Resident Editors: Dana Osdoba, Pharm.D., Anjoli Punjabi, Pharm.D., M.Ph., Thakul Rattanasuwan, Pharm.D. Faculty Editor: Jean Moon, Pharm.D., BCACP Volume 16, Issue 2 – Second Quarter 2018 Serotonin Syndrome: What is the Risk When Co-Prescribing a Research Updates Triptan With a Selective Serotonin Reuptake Inhibitor (SSRI) or Serotonin Syndrome: What is the Risk When Co- Selective Norepinephrine Reuptake Inhibitor (SNRI)?1 Prescribing a Triptan With a Selective Serotonin Reuptake Inhibitor (SSRI) or Selective Brittany Bailey, Pharm.D. Norepinephrine Reuptake Inhibitor (SNRI)? Avera Marshall Regional Medical Center Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout Background: Serotonin syndrome(SS) or serotonin toxicity is a potentially life-threatening diagnosis caused by an excessive amount of serotonin in Primary Literature Review: Effect of Opioid vs Non- the central nervous system (CNS). Symptoms of serotonin syndrome may opioid Medications on Pain-Related Function in include agitation, diaphoresis, muscle rigidity or spasms (clonus), tremor, Patients with Chronic Back Pain or Hip or Knee Osteoarthritis Pain – The SPACE Randomized and hyperthermia. The Hunter Toxicity Criteria and the Sternbach Criteria Clinical Trial are diagnostic tools for serotonin syndrome. Serotonin or 5- hydroxytryptamine (5-HT) is a neurotransmitter which may bind with Two is Company, but is Three Really a Crowd? different 5-HT receptors in the body leading to effects on the enteric Once Daily Single-Inhaler Triple versus Dual nervous system, CNS, respiratory function, and cardiovascular system. Therapy in Patients with COPD Triptans are 5-HT 1b/1d receptor agonists leading to vasoconstriction and Therapeutic Thoughts reduced inflammation to aid in migraine relief. The mechanism of SSRI’s is to block the reuptake of serotonin leading to increased levels of A Closer Look at the Updated ADA Standards of serotonin available to bind the 5-HT receptors. This is compared to SNRIs Medical Care Recommendations for Patients with which block reuptake of serotonin, norepinephrine, and to a smaller extent Diabetes and ASCVD dopamine. In 2006, the US Food and Drug Administration (FDA) Benefit of Adding Ezetimibe to Statin published an advisory on the risk of serotonin syndrome with the combined use of a triptan with SSRI or SNRI therapy. The alert stated From the Pharmacy Press "Potentially Life-Threatening Serotonin Syndrome with Combined Use of SSRIs or SNRIs and Triptan Medications." There is a lack of evidence Cost of Prescription Drug-Related Morbidity and Mortality available to show the specific risk associated with combined medication use. A Pilot Study for Antimicrobial Stewardship Post- Discharge: Avoiding Pitfalls at the Transitions of Objective: To assess the risk of SS with concomitant use of triptans and Care SSRI or SNRI antidepressants. Increasing Access to Hepatitis C Medications: A Program Model to Obtain Prior Authorization Study Design: This was a 14 year, retrospective database study using Approval the Partners Research Patient Data Registry. This data review searched for patients who received prescriptions for both a triptan and SSRI or Miscellaneous News SNRI from January 1, 2001 to December 31, 2014 in Boston, Improving Medication Adherence Through Massachusetts and surrounding areas. Co-prescription was defined as Smartphone Apps receiving at least one prescription for a triptan and one for a SSRI/SNRI during the study period. Diagnosis of SS was determined by review of the Reducing Nicotine Content of Cigarettes- Public Health Implications electronic medical record. Serotonin syndrome does not have its own ICD-9 code but is part of “other extrapyramidal diseases and abnormal movement disorders” (ICD-9 code 333.99). Information regarding medication use was determined from lists of medications prescribed by clinicians in this healthcare network and from clinician notes on the date of the event. Then, cases were reviewed by three individuals to verify accuracy of data abstraction and application of diagnostic criteria. Those defined as “possible cases” of SS related to co- inhibitor, compared to allopurinol, a purine base prescription were those in which SS was suspected but analogue xanthine oxidase inhibitor, in patients with gout did not meet diagnostic criteria or triptan ingestion did and history of major CV disease. not occur during the same time as the event. For this study, it was assumed that subjects were at risk of Study Design: This trial was a multicenter, randomized, serotonin syndrome for one full year during the time that double-blind noninferiority trial. Takeda Pharmaceuticals co-prescription occurred. funded this trial and participated in trial design, conduct and monitoring along with an independent data safety Results: From the search, 47,968 subjects were monitoring committee. Eligible participants were male prescribed a triptan of which 19,017 were co-prescribed ≥50 years of age or female ≥55 years of age with history a SSRI or SNRI. Of those prescribed both a triptan and of major CV or cerebrovascular disease defined as at SSRI/SNRI, 229 had a reported diagnosis of least one of the following: myocardial infarction (MI), extrapyramidal symptoms of which 17 cases were hospitalization for unstable angina, coronary or cerebral suspected SS. Of those 17, seven subjects actually met revascularization procedure, stroke, hospitalized the criteria for SS. Four of these seven subjects met the transient ischemic attack (TIA), peripheral vascular Sternbach and Hunter criteria, two met the Sternbach disease, or diabetes with evidence of microvascular or criteria only and, one met the Hunter criteria only. From macrovascular disease. Participants had a diagnosis of consideration of 15 possible cases per 30,928 person- gout according to the American Rheumatism Association years of exposure to co-prescription, the incidence rate (ARA) definition and met additional criteria including was 2.3 cases per 10,000 person-years (95% CI 0.6- serum uric acid level ≥7.0 mg/dL at screening or ≥6.0 3.9). Only two of the seven cases of SS occurred when mg/dL at screening plus inadequately controlled gout, as patients were receiving co-prescriptions at the same pre-defined by the investigators. time as the event (definite cases), thus providing an incidence rate of 0.6 cases per 10,000 person-years At the screening visit, previous gout therapy was (95% CI 0-1.5). Despite the publication of the FDA risk discontinued for a 1 to 3 week washout period. advisory in 2006, there has been an increasing trend of Participants were initiated on colchicine 0.6 mg daily. triptan prescribing and co-prescribing when comparing This was given as monotherapy during the washout incidence from 2001 to 2014. However, the increase in period and continued concomitantly with study drug for a triptan prescriptions did not increase the incidence in SS total of 6 months of colchicine therapy. Participants were diagnosis. randomized and stratified by renal function to received either febuxostat or allopurinol once daily as study drug. Conclusions: The risk of SS from co-prescription of Initial allopurinol dose was renal-adjusted and doses for triptan with SSRI or SNRI was low and the trial showed both allopurinol and febuxostat were titrated up based on no life-threatening cases of SS. These results spark serum urate levels following a pre-defined protocol. doubt regarding the validity of the FDA advisory which should be considered for revision. The primary endpoint was a composite measure including first occurence of CV death, non-fatal MI, Key Point: A significant increase in SS events was not nonfatal stroke, and urgent revascularization for unstable seen when triptan therapy was combined with SSRI or angina. The individual components of the primary SNRI medications. composite were measured as secondary endpoints and death from any cause was measured as a safety Cardiovascular Safety of Febuxostat or Allopurinol endpoint. To assess non-inferiority, the CARES trial was in Patients with Gout2 designed to accrue a total of 624 primary events. Non- Kaity Kuske, Pharm.D. inferiority determination would be made if the upper Smiley’s Family Medicine Clinic bound of the hazard ratio (HR) was less than 1.3. Background: Patients with a diagnosis of gout have an Results: A total of 6190 participants were included in increased risk of cardiovascular (CV) events making CV the modified intention-to-treat analysis. High rates of safety of medications used for gout a concern. Early discontinuation were noted for both febuxostat and febuxostat development trials suggested modestly allopurinol groups, 57.3% and 55.9%, respectively. The higher CV event rates when compared with allopurinol median duration of exposure and duration of follow-up and placebo. As an FDA requirement the CARES trial, were 728 days and 968 days for febuxostat and 719 Cardiovascular Safety of Febuxostat or Allopurinol in days and 942 days for allopurinol, respectively. The Patients with Gout and Cardiovascular Morbidities, was modified intention to treat analysis in this trial included conducted. participants who received at least one dose of trial medication. Therefore, patients who discontinued Objective: The purpose of this trial was to assess CV therapy were included in the analysis rates. safety of febuxostat, a non-purine xanthine oxidase 2 The primary composite outcome occurred in 10.8% of there is evidence that non-opioid alternatives can be patients in the febuxostat group and 10.4% of patients in equally effective. the allopurinol group. The HR for primary composite outcome was 1.03 [97% CI 0.87 - 1.23] demonstrating Objective: This randomized clinical trial aimed to non-inferiority of febuxostat. The secondary endpoint of compare opioid therapy vs non-opioid therapy over 12 CV death comparing febuxostat and allopurinol was HR months for primary care patients suffering from chronic 1.34 [95% CI 1.03 - 1.73] and death from any cause was back pain or hip or knee osteoarthritis pain of at least HR 1.22 [95% CI 1.01 - 1.47].