The Hospice Clinician Blog

The American College of Gastroenterology (ACG) released new treatment guidelines on the diagnosis and management of gastroesophageal reflux disease (GERD) in the March issue of The American Journal of Gastroenterology. This blog post will present highlights from the updated guidelines, particularly those that are most relevant to the management of GERD in the hospice setting. Some of the recommendations may surprise you, as many of these recommendations are not routinely followed in clinical practice.

Management of GERD

• Head of bed elevation and avoidance of meals 2 – 3 H before bedtime should be recommended for patients with nocturnal GERD.
• Routine global elimination of foods that can trigger reflux (including chocolate, caffeine, alcohol, acidic and/or spicy foods) is not recommended in the treatment of GERD, as there is no evidence that this practice reduces symptoms. Selective elimination could be considered if patients note correlation with GERD symptoms and improvement with elimination.
• An 8-week course of a PPI is the therapy of choice for symptom relief and healing of erosive esophagitis. There are no major differences in efficacy between the different PPIs.
• With the exception of omeprazole/sodium bicarbonate (Zegerid) and dexlansoprazole (Dexilant), PPIs should be administered 30 – 60 min before a meal for maximal pH control.
• PPI therapy should be initiated at once-a-day dosing, ideally before the first meal of the day.
• In patients with partial response to PPI therapy, increasing the dose to twice daily therapy or switching to a different PPI may provide additional symptom relief.
• For most patients, PPIs should be discontinued after 8 weeks of therapy. Maintenance PPI therapy should be administered for GERD patients who continue to have symptoms after their PPI is discontinued and in patients with complications including erosive esophagitis and Barrett’s esophagus. For patients who require long-term PPI therapy, it should be administered in the lowest effective dose, including the option of on-demand or intermittent therapy.
• Bedtime H2RA therapy can be added to daytime PPI therapy in patients with night-time reflux if needed, but may be associated with the development of tachyphylaxis after several weeks of usage. Otherwise, there is no benefit in combining a PPI and an H2RA for the management of GERD.
• Prokinetic therapy (e.g., metoclopramide) should not be used in GERD patients unless gastroparesis is also present.
• There is no role for sucralfate in GERD patients.

Risks Associated with PPIs

• In two recent reviews, there was no supporting clinical evidence to document the development of B12 deficiency in chronic PPI users. However, recent studies have suggested that in elderly institutionalized long-term PPI users, B12 deficiency is more likely to develop and should be considered in this cohort.
• PPI therapy can be a risk factor for Clostridium difficile infection and should be used with care in patients at risk.
• PPI usage may increase the risk of community-acquired pneumonia.
• PPI therapy does not need to be altered in concomitant clopidogrel (Plavix) users, despite the FDA’s initial warnings on this combination, as clinical data has not demonstrated the suspected increased risk for adverse cardiovascular events.

Reference: Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroeneterol 2013; 108: 308-328.

Access the complete guidelines here: http://gi.org/wp-content/uploads/2013/03/ACG_Guideline_GERD_March_2013.pdf

Hospice patients with COPD, lung cancer, or other respiratory illness frequently use inhaled respiratory medications to combat symptoms of shortness of breath and lung inflammation. There are many types of inhaled medications, and many agents within each subclass, which complicates the use of these medications and often leads to substantial therapeutic overlap within a patient’s medication regimen.

Furthermore, these medications are almost universally expensive. Most are available only as brand name medications, and the complex delivery devices increase the cost of these products.

Download the Outcome Resources Inhaled Medications Chart to help you sort through the many therapies available. The chart groups the medications by therapeutic class and will help you compare dosing regimens, mode of delivery, and cost.

Insomnia is a common complaint in hospice care, and the “Z drugs” – zolpidem (Ambien, others), zaleplon (Sonata) and eszopiclone (Lunesta) are commonly used to treat it. These non-benzodiazepine hypnotic medications, which act on the GABA receptor in a similar fashion to the benzodiazepines, have substantial risks which need to be weighed carefully against their potential benefits. These risks – including falls, fractures, driving incidents, memory loss, daytime fatigue, tolerance and addiction – tend to be more pronounced in our hospice patient population due to advanced age and comorbidities. Recently, the FDA has made many changes to the labeling of these drugs (particularly zolpidem) as new information has come to light regarding their side effects.

Back in January of this year, the FDA reduced the recommended initial dose of zolpidem products, because the use of the higher dose can increase the risk of next-day impairment of driving and other activities that require full alertness – especially in women. The following recommendations were made (please see our blog post for complete information regarding this warning):

• 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.

This month, the FDA further heightened its warning regarding extended-release zolpidem (Ambien CR), advising that patients taking extended-release zolpidem should not drive or engage in any activity requiring mental alertness during the entire day after taking the drug, because of the profound “hangover” effect with the extended-release product.

Recently, a study was published in the British Medical Journal (1) examining the clinical efficacy of these medications in the treatment of insomnia. According to the investigators, previous meta-analyses of the Z drugs have been prone to publication bias, such as unavailability of unpublished trials and selective reporting of results. In their meta-analysis, they used only data provided to the FDA for drug approval. Since drug companies are required to provide information on all sponsored trials, published or not, when applying for drug approval, their claim is that the FDA files contain a more complete and less biased dataset of published and unpublished trials.

Thirteen clinical trials with 4,378 participants met the inclusion criteria. The meta-analysis of the study results found that, while the Z drugs do improve objective and subjective sleep latency compared with placebo, the effect size is small and of questionable clinical significance (a difference relative to placebo of 22 minutes for polysomnographic sleep latency and only 7 minutes for subjective sleep latency) – and the placebo response accounted for about half of the total drug response. They also found that the drugs had a greater effect on sleep latency when used in larger doses, for longer durations, and in younger patients – none of which typically apply to our hospice patient population.

According to the investigators, the data suggest that the placebo response is a major contributor to the effectiveness of the Z drugs, and that the remaining effect contributed by the drug itself needs to be balanced against the associated harms. The substantial proportion of the drug response accounted for by the placebo response indicates how important it is that we first address non-pharmacologic factors in the treatment of insomnia, such improved sleep hygiene and psychological interventions. The Z drugs should be used only after very careful consideration, especially in patients of very advanced age, female patients, and patients with comorbid cognitive dysfunction, renal or hepatic impairment, or high fall risk. They should be used at the lowest possible dose for the shortest possible treatment duration, and extended-release zolpidem should perhaps be completely avoided.

Reference: Huedo-Medina TB, Kirsch I, Middlemass J, et al. Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration. British Medical Journal 2012; 345: 8343.

Photo Credit

Dr. Julia Harder, PharmD CGP

In what many have found to be a surpising decision, the FDA has decided not to block generic versions of the original Opana ER (extended-release oxymorphone). Endo Pharmaceuticals, Inc. is the sponsor of the original Opana ER (no longer on the market) and the reformulated version, designed to be more difficult to abuse and misuse. Endo claims that allowing generic versions of the original, non-abuse-deterrent version of Opana ER will lead to an increase in drug abuse and misuse, and therefore petitioned that the FDA block all new applications for generic versions of the original Opana ER, as well as suspend the manufacture of the generics already on the market (by Actavis and Impax Pharmaceuticals). Endo's citizen petition to the FDA cited company data showing that the abuse rate of new Opana ER was 79% lower than the abuse rate of generic, non-tamper-resistant versions.

The FDA denied Endo’s petition, a controversial decision from the agency who says it will “continue to encourage the development of abuse-deterrent formulations of opioids.” After an extensive review, the FDA concluded that the original formulation of Opana ER “was not withdrawn from the market for reasons of safety or effectiveness” – in other words, that Endo's new abuse-deterrent formula doesn't actually prevent drug abuse significantly better than the earlier version. As a result of the FDA’s decision, generic versions of the original formulation can continue to be approved and marketed.

Specifically, the FDA’s conclusions include:

• While there is an increased ability of the reformulated version of Opana ER to resist crushing relative to the original formulation, study data show that the reformulated version’s extended-release features can be compromised when subjected to other forms of manipulation, such as cutting, grinding, or chewing, followed by swallowing.
• Reformulated Opana ER can be readily prepared for injection, despite Endo’s claim that these tablets have “resistance to aqueous extraction (i.e., poor syringeability)” and information on how to do so is readily available in the public space. It also appears that reformulated Opana ER can be prepared for snorting using commonly available tools and methods.
• One of the post-marketing investigations suggested the troubling possibility that a higher percentage of reformulated Opana ER abuse is via injection than was the case with the original formulation.

The FDA also refused Endo's bid for new labeling language that would describe Opana ER's "abuse-deterrent properties." Douglas Throckmorton from the FDA’s Center for Drug Evaluation and Research told the Wall Street Journal: "We think the public health would not be served if a company can market itself as 'abuse deterrent,' if the scientific evidence did not support that claim."

The FDA's decision comes just month after it said it would not approve any generic versions of the original OxyContin formulation. That decision led many to expect that the FDA would approve Endo’s petition. However, the FDA’s decision drew a clear distinction between Opana ER and OxyContin. In the decision document, the FDA rejected Endo's assertion that the abuse-deterrent properties of the reformulated Opana ER are “virtually identical” to the reformulated OxyContin, calling this claim "misplaced and without merit."

Endo was "surprised and extremely disappointed" by the FDA decision, said Ivan Gergel, the company's chief scientific officer. "We believe the approval of non-abuse-deterrent opioids will contribute to a significant increase in prescription drug abuse." Indeed, allowing generic Opana ER to remain on the market will be troubling to some law-enforcement and community-based groups, since there was an increase in abuse of older Opana formulations after OxyContin launched its reformulated drug in 2010.

Furthermore, the Opana ER decision illustrates how challenging it will be for companies trying to convince the FDA a painkiller is abuse-deterrent, and sets the precedent that the FDA’s standards are high in this regard.
 

Dr. Julia Harder, PharmD, CGP

At Outcome Resources, we have noticed many costly claims for brand name Vicodin (hydrocodone/acetaminophen). Typically, when a prescriber writes a prescription for a brand-name medication for which a generic equivalent is available, the dispensing pharmacy will substitute the generic version, unless the prescriber specifically indicates on the prescription that no generic substitution is allowed. When the prescription is for a combination product like Vicodin, the strengths of all ingredients must be equal in order for generic substitution to be allowed -- so if a prescriber writes for Vicodin 5/500, only generic hydrocodone/APAP in the specific combination of 5 mg of hydrocodone + 500 mg of acetaminophen can be dispensed.

In order to avoid adverse events associated with acetaminophen toxicity, most importantly liver failure, the FDA has recently limited the acetaminophen content of acetaminophen-containing prescription products. These products, such as Vicodin, can now contain no more than 325 mg of acetaminophen per tablet. Vicodin brand products, which previously contained 500 mg of acetaminophen per tablet, have been reformulated to contain only 300 mg of acetaminophen per tablet. Available strengths now include:

• Vicodin -- 5 mg hydrocodone/300 mg acetaminophen
• Vicodin ES -- 7.5 mg hydrocodone/300 mg acetaminophen
• Vicodin HP -- 10 mg hydrocodone/300 mg acetaminophen

Now, when a prescriber writes a prescription for Vicodin, pharmacies may only dispense a generic substitute that contains 300 mg acetaminophen per tablet -- and there is only one generic manufacturer currently making hydrocodone/APAP combination products containing 300 mg of acetaminophen. This single-source generic version of Vicodin is just as expensive as the brand name product. So whether the pharmacies dispense brand-name Vicodin or the single-source generic version, the cost to the hospice is high.

To avoid this increased cost, hospice prescribers need to write for generic hydrocodone/APAP, and specify an acetaminophen content of 325 mg (e.g., hydrocodone/APAP 5/325 1 tablet orally every 4 hours as needed). There are many generic hydrocodone/APAP products that contain 325 mg of acetaminophen, and the cost of these products is substantially lower. The slightly increased amount of acetaminophen contained in these products (325 mg versus 300 mg) will not be clinically significant.

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Our clinical pharmacists analyze our hospice partners medication utilization every month and help alert them to situations such as these to reduce costs. Does your hospice have a proactive pharmacy partner? Find out More Information.

Dr. Jim Joyner, PharmD, CGP

One question from our hospice partners that we hear frequently is: 

Is it legal to fax a Schedule II prescription to the pharmacy for our hospice patients?  

Federal law (Controlled Substances Act) pertaining to Schedule II prescriptions is quite strict in this regard and in most cases pharmacies cannot legally fill a Schedule II prescription that has been faxed to them. They must have the original written prescription in hand at the time the controlled substance is actually dispensed, however, there are some important exceptions to this rule.

The Drug Enforcement Agency (DEA) has granted three exceptions to the facsimile Schedule II prescription requirements.  The fax of a Schedule II prescription may serve as the original prescription in each of these three situations as follows:

1. A patient enrolled in a hospice care program certified and/or paid for by Medicare or a hospice program licensed by the State.   The prescriber needs to note on the prescription that it is for a hospice patient.  The fax will serve as the original written prescription and no further documentation is required.
2. A resident of a long-term care facility.   The fax will serve as the original written prescription and no further documentation is required.
3. A prescription for a schedule II narcotic to be compounded for the direct administration to a patient by parenteral, intravenous, intramuscular, subcutaneous, or intraspinal infusion.   The fax will serve as the original written prescription and no further documentation is required.

Reference: (21 C.F.R.  Section 1306.11 (e), (f), and (g))
More information can be found at these websites:
Code of Federal Regulations (C.F.R.), Title21, Parts 1300-1321, Drug Enforcement Administration implementing regulations pertaining to the Controlled Substances Act:
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=1306.11 <Assessed 05/02/2013>

Drug Enforcement Administration Pharmacists Manual
http://www.deadiversion.usdoj.gov/pubs/manuals/pharm2/ <Assessed 05/02/2013>

Drug Enforcement Practitioners Manual
www.deadiversion.usdoj.gov/pubs/manuals/pract/index.html  <Assessed 05/02/2013>

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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).

Photo Credit

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.