The Hospice Clinician Blog

Hospice Medication Update: Oxycodone Oral Solution Availability

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.

High-Dose Donepezil Approved for Moderate to Severe Alzheimer's Disease

The FDA has approved donepezil (Aricept) 23 mg once daily for the treatment of patients with moderate to severe Alzheimer’s disease who have been using 10 mg daily for at least 3 months. This approval comes at an opportune moment for the manufacturers of Aricept (Eisai Inc. and Pfizer Inc.), as the 5 mg and 10 mg strengths of Aricept go off patent in November of this year. The new 23 mg strength is expected to be available this month and the manufacturers will have 3 years of market exclusivity.

The FDA’s approval was based on the results of a clinical trial (Ref.1) comparing the 23 mg and 10 mg strengths. The randomized, double-blind, multicenter study enrolled 1467 patients age 45-90 with probable AD and a Mini Mental Status Exam score of 0 – 20 (indicating moderate to severe cognitive impairment) who had been receiving donepezil 10 mg daily for at least 12 weeks. Patients were randomized to 24 weeks of treatment with either high-dose donepezil (23 mg daily) or continued treatment with standard-dose donepezil (10 mg daily).

The two primary effectiveness measures were cognition and global functioning. Cognition was measured using the Severe Impairment Battery (SIB), a validated clinical instrument used to rate 9 aspects of cognition, including social interaction skills, memory, orientation, language, attention, praxis, visuospatial ability, construction and orientation to name. Scores on the SIB range from 0 to 100, where lower scores indicate greater impairment. There was a statistically significant difference between the two groups in the change from baseline SIB score: +2.6 in the 23 mg group vs. +0.4 in the 10 mg group (P = 0.0001). However, the study did not address the clinical significance of these changes.

Global functioning, the second primary outcome measure, was assessed using the Clinician’s Interview-Based Impression of Change Plus Caregiver Input (the CIBIC-Plus). The CIBIC-Plus examines four major areas of patient function: general, cognitive, behavioral and activities of daily living. It combines the assessment of a skilled clinician based upon his/her observations of the patient with information supplied by a caregiver familiar with the patient’s behavior. The CIBIC-plus is scored as a seven-point categorical rating, ranging from a score of 1, indicating “markedly improved,” to a score of 4, indicating “no change,” to a score of 7, indicating “markedly worse.” The between-treatment difference in CIBIC-Plus score was not statistically significant (4.23 vs. 4.29, P = 0.1789).

Study discontinuation due to medication adverse effects were far more common in the high-dose donepezil group (18.6% vs. 7.9%). The most common adverse effects leading to study discontinuation, in order of prevalence, were vomiting, diarrhea, nausea and dizziness. The following table compares the percentage of patients in each group experiencing adverse effects:

ADVERSE EFFECT	23 mg/day (% of patients)	10 mg/day (% of patients)
Nausea	12	3
Vomiting	9	3
Diarrhea	8	5
Weight Loss	5	3
Anorexia	5	2
Dizziness	5	3

Photo Credit

Pediatric Palliative Symptom Management

 

This final article in our pediatric series will focus on the management of some of the most common non-pain symptoms encountered in pediatric palliative care. Research is notoriously lacking in this area, so much of what is done in pediatric palliative care is derived from the general pediatric population, from adult palliative care, or simply from clinical experience.

Specific symptom complexes that are addressed include: anxiety & depression, agitation, insomnia, anorexia-cachexia, nausea-vomiting, constipation, and dyspnea. Specific medication strategies will be presented for managing each of these troubling symptoms in pediatric hospice patients. 

Download the complete copy of Part 3 of our Pediatric Palliative Care Series: Pediatric Palliative Symptom Management. This article includes common non-pain symptoms such as depression, agitation, and dyspnea.

New Hospice Medication Update: Butrans

The FDA has recently approved Butrans, a new transdermal opioid patch. The opioid in Butrans, buprenorphine, has been available in the U.S . for several years in the form of Suboxone and Subutex sublingual tablets. The buprenorphine patch has been used for the management of chronic pain in Europe for years under the brand name of Norspan, but it is new to the U.S. market.

The transdermal patch is available in three strengths, 5mcg/hr, 10mcghr, and 20mcg/hr and provides continuous release of the medication for seven days. It is classified as a DEA schedule III controlled substance, similar to moderate-strength opioids such as Vicodin or Norco. Butrans is indicated for chronic severe non-malignant pain when lower doses of strong opioids are indicated. The highest strength Butrans patch (20mcg/hr) is approximately equivalent to 50mg of oral morphine per day. Doses greater than 20mcg/hr are not recommended due to the potential for adverse cardiac effects (QTc prolongation).

Buprenorphine is a partial mu opioid agonist. This means that, even though buprenorphine is an opioid that can produce typical opioid agonist effects (analgesia) and side effects (euphoria and respiratory depression) in hospice patients, its maximal effects are less than those of full agonists such as morphine and methadone. The agonist effects of buprenorphine increase linearly with increasing doses of the drug until at moderate doses they reach a plateau and no longer continue to increase with further increases in dose—the “ceiling effect.” For this reason, buprenorphine is believed to have a lower risk of abuse, addiction, and side effects compared to full opioid agonists. In high doses, buprenorphine may actually trigger some opioid withdrawal symptoms in persons who have been receiving other opioids and have developed some physical dependence, however, this effect may not be clinically significant at the lower doses employed with the transdermal patch.

The Butrans patch is not indicated for management of short-term post-operative pain, but may be beneficial for management of chronic severe pain in hospice patients who are vomiting or have swallowing difficulties. The eventual role of the Butrans patch in chronic pain management is still being established. Cost for the new drug was not available at the time of this post, however, as with all new branded medications, we can expect a hefty price-tag.

http://www.purduepharma.com/PI/prescription/ButransPI.pdf 

FDA Approves Generic Fentora and Generic Effexor XR

The FDA has approved a generic version of Fentora (fentanyl) buccal tablets, which will be manufactured by Watson Pharmaceuticals. Fentanyl buccal tablets will be available in 100, 200, 300, 400, 600 and 800 mcg strengths. The tablets are designed to be placed between the upper gum and cheek, near the back teeth. Medication is absorbed transmucosally while the tablet dissolves, which takes 15 to 25 minutes.

The FDA has also approved the first generic version of Effexor XR capsules (venlafaxine hydrochloride) to treat major depressive disorder. Venlafaxine extended-release capsules in 37.5, 75 and 150 mg strengths have been approved to be manufactured by TEVA Pharmaceuticals.

 

Teva Effexor XR 37.5 mg

Series on Pediatric Hospice & Palliative Care Patients

The July issue of The Clinician, our quarterly clinical newsletter, will feature the final article in our three-part series on pediatric palliative care. In the upcoming article, Julia Harder, PharmD, will discuss the management of some of the most common non-pain symptoms encountered in pediatric palliative care. Specific symptom complexes that will be addressed include: anxiety & depression, agitation, insomnia, anorexia-cachexia, nausea-vomiting, constipation, and dyspnea. Specific medication strategies will be presented for managing each of these troubling symptoms in pediatric hospice patients. All clients of Outcome Resources receive complimentary copies of The Clinician each quarter. Previous issues of The Clinician can be obtained by contacting Jim Joyner, PharmD, at jjoyner@outcomeresources.com Be sure to check the Blog for the upcoming Part 3 in the series.

Dowload Part 1 of Pediatric Palliative Care Series: Current Concepts in Drug Therapy

Dowload Part 2 of Pediatric Palliative Care Series: Pain Management

Pain Management in Hospice Patients: Buprenorphine (Subutex, Suboxone)

Buprenorphine (Subutex, Suboxone) tablets are now being used to treat severe pain, not just opioid addiction. Since 2002 Buprenorphine has been widely used to treat opioid addiction by preventing the symptoms of opioid withdrawal.

More recently it is being used to treat severe pain, although the tablets only have an FDA approved indication for addiction treatment at this time. Subutex contains buprenorphine alone, and Suboxone contains buprenorphine and naloxone. The naloxone is there to prevent opioid effects if patients try to inject it.

Buprenorphine is a strong opioid with analgesic properties similar to morphine, methadone, oxycodone, hydromorphone, and fentanyl. It has an advantage over these traditional full agonist opioids in that there is less risk for psychological or physical dependence and it results in fewer withdrawal symptoms when it is stopped. There is also less risk for psychotomimetic effects (delusions, hallucinations). The FDA has recognized the lower risk factor for abuse with Buprenorphine and has assigned it a Schedule III controlled drug classification as opposed to the more stringent Schedule II classification seen with other strong opioids.

Some subtle differences in Buprenorphine pharmacology may account for the decreased risks seen when comparing to more traditional strong opioids. Drugs such as Morphine, Methadone, Fentanyl and others are full-agonists at the mu opioid receptor which means they bind tightly to the drug receptor sites in the body. Withdrawal of therapy for drugs with complete and tight binding at their receptor sites is associated with significant withdrawal symptoms. Buprenorphine is a partial-agonist the mu opioid receptor and is actually an antagonist at the kappa opioid receptor. It essentially is loosely bound to the mu receptor. This partial agonist property and the mixed agonist-antagonist activity may result in a decreased potential for abuse, withdrawal, and psychotomimetic effects in patients using Buprenorphine.

Subutex and Suboxone are available in tablets for sublingual administration. They are not effective by the oral route. Strengths are 2mg and 8mg tablets. The dosage range is 2 to 16mg three to four times a day for pain (instead of once a day for addiction treatment). Unlike traditional full-agonist strong opioids (morphine, methadone, fentanyl, oxycodone, and hydromorphone), Buprenorphine seems to have a "ceiling dose" after which increased doses produce no increase in opioid agonist effects.

This was demonstrated in clinical trials at doses of 16 to 32mg. The onset of action of the tablets is about 15 minutes, with peak activity at 60 minutes and a duration of analgesic activity of 6 to 8 hours. There is also an injectable solution available for intramuscular or intravenous administration. This injectable solution carries an FDA approved indication for the treatment of severe pain. The IM/IV dosage is 0.3mg at six hour intervals as necessary. IV doses should be administered slowly over 2 minutes.

The cost of a 15 day supply of a mid-range dose of Subutex (4mg three times per day) is in the range of $360.00. This makes Subutex one of the highest, if not the highest cost opioid drug on the market. The role of Buprenorphine in the management of chronic pain is still being defined. It has some significant advantages including: a lower potential for psychotomimetic side effects, lower abuse potential, reduced potential for severe withdrawal reactions, and no requirement for a schedule II triplicate prescription. Due to the fact that its duration of action is only 6 to 8 hours, Burprenorphine does not have the characteristics of a desirable long acting opioid that one would use for maintenance therapy of severe chronic pain. The greatest negative is the extremely high cost which makes it an unrealistic option for most hospice organizations at this time. The evolving role for Buprenorphine in the management of pain may be one that is targeted at acute severe pain in the hospital and clinic setting.

Proton Pump Inhibitors and Hospice Patients

In my original article, three years ago, I described the patterns of indiscriminate overuse of the proton pump inhibitor drugs (PPI medications) and cited some medical literature reports of increased risk of hip fracture and increased risk of infection related to their long-term use. At that time, I cautioned against the use of the PPI drugs for periods longer than 3 months for most patients and advocated for withdrawal of PPI therapy in any patient on long-term therapy that had not exhibited recent symptoms and had no established indication for continued use.   Now, the issue of PPI potential adverse effects is in the news again.

Fast-forward three years: Last month, the FDA issued a formal warning regarding the increased risk of fractures of the hip, wrist, and spine with long-term use of the PPI drugs (based on review of epidemiological studies). The majority of the studies evaluated individuals 50 years of age or older and the increased risk of fracture was primarily observed in this age group. The greatest increased risk for fractures in these studies involved people who had been taking prescription proton pump inhibitors for at least one year. FDA recommends healthcare professionals should consider whether a lower dose or shorter duration of PPI therapy would adequately treat the patient's condition.

An article in last year's American Journal of Gastroenterology (March 2009) amplified upon additional concerns associated with long-term PPI usage. The researchers from the University of Michigan, Department of Family Medicine, strongly advocated for clinicians to use the lowest dosage of PPI drug necessary for the shortest period of time to achieve the desired therapeutic goals. Concerns cited for their recommendation included the following risks; potential for Clostridium difficile-associated diarrhea, community acquired pneumonia, hip fracture, and vitamin B12 deficiency. The authors suggested the use of "step-down", or "on-demand" PPI therapy for treatment of GERD, and eliminating the use of PPI drugs for prophylaxis of "stress" ulcers outside of the ICU. 

The conclusion of the article in The Clinician Newsletter from 3 years ago is still appropriate today. Given the concerns over potential adverse effects, the documented overuse of these drugs, and the relatively high cost, clinicians should consider using these drugs at the lowest effective doses for the shortest possible durations. Serious consideration should be given to withdrawal of PPI therapy in any hospice patient on long-term therapy who has not exhibited symptoms within the previous 3 months and has no established indication for continued use.  

Some of the commonly used PPIs are listed below (many are now available in OTC formulations): Aciphex (rabeprazole), Nexium (esomeprazole), Prevacid (lansoprazole), Prilosec (omeprazole), Protonix (pantoprazole)

New FDA Approvals of Pain Medications for Hospice Patients

Intranasal Ketorolac Approved

The FDA has approved Roxro Pharma's Sprix (ketorolac tromethamine) nasal spray for the short-term (up to 5 days) management of acute moderate to moderately severe pain that requires analgesia at the opioid level. Sprix is rapidly absorbed through the nasal mucosa, achieving peak blood levels as quickly as ketoroloac administered as an intramuscular injection, and provides acute pain relief for outpatients with a nonnarcotic and easy-to-administer alternative to other commonly prescribed opioid medications.  

Sprix Photo

OTC Pain Relief Patch Approved

The FDA has approved Hisamitsu's Salonpas Pain Relief Patch and Salonpas Arthritis Pain (methyl salicylate 10% and I-menthol 3%) for the temporary relief of mild to moderate muscle and joint aches and pains associated with arthritis, sprains, strains, bruises, and simple backaches. The patches are effective for up to 12 hours and can be used as an alternative for patients who have difficulty swallowing. The product is the only FDA-approved OTC pain relief patch on the market.

 

 

Revised Labeling & Warnings for Hospice Medications

Revised Proton Pump Inhibitors Labeling

The FDA has revised labeling for prescription and OTC proton pump inhibitors (PPIs), to include new safety information about a possible increased risk of hip, wrist, and spine fracture associated with the use of these medications. The new safety information is based on the FDA's review of 7 epidemiological studies that found those at greatest risk for these fractures received high doses of PPIs or had used them for 1 year or more. The majority of the studies evaluated individuals 50 years of age and older, with increased fracture risk primarily observed in this age group. However, randomized clinical trials of PPIs have not found an increased risk of fracture of the hip, wrist, or spine.

Revised Warning Sections for Ultram and Ultracet

Ortho-McNeil-Janssen and the FDA are notifying health care professionals of changes to the Warnings section of the prescribing information for Ultram (tramadol) and Ultracet (tramadol/acetaminophen). The revised information highlights the risk of suicide for patients who are addiction prone or taking tranquilizers or antidepressant drugs, as well as the risk of overdosage. Tramadol-related deaths have occurred in patients with previous histories of emotional disturbance or suicidal ideation or attempts, as well as in those who have previously misused tranquilizers, alcohol, and other CNS-active drugs.