Geriatric Nursing 35 (2014) 306e307
Contents lists available at ScienceDirect
Geriatric Nursing journal homepage: www.gnjournal.com
Pharmacy Column
William Simonson, PharmD, CGP, FASCP
New sedative/hypnotic dosing guidelines William Simonson, PharmD, CGP, FASCP Independent Consultant Pharmacist, Senior Research Professor (Pharmacy Practice), Oregon State University, Corvallis, OR, USA
Recently, the FDA reduced the recommended dose of eszopiclone (LunestaÒ) after recognizing that some individuals taking this sedative/hypnotic as a sleep aide may experience complications relating to excessive levels of the drug in the body. This recommendation is based partly on a study of 91 healthy adults ages 25e 40 which found that, after taking a 3 mg dose, which is the largest commercially available dose, subjects were more likely to experience severe psychomotor and memory impairment. In a press release the FDA stated that persons taking this drug may have impaired memory, coordination and driving skills as long as 11 h after taking the drug.1 Based on these new recommendations the new official LunestaÒ prescribing information (also known as the package insert) recommends a starting dose of 1 mg for adult men and women rather than the previously recommended starting dose of 2 mg for most non-elderly patients, and recommends a maximum dose of 3 mg. The prescribing information does not specify an initial geriatric dose, so I assume, based on the wording, it is 1 mg. However, what I do find interesting is that the prescribing information still states that the recommended dosage for geriatric or debilitated patients should not exceed 2 mg. In light of these new findings of side effects in healthy younger adults, I’d like to recommend that the manufacturer, Sunovion Pharmaceuticals, take a closer look at geriatric patients taking the 2 mg dose to see if it will put this vulnerable group at additional risk of side effects such as residual drowsiness or impaired memory. What an elderly person certainly does not need is drug-induced memory impairment and, while some people who don’t understand the geriatric patient may think that residual drowsiness in the morning is not a big problem, those of us in the field are well aware that residual drowsiness could result in a fall, perhaps as a person attempts to navigate to the bathroom in the middle of the
E-mail address: [email protected]. 0197-4572/$ e see front matter Ó 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.gerinurse.2014.06.003
night or early in the morning. In that case the results could be catastrophic, or even fatal. In 2013 the FDA took similar action when it lowered the recommended dose of a number of products containing the sedative/ hypnotic zolpidem (AmbienÒ) for similar reasons.2 These products include the brand name drugs AmbienÒ, Ambien CRÒ, EdluarÒ, and ZolpimistÒ as well as the generic versions of AmbienÒ and Ambien CRÒ. The FDA found that, in some patients, zolpidem blood levels were high enough the morning after the drug was taken to cause impairment of activities that required alertness. They found that this impairment was most likely to occur in individuals taking the extended release forms of the drug rather than the immediate release products. And it was also determined that women eliminate the drug from the body more slowly than men, making women more likely to experience side effects relating to higher levels of the drug in the body. Consequently, the FDA lowered the recommended dose of zolpidem for women and, while they didn’t formally lower the recommended dose for men, they did recommend that health professionals also consider using a lower dosage in men. According to pharmacokinetic principles, and just plain common sense, the lower dose in both men and women will result in lower levels of drug in the body the next morning and a decreased chance of adverse side effects. The FDA has informed manufacturers that the new recommended dose for women should be lowered from 10 mg to 5 mg for the immediate-release products (AmbienÒ, EdluarÒ and ZolpimistÒ) and from 12.5 to 6.25 mg for the extended release product, Ambien CRÒ. Dosing recommendations are slightly different for men in that the FDA recommends that health professionals consider prescribing the lower doses (5 mg and 6.25 mg respectively). As expected, recommended doses for geriatric patients and patients with impaired hepatic function are also lower as follows:
W. Simonson / Geriatric Nursing 35 (2014) 306e307
Ambien CRÒ (extended release), 6.25 mg immediately before bedtime Zolpidem (immediate release for males or females), 5 mg immediately before bedtime. Zolpidem is also available as a sub-lingual dosage form (brand name IntermezzoÒ) which is indicated to help people return to sleep after middle-of-the-night awakenings but only if they have a minimum of 4 h of bedtime remaining prior to their planned waking time. For this product the usual adult dose for women is 1.75 mg and for men 3.5 mg and for geriatric patients and patients with hepatic impairment the recommended dose is 1.75 mg. In its press releases the FDA further states “To decrease the potential risk of impairment with all insomnia drugs, health care professionals should prescribe, and patients should take, the lowest dose capable of treating the patient’s insomnia.” This dosing principle can be applied through scientific principles. Scientists and clinicians study the pharmacokinetic properties of drugs to see how they are absorbed into and distributed throughout the body as well as how they are eliminated via the liver, kidneys or other tissues. When the principles of pharmacokinetics are applied to patients it is known as clinical pharmacokinetics and this aspect of pharmaceutical science makes possible the calculation of drug dosages and the modification of dosage regimens to reflect age-related changes that may influence the drug’s activity in the body and its effect on the patient.3 While these new recommendations pertain to both geriatric and non-geriatric adults, the lower geriatric dosage recommendations validate the age-old mantra in geriatric drug therapy of “start low and go slow.” This is a principle based on our understanding that certain drugs may work differently in older individuals including being more slowly eliminated. When this mantra is followed, geriatric patients are first given the lowest possible effective dose of
307
a medication while being observed to see if benefits are achieved without unacceptable adverse side effects. Then, and only then, is an increase in dosage considered, and implemented slowly, rather than in big leaps. As a class, it is well-known that sedative/hypnotics including eszopiclone and zolpidem may cause sedation and residual drowsiness the next morning. This is also true with other drug classes that depress the central nervous system. The chance of sedation and residual drowsiness was already reflected in the official prescribing information for eszopiclone and zolpidem as well as other sedative/hypnotics with many of these products specifying a geriatric dosage recommendation that is typically onehalf the dose recommended for healthy non-elderly adults. A particular concern that I have with zolpidem is that, despite feeling fully awake, there is concern that any activity requiring alertness may be impaired. This could make it very difficult for nurses, pharmacists and others health care workers or family members to determine if a patient is experiencing side effects that might be impairing their function. This concern argues strongly in favor of the FDA’s recommendation of using the lowest dose possible and reflecting again on the previously mentioned geriatric drug therapy mantra, “Start Low and Go Slow!” References 1. FDA Drug Safety Communication, May 15, 2014: FDA Warns of Next-day Impairment With Sleep Aid Lunesta (Eszopiclone) and Lowers Recommended Dose. Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/ UCM397277.pdf; Accessed 03.06.14. 2. FDA Drug Safety Communication, January 10, 2013: Risk of Next-morning Impairment After Use of Insomnia Drugs; FDA Requires Lower Recommended Doses for Certain Drugs Containing Zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist). Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/ UCM335007.pdf; Accessed 03.06.14. 3. Delafuente JC. Geriatric primer: pharmacokinetic and pharmacodynamic alterations in the geriatric patient. Consult Pharm. 2008 April;23(4):324e334.
Contents lists available at ScienceDirect
Geriatric Nursing journal homepage: www.gnjournal.com
Pharmacy Column
William Simonson, PharmD, CGP, FASCP
New sedative/hypnotic dosing guidelines William Simonson, PharmD, CGP, FASCP Independent Consultant Pharmacist, Senior Research Professor (Pharmacy Practice), Oregon State University, Corvallis, OR, USA
Recently, the FDA reduced the recommended dose of eszopiclone (LunestaÒ) after recognizing that some individuals taking this sedative/hypnotic as a sleep aide may experience complications relating to excessive levels of the drug in the body. This recommendation is based partly on a study of 91 healthy adults ages 25e 40 which found that, after taking a 3 mg dose, which is the largest commercially available dose, subjects were more likely to experience severe psychomotor and memory impairment. In a press release the FDA stated that persons taking this drug may have impaired memory, coordination and driving skills as long as 11 h after taking the drug.1 Based on these new recommendations the new official LunestaÒ prescribing information (also known as the package insert) recommends a starting dose of 1 mg for adult men and women rather than the previously recommended starting dose of 2 mg for most non-elderly patients, and recommends a maximum dose of 3 mg. The prescribing information does not specify an initial geriatric dose, so I assume, based on the wording, it is 1 mg. However, what I do find interesting is that the prescribing information still states that the recommended dosage for geriatric or debilitated patients should not exceed 2 mg. In light of these new findings of side effects in healthy younger adults, I’d like to recommend that the manufacturer, Sunovion Pharmaceuticals, take a closer look at geriatric patients taking the 2 mg dose to see if it will put this vulnerable group at additional risk of side effects such as residual drowsiness or impaired memory. What an elderly person certainly does not need is drug-induced memory impairment and, while some people who don’t understand the geriatric patient may think that residual drowsiness in the morning is not a big problem, those of us in the field are well aware that residual drowsiness could result in a fall, perhaps as a person attempts to navigate to the bathroom in the middle of the
E-mail address: [email protected]. 0197-4572/$ e see front matter Ó 2014 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.gerinurse.2014.06.003
night or early in the morning. In that case the results could be catastrophic, or even fatal. In 2013 the FDA took similar action when it lowered the recommended dose of a number of products containing the sedative/ hypnotic zolpidem (AmbienÒ) for similar reasons.2 These products include the brand name drugs AmbienÒ, Ambien CRÒ, EdluarÒ, and ZolpimistÒ as well as the generic versions of AmbienÒ and Ambien CRÒ. The FDA found that, in some patients, zolpidem blood levels were high enough the morning after the drug was taken to cause impairment of activities that required alertness. They found that this impairment was most likely to occur in individuals taking the extended release forms of the drug rather than the immediate release products. And it was also determined that women eliminate the drug from the body more slowly than men, making women more likely to experience side effects relating to higher levels of the drug in the body. Consequently, the FDA lowered the recommended dose of zolpidem for women and, while they didn’t formally lower the recommended dose for men, they did recommend that health professionals also consider using a lower dosage in men. According to pharmacokinetic principles, and just plain common sense, the lower dose in both men and women will result in lower levels of drug in the body the next morning and a decreased chance of adverse side effects. The FDA has informed manufacturers that the new recommended dose for women should be lowered from 10 mg to 5 mg for the immediate-release products (AmbienÒ, EdluarÒ and ZolpimistÒ) and from 12.5 to 6.25 mg for the extended release product, Ambien CRÒ. Dosing recommendations are slightly different for men in that the FDA recommends that health professionals consider prescribing the lower doses (5 mg and 6.25 mg respectively). As expected, recommended doses for geriatric patients and patients with impaired hepatic function are also lower as follows:
W. Simonson / Geriatric Nursing 35 (2014) 306e307
Ambien CRÒ (extended release), 6.25 mg immediately before bedtime Zolpidem (immediate release for males or females), 5 mg immediately before bedtime. Zolpidem is also available as a sub-lingual dosage form (brand name IntermezzoÒ) which is indicated to help people return to sleep after middle-of-the-night awakenings but only if they have a minimum of 4 h of bedtime remaining prior to their planned waking time. For this product the usual adult dose for women is 1.75 mg and for men 3.5 mg and for geriatric patients and patients with hepatic impairment the recommended dose is 1.75 mg. In its press releases the FDA further states “To decrease the potential risk of impairment with all insomnia drugs, health care professionals should prescribe, and patients should take, the lowest dose capable of treating the patient’s insomnia.” This dosing principle can be applied through scientific principles. Scientists and clinicians study the pharmacokinetic properties of drugs to see how they are absorbed into and distributed throughout the body as well as how they are eliminated via the liver, kidneys or other tissues. When the principles of pharmacokinetics are applied to patients it is known as clinical pharmacokinetics and this aspect of pharmaceutical science makes possible the calculation of drug dosages and the modification of dosage regimens to reflect age-related changes that may influence the drug’s activity in the body and its effect on the patient.3 While these new recommendations pertain to both geriatric and non-geriatric adults, the lower geriatric dosage recommendations validate the age-old mantra in geriatric drug therapy of “start low and go slow.” This is a principle based on our understanding that certain drugs may work differently in older individuals including being more slowly eliminated. When this mantra is followed, geriatric patients are first given the lowest possible effective dose of
307
a medication while being observed to see if benefits are achieved without unacceptable adverse side effects. Then, and only then, is an increase in dosage considered, and implemented slowly, rather than in big leaps. As a class, it is well-known that sedative/hypnotics including eszopiclone and zolpidem may cause sedation and residual drowsiness the next morning. This is also true with other drug classes that depress the central nervous system. The chance of sedation and residual drowsiness was already reflected in the official prescribing information for eszopiclone and zolpidem as well as other sedative/hypnotics with many of these products specifying a geriatric dosage recommendation that is typically onehalf the dose recommended for healthy non-elderly adults. A particular concern that I have with zolpidem is that, despite feeling fully awake, there is concern that any activity requiring alertness may be impaired. This could make it very difficult for nurses, pharmacists and others health care workers or family members to determine if a patient is experiencing side effects that might be impairing their function. This concern argues strongly in favor of the FDA’s recommendation of using the lowest dose possible and reflecting again on the previously mentioned geriatric drug therapy mantra, “Start Low and Go Slow!” References 1. FDA Drug Safety Communication, May 15, 2014: FDA Warns of Next-day Impairment With Sleep Aid Lunesta (Eszopiclone) and Lowers Recommended Dose. Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/ UCM397277.pdf; Accessed 03.06.14. 2. FDA Drug Safety Communication, January 10, 2013: Risk of Next-morning Impairment After Use of Insomnia Drugs; FDA Requires Lower Recommended Doses for Certain Drugs Containing Zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist). Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/ UCM335007.pdf; Accessed 03.06.14. 3. Delafuente JC. Geriatric primer: pharmacokinetic and pharmacodynamic alterations in the geriatric patient. Consult Pharm. 2008 April;23(4):324e334.
