Jennifer Chen, PharmD, CGP
Fixed-dose combination therapy offers convenient dosing and improves compliance; however, their place in hospice therapy is limited and these novel inhalers are expensive. This article will discuss new fixed-dose combination therapies, their limitation and the cost-effective alternative for hospice patients.
Inhaled bronchodilators are the cornerstone of treatment in COPD. Both long-acting muscarinic antagonists (LAMAs) and long- acting beta 2-adrenergic agonists (LABAs) are used as long-term maintenance treatment of airflow obstruction in patients with COPD. The fixed-dose combination inhalers are designed to provide extra bronchodilation compared with either therapy alone. Currently, Anoro Ellipta (umeclidinium-vilanterol) and Stiolto Respimat (tiotropium-olodaterol) are the only FDA approved LAMA/LABA combinations available on the market that may be given in a convenient once daily dosing.
Two new LAMA/LABA combination inhalers received FDA approvals but not yet available on the market. Utibron Neohaler (glycopyrrolate-indacaterol) and Bevespi Aerosphere (glycopyrrolate-formoterol), approved in Oct 2015 and April 2016, respectively, offer another option of LAMA/LABA dual combination bronchodilator to patients with COPD. Both inhalers contain the same long-acting muscarinic antagonist, glycopyrrolate, with the different LABAs (indicaterol versus formoterol). Both of these new inhalers are given twice daily.
One of the notable differences between all of these products is the type of inhalation device used. Anoro Ellipta and Utibron Neohaler deliver medication via a dry powder inhaler whereas Stiolto Respimat and Bevespi Aerosphere use a metered-dose inhaler. Both of these devices are breath-actuated, that is, requiring effective positive respiratory effort to inhale medication.
Inhaled corticosteroid (ICS) therapy is recommended as combination treatment with LABA for patients with a history of frequent acute exacerbations of their COPD. Breo Ellipta, approved in April 2015, combines the new LABA vilanterol with an inhaled corticosteroid already on the market, fluticasone. Vilanterol allows this product to be dosed once daily compared with existing ICS/LABA combination products that are dosed twice daily including Advair Diskus (fluticasone-salmeterol), Symbicort (budesonide-formoterol) and Dulera (mometasone-formoterol).
Long-term ICS treatment is associated with multiple adverse effects including fractures, oral fungal overgrowth and respiratory infections. Therefore, treatment with ICS in patients with COPD should be carefully evaluated when assessing the risk/benefit ratio due to the risk of pneumonia. Their benefit in patients at low risk of exacerbations is questionable1.
Place in hospice therapy
The major disadvantage of these combination therapies for the hospice patient is the method in which the medication is delivered via a metered-dose inhaler or a dry powder inhaler. In patients with advanced disease, who may not have enough positive inhalation, nebulized therapies may be more efficacious than inhalers. Therefore, the combination treatment of short-acting muscarinic antagonist (SAMAs) and short-acting beta 2- adrenergic agonist (SABAs), such as DuoNeb (ipratropium-albuterol) is usually recommended as an alternative. Routine use of DuoNeb should provide an equivalent coverage compared to LAMA/LABA combination products. Although the dosing frequency (four times daily) may be considered as a drawback compared to the long-acting combination products, the short-acting combination therapy may also be used on as-needed basis for acute management of dyspnea in addition to the scheduled dosing. Since the newer combination products are generally cost prohibitive, DuoNeb also serves a cost-effective alternative for hospice patients. In cases where a patient has high risk of exacerbation, a low dose oral corticosteroid may be considered and they are inexpensive compared to inhaled corticosteroids.
A complete chart on inhaled respiratory medications with dosing information and pricing can be found in the Clinical Resources in our member section.
Jim Joyner, Pharm.D., C.G.P.
CMS has established very restrictive regulatory criteria for the use of Haloperidol and other psychotropic drugs for patients who reside in the SNFs. These criteria include restrictions on indications for use, duration of therapy, daily dose limits, monitoring, and more. The information is spelled out in F-329 Unnecessary Drugs (CMS Skilled Nursing Facility Regulations). The regulations are intended for nursing home patients who are NOT being treated under “end of life care” and this is clearly spelled out in F-329.
F-329 Unnecessary Drugs contains specific language that provides an exception to the specific criteria for antipsychotic drug use (including Haloperidol) for hospice patients in the SNF. Subsection 483.25 (l) in this F-tag contains an extensive table (Table 1) which lists examples of numerous medications for which CMS is concerned about, including all antipsychotic drugs. At the end of this extensive table is a section titled, simply, “Exception”. Here is the exact language:
This means that when Haloperidol (or any antipsychotic drug) is being used for managing symptoms at end-of-life in the SNF, the regulatory criteria on max dosage, duration of therapy or related issues do not apply. Haloperidol is used extensively in hospice and palliative care for management of terminal delirium, severe agitation of end-stage dementia, and for management of nausea – vomiting. It is highly effective for these indications and generally well tolerated in many hospice patients, however in many cases, doses greater than 2 mg per day are required and are clinically appropriate. Haloperidol is recommended as a drug of choice for terminal delirium by several well respected palliative care experts and organizations (references available upon request if you need them).
Make sure that the patient’s health record clearly indicates that the patient is under hospice for ‘end of life’ care.
|Thank you! We've been getting pushback from NH Facilities recently on what would normally be considered mild dosages for a hospice patient. I've passed out copies of this to all our Nurses.
Posted 5/20/2016 07:13:16 AM
|How does this relate to the more recent CMS initiative to decrease anti-psychotic use in LTCFs by 15%? We have facilities whose star ratings are being affected by the use of Haldol for N/V. Additionally, a patient cannot utilize the hospice benefit and the SNF benefit simultaneously so wouldn't that immediately eliminate our patient population?
-- Jess Smith
Posted 5/2/2016 12:56:58 PM
Jennifer Chen, PharmD, CGP
Last year, the FDA released a drug safety communication, which cautioned the use of SGLT2 inhibitors, due to case reports of ketoacidosis in patients who were being treated with these medications. Recently, the FDA has updated the labels for SGLT2 inhibitors to include the risks for both ketoacidosis and serious urinary tract infections. Patients in these case reports were found to start with urinary tract infection, which then progressed to potentially fatal urosepsis and pyelonephritis that required hospitalization or dialysis to treat kidney failure. Patients who continue to take these medications should be taught to recognize the symptoms of ketoacidosis, which include nausea, vomiting, abdominal pain, fatigue and difficulty breathing. Ketoacidosis can occur even if their blood glucose is not excessively high. Patients with suspected ketoacidosis should stop taking the SGLT2 inhibitor and receive treatment promptly. Clinicians are encouraged to report any side effects to the FDA MedWatch program.
SGLT2 inhibitor is a class of diabetic medication that works by stopping glucose from being reabsorbed into the blood. Medications in this class include Invokana (canagliflozin), Farxiga (dapagliflozin), and Jardiance (empagliflozin).
The FDA imposed the Risk Evaluation and Mitigation Strategy (REMS) for rosiglitazone-containing type 2 diabetic medications in 2010 due the concern of possible increased cardiovascular risk. It required healthcare providers to obtain a special certification in order to prescribe rosiglitazone and patients receiving rosiglitazone must be enrolled in the REMS program. In 2013, the FDA lifted the restrictions for the prescribing and use of rosiglitazone based on the data from RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes) trial. The RECORD trial demonstrated no elevated cardiovascular risk. Recently, the FDA has lifted the entire REMS requirements for rosiglitazone-containing medications, which includes Avandia (rosiglitazone), Avandamet (rosiglitazone-metformin) and Avandaryl (rosiglitazone-glimepiride) on the basis of post-marketing data and the RECORD trial. However, most of these medications have either been removed from the market (Avandamet and Avandaryl) or are rarely used in patients (Avandia).
The FDA gave final approval in December 2015 to Basaglar (a copycat version of insulin glargine). Basaglar was not approved as a “biosimilar” product although it was demonstrated to be similar enough to another insulin glargine on the market (Lantus) regarding its effectiveness and safety. It is administered subcutaneously with the manufacturer’s KwikPen injector once daily at any time of the day. Being as the first “follow-on” insulin glargine product, Basaglar received much attention for potentially lower costs. Basaglar has already launched in the UK under the brand name of Abasaglar and is priced 15% lower than Lantus (listed price of £35.28 for Abasaglar and £41.50 for Lantus according to UK Medicines Information). Pricing for Basaglar in the US is unknown at this time and the drug will not be available until after December this year.
1. FDA. FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. http://www.fda.gov/Drugs/DrugSafety/ucm475463.htm Accessed on January 10, 2016.
2. FDA. Rosiglitazone-containing Diabetes Medicines: Drug Safety Communication - FDA Eliminates the Risk Evaluation and Mitigation Strategy (REMS). http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm477601.htm Accessed on December 28, 2015.
3. FDA. FDA approves Basaglar, the first “follow-on” insulin glargine product to treat diabetes. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm477734.htm Accessed on December 28, 2015.
Esther Liu, PharmD, MSIA, CGP
The Center for Medicare and Medicaid Services (CMS) released a new online dashboard that contains some interesting analyses of Medicare Part D drug utilization. The new dashboard presents drug data collected from Medicare Part B and Part D providers from 2010 to 2014. In an analysis of the top 15 drugs by total annual cost for Medicare Part D 2014, 10 out of the top 15 high cost medications are drugs that commonly show up on newly admitted hospice patients’ medication profiles. The remaining 5 medications are all specialty medications used for chemotherapy, immunotherapy or hepatitis C treatment. These 5 medications are curative in nature and are not typically encountered by hospice providers.
The 10 high cost drugs identified by the analysis are Nexium, Crestor, Abilify, Advair, Spiriva, Lantus, Januvia, Duloxetine, Lyrica, and Namenda.
Outcome Resources also targets these medications for our hospice providers in patient medication reviews and monthly drug utilization reviews. Many of these can be switched to a more cost-effective alternative or safely discontinued at the end of life. Below are the common recommendations provided by Outcome Resources clinicians to manage hospice patients who are on the drugs listed above:
If you are interested to learn more about the Medicare Drug Spending Dashboard 2014, the direct link is: <https://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/Dashboard/Medicare-Drug-Spending/Drug_Spending_Dashboard.html>
Jennifer Chen, PharmD
Proton pump inhibitors (PPIs) and histamine H2 antagonists (H2 blockers) are the most common medications prescribed for the treatment of gastroesophageal reflux disease (GERD) or peptic ulcer disease (PUD). The treatment usually begins with antacids or over-the-counter H2 blockers for mild symptoms. Then steps up to PPIs or higher dose of H2 blockers for moderate to severe symptoms. Occasionally, PPI and H2 blocker may be combined to treat certain patients. This article will discuss the appropriateness of combination therapy and its associated risk.
Hospice patients are predisposed to PUD due to many risk factors including the age-related change in gastric mucosal defense, serious illness and long-term use of NSAID. The majority of patients are managed clinically with a once daily dose of a PPI. The unofficial use of twice daily dosing of PPI or the addition of a nighttime H2 blocker to the daytime PPI therapy may be required for optimal control in a subset of patients such as those with Barrett’s esophagus or extra-esophageal disease (1).
PPIs and H2 blockers have overlapping mechanisms of actions, which ultimately suppress gastric acid secretion, but at different stages of production. When used together, the extensive acid suppression therapy may decrease the absorption of certain nutrients (i.e. vitamin B12, iron and calcium), which are dependent upon an acidic environment to be absorbed in the stomach. There is also a significant risk of hip fractures with long-term PPI treatment. This risk theoretically may be further increased with the combination therapy due to impaired calcium absorption. Combination therapy may also increase the risk of gastrointestinal infections. A recent meta-analysis evaluated Clostridium difficle (C.diff) infections in patients receiving PPIs and found an association between PPI use and an increased risk of C diff (2). H2 blockers have been showed to carry a lower risk for gastrointestinal infection compared to PPIs. However, when both PPIs and H2 blockers are used together, the further reduction of gastric acid may allow for bacteria to multiply in the digestive system and the risk of infection may be increased.
In general, long-term combination therapy does not offer any additional benefit for the management of GERD and may only be appropriate in a particular subset of patients (i.e. Barrett’s esophagus or extra-esophageal disease). Practitioners are encouraged to re-evaluate patient’s condition and consider discontinuation if patient no longer exhibits symptoms or has no indication for continued use. Since PPIs provide superior acid suppression, healing rates and symptom relief compared to H2 blockers, our recommendation is to discontinue H2 blockers over PPIs. If it is determined PPI is no longer indicated for a patient, it should be tapered to avoid rebound acid reflux. For patients who require long-term PPI therapy, the lowest effective dose should be considered.
Jennifer Chen, PharmD
Entacapone is a reversible and selective inhibitor of catechol-O-methyltransferase (COMT). By disrupting levodopa breakdown, the COMT inhibitors can potentiate the effect of levodopa for managing the motor symptoms of Parkinson’s disease. Therefore, entacapone is used as adjunctive treatments in patients who are experiencing “wearing off” or other motor complications during treatment with carbidopa-levodopa.) It is available alone as Comtan® or in a fixed-dose combination with carbidopa-levodopa as Stalevo®.
In August 2010, FDA alerted patients and health care professionals about the increased risk of cardiovascular events and death with the use of Stalevo. The possible safety issue was observed in a clinical trial called Stalevo Reduction in Dyskinesia Evaluation in Parkinson’s disease (STRIDE-PD) and in meta-analysis involving 15 clinical trials comparing Stalevo with carbidopa-levodopa. Since carbidopa-levodopa has been used extensively and has not been associated with cardiovascular risk, the FDA was concerned that entacapone might have been responsible for the increased risk. It was difficult to draw conclusions from these clinical trials because they were not designed to evaluate entacapone’s cardiovascular safety.
Until recently, two studies were examined to understand the significance of cardiovascular risk with entacapone. One was a retrospective cohort study using data from an electronic commercial insurance database and found the risk for myocardial infarction was not significantly increased in patients 18 to 64 years old with Parkinson’s disease treated with entacapone compared to the control group(1). The other study assessed the risk of myocardial infarction, stroke or death in Medicare patients at least 65 years old with Parkinson’s disease and the result did not support an associate between entacapone use and increased cardiovascular risks(2).
Therefore, on October 26, 2015, the FDA announced that entacapone does not carry an increased risk of cardiovascular events based on recent studies. However, patients and health care professionals are still encouraged to report side effects with Comtan or Stalevo to the FDA.
We want to share some exciting news with you regarding Outcome Resources!
On October 30, Hospice Pharmacy Solutions merged Outcome Resources into its operation. The merger is very beneficial for our clients as we will be able to offer you additional unique and innovative solutions geared specifically to the hospice industry.
The business will be headquartered in Dallas, which is a central location, and operate as Hospice Pharmacy Solutions, LLC. In approximately six months, we will retire the Outcome Resources name.
We want to reassure you that while the name is changing, the exceptional service you have come to expect from Outcome Resources remains the same. This merger gives us the ability to enhance our programs and provide hospices valuable resources to better serve their patients.
You can find more details in this press release, including the new leadership structure.
We’d like to once again thank you for your services to patients and their families at a most vulnerable time in their lives. The work you do is honorable, and we are proud to support your mission.
Stephanie Cheng, PharmD, MPH
The FDA granted accelerated approval of Praxbind (idarucizumab) on October 16, 2015 for use as a specific reversal agent of the anticoagulant effects of Pradaxa (dabigatran etexilate) during emergency surgery/urgent procedures or in episodes of life-threatening or uncontrolled bleeding. This is the first drug to be approved for this indication. Praxbind is currently not available on the market yet; however, the manufacturer stated that it will be available from major U.S. hospital pharmacy distributors as quickly as possible.
Pradaxa (dabigatran) had been given FDA approval in 2010 as the first direct thrombin inhibitor for the indications of (1) to reduce the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (2) for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for 5-10 days and (3) to reduce the risk of recurrence of DVT and PE in patients who have been previously treated. Unlike Coumadin (warfarin), Pradaxa does not require extensive lab monitoring and is given as 75mg BID or 150mg BID. However, there had been no antidotes to its anticoagulant affect until this point.
Praxbind (idarucizumab) is a monoclonal antibody fragment that is to be given IV only at a recommended dose of 5g, provided as two separate 2.5g/50mL vials to be given consecutively. Praxbind specifically binds to Pradaxa and does not interfere with the anticoagulant effects of other anticoagulants or the coagulation cascade.
Under the accelerated approval process, the FDA approves medications for serious conditions that fill an unmet medical need based on an intermediate clinical endpoint in a clinical trial that is reasonably likely to predict a clinical benefit to patients. This allows patients to gain earlier access to promising new medications, but the company is still required to submit additional clinical information after approval to support the clinical benefits of the drug.
Due to the accelerated approval process, Praxbind has only been studied in healthy patients (i.e. patient who do not require an anticoagulant) in 3 clinical trials of a total of 224 subjects. Therefore, the safety and risk profile for patients who do require an anticoagulant has not been assessed. Additionally, because the clinical trials were conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to other drugs and the rates may not reflect those observed in clinical practice.
Currently, there are no contraindications for Praxbind. However there are warnings and precautions in regards to (1) increased thromboembolic risks to the patient’s underlying disease due to reversal of dabigatran’s anticoagulant effects (2) re-elevation of coagulation markers (i.e. activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT)) (3) Hypersensitivity reaction and (4) risk of serious adverse reactions in patients with hereditary fructose intolerance due to sorbitol excipient.
The role of Praxbind in the hospice setting will be limited, due to the limited use of Pradaxa and expense. Anticoagulant use in generally is not recommended in hospice patients due to the risk of bleeding, especially in the unpredictable declining status of hospice patients. Exception to this is if the patient has a high level of function, relatively longer prognosis for life and a reasonable quality of life, who is deemed to be at high-risk for thrombotic events. However, Praxbind does provide a safety net for life-threatening or uncontrolled bleeding in patients using Pradaxa in an otherwise helpless situation, as no other antidote for Pradaxa had been available up until this point.
Jim Joyner, PharmD, CGP
Rytary is the brand name for a new formulation of “extended-release” carbidopa-levodopa that has recently become available in the U.S. in capsule form. It is indicated for the treatment of mild to moderate to severe Parkinson’s disease. Clinical trials with this new formulation were conducted comparing Rytary with immediate-release carbidopa-levodopa tablets. The study results indicated significant improvements in a patient’s ability to move and perform activities of daily living, as well as experiencing significantly more “on” time and less “off” time without dyskinesia. There are currently no published studies comparing Rytary with the “controlled-release” carbidopa-levodopa tablet (originally Sinemet CR, although generics are now available). The Sinemet CR tablet is formulated as an erodible polymer matrix that slows the release of medication from the tablet. The Rytary capsule contains both immediate-release and extended-release beads. Clinically significant differences in patient response to these two “extended-release” products should be anticipated because of the difference in formulation.
“Controlled or “extended” release carbidopa-levodopa preparations have been formulated in attempts to achieve a steadier climb to peak plasma concentrations that are less extreme and provide greater duration of anti-Parkinson effects. Both Rytary and the older Sinemet CR tablet are formulated to achieve this objective, but use different technology to control dissolution rates. Both dosage forms have been shown to provide more “on” time, less “off” time, and less dyskinesia for Parkinson’s patients than the immediate-release tablets. It remains to be seen how much of an advantage, if any, the new extended-release capsule (Rytary) has over the older extended-release tablet (Sinemet CR).
Rytary is not a generic equivalent to either the immediate release, nor the controlled release carbidopa-levodopa. The manufacturer provides a conversion table for guidance on converting from carbidopa-levodopa immediate release to Rytary.
Available combination strengths of Rytary Extended Release Capsules are as follows: 23.75mg/95mg, 36.25mg/145mg, 48.75mg/195mg, and 61.25mg/245mg.
The starting dose for Rytary in levodopa naïve patients is 23.75mg/95mg three times per day for 3 days. On day 4, the dose may be increased to 36.25mg/145mg three times daily. Further dosage increases may be employed based upon patient response, up to a maximum recommended dose of 97.5mg/390mg three times a day. Capsules should be swallowed whole and should not be chewed or crushed. For patients that cannot swallow capsules whole, Rytary capsules may be opened and the contents can be sprinkled on to a small amount of applesauce for immediate consumption.
Most common adverse effects noted with Rytary were nausea and headache (similar to immediate release carbidopa-levodopa in the comparison trial).
Rytary may offer a significant advantage in Parkinson’s patients who are not able to achieve adequate periods of “on” time during the waking hours, or those who exhibit troublesome dyskinesia with carbidopa-levodopa immediate-release tablets. There is currently no data available to demonstrate any clinical advantage of Rytary over the carbidopa-levodopa CR (controlled release) tablets. From a practical standpoint, Rytary does have an advantage over the “CR tablets” for patients that cannot swallow whole pills, since the carbidopa-levodopa tablets should be swallowed whole and should not be chewed or crushed. As with most new products, Rytary is expensive with a mid-range dosage expected to cost the hospice between $300 - $400 per month.
Jennifer Chen, PharmD
DEA has announced that the 10th annual National Prescription Drug Take-Back will take place on September 26th from 10am to 2pm local time in every state except Pennsylvania and Delaware, where it will take place on September 12th. This is a great opportunity for the public to dispose unwanted and expired medications. These types of medications in the house are a leading cause of accidental poisoning. In addition, inappropriate disposable of medications may also lead to potential safety and health hazards. Check your own medicine cabinets and advise your patients, friends and families. Help get those drugs out of homes and reduce the threat of prescription drug abuse.
What should you do if you miss this event?
Another option for long-term care facilities to dispose of unwanted medications is to transfer those medicines to collectors registered with the DEA. These DEA-authorized collectors safely and securely collect and dispose of pharmaceuticals containing controlled substances and other medicines. In your community, authorized collection sites may be retail pharmacies or hospital pharmacies. These sites may also offer mail-back programs or collection receptacles (or “drop-boxes”) to assist the public in safely disposing of medications. Click here to locate a DEA-authorized collector in your area.
If there is no take-back program or DEA-authorized collectors available in your area, you may also dispose of medicines in household trash or flush certain medicines down the toilet (be sure to know the law in your state before recommending medications to be flushed; for example, flushing medications down the toilet is not recommended in California). The FDA provides an updated list on the drugs recommended for disposal by flushing (last updated in February 2015). For more information on proper drug disposal, please review our previous blog posts on the topic of proper drug disposal.
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