Baclofen and Risk of Encephalopathy
The 30-day risk of encephalopathy was at least two times as high in patients treated with the muscle relaxant baclofen when compared with other muscle relaxants, tizanidine or cyclobenzaprine. This was demonstrated in an active comparator study conducted using new user data from the Geisinger Health System, a large tertiary health care system in Pennsylvania.
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Baclofen is a GABA agonist, and case reports and recent population-based studies have linked its use to encephalopathy in patients with kidney disease. It's thought that this encephalopathy is related to baclofen's effect on GABAB receptors, that excessive activation can reduce the release of neurotransmitters, resulting in disorientation and other cognitive impairments, and can also decrease cerebral blood flow and metabolic activity, leading to more severe symptoms.
The study examined results in patients age 18 and older who were studied in two separate paired cohorts; cohort 1 compared baclofen and tizanidine, and cohort 2 compared baclofen and cyclobenzaprine. It balanced the cohorts on 45 patient characteristics and conducted subgroup analyses based on age, estimated GFR, sex, and concomitant opioid use.
In cohort 1, the 30-day risk of encephalopathy was 64.7 per 1,000 person-years with baclofen compared to 28.3 per 1,000 person-years with tizanidine. The 30-day risk in cohort 2 was 52.6 per 1,000 person-years with baclofen compared to 22.3 per 1,000 person-years with cyclobenzaprine. The elevated risk, apparent as early as 30 days, persisted through the first year of treatment. In cohort 1, the subdistribution hazard ratio (SHR) of elevated encephalopathy risk at 30 days was 2.29; at 1 year, SHR with baclofen was 1.32. In cohort 2, the SHR at 30 days was 2.35; at 1 year, SHR with baclofen was 1.94. This increased risk remained consistent in all subgroup analyses.
These findings may inform shared treatment decisions between patients and prescribers. Doctors and other prescribers could consider the use of alternative muscle relaxants or initiate baclofen at a lower dose, especially in patients with kidney disease. Patients should be educated to watch for the signs of the toxic effects, and health care providers should monitor for them. Finally, it might be appropriate for regulatory agencies to consider issuing warning labels about the potential risk, particularly in patients with chronic kidney disease. (Hwang, Y. J., et al. (2023). Baclofen and the risk of encephalopathy: A real-world, active-comparator cohort study. Mayo Clin Proceed, 98(5), 676&en688. Retrieved June 2023 from https://www.mayoclinicproceedings.org/article/S0025-6196(22)00649-8/fulltext; Muanda, F. T., et al. (2023). Reviewing the evidence of the association between baclofen and encephalopathy. Mayo Clin Proceed, 98(5), 647–649. Retrieved June 2023 from https://www.mayoclinicproceedings.org/article/S0025-6196(23)00134-9/fulltext)
Released: June 2023
Nursing Drug Handbook
© 2023 Wolters Kluwer
Dupilumab Appears to be Superior Biologic for Asthma
A study using data from a single integrated health system suggests that dupilumab has the lowest overall risk of asthma-related exacerbations when compared with omalizumab and mepolizumab. Multiple biologics have been approved for treatment of asthma, but head-to-head comparisons of these biologics are lacking. Researchers conducted a retrospective cohort study that emulated a hypothetical randomized trial, a target trial to compare the effectiveness of these biologics in reducing asthma exacerbations and improving lung function.
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The agents in the analysis were omalizumab, an anti-IgE biologic approved for allergic asthma with sensitivity to perennial allergens and IgE levels between 30 and 700 kU/L; mepolizumab, an anti-IL-5 biologic effective in eosinophilic asthma with blood eosinophil counts of at least 150 cells/microliter; and dupilumab, an anti-IL-4 receptor biologic effective in both allergic and eosinophilic asthma. Using the integrated health records from the Massachusetts General Bingham Research Patient Data Registry, the study examined results for adults with moderate to severe asthma and no other chronic lung diseases; participants included 68 patients receiving dupilumab, 68 omalizumab, and 65 mepolizumab. Researchers examined for incidence of asthma-related exacerbations and change in baseline FEV1 value over 12 months of follow-up. Clinically significant exacerbations were defined as emergency department visits or hospitalizations with a primary diagnostic code for asthma or an outpatient prescription for corticosteroids in patients with asthma. Over 12 months of follow-up, asthma-related exacerbations occurred in 17 patients in the dupilumab group (25.0%), 28 patients in the mepolizumab group (43.1%), and 27 patients in the omalizumab group (39.7%). The number of exacerbations recorded and their incidence were as follows:
- dupilumab: 31 exacerbations (0.46 per person-year)
- omalizumab: 63 exacerbations (0.93 per person-year)
- mepolizumab: 86 exacerbations (1.32 per person-year)
The adjusted incidence rate ratios (IRR) were 0.28 for dupilumab versus mepolizumab, 0.36 for dupilumab versus omalizumab, and 0.78 for omalizumab versus mepolizumab. Results were similar for adjusted IRR in patients with eosinophil counts of at least 300 cells/microliter: 0.26 for dupilumab versus mepolizumab and 0.33 for dupilumab versus omalizumab.
At 12 months' follow-up, change from baseline in prebronchodilator FEV1 values was greater in patients receiving dupilumab than in those receiving mepolizumab (mean difference, 0.11 L) or in those receiving omalizumab (mean difference, 0.082 L), but were not statistically significant. (Akenroye, A. T., et al. (2023). Comparative effectiveness of omalizumab, mepolizumab, and dupilumab in asthma: A target trial emulation. J Allergy Clin Immunol, 151(5), 1269–1276. Retrieved June 2023 from https://www.jacionline.org/article/S0091-6749(23)00144-6/fulltext)
Released: June 2023
Nursing Drug Handbook
© 2023 Wolters Kluwer
Prophylactic Antiemetics before Apomorphine to Treat Parkinson Disease May Be Unnecessary
Post hoc analysis of data from the dose optimization phase of an open-label, long-term safety and efficacy study of sublingual apomorphine (SL-APO) in patients with Parkinson disease demonstrated rates of nausea and vomiting similar to those seen with other dopaminergic medications and with other apomorphine preparations. Nausea is common in patients with Parkinson disease, and many Parkinson disease medications in particular, levodopa and dopamine agonists can exacerbate nausea and vomiting. Because prophylactic antiemetics were used in clinical trials of apomorphine but not in trials of other dopamine agonists, the FDA recommends their use. This study evaluated the need for such antiemetics. U.S. prescribing information recommends prophylactic use of trimethobenzamide, but it has been in short supply and the alternative, domperidone, is not approved for use in the United States.
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Eligible patients had idiopathic Parkinson disease, were responsive to and were receiving stable doses of carbidopa-levodopa (with or without adjunctive medications), and had experienced at least one OFF episode per day with at least 2 hours of daily OFF time. During sequential office visits, patients underwent dose optimization (10 to 35 mg at 5-mg increments) when in an OFF state to determine the individualized dose that resulted in a tolerable FULL ON within 45 minutes. FULL ON was considered to be achieved when SL-APO treatment produced benefits in mobility, stiffness, and slowness; achieved adequate motor function to perform normal activities of daily living; and resulted in a response comparable or better than the patient's former responses to Parkinson disease medications. Once such a tolerable FULL ON dose was identified for the individual patient, the patient progressed into an open-label maintenance phase.
The dose optimization population in the study included 449 patients; most were male (66.4%), white (96.0%), and had a mean age of 64.3 years. Of these 449 patients, 82.2% were new patients with no prior exposure to SL-APO, and all patients were also receiving carbidopa-levodopa. In the dose optimization phase of the trial, 88.4% (n = 397) successfully achieved an effective and tolerable dose; of these patients, 12.3% (n = 49) and 1.3% (n = 5) experienced vomiting during the optimization phase. Among those who had nausea and vomiting during dose optimization and continued into the long-term maintenance phase of the study, nausea occurred in 44.9% (22/49) and vomiting in 40.0% (2/5) during maintenance. Among those who had not experienced nausea and vomiting during dose optimization, 19.1% went on to report nausea and vomiting during maintenance.
Of the patients in the dose optimization phase, 43.7% (n = 196) didn't use an antiemetic during that phase of the study; most of these patients (169/196) achieved an effective and tolerable SL-APO dose. Nausea and vomiting were uncommon in these patients: 12.2% (n = 24) had nausea, and 0.5% (n = 1) experienced vomiting. Nausea and vomiting were also seen among the 56.3% (n = 253) of patients who had used an antiemetic at any time during that phase of the study: 17.0% (n = 43) had nausea, and 2.4% (n = 6) experienced vomiting. Of the 67 patients who did experience nausea and the 7 who experienced vomiting, all events were mild to moderate, except for 1 severe occurrence of each.
Importantly, less than half of all patients in this analysis who experienced nausea and vomiting went on to experience these events again during maintenance treatment, suggesting that patients can develop tolerance to those side effects over time. The choice of using prophylactic antiemetics should be made based on the individual's risks and benefits, as there may be patients who find it lessens their symptoms, but this research demonstrates that it's not necessary for most patients initiating SL-APO for treatment of OFF episodes in Parkinson disease. (Hauser, R. A., et al. (2023). Dose optimization of apomorphine sublingual film for OFF episodes in Parkinson's Disease: Is the prophylactic use of an antiemetic necessary? J Parkinson Dis, 13(3), 403–414. Retrieved June 2023 from https://content.iospress.com/articles/journal-of-parkinsons-disease/jpd223537)
Released: June 2023
Nursing Drug Handbook
© 2023 Wolters Kluwer
Spironolactone for Acne Vulgaris
The Spironolactone for Adult Female Acne (SAFA) trial evaluated the effectiveness of the potassium-sparing diuretic against persistent facial acne in adult women in the UK when given in addition to standard topical treatments. Treatment guidance for acne recommends fixed-combination topical preparations containing retinoids, benzoyl peroxide, and antibiotics as first-line treatments. One-third of people under care for acne in the UK receive secondary treatment with long courses of oral antibiotics; given the increasing prevalence of antibiotic resistance, looking for an alternative is important. Spironolactone, which has been used off-label to treat acne, has been suggested as that alternative.
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In the pragmatic, multicenter, phase 3, double-blind, randomized controlled trial, study participants were older than age 18 with facial acne for at least 6 months, with acne of sufficient severity to warrant treatment by oral antibiotics, as judged by a clinician, and with an IGA of at least 2; 342 participants were included in the primary analysis. They were randomly assigned to either 50 mg/day spironolactone (n = 176) or matched placebo (n = 166) for 6 weeks, increasing to 100 mg/day up to week 24. At 24 weeks, the study was unblinded, and patients could choose to continue or start spironolactone. The mean age at baseline was 29.2 years; 46% had mild acne, 40% had moderate acne, and 13% had severe acne. Each participant underwent baseline assessments, including pregnancy tests, blood tests to exclude abnormal kidney function or hyperkalemia, a baseline photo, and contraceptive counseling. They were followed up at 6 weeks and 12 weeks, with a primary outcome assessment at 12 weeks, and longer-term follow-up by questionnaires from 24 weeks up to 52 weeks.
Researchers measured effectiveness through the Acne-Specific Quality of Life questionnaire (Acne-QOL), which contains 19 questions organized into four domains (self-perception, social role, emotional role, and acne symptoms); each subscale has a range of 0 to 30, in which higher scores reflect improved QOL. Mean Acne-QOL acne symptoms subscale score was 13.2 for spironolactone at baseline and 12.9 for placebo. At week 12, scores had improved to 19.2 in the spironolactone group and 17.8 in the placebo group. The difference, 1.27, was small, but was statistically significant. At 24 weeks, the difference was greater: 3.45 (acne symptom subscale score 2.12 with spironolactone and 17.4 with placebo). More participants in the spironolactone group self-reported acne improvement than in the placebo group. No significant differences were noted at week 12 (72% of participants versus 68%), but the difference at week 24 (82% versus 63%) was significant (odds ratio, 1.16). The IGA of treatment success was demonstrated in 31/168 (19%) of those given spironolactone and in 9/160 (6%) of those given placebo. Most adverse reactions were mild; they were slightly more common in the spironolactone group, with more headaches reported than with placebo (20% versus 12%).
Spironolactone improved acne on all outcomes tested, with significant differences at 24 weeks. It offers a useful alternative to oral antibiotics for women with persistent acne when first-line topical treatments have not worked. (Santer, M., et al. (2023). Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: Pragmatic, multicentre, phase 3, double blind, randomised controlled trial. BMJ; 381, e074349. Retrieved June 2023 from https://www.bmj.com/content/381/bmj-2022-074349; Santer, M., & Layton, A. (2023). What do we know about prescribing spironolactone for acne? BMJ, 381, 1114. Retrieved June 2023 from https://www.bmj.com/content/381/bmj.p1114)
Released: June 2023
Nursing Drug Handbook
© 2023 Wolters Kluwer