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.
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.
FDA is notifying the public and healthcare professionals of new information about zolpidem, an insomnia drug that is widely prescribed both in the general patient population and in hospice in particular. FDA recommends that the bedtime dose be lowered because new data show that blood levels in some patients may be high enough the morning after use to impair activities that require alertness, including driving. This announcement focuses on zolpidem products approved for bedtime use, which are marketed as generics and under the brand names Ambien (immediate-release zolpidem, 5 mg and 10 mg), Ambien CR (extended-release zolpidem, 6.25 mg and 12.5 mg), Edluar (zolpidem sublingual tablets, 5 mg and 10 mg), and Zolpimist (zolpidem oral spray, 5 mg per actuation).**
Driving simulation and laboratory studies recently submitted to FDA indicate that zolpidem blood levels above approximately 50 ng/mL appear capable of impairing driving to a degree that increases the risk of a motor vehicle accident. In pharmacokinetic trials of 10 mg Ambien (or bioequivalent zolpidem products) that included approximately 250 men and 250 women, about 15% of women and 3% of men had zolpidem concentrations that exceeded 50 ng/mL approximately 8 hours post-dosing. Three measurements in women and one in men were ≥90 ng/mL at about 8 hours after use.
A higher percentage of both men and women experience potentially impairing morning zolpidem levels after use of extended-release zolpidem products (Ambien CR or generic equivalents). In pharmacokinetic trials of zolpidem extended-release 12.5 mg, approximately 33% of women and 25% of men had zolpidem blood concentrations exceeding 50 ng/mL approximately 8 hours post-dosing. About 5% of patients had blood levels ≥100 ng/mL.
In studies of zolpidem extended-release 6.25 mg, at 8 hours after dosing, about 15% of adult women and 5% of adult men had a zolpidem level of ≥50 ng/mL, whereas for both elderly men and women, about 10% had such a zolpidem level.
Because use of lower doses of zolpidem will result in lower blood levels in the morning, FDA is requiring the manufacturers of Ambien, Ambien CR, Edluar, and Zolpimist to lower the recommended dose.
• For immediate-release zolpidem products (Ambien, Edluar, Zolpimist), the recommended initial dose for women should be lowered from 10 mg to 5 mg, immediately before bedtime.
• For extended-release zolpidem products (Ambien CR), the recommended initial dose for women should be lowered from 12.5 mg to 6.25 mg.
• Health care professionals should consider prescribing a lower initial dose in men as well. In many men, the lower dose provides sufficient efficacy.
• For both men and women, the 5 mg dose could be increased to 10 mg if needed, with the understanding that the higher dose is more likely to impair next-morning driving and other activities that require full alertness.
FDA urges health care professionals to caution all patients (men and women) who use these products about the risks of next-morning impairment for activities that require complete mental alertness, including driving. Inform patients that impairment from sleep drugs can be present despite feeling fully awake. Encourage patients to read the Medication Guide when they receive their zolpidem prescription, and report adverse events involving zolpidem or other insomnia drugs to FDA’s MedWatch program.
FDA is continuing to evaluate the risk of impaired mental alertness with other insomnia drugs, including zaleplon (Sonata), eszopiclone (Lunesta), and over-the-counter medications.
**The recommended doses of Intermezzo, a lower dose zolpidem product approved for middle-of-the-night awakenings, are not changing. At the time of Intermezzo’s approval in November 2011, the label already recommended a lower dosage for women (1.75 mg) than for men (3.5 mg).
The FDA has recently approved Silenor for management of insomnia; specifically for insomnia that is characterized by an inability to stay asleep during the night. Silenor is actually not a new drug. It is the latest incarnation of a drug that has been around for over 40 years, Doxepin. Doxepin is a tricyclic antidepressant drug, similar to Amitriptyline (Elavil) and Nortriptyline (Pamelor). You may be familiar with it by another brand-name, Sinequan. Doxepin, in the form of Sinequan, is approved for the management of depression and has been used for this indication since it’s original release in 1969.
Doxepin has significant sedative effects which may provide some benefit in persons suffering from insomnia if taken at bedtime. The drug has a relatively long elimination half-life of 17 hours which confers a long duration of effect throughout the night. The recommended initial dose of Silenor for insomnia is 6mg at bedtime for adult patients under 65 years of age and 3mg for patients 65 years or older. In contrast, the doxepin dose for management of depression will usually range from 50mg – 100mg for patients under 65 years of age. Silenor is contraindicated in persons with Glaucoma or Urinary Retention. Both the 3mg and the 6mg strengths seemed to be well tolerated in the clinical trials. The percentage of patients that discontinued Silenor therapy because of adverse effects was similar to that for placebo. Clinicians familiar with Doxepin for depression management generally associate this drug with a relatively high incidence of adverse effects, mostly anticholinergic in nature. The reasonable tolerability of Silenor observed in the clinical trials for insomnia is likely related to the low doses that are used for insomnia as compared to the much higher doses used for depression. The efficacy of this drug for insomnia compared to placebo was supported by six double-blind studies lasting up to 3 months that included over 1400 patients, aged 18 to 93.
The cost of Silenor is prohibitive. The cost for the 3mg and the 6mg strengths is the same at $6.60 per dose based upon average wholesale price (AWP). This works out to about $100.00 for a 15 day supply at 6mg per night. This does NOT compare favorably to one of the most commonly used sedative-hypnotic drugs used in hospice, Temazepam 15mg. The cost of a 15 day course of Temazepam 15mg at bedtime is about $11.00. Another option available to clinicians would be to consider the use of the old generic Doxepin which is available in the lowest strength as a 10mg capsule. This dosage is slightly higher than the Silenor 6mg, however, the cost differential is huge. A 15 day supply of Doxepin 10mg at bedtime is about $6.50 (a 94% discount off the price of Silenor). There are no studies available comparing the safety and side-effect profile between 6mg and 10mg of Doxepin, however, we know that this drug has been used safely in doses up to 100mg in the management of depression. I cannot recommend the use of Silenor because of the extremely high cost coupled with the availability of the other cost-effective options mentioned. The selection of 6mg as the dosage of Silenor for insomnia seems arbitrary and is probably more related to economics than therapeutics, given the fact that we already have an inexpensive 10mg doxepin dosage-form available.
At Outcome Resources, our goal is to help hospices succeed! Through clinical consultation, reporting, and education programs, Outcome Resources assists hospices of all sizes to focus on best patient care while controlling medication costs. Contact Us or Request an Information Kit to learn more about the benefits available to your hospice through a partnership with Outcome Resources.
|This is both street smart and inteliglent.
Posted 9/18/2012 10:14:56 AM
|Just what we need in hospice, another expensive drug that really has no benefit over currently available products; however, the dosage form is novel.
-- Linda McMahan, R. Ph.
Posted 6/2/2012 05:46:10 PM
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