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

Low- versus high-dose calcium supplements and risk of preeclampsia (January 2024)

In populations with low baseline dietary calcium intake, the World Health Organization recommends 1500 to 2000 mg/day calcium supplementation for pregnant individuals to reduce their risk of developing preeclampsia. However, a recent randomized trial that evaluated low (500 mg) versus high (1500 mg) calcium supplementation in over 20,000 nulliparous pregnant people residing in two countries with low dietary calcium intake found low and similar rates of preeclampsia in both groups [1]. These findings suggest that a 500 mg supplement is sufficient to reduce the risk of preeclampsia in these populations. For pregnant adults in the United States, we prescribe 1000 mg/day calcium supplementation, which is the recommended daily allowance to support maternal calcium demands without bone resorption. (See "Preeclampsia: Prevention", section on 'Calcium supplementation'.)

Guidelines for fever management in critically ill patients (November 2023)

Updated guidelines on the management of fever in the intensive care unit have been recently published by the Society for Critical Care Medicine and the Infectious Diseases Society of America [2]. Differences with the previous guidelines include an emphasis on the use of core methods when feasible (eg, pulmonary artery catheter, bladder, esophageal) and oral or rectal measurement when not feasible. Also promoted was the use of bedside imaging (eg, ultrasonography) in the evaluation process and biomarkers to facilitate duration of antimicrobial therapy. We agree with the recommendations, most of which were based upon weak evidence. (See "Fever in the intensive care unit", section on 'Temperature measurement'.)

Acetylcysteine dosing and stopping criteria for acetaminophen poisoning (November 2023)

An expert panel of toxicologists from the United States and Canada have published consensus guidelines for the management of acetaminophen poisoning [3]. Many acetylcysteine protocols exist; they recommend that whichever regimen is chosen, it should deliver at least 300 mg/kg acetylcysteine orally or intravenously during the first 20 to 24 hours. A patient with a reliable history of ingesting >30 g of acetaminophen should receive acetylcysteine as soon as possible. The panel also recommended that duration of acetylcysteine should be based on clinical endpoints rather than a predetermined time. All of the following criteria should be met before stopping acetylcysteine: a clinically well patient, acetaminophen concentration <10 mcg/mL, international normalized ratio <2, and AST/ALT normal or decreased 25 to 50 percent from their peak concentration. We agree with the panel's recommendations. (See "Acetaminophen (paracetamol) poisoning: Management in adults and children", section on 'Choice of protocol' and "Acetaminophen (paracetamol) poisoning: Management in adults and children", section on 'Duration of treatment (stopping criteria)'.)

Global inappropriate medication use in older adults (September 2023)

Inappropriate medication use is common among older adults. In a meta-analysis of 94 studies representing over 371 million older adults in 17 countries, the prevalence of potentially inappropriate medication (PIM) use was over 37 percent, with benzodiazepines being the most common medication [4]. The study also showed that PIM use has increased over the past 20 years, especially in high-income countries. Deprescribing of inappropriate medications is a priority among older adults. (See "Drug prescribing for older adults", section on 'Inappropriate medications'.)

Over-the-counter opioid antagonist for opioid overdose (September 2023)

Drug overdose is a major public health problem; opioids were reported to be involved in nearly 80 percent of the 600,000 overdose deaths worldwide in 2019. The increasing rate of fatal overdose is driven by the presence of the synthetic opioid fentanyl. Naloxone 4 mg nasal spray rapidly reverses the effects of opioid overdose and is now the first opioid antagonist agent available for over-the-counter purchase in the United States [5]. The increased availability is part of an ongoing effort by the US Food and Drug Administration Overdose Prevention Framework to encourage harm reduction through developing and expanding access to novel overdose reversal products. (See "Prevention of lethal opioid overdose in the community", section on 'Community-based naloxone'.)

Consensus statement on acetaminophen poisoning (August 2023)

An expert panel of toxicologists from the United States and Canada have published consensus guidelines for the management of acetaminophen poisoning [3]. The guidelines broadly cover treatment of acute or repeated supratherapeutic ingestions in adults and children including indications and administration of acetylcysteine therapy, laboratory assessment, monitoring, enhanced elimination techniques, and indications for consultation with a liver transplant team. The guidelines also cover special situations including ingestion of extended-release formulations, co-ingestion of anticholinergics or opioids, high-risk (ie, very large dose) ingestions, young children, pregnancy, elevated weight, and patients for whom the time of ingestion is unknown or unreliable. In addition, the statement introduces a revised Rumack-Matthew nomogram with a specific treatment line for high-risk ingestions. (See "Acetaminophen (paracetamol) poisoning in adults: Pathophysiology, presentation, and evaluation", section on 'Evaluation and diagnosis' and "Clinical manifestations and diagnosis of acetaminophen (paracetamol) poisoning in children and adolescents", section on 'Evaluation and diagnosis'.)

DRUG INTERACTIONS

Cannabinoid-drug interactions (November 2023)

Data are scarce on the effects of cannabinoids on prescribed medications. In a pharmacokinetic study that evaluated blood levels of common medications (eg, losartan, omeprazole, midazolam) in 18 healthy adults, standardized cannabidiol (CBD) extract demonstrated potential to moderately inhibit the hepatic enzyme CYP2C19 and weakly inhibit CYPs 2C9, 3A4, and 1A2 [6]. Previous data have shown that CBD can also inhibit P-glycoprotein (P-gp) multidrug efflux pumps. Patients using cannabinoids in conjunction with narrow safety index medications cleared through CYP metabolism, including warfarin (2C9), phenytoin (2C19), dabigatran, digoxin, and tacrolimus (3A4 and P-gp), may be subject to adverse drug-cannabinoid interactions (table 1). Such patients may require closer monitoring and therapy modification. Specific interactions may be analyzed by use of the drug interactions tool included in UpToDate. (See "Medical use of cannabis and cannabinoids in adults", section on 'Drug-drug interactions'.)

DRUG OR INDICATION WITHDRAWALS

Copanlisib withdrawn from the market (November 2023)

While previously approved by the US Food and Drug Administration for the treatment of multiply relapsed follicular lymphoma (FL), the phosphoinositide 3-kinase (PI3K) inhibitor copanlisib has been voluntarily withdrawn from the market by its manufacturer [7]. While initial studies suggested efficacy, subsequent studies did not confirm a favorable risk-to-benefit ratio. There are now no PI3K inhibitors with regulatory approval for FL. Patients who began treatment with copanlisib and are experiencing benefit with acceptable levels of toxicity may choose to continue the drug; the manufacturer is exploring access options. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Other novel agents'.)

Avoidance of PARP inhibitors as maintenance for platinum-sensitive relapsed ovarian cancer (September 2023)

For advanced epithelial ovarian cancer (EOC) with platinum-sensitive relapse, poly(ADP-ribose) polymerase (PARP) inhibitors were previously an option for maintenance therapy, irrespective of the presence of a BRCA mutation. However, this strategy no longer has regulatory approval in the United States for patients with BRCA wildtype cancers due to a lack of survival benefit in this population [8-10]. For patients with BRCA wildtype cancers and platinum-sensitive relapse, we use bevacizumab with platinum-based chemotherapy rather than a PARP inhibitor and continue as maintenance treatment. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-sensitive disease", section on 'PARP inhibitors no longer used'.)

FDA withdrawal of oxandrolone approval (August 2023)

The anabolic steroid oxandrolone, first approved in 1964, had been used for promoting weight gain in cachexia and to attenuate hypermetabolism in burn injury and other catabolic states. Longstanding concern with serious adverse effects (eg, hepatotoxicity, lipid alterations, cancer risks) and lack of evidence of efficacy had been communicated as early as the 1980s by the US Food and Drug Administration (FDA) Endocrinologic and Metabolic Drugs Advisory Committee. Following a recent safety review, FDA advised manufacturers that currently available data did not support its continued use, and approval was voluntarily withdrawn as of June 2023 [11]. (See "Hypermetabolic response to moderate-to-severe burn injury and management", section on 'Attenuation of the hypermetabolic response'.)

ADVERSE REACTIONS AND WARNINGS

Hearing impairment after teprotumumab for thyroid eye disease (January 2024)

Teprotumumab, an insulin-like growth factor 1 receptor inhibitor, is a relatively new, effective treatment for moderate-to-severe thyroid eye disease. In the initial clinical trials, hearing abnormalities were reported in approximately 10 percent of patients, but audiograms were not routinely performed. In a subsequent prospective study evaluating hearing outcomes before and after teprotumumab therapy in 52 patients, 21 percent had a decline in hearing on audiometry immediately after completing therapy, which persisted after six months in 5 patients [12]. Most patients with hearing loss had baseline hearing dysfunction. It is important to discuss potential adverse hearing effects prior to initiating therapy and review symptoms at each visit. It is reasonable to obtain baseline audiometry in all patients and repeat in individuals who report any change in hearing. (See "Treatment of thyroid eye disease", section on 'Teprotumumab'.)

Risk of fractures with benzodiazepine receptor agonists (January 2024)

Benzodiazepine receptor agonists (BZRAs), including benzodiazepines and nonbenzodiazepine BZRAs such as zolpidem, can cause excess drowsiness and imbalance leading to falls and fractures. In a recent meta-analysis of 20 observational studies in over six million individuals, BZRAs were associated with increased risk of osteoporotic fractures across a range of drug classes and fracture types, with odds ratios ranging from 1.2 to 1.4 [13]. Most but not all studies included adults 50 years of age or older. These data reinforce the need for caution in prescribing BZRAs for insomnia and other indications, particularly in older adults. (See "Pharmacotherapy for insomnia in adults", section on 'Special populations'.)

Rare secondary T cell lymphomas after chimeric antigen receptor (CAR)-T cell therapy (December 2023)

Chimeric antigen receptor (CAR)-T cell therapy is effective for treatment of relapsed or refractory B cell lymphomas, multiple myeloma, and other disorders, but it may be associated with severe and potentially fatal adverse effects (AEs). Reports are now emerging of secondary T cell lymphomas in patients treated with CD19- and B cell maturation antigen (BCMA)-directed CAR-T cell therapy, some of which have CAR-positive malignant cells [14]. Although rare, the actual incidence is not well defined and it is uncertain if they are associated with all CAR-T cell products. US Food and Drug Administration (FDA)-approved CAR-T cell products include warnings about potential secondary malignancies, but at present, no regulatory action has been taken and no product has been recalled. Patients receiving CAR-T cell therapy should be monitored for development of new malignancies, and any such events should be reported to the manufacturer and to the FDA AE Reporting System (FAERS) [15]. The overall benefits of CAR-T cell products continue to outweigh potential risks for approved uses, but patients should be monitored and events reported. (See "Diffuse large B cell lymphoma (DLBCL): Suspected first relapse or refractory disease in patients who are medically fit", section on 'Relapse <12 months or primary refractory DLBCL'.)

Macular changes related to pentosan polysulfate sodium (November 2023)

Macular eye disease has been reported in patients who have taken pentosan polysulfate sodium (PPS), which is used for the treatment of interstitial cystitis. In a prospective cohort study of 26 eyes with PPS maculopathy and >3000 g cumulative PPS exposure, progression of macular changes continued 13 to 30 months after drug cessation [16]. Median visual acuity decreased slightly; most patients reported progression of symptoms, including difficulty in low-light environments and blurry vision. These results indicate that PPS maculopathy progresses despite drug discontinuation, underscoring the importance of regular screening for maculopathy in patients with current or prior PPS exposure. (See "Interstitial cystitis/bladder pain syndrome: Management", section on 'Pentosan polysulfate sodium as alternative'.)

Glucagon-like peptide 1 (GLP-1) receptor agonists may increase risk of aspiration during anesthesia (July 2023)

Patients who take glucagon-like peptide 1 (GLP-1) receptor agonists (eg, semaglutide, liraglutide) for weight loss or diabetes may be at increased risk of aspiration during anesthesia due to delayed gastric emptying. In 2023, the American Society of Anesthesiologists suggested holding the day-of-surgery or weekly dose of GLP-1 agonists prior to elective surgery because of case reports of aspiration [17]. For patients who have not held their GLP-1 (ie, no drug on day of procedure/surgery for daily dosing, no drug in the week prior to procedure/surgery for weekly dosing), gastric ultrasound can be used to assess for gastric contents or a rapid sequence induction and intubation should be considered. (See "Rapid sequence induction and intubation (RSII) for anesthesia", section on 'Patients taking GLP-1 receptor agonists'.)

RECENT APPROVALS - ANTIMICROBIALS

Taurolidine catheter locks for the prevention of hemodialysis catheter-related bloodstream infections (December 2023)

Catheter-related bloodstream infections (CRBSIs) are an important cause of morbidity and mortality in patients on hemodialysis. In a randomized trial of nearly 800 patients on maintenance hemodialysis via a tunneled central venous catheter, a catheter lock solution containing taurolidine, an antimicrobial agent, plus heparin reduced the incidence of CRBSI compared with a heparin control lock solution (2 versus 8 percent) over a mean of 200 days [18]. No trial participants used chlorhexidine-coated catheter caps, which are commonly used to reduce the risk of CRBSI. Based on these results, taurolidine lock solutions are a reasonable alternative to chlorhexidine-coated catheter caps to help prevent CRBSIs in select patients. (See "Tunneled hemodialysis catheter-related bloodstream infection (CRBSI): Management and prevention", section on 'Methods we use'.)

Sulbactam-durlobactam for Acinetobacter infections (November 2023)

Antibiotic options for infections due to Acinetobacter spp are limited due to high rates of resistance. The US Food and Drug Administration recently approved a new beta-lactam/beta-lactamase inhibitor antibiotic, sulbactam-durlobactam. In an international randomized trial of 125 patients with carbapenem-resistant Acinetobacter infection (mainly hospital-acquired or ventilator-associated pneumonia), sulbactam-durlobactam resulted in a trend toward lower all-cause mortality that was not statistically significant (19 versus 32 percent) and a higher clinical cure rate (62 versus 40 percent) compared with colistin [19]. We reserve this agent for patients with hospital-acquired pneumonia or bacteremia due to susceptible Acinetobacter baumannii complex isolates that are resistant to other first-line agents (ie, other beta-lactams, carbapenems, and fluoroquinolones). (See "Acinetobacter infection: Treatment and prevention", section on 'First-line antibiotics'.)

Rezafungin for invasive candidiasis (August 2023)

Echinocandins are the treatment of choice for initial treatment of invasive candidiasis. A new echinocandin, rezafungin, has been approved by the US Food and Drug Administration and is now available for adults 18 years or older with candidemia or invasive candidiasis who have limited alternative options [20]. Approval was based on two randomized trials that found no difference in overall mortality, clinical cure, or mycological eradication with rezafungin compared with caspofungin [21,22]. Of note, the trials excluded children, patients with severe liver disease, and patients with endocarditis, osteomyelitis, prosthetic joint infection, central nervous system infection, or eye infection. Rezafungin is unique in that it is administered as a once-weekly infusion, which is practical for outpatient echinocandin therapy; however, we continue to favor the other echinocandins for initial inpatient management and oral azole therapy for step-down therapy. (See "Management of candidemia and invasive candidiasis in adults", section on 'Non-neutropenic patients'.)

RECENT APPROVALS - DERMATOLOGIC AND ALLERGY THERAPIES

Topical roflumilast for seborrheic dermatitis (January 2024)

Seborrheic dermatitis is a chronic, relapsing dermatitis involving areas rich in sebaceous glands (eg, scalp, face) that requires repeated or long-term maintenance treatment with topical anti-inflammatory agents. In a randomized trial that included 226 adults with moderate to severe seborrheic dermatitis, topical roflumilast, a potent phosphodiesterase-4 inhibitor with anti-inflammatory properties, was more effective than vehicle in achieving an Investigator Global Assessment score of clear/almost clear at eight weeks (74 versus 41 percent, respectively) [23]. Treatment was generally well tolerated. These findings contributed to approval by the US Food and Drug Administration of roflumilast 0.3% foam for the treatment of seborrheic dermatitis in adults and children older than nine years [24]. (See "Seborrheic dermatitis in adolescents and adults", section on 'Topical anti-inflammatory agents'.)

RECENT APPROVALS - ENDOCRINE AND KIDNEY DISEASE THERAPIES

Fezolinetant, a neurokinin 3 receptor antagonist for hot flashes (August 2023)

Hormone therapy remains the most effective treatment for hot flashes. However, a new class of nonhormonal drugs, neurokinin 3 receptor (NK3R) antagonists, appears to be a reasonable alternative for those who cannot take hormone therapy. The first NK3R antagonist to be approved and available for clinical use is fezolinetant. In one trial of over 500 postmenopausal women with moderate-to-severe hot flashes, fezolinetant significantly reduced hot flash frequency and severity when compared with placebo [25,26]. After 12 weeks of therapy, the mean reductions in hot flash frequency for fezolinetant 45 mg, 30 mg, or placebo were 64, 59, and 45 percent, respectively. Women receiving fezolinetant 45 mg also had significant improvements in sleep disturbances when compared with placebo. (See "Menopausal hot flashes", section on 'Neurokinin 3 receptor antagonist'.)

RECENT APPROVALS - HEMATOLOGIC AND ANTICOAGULANT

Gene editing for beta thalassemia (January 2024)

Gene editing makes permanent changes in a cell's DNA. The gene editing construct exagamglogene autotemcel (exa-cel; brand name: Casgevy) was recently approved for transfusion-dependent beta thalassemia [27]. Exa-cel uses CRISPR/Cas9 editing to disrupt the BCL11A gene in autologous hematopoietic stem cells, which increases the percentage of fetal hemoglobin (Hb F). Preliminary studies demonstrated efficacy in patients undergoing autologous transplantation using hematopoietic stem cells treated with this construct [28]. This may be an option for patients who would otherwise choose allogeneic transplantation. (See "Management of thalassemia", section on 'Gene therapy and other stem cell modifications'.)

Gene therapy and gene editing in sickle cell disease (September 2023, Modified December 2023)

Several strategies are under study for individuals with sickle cell disease (SCD) who are seeking curative therapy. In December 2023, the US Food and Drug Administration approved two autologous cell-based therapies [29-31]:

●Lovotibeglogene autotemcel (lovo-cel) uses lentivirus-based gene therapy to introduce the antisickling beta globin variant T87Q and produce hemoglobin A with antisickling properties.

●Exagamglogene autotemcel (exa-cel) uses gene editing to disrupt the BCL11A gene and reverse the gamma globin to beta globin switch.

In a previous study, three individuals with SCD who were treated with a different gene editing approach (disrupting the gamma globin promotor) had marked reduction in vaso-occlusive complications and transfusion requirements [32,33]. All current gene therapy and gene editing approaches for SCD require autologous hematopoietic cell transplantation with myeloablative conditioning. (See "Investigational therapies for sickle cell disease", section on 'Gene therapy and gene editing'.)

Pirtobrutinib in relapsed CLL/SLL (July 2023, Modified December 2023)

Noncovalent Bruton tyrosine kinase (BTK) inhibitors such as pirtobrutinib are active in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with progression on a prior covalent BTK inhibitor (eg, ibrutinib, acalabrutinib, zanubrutinib). In a phase 1/2 trial including 247 such patients, pirtobrutinib was associated with an overall response rate of 82 percent and median progression-free survival of 19.6 months [34]. Response rates were similar irrespective of prior exposure to venetoclax or presence of BTK C481 mutations, which frequently arise upon progression on a covalent BTK inhibitor. Based on these results, the US Food and Drug Administration granted accelerated approval for pirtobrutinib in adults with CLL/SLL who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor. We consider pirtobrutinib an option in this setting. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Pirtobrutinib'.)

Pegcetacoplan self-injector for adults with paroxysmal nocturnal hemoglobinuria (November 2023)

Pegcetacoplan is a pegylated peptide that can inhibit both intravascular and extravascular hemolysis in adults with paroxysmal nocturnal hemoglobinuria (PNH). The US Food and Drug Administration (FDA) recently approved pegcetacoplan in a single-use self-injector for use by the patient or caregiver after training in preparation and administration [35]. As with other complement inhibitors, pegcetacoplan is contraindicated in patients with severe infections, and the FDA label has a boxed warning about increased risk for meningococcal infections. We consider the pegcetacoplan self-injector an acceptable method for treatment of adults with symptomatic PNH. (See "Treatment and prognosis of paroxysmal nocturnal hemoglobinuria", section on 'Pegcetacoplan'.)

Motixafortide plus G-CSF for mobilization in patients with multiple myeloma (September 2023)

In patients undergoing autologous hematopoietic cell transplantation (HCT) for multiple myeloma (MM), granulocyte colony-stimulating factor (G-CSF) is used to mobilize peripheral blood progenitor cells (PBPCs); G-CSF is used either alone, in combination with the chemokine receptor type 4 (CXCR4) inhibitor plerixafor, or after cyclophosphamide. In a randomized trial, the addition of a new CXCR4 inhibitor motixafortide to G-CSF decreased the number of apheresis sessions required [36]. These results led to its approval by the US Food and Drug Administration for use with G-CSF for PBPC mobilization in patients with MM undergoing autologous HCT [37]. For most patients, we initiate G-CSF alone rather than with a CXCR4 inhibitor, reserving the CXCR4 inhibitor for those with a suboptimal response to single-agent G-CSF. (See "Multiple myeloma: Use of hematopoietic cell transplantation", section on 'G-CSF-based stimulation'.)

Bispecific antibodies in heavily pretreated multiple myeloma (August 2023)

Bispecific antibodies used in multiple myeloma (MM) are monoclonal antibodies directed at both CD3 on the patient's T cells and another antigen on the tumor (B cell maturation antigen [BCMA] or GPRC5D). In phase 2 trials in heavily pretreated patients with MM, the following have been observed:

●The anti-BCMA bispecific antibody elranatamab was associated with a response rate of 61 percent, and one-half had not progressed at 15 months [38]. Toxicity was similar to that seen with teclistamab (another anti-BCMA bispecific antibody).

●The anti-GPRC5D bispecific antibody talquetamab was associated with an overall response rate of approximately 73 percent, and most responses were maintained for at least nine months [39]. In addition to adverse reactions commonly seen with other bispecific antibodies, talquetamab was associated with oral toxicity, weight loss, skin reactions, and nail changes in most patients.

Based on these and other data, the US Food and Drug Administration approved both elranatamab and talquetamab for patients who have received at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. An anti-BCMA therapy such as elranatamab is our preferred treatment for penta-refractory MM (algorithm 1). In contrast, we typically reserve talquetamab for penta-refractory MM that is also refractory to alkylators and anti-BCMA therapies, given uncertainties regarding administration, toxicities, and long-term efficacy. (See "Multiple myeloma: Treatment of third or later relapse", section on 'Bispecific antibodies' and "Multiple myeloma: Treatment of third or later relapse", section on 'Talquetamab'.)

Quizartinib approved for AML with FLT3 internal tandem duplication (August 2023)

For acute myeloid leukemia (AML) with mutated FLT3, addition of the tyrosine kinase inhibitor (TKI) midostaurin to intensive induction therapy has improved survival outcomes; other novel TKIs are emerging. The US Food and Drug Administration has approved use of quizartinib, another TKI, with chemotherapy for patients with AML with FLT3 and internal tandem duplications (ITD) based on overall survival benefits compared with chemotherapy alone, with minimal added toxicity [40]. The cardiac QT interval should be assessed and hypokalemia and hypomagnesemia corrected before treatment, as quizartinib prolongs the QT interval and has been associated with torsade de pointes and cardiac arrest. For patients with FLT3-mutated AML, we recommend addition of either midostaurin (for any FLT3 mutation) or quizartinib (for FLT3-ITD) to intensive induction chemotherapy. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'AML with mutated FLT3'.)

RECENT APPROVALS - NEUROLOGIC AND PSYCHIATRIC

Vamorolone for Duchenne muscular dystrophy (December 2023)

Glucocorticoid treatment with prednisone or deflazacort for Duchenne muscular dystrophy (DMD) is associated with improved motor function, but adverse effects include weight gain, slowing of growth, and bone loss. Vamorolone, a novel steroid, was designed to reduce adverse effects of glucocorticoid therapy for DMD. In the VISION-DMD trial, vamorolone treatment led to improvement on several motor outcomes compared with placebo, while efficacy was similar compared with prednisone [41]. Prednisone treatment (but not vamorolone) led to growth deceleration and bone biomarker abnormalities. Based on these findings, the US Food and Drug Administration approved vamorolone for children age ≥2 years with DMD [42]. We suggest glucocorticoid treatment for children with DMD and anticipate using vamorolone as an alternative to prednisone and deflazacort. (See "Duchenne and Becker muscular dystrophy: Glucocorticoid and disease-modifying treatment", section on 'Benefits of glucocorticoid therapy'.)

Eplontersen for polyneuropathy related to hereditary transthyretin amyloidosis (November 2023)

Hereditary transthyretin amyloidosis (ATTR) is a rare but serious form of amyloidosis that can cause a rapidly progressive, sensory-motor and autonomic polyneuropathy. The efficacy of eplontersen, an antisense oligonucleotide that inhibits hepatic production of transthyretin (TTR), was evaluated in an open-label trial in nearly 170 patients with ATTR amyloidosis and polyneuropathy who received this agent for up to 66 weeks [43]. Patients treated with eplontersen had greater reductions in serum TTR concentrations, less neuropathy-related impairment, and better quality of life compared with historical controls receiving placebo. This trial contributed to US Food and Drug Administration approval of eplontersen in December 2023 for treatment of polyneuropathy of ATTR in adults [44]. (See "Overview of amyloidosis", section on 'Therapies for individual amyloid types'.)

New biologic agents for treatment of myasthenia gravis (July 2023, Modified October 2023)

Treatment options for acute and chronic immunosuppression in patients with myasthenia gravis (MG) continue to expand.

●Rozanolixizumab is a monoclonal antibody that binds to the Fc receptor to promote lysosomal degradation of IgG autoantibodies. In a randomized trial of 200 patients with acetylcholine receptor-positive or muscle-specific tyrosine kinase-positive MG, improvement in baseline symptoms by day 43 was greater among those assigned to rozanolixizumab (six-week course of weekly infusions at 7 or 10 mg/kg) than placebo [45]. These results led to approval by the US Food and Drug Administration (FDA) in June 2023 [46].

●Zilucoplan is a novel complement C5 inhibitor designed to prevent the autoimmune destruction of the postsynaptic membrane. In a randomized trial of 174 patients with generalized MG, patients assigned to zilucoplan (once daily subcutaneous self-injection of 0.3 mg/kg) had greater improvement in baseline symptoms at 12 weeks than those assigned to placebo [47]. These results led to FDA approval in October 2023 [48].

As with other antibody-based biologic agents, both agents may be considered early in the course of disease instead of glucocorticoids, as a bridge therapy to slower-acting agents, or as chronic maintenance therapy. (See "Chronic immunotherapy for myasthenia gravis", section on 'Rozanolixizumab' and "Chronic immunotherapy for myasthenia gravis", section on 'Zilucoplan'.)

Valbenazine in patients with Huntington disease chorea (August 2023)

Vesicular monoamine transporter type 2 (VMAT2) inhibitors such as valbenazine are showing utility for chorea in patients with Huntington disease (HD). In a 12-week randomized trial in 128 patients with HD, valbenazine improved chorea severity compared with placebo and was well tolerated [49], leading to its approval by the US Food and Drug Administration for patients with HD and chorea [50]. For most HD patients with chorea that interferes with function, we suggest a VMAT2 inhibitor (valbenazine, deutetrabenazine, or tetrabenazine) as first-line therapy (algorithm 2). Where available, valbenazine or deutetrabenazine may be preferred over tetrabenazine due to their longer half-lives and more convenient dosing. A major exception is patients with depression, in whom VMAT2 inhibitors should be avoided due to risk of worsening depression and suicidality. (See "Huntington disease: Management", section on 'Valbenazine'.)

Gene therapy for Duchenne muscular dystrophy (August 2023)

Delandistrogene moxeparvovec is a microdystrophin transgene delivered by an adeno-associated virus vector. The drug received accelerated approval from the US Food and Drug Administration (FDA) for the treatment of ambulatory males, ages four through five years, with Duchenne muscular dystrophy (DMD) who have a pathogenic variant in the DMD gene [51]. FDA approval was based upon the surrogate outcome of increased dystrophin production, as shown in a placebo-controlled trial of 41 patients with DMD [52]. There was no improvement in functional outcome with delandistrogene moxeparvovec treatment compared with placebo, but a subgroup analysis suggested possible improvement with active treatment for the four- to five-year age group. Despite lack of proven benefit, we anticipate that most eligible patients and their families will request treatment. (See "Duchenne and Becker muscular dystrophy: Glucocorticoid and disease-modifying treatment", section on 'Delandistrogene moxeparvovec'.)

Zuranolone for severe postpartum depression (August 2023)

For patients with severe postpartum depression who prioritize rapid improvement, we suggest initial therapy with brexanolone; however, the agent requires continuous intravenous infusion for 60 hours in an inpatient facility. Recently, the US Food and Drug Administration approved zuranolone for postpartum depression; clinical availability is anticipated by the end of 2023 [53,54]. Zuranolone is an oral agent that is administered over 14 days, has a similar mechanism of action to brexanolone, and can also result in rapid remission of symptoms. We expect that some patients will prefer zuranolone over the infusion required for brexanolone. (See "Severe postpartum unipolar major depression: Choosing treatment", section on 'Treatment that is approved but not yet available'.)

New buprenorphine formulation for opioid use disorder (August 2023)

Buprenorphine, an opioid agonist used in the treatment of opioid use disorder, suppresses withdrawal symptoms and craving and blocks the effects of other opioids, thereby reducing opioid use. In 2023, the US Food and Drug Administration approved a new long-acting subcutaneous formulation of buprenorphine-XR (Brixadi) that is available in weekly or monthly formulations and does not require stabilization on sublingual buprenorphine [55]. Prior studies had demonstrated similar response rates and urine toxicology outcomes with this formulation compared with sublingual formulations. This option provides a long-acting alternative that may improve adherence while limiting misuse or diversion. (See "Opioid use disorder: Pharmacologic management", section on 'Injectable buprenorphine'.)

RECENT APPROVALS - ONCOLOGIC

Maintenance eflornithine in high-risk neuroblastoma (January 2024)

For patients with high-risk neuroblastoma (HRNBL), there is interest in investigating novel maintenance therapies such as eflornithine, an ornithine decarboxylase inhibitor. In an externally controlled analysis of almost 100 patients with HRNBL who completed multimodality treatment and maintenance immunotherapy, extended maintenance therapy with eflornithine was associated with improved overall survival (hazard ratio 0.38) [56]. Based on these data, the US Food and Drug Administration approved eflornithine as maintenance therapy in patients with HRNBL who achieve at least a partial response to prior systemic agents and complete maintenance immunotherapy. Since maintenance eflornithine is not standard across all institutions, this agent may be offered on a case-by-case basis. (See "Treatment and prognosis of neuroblastoma", section on 'Eflornithine'.)

Repotrectinib in advanced ROS1-positive NSCLC (January 2024)

Studies are evaluating novel tyrosine kinase inhibitors (TKIs) in advanced ROS1-positive non-small cell lung cancer (NSCLC). In a study of repotrectinib in 71 patients with such cancers who were naïve to TKIs, the median progression-free survival (PFS) was 36 months and the 18-month overall survival (OS) rate was 88 percent. Among 56 patients with one prior TKI and no chemotherapy, the median PFS was 9 months and OS was 25 months [57]. These data contributed to regulatory approval of repotrectinib in the United States [58]. We consider repotrectinib to be an acceptable initial treatment option for patients with advanced ROS1-positive NSCLC. (See "Personalized, genotype-directed therapy for advanced non-small cell lung cancer", section on 'ROS1 rearrangements'.)

Mirvetuximab soravtansine in folate receptor alpha-positive ovarian cancer (December 2023)

Mirvetuximab soravtansine (MIRV) is a folate receptor (FR) alpha-directed antibody and microtubule inhibitor conjugate that is being evaluated for platinum-resistant, FR alpha-positive epithelial ovarian cancer (EOC). In a randomized trial of MIRV versus investigator's choice chemotherapy in 453 patients with such cancers, MIRV improved objective response rates (42 versus 16 percent), progression-free survival (5.6 versus 4.0 months), and overall survival (16.5 versus 12.8 months) [59]. Grade ≥3 adverse events were less common in the MIRV group (42 versus 54 percent). Based on these results, MIRV has regulatory approval in the United States for FR alpha-positive, platinum-resistant EOC that has been treated with one to three prior systemic treatment regimens. (See "Medical treatment for relapsed epithelial ovarian, fallopian tube, or peritoneal cancer: Platinum-resistant disease", section on 'Mirvetuximab soravtansine'.)

Gemcitabine plus cisplatin and pembrolizumab for advanced cholangiocarcinoma (November 2023)

Advanced cholangiocarcinoma is an aggressive disease with poor survival outcomes, so there is interest in investigating novel approaches, such as the addition of immunotherapy to chemotherapy. In a placebo-controlled, phase III trial of over 1000 patients with treatment-naïve, locally advanced or metastatic biliary tract cancers, the addition of pembrolizumab to gemcitabine plus cisplatin improved overall survival (median 13 versus 11 months) with an acceptable toxicity profile [60]. Based on these data, pembrolizumab, in combination with gemcitabine plus cisplatin, was approved by the US Food and Drug Administration for the treatment of locally advanced unresectable or metastatic biliary tract cancer [61]. We consider this combination to be an appropriate initial treatment option in fit patients with advanced or metastatic cholangiocarcinoma and no hyperbilirubinemia. (See "Systemic therapy for advanced cholangiocarcinoma", section on 'Gemcitabine plus cisplatin and pembrolizumab'.)

Overall survival with adjuvant atezolizumab in resected non-small cell lung cancer (October 2023)

Longer-term overall survival (OS) data are emerging for adjuvant immune checkpoint inhibitors in resected non-small cell lung cancer (NSCLC). In a previously reported randomized trial in 882 patients with stage II to III NSCLC who had undergone surgery and adjuvant cisplatin-based chemotherapy, adjuvant atezolizumab resulted in OS hazard ratios of 0.95 overall, 0.71 among those with programmed death-ligand 1 (PD-L1) tumor cell (TC) ≥1 percent, and 0.43 among those with PD-L1 TC ≥50 percent [62]. OS results remain immature. Based on results from this trial, atezolizumab is approved by the US Food and Drug administration (FDA) as adjuvant treatment following resection and platinum-based chemotherapy for stage II to III NSCLC whose tumors have PD-L1 TC ≥1 percent, as determined by an FDA-approved test [63]. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'Adjuvant immunotherapy'.)

Perioperative checkpoint inhibitors in resectable non-small cell lung cancer (June 2023, Modified October 2023)

Trials are evaluating the role of immune checkpoint inhibitors in resectable non-small cell lung cancer (NSCLC). In a randomized trial in almost 400 patients with resectable stage II to IIIB NSCLC, the addition of neoadjuvant pembrolizumab to cisplatin-based chemotherapy, followed by adjuvant pembrolizumab, improved event-free survival rates (62 versus 41 percent at 24 months) and overall survival (median not reached versus 52 months, hazard ratio 0.72) relative to chemotherapy alone [64,65]. In a separate randomized trial in over 800 patients, the addition of perioperative durvalumab to chemotherapy improved event-free survival rates (63 versus 52 percent at 24 months) [66]. Pembrolizumab has been approval by the US Food and Drug Administration (FDA) in patients with resectable NSCLC ≥4 cm or with node-positive disease, in combination with platinum-based chemotherapy as neoadjuvant treatment, with continuation as a single agent in the adjuvant setting [67]. Perioperative durvalumab does not have FDA approval. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'Neoadjuvant/perioperative immunotherapy'.)

Cemiplimab in advanced non-small cell lung cancer (September 2023)

Trials are reporting long-term outcomes of immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC). In a randomized trial among 565 patients with advanced NSCLC with programmed death-ligand 1 (PD-L1) of ≥50 percent, cemiplimab improved overall survival relative to platinum-doublet chemotherapy at 35 months’ follow-up (26 versus 13 months), with fewer grade 3–4 treatment-emergent adverse events (18 versus 40 percent) [68]. Based on results from this trial, cemiplimab has regulatory approval in the United States for use in patients with advanced NSCLC with PD-L1 of ≥50 percent without an EGFR, ROS1, or ALK genetic aberration [69], and we consider it to be an appropriate option in this setting. (See "Initial management of advanced non-small cell lung cancer lacking a driver mutation", section on 'Data regarding checkpoint inhibitor monotherapy'.)

Sacituzumab govitecan in hormone receptor-positive, HER2-negative metastatic breast cancer (August 2023)

Sacituzumab govitecan (SG) is an antibody-drug conjugate that previously showed progression-free survival benefits over clinician's choice of therapy in patients with metastatic, heavily pretreated, hormone receptor (HR)-positive, HER2-negative breast cancer; overall survival results from that randomized trial are now available. Among 543 patients, the overall survival with SG was 14.4 versus 11.2 months with clinician's choice of therapy [70]. SG has regulatory approval in the United States for patients with unresectable locally advanced or metastatic HR-positive, HER2-negative breast cancer who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting [71,72]. (See "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer", section on 'Sacituzumab govitecan'.)

Belzutifan for advanced clear cell renal carcinoma (January 2023)

For patients with advanced clear cell renal carcinoma (RCC), studies are evaluating targeted agents such as belzutifan, a small molecule inhibitor of hypoxia-inducible factor 2 alpha (HIF-2a). In a randomized trial in approximately 750 patients with treatment-refractory advanced or metastatic clear cell RCC, belzutifan improved progression-free survival (PFS) over everolimus (18-month PFS 23 versus 9 percent) and was well tolerated [73]. Based on these data, the US Food and Drug Administration approved belzutifan for patients with advanced RCC following treatment with an immune checkpoint inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. (See "Systemic therapy of advanced clear cell renal carcinoma", section on 'Belzutifan'.)

RECENT APPROVALS - OTHER

Mirikizumab for moderate to severe ulcerative colitis (August 2023, Modified January 2024)

Therapeutic options for adults with moderate to severe ulcerative colitis (UC) are expanding. In an induction trial comparing mirikizumab (a monoclonal antibody that targets the p19 subunit of interleukin-23) with placebo in nearly 1300 patients, mirikizumab (300 mg intravenously every four weeks) resulted in higher rates of clinical remission after 12 weeks (24 versus 13 percent) [74]. In the maintenance trial including over 500 patients, mirikizumab (200 mg subcutaneously every four weeks) resulted in higher rates of clinical remission after 40 weeks (50 versus 25 percent). Based on these data, the US Food and Drug Administration approved mirikizumab for moderate to severe UC [75]. We anticipate using mirikizumab as first- or second-line therapy for adults with moderate to severe UC. (See "Management of moderate to severe ulcerative colitis in adults", section on 'Anti-interleukin antibody-based therapy'.)

COVID-19 MANAGEMENT

Adjunctive immunomodulators for severe COVID-19 (August 2023)

For patients hospitalized for COVID-19 who require high-flow oxygen or ventilatory support, we suggest adding baricitinib or tocilizumab to dexamethasone to further reduce mortality. Other immunomodulatory agents may also improve outcomes. In a randomized trial of patients with severe COVID-19, most of whom were on remdesivir and glucocorticoids, infliximab and abatacept each reduced 28-day mortality compared with placebo (10 and 11 versus 15 percent) but did not improve time to clinical improvement [76]. The trial did not detect a benefit with cenicriviroc. Despite their potential efficacy, we do not routinely use infliximab or abatacept for COVID-19, because they do not offer clear advantages over baricitinib or tocilizumab, which have more established benefit and, in the United States, are approved for this indication. (See "COVID-19: Management in hospitalized adults", section on 'Limited roles for alternative immunomodulators'.)

COVID-19 VACCINATION

COVID-19 vaccination and relapse of glomerular disease (September 2023)

Despite their increased risk of severe COVID-19, many patients with glomerular disease are reluctant to vaccinate against COVID-19 because of the potential risk of vaccine-associated disease relapse. In a prospective cohort study of over 2000 patients with biopsy-proven minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or IgA nephropathy, COVID-19 vaccination was not associated with worsening of glomerular disease activity (defined by an increase in proteinuria) or with a decrease in estimated glomerular filtration rate (eGFR) [77]. These results support our practice of administering COVID-19 vaccinations to most patients with glomerular disease, though our specific recommendations depend on disease type and the temporal relationship between prior COVID-19 vaccination and disease activity. (See "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension", section on 'COVID-19 vaccine-associated glomerular disease'.)

Updated COVID-19 mRNA vaccine recommendations (September 2023)

The US Food and Drug Administration and Centers for Disease Control and Prevention have updated COVID-19 vaccine authorizations and recommendations [78,79]. Available COVID-19 vaccines have been updated to target Omicron variant XBB.1.5 (Moderna COVID-19 vaccine 2023-2024 formula, Pfizer COVID-19 vaccine 2023-2024 formula, and Novavax 2023-2024 formula); bivalent vaccines are no longer available. An updated 2023-2024 formula vaccine is recommended for all individuals aged six months and older. Immunocompetent individuals five years and older should receive one updated vaccine, regardless of prior vaccination history. For individuals who are four years or younger or have an immunocompromising condition (table 2), the number of recommended updated vaccines depends on their vaccination history. Our approach to COVID-19 vaccination is consistent with these recommendations. (See "COVID-19: Vaccines", section on 'Indications and vaccine selection' and "COVID-19: Vaccines", section on 'Benefits of vaccination'.)

VACCINES - OTHER

2024 immunization schedule for adults (January 2024)

The United States Centers for Disease Control and Prevention has published the 2024 immunization schedule for adults (figure 1 and figure 2) [80]. Respiratory syncytial virus (RSV) vaccine is a new addition to the schedule; it is recommended for pregnant people 32 to 36 weeks' gestation during RSV season and is an option for adults ≥60 years of age. Mpox vaccine has also been added and is recommended for adults of all ages who are at risk for infection. Other changes include updates to COVID-19, polio, and meningococcal vaccine recommendations. Our approach to immunization is largely consistent with these updated recommendations. (See "Standard immunizations for nonpregnant adults", section on 'Immunization schedule for nonpregnant adults'.)

R21/Matrix-M vaccine to prevent malaria in children (November 2023)

In October 2023, the World Health Organization (WHO) approved the R21/Matrix-M vaccine for prevention of malaria in children [81]. In a placebo-controlled randomized trial of 4800 children (age 5 to 36 months) in four African countries, 12-month efficacy of a three-dose vaccine series against clinical malaria was 75 percent at sites with seasonal transmission and 68 percent at sites with year-round transmission; these data are under peer review prior to publication [82]. The vaccine was well tolerated. Injection site pain and fever were the most frequent adverse events. Together with the RTS,S/AS01 vaccine (recommended by the WHO in 2021), this approval is expected to facilitate sufficient vaccine supply to benefit all children living in areas where malaria is a public health risk. (See "Malaria: Epidemiology, prevention, and control", section on 'R21/Matrix-M vaccine'.)

Updated guidance for pneumococcal vaccination in children in the Unites States (October 2023)

The Centers for Disease Control and Prevention (CDC) has provided updated guidance for pneumococcal vaccination, endorsing use of either the 15-valent or 20-valent pneumococcal conjugate vaccine (PCV15 or PCV20) for routine vaccination in infancy and childhood [83]. The primary vaccine schedule otherwise remains unchanged. For infants who previously received the 13-valent vaccine (PCV13), the series may be completed with PCV15 or PCV20; restarting the series is not necessary. Children with high-risk conditions(table 31) may require additional pneumococcal vaccination with either PCV20 or the polysaccharide vaccine (PPSV23) after age two years if their primary series did not include at least one dose of PCV20. We agree with the updated CDC guidance. Guidelines for pneumococcal vaccination in other countries may differ. (See "Pneumococcal vaccination in children", section on 'In the United States'.)

Immunoprophylaxis for severe respiratory syncytial virus in infants (October 2023)

Nirsevimab is a new monoclonal antibody that targets the prefusion conformation of the respiratory syncytial virus (RSV) F glycoprotein [84]. It has a longer half-life than palivizumab, an existing antibody that requires five monthly injections to provide immunoprophylaxis against severe RSV infection. The efficacy and safety of nirsevimab were demonstrated in two randomized placebo-controlled trials, one involving 1490 infants ≥35 weeks' gestation and the other involving >1400 preterm infants (29 to <35 weeks' gestation) [85,86]. In both trials, a single intramuscular dose of nirsevimab lowered rates of RSV-related medical evaluation and hospital admissions for RSV. In line with American Academy of Pediatrics and United States Centers for Disease Control and Prevention guidance, we now recommend that infants <8 months old receive one dose of nirsevimab during their first RSV season if the birthing parent did not receive RSV vaccination between 32 and 36 weeks of gestation and at least 14 days prior to delivery. Palivizumab may be used in high-risk infants if nirsevimab is not available. (See "Respiratory syncytial virus infection: Prevention in infants and children", section on 'Immunoprophylaxis'.)

Respiratory syncytial virus vaccination in pregnancy (April 2023, Modified October 2023)

Respiratory syncytial virus (RSV) is a major cause of morbidity and mortality in infants. In October 2023, the United States Centers for Disease Control and Prevention, along with guidelines from other expert groups, endorsed RSV vaccination of pregnant individuals to reduce severe RSV infections in their infants [87-90]. Nirsevimab, a monoclonal antibody that can be given to infants postnatally to reduce the risk of severe RSV, has also been recently approved and endorsed by expert guidance panels. In settings where nirsevimab is not available, we suggest vaccination of pregnant individuals between 32 0/6 and 36 6/7 weeks of gestation in September through January (in the northern hemisphere) with inactivated nonadjuvanted recombinant RSV vaccine (RSVPreF; Abrysvo). In settings where both maternal vaccination and nirsevimab are available, the optimal preventive strategy remains uncertain, and, in most cases, it will not be possible to use both. For such patients, both options should be discussed and shared decision-making undertaken. (See "Immunizations during pregnancy", section on 'Choosing the optimal strategy'.)

ACIP recommendations for 2023-24 seasonal influenza vaccination (September 2023)

The Advisory Committee on Immunization Practices (ACIP) issued new recommendations for seasonal influenza vaccination in August 2023 (table 4) [91]. The antigenic composition has been updated. In addition, the ACIP now states that egg allergy alone no longer necessitates additional safety measures for influenza vaccination, including with egg-based vaccines, beyond those recommended for any recipient of any vaccine, regardless of severity of previous reaction to egg. All vaccines should be administered in settings where personnel and equipment needed for prompt recognition and treatment of acute hypersensitivity reactions are available. This is consistent with our previous guidance. (See "Seasonal influenza vaccination in adults", section on 'Antigenic composition'.)