The Hospice Clinician Blog

By: Jim Joyner, Pharm.D., C.G.P

The commonly used antibiotic, Azithromycin (Z-Pak, Zithromax), was recently discussed in the medical news due to a report of increased risk for serious cardiac adverse effects associated with its use.  This incidence of risk is quite low, but due to the potentially serious nature it has resulted in an advisory memorandum by the FDA.  Specifically, there is a small risk of prolongation of the QT interval on the ECG which may progress to a serious cardiac arrhythmia known as Torsades des Pointes (TdP).   TdP can lead to ventricular fibrillation and sudden death.  In light of this recent focus on the issue of drug-induced QTc prolongation, this seems like an appropriate time to review and discuss other medications which also have the potential to cause this problem, especially since some of them are encountered frequently in the medication regimens for hospice patients.  

There are 34 specific medications available for use in the U.S. which have substantial evidence that supports the conclusion that they may prolong the QT interval and have a risk of TdP when used as directed according to approved labeling.(1) The list encompasses certain drugs from a variety of different pharmacologic classes including:

  8 different antiarrhythmic drugs, 
  6 antibiotics, 
  5 antipsychotics, 
  2 antinausea drugs,
  2 antidepressant drugs,
  2 anticancer drugs,
  2 non-sedating antihistamines, 
  2 antimalarial drugs,
  1 opioid,
  1 antiangina drug, 
  1 cholesterol lowering drug,
  1 anesthetic,
  1 GI stimulant drug

For a complete listing of all of the medications, and detailed information about drug-induced QT prolongation check out this link:
www.azert.org/medical-pros/drug-lists.htm

Five of the drugs on this list are quite commonly used in hospice to provide palliative management of a variety of symptoms.  Those drugs include:  Chlorpromazine (Thorazine), Citalopram (Celexa), Escitalopram (Lexapro), Haloperidol (Haldol), and Methadone (Dolophine).  

The incidence of this adverse cardiac effect has not been established for any of these drugs and the majority of patients take these drugs without any problem of a prolonged QT interval or arrhythmia.   It is also possible that some patients may have a prolonged QT interval while taking these drugs and exhibit no negative symptoms or effects.   In those cases this event would go unnoticed unless an ECG was done.   This adverse effect appears to be dose-related and has been associated with patients receiving higher dosages.

Awareness of the following risk factors for QT prolongation and TdP may help reduce the risks for this adverse effect when considering the use of these drugs(2) :

• Cardiac disease (MI, CHF, cardiomyopathy, congenital long QT syndrome, bradycardia)
• Low potassium or magnesium levels  (may occur with diuretic  usage)
• High drug doses (i.e.;  methadone > 200mg/day)
• Combined use of multiple drugs  which can prolong  QT
• Clinically significant drug interactions that can result in excessively elevated blood levels of a drug identified as having  QT prolongation potential

There are reports of several other drugs, commonly used in hospice ( not on the list above) where substantial evidence supports the conclusion that these drugs may also cause QT prolongation but will only present a risk of causing TdP in certain conditions such as over-dosage,  significant drug interaction, or in a patient with pre-existing cardiac disease risk factors.(1,2)

The drugs listed below can prolong QT but do not have the higher level of risk for causing TdP as the list of 34 drugs above: Amitriptyline (Elavil), Diphenhydramine (Benadryl), Doxepin (Sinequan), Fluoxetine,(Prozac) Nortriptyline (Pamelor), Paroxetine (Paxil), Mirtazapine (Remeron), Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone (Risperdal),  and Ziprasidone (Geodon).

In conclusion, the risks and benefits of using these drugs must be assessed on a case by case basis.  There is no general guideline, nor consensus about when to stop therapy or decrease  a dosage with one of these drugs if one is concerned about prolonged QT or TdP.   A reasonable approach to the problem in hospice care would include the following:

• Avoid the use of a drug known to cause TdP in a patient with the risk factors described above, unless there is no reasonable alternative available
• Reduce correctable risk factors if possible (low potassium or magnesium)
• Exercise caution when using  multiple drugs known to cause TdP or prolonged QT, and utilize doses at the lower end of the therapeutic range when combining these drugs
• Exercise caution when using  high doses of drugs known to cause TdP  (methadone in doses  > 200mg/day)
• Avoid clinically significant drug interactions  which may result in significantly elevated levels of the drugs identified with a potential for prolonged QT and TdP

Reference:
(1.) Arizona Center for Education and Research on Therapeutics
      University of Arizona.   www.azcert.org
(2.) Yap, Camm:  Heart. 2003 November; 89(11): 1363–1372

Photo Credit

There are several choices available among the antipsychotic (neuroleptic) drug class for managing psychotic symptoms and end-of-life delirium in hospice patients.   The range in cost from the least expensive to some of the most expensive antipsychotics is very broad.   Equivalent dose costs can range from as low as $20 per month (Haloperidol 1mg twice a day) to more than $600 per month (Abilify 5mg daily).    Efficacy of the various antipsychotic drugs for managing these symptoms in hospice patients is comparable, so the higher cost agents may not be justified when based solely on any clinical evidence of ability to control symptoms. (1, 2)     The newer atypical antipsychotics which are significantly higher in cost may have the advantage of lower potential for side-effects, specifically involuntary movement disorders, in certain select groups of patients.    This would include patients with a history of drug induced extrapyramidal symptoms (EPS) or a diagnosis of Parkinson’s disease.   An atypical antipsychotic may be justified in one of these types of patients.   Risperidone should be the primary drug considered in this situation since it is the most cost-effective of the atypical group.   

A table of antipsychotic dose equivalents and corresponding estimated costs to the hospice is provided below.   The dose equivalents were taken from an article that appeared in the Journal of Clinical Psychiatry in 2003.(3)   The dose equivalents were determined by the researcher after an exhaustive review of published studies of fixed dose antipsychotics up until June of 2002.  The search included; Medline, the bibliographies of identified reports, published meta-analyses and reviews,  Cochrane reviews, Freedom of Information Act material from the FDA, and abstracts from several scientific meetings from 1997 – 2002.   The dosage equivalence for the various antipsychotics was reported as “minimal effective dose” equivalents.    Most of the reports reviewed to come up with this data were probably not studies that included hospice or terminally ill patients, so keep in mind that “minimal effective” doses in the terminally ill may be lower than that in other populations.   The dosage ratios between the drugs, however, would probably still hold true when considering converting from one drug to another. 
 
The table below may be useful in estimating comparative antipsychotic drug costs for a hospice patient, as well as providing an equivalency guide for conversion from one antipsychotic drug to another more cost-effective agent. 

*All prices are for the generic version of the drug, except Abilify because there is no generic available at this time.
 

References:
1) Boustani, M.  J. General Internal Med. 2009; 24: 848-853
2) Cochrane Database Syst. Rev. 2007 April 18 (2): CD005594
3) Woods SW.   J. Clin. Psychiatry.  2003 Jun;64(6):663-7.

The first generic versions of Zyprexa® have hit the market, after the FDA approved generic olanzapine tablets and oral disintegrating tablets about 3 weeks ago. This is a welcome addition to the lineup of generic antipsychotics, as Zyprexa® is one of the more expensive antipsychotics on the market.

However, so far the cost savings are minimal. For example, the average wholesale price (AWP) for generic olanzapine 5 mg is $13.20 per tablet, compared to just $14.68 per tablet for brand Zyprexa® 5 mg. The generic olanzapine oral disintegrating tablets (5 mg) are around $14 per tablet, while brand Zyprexa Zydis® 5 mg will cost $15.86 per tablet.

When it is appropriate for your hospice patients, continue to use the less expensive antipsychotics such as haloperidol and risperidone.

View the Approval on FDA.gov

"