing has been attained. Followup ECGs can be performed every 12-18 months thereafter unless indicated sooner for clinically suspicious events, increases in dosage, or new medications.
   
Per product labeling, LAAM should not be started in patients with a QTc interval greater than 430 msec [male] or 450 msec [female]; or in patients having conditions which may lead to QT prolongation such as:
   
  a)
 clinically significant bradycardia ( <50 bpm),
   
  b)
 clinically significant cardiac disease,
   
  c)
 treatment with Class IA or Class III anti-arrhythmics,
   
  d)
 treatment with monoamine oxidase inhibitors (MAOIs),
   
  e)
 concomitant treatment with other drugs known to prolong the QT interval, and
   
  f)
 electrolyte imbalance, in particular hypokalemia and hypomagnesemia.
   
All potential LAAM patients are to have medical histories updated with emphasis on a family history (of long QT syndrome, cardiac conduction defects, arrhythmias, syncopal attacks, seizures, and sudden or unexpected death); and personal history (of long QT syndrome, cardiac conduction defects, arrhythmias, syncopal attacks, seizures, palpitations, dizziness, and light-headedness).
   
Update drug/medication history:
   
  a)
 List all concomitant pharmacologic agents, including prescribed medications, OTC agents, herbal preparations, dietary supplements, illicit substances and alcohol. Results of laboratory tests, including urine toxicology screens, should be taken into consideration when compiling this list, especially for cocaine and amphetamines (which increase risk).
   
  b)
 Patients should be advised to inform the program physician of any additional medications being prescribed, prior to starting them (and to inform any prescribing physician that they are already taking a medication that prolongs the QT interval).
   
  c)

Of special importance are drugs/medications that may affect cardiac function or metabolically interact with LAAM.
Medications can be checked against those previously reported to prolong QT at www.torsades.org.

LAAM is metabolized to active metabolites by the cytochrome P450 isoform, CYP3A4. Therefore, the addition of drugs that induce this enzyme (such as rifampin, phenobarbital, phenytoin, ritonavir, and St. John's wort) or inhibit this enzyme (such as ketoconazole, itraconazole, erythromycin, amiodarone, cimetidine, saquinavir, and grapefruit juice) could increase the levels of parent drug or its active metabolites in a patient that had previously been at steady-state, and this could potentially precipitate serious arrhythmias, including torsade de pointes.

Caution should be used when prescribing concomitant drugs known to induce hypokalemia or hypomagnesemia as they may precipitate QT prolongation and interact with LAAM. These would include diuretics, laxatives, and supraphysiological use of steroid hormones with mineralocorticoid potential , as well as alcohol intake at a level to cause significant fluid and electrolyte disturbance.

   
The program physician should document the risks/benefits of beginning LAAM therapy in the patient record, following a discussion of such risks and benefits with the patient. Patients with higher risk profiles may be managed more safely without the use of LAAM. Concern with the QTc phenomenon should not necessarily deter the use of LAAM by fully informed and carefully screened patients who would prefer LAAM and would benefit from its use.

Drugs That Prolong the QT Interval and/or Induce Torsade de Pointes
The charts beginning on the following page (updated 10/23/01) are adapted from a list maintained and frequently updated by the Department of Pharmacology at Georgetown University Center for Education and Research on Therapeutics (CERT) and is available at or . This site contains information from FDA-approved drug labeling and cases reported in the literature, and also includes a list of drugs to avoid in patients with congenital long QT syndrome. Check the Web site for the latest listings and updates.

Note: Charts of this type can serve as a reference guide only; professional judgment and consultation with other appropriate sources is recommended prior to making clinical decisions in specific situations. Also, due to rapidly expanding knowledge in this area, one should recognize that any such list may require frequent updating.

QT = Prolongation is mentioned in the FDA-approved labeling as a known action of the drug. TdP = The FDA-approved labeling includes mention of cases or a risk of Torsade de Pointes (TdP). Cases in Lit = There are case reports of TdP in the medical literature. Females>Males = Substantial evidence indicates greater risk (usually two-fold) of TdP in women. + = Additional brands are on the market.

NOTES:
Quinine may also be of concern, as cases of conduction abnormalities and arrhythmia due to cardiotoxicity of this drug, as a diluent in combination with heroin and other illicit drugs, have been reported. In patients with QT interval prolongation and a positive urine screen for quinine, a repeat ECG subsequent to eliminating illicit drug use may be advised to determine if the QT interval reverts to normal range (personal communication, Barry Stimmel, MD, October 30, 2001).

Caution should be exercised when prescribing concomitant drugs known to induce hypokalemia or hypomagnesemia as they may precipitate QT prolongation and interact with ORLAAM and/or drugs listed in the above table. These would include diuretics, laxatives, and supraphysiological use of steroid hormones with mineralocorticoid potential, as well as alcohol intake at a level to cause significant fluid and electrolyte disturbance (personal communication, Gregory Hicks, PharmD, Roxane Laboratories, Inc., October 28, 2001; also in ORLAAM PI, 2001).

Drugs to Avoid in Patients with Congenital Long QT Syndrome
The following charts (updated 10/23/01) are adapted from a list maintained and frequently updated by the Department of Pharmacology at Georgetown University Center for Education and Research on Therapeutics (CERT) and is available at or.

Drugs listed are potential triggers for torsade de pointes or ventricular fibrillation in the presence of a long QT interval. People who have a prolonged QT interval, due either to congenital long QT syndrome or due to a QT-prolonging effect of medications or certain heart muscle diseases, are generally advised to avoid use of these medications if possible. Additionally, patients with a long QT interval should avoid drugs that prolong the QT interval as listed at www.torsades.org.