Viibryd (vilazodone) was approved in 2011 by FDA for the treatment of major depression. The usual dosage is 40mg once daily with a titration schedule of 10mg for 7 days follow with 20mg for 7 days when initiating therapy. The manufacturer recommended titrating vilazodone when initiating therapy in order to reduce incidences of the most common side effects such as nausea, vomiting and insomnia. The efficacy of this product was established in an 8 week trial and the long-term effect of this product remains unknown. The vilazodone compound is structurally similar to trazodone, but its efficacy is thought to be related to its enhancement of serotonergic activity in the CNS through selective serotonin reuptake inhibition similarly to SSRIs (Selective Serotonin Reuptake Inhibitors). Vilazodone is also a partial agonist at serotonergic 5-HT1A receptors like aripiprazole; however, the result of this action on serotonergic transmission and its role in vilazodone's antidepressant effect are unknown. Clinically, vilazodone is believed to share a similar side effect profile to the SSRIs (citalopram, sertraline, etc.), but with a lower incidence of sexual dysfunction. However, there is no head-to-head comparison between vilazodone and other antidepressants so the clinical advantage of vilazodone for patients is unclear. Due to the limited clinical experience with vilazodone, it is not recommended to be used as a first choice to manage depression because there are many similar low-cost alternatives with tremendous clinical experience available on the market. The recommended first choice for treatment of major depression should remain the generic SSRIs, such as citalopram. The application of vilazodone in hospice practice is limited at this time due to higher cost and very limited clinical experience with its use. Unless the patient came to hospice already stabilized on vilazodone, it would not be a likely choice for depression management in this population.
In hospice, as many of our patients have difficulty swallowing, we are frequently faced with the question of whether or not medications can be crushed or capsules opened for easier administration. The Institute for Safe Medication Practices (ISMP) publishes a very helpful guideline entitled “Oral Dosage Forms That Should Not Be Crushed”, or the “Do Not Crush” list.
There are a number of reasons why a medication should not be crushed. By far the most common reason is when a medication has built-in extended-release properties. For these medications, crushing disrupts the extended-release formulation, resulting in a “dose dumping” effect in which the entire dose, meant to be released over a long period of time (like 12 or 24 hours), is released all at once, immediately. This can result in profound side effects and can even be fatal (such as with extended-release opioids).
Less frequently, medications can’t be crushed because they are too irritating to the stomach or esophageal lining, or because they are particularly toxic or teratogenic. Sometimes, the medication simply tastes bad.
The recently updated 2013 version of the ISMP’s Do Not Crush list can be found here. We recommend consulting this list as a useful reference when determining options for administering medications in a patient with swallowing difficulty.
Dr. Julia Harder, PharmD, CGP
Two years ago, the FDA issued a warning that doses of citalopram (Celexa) exceeding 40 mg per day may cause prolongation of the cardiac QT interval, which can result in potentially fatal cardiac arrhythmias including Torsades de Pointes (please see our previous blog post on the FDA’s warning for more information). In addition, the maximum recommended dose of citalopram for patients greater than 60 years of age – most of the patients we treat in hospice – was reduced to 20 mg per day because of further increased risk of adverse cardiac outcomes in the geriatric population.
A recent study (see reference below) published in the American Journal of Psychiatry offers some evidence that contradicts the FDA’s warnings. In this study, doses of citalopram greater than 40 mg daily were not associated with increased risk of ventricular arrhythmia or all-cause mortality (cardiac and non-cardiac) as compared to lower doses.
This was a cohort study conducted using Veterans Health Administration data between 2004 and 2009. The study included almost a million depressed patients who were prescribed either citalopram (n = 618,450) or sertraline (n = 365,898). Sertraline was used as a comparison because it is also a selective serotonin reuptake inhibitor (SSRI), like citalopram, but does not have any warnings regarding adverse cardiac effects. Statistical analysis examined the association between antidepressant dosing and adverse outcomes including ventricular arrhythmia and all-cause (cardiac and non-cardiac) mortality.
The results were surprising in that higher doses of both antidepressants were actually associated with fewer adverse outcomes. Citalopram daily doses > 40 mg were associated with lower risks of ventricular arrhythmia (adjusted hazard ratio = 0.68, 95% CI = 0.61–0.76) and all-cause mortality (adjusted hazard ratio = 0.94, 95% CI = 0.90–0.99) compared with daily doses of 1–20 mg. Citalopram daily doses of 21–40 mg were associated with lower risks of ventricular arrhythmia (adjusted hazard ratio = 0.80, 95% CI = 0.74–0.86) compared with dosages of 1–20 mg/day but did not have significantly different risks of mortality. The sertraline cohort revealed similar findings, except there were no significant associations between daily dose and mortality. According to the authors, “these results raise questions regarding the continued merit of the FDA warning.”
The FDA’s warning was initially prompted by post-marketing reports of QT interval prolongation and Torsades de Pointes associated with citalopram. The FDA evaluated the results of a thorough QT study assessing the effects of 20 mg and 60 mg doses of citalopram on the QT interval in adults. In this randomized, multi-center, double-blind, placebo-controlled trial, 119 subjects received citalopram 20 mg per day, citalopram 60 mg per day, and placebo in a crossover fashion (meaning each individual received all three interventions for comparison).
Compared to placebo, maximum mean prolongations in the individually corrected QT intervals were 8.5 milliseconds (ms) for 20 mg citalopram and 18.5 ms for 60 mg citalopram. For 40 mg citalopram, prolongation of the corrected QT interval was estimated to be 12.6 ms. Let’s put these numbers in perspective. In adult males a QT interval greater than 450 ms is considered prolonged and between 430 and 450 ms is considered borderline. For females, a QT interval greater than 470 ms is considered prolonged and between 450 and 470 ms is considered borderline. So, you can see that a QT interval increase of nearly 20 ms (as may potentially be seen with the 60 mg dose) could be clinically significant.
As a result of this QT study, the FDA determined that citalopram causes dose-dependent QT interval prolongation and should no longer be used at doses above 40 mg per day. Safety information about the potential for QT interval prolongation and Torsades de Pointes with drug dosage and usage recommendations were added to the package inserts of Celexa and its generic equivalents.
How can we make sense of this conflicting data? While the recent Veterans Health Administration study looked at an incredibly large number of patients, it’s important to keep in mind that, as a cohort study, it can only demonstrate an association, not cause-and-effect. In other words, we cannot determine conclusively whether the antidepressant dose was the direct cause of the varying risks of arrhythmia and mortality, or whether other factors came into play. While the authors did attempt to correct for potentially confounding variables, it is impossible to completely do so with an observational study. Randomized controlled trials (RCTs), which more comprehensively account for confounding variables and are prospective (rather than retrospective) in nature, are considered superior forms of evidence to observational studies like cohort studies. The FDA’s study, though it looked at a much smaller number of patients, was an RCT using a crossover design to demonstrate conclusively the dose-dependent QT prolongation caused by citalopram. So, while the Veterans Health Administration data do raise questions, do not dismiss the FDA’s warnings about citalopram at this time. Especially in the hospice population, where many of our patients are already at an increased risk of QT prolongation and cardiac arrhythmia, it’s important to stick to the dosing limits currently included in citalopram drug labeling. For more comprehensive information about QT prolongation, including risk factors and which other medications may cause it, please see this blog post.
Zivin K, Pfeiffer PN, Bohnert ASB, et al. Evaluation of the FDA warning against prescribing citalopram at doses exceeding 40 mg. Am J Psychiatry. 2013; 170: 642-650.
Dr. Julia Harder, PharmD CGP
With so many different benzodiazepines available, each with its own distinct pharmacokinetic profile, it can sometimes be difficult to choose an appropriate agent to match a patient’s needs. We’ve developed this Benzodiazepines Chart to help you compare the benzodiazepines, understand their similarities and differences, and make patient-specific selections.
You will notice that the chart places emphasis on the pharmacokinetics of each agent. That’s because the pharmacokinetics are the main way in which the benzodiazepines differ from one another. Primarily, we focus on the half-life (which tells you something about the medication’s duration of action) and the speed of onset. In hospice patients, we want to avoid the benzodiazepines with very long half-lives, as these agents stick around for days, and many have metabolites that accumulate (especially in the elderly). We may also want to avoid benzodiazepines with very short half-lives (such as midazolam), except in specific circumstances.
Route of administration is frequently important in hospice. Most benzodiazepines can only be given PO, but a select few can be given sublingually or via injection, and diazepam can be given rectally. You will see on the chart which routes of administration, and which dosage forms, are available for each agent.
“Typical and Max Dosing” is there mainly to give you a feel for where most patients should be. But the therapeutic dose and the maximum daily dose sometimes depend on indication (anxiety versus seizure disorder, for example). For more precise dosing you may need to consult a comprehensive dosing reference, and always titrate to your patient’s needs.
We’ve also included a “Comparative Oral Dose” column to help you convert from one agent to another. Please keep in mind that these numbers are only estimates. In some cases, especially for those benzodiazepines that are not as well studied, the numbers vary widely depending on which reference you consult. In other cases (such as converting from lorazepam to alprazolam, for example), the conversion ratios are pretty consistent. But, each patient is unique and we can never completely predict how a specific patient will respond to one medication versus another. So, you will need to use your clinical judgment any time you convert a patient from one benzodiazepine to another, and should always monitor the patient very closely.
The chart does not include pricing information. Pricing is fairly consistent across this medication category, with a few notable exceptions which you will find in the “Comments” column.
We hope you find this chart useful in your hospice practice, and welcome any questions or comments here on the 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
Risks Associated with PPIs
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):
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.
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:
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:
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.
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.
|The cost of a medication does not solely depend on the amount of active ingredient contained within it. Intuitively, it would seem that this should be the case, but experience shows us it is not. Competition in the marketplace is a major determinant of medication cost, and at the moment, there is only one generic manufacturer making hydrocodone/APAP combination products containing 300 mg of acetaminophen -- so they can charge more. When more generic manufacturers start making these products, the cost will go down.
Vicodin and Lortab used to be therapeutically equivalent, when Vicodin contained 500 mg of acetaminophen per tablet. Now that Vicodin has been reformulated to contain 300 mg of acetaminophen per tablet, they no longer are. Now we have Lortab (500 mg APAP), Norco (325 mg APAP), and Vicodin (300 mg APAP) -- plus generic versions of all of these... So confusing! In my opinion, the easiest way for prescribers to get the exact product they want is to write for generic hydrocodone/APAP and specify the strength of each component (for now, avoiding the 300 mg APAP products because they are so much more expensive).
-- Julia Harder
Posted 6/3/2013 08:18:27 AM
|Excuse my ignorance, but why would a medication containing 25 less mg of acetamenaphen cost more money to make than the usual 325mg that have been used for years? Also I have found that prescribers 75-80% of the time order Lortab 7.5/325 or 10/325 which in brand or genetic form is less expensive and if I learned anything in pharmacology class there would be no difference in the medication Vicodin vs Lortab or have I been taught incorrectly?
-- G Faulk, RN
Posted 5/27/2013 09:48:39 PM
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:
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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