Mitigation Strategy Program Research Articles

The future of iPLEDGE: We pledge for more inclusive access to isotretinoin.

The use of isotretinoin, the most effective treatment for acne, is limited by its side effects, particularly teratogenicity. To prevent fetal exposure to isotretinoin, iPLEDGE, a Risk Evaluation and Mitigation Strategies (REMS) program was introduced, under which females are required to use two forms of contraception (or abstinence) and undergo a 30-day waiting period before initiation and subsequent monthly pregnancy testing followed by a 7-day period to retrieve isotretinoin. Despite these strict regulations, pregnancies in isotretinoin users still persist, along with the unintended effects of increased consumer anxiety, increased administrative burden, and healthcare disparities,1 which raises the question: Is iPLEDGE doing more harm than good? Females and non-White patients are not only under-prescribed isotretinoin but are also more likely to face interruptions and early termination of treatment than male and White patients.2 For example, females are two times more likely to terminate treatment early and Black females are nine times more likely to miss a prescription window.2 The gender-binary categorization of iPLEDGE also forces transgender patients to register inconsistently with their self-identity, resulting in a feeling of stigmatization. Further, the iPLEDGE materials are above the national readability level which marginalizes non-English-speaking and low-literacy patients.3 The lack of online questionnaires in other REMS coupled with missed windows caused by patients’ confusion with the process justifies re-evaluation of the requirement for isotretinoin.2, 4 While other REMS for teratogenic medications such as ambrisentan (for pulmonary arterial hypertension) and phentermine/topiramate (for weight loss) require monthly pregnancy testing, they lack the 30-day waiting period, 7-day prescription window, patient questionnaires, and registration for males which challenges the need for these requirements for isotretinoin.4 The intent of the 30-day waiting period may be to allow contraception-naïve patients to become protected; however, its purpose is futile, given that most tier 1 and 2 contraception methods are either effective immediately if timed appropriately to the menstrual cycle or at the most 7 days after implementation.5 Further, the monthly follow-ups are time-consuming and financially burdensome, whereby loss of follow-up is a leading cause for early termination.2 Hence, options of telemedicine and home-pregnancy testing, and individualizing follow-up frequency may increase treatment adherence. While there are patient limitations to telemedicine usage such as digital literacy and Internet access, the allowance of multiple telemedicine options such as video, audio, asynchronous store-and-forward, and secure messaging as well as incorporation of an interpreter line may help cater to each patient's technology accessibility while increasing accessing to care.1, 6 By shifting focus to childbearing potential instead of gender,1 the program can expand access for transgender patients and pre-pubertal patients receiving isotretinoin for non-acne reasons such as congenital ichthyosis. The future of iPLEDGE should be one that improves drug safety and accessibility while reducing gender, racial, and socioeconomic disparities in treatment.

Medication abortion: Advocating for mifepristone dispensing by pharmacists

Medication abortion consisting of an oral regimen of mifepristone and misoprostol has been available in the United States since 2000 when mifepristone was approved by the Food and Drug Administration (FDA) for this indication [1]. Special access and use restrictions have been imposed by the FDA since initial approval, and in 2008 mifepristone was transitioned into a Risk Evaluation and Mitigation Strategy (REMS) program. REMS programs are designed to ensure that benefits outweigh the risks for medications with serious safety concerns, and often strictly regulate access [2].

Impact of risk evaluation and mitigation strategy (REMS) programs

Impact of risk evaluation and mitigation strategy (REMS) programs

A Multi-modal Approach to Evaluate the Impact of Risk Evaluation and Mitigation Strategy (REMS) Programs

Since 2007, the US Food and Drug Administration has had the authority to require risk evaluation and mitigation strategy (REMS) programs for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks. Such programs can include requirements for patient monitoring, restrictions on dispensing or administration, and physician and pharmacy training and certification. However, there has been only scattered evidence on the impact of REMS programs on informed decision making, medication access, or patient outcomes. The objective of this article was to describe a study that researchers at Brigham and Women's Hospital and Harvard Medical School will conduct in partnership with the Food and Drug Administration's Office of Surveillance and Epidemiology to investigate systematically how REMS programs have operated in practice. Investigations include health insurance claims-based analyses to understand patterns of drug use, adherence to safety requirements, and patient outcomes under REMS programs; surveys and interviews to understand physician and patient experiences with REMS; and REMS program material-based and interview-based analyses to understand the effectiveness of risk communication in REMS programs. These research activities will evaluate the performance of REMS programs, provide information on the benefits and burdens to patients and healthcare providers, and generate recommendations for actionable steps to improve REMS programs overall.

Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline.

This guideline establishes clinical practice recommendations for the treatment of central disorders of hypersomnolence in adults and children. The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine to develop recommendations and assign strengths to each recommendation, based on a systematic review of the literature and an assessment of the evidence using the GRADE process. The task force provided a summary of the relevant literature and the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations. The following recommendations are intended to guide clinicians in choosing a specific treatment for central disorders of hypersomnolence in adults and children. Each recommendation statement is assigned a strength ("strong" or "conditional"). A "strong" recommendation (ie, "We recommend…") is one that clinicians should follow under most circumstances. A "conditional" recommendation (ie, "We suggest…") is one that requires that the clinician use clinical knowledge and experience and strongly consider the individual patient's values and preferences to determine the best course of action. Under each disorder, strong recommendations are listed in alphabetical order followed by the conditional recommendations in alphabetical order. The section on adult patients with hypersomnia because of medical conditions is categorized based on the clinical and pathological subtypes identified in ICSD-3. The interventions in all the recommendation statements were compared to no treatment. We recommend that clinicians use modafinil for the treatment of narcolepsy in adults. (STRONG). We recommend that clinicians use pitolisant for the treatment of narcolepsy in adults. (STRONG). We recommend that clinicians use sodium oxybate for the treatment of narcolepsy in adults. (STRONG). We recommend that clinicians use solriamfetol for the treatment of narcolepsy in adults. (STRONG). We suggest that clinicians use armodafinil for the treatment of narcolepsy in adults. (CONDITIONAL). We suggest that clinicians use dextroamphetamine for the treatment of narcolepsy in adults. (CONDITIONAL). We suggest that clinicians use methylphenidate for the treatment of narcolepsy in adults. (CONDITIONAL). We recommend that clinicians use modafinil for the treatment of idiopathic hypersomnia in adults. (STRONG). We suggest that clinicians use clarithromycin for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use methylphenidate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use pitolisant for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use sodium oxybate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use lithium for the treatment of Kleine-Levin syndrome in adults. (CONDITIONAL). We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to dementia with Lewy bodies in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). We suggest that clinicians use sodium oxybate for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to myotonic dystrophy in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to multiple sclerosis in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). We suggest that clinicians use sodium oxybate for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2021;17(9):1881-1893.

Med Check: Rapid Blood Test for Concussion; REMS for Some Fentanyl Products; Phase 3 for Troriluzole for OCD; Remote Neuromodulation Device for Adolescent Migraine

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: Rapid Blood Test for Concussion; REMS for Some Fentanyl Products; Phase 3 for Troriluzole for OCD; Remote Neuromodulation Device for Adolescent MigraineTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:10 Feb 2021https://doi.org/10.1176/appi.pn.2021.2.1FDA Approves Rapid Blood Test for ConcussionsIn January the FDA approved Abbott’s i-STAT Alinity handheld device for detecting mild traumatic brain injury (TBI), the company announced. Test results are available within 15 minutes using plasma that is placed into a test cartridge. The test was developed in collaboration with the U.S. Department of Defense.The test measures glial fibrillary acidic protein and ubiquitin carboxyl-terminal hydrolase L1 in blood plasma—two biomarkers that indicate brain injury when they are elevated. According to a statement by the company, the device provides test results with 95.8% sensitivity and greater than 99% negative predictive value. A negative test can rule out the need for a CT scan, and having a blood test available could reduce the number of unnecessary CT scans, according to the company.FDA Toughens REMS for Some Fentanyl ProductsIn December the Food and Drug Administration (FDA) took steps to strengthen the Risk Evaluation and Mitigation Strategy (REMS) program for transmucosal immediate-release fentanyl (TIRF).“To use the TIRF medicines safely, these patients must be opioid tolerant based on concurrent regular use of another opioid medication,” the FDA wrote in a statement. “Despite the decline in the use of TIRF medicines in recent years, data have suggested that prescribing of TIRF medicines still occurs in patients who are not opioid tolerant. With this in mind, the FDA finalized modifications to the REMS program to address the persistence of these concerning prescribing practices.”The TIRF REMS program now requires the following:Prescribers must document a patient’s opioid tolerance with each prescription of a TIRF medicine for outpatient use.Outpatient pharmacies dispensing TIRF medicines must document and verify a patient’s opioid tolerance before dispensing.Inpatient pharmacies must develop internal policies and procedures to verify opioid tolerance in patients who require TIRF medicines while hospitalized.A new patient registry will monitor for accidental exposure, misuse, abuse, addiction, and overdose.Phase 3 Trial Enrollment Begins for Troriluzole for OCDBiohaven has begun enrollment for a phase 3 trial to assess the efficacy and safety of 280 mg troriluzole once per day in patients with obsessive-compulsive disorder (OCD), the company announced in January. The trial will include two double-blind, placebo-controlled studies with approximately 600 patients in each. Troriluzole normalizes synaptic levels of glutamate, a key neurotransmitter implicated in OCD.Biohaven is pressing forward with the phase 3 trial even though troriluzole did not meet its primary endpoint in a previous trial, wherein scores on the Yale-Brown Obsessive-Compulsive Scale for patients who took troriluzole were not statistically significantly better than those who took placebo after 12 weeks. In the previous trial, scores in patients who took troriluzole dropped an average of 5.9 points from baseline, compared with 4.9 points in those who took placebo. However, after eight weeks, there was a 1.5-point gap in scores between the troriluzole group and the placebo group.Remote Neuromodulation Device Shows Promise For Adolescent MigraineA study in Headache suggests that Nerivio, a wearable device approved for treating migraine in adults, may also be helpful in treating the condition in adolescents, manufacturer Theranica announced in December. The device, which is worn with an arm band and controlled through an app on the patient’s smartphone, uses remote electrical neuromodulation to activate the body’s natural ability to modulate pain.Researchers evaluated 45 patients aged 12 to 17 with a history of episodic and chronic migraines who completed at least one treatment with Nerivio. Over the course of the 12-week study, the device treated 159 migraine headaches, 49% of which were moderate and 33% of which were severe at baseline. Two hours after treatment, 71% of participants reported pain relief and 35% reported being free of pain, results that were sustained for 24 hours in 90% of cases. At two hours, 69% of patients experienced improved functional ability, which was defined as the ability to do schoolwork and perform “usual activities.” There were no device-related serious adverse events. ■“Remote Electrical Neuromodulation for Acute Treatment of Migraine in Adolescents” is posted here. ISSUES NewArchived

Navigating iPLEDGE enrollment for transgender and gender-diverse patients: A guide for providing culturally competent care

To the Editor: Acne is a common condition among transgender and gender-diverse individuals, but the mandatory iPLEDGE program for monitoring isotretinoin treatment is insensitive to this population.1,2 The US Food and Drug Administration implemented the iPLEDGE risk evaluation and mitigation strategy program to prevent pregnancy while taking isotretinoin, a teratogenic medication. In iPLEDGE, providers must register patients as either male or female rather than solely by their reproductive potential.

The Xyrem® (Sodium Oxybate) Risk Evaluation and Mitigation Strategy (REMS) Program in the USA: Results From 2016 to 2017.

BackgroundSodium oxybate, which is approved for the treatment of cataplexy or excessive daytime sleepiness in patients with narcolepsy, is available in the USA only through the restricted-distribution Xyrem® Risk Evaluation and Mitigation Strategy Program (Xyrem REMS Program, XRP). The XRP requires prescriber enrollment and certification, patient enrollment, and prescriber attestation of patient counseling. Sodium oxybate is dispensed only by the certified pharmacy. After pharmacist/patient counseling, sodium oxybate is shipped only to enrolled patients, with documentation of safe use. Documentation of enrollments, prescriptions, counseling, shipments, and adverse events in a central database, and risk management reporting of any suspicion of abuse, misuse, or diversion, ensure provider notification and facilitate monitoring.ObjectiveThis analysis reports data from the XRP regarding assessment of the risks of serious adverse outcomes that may result from inappropriate prescribing, abuse, misuse, and diversion.MethodsData collected from December 2016 to December 2017 were analyzed.ResultsPrescriptions were from enrolled prescribers (n = 4524); 17,037 patients received one or more shipment of sodium oxybate. No patients were shipped sodium oxybate under more than one name/identifier or after being disenrolled; no individual patient had overlapping active prescriptions. Sodium oxybate was dispensed in 146,426 shipments containing 375,173 bottles; of those, 13 shipments (0.009%) and 26 bottles (0.007%) were lost in delivery and not recovered. Notifications regarding potential abuse (n = 31), misuse (n = 343), or diversion (n = 22) were discussed with prescribers. Most patients and prescribers were aware of the main safety risks of sodium oxybate.ConclusionsThe XRP maintains controlled access to sodium oxybate; additional prescriber education on safety risks may be warranted.

Mifepristone’s REMS Criteria: Dangerous During COVID-19 and Beyond

At a time when COVID-19 transmission is peaking, millions of women have reduced access to family planning care. On January 12th, 2021, the Supreme Court ruled to reinstate the Risk Evaluation and Mitigation Strategy (REMS) program for mifepristone, which requires patients to go to a hospital, clinic, or medical office to pick up the medication in person and sign a disclosure form. Mifepristone is a drug used in combination with misoprostol to end pregnancies, either for induced medical abortion or miscarriage management. And while there are numerous studies suggesting it is safe for patients to receive all physician consultations for mifepristone via telemedicine and take both prescriptions at home without medical supervision, mifepristone is the only FDA- approved drug with this specific dispensing requirement 1.

Changes in Erythropoiesis Stimulating Agent Use Under a Risk Evaluation and Mitigation Strategy (REMS) Program.

Risk evaluation and mitigation strategy (REMS) programs are intended to improve safe use of US Food and Drug Administration-approved drugs. However, controversy exists over whether they consistently accomplish this goal. We aimedto assess how initiation of the erythropoiesis stimulating agents (ESAs) darbepoetin alfa and epoetin alfa changed following implementation and enforcement (following a 1-year post-implementation grace period) of a prominent REMS program warning physicians against use in cancer patients with hemoglobin above 10g/dL. Using claims data from a large US commercial insurance company, we conducted interrupted time-series analyses of darbepoetin alfa and epoetin alfa initiation among adult cancer patients in the 12 months before REMS program implementation, after REMS program implementation, and after REMS program enforcement. We also evaluated differences in inappropriate initiation (hemoglobin tests all above 10g/dL in the prior month) between the periods. In total, we identified 3456 darbepoetin alfa initiators and 2632 epoetin alfa initiators. Over the study period, the monthly number of initiators per 100,000 patients with cancer fell from 119 to 32 for darbepoetin alfa and from 82 to 34 for epoetin alfa. However, non-significant post-REMS program implementation level and slope changes per 100,000 adult patients with cancer were observed for darbepoetin alfa (level0.03 [95% confidence interval (CI) -14.98 to 15.05]; slope 1.94 [95% CI -0.22 to 4.10]) and epoetin alfa (level -4.10 [95% CI -16.85 to 8.65]; slope -0.52 [95% CI -2.35 to 1.32]). Non-significant post-REMS program enforcement level and slope changes were also seen for both drugs (darbepoetin alfa level 1.58 [95% CI -0.58 to 3.74,slope -0.28 [95% CI -15.29 to 14.73]; epoetin alfa level 1.58 (95% CI -0.26 to 3.42],slope 5.74 [95% CI -7.01 to 18.49]). Finally, non-significant changes in inappropriate darbepoetin alfa (60% vs. 53% vs. 57%, p = 0.68) and epoetin alfa (53% vs. 53% vs. 46%, p = 0.41) initiation were observed between the three study periods. REMS program implementation and enforcement were not associated with significant changes in ESA initiation, adding to concerns over the degree to which certain REMS programs enhance patient safety.

An Examination of State and Federal Opioid Analgesic and Continuing Education Policies: 2016-2018.

IntroductionOpioid overdose deaths in the United States have climbed sharply over the past two decades. Simultaneously, increased awareness of inadequately treated chronic pain has resulted in increased opioid analgesic prescribing. The correlation between these two phenomena has led policymakers to posit that they are causally linked, and to implement policy changes supporting safe opioid prescribing.PurposeTo evaluate the impact of its Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) program, the US Food and Drug Administration (FDA) requested the opioid manufacturers responsible for implementing that program provide information regarding opioid policy changes from 2016 to 2018. FDA also requested a survey of state requirements for pain and opioid prescribing continuing education (CE), the number of prescribers affected by those requirements, the extent to which a REMS-compliant CE program would meet each state’s requirements, and the number of relevant CE programs available.ResultsResults indicate that 527 federal and state opioid-related policies (statutes, rules/regulations, and guidelines) were approved during the 2016–2018 study period. While the largest number of these policies focused on prescription drug monitoring programs, 170 specifically imposed limits on opioid prescribing and an additional 35 specifically referred to, or incorporated, the Centers for Disease Control and Prevention opioid prescribing guideline. We also found that 46 states and the District of Columbia mandated some amount of pain or opioid prescribing CE for prescribers renewing their licenses. These mandates potentially affected as many as 1.7 million prescribers. In 69% of cases, a REMS-compliant CE program would fully meet the state mandates for various types of prescribers.ConclusionThe severity and complexity of the problems of pain management and opioid overdose have led to large-scale intervention by policymakers. Assessing the impact of these changes is difficult, at best, but will be necessary if interventions are to be refined to increase their effectiveness.

Pexidartinib: first approved systemic therapy for patients with tenosynovial giant cell tumor.

Pexidartinib is an orally administered small molecule tyrosine kinase inhibitor. Phase III ENLIVEN study results provided clinical evidence for US FDA approval for treatment of adult patients with symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Recommended dosage is 400 mg orally twice daily on an empty stomach. Long-term follow-up in pooled analyses showed increased response rates compared with those observed in ENLIVEN. Patients on pexidartinib also experience meaningful improvements in range of motion. Side effects associated with pexidartinib are generally manageable; however, there is a risk of potentially life-threatening mixed or cholestatic hepatotoxicity and pexidartinib has a Risk Evaluation and Mitigation Strategy (REMS) program to ensure appropriate monitoring.

Evaluation of patient and healthcare provider (HCP) knowledge, attitudes, and behavior for safety and use of pexidartinib.

e23580 Background: Pexidartinib, a kinase inhibitor, is approved for treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not amenable to improvement with surgery. Due to risk of serious and potentially fatal liver injury, pexidartinib is available via a Risk Evaluation and Mitigation Strategy (REMS) Program. A requirement of the REMS is to conduct a qualitative evaluation of stakeholder Knowledge, Attitudes, and Behavior (KAB) of risks via surveys. The objective of the qualitative evaluation is to review key risk message questions with respect to understanding, relevance, clarity and provide recommendations on alternative language, phrasing, and structure. Methods: Anonymized, one-on-one 45–60-min phone interviews with patients and HCPs were conducted by UBC. Patients ≥18 y, diagnosed with TGCT (prioritized) or metastasis/sarcoma of the connective tissue, with different levels of education and fluent reading/speaking English were included. To participate, HCPs were required to treat patients with TGCT (prioritized) or metastasis/sarcoma of the connective tissue, treat patients ≥75% of their time, and clearly read/speak English. Participants were required to complete an Interview Release Form (IRF) and confirm access to a computer/tablet. Participants had little/no familiarity with pexidartinib materials. All interviews followed a standard process, used a pre-scripted guide on general instructions, confidentiality, safety event reporting, rapport building and assessment of health literacy (patients only). Feedback regarding understanding, relevance, and clarity were used to recommend potential alternate language/phrasing. To receive compensation participants were required to execute/return the IRF. Results: Twelve patients were interviewed, majority 67% had TGCT; mean age 52 y; 58% female; 42% reported some college/associates degree. 12 HCPs were interviewed, 67% treated patients with TGCT; 100% male; mean years practicing 22; all spent 75% or more time seeing patients; primary specialty Orthopedics. Areas of confusion/misunderstanding were reported, and questions were then revised. Patient findings: complexity and wordiness; HCP findings: repetition/difficulty reading, and some terminology was not self-explanatory. Conclusions: Feedback from HCPs and patients was received to improve the key risk messages of the KAB. Qualitative research is recommended to improve comprehension and data quality collected.

Clozapine and hematologic adverse reactions: Impact of the Risk Evaluation and Mitigation Strategy program.

IntroductionIn October 2015, the Food and Drug Administration (FDA) instituted an update to the mandatory Risk Evaluation and Mitigation Strategy (REMS) program for clozapine to improve safety monitoring of hematologic events. However, the impact of the clozapine REMS program on reporting of hematologic adverse events has not been quantified.MethodsWe assessed adverse event reports for agranulocytosis, granulocytopenia, leukopenia, and neutropenia from the FDA Adverse Event Reporting System (FAERS) for a 1-year time period before (October 2014 to September 2015, pre-REMS) and after (October 2015 to September 2016, post-REMS) the implementation of the clozapine REMS program. The AERSMine platform was used to capture historical effect estimates (October 2004 to September 2014). Reporting odds ratios (ROR), proportional reporting ratios (PRR), and corresponding Taylor series 95% confidence intervals (CIs) were calculated for hematologic events with clozapine compared with all other medications using OpenEpi.ResultsReporting rates for agranulocytosis, granulocytopenia, leukopenia, and neutropenia with clozapine all increased from the pre-REMS to post-REMS time frames, ranging from a 2-fold increase with leukopenia to a 40-fold increase with neutropenia; the composite measure of all hematologic reports had a 12-fold increase. During the post-REMS time frame, the ROR increased by 1691% (111.4, 95% CI 100.6-123.4) compared with the pre-REMS time frame (7.1, 95% CI 5.2-9.6), and the PRR increased by 1280% (83.1, 95% CI 76.8-90.0 vs 6.9, 95% CI 5.1-9.4) for the composite outcome.DiscussionWe observed significant increases in reports of hematologic adverse events with clozapine after the introduction of the clozapine REMS program. Future research should explore the impact of the less stringent exclusionary and discontinuation criteria on utilization (eg, expanded access) and clinical outcomes (eg, treatment effectiveness and adverse events).

Pexidartinib for the treatment of adult patients with symptomatic tenosynovial giant cell tumor: safety and efficacy

ABSTRACT Introduction Tenosynovial giant cell tumor (TGCT) is a benign clonal neoplastic proliferation arising from the synovium often causing pain, swelling, joint stiffness, and reduced quality of life. The optimal treatment strategy in patients with diffuse-type TGCT (dt-TGCT) is evolving. Surgery is the main treatment, with a high recurrence rate and surgery-related morbidity. Radiotherapy is associated with important side effects. TGCT cells overexpress colony-stimulating factor 1 (CSF1). Pexidartinib (Turalio™) is a selective CSF1 R inhibitor, which was recently approved by the FDA for the treatment of TGCT. Areas covered This article reviews the pharmacological properties, clinical efficacy, and safety of pexidartinib. Expert opinion Pexidartinib was effective with an acceptable safety profile for advanced TGCT in phase I–III studies. The phase III trial (ENLIVEN) in unresectable TGCT met its primary endpoints of overall response rate. These results led to FDA approval for this TGCT population. Mixed or cholestatic hepatotoxicity was observed in rare cases. For this reason, pexidartinib is currently available only through a Risk Evaluation and Mitigation Strategy (REMS) Program in the USA. TGCT significantly impairs patients’ quality of life. The approval of pexidartinib has changed the therapeutic armamentarium for this condition. However, strict monitoring of liver function is warranted.

Occurrence of Pulmonary Oil Microembolism After Testosterone Undecanoate Injection: A Postmarketing Safety Analysis

BackgroundThe Aveed Risk Evaluation and Mitigation Strategy program was instituted because of potential risk of pulmonary oil microembolism (POME) and/or anaphylaxis after intramuscular injection of Aveed (testosterone undecanoate), indicated for treatment of adult male patients with congenital or acquired primary hypogonadism or hypogonadotropic hypogonadism.AimTo analyze the reporting rate of POME associated with testosterone undecanoate administration (750 mg/3 mL) during postmarketing surveillance.MethodsThe Endo Pharmaceuticals Inc database was searched for POME reports occurring from testosterone undecanoate approval on March 5, 2014, through June 30, 2018. Each case was reviewed and adjudicated by a drug safety physician to confirm the reported event had predefined clinical characteristics consistent with POME.OutcomesAnnual rate and clinical features of spontaneously reported POME cases were characterized.ResultsDuring the 4.3-year period, 90,092 doses of intramuscular testosterone undecanoate were distributed via an Aveed Risk Evaluation and Mitigation Strategy program to health-care professionals for patient treatment. Of 633 individual case safety reports in the Endo Pharmaceuticals Inc safety database, 28 spontaneously reported adverse events were classified as POME, for a yearly spontaneously reported adverse event per-injection rate of <0.1%. Most (21/22) events resolved, and of those with a resolution time reported, most (13/17) resolved in ≤30 minutes. More than 60% (13/21) of patients required no medical intervention (ie, the POME event resolved spontaneously). One fatality was reported 18 months after a documented POME event and appeared unrelated to the reported testosterone undecanoate injection or subsequent injections after the POME event. In 3 out of 4 POME cases with symptoms serious enough to require an emergency room visit, issues with injection technique or dosing were identified as a potential contributing factor.Clinical ImplicationsInjection technique and proper product usage are key elements in the prevention of POME events.Strengths & LimitationsThe reported rate of POME events was determined from a real-world clinical practice patient population; however, postmarketing safety data typically are underreported and retrospective in nature.ConclusionPOME events appear to be rare, with resolution occurring quickly without medical intervention in most cases.Pastuszak AW, Hu Y, Freid JD. Occurrence of Pulmonary Oil Microembolism After Testosterone Undecanoate Injection: A Postmarketing Safety Analysis. Sex Med 2020;8:237–242.

Brexanolone for postpartum depression.

Postpartum depression (PPD) is defined as a major depressive episode occurring during pregnancy or within 4 weeks of delivery that may have significant consequences for mother and infant. Antidepressants are used to treat PPD, but their effectiveness may be limited by a slow time to peak effect. Brexanolone is Food and Drug Administration-approved for the management of PPD; its use requires patient participation in a risk evaluation and mitigation strategies (REMS) program. This review evaluates the efficacy and safety of brexanolone in PPD. Four completed studies, 1 quasi-experimental study and 3 randomized controlled trials (RCTs), were reviewed. Females who had moderate or severe PPD during the third trimester or within 4 weeks of delivery and were less than 6 months postpartum at initiation of therapy were included. Improvement in Hamilton Rating Scale for Depression (HAM-D) scores was assessed in addition to safety outcomes and scores on other depression rating scales. All studies demonstrated statistical improvement in HAM-D scores from baseline with brexanolone vs placebo use at the end of infusions (ie, hour 60). Results with regard to sustained HAM-D score improvements were mixed in the RCTs at 30-day follow-up. The most frequent adverse events in brexanolone-treated patients were sedation, dizziness, somnolence, and headache. The severe or serious adverse effect of presyncope, syncope, or loss of consciousness was reported by 4% of participants. With a rapid onset of action, brexanolone could be considered advantageous over traditional therapies for PPD in patients for whom a rapid response is required due to severity of disease. Significant concerns remain regarding sustained effect and use in patients outside of the clinical trial setting.

Compliance with the riociguat risk evaluation and mitigation strategies program at an academic medical center

Compliance with the riociguat risk evaluation and mitigation strategies program at an academic medical center

Poorly designed REMS for opioids hampers FDA's evaluation of impact

The Risk Evaluation and Mitigation Strategy (REMS) program designed to facilitate safer prescribing of extended‐release/long‐acting opioids cannot be sufficiently evaluated because of major flaws in the program's design, concludes a review published online Dec. 30, 2019, in JAMA Internal Medicine. The review's corresponding author told ADAW that the Food and Drug Administration (FDA) and opioid manufacturers have not taken advantage of evaluation methods that had become standard scientific procedure well before the REMS was instituted in 2012.

Brexanolone for Postpartum Depression: Clinical Evidence and Practical Considerations.

Our aim was to review the efficacy, safety, and pharmacology of brexanolone (Zulresso), a new antidepressant with a novel mechanism of action, in the treatment of postpartum depression (PPD). Pertinent data and information were obtained via PubMed (1993 to August 2018). Articles published in English that evaluated the safety and efficacy of brexanolone and other off-label PPD treatments were included. Literature regarding epidemiology and pathophysiology of PPD was also selected. Brexanolone, administered as an intravenous infusion over 60hours, produced a statistically significant and clinically meaningful reduction in Hamilton Depression Rating Scale (HAM-D) scores compared with placebo at both 60 and 90μg/kg/hour in patients with moderate to severe PPD. Brexanolone groups had higher response and remission rates compared with placebo. Common adverse effects were somnolence, dizziness, and headache. A small percentage (4%) of patients required cessation of therapy due to excessive sedation or loss of consciousness. Although the evidence for brexanolone as a novel treatment for PPD looks promising, a Risk Evaluation and Mitigation Strategies (REMS) program requirement and the logistics of prolonged infusions serve as barriers to treatment. A discussion of these obstacles as well as pharmacokinetics, monitoring, and dosing is provided. Brexanolone is a novel antidepressant indicated for the treatment of PPD. Clinical trials demonstrated that brexanolone significantly reduces depression scores in women with moderate to severe PPD. Due to risk of oversedation and loss of consciousness, a REMS program will be put in place to mitigate the risk of adverse events.