Delirium is an acute state of mental confusion resulting from diffuse brain dysfunction. Other terms that are commonly used to refer to delirum include: acute confusional state, metabolic encephalopathy, and severe agitation. It has been estimated that delirium occurs in 30-80% of terminally ill patients. Delirium is a major cause for distress among patients, family members, and healthcare providers. The approach to management of delirium in the terminally ill hospice patient should be targeted at both relief of symptoms and correction of the cause. In advance of our next blog article discussing the role of the various medications that are used to manage delirium in hospice & palliative care patients, an understanding of the clinical presentation and possible causes is appropriate.

The Clinical Presentation of delirium consists of a collection of core features characterized by a profound disturbance of consciousness and cognition, psychomotor abnormalities, as well as changes in awareness and emotional state. Symptoms may include hallucinations, delusions, confusion, agitation, tremor, myoclonus, insomnia, or somnolence and withdrawal. Altered sensorium may be visual, auditory, or tactile. The onset of symptoms is usually within hours or days and the severity will fluctuate. There are three clinical subtypes of delirium; hyperactive, hypoactive, and mixed. Hyperactive delirium is the easiest to recognize with symptoms of confusion with or without agitation, hallucinations, delusions, myoclonus. Hypoactive delirium presents with confusion and somnolence with or without withdrawal. Mixed delirium is a combination of the other two subtypes and the features may alternate.

The etiology of delirium is sometimes multifactorial which can make it difficult to identify a cause. Since many cases of delirium are reversible by identifying and treating the underlying cause, the clinician should not be deterred from  looking for one (refer to Table Below). Careful assessment of the patient will provide useful information that may be used to help guide the treatment strategy. Questioning the patient specifically about hallucinations and delusional thoughts may be necessary since patients will not often volunteer this information. Assessment tools such as the Mini-mental Status Exam (MMSE) or a clock-drawing exercise may be helpful in identification of early stages of delirium. Patients with suspected delirium should be assessed for clinical signs of drug toxicity, dehydration, or infection. Other diagnostic tests such as O2 saturation, CBC, urinalysis, electrolytes, or calcium serum levels may be helpful to establish or rule-out a cause in selected patients.

Rule out current medications as the underlying cause of delirium. One of the first steps the clinician should take is to determine if one or more prescribed medications may be causing the delirium. In some cases a change in medication or reduction in dosage may result in significant improvement. Our next article will discuss this in more detail, as well as appropriate medication selection for the symptomatic treatment of delirium in the hospice patient.

Delirium is common in palliative care patients and clinicians should always be alert to the signs and symptoms. All Outcome Resources Clients have access to consult with experienced clinical pharmacists on an unlimited basis, so do not hesitate to call for advice or guidance regarding delirium in general or in regards to a specific patient. Be sure to check our next Blog Article for more information on Delirium and medications.

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We have recently received a number of questions about the risks of tardive dyskinesia (TD) associated with the use of Metoclopramide (Reglan). Increased interest in this subject follows a recent FDA safety warning letter on Metoclopramide that was issued this past November. Tardive dyskinesia is disorder characterized by abnormal involuntary movements of the face, tongue, and/or trunk and extremities. Treatment with Metoclopramide can cause TD. TD evolves slowly. It often starts with only mild and subtle movements of the tongue that can gradually progress, over a period of months, into much more pronounced movement disorders involving the face and body.   Metoclopramide therapy should be stopped in any patient that develops signs or symptoms of TD. In many patients the signs and symptoms will lessen or resolve completely with discontinuation of the drug, however, in some patients the condition may be irreversible.  

The risk of developing TD with metoclopramide increases with longer durations of treatment and the total cumulative dose. A total course of therapy with Metoclopramide should not exceed 12 weeks since the risk for developing TD seems to increase significantly with exposure periods that are longer than that. It is rare for TD to develop in patients using Metoclopramide for periods less than 3 months. The concomitant use of antipsychotic drugs (haloperidol, chlorpromazine, risperidone etc.) also adds to the risk for TD. The risk for a hospice patient developing TD secondary to metoclopramide or antipsychotic drug exposure is generally low since the course of therapy is usually less than 12 weeks.  

The FDA has announced a withdrawal of all Propoxyphene products from the market due to serious risks of cardiac toxicity. This includes Darvon, Darvocet, and all generic versions. Health professionals have been instructed to cease prescribing and dispensing of these products. In addition the FDA has recommended that patients with prescriptions for propoxyphene products be contacted and asked to stop taking the medication. Outcome Resources clients may contact our clinical department and speak to a clinical pharmacist for appropriate guidance on alternative analgesic therapy.

Propoxyphene: Withdrawal - Risk of Cardiac Toxicity
Sold as Darvon, Darvocet, and generics

AUDIENCE: Pain management, Pharmacy

ISSUE: FDA notified healthcare professionals that Xanodyne Pharmaceuticals has agreed to withdraw propoxyphene, an opioid pain reliever used to treat mild to moderate pain, from the U.S. market at the request of the FDA, due to new data showing that the drug can cause serious toxicity to the heart, even when used at therapeutic doses. FDA concluded that the safety risks of propoxyphene outweigh its benefits for pain relief at recommended doses. FDA requested that the generic manufacturers of propoxyphene-containing products remove their products as well.

BACKGROUND: FDA’s recommendation is based on all available data including data from a new study that evaluated the effects that increasing doses of propoxyphene have on the heart (see Data Summary in Drug Safety Communication). The results of the new study showed that when propoxyphene was taken at therapeutic doses, there were significant changes to the electrical activity of the heart: prolonged PR interval, widened QRS complex and prolonged QT interval. These changes can increase the risk for serious abnormal heart rhythms.

RECOMMENDATION: FDA recommends that healthcare professionals stop prescribing and dispensing propoxyphene-containing products to patients, contact patients currently taking propoxyphene-containing products and ask them to discontinue the drug, inform patients of the risks associated with propoxyphene, and discuss alternative pain management strategies. Patients were advised to dispose of unused propoxyphene in household trash by following the recommendations outlined in the Federal Drug Disposal Guidelines.

Read the MedWatch safety alert, including links to the Drug Safety Communication, News Release, and supporting documents, at:

http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm234389.htm

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As flu season begins questions arise as to whether or not hospice patients should be vaccinated. There is no clear recommendation that applies to all hospice patients. Hospice patients are not uniform and have varying states of health, life expectancy, and variable risks of contracting or transmitting the flu depending upon where they reside and the condition of their immune system. The decision to vaccinate a hospice patient should be approached individually on a case by case basis. A hospice patient with a short life expectancy and minimal exposure to others probably should not be vaccinated, conversely a hospice patient with a reasonable current quality of life, functionality, and a life expectancy measured in months may benefit from a vaccination.   

The CDC does not provide any specific guidance pertaining to hospice patients and the flu vaccine. They recommend vaccination for the following:

• Children 6 months to 18 years
• Adults over 50
• Anyone living in a long-term care facility
• Anyone with a weakened immune system
• People who have frequent contact with the public
• Pregnant women
• Anyone with a chronic medical condition
• Caregivers, health care workers, family members, and friends of individuals considered high risk

Residents in long-term care facilities, regardless of whether they are on hospice or not, are almost always vaccinated. This is done not only as a measure to protect the individual from influenza infection, but also to prevent transmission to other residents. The decision to vaccinate hospice patients residing in long-term care facilities may have more to do with reducing transmission throughout the facility, than protecting the individual from infection. Many hospice patients have significantly weakened immune systems, however, they may still be able to mount some response to the vaccination that would confer benefits against disease. The inactivated virus vaccine for injection (flu shot) is recommended for patients with a weakened immune system. The nasal spray (FluMist) is a live weakened virus that is not generally recommended for hospice patients due to increased risk for this product to induce actual infection in the immuno-compromised patient. 

Flu vaccine is definitely NOT recommended for the following people:

• Anyone allergic to eggs
• Anyone who has a history of GBS (Guillain-Barre Syndrome)
• Anyone who has had an adverse reaction to the vaccine
• Infants under 6 months old

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OCTOBER 2010

Hospices nationwide are reporting a significant shortage of Oxycodone 20mg/ml oral concentrate.  Only one of the four companies that manufacture Oxycodone 20mg/ml oral concentrate is currently producing and shipping this product to pharmacies and wholesalers.  The product supply has been intermittent and frequently on back order.  This company is Lannett.  Lannett has indicated that its production has been limited intermittently to comply with Drug Enforcement Administration (DEA) restrictions on supply quotas of raw materials.  It is shipping product at 2 to 3 week intervals as it becomes available.  The other three manufacturers are currently not supplying any Oxycodone 20mg/ml oral concentrate.  Mallinckrodt has discontinued its product.  Glenmark and Xanodyne products are both on “long-term” back order and the companies cannot estimate a release date.  This leaves only one manufacturer of Oxycodone 20mg/ml at the current time and they are somewhat ham-strung by quotas established by DEA on the amount of raw material that can be acquired per year.  At the current time, it does not appear that DEA plans to take any action to relax these quota restrictions.

One alternative for Oxycodone 20mg/ml  is the use of Oxycodone immediate release tablets and capsules which are available in 5mg, 15mg, and 30mg strengths.  We are just coming off of a shortage of these Oxycodone oral solid dosage-form products that was recently resolved at the end of August.   Another alternative would be morphine 20mg/ml oral concentrate.  A recent shortage of this product was also just resolved at the beginning of September, so we may expect supply issues might surface again because of increased use due the current Oxycodone oral concentrate shortage.   Outcome Resources clinical pharmacists are available to assist our hospice clients with opioid conversion calculations and advice on therapeutic alternatives. 

Reasons for the shortages in the various opioids that we have experienced during the past year are directly related to FDA’s action last year warning suppliers of unapproved products to submit their product to FDA for approval or discontinue production to avoid enforcement actions. See our Blog Article "Hospices, Opioids, and the FDA REMS" for more background on this issue. Most of the immediate release opioid oral and liquid dosage forms (morphine, oxycodone, and hydromorphone) have been in the marketplace for many decades but were not FDA approved products.  Some suppliers have chosen to submit to the FDA approval process, however, many have ceased production.  DEA quota restrictions on raw materials for individual manufacturers of opioid drugs apparently have not been relaxed enough to compensate for the decrease in the number of manufacturers still producing these products.

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Old drug, new dosage form: Exalgo

The strong opioid, hydromorphone, is once again available as an extended release tablet providing long-acting opioid effects. The FDA recently approved Exalgo which is a once-a-day long-acting tablet providing hydromorphone in 8mg, 12mg, and 16mg strengths. It is indicated for the management of moderate to severe pain in opioid tolerant patients (such as hospice patients) who require continuous, around the clock opioid analgesia for an extended period of time. It is not intended for PRN use. Short-acting hydromorphone (Dilaudid) tablets, oral solution, or suppositories may be used on a PRN basis.

Patients must be able to swallow whole tablets since Exalgo cannot be crushed, chewed, or dissolved. It may be taken with or without food. Another long-acting hydromorphone product, Pallidone, was available for a brief time in the U.S. several years ago, but was pulled from the market in 2005 due to fatalities encountered when the drug was taken with alcohol. It was determined that alcohol hampered the extended release mechanism of Pallidone, resulting in dose dumping and subsequent toxic blood levels of the drug. An in vivo study examined the effect of alcohol on the bioavailability of a single dose of 16mg Exalgo in healthy, fasted or fed volunteers. The results showed that changes in the hydromorphone blood levels (mean AUC0.oc) were not statistically significant after co-administration with 40% alcohol. Recent advances in extended release tablet technology apparently have conferred better protection against alcohol interference with the drug release, however, patients are still advised to avoid alcohol while taking this drug.

The price will be in the range of $15.00 per tablet for the 12mg strength.

For More Information: http://exalgo.com/

Photo Credit

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Megestrol acetate (MA) is a progestin that has been used
as an appetite stimulant and weight loss remedy in variety of
clinical conditions. Many are more familiar with the highly
recognizable brand-name, Megace. Although the weight
loss indication for MA is only approved for treatment of
anorexia and cachexia in patients with AIDS, it has been widely
used for the treatment of weight loss in cancer patients, frail
nursing home residents, dementia patients, and frail elderly
patients in the community with non-cancerous serious
chronic health conditions.

Studies in patients with cancer and AIDS have shown MA to be an effective appetite stimulant that is associated with weight gain (1-4). Alternatively, studies in geriatric patients including mostly nursing home residents have failed to demonstrate similar consistent benefits (1,2,5,6,13). Reports on the clinical significance of MA induced weight gain vary considerably. Some clinicians believe that the weight gains that have been achieved with MA are not related to reversing the catabolic state of advanced disease, but reflect only increased body fat or water retention (12).

There has been widespread use of MA for treatment of weight loss in elderly nursing home residents in the past several years. This has been fueled by intense pressure on skilled nursing facilities to prevent and aggressively treat “unintended weight loss”. This pressure on the nursing homes is the result of scrutiny from both State and Federal regulatory agencies to monitor weight loss and potentially levy monetary penalties on facilities for deficiencies in this area. A dramatic increase in the utilization of MA for weight loss became very apparent starting in 2000 to 2001, coinciding with increased regulatory focus on weight loss in the nursing home industry.

The high cost of this drug coupled with the high volume of use in non-approved applications stimulated numerous clinical reviews and research reports regarding its effectiveness for treatment of weight loss and its adverse effects potential during the past few years. The majority of these studies have been conducted in geriatric patients. To date, the reports in the medical literature indicate only modest benefits at best and a potential for serious adverse events (6).

A retrospective study by Bodenner, et al. in The American Journal of Geriatric Pharmacology (June 2007), concluded that megestrol acetate was associated with an increase in death among elderly nursing home residents being treated for weight loss. A statistical analysis by the authors demonstrated that the survival time of those patients receiving MA was on average 7.3 months less than case matched cohorts who did not receive MA and this was
determined to be highly significant. Furthermore their results found no significant increase in weight for their study population of 709 nursing home residents.

Deep venous thrombosis (DVT) is another potentially devastating adverse effect that has been associated with the use of MA for treatment of weight loss in elderly patients. In a 2003 article by Kropsky, et al, reported a 4.9% incidence of DVT in elderly nursing home residents receiving MA for treatment of weight loss (7). The average age of the patients was 87 and the average duration of therapy was 183 days. DVT has been identified as a significant risk of MA therapy in geriatric patients by other researchers as early as 2000 in the Journal of the American Medical Directors Association and again in a 2003 review of cases by Marshall, et al (8,9).

Megestrol induced hormonal influences have also been reported including: adrenal suppression; and suppression of testosterone levels in men resulting in loss of lean muscle mass (10,11). Depressed testosterone levels may be one reason MA does not produce weight gains in men as well as it does in women (10, 11, 13). Doses used for the treatment of weight loss are usually in the range to 400mg to 800mg per day in single or divided doses. Doses above 800mg per day have not been shown to have any additional benefit. Reports on MA efficacy in the treatment of weight loss have yielded conflicting results with study participants both gaining or losing weight on MA therapy. A 2002 study of 152 elderly California nursing home residents found that only 28% of patients achieved a 5% weight gain after an average duration of treatment of nearly 4 months with MA. (13). A retrospective study of elderly patients at a Florida VA Medical Center in 2005 demonstrated mixed results. In this study of 57 patients treated with MA; 40% of the patients gained weight, 49% lost weight, and 11% had no change over a 12 month period.

Identification of particular patient characteristics which could predict a positive response to MA would be beneficial, however, more research is needed to shed some light on this. There is sufficient evidence to formulate some guidelines about which patients are at high-risk for potentially serious MA adverse effects. MA therapy should be considered very cautiously, if at
all in the following types of patients due to serious risks outweighing potential benefits:

• History of thromboembolic disease
• Bed-bound, or otherwise immobile
• Heart failure
• Elderly nursing home residents

Alternative pharmacologic interventions for appetite stimulation and treatment of weight loss have included various agents from different pharmacologic classes: the steroid dexamethasone (Decadron); the cannabinoid dronabinol (Marinol); the antidepressant mirtazapine (Remeron); and the antihistamine cyproheptadine (Periactin). None of these drugs have been proven to be more effective than megestrol acetate and all have potential side effects of varying significance, however, none have been associated with an increased risk of death in the elderly or increased risk of DVT.

Dexamethasone has been shown to be equally efficacious as MA when used as an appetite stimulant, however, it is associated with more potential for side effects. Dronabinol was not as effective as MA for appetite stimulation or weight gain and has been associated with adverse effects upon the central nervous system which may be especially problematic in the elderly. Mirtazapine has been shown to result in significant weight gains in patients treated for depression and may have the lowest side effect potential of all the drugs mentioned in this article. Cyproheptadine is a less potent appetite stimulant with the potential for sedation, delirium, and anticholinergic side effects which are especially problematic in the elderly.

In conclusion, MA has been shown to increase the appetite and induce weight gain in non-geriatric adult patients with cancer or AIDS. The weight gain may be due to increased fat production or water retention. At this time megestrol acetate should not be given to geriatric patients or patients with an underlying predisposition to thromboembolic events because the risks for serious adverse events do not outweigh the potential benefits of therapy.

References:
1. Farrar AIDS Patient Care 1999;13:149-51
2. Cochrane Database Syst Rev 2005;(2):CD004310
3. Karcic, etal J Nutr Health Aging 2002;6:191-200
4. Ottery, et al Semin Oncol 1998;25(2 Suppl 6):35-44
5. Yeh et al. J Amer Geriatr Soc 2000;48:485-92
6. Bodenner, et al. The American Journal of Geriatric Pharmacology 2007;5(2):137-146
7. Kropsky, eta al. Journal of the American Medical Directors Association 2003;4:255-256
8. Bolen, et al Jouranal of the American Medical Directors Association 2000;48:248-52
9. Marshall, LL The Consultant Pharmacist 2003;18:764-63
10. Goodman, Cagliero European Journal of Gynecology & Oncology 2000;21:1117-118
11. Morley, Thomas Annals of Long Term Care 2003:6s:1-11
12. Lambert, et al. J. Clin. Endocrinol. Metab. 2002;87:2100-2106
13. Joyner, et al. ASCP Annual Meeting 2002; Poster presentation

Photo Credit http://www.flickr.com/photos/eflon/4636267865/

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Dr. Jim Joyner, Pharm.D., Director of Clinical Operations for Outcome Resources, will be providing a clinical presentation at the upcoming 34th Annual Conference of The Carolinas Center for Hospice and End of Life Care on October 6^th in Myrtle Beach, South Carolina. The title of the presentation is “Medication Management of Delirium and Chronic Agitation in the Hospice Patient." This presentation will explore delirium in the hospice patient and the relationship to medication from both a treatment perspective and as a possible cause for the condition.

For more information and to register for the Conference, contact The Carolinas Center for Hospice & End of Life Care.

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A study published in this month’s issue of the New England Journal of Medicine demonstrated the value of early palliative care services in the treatment of patients with advanced lung cancer. A total of 151 patients recently diagnosed with metastatic non-small-cell lung cancer were randomized to either routine cancer care or routine cancer care plus palliative care. Patients assigned to early palliative care met with a member of the palliative care team, which consisted of board-certified palliative care physicians and advanced-practice nurses, within 3 weeks after enrollment and at least monthly thereafter until death. Additional visits with the palliative care service were scheduled at the discretion of the patient, oncologist, or palliative care provider.

General guidelines for the palliative care visits were adapted from the National Consensus Project for Quality Palliative Care and were included in the study protocol. Specific attention was paid to assessing physical and psychosocial symptoms, establishing goals of care, assisting with decision making regarding treatment, and coordinating care on the basis of the individual needs of the patient.

More than half (54%) of patients in the standard care group received aggressive end-of-life care (defined as chemotherapy within 14 days before death, no hospice care, or admission to hospice 3 days or less before death), compared to 33% in the palliative care group (p = 0.05). Despite receiving less aggressive end-of-life care, patients in the palliative care group had significantly longer survival than those in the standard care group (median survival: 11.6 vs. 8.9 months; p = 0.02). Furthermore, patients assigned to early palliative care had significantly higher scores on quality-of-life measures than did those assigned to standard care, and depression was less than half as common in the palliative care group.

While costs of care were not specifically addressed, the study did show that early palliative care for patients with advanced cancer can alter the use of health care services, including care at the end of life. In addition to receiving less aggressive end-of-life care, significantly more patients in the early palliative care had resuscitation preferences documented in their medical record. These results indicate that timely introduction of palliative care may serve to mitigate unnecessary and burdensome personal and societal costs. Future research will be needed to investigate whether palliative care can indeed reduce healthcare expenditures, and whether the early introduction of palliative care can extend survival in other types of cancer and life-limiting illnesses.

Temel JS, Greer JA, Muzikansky A, Gallagher ER, Admane S, Jackson VA, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med 2010;363:733-742. The full text is available online at http://www.nejm.org/doi/full/10.1056/NEJMoa1000678.

Photo Credit: erika_herzog

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Our hospice partners have been telling us about difficulty in obtaining oxycodone oral solution and dramatically increasing cost when available.  Several of the generic manufacturers for oxycodone solution have discontinued production recently. This is in response to FDA action starting last year to remove “unapproved drugs” from the market-place. For a variety of mostly historical reasons, some drugs, mostly older products, continue to be marketed in the United States without required FDA approval.  The FDA has expressed their concern that the lack of evidence demonstrating that these unapproved drugs are safe and effective is a significant public health concern. Many of these products have been in widespread use in the United States for decades with proven track records of efficacy and safety, however, the FDA considers all of the unapproved products to be marketed illegally and has taken action to force the manufacturers to discontinue them or apply for FDA approval.

FDA sent warning letters to several suppliers of unapproved narcotic medications (including morphine, oxycodone, and hydromorphone) last year.  These companies were given a specified time-frame to stop manufacturing new product, until they went through a formal process for approval of their products with FDA.  Wholesale distributors were instructed to stop shipping “unapproved” product.  The following manufacturers: Mallinckrodt, Lannett, and Glenmark, have stopped production of all oxycodone solutions in accordance with the unapproved drug ruling by FDA.   As far as we can tell that leaves only one manufacturer (Xanodyne Pharmaceuticals) that has an “approved” oxycodone solution product on the market. They market their product as the brand name Roxicodone and it is significantly more expensive than the discontinued “unapproved products”.    

More detailed information can be found on the FDA website at www.fda.gov.

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