The Hospice Clinician Blog

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 After an extensive review, the FDA concluded that the original formulation of Opana ER “was not withdrawn from the market for reasons of safety or effectiveness” – in other words, that Endo's new abuse-deterrent formula doesn't actually prevent drug abuse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>

Photo Credit

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.

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

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

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

By: Jim Joyner, Pharm.D., C.G.P

The commonly used antibiotic, Azithromycin (Z-Pak, Zithromax), was recently discussed in the medical news due to a report of increased risk for serious cardiac adverse effects associated with its use.  This incidence of risk is quite low, but due to the potentially serious nature it has resulted in an advisory memorandum by the FDA.  Specifically, there is a small risk of prolongation of the QT interval on the ECG which may progress to a serious cardiac arrhythmia known as Torsades des Pointes (TdP).   TdP can lead to ventricular fibrillation and sudden death.  In light of this recent focus on the issue of drug-induced QTc prolongation, this seems like an appropriate time to review and discuss other medications which also have the potential to cause this problem, especially since some of them are encountered frequently in the medication regimens for hospice patients.  

There are 34 specific medications available for use in the U.S. which have substantial evidence that supports the conclusion that they may prolong the QT interval and have a risk of TdP when used as directed according to approved labeling.(1) The list encompasses certain drugs from a variety of different pharmacologic classes including:

  8 different antiarrhythmic drugs, 
  6 antibiotics, 
  5 antipsychotics, 
  2 antinausea drugs,
  2 antidepressant drugs,
  2 anticancer drugs,
  2 non-sedating antihistamines, 
  2 antimalarial drugs,
  1 opioid,
  1 antiangina drug, 
  1 cholesterol lowering drug,
  1 anesthetic,
  1 GI stimulant drug

For a complete listing of all of the medications, and detailed information about drug-induced QT prolongation check out this link:
www.azert.org/medical-pros/drug-lists.htm

Five of the drugs on this list are quite commonly used in hospice to provide palliative management of a variety of symptoms.  Those drugs include:  Chlorpromazine (Thorazine), Citalopram (Celexa), Escitalopram (Lexapro), Haloperidol (Haldol), and Methadone (Dolophine).  

The incidence of this adverse cardiac effect has not been established for any of these drugs and the majority of patients take these drugs without any problem of a prolonged QT interval or arrhythmia.   It is also possible that some patients may have a prolonged QT interval while taking these drugs and exhibit no negative symptoms or effects.   In those cases this event would go unnoticed unless an ECG was done.   This adverse effect appears to be dose-related and has been associated with patients receiving higher dosages.

Awareness of the following risk factors for QT prolongation and TdP may help reduce the risks for this adverse effect when considering the use of these drugs(2) :

• Cardiac disease (MI, CHF, cardiomyopathy, congenital long QT syndrome, bradycardia)
• Low potassium or magnesium levels  (may occur with diuretic  usage)
• High drug doses (i.e.;  methadone > 200mg/day)
• Combined use of multiple drugs  which can prolong  QT
• Clinically significant drug interactions that can result in excessively elevated blood levels of a drug identified as having  QT prolongation potential

There are reports of several other drugs, commonly used in hospice ( not on the list above) where substantial evidence supports the conclusion that these drugs may also cause QT prolongation but will only present a risk of causing TdP in certain conditions such as over-dosage,  significant drug interaction, or in a patient with pre-existing cardiac disease risk factors.(1,2)

The drugs listed below can prolong QT but do not have the higher level of risk for causing TdP as the list of 34 drugs above: Amitriptyline (Elavil), Diphenhydramine (Benadryl), Doxepin (Sinequan), Fluoxetine,(Prozac) Nortriptyline (Pamelor), Paroxetine (Paxil), Mirtazapine (Remeron), Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone (Risperdal),  and Ziprasidone (Geodon).

In conclusion, the risks and benefits of using these drugs must be assessed on a case by case basis.  There is no general guideline, nor consensus about when to stop therapy or decrease  a dosage with one of these drugs if one is concerned about prolonged QT or TdP.   A reasonable approach to the problem in hospice care would include the following:

• Avoid the use of a drug known to cause TdP in a patient with the risk factors described above, unless there is no reasonable alternative available
• Reduce correctable risk factors if possible (low potassium or magnesium)
• Exercise caution when using  multiple drugs known to cause TdP or prolonged QT, and utilize doses at the lower end of the therapeutic range when combining these drugs
• Exercise caution when using  high doses of drugs known to cause TdP  (methadone in doses  > 200mg/day)
• Avoid clinically significant drug interactions  which may result in significantly elevated levels of the drugs identified with a potential for prolonged QT and TdP

Reference:
(1.) Arizona Center for Education and Research on Therapeutics
      University of Arizona.   www.azcert.org
(2.) Yap, Camm:  Heart. 2003 November; 89(11): 1363–1372

Photo Credit

Esther Liu, PharmD

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

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

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

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

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