HHS Public Access Author manuscript Author Manuscript
Ann Longterm Care. Author manuscript; available in PMC 2016 June 21. Published in final edited form as: Ann Longterm Care. 2016 January ; 24(1): 25–30.
Implications of Recent Drug Approvals for Older Adults Christine Eisenhower, PharmD, BCPS1, Michael Koronkowski, PharmD2, and Zachary Marcum, PharmD, PhD3
Author Manuscript
1University
of Rhode Island College of Pharmacy, Kingston, RI
2University
of Illinois at Chicago, College of Pharmacy, Chicago, IL
3University
of Washington School of Pharmacy, Seattle, WA
Abstract More than 100 medications were approved by the US Food and Drug Administration as new drugs or for new indications in 2014 and 2015. Several of the new drugs may benefit older adults, but adverse events and pharmacokinetic changes due to aging must be considered. This article will focus on three recently approved drugs that are marketed for chronic conditions that can affect older adults: suvorexant, for treatment of insomnia; edoxaban, for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for treatment of venous thromboembolism; and droxidopa, for treatment of symptomatic neurogenic orthostatic hypotension. Information about indications, mechanisms of action, dosing, efficacy, and safety are reviewed. The place of each agent in therapy for older adults is also discussed.
Author Manuscript
Keywords older adults; new drug approvals; suvorexant; edoxaban; droxidopa
Author Manuscript
More than 70 medications were approved by the US Food and Drug Administration (FDA) as new drugs or for new indications in 2014, and there were more than 50 approvals in 2015.1 Several of these new drugs may benefit older adults, but clinicians must consider adverse events and pharmacokinetic changes due to aging. In addition, older adult participants in the clinical trials necessary for drug approval are often healthier and younger than those who are prescribed medications in practice.2 Therefore, it is important to consider age limitations in trials as well as differences in safety and efficacy in older versus younger age groups. In particular, overall trial demographics should be evaluated to determine if new medications have been studied in older adults with renal or hepatic impairment and common comorbidities.
Address correspondence to: Christine Eisenhower, PharmD, BCPS, Dept of Pharmacy Practice, Suite 244, URI College of Pharmacy, 7 Greenhouse Rd, Kingston, RI 02881, Phone: (401) 874-7662, [email protected]. Disclosures: Dr. Koronkowski is a consultant for OptumRx and received research grants from the Illinois Department on Aging and the US Department of Health and Human Services, Geriatric Workforce Program.
Eisenhower et al.
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Author Manuscript
Suvorexant
Author Manuscript
This article will review the efficacy, safety, cost, and place in therapy for three drugs approved in 2014–15, as presented at the 2015 Annual Scientific Meeting of the American Geriatrics Society (May 15–17; Washington, DC).
Efficacy and Safety
Suvorexant is a novel orexin receptor antagonist approved for the treatment of primary insomnia that improves both sleep onset and maintenance.3 The orexin neuropeptide signaling system supports wakefulness, and suvorexant blocks the binding of orexin neuropeptides to receptors, thus suppressing the wake drive. Initial dosing of oral suvorexant is 10 mg daily, with a maximum approved dose of 20 mg daily. For older adults, there are no dosage adjustments for renal impairment or advanced age.3 Suvorexant is scheduled as a controlled substance (C-IV)4 because adverse effects, such as amnesia and problems performing sleep-related activities (eg, walking, eating, driving), may be similar to those found in zolpidem.3 The estimated average wholesale price (AWP) of suvorexant is $316 for a 30-day supply of 10-mg, 15-mg, or 20-mg tablets.5
Author Manuscript
Suvorexant has been studied versus placebo in two randomized, double-blind, parallelgroup, phase 3 trials whose primary objective was to evaluate the efficacy of suvorexant over 3 months, based on subjective information from patients’ sleep diaries: subjective total sleep time (sTST), subjective time to sleep onset (sTSO), wakefulness after persistent sleep onset (WASO), and latency to onset of persistent sleep (LPS).6 There were 1021 patients enrolled in the first trial and 1009 patients in the second trial, and the average patient in each trial was 55–57 years of age, female, normal weight, white, and had a baseline sTST of 298–322 minutes and a baseline sTSO of 63–86 minutes. Patients were randomized to receive suvorexant 40 mg or 20 mg daily if they were younger than 65 years of age, or suvorexant 30 mg or 15 mg daily if they were 65 years or older. Patients receiving suvorexant in the study gained 10.7–22.1 more minutes of sleep per night and fell asleep 5.2–7.6 minutes faster than patients receiving placebo.6 Results for sTST and sTSO are shown in Table 1. Although improvements in sTST and sTSO were statistically significant versus placebo, the clinical significance of these improvements to the individual patient should be considered.
Author Manuscript
A 2014 study by Michelson and colleagues evaluated the safety and efficacy of suvorexant over 1 year.7 The average patient in this study was 61–62 years old, female, overweight, and white.7 Patients were randomized to receive suvorexant 30 mg daily if 65 years of age or older or 40 mg daily if younger than 65 years of age.7 Eleven percent of patients in the suvorexant group discontinued due to adverse events, and a total of 63% of participants completed 1 year of the study. The most prevalent adverse event was mild-to-moderate somnolence (4% vs 1% with placebo), which was also the most common reason for discontinuation.7 Somnolence occurred most frequently during the first 3 months of the study (11% with suvorexant vs 2% with placebo) and decreased in incidence as the study went on (3% with suvorexant vs less than 1% with placebo). Other common adverse events were fatigue and dry mouth (6.5% and 5.0% with suvorexant, respectively, vs 1.9% and 1.6% with placebo, respectively).7
Ann Longterm Care. Author manuscript; available in PMC 2016 June 21.
Eisenhower et al.
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Author Manuscript
At the end of 1 year, patients who received suvorexant were randomized to a 2-month discontinuation trial.7 No significant differences in the incidence of rebound insomnia and withdrawal effects were observed between patients who continued suvorexant (n=152) and those who abruptly discontinued (n=161).7 Thus, this study demonstrated tolerability over 1 year, as well as safety of abrupt discontinuation with high doses of suvorexant. In terms of efficacy, improvement in sTST from Month 1 to Month 12 with suvorexant (from 16.2 minutes to 30.5 minutes) was significantly greater than with placebo (from 16.2 minutes to 38.8 minutes). Place in Therapy
Author Manuscript
Prescribing information for suvorexant states that 829 patients in clinical trials of the drug were 65 years of age or older, and 159 patients were 75 years or older.3 The manufacturer reports that there were no significant differences in safety and efficacy for older patients versus younger patients,3 even considering the administration of high doses in several studies. However, a small study in healthy older adults awakened during the night suggested that their balance might be impaired.3 In addition, patients who are female and/or obese may be exposed to higher levels of suvorexant and therefore be more susceptible to its effects. Use of suvorexant is contraindicated for patients with a history of narcolepsy, due to antagonism of orexin receptors by the drug.3 Adverse effects can be potentiated by concomitant use of central nervous system (CNS) depressants.3,5
Author Manuscript
Suvorexant has not been studied in patients with a history of obstructive sleep apnea, chronic obstructive pulmonary disease, substance abuse, certain neurologic disorders (including cognitive impairment), or major psychiatric illness.3 At this time, no published studies directly compare suvorexant to other agents that are approved by the FDA for the treatment of insomnia, including eszopiclone, zaleplon, zolpidem (both immediate- and controlledrelease), temazepam (short-term use), and ramelteon (sleep onset only). Suvorexant has also not been compared to the non–FDA approved agent melatonin, which is used to reduce sleep-onset latency. Thus, comparative effectiveness research is needed.
Author Manuscript
The American Geriatrics Society 2015 Beers Criteria Update warns against the use of both benzodiazepines and non-benzodiazepine hypnotics for insomnia because of increased risk of cognitive impairment, delirium, falls and fractures, and motor vehicle accidents.8 In addition, there may be minimal improvement in insomnia with non-benzodiazepine hypnotics.8 Although suvorexant is approved for the treatment of primary insomnia, the drug should be avoided for the treatment of insomnia in older adults based on the limited efficacy of suvorexant in clinical trials and the similarity of its adverse event profile to benzodiazepine and non-benzodiazepine hypnotics. Non-pharmacological strategies such as sleep hygiene and structured cognitive behavioral therapies for insomnia remain first-line treatments for chronic insomnia.9
Edoxaban Edoxaban is a factor Xa inhibitor approved for: 1) the prevention of stroke and systemic embolism (SE) in patients with non-valvular atrial fibrillation (NVAF); and 2) the treatment
Ann Longterm Care. Author manuscript; available in PMC 2016 June 21.
Eisenhower et al.
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Author Manuscript
of deep vein thrombosis (DVT) and pulmonary embolism (PE) after 5–10 days of a parenteral anticoagulant.10 Edoxaban selectively inhibits free factor Xa and prothrombinase activity, thereby preventing thrombin-induced platelet aggregation.10 Dosing is based on indication and creatinine clearance (CrCl). Blister-pack dispensing may be helpful for older adults who are managing their own medications and have multiple medications or mild cognitive impairment. The estimated AWP of edoxaban is $332 for a 30-day supply of each 15-mg, 30-mg, or 60-mg tablets.11
Author Manuscript
The normal dosing of edoxaban for patients with NVAF is 60 mg daily with or without food, and there are no dosage adjustments for advanced age.10 Results from the ENGAGE AFTIMI 48 (Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation– Thrombolysis in Myocardial Infarction 48) trial demonstrated an increased risk of ischemic stroke versus warfarin in patients with a CrCl (according to the Cockcroft-Gault equation) >95 mL/min; edoxaban should not be prescribed to such patients in practice.10 In addition, edoxaban should be adjusted to 30 mg daily if CrCl is 15–50 mL/min.10 Clinicians should be aware that patients with a CrCl
Ann Longterm Care. Author manuscript; available in PMC 2016 June 21. Published in final edited form as: Ann Longterm Care. 2016 January ; 24(1): 25–30.
Implications of Recent Drug Approvals for Older Adults Christine Eisenhower, PharmD, BCPS1, Michael Koronkowski, PharmD2, and Zachary Marcum, PharmD, PhD3
Author Manuscript
1University
of Rhode Island College of Pharmacy, Kingston, RI
2University
of Illinois at Chicago, College of Pharmacy, Chicago, IL
3University
of Washington School of Pharmacy, Seattle, WA
Abstract More than 100 medications were approved by the US Food and Drug Administration as new drugs or for new indications in 2014 and 2015. Several of the new drugs may benefit older adults, but adverse events and pharmacokinetic changes due to aging must be considered. This article will focus on three recently approved drugs that are marketed for chronic conditions that can affect older adults: suvorexant, for treatment of insomnia; edoxaban, for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for treatment of venous thromboembolism; and droxidopa, for treatment of symptomatic neurogenic orthostatic hypotension. Information about indications, mechanisms of action, dosing, efficacy, and safety are reviewed. The place of each agent in therapy for older adults is also discussed.
Author Manuscript
Keywords older adults; new drug approvals; suvorexant; edoxaban; droxidopa
Author Manuscript
More than 70 medications were approved by the US Food and Drug Administration (FDA) as new drugs or for new indications in 2014, and there were more than 50 approvals in 2015.1 Several of these new drugs may benefit older adults, but clinicians must consider adverse events and pharmacokinetic changes due to aging. In addition, older adult participants in the clinical trials necessary for drug approval are often healthier and younger than those who are prescribed medications in practice.2 Therefore, it is important to consider age limitations in trials as well as differences in safety and efficacy in older versus younger age groups. In particular, overall trial demographics should be evaluated to determine if new medications have been studied in older adults with renal or hepatic impairment and common comorbidities.
Address correspondence to: Christine Eisenhower, PharmD, BCPS, Dept of Pharmacy Practice, Suite 244, URI College of Pharmacy, 7 Greenhouse Rd, Kingston, RI 02881, Phone: (401) 874-7662, [email protected]. Disclosures: Dr. Koronkowski is a consultant for OptumRx and received research grants from the Illinois Department on Aging and the US Department of Health and Human Services, Geriatric Workforce Program.
Eisenhower et al.
Page 2
Author Manuscript
Suvorexant
Author Manuscript
This article will review the efficacy, safety, cost, and place in therapy for three drugs approved in 2014–15, as presented at the 2015 Annual Scientific Meeting of the American Geriatrics Society (May 15–17; Washington, DC).
Efficacy and Safety
Suvorexant is a novel orexin receptor antagonist approved for the treatment of primary insomnia that improves both sleep onset and maintenance.3 The orexin neuropeptide signaling system supports wakefulness, and suvorexant blocks the binding of orexin neuropeptides to receptors, thus suppressing the wake drive. Initial dosing of oral suvorexant is 10 mg daily, with a maximum approved dose of 20 mg daily. For older adults, there are no dosage adjustments for renal impairment or advanced age.3 Suvorexant is scheduled as a controlled substance (C-IV)4 because adverse effects, such as amnesia and problems performing sleep-related activities (eg, walking, eating, driving), may be similar to those found in zolpidem.3 The estimated average wholesale price (AWP) of suvorexant is $316 for a 30-day supply of 10-mg, 15-mg, or 20-mg tablets.5
Author Manuscript
Suvorexant has been studied versus placebo in two randomized, double-blind, parallelgroup, phase 3 trials whose primary objective was to evaluate the efficacy of suvorexant over 3 months, based on subjective information from patients’ sleep diaries: subjective total sleep time (sTST), subjective time to sleep onset (sTSO), wakefulness after persistent sleep onset (WASO), and latency to onset of persistent sleep (LPS).6 There were 1021 patients enrolled in the first trial and 1009 patients in the second trial, and the average patient in each trial was 55–57 years of age, female, normal weight, white, and had a baseline sTST of 298–322 minutes and a baseline sTSO of 63–86 minutes. Patients were randomized to receive suvorexant 40 mg or 20 mg daily if they were younger than 65 years of age, or suvorexant 30 mg or 15 mg daily if they were 65 years or older. Patients receiving suvorexant in the study gained 10.7–22.1 more minutes of sleep per night and fell asleep 5.2–7.6 minutes faster than patients receiving placebo.6 Results for sTST and sTSO are shown in Table 1. Although improvements in sTST and sTSO were statistically significant versus placebo, the clinical significance of these improvements to the individual patient should be considered.
Author Manuscript
A 2014 study by Michelson and colleagues evaluated the safety and efficacy of suvorexant over 1 year.7 The average patient in this study was 61–62 years old, female, overweight, and white.7 Patients were randomized to receive suvorexant 30 mg daily if 65 years of age or older or 40 mg daily if younger than 65 years of age.7 Eleven percent of patients in the suvorexant group discontinued due to adverse events, and a total of 63% of participants completed 1 year of the study. The most prevalent adverse event was mild-to-moderate somnolence (4% vs 1% with placebo), which was also the most common reason for discontinuation.7 Somnolence occurred most frequently during the first 3 months of the study (11% with suvorexant vs 2% with placebo) and decreased in incidence as the study went on (3% with suvorexant vs less than 1% with placebo). Other common adverse events were fatigue and dry mouth (6.5% and 5.0% with suvorexant, respectively, vs 1.9% and 1.6% with placebo, respectively).7
Ann Longterm Care. Author manuscript; available in PMC 2016 June 21.
Eisenhower et al.
Page 3
Author Manuscript
At the end of 1 year, patients who received suvorexant were randomized to a 2-month discontinuation trial.7 No significant differences in the incidence of rebound insomnia and withdrawal effects were observed between patients who continued suvorexant (n=152) and those who abruptly discontinued (n=161).7 Thus, this study demonstrated tolerability over 1 year, as well as safety of abrupt discontinuation with high doses of suvorexant. In terms of efficacy, improvement in sTST from Month 1 to Month 12 with suvorexant (from 16.2 minutes to 30.5 minutes) was significantly greater than with placebo (from 16.2 minutes to 38.8 minutes). Place in Therapy
Author Manuscript
Prescribing information for suvorexant states that 829 patients in clinical trials of the drug were 65 years of age or older, and 159 patients were 75 years or older.3 The manufacturer reports that there were no significant differences in safety and efficacy for older patients versus younger patients,3 even considering the administration of high doses in several studies. However, a small study in healthy older adults awakened during the night suggested that their balance might be impaired.3 In addition, patients who are female and/or obese may be exposed to higher levels of suvorexant and therefore be more susceptible to its effects. Use of suvorexant is contraindicated for patients with a history of narcolepsy, due to antagonism of orexin receptors by the drug.3 Adverse effects can be potentiated by concomitant use of central nervous system (CNS) depressants.3,5
Author Manuscript
Suvorexant has not been studied in patients with a history of obstructive sleep apnea, chronic obstructive pulmonary disease, substance abuse, certain neurologic disorders (including cognitive impairment), or major psychiatric illness.3 At this time, no published studies directly compare suvorexant to other agents that are approved by the FDA for the treatment of insomnia, including eszopiclone, zaleplon, zolpidem (both immediate- and controlledrelease), temazepam (short-term use), and ramelteon (sleep onset only). Suvorexant has also not been compared to the non–FDA approved agent melatonin, which is used to reduce sleep-onset latency. Thus, comparative effectiveness research is needed.
Author Manuscript
The American Geriatrics Society 2015 Beers Criteria Update warns against the use of both benzodiazepines and non-benzodiazepine hypnotics for insomnia because of increased risk of cognitive impairment, delirium, falls and fractures, and motor vehicle accidents.8 In addition, there may be minimal improvement in insomnia with non-benzodiazepine hypnotics.8 Although suvorexant is approved for the treatment of primary insomnia, the drug should be avoided for the treatment of insomnia in older adults based on the limited efficacy of suvorexant in clinical trials and the similarity of its adverse event profile to benzodiazepine and non-benzodiazepine hypnotics. Non-pharmacological strategies such as sleep hygiene and structured cognitive behavioral therapies for insomnia remain first-line treatments for chronic insomnia.9
Edoxaban Edoxaban is a factor Xa inhibitor approved for: 1) the prevention of stroke and systemic embolism (SE) in patients with non-valvular atrial fibrillation (NVAF); and 2) the treatment
Ann Longterm Care. Author manuscript; available in PMC 2016 June 21.
Eisenhower et al.
Page 4
Author Manuscript
of deep vein thrombosis (DVT) and pulmonary embolism (PE) after 5–10 days of a parenteral anticoagulant.10 Edoxaban selectively inhibits free factor Xa and prothrombinase activity, thereby preventing thrombin-induced platelet aggregation.10 Dosing is based on indication and creatinine clearance (CrCl). Blister-pack dispensing may be helpful for older adults who are managing their own medications and have multiple medications or mild cognitive impairment. The estimated AWP of edoxaban is $332 for a 30-day supply of each 15-mg, 30-mg, or 60-mg tablets.11
Author Manuscript
The normal dosing of edoxaban for patients with NVAF is 60 mg daily with or without food, and there are no dosage adjustments for advanced age.10 Results from the ENGAGE AFTIMI 48 (Effective aNticoaGulation with factor xA next GEneration in Atrial Fibrillation– Thrombolysis in Myocardial Infarction 48) trial demonstrated an increased risk of ischemic stroke versus warfarin in patients with a CrCl (according to the Cockcroft-Gault equation) >95 mL/min; edoxaban should not be prescribed to such patients in practice.10 In addition, edoxaban should be adjusted to 30 mg daily if CrCl is 15–50 mL/min.10 Clinicians should be aware that patients with a CrCl
