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.

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Proton pump inhibitors (PPIs) are commonly used in hospice for patients with gastroesophageal reflux disease (GERD), peptic ulcer disease (PUD), symptoms of gastric upset or nausea, or GI protection when patients are taking medications such as NSAIDs or steroids. There are currently 6 PPIs on the market, and while there is no clinically significant difference between the PPIs in terms of efficacy or side effects, there are important differences between them in terms of dosing, administration and cost. Click here to download a chart which compares the PPIs and can be used to help you select the most cost-effective PPI for your hospice patients.

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

The FDA has approved BREO ELLIPTA for the long-term, once-daily, maintenance treatment of COPD. BREO contains 100 micrograms fluticasone furoate (an inhaled corticosteroid, or ICS) and 25 micrograms vilanterol (a long-acting beta-agonist, or LABA) administered using ELLIPTA, a new dry powder inhaler (DPI). There are currently three other ICS/LABA combination products on the market: Advair (fluticasone propionate/salmeterol), Symbicort (budesonide/formoterol) and Dulera (mometasone/formoterol). The difference between BREO ELLIPTA and these other three products is that BREO ELLIPTA is approved for once daily use, while all the other products must be used twice daily.

The safety and efficacy of Breo Ellipta were evaluated in 7,700 patients with a clinical diagnosis of COPD. Those treated showed improved lung function and reduced exacerbations compared to placebo. Therefore, BREO ELLIPTA will carry two indications: the maintenance treatment of airflow obstruction in patients with COPD, and the reduction of exacerbations of COPD in patients with a history of exacerbations.

As with all other LABAs, BREO ELLIPTA will carry a boxed warning that LABAs increase the risk of asthma-related death. The safety and efficacy of Breo Ellipta in patients with asthma have not been established, and it is not approved for the treatment of asthma. Futhermore, BREO ELLIPTA should not be used as a rescue therapy to treat acute bronchospasm.

BREO ELLIPTA may cause serious side effects, including increased risks of pneumonia and bone fractures. The most common side effects reported by patients included inflammation nasopharyngitis, upper respiratory tract infection, headache, and oral candidiasis.

BREO ELLIPTA was developed by GlaxoSmithKline in collaboration with San Francisco-based Theravance, and is expected to be available in the USA during the third quarter of 2013. The cost of the therapy is not known at this time, but given that it is a new drug formulation in a novel inhaler design, there is likely to be a price premium compared with other therapies.

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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Dr. Julia Harder, PharmD CGP

The FDA has expanded the indications for oral lubiprostone (Amitiza®, Sucampo Pharmaceuticals Inc/Takeda Pharmaceuticals USA Inc.) to include opioid-induced constipation in chronic pain patients, at a dose of 24 mcg twice daily. This is the third indication for lubiprostone, which is already approved for the treatment of chronic idiopathic constipation in adults, also at a dose of 24 mcg twice daily, and irritable bowel syndrome (IBS) with constipation in women 18 years of age and older, at a dose of 8 mcg twice daily.

Opioids cause constipation via multiple mechanisms. When opioids bind to peripheral opioid receptors in the gastrointestinal (GI) tract, two main things happen:

1. Gastrointestinal motility is slowed. This is why we recommend stimulant laxatives, such as senna or bisacodyl, to help accelerate GI motility.
2. Electrolyte and water absorption is increased. Osmotic laxatives, like milk of magnesia, polyethylene glycol or sorbitol, that help draw fluids back into the intestinal lumen, counteract this effect and can also be helpful in the treatment of opioid-induced constipation.

Lubiprostone targets the second mechanism. it is a specific activator of CIC-2 chloride channels in the intestinal epithelium, which counteracts the increased electrolyte absorption caused by opioids, and helps increase the amount of fluid that remains in the GI tract. Approval for the new indication was based on results of three phase III, placebo-controlled trials of patients receiving opioids including morphine, oxycodone, and fentanyl for non-cancer pain. At a dose of 24 mcg twice daily, two of the three studies met their primary efficacy endpoint.

According to the manufacturers, the effectiveness of lubiprostone in patients taking methadone has not been established, and it is possible that lubiprostone will be ineffective in patients taking methadone. In the 3 clinical trials that led to the drug’s approval, methadone was not included. In other clinical trials, methadone appeared to prevent beneficial effects of lubiprostone, and laboratory studies have demonstrated that methadone blocks lubiprostone’s stimulation of CIC-2 channels.

How should we use lubiprostone in hospice and palliative care?

• Stimulant laxatives should remain the first-line therapy for patients with opioid-induced constipation.
• Osmotic laxatives such as milk of magnesia, polyethylene glycol and sorbitol are great add-ons when stimulant laxatives aren’t enough. Osmotic laxatives should generally by tried before moving to lubiprostone. They are less expensive (the average cost of a 15-day supply of Amitiza® is $150), and efficacy is better established (only 2 of 3 trials of lubiprostone demonstrated efficacy).
• Lubiprostone should not be used in patients taking methadone.
• The manufacturers recommend lower doses in patients with moderate to severe hepatic impairment. For patients with moderately impaired hepatic function (Child-Pugh Class B), the recommended starting dose is 16 mcg twice daily. For patients with severely impaired hepatic function (Child-Pugh Class C), the recommended starting dose is 8 mcg twice daily. If this dose is tolerated but the patient has not adequately responded, doses can then be escalated to full dosing with appropriate patient monitoring.

Julia Harder, PharmD, CGP

On Tuesday April 16th, the same day that the patent on the old, non-abuse-deterrent OxyContin formulation was set to expire, the FDA decided to block potential generic versions of the original formulation from being produced. The FDA has issued a statement that it will not approve any abbreviated new drug applications for generics that are based on the original formulation.

The FDA approved the original formulation of OxyContin in 1995. This formulation did not have any abuse-deterrent properties. Drug abusers found that crushing the extended-release tablets enabled rapid release of the drug all at once, producing a fast, powerful high when snorted, injected or even sprinkled on food. OxyContin became known as "hillbilly heroin." That abuse, the FDA said, increased "the risk of serious adverse events, including overdose and death."

In April 2010, the FDA approved Purdue’s reformulated version of OxyContin, designed to resist abuse. The tablets are harder to crush, break or dissolve, and instead of becoming a fine, snortable powder when crushed or broken, a viscous hydrogel is formed, that cannot be easily snorted or injected. Purdue voluntarily withdrew the original OxyContin formulation once the new abuse-deterrent version became available.

The OxyContin reformulation did decrease OxyContin abuse, as demonstrated in a study published in the New England Journal of Medicine in July 2012 (read more about this study here). According to the researchers, before the release of abuse-deterrent OxyContin, 35.6% of patients entering treatment programs throughout the United States were using OxyContin as the primary drug of abuse. Twenty-one months later, after the release of the abuse-deterrent formulation, just 12.8% selected OxyContin as their drug of choice.

The FDA’s decision to block generic OxyContin most certainly represents a win for Purdue Pharma LP, the manufacturer. OxyContin has long been one the nation's top-selling prescription painkillers with sales of more than $2.8 billion last year. The FDA’s decision effectively protects Purdue from lower-price competition by requiring generic companies to develop their own abuse-deterrent designs. Purdue’s abuse-resistant formulation doesn’t go off patent until 2025.

The FDA’s decision also represents a win for those concerned about a resurgence of OxyContin abuse. In a statement, Republican Representative Hal Rogers of Kentucky, a state with a high level of OxyContin abuse, called the FDA decision not to approve generic OxyContin "a huge win for our region and for the thousands of families who have seen painkillers become pain makers. The FDA undoubtedly saved our nation from another deadly tidal wave of oxycodone abuse and overdoses."

Unfortunately for hospice care providers, the FDA’s decision also means that the price of OxyContin is unlikely to decrease any time soon. One of the struggles we face in hospice is the high price of almost every long-acting opioid available on the market today. The following chart compares the cost to the hospice (based on average wholesale price, or AWP) of a 15-day supply of equianalgesic doses of some of the more commonly-prescribed long-acting opioids.

Dose                                               Cost
OxyContin 80 mg PO Q12H                   $422
Opana ER 40 mg PO Q12H                    $400
Fentanyl patch 100 mcg Q72H              $189
Morphine ER tablet 100 mg PO Q12H    $106
Avinza 180 mg PO Q24H                        $500
Kadian 200 mg PO Q24H                        $420
Methadone 10 mg PO Q12H                    $12

With the exception of methadone and the lowest strengths of extended-release (12-hour) morphine, long-acting opioids generally cost at least $100 per prescription, and often cost 4-5 times that. Of the long-acting opioids most commonly used in hospice care (morphine ER, fentanyl patch, OxyContin and methadone), OxyContin is, by far, the most expensive – and is likely to remain that way for quite some time.