What's new in drug therapy

The following material represents a subset of new drugs, drug approvals, drug warnings, and drugs removed from the market from the past six months. This is not a complete list; it includes those topics considered by the authors and editors to be of particular interest or importance. For a complete list of new drug approvals, see /lco/action/index/newapprovals/patch_f (an additional subscription may be required).

You can check drug interactions by going to the Lexicomp drug interactions program included with UpToDate.

GENERAL DRUG THERAPY

Removal of X-waiver requirement to prescribe buprenorphine for opioid use disorder (February 2023)

Previously, in order to prescribe buprenorphine for opioid use disorder (OUD) in the United States, clinicians had to apply for a federally required DATA Waiver (X-Waiver). In January 2023, the Consolidated Appropriations Act of 2023 removed this requirement and allowed clinicians with schedule III authority on their Drug Enforcement Administration (DEA) registration to prescribe buprenorphine for OUD treatment if permitted by applicable state law [1]. We believe this change will encourage buprenorphine prescribing and thus prevent opioid overdose. (See "Acute opioid intoxication in adults", section on 'Prevention of recurrent opioid overdose'.)

Changes to heart failure therapy in patients recently hospitalized for heart failure (February 2023)

Patients with heart failure (HF) benefit from optimal medical therapy, but it is unclear whether patients recently hospitalized with HF can safely undergo rapid changes to their pharmacologic regimen. In a trial in nearly 1100 patients hospitalized with HF who were randomly assigned to high-intensity care (drug adjustment to target within two weeks of discharge and clinical surveillance) or to usual care, patients assigned to high-intensity care were more likely to achieve target doses of primary therapies for HF with reduced ejection fraction (eg, sacubitril-valsartan, beta blockers) and had a lower risk of hospital readmission by 180 days [2]. Although overall adverse effects were more frequent in the high-intensity care group, rates of serious adverse events were similar between the groups. In highly selected inpatients scheduled for discharge who can reliably undergo frequent observation in the outpatient setting, HF medications can be added or adjusted toward their target doses. (See "Treatment of acute decompensated heart failure: Specific therapies", section on 'Approach to long-term therapy in hospitalized patients'.)

Torsemide or furosemide for diuresis after heart failure hospitalization (January 2023)

Torsemide and furosemide have different pharmacologic properties, but it is unknown whether one agent is superior to the other in patients with heart failure (HF). In a trial in nearly 2900 patients hospitalized with HF who were randomly assigned to treatment with furosemide or torsemide prior to discharge, the rates of all-cause mortality and all-cause hospitalization at 12 months were similar between the groups [3]. However, immediate crossover between treatments and the open-label design may have obscured differences in diuretic efficacy. In patients recovering from acutely decompensated HF without known resistance to a specific diuretic, furosemide and torsemide are reasonable options for outpatient diuresis. (See "Use of diuretics in patients with heart failure", section on 'Choice of loop diuretic'.)

FDA changes to mifepristone REMS restrictions (January 2023)

Mifepristone (a progesterone receptor antagonist used for management of some abortions and pregnancy loss) is available in the United States with Risk Evaluation and Mitigation Strategy (REMS) restrictions; only mifepristone REMS-registered health care providers can prescribe the drug and, until 2023, only registered mail-order pharmacies and provider clinics could dispense the drug. In January 2023, the US Food and Drug Administration (FDA) expanded access by allowing mifepristone prescriptions from a registered prescriber to be filled and dispensed by mifepristone-registered retail pharmacies [4]. Depending on state abortion bans and restrictions, this expansion may increase patient access to mifepristone, especially those seeking alternative methods to in-person care. (See "Overview of pregnancy termination", section on 'REMS restrictions'.)

CDC updates opioid prescribing guidelines (November 2022)

The United States Centers for Disease Control and Prevention (CDC) has published a new guideline for prescribing opioids for acute, subacute, and chronic pain, updating their 2016 guideline (table 1). The guideline is intended for clinicians who prescribe opioids to outpatients ≥18 years of age and does not apply to pain related to sickle cell disease, cancer, palliative care, or end of life care [5]. (See "Use of opioids in the management of chronic non-cancer pain", section on 'Opioid therapy in the context of the opioid epidemic'.)

Morning versus bedtime dosing of once-daily antihypertensive medications (October 2022)

The best time of day to take once-daily antihypertensive medications was previously controversial, and some studies found that bedtime dosing lowered nocturnal blood pressure and improved cardiovascular outcomes. In the largest and most rigorous trial (ie, the Treatment In the Morning or Evening [TIME] study), more than 21,000 adults with hypertension were randomly assigned to take their antihypertensive medications in the morning or the evening [6]. At approximately five years, rates of cardiovascular outcomes were similar between the groups, as were adverse events. This study indicates that patients can take their once-daily antihypertensive medications at a time that they find most suitable. (See "Choice of drug therapy in primary (essential) hypertension", section on 'Bedtime versus morning dosing'.)

Antibiotic prophylaxis against endocarditis before invasive dental procedures (September 2022)

The efficacy of antibiotic prophylaxis for prevention of infective endocarditis (IE) has not been established. A case-crossover analysis and cohort study performed in nearly 8 million individuals identified an association between invasive dental procedures (particularly extractions and oral surgery) and subsequent IE in individuals at high IE risk [7]. Antibiotic prophylaxis was associated with reduced risk of IE after these procedures. These findings support administration of antibiotic prophylaxis to individuals with high IE risk undergoing invasive dental procedures. (See "Prevention of endocarditis: Antibiotic prophylaxis and other measures", section on 'Impact of procedures on risk of endocarditis'.)

DRUG INTERACTIONS

Serotonin syndrome after serotonin reuptake inhibitor overdose (February 2023)

The serotonin syndrome is a clinical diagnosis (algorithm 1) that may occur after administration or overdose of serotonergic agents (table 2). In a retrospective cohort of over 2200 patients admitted to a regional toxicology service for an overdose of a serotonin selective reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI), 269 (14 percent) developed serotonin syndrome [8]. The incidence of serotonin syndrome was slightly higher in patients who ingested an SNRI (desvenlafaxine, venlafaxine) compared with an SSRI. However, coingestion of the monoamine oxidase inhibitor (MAOI) moclobemide was associated with a fivefold increased risk of serotonin syndrome. In patients who have ingested an SNRI or SSRI, coingestion of an MAOI markedly increases the probability that they will develop serotonin syndrome. (See "Serotonin syndrome (serotonin toxicity)", section on 'Epidemiology'.)

DRUG OR INDICATION WITHDRAWALS

Lack of survival benefit for atezolizumab as initial therapy in advanced urothelial carcinoma (January 2023)

Atezolizumab, a programmed cell death ligand-1 (PD-L1) inhibitor, was previously approved by the US Food and Drug Administration (FDA) for patients with advanced or metastatic urothelial carcinoma (mUC) in patients ineligible for any platinum-based chemotherapy and in those with PD-L1 positive cancers ineligible for cisplatin-based chemotherapy. However, in a randomized phase III trial of over 1000 patients with treatment-naïve mUC, the addition of atezolizumab to platinum-based chemotherapy failed to improve overall survival [9]. Based on these data, the FDA withdrew regulatory approval for atezolizumab for the above indications, and we no longer use it as initial therapy for patients with platinum-ineligible mUC [10]. (See "Treatment of metastatic urothelial cancer of the bladder and urinary tract", section on 'Other agents'.)

Belantamab mafodotin withdrawn from market (December 2022)

Belantamab mafodotin is being withdrawn from the market beginning November 2022, although it remains accessible through the manufacturer for patients who started treatment prior to its withdrawal [11]. The antibody drug conjugate targeting B-cell maturation antigen (BCMA) had received accelerated approval in the United States for patients with relapsed or refractory multiple myeloma (MM) based on response data from two uncontrolled open-label trials (DREAMM-1 and DREAMM-2). However, initial results of a randomized phase 3 trial (DREAMM-3) of belantamab mafodotin versus pomalidomide and dexamethasone in relapsed or refractory MM have not confirmed clinical benefit, leading to market withdrawal. (See "Multiple myeloma: Treatment of third or later relapse", section on 'Belantamab mafodotin'.)

ADVERSE REACTIONS AND WARNINGS

Oral isotretinoin for acne and psychiatric outcomes (March 2023)

Patients are counseled about potential psychiatric adverse effects of oral isotretinoin because of uncertainty about the impact of isotretinoin on risk for depression and suicidal behavior. A retrospective cohort study with over 150,000 patients found an increase in suicidal ideation among patients with a history of acne treated with isotretinoin when compared with patients treated with oral antibiotics, but found no increase in risk for suicidal attempts or major depressive disorder [12]. Risk for several other psychiatric conditions was lower in the patients treated with isotretinoin. This study provides additional support for the relative safety of isotretinoin therapy for multiple psychiatric conditions, but also supports continued investigation of the relationship between isotretinoin and psychiatric outcomes, particularly suicidal ideation. (See "Oral isotretinoin therapy for acne vulgaris", section on 'Psychiatric effects'.)

Resistant P. aeruginosa outbreak associated with artificial tears (February 2023)

In January 2023, a multistate outbreak caused by a rare strain of extensively drug-resistant Pseudomonas aeruginosa was reported by the United States Centers for Disease Control and Prevention (CDC) [13]. The outbreak was associated with use of artificial tears, especially the over-the-counter EzriCare brand. Clinical infections included keratitis, endophthalmitis, respiratory infections, urinary tract infections, and sepsis. The strain is resistant to almost all available antibiotics (a subset of strains were susceptible to cefiderocol). The CDC recommends immediate discontinuation of EzriCare artificial tears until further notice. (See "Principles of antimicrobial therapy of Pseudomonas aeruginosa infections", section on 'Epidemiology of resistance' and "Dry eye disease", section on 'Artificial tears'.)

Association between tamoxifen and endometrial pathology in patients with breast cancer (January 2023)

Tamoxifen, a selective estrogen receptor modulator, is used as adjuvant therapy or chemoprevention for selected patients with hormone-sensitive breast cancer or at increased risk for breast cancer; however, it is associated with an increased risk for uterine pathology. In one of the largest studies, a retrospective study including over 78,000 premenopausal patients (mean age 42 years) with breast cancer in Korea who were followed for an average of six years, those treated with versus without tamoxifen had higher rates of uterine disease (32 versus 7 per 1000 person-years), including (in descending order of frequency) endometrial polyps, endometrial hyperplasia, endometrial cancer, and other uterine cancers (rare) [14]. We discuss these risks with all patients when counseling about the use of tamoxifen. (See "Abnormal uterine bleeding and uterine pathology in patients on tamoxifen therapy", section on 'Risks and management of uterine pathology'.)

Medication-related osteonecrosis of the jaw in patients with cancer (January 2023)

Antiresorptive therapy controls bone pain and reduces skeletal-related events in patients with bone metastases. A 2022 position paper from the American Association of Oral Maxillofacial Surgeons defines medication-related osteonecrosis of the jaw (MRONJ) as a complication of antiresorptive therapy, used either alone or in combination with immune modulators or antiangiogenic agents [15]. Nevertheless, the guideline advises that MRONJ is uncommon, and that oncology patients should receive antiresorptive agents if indicated, even if they are at risk of developing MRONJ or had MRONJ in the past. (See "Medication-related osteonecrosis of the jaw in patients with cancer", section on 'Osteoclast inhibitors'.)

Risk of drug overdose in young people prescribed benzodiazepines for sleep disorders (December 2022)

Prescription database studies indicate that benzodiazepines are commonly prescribed for insomnia, despite risks and the availability of safer options. In a recent cohort study in the United States that included over 90,000 children and young adults (age 10 to 29 years) with a sleep disorder who were prescribed a new insomnia medication, benzodiazepines were associated with increased risk of drug overdose in the next six months compared with alternative insomnia medications (trazodone, hydroxyzine, zolpidem, zaleplon, eszopiclone) [16]. Risk was highest among individuals who had also received an opioid prescription in the preceding three months. We do not prescribe benzodiazepines for insomnia in patients taking opioids or in those with a substance use disorder. (See "Pharmacotherapy for insomnia in adults", section on 'Shared warnings and precautions'.)

RECENT APPROVALS - ANTIMICROBIALS

Lenacapavir for treatment of multidrug-resistant HIV (February 2023)

In 2022, the capsid inhibitor lenacapavir was approved for use in the United States as part of a combination regimen for patients with multidrug-resistant HIV-1 [17]. Capsid inhibitors impact key steps necessary for viral entry and virion assembly. In clinical trials evaluating lenacapavir, approximately 80 percent achieved a viral load of less than 50 copies per milliliter by 26 weeks, and none of the patients developed serious adverse events [18]. Patients with multidrug-resistant HIV should be managed in conjunction with an HIV specialist. (See "Overview of antiretroviral agents used to treat HIV", section on 'Capsid inhibitors'.)

Ibrexafungerp for recurrent vulvovaginal candidiasis (December 2022)

Treatment of recurrent vulvovaginal candidiasis (RVVC) has mainly consisted of long-term use of azole drugs such as fluconazole. In a phase 3 trial evaluating extended treatment with either ibrexafungerp, a novel triterpenoid antifungal, or placebo after initial fluconazole treatment in patients with RVVC, more patients receiving extended ibrexafungerp remained without evidence of RVVC four weeks from final dose (65 versus 53 percent). Based on this trial, the US Food and Drug Administration recently approved RVVC as a new indication for use of ibrexafungerp [19]. Although the duration of treatment benefit and efficacy against non-Candida species are not yet known, ibrexafungerp offers patients with RVVC another treatment option. (See "Candida vulvovaginitis: Treatment", section on 'Triterpenoid extended treatment'.)

RECENT APPROVALS - DERMATOLOGIC AND ALLERGY THERAPIES

Topical ruxolitinib for limited nonsegmental vitiligo (October 2022)

Vitiligo is a difficult-to-treat autoimmune skin disease characterized by depigmented patches. In two recent identical randomized trials that included 674 patients with nonsegmental vitiligo involving ≤10 percent of total body surface area, more patients assigned to twice daily ruxolitinib 1.5% cream (a topical Janus kinase inhibitor) achieved a 75 percent reduction in the facial Vitiligo Area Scoring Index at 24 weeks, compared with vehicle (30 versus 7 percent [trial 1] and 31 percent versus 11 percent [trial 2]) [20]. Ruxolitinib-related adverse events included acne and pruritus at the site of application and nasopharyngitis. These studies were the basis for the US Food and Drug Administration approval for this indication. However, due to safety concerns related to systemic absorption of ruxolitinib, we continue to suggest topical corticosteroids and topical calcineurin inhibitors as initial treatments for limited vitiligo. (See "Vitiligo: Management and prognosis", section on 'Localized disease'.)

Oral deucravacitinib for moderate to severe plaque psoriasis (October 2022)

Tyrosine kinase inhibition represents a novel approach to psoriasis treatment. Two phase 3 trials support efficacy of oral deucravacitinib, a selective tyrosine kinase 2 inhibitor, for moderate to severe plaque psoriasis [21,22]. In the POETYK PSO-1 and POETYK PSO-2 trials, adults with moderate to severe plaque psoriasis were randomly assigned to deucravacitinib, placebo, or apremilast. At week 16, patients treated with deucravacitinib were more likely to achieve at least 75 percent improvement in the Psoriasis Area and Severity Index score than patients in the placebo or apremilast groups (58, 13, and 35 percent in POETYK PSO-1 and 53, 9, and 40 percent in POETYK PSO-2, respectively). Serious adverse effects were infrequent in both trials. These findings support deucravacitinib as an effective oral treatment for psoriasis and contributed to FDA approval of deucravacitinib for moderate to severe psoriasis in adults who are candidates for systemic therapy or phototherapy. Additional study will be useful for determining long-term efficacy and safety. (See "Treatment of psoriasis in adults", section on 'Deucravacitinib'.)

RECENT APPROVALS - ENDOCRINE AND KIDNEY DISEASE THERAPIES

Targeted-release budesonide for IgA nephropathy (February 2023)

An oral targeted-release formulation of the glucocorticoid budesonide (TRF-budesonide) has been designed to release the drug in the distal ileum in patients with immunoglobulin A nephropathy (IgAN) to target the presumed site of production of aberrantly galactosylated IgA1 while limiting systemic glucocorticoid absorption. The efficacy and safety of this agent were evaluated in a randomized phase 3 trial of 199 patients with IgAN and persistent proteinuria despite optimized renin-angiotensin system blockade [23]. Treatment with TRF-budesonide, compared with placebo, resulted in a greater reduction in proteinuria from baseline and a slower rate of estimated glomerular filtration rate decline at nine months; while rates of adverse effects were similar between the groups, rates of adverse events leading to treatment discontinuation were higher in the TRF-budesonide group. Pending data on longer-term outcomes with TRF-budesonide, we continue to suggest initial therapy with oral systemic glucocorticoids plus supportive care for patients with IgAN at high risk for disease progression. (See "IgA nephropathy: Treatment and prognosis", section on 'Other regimens'.)

Immunotherapy to delay type 1 diabetes (December 2022)

Immunotherapies have been investigated extensively as a means of preserving pancreatic beta cell function and thereby delaying or preventing progression to type 1 diabetes in high-risk individuals. Teplizumab is the first disease-modifying immunotherapy for type 1 diabetes to receive regulatory approval in the United States [24]. Teplizumab, administered as a single 14-day course of daily intravenous infusions, delays the diagnosis of type 1 diabetes by a median of two years in individuals at high risk for developing the disease (ie, abnormal glucose tolerance and presence of at least two diabetes autoantibodies). Adverse effects include transient lymphopenia, rash, anemia, and fever. The clinical use of teplizumab remains uncertain and will require additional data regarding its benefits and risks, as well as the development of clearly delineated strategies for identifying optimal candidates for treatment. (See "Prevention of type 1 diabetes mellitus", section on 'Teplizumab'.)

Abaloparatide for men at high risk for osteoporotic fracture (January 2022)

Abaloparatide is a synthetic analog of parathyroid hormone-related protein (PTHrP) administered as a daily subcutaneous injection, which increases spine and hip bone mineral density (BMD) and reduces the risk of vertebral and nonvertebral fractures in postmenopausal women. It recently received regulatory approval in the United States to increase bone density in men at high risk for osteoporotic fracture based on the results of a 12-month trial comparing abaloparatide with placebo in 228 men with osteoporosis, approximately 35 percent of whom had prevalent vertebral fractures [25]. Abaloparatide increased BMD at the lumbar spine and total hip more than placebo; fractures were infrequent in both groups. Anabolic agents like abaloparatide are options for osteoporosis treatment in men with severe osteoporosis or for those who have contraindications or intolerance to bisphosphonates. (See "Treatment of osteoporosis in men", section on 'Contraindications/intolerance to any bisphosphonates'.)

RECENT APPROVALS - HEMATOLOGIC AND ANTICOAGULANT

Extended half-life factor VIII for hemophilia A (February 2023)

Factor products that require less frequent intravenous administration are desirable for people with hemophilia. Factor VIII requires von Willebrand factor (VWF) for stability, and half-life extension has been limited due to the half-life of VWF. A new product circumvents this problem by fusing a form of factor VIII to the relevant VWF domain; in a study involving 133 individuals with severe hemophilia A, this product could be administered once weekly and dramatically reduced bleeding rates [26]. This product was approved by the US Food and Drug Administration in February 2023, and availability is expected in April. (See "Gene therapy and other investigational approaches for hemophilia", section on 'Efanesoctocog alfa (factor VIII-VWF fusion)'.)

Zanubrutinib versus ibrutinib in relapsed CLL (December 2022, Modified January 2023)

The Bruton tyrosine kinase (BTK) inhibitors ibrutinib, acalabrutinib, and zanubrutinib are effective treatments for chronic lymphocytic leukemia (CLL). In a multicenter, open label, phase 3 trial (ALPINE) of >650 patients with relapsed or refractory CLL, when compared with ibrutinib, zanubrutinib improved progression-free survival and had less overall toxicity, including less cardiotoxicity [27]. Overall survival data are immature. Based on these and other data, the US Food and Drug Administration has approved zanubrutinib for the treatment of chronic lymphocytic leukemia. For patients who are candidates for a BTK inhibitor, we now suggest zanubrutinib or acalabrutinib rather than ibrutinib. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Zanubrutinib'.)

Mosunetuzumab for multiply relapsed follicular lymphoma (August 2022, Modified January 2023)

Mosunetuzumab is a bispecific T cell engager (BiTE) monoclonal antibody directed at both CD20 on follicular lymphoma (FL) cells and CD3 on cytotoxic T cells. In a single-arm, multicenter phase 2 study of mosunetuzumab in 90 patients with FL relapsed after at least two prior lines of treatment, there were high response rates (60 percent complete, 20 percent partial), with a median duration of response of 23 months [28]. The most common adverse event was cytokine release syndrome, which was predominantly grade 1 or 2 and confined to the first cycle. These results led to approval of mosunetuzumab by the US Food and Drug Administration and European Medicines Agency for this population. Where available, we consider mosunetuzumab an option for patients with multiply relapsed FL with short prior remission durations (eg, <24 months). (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Mosunetuzumab'.)

Bispecific T cell engager (BiTE) teclistamab in multiple myeloma (November 2022)

Therapies that target the B cell maturation antigen (BCMA) are a preferred treatment option for patients with penta-refractory multiple myeloma (MM), defined as disease refractory to an anti-CD38 monoclonal antibody, lenalidomide, pomalidomide, bortezomib, and carfilzomib (algorithm 2). In a single-arm, phase 2, multicenter trial (MajesTEC-1) of the first-in-class anti-BCMA bispecific T-cell engager (BiTE) teclistamab in multiply relapsed MM, objective responses were seen in 63 percent, with an estimated progression-free survival of 11 months [29]. At least one grade 3 or 4 toxicity was reported in 95 percent of patients, with hematologic toxicity being most common. Cytokine release syndrome occurred in 73 percent and was usually grade 1 or 2. Based on this data, teclistamab has received accelerated approval by the US Food and Drug Administration for treatment of adults with relapsed, refractory MM after four or more lines of systemic therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody [30]. The use of teclistamab and other BCMA-directed therapies is individualized, weighing disease tempo, availability of other treatments, and expected toxicity. (See "Multiple myeloma: Treatment of third or later relapse".)

RECENT APPROVALS - NEUROLOGIC AND PSYCHIATRIC

Zavegepant for acute treatment of migraine in adults (March 2023)

Several calcitonin gene-related peptide (CGRP) receptor antagonists are available by oral formulation for acute migraine treatment. Zavegepant is the first CGRP-receptor antagonist to be approved for intranasal administration [31]. In a trial of 1405 adult patients with migraine, those assigned to zavegepant 10 mg were more likely to be pain free at two hours than patients assigned to placebo (24 versus 15 percent); resolution of the most bothersome acute symptom (eg, photophobia, nausea) was also more common with zavegepant (40 versus 31 percent) [32]. Nasal administration of a CGRP-receptor antagonist provides rapid absorption and may be preferred for patients with nausea/vomiting who are unable to tolerate oral options. (See "Acute treatment of migraine in adults", section on 'CGRP antagonists'.)

Sublingual dexmedetomidine for agitation in patients with schizophrenia (February 2023)

In 2022, the US Food and Drug Administration approved the sublingual form of dexmedetomidine for mild to moderate agitation in individuals with schizophrenia; the trial supporting the approval was recently published. Among 380 participants with schizophrenia, those randomly assigned to dexmedetomidine (180 or 120 mcg) had greater improvements in symptoms of agitation at two hours compared with placebo; improvements were apparent at 20 and 30 minutes [33]. Adverse effects, mainly somnolence, dry mouth, and dizziness, were more common with dexmedetomidine (37 to 40 versus 15 percent). The sublingual formulation avoids the need for intramuscular medication administration and thus potentially improves the patient experience and allows for broader use in psychiatric settings. (See "Psychosis in adults: Initial management", section on 'Psychiatric symptoms'.)

Ublituximab in patients with multiple sclerosis (January 2023)

Ublituximab, a recombinant monoclonal antibody that targets B cells, was approved by the US Food and Drug Administration in December 2022 for the treatment of adults with relapsing forms of multiple sclerosis (MS). Its efficacy was established in two identical randomized trials comparing intravenous ublituximab with oral teriflunomide [34]. At 95 weeks in both trials, the annualized relapse rate and the mean number of gadolinium-enhancing brain lesions on MRI were lower with ublituximab. Common adverse effects of ublituximab include infusion reactions and upper respiratory tract infections; as with other B cell depleting therapies, there is also a risk of life-threatening infections. Although its role in clinical practice is not yet defined, ublituximab will likely be used in a similar manner to other high-efficacy disease-modifying therapies for relapsing forms of MS. (See "Disease-modifying therapies for multiple sclerosis: Pharmacology, administration, and adverse effects", section on 'Ublituximab'.)

Sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis (October 2022)

Sodium phenylbutyrate-taurursodiol (PB-TURSO) is a combination of two orally available drugs that each reduce neuronal cell death in preclinical models of amyotrophic lateral sclerosis (ALS). In a randomized trial of 137 patients with ALS (75 percent also taking riluzole and/or edaravone) who were within 18 months of symptom onset, patients assigned to PB-TURSO showed a slower median rate of monthly functional decline than those assigned to placebo by 24-week follow-up [35]. There were nonsignificant trends toward slower decline in both vital capacity and muscle strength with treatment. In a subsequent analysis of patients who continued open-label treatment (up to 35 months), those originally randomized to PB-TURSO had a longer median time to tracheostomy (26 versus 19 months) and a longer median time to first hospitalization [36]. Based on these results, the combination product received regulatory approval in the United States and Canada [37,38]. We now suggest use of PB-TURSO for all patients with ALS, along with riluzole (prioritized as initial therapy) and edaravone. (See "Disease-modifying treatment of amyotrophic lateral sclerosis", section on 'Efficacy'.)

RECENT APPROVALS - ONCOLOGIC

Nivolumab for pediatric patients with advanced melanoma (March 2023)

In pediatric patients with advanced melanoma, there are limited data to guide systemic treatment options. In February 2023, the US Food and Drug Administration (FDA) granted regulatory approval for nivolumab in pediatric patients (age 12 years and older) for the following indications [39]: unresectable or metastatic melanoma, as a single agent or in combination with ipilimumab, and advanced or metastatic melanoma that has been completely resected, as adjuvant therapy for one year. These approvals are based on trials of these regimens in adult patients and pharmacokinetic studies in pediatric patients that demonstrate similar exposure to nivolumab as that reported in adults. We agree with use of nivolumab in children with these indications. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Adjuvant nivolumab' and "Overview of the management of advanced cutaneous melanoma", section on 'Pediatric and adolescent patients'.)

Nadofaragene firadenovec for Bacillus Calmette-Guerin-unresponsive non-muscle invasive bladder cancer (March 2023)

For patients with Bacillus Calmette-Guerin (BCG)-unresponsive non-muscle invasive bladder cancer (NMIBC), there is interest in new treatments such as nadofaragene firadenovec, a recombinant adenovirus vector. In a nonrandomized trial in patients with BCG-unresponsive NMIBC, among 103 patients with carcinoma in situ (CIS), 53 percent experienced a complete response within three months of treatment with nadofaragene firadenovec [40,41]. Based on these data, the US Food and Drug Administration approved nadofaragene firadenovec for the treatment of high-risk BCG-unresponsive NMIBC with CIS (with or without papillary tumors). Although we typically suggest radical cystectomy in such patients, we consider nadofaragene firadenovec to be one acceptable alternative for those who are ineligible for or decline radical cystectomy. (See "Management of recurrent or persistent non-muscle invasive bladder cancer", section on 'Nadofaragene firadenovec'.)

Elacestrant in ESR1-mutated advanced hormone receptor-positive, HER2-negative breast cancer (February 2023)

Elacestrant is an oral selective estrogen receptor down-regulator that now has regulatory approval in the United States for use in postmenopausal women and men with Elacestrant is an oral selective estrogen receptor down-regulator that now has regulatory approval in the United States for use in postmenopausal women and men with -mutated advanced hormone receptor-positive, HER2-negative breast cancer that has progressed on at least one line of prior endocrine therapy [42]. Given previously demonstrated progression-free survival benefits over fulvestrant in this setting, as well as the ease of oral administration, we now suggest its use for such patients. (See "Treatment for hormone receptor-positive, HER2-negative advanced breast cancer", section on 'ESR1 mutation-positive'.)

Tucatinib plus trastuzumab for HER2-positive metastatic colorectal cancer (January 2023)

For patients with HER2-positive metastatic colorectal cancer (CRC), there is interest in investigating novel therapies such as tucatinib, a selective inhibitor of HER2 and HER3. In a phase II trial of over 80 patients with HER2-positive, RAS wild-type, chemotherapy-refractory metastatic CRC, the combination of tucatinib plus trastuzumab demonstrated an objective response rate of 38 percent [43]. Based on these data, the US Food and Drug Administration granted accelerated approval for tucatinib in combination with trastuzumab in adult patients with RAS wild-type, HER2-positive unresectable or metastatic CRC that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, and we consider this to be an appropriate option for this population. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RAS wild-type, HER2 overexpressors'.)

Atezolizumab for advanced alveolar soft part sarcoma (January 2023)

For patients with metastatic alveolar soft part sarcoma (ASPS), treatment options are limited and there is interest in investigating novel therapies. In a phase II trial (Study ML39345) in almost 50 adult and pediatric patients with unresectable or metastatic ASPS, atezolizumab demonstrated an objective response rate of 24 percent and was well tolerated [44]. For patients with unresectable or metastatic ASPS who have limited but progressive extracranial disease burden, we suggest single-agent immunotherapy rather than surveillance, and we consider atezolizumab to be one appropriate treatment option. (See "Uncommon sarcoma subtypes", section on 'Limited, progressive disease burden'.)

Mirvetuximab soravtansine in platinum-resistant epithelial ovarian cancer (November 2022)

Mirvetuximab soravtansine is a folate receptor alpha-directed antibody and microtubule inhibitor conjugate that has regulatory approval in the United States for folate receptor-alpha positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer (EOC) that has previously been treated with one to three prior systemic treatment regimens [45]. In an earlier randomized trial in patients with platinum-resistant EOC, the agent resulted in a nonsignificant trend towards better progression-free survival compared with investigator's choice chemotherapy in those with folate receptor-alpha high tumors (hazard ratio 0.69), with better tolerability. We consider mirvetuximab soravtansine to be an appropriate later-line option in platinum-resistant EOC. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease", section on 'Other agents'.)

Immune checkpoint inhibitor combinations plus chemotherapy in advanced NSCLC (November 2022)

The addition of immune checkpoint inhibitors to chemotherapy improves survival in advanced non-small cell lung cancer (NSCLC), with new combinations being investigated. In preliminary results of Study 16113, among 466 patients randomly assigned to chemotherapy with or without cemiplimab, the cemiplimab group experienced an improvement in median overall survival (22 versus 13 months), with low rates of serious adverse events [46]. Similarly, in the POSEIDON trial, the addition of tremelimumab plus durvalumab to chemotherapy improved median survival (15 versus 11 months), with acceptable rates of grade ≥3 toxicity [47]. These results have led to US Food and Drug Administration approvals of combinations of cemiplimab as well as tremelimumab/durvalumab with chemotherapy in advanced NSCLC lacking certain driver mutations. (See "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'Cemiplimab plus chemotherapy'.)

Tissue-agnostic approval of selpercatinib for RET fusion-positive solid tumors (November 2022)

Selpercatinib has received a tissue-agnostic, accelerated approval from the US Food and Drug Administration for treatment of adult patients with locally advanced or metastatic solid tumors and a rearranged during transfection (RET) gene fusion with disease progression on or following prior systemic treatment or those who have no satisfactory alternative treatment options. Approval was based on the phase 1/2 LIBRETTO-001 basket trial of 41 patients with a variety of solid tumors containing an RET fusion gene, in which the objective response rate was 44 percent and median duration of response was 24.5 months [48]. The most common grade 3 or worse treatment-emergent adverse events were hypertension and elevated serum transaminases. (See "Systemic therapy for nonoperable metastatic colorectal cancer: Approach to later lines of systemic therapy", section on 'RET fusion-positive tumors' and "Malignant salivary gland tumors: Treatment of recurrent and metastatic disease".)

Eflapegrastim for chemotherapy-induced neutropenia (September 2022)

The US Food and Drug Administration has approved eflapegrastim, a novel long-acting formulation of granulocyte colony stimulating factor (G-CSF), to decrease the incidence of infection in adult patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia [49]. Approval was based on two separate trials of patients with early-stage breast cancer treated with docetaxel plus cyclophosphamide and randomized to eflapegrastim or pegfilgrastim. Efficacy was comparable, but despite the lower G-CSF dose with eflapegrastim, the incidence of adverse events (ie, bone pain, injection site reactions) was not lower in either trial. Given the available data, these two medications appear clinically similar, and agent selection may depend largely on institutional formulary and insurance constraints. (See "Use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation", section on 'Eflapegrastim'.)

Sodium thiosulfate to reduce cisplatin ototoxicity in children with nonmetastatic solid tumors (September 2022)

Sodium thiosulfate (STS) has been approved by the US Food and Drug Administration to decrease the risk of cisplatin-related ototoxicity in pediatric patients aged 1 month or older with a localized, nonmetastatic solid malignancy [50]. Approval was based on two randomized trials, the Children's Oncology Group ACCL0431 trial and the SIOPEL-6 trial, which both demonstrated a lower incidence of ototoxicity among children treated with STS in the setting of hepatoblastoma or a solid tumor including germ cell cancer, medulloblastoma, neuroblastoma, or osteosarcoma. Given ongoing concerns about possible inferior oncologic outcomes, the approval was not extended to individuals with a metastatic solid tumor. The approved dose is based on actual body weight, as outlined in the US prescribing information [51]. (See "Overview of neurologic complications of platinum-based chemotherapy", section on 'Strategies'.)

RECENT APPROVALS – PULMONARY AND CRITICAL CARE

Approval of albuterol-budesonide for asthma in the United States (January 2023)

International guidelines have increasingly embraced concomitant use of as-needed inhaled glucocorticoid and a short-acting beta-agonist (SABA) as a therapeutic option for asthma, but combination inhalers have limited availability. A combination inhaler (albuterol-budesonide) has now been approved by the US Food and Drug Administration (FDA) for as-needed therapy in patients ≥18 years with asthma [52]. Although use of as-needed albuterol-budesonide is a reasonable approach for patients with mild persistent asthma or for those with intermittent asthma at high risk for serious exacerbations, it may not be widely available until early 2024. (See "Treatment of intermittent and mild persistent asthma in adolescents and adults", section on 'Combination inhaled glucocorticoid and short-acting beta-agonist as needed'.)

RECENT APPROVALS - OTHER

Fecal microbiota rectal suspension for preventing recurrent Clostridioides difficile infection (March 2023)

In 2022, the US Food and Drug Administration approved a fecal microbiota rectal suspension live biotherapeutic product (Rebyota) for preventing recurrent Clostridioides difficile infection (CDI) in adults with ≥2 prior episodes [53]. It is administered rectally via an enema 24 to 72 hours after the last dose of antibiotics for CDI treatment. In clinical trials of this product, 71 percent of participants did not have a recurrence within eight weeks of their prior CDI and none had a serious adverse event [54]. It remains to be seen how this new fecal microbiota rectal suspension will compare with traditional methods of fecal microbiota transplantation and with bezlotoxumab and whether it is a cost-effective preventive tool for CDI recurrences. (See "Fecal microbiota transplantation for treatment of Clostridioides difficile infection", section on 'Stool-based products'.)

Dupilumab for eosinophilic esophagitis (January 2023)

Therapeutic options for eosinophilic esophagitis (EoE) are expanding. In a two-part trial in patients with EoE that had not responded to proton pump inhibitor therapy, weekly dupilumab resulted in higher rates of histologic improvement after 24 weeks relative to placebo (part A [weekly dupilumab]: 60 versus 5 percent, and part B [dupilumab every 2 weeks]: 59 versus 6 percent) [55]. Dupilumab also improved dysphagia symptom scores. Based on these findings, the US Food and Drug Administration approved dupilumab for EoE in patients ≥12 years of age who weigh ≥40 kg [56]. Future studies will help to inform the role of dupilumab in EoE management. (See "Treatment of eosinophilic esophagitis (EoE)", section on 'Options for nonresponders'.)

Trial of intravenous immune globulin for dermatomyositis (November 2022)

Intravenous immune globulin (IVIG) has been used in the treatment of dermatomyositis (DM) based on limited observational data and small randomized trials. In a new randomized trial of 95 patients with DM, the percentage of patients who achieved a response of at least minimal improvement based on a composite score of disease activity was higher among those who received IVIG compared with placebo (79 versus 44 percent) at 16 weeks [57]. IVIG was associated with more adverse events, including thromboembolic events. Based on these results, the US Food and Drug Administration approved IVIG for the treatment of adults with dermatomyositis. More data are needed to help determine the potential role of IVIG as first-line therapy for patients with DM. (See "Treatment of recurrent and resistant dermatomyositis and polymyositis in adults", section on 'Intravenous immune globulin'.)

COVID-19 MANAGEMENT

Tixagevimab-cilgavimab (Evusheld) no longer authorized for prevention of COVID-19 (January 2023)

The monoclonal antibody combination of tixagevimab-cilgavimab had previously been an effective option for pre-exposure prophylaxis against COVID-19 in certain individuals expected to have suboptimal protection from vaccination or unable to receive vaccination. However, it is not active against certain Omicron subvariants (including BQ.1/BQ.1.1, XBB, and its derivatives XBB.1 and XBB.1.5) (table 3), which accounted for over 90 percent of circulating variants in the United States as of January 2023. Because the emergency use authorization for tixagevimab-cilgavimab is contingent on a lower prevalence of resistant variants, it is no longer authorized in the United States [58]. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Monoclonal antibodies ineffective for pre-exposure prophylaxis'.)

Nirmatrelvir-ritonavir in vaccinated individuals with COVID-19 (October 2022)

A large randomized trial previously demonstrated that nirmatrelvir-ritonavir (Paxlovid) substantively reduced hospitalization and death in unvaccinated individuals with COVID-19 and risk factors for severe disease; accumulating observational data suggest that high-risk vaccinated individuals also benefit. In a study of 1130 vaccinated adults who received nirmatrelvir-ritonavir within five days of COVID-19 diagnosis and 1130 controls matched for age, gender, race, and comorbidities, nirmatrelvir-ritonavir was associated with a lower rate of emergency department visits, hospitalization, and death (odds ratio 0.5) [59]. All 10 deaths were among those who had not been treated. In another study, nirmatrelvir-ritonavir was associated with a reduction in hospitalization from 59 to 15 cases per 100,000 person-days among mostly vaccinated patients ≥65 years old [60]. Despite the limitations of observational data, these data highlight the potential clinical impact of nirmatrelvir-ritonavir among vaccinated individuals with Omicron subvariant infection and support our recommendations to treat patients at risk for severe disease, including otherwise healthy individuals ≥65 years old, regardless of vaccination status (algorithm 3). (See "COVID-19: Management of adults with acute illness in the outpatient setting", section on 'Efficacy and rationale'.)

COVID-19 VACCINATION

New urticaria in the weeks after COVID-19 vaccination (March 2023)

Urticaria with or without angioedema has been reported in association with coronavirus disease 2019 (COVID-19) as well as messenger ribonucleic acid (mRNA) vaccines and boosters, particularly the Moderna mRNA booster. In a study of over 3.5 million adults from two cohorts who received a first booster dose of COVID-19 vaccine, the crude incidence of chronic spontaneous urticaria was approximately 2 cases per 100,000 persons [61]. Of the 800 patients in two cohorts with newly diagnosed urticaria, more than 90 percent of cases were temporally associated with receiving the Moderna vaccine. Urticaria appeared between one and two weeks after vaccination, occurred most days of the week, and, in most patients, resolved in two to six months. This phenomenon is reminiscent of urticaria associated with viral infections, does not constitute an allergy, and is not a reason to avoid future vaccinations or boosters, although affected patients may prefer to choose a different product. (See "New-onset urticaria", section on 'COVID-19 vaccines and boosters'.)

VACCINES - OTHER

Expanded ACIP recommendations for oral cholera vaccine (October 2022)

CVD 103-HgR (Vaxchora) is a single-dose, live attenuated oral cholera vaccine derived from Vibrio cholerae serotype O1; it was licensed by the US Food and Drug Administration and recommended by the Advisory Committee on Immunization Practices (ACIP) in 2016 for adults age 18 to 64 years traveling to areas of active cholera transmission. In 2022, the ACIP expanded the age group to include individuals age 2 to 17 years who meet these criteria [62]. Thus far, assessment of CVD 103-HgR vaccine benefit in children has been based on safety and immunogenicity data rather than direct assessment of vaccine efficacy. We are in agreement with this guidance. (See "Cholera: Clinical features, diagnosis, treatment, and prevention", section on 'For travelers to high-risk areas'.)

Updated recommendations for pneumococcal vaccination in children and adolescents (September 2022)

Updated guidance from the Advisory Committee on Immunization Practices (ACIP) permits interchangeable use of the recently licensed 15-valent pneumococcal conjugate vaccine (PCV15) and 13-valent PCV (PCV13) for routine infant immunization and immunization of high-risk children and adolescents (table 4) [63]. PCV15 contains the 13 serotypes included in PCV13 plus serotypes 22F and 33F (table 5), which accounted for 15 to 23 percent of invasive pneumococcal disease cases in children <18 years in the United States during 2018 to 2019. In prelicensure randomized trials, PCV15 demonstrated immunogenicity and safety similar to those of PCV13. We agree with the ACIP recommendations for PCV15. Clinical trials of the 20-valent PCV in children are ongoing. (See "Pneumococcal vaccination in children", section on 'Conjugate vaccines'.)