The Hospice Clinician Blog

Next week is NHPCO's 28th Annual Management & Leadership Conference. The Conference is being held at the Gaylord National Resort in National Harbor, Maryland and the Outcome Resources team looks forward to seeing you there! If you have the chance to attend this year, stop by Booth #617 in the Exhibit Hall. We will have a special treat for the first 100 attendees that come by at the Opening Reception on April 25th from 5:30pm - 7:30pm. You may also request your invitation to our VIP Cocktail Reception, or join us on April 26th from 10am – 11am for a book signing with Ken Ross. We are also looking forward to attending the National Hospice Foundation Gala, and will be honoring Dianne Gray as our Pediatric Palliative Care Champion. Be sure to stop by to get your questions answered about why not all Pharmacy Benefit Managers are the same. If you are not attending, click the link below to download your Hospice Pharmacy Information Kit or request a Complimentary Hospice Pharmacy Consultation to learn more.

Take a look at some of the benefits available to your hospice through a partnership with Outcome Resources:
• With one contract, your hospice receives one low discounted rate on ALL medications
• Your patients have their choice of pharmacies (including mail order options) while your hospice receives one clear and concise invoice
• Unlimited Access to a team of experienced PharmDs for patient consults, drug information, and education programs
• Easier management of hospice patients in skilled facilities since all closed-door pharmacies are included on your invoice
• With custom-tailored plan design and formulary control, you are in control of the medications that are dispensed and paid for by hospice
• Your pharmacies are paid electronically every 15 days and processing claims through our program means fast and easy dispensing along with reduced chance for error
• Detailed reports, invoices, and patient medication information means you always have management tools at your fingertips
• Dedicated lines of communication with your Account Claims Manager and Pharmacists to eliminate time-wasting transfers and phone trees
• Partnership with a company dedicated solely to hospices - we understand your specific complex requirements.

Join us at the Conference, on Facebook, Twitter, or Contact Us directly, and we look forward to speaking with you soon!

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

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Esther Liu, PharmD

On Jan 15, the FDA approved switching the prescription status for Oxybutynin patch to over-the counter as the brand name, Oxytrol for Women.

Oxytrol for Women (OTC) is only approved for the treatment of overactive bladder in women ages 18 years and older. Oxytrol (RX) will remain available for men with overactive bladder by prescription only. The guidance regarding to how the sales can be restricted to women ages 18 years and older is not yet available at the retail level.

Overactive bladder is a condition characterized by symptoms of leaking urine (urinary incontinence), feeling the sudden and urgent need to urinate, and frequent urination due to the over activities of the bladder muscle. Overactive bladder affects an estimated 33 million Americans with the majority of whom are older women.

Oxytrol for Women contains oxybutynin which helps relax the bladder muscle. Oxytrol for Women is a patch that is applied to the skin every four days. The patch delivers 3.9 milligrams of oxybutynin per day. Oxybutynin belongs to a class of drugs known as anticholinergics. It is the first drug in this class to be made available over-the-counter for treatment of overactive bladder.  The oxybutynin tablets will continue to require a prescription.

Oxytrol for Women is not yet available in the market, but it will probably remain at high cost when it becomes available OTC in comparison to the generic oral formulation of oxybutynin, which will continue to require a prescription.

FDA is notifying the public and healthcare professionals of new information about zolpidem, an insomnia drug that is widely prescribed both in the general patient population and in hospice in particular. FDA recommends that the bedtime dose be lowered because new data show that blood levels in some patients may be high enough the morning after use to impair activities that require alertness, including driving. This announcement focuses on zolpidem products approved for bedtime use, which are marketed as generics and under the brand names Ambien (immediate-release zolpidem, 5 mg and 10 mg), Ambien CR (extended-release zolpidem, 6.25 mg and 12.5 mg), Edluar (zolpidem sublingual tablets, 5 mg and 10 mg), and Zolpimist (zolpidem oral spray, 5 mg per actuation).**

Data Summary
Driving simulation and laboratory studies recently submitted to FDA indicate that zolpidem blood levels above approximately 50 ng/mL appear capable of impairing driving to a degree that increases the risk of a motor vehicle accident. In pharmacokinetic trials of 10 mg Ambien (or bioequivalent zolpidem products) that included approximately 250 men and 250 women, about 15% of women and 3% of men had zolpidem concentrations that exceeded 50 ng/mL approximately 8 hours post-dosing. Three measurements in women and one in men were ≥90 ng/mL at about 8 hours after use.

A higher percentage of both men and women experience potentially impairing morning zolpidem levels after use of extended-release zolpidem products (Ambien CR or generic equivalents). In pharmacokinetic trials of zolpidem extended-release 12.5 mg, approximately 33% of women and 25% of men had zolpidem blood concentrations exceeding 50 ng/mL approximately 8 hours post-dosing. About 5% of patients had blood levels ≥100 ng/mL. 

In studies of zolpidem extended-release 6.25 mg, at 8 hours after dosing, about 15% of adult women and 5% of adult men had a zolpidem level of ≥50 ng/mL, whereas for both elderly men and women, about 10% had such a zolpidem level.

Recommendation
Because use of lower doses of zolpidem will result in lower blood levels in the morning, FDA is requiring the manufacturers of Ambien, Ambien CR, Edluar, and Zolpimist to lower the recommended dose.

• For immediate-release zolpidem products (Ambien, Edluar, Zolpimist), the recommended initial dose for women should be lowered from 10 mg to 5 mg, immediately before bedtime.
• For extended-release zolpidem products (Ambien CR), the recommended initial dose for women should be lowered from 12.5 mg to 6.25 mg.
• Health care professionals should consider prescribing a lower initial dose in men as well. In many men, the lower dose provides sufficient efficacy.
• For both men and women, the 5 mg dose could be increased to 10 mg if needed, with the understanding that the higher dose is more likely to impair next-morning driving and other activities that require full alertness.

FDA urges health care professionals to caution all patients (men and women) who use these products about the risks of next-morning impairment for activities that require complete mental alertness, including driving. Inform patients that impairment from sleep drugs can be present despite feeling fully awake. Encourage patients to read the Medication Guide when they receive their zolpidem prescription, and report adverse events involving zolpidem or other insomnia drugs to FDA’s MedWatch program.

FDA is continuing to evaluate the risk of impaired mental alertness with other insomnia drugs, including zaleplon (Sonata), eszopiclone (Lunesta), and over-the-counter medications.

**The recommended doses of Intermezzo, a lower dose zolpidem product approved for middle-of-the-night awakenings, are not changing. At the time of Intermezzo’s approval in November 2011, the label already recommended a lower dosage for women (1.75 mg) than for men (3.5 mg).

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Esther Liu, PharmD

Recently, Abbott Laboratories took the initiative to introduce the newly formulated Vicodin, Vicodin ES and Vicodin HP tablets with a lower acetaminophen content of 300mg. This was changed to meet the recent FDA mandate to limit the amount of acetaminophen in prescription drug products to 325mg or less per tablet.  FDA’s efforts are aimed at reducing intake of acetaminophen and minimizing toxicity associated with high daily dosage.   The other impacted brand and generic manufacturers may follow Abbott’s step to start changing their formulations  in the future,  however, there are still quite a few active generic hydrocodone/acetaminophen combination products on the market with higher acetaminophen contents including 325mg, 500mg, 650mg, and 750mg. Due to the change of acetaminophen content for Vicodin brand, generic substitution by the pharmacy will be strictly limited to just a couple of generic options that actually match the new Vicodin formulation.   The combination products which contain 300mg of acetaminophen (both the new brand name Vicodin formulation and the few generics available) are more expensive compared to the older combination products that contain 325mg of acetaminophen.

To ensure the appropriate dosage and the most cost effective option is selected for your hospice patients, it is recommended to spell out the generic name for any acetaminophen combination products and specify the strength desired when writing an order.

Below is a list of the common hydrocodone/acetaminophen combination products:

Vicodin = hydrocodone/APAP 5mg/300mg
Vicodin ES = hydrocodone/APAP 7.5mg/300mg
Vicodin  HP= hydrocodone/APAP 10mg/300mg
Norco = hydrocodone/acetaminophen 5mg/325mg
Norco = hydrocodone/acetaminophen 7.5mg/325mg
Norco = hydrocodone/acetaminophen 10mg/325mg
Lortab = hydrocodone/acetaminophen 5mg/500mg
Lortab = hydrocodone/acetaminophen 7.5mg/500mg
Lortab = hydrocodone/acetaminophen 10mg/500mg
hydrocodone/acetaminophen 7.5mg/650mg
hydrocodone/acetaminophen 10mg/650mg
hydrocodone/acetaminophen 7.5mg/750mg
hydrocodone/acetaminophen 10mg/750mg

You may visit the following website for more information about the FDA mandate of acetaminophen limit: http://www.fda.gov/drugs/drugsafety/ucm239821.htm

The DEA is proposing new regulations for the disposal of controlled substances, in accordance with the Secure and Responsible Drug Disposal Act of 2010. The DEA expects that these expanded methods of disposal will decrease the supply of controlled substances available for misuse, abuse, and accidental ingestion, and protect the environment from potentially harmful contaminants.

The rule proposes three voluntary options for drug disposal: (1) take-back events, (2) mail-back programs, and (3) collection receptacles.

Take-Back Events: These are already happening, and the DEA will continue to authorize law enforcement agencies to voluntarily hold take-back events, where controlled and non-controlled substances can be dropped off for disposal. For example, the DEA has previously sponsored “National Drug Take-Back Days”, in which DEA and law enforcement agents set up drug drop-off sites throughout the country. The DEA’s first five National Take-Back Days resulted in the removal from circulation of more than 2 million pounds (over a thousand tons) of prescription drugs. The sixth National Take-Back Day is scheduled for April 27, 2013.

Mail-Back Programs: The DEA proposes to grant law enforcement agencies and retail pharmacies the authority to conduct mail-back programs, in which drugs could be mailed to a location for destruction. All mail-back programs must provide specific mail-back packages to the public, either at no cost or for a fee, and collectors that conduct mail-back programs must have and utilize an on-site method of destruction (guidelines for this will be provided by the DEA).
   
Collection Receptacles: Finally, and perhaps most importantly, the proposal would authorize retail pharmacies and law enforcement agencies to maintain a collection receptacle at their physical location. This receptacle would be a secure drop-box (the DEA would provide precise security requirements) in which unused or unwanted medications could be discarded by the public. Furthermore, retail pharmacies would be authorized to maintain collection receptacles at long term care facilities. Due to fears of insufficient security, hospitals would not be authorized to main a drop-box, but many hospitals are co-located with registered retail pharmacies as a convenient service for outpatients, and medications could be discarded there.

While the DEA only deals with the regulation of controlled substances, it is important to note that all of the above apply to the disposal of non-controlled substances as well. The DEA will not be requiring collectors to count or inventory the medications collected, however there will be some recordkeeping requirements.

This long-awaited and much needed expansion of drug disposal options will help tremendously in hospice, where patients very commonly use controlled substances which may remain unused at the end of life. With new and more convenient options, no longer will families of hospice patients turn to inappropriate disposal, or keep dangerous medications around only to have them end up in the wrong hands. Pharmacies will no longer have to turn away patients or caregivers wanting to dispose of unused medications, and then worry about where those medications might end up.

Tell us: Do you foresee these new regulations having a positive impact on your hospice practice? What issues, if any, do you anticipate?
 

Qualitest, a subsidiary of Endo Health Solutions, has issued a voluntary nationwide recall for 101 lots of hydrocodone/acetaminophen 10 mg/500 mg. It is possible that a number of tablets from the affected lots may contain more than the labeled amount of hydrocodone and/or acetaminophen. The affected lots were distributed between Feb. 20, 2012 and Nov. 19, 2012 to wholesale distributors and retail pharmacies nationwide.

Products included in the recall have the following NDC numbers and lot numbers beginning with the letter “C”.

NDC NUMBER            BOTTLE COUNT

0603-3888-16                 30

0603-3888-20                 60

0603-3888-02                 90

0603-3888-21                 100

0603-3888-22                 120

0603-3888-26                 150

0603-3888-04                 180

0603-3888-28                 500

0603-3888-32                 1000

Consumers who have the affected lots should contact Qualitest at 1-800-444-4011. Healthcare professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program at www.fda.gov/MedWatch/report.htm.

The FDA is notifying health care professionals that the 32 mg, single IV dose of the anti-nausea drug Zofran (ondansetron hydrochloride) will no longer be marketed because of the potential for QT prolongation, which may result in potentially fatal cardiac arrhythmia. The 32 mg dose has been removed from the Zofran drug label. FDA is now working with the manufacturers of all ondansetron 32 mg injectable products (brand and generic) to voluntarily recall them from the market. These drugs are sold pre-mixed in solutions of either dextrose or sodium chloride in plastic containers.

A previous Drug Safety Communication, issued on June 29, 2012, communicated that the 32 mg single IV dose should be avoided due to the risk of QT prolongation, which can lead to torsades de pointes. Instead of a single 32 mg IV dose, the FDA recommends an IV regimen of 0.15 mg/kg (or a max dose of 16 mg) every 4 hours for three doses to prevent chemotherapy-induced nausea and vomiting. In addition, oral ondansetron remains effective for the prevention of chemotherapy-induced nausea and vomiting.

FDA anticipates that generic ondansetron 32 mg products will be removed from the market through early 2013. FDA does not anticipate that removal of the 32 mg IV dose of ondansetron currently sold as pre-mixed injections will contribute to a drug shortage of IV ondansetron, as the 32 mg dose makes up a very small percentage of the current market.

The management of constipation in hospice patients is notoriously challenging.

Constipation is the one side effect of opioids to which patients do not develop tolerance – which means it is nearly ubiquitous among patients taking opioids routinely. In addition to opioids, hospice patients take many other medications that cause constipation, including the many different medications with anticholinergic properties. Furthermore, hospice patients often have fluctuating dietary and fluid intake and gradually decreasing levels of physical activity and movement, which contribute to constipation.

There are 4 common pitfalls that we should be aware of in the management of constipation in the hospice population. These are:

1. Docusate alone

For the treatment of constipation, docusate is generally ineffective when used alone. The role for monotherapy with docusate is mainly for patients who are having regular bowel movements, but are producing dry, hard stool that is causing discomfort or straining. In hospice, we normally encounter patients who are NOT producing regular bowel movements, especially in the setting of opioid-induced constipation, where the source of the constipation is slowed gastrointestinal motility. When patients are not producing regular bowel movements (regardless of the consistency of the stool), a stool softener alone is insufficient. The popular phrase is that with a stool softener alone you have “all mush and no push”. Docusate can be used, and should be used if the consistency of the stool is hard and dry, but it should be combined with a stimulant laxative (such as senna or bisacodyl) or an osmotic laxative (such as Miralax or milk of magnesia) in order to help the GI contents move along.

2. Magnesium-based laxatives in renal impairment

Many of our patients have impaired renal function, and for these patients, magnesium-based laxatives (such as milk of magnesia) should be avoided as they can lead to electrolyte imbalances. The problem stems from the fact that up to 20% of the magnesium in magnesium salts may be absorbed systemically. Impaired kidneys do not eliminate all that extra magnesium effectively, and hypermagnesemia can result. As an alternative, use polyethylene glycol (Miralax) in patients with renal impairment, which has the same mechanism of action (osmotic laxative) but does not carry the same risk of electrolyte imbalance.

3. Bulk-forming laxatives in patients taking routine opioids

Bulk-forming laxatives, such as psyllium (Metamucil) and methylcellulose (Citrucel) can actually WORSEN constipation when patients are taking opioids. This is because, in the setting of the impaired GI motility that is induced by opioids, bulk-forming laxatives are not adequately propelled through the GI tract. The colon stretches to accommodate the bulk, but does not respond with adequate propulsive action due to the opioid effects. The result is painful, colicky GI symptoms, and potentially complete GI obstruction. For this reason, bulk-forming laxatives should be avoided in patients taking opioids.

4. Overlapping mechanisms of action

Because constipation is so common, and so difficult to treat, we often end up trying to attack it by adding on one laxative after another, using everything in our armamentarium in an attempt to resolve the issue. This often results in therapeutic duplication, which is not only ineffective, but is also costly and increases the risk of side effects. When managing constipation, it is important to keep in mind the underlying mechanism of action of each laxative, and to choose just one medication from each group when combining multiple therapies. Use this chart to help:

Bulk-Formers (hold water in stool to increase bulk-
stimulating peristalsis)

Psyllium (Metamucil)

Methylcellulose (Citrucel)

Calcium polycarbophil (FiberCon)

Stool softeners (facilitate admixture of fat and water to soften stool)

Docusate (Colace)

Stimulant/irritant laxatives (direct stimulant action on intestinal mucosa or nerve plexus)

Senna

Bisacodyl (Dulcolax)

Cascara sagrada

Osmotic laxatives (attract/retain water in intestinal lumen, increasing intraluminal pressure)

Magnesium hydroxide (milk of magnesia), magnesium citrate)
Sodium phosphate (Fleet)
Polyethylene glycol (Miralax)
Lactulose
Sorbitol

Lubricant/emollient laxatives (impairs colonic absorption of fecal water; softens stool)

Glycerin (Fleet)

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Extreme agitation, aggressiveness, and psychosis are common among patients with Alzheimer’s disease, especially in end-stage disease when we, as hospice care providers, typically encounter patients. These symptoms cause distress to everyone involved, including the patients themselves, caregivers, and hospice staff, and are associated with more rapid cognitive decline and increased health care costs. Antipsychotics are often prescribed, despite being associated with only low to moderate efficacy and findings of increased mortality (1.6 to 1.7 times that of placebo) which prompted the addition of a black box warning regarding use of these medications in elderly patients with dementia-related psychosis.

Even if antipsychotic drugs are effective, they are often discontinued because of concern about adverse effects and because of federal regulations that urge discontinuation after 3-6 months of treatment. Among patients with Alzheimer's disease who have had a response to antipsychotic medication for psychosis or agitation–aggression, the risk of a recurrence of symptoms after discontinuation of the medication has not been established. A study published in the New England Journal of Medicine questions the wisdom of arbitrarily or abruptly stopping antipsychotic therapy in patients with Alzheimer’s disease.

In the multicenter Antipsychotic Discontinuation in Alzheimer's Disease (ADAD) trial, Alzheimer’s disease patients with psychosis or agitation–aggression initially received open-label risperidone treatment. According to the authors, this therapy was chosen because of studies showing the efficacy of risperidone in large samples and the absence of severe side effects at low doses. Patients who had a response to this therapy were then randomly assigned to continued risperidone therapy or to discontinuation of risperidone and a switch to placebo at specified time points; the risk of relapse was then compared among the groups.

Study Design

In phase A of the study, the investigators administered open-label, flexible-dose risperidone for 16 weeks (180 patients). At 16 weeks, patients who had not had a response to risperidone therapy exited the study. Patients who had a response (110 patients) entered phase B of the study and were randomly assigned, in a double-blind fashion, to one of three regimens: continued risperidone therapy for 32 weeks (group 1), risperidone therapy for 16 weeks followed by placebo for 16 weeks (group 2), or placebo for 32 weeks (group 3).
Patients were eligible for participation in the study if they were outpatients or residents of assisted-living facilities or nursing homes, were 50 to 95 years of age, and met the DSM-IV criteria for dementia and the criteria for probable Alzheimer's disease. In addition, eligible patients had a score on the Neuropsychiatric Inventory (NPI) of 4 or more at both screening and baseline on the delusions or hallucinations subscale (psychosis score) or the agitation–aggression subscale (agitation score) a score of 2 to 26 on the Mini–Mental State Examination (MMSE).

Results

During the first 16-week period of phase B, the group that was randomly assigned to receive placebo (group 3), as compared with the groups that continued to receive risperidone (groups 1 and 2), had an increased risk of relapse (hazard ratio 1.94; P=0.02). During the second 16-week period of phase B, the group that discontinued risperidone at 16 weeks and was switched to placebo (group 2), as compared with the group that continued to receive risperidone (group 1), had an increased risk of relapse (hazard ratio 4.88; P=0.02).
In terms of adverse effects, there were no differences between groups. A total of 11 serious adverse events occurred during phase B, with no significant between-group differences during either 16-week period. Three deaths occurred during phase A in the total cohort of 180 patients, and 3 deaths (2 in patients receiving risperidone and 1 in a patient receiving placebo) occurred during phase B in the cohort of 110 patients who had undergone randomization, with no pattern observed with respect to the cause of death.

Discussion

Among patients with Alzheimer's disease whose symptoms of psychosis or agitation had decreased while they were receiving risperidone, the time to a relapse was shorter among those who discontinued risperidone and received placebo during the first 16 weeks after randomization than among those who continued to receive risperidone, and the risk of relapse was nearly double (60% vs. 33%). These findings were corroborated in the second 16-week period after randomization. Therefore, among patients who had a sustained response to risperidone for 4 to 8 months, subsequent discontinuation was associated with an increased risk of relapse for at least another 4 months.
However, the authors were careful to point out that although discontinuation of risperidone resulted in an increased risk of relapse, risperidone was not highly effective in achieving and maintaining a reduction in symptoms of psychosis and agitation in patients with Alzheimer's disease. Among patients who had had a response in phase A and continued to receive risperidone in phase B, a large proportion had a relapse or dropped out. The rates of discontinuation of risperidone treatment for any reason were 38% in the total cohort during phase A, 68% in group 1 during the 32 weeks of phase B, and 29% in group 2 during the 16 weeks in phase B in which they received risperidone.
According to the authors, these findings suggest that patients with psychosis or agitation–aggression who have a sustained response to antipsychotic treatment for 4 to 8 months have a significantly increased risk of relapse for at least 4 months after discontinuation, and this finding should be weighed against the risk of adverse effects with continued antipsychotic treatment. If an antipsychotic is discontinued for reasons other than a severe adverse reaction, it should be gradually tapered over weeks, with close monitoring for relapse.

Reference
Devanand DP, Mintzer J, Schultz SK, et al. Relapse risk after discontinuation of risperidone in Alzheimer’s Disease. N Engl J Med 2012; 367: 1497-1507.

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