Your activity: 44 p.v.
your limit has been reached. plz Donate us to allow your ip full access, Email: sshnevis@outlook.com

What's new in drug therapy

What's new in drug therapy
Authors:
Diane MF Savarese, MD
Jonathan M Zand, PharmD BCPS
Literature review current through: Feb 2022. | This topic last updated: Feb 25, 2022.

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 http://www.lexi.com/home/newdrugs/.

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

COVID-19 MANAGEMENT

Treatment of COVID-19 in outpatients at risk for severe disease (November 2021, Modified February 2022)

Nirmatrelvir-ritonavir, the monoclonal antibody sotrovimab, remdesivir, and high-titer convalescent plasma have all been shown to reduce the risk of hospitalization when given early in the course of COVID-19 [1-4]. For outpatient adults who have mild-to-moderate COVID-19 and are at risk for progression to severe disease (table 1), we recommend treatment with either nirmatrelvir-ritonavir or sotrovimab. When these are not available, we consider remdesivir and convalescent plasma, which may be complicated to administer, as alternatives. If none are feasible options, molnupiravir is an alternative, but it may be less effective and potentially teratogenic [5]. Bebtelovimab is an alternative monoclonal antibody that is active against Omicron, but there are limited data to support its use [6]. When supplies are limited, these treatments should be prioritized for immunocompromised individuals expected to have a suboptimal vaccine response and unvaccinated or incompletely vaccinated individuals at highest risk for severe disease (table 2) [7]. (See "COVID-19: Outpatient evaluation and management of acute illness in adults".)

COVID-19 VACCINATION

COVID-19 vaccination in pregnancy improves infant outcomes (February 2022)

COVID-19 vaccination of pregnant women reduces serious maternal and pregnancy morbidity from infection. In an analysis of data from 20 pediatric hospitals in the United States during a period of Delta and Omicron variant circulation, infants <6 months of age were 61 percent less likely to be hospitalized with COVID-19 if their mothers became fully vaccinated with an mRNA COVID-19 vaccine during pregnancy [8]. Furthermore, 88 percent of the intensive care unit admissions for COVID-19 and the only death occurred among infants of unvaccinated mothers. Thus, maternal vaccination also appears to protect infants in the first six months of life. (See "COVID-19: Overview of pregnancy issues", section on 'Safety and efficacy'.)

COVID-19 vaccination improves outcomes of infected pregnant patients (February 2022, Modified February 2022)

A recent population-based study of over 18,000 pregnant patients in Scotland provides the first evidence of more favorable pregnancy outcomes among those who have received COVID-19 vaccination [9]. In pregnant patients with COVID-19, unvaccinated individuals represented a significantly higher proportion of COVID-19-associated hospital admissions (77 percent), COVID-19-associated critical care admissions (98 percent), and perinatal deaths (100 percent of stillbirths and neonatal deaths). The perinatal death rate in the vaccinated cohort was similar to historical background rates and the rates in pregnant people without COVID-19. These findings further support universal recommendations for pregnant people to be up-to-date with COVID-19 vaccination. (See "COVID-19: Overview of pregnancy issues", section on 'Safety and efficacy'.)

Booster doses of COVID-19 vaccines for individuals 12 years or older (October 2021, Modified February 2022)

Several countries have introduced booster doses of COVID-19 vaccines because of potentially attenuated vaccine effectiveness due to waning efficacy and variants. The US Food and Drug Administration has authorized and the Centers for Disease Control and Prevention (CDC) recommends a booster dose for all individuals 12 years or older [10-13]. The booster dose is given five months after a primary BNT162b2 (Pfizer) or mRNA-1273 (Moderna) series for most patients (or three months after the primary series for immunocompromised patients) and two months after a primary Ad26.COV2.S (Johnson & Johnson) series. Any vaccine authorized for the patient's age group can be used for the booster dose, regardless of the vaccine used for the primary series; in general, we favor one of the mRNA vaccines over Ad26.COV2.S. We recommend booster doses for eligible individuals, based on trials and observational evidence suggesting improved vaccine efficacy following a booster dose. (See "COVID-19: Vaccines", section on 'Role of booster vaccinations/waning efficacy'.)

Additional COVID-19 vaccine primary series dose for immunocompromised individuals (August 2021, Modified February 2022)

COVID-19 vaccines are less effective among patients with certain immunocompromising conditions than in the general population; additional vaccine doses have been associated with improved effectiveness in this population. We agree with recommendations from the Advisory Committee on Immunization Practices (ACIP) in the United States that individuals with such conditions (table 3) receive an additional mRNA vaccine dose as part of their primary COVID-19 vaccine series (eg, following two doses of an mRNA vaccine or one dose of Ad26.COV2.S vaccine) [14,15]. This additional primary series dose is distinct from the booster dose, which such patients should additionally receive, although at a shorter interval than recommended for the general population. (See "COVID-19: Vaccines", section on 'Immunocompromised individuals'.)

COVID-19 vaccination does not affect fertility (January 2022)

Possible cross-reactivity between antibodies to the SARS-CoV-2 virus's spike protein and a protein involved in embryo development raised concerns for impaired fertility following either viral infection or vaccination. In the largest retrospective cohort study comparing 222 vaccinated with 983 unvaccinated females undergoing in vitro fertilization (IVF) between February and September 2021, outcomes of ovarian stimulation and embryo transfer were similar for both groups, including similar fertilization and clinical pregnancy rates [16]. These data add to the body of evidence supporting lack of negative effects of vaccination on fertility or IVF cycles. (See "In vitro fertilization: Overview of clinical issues and questions", section on 'No proven effect'.)

Third mRNA COVID-19 vaccine dose and Omicron immunogenicity among cancer patients (January 2022, Modified January 2022)

The Omicron variant of SARS-CoV-2 partially evades vaccine-induced immunity, but for mRNA COVID-19 vaccine recipients in the general population, a third vaccine dose increases neutralizing activity against Omicron; comparable data in cancer patients are lacking. In a prospective cohort study, a third vaccine dose of the mRNA vaccine BNT162b2 was associated with a higher likelihood of detectable neutralizing activity against Omicron in patients with cancer, although the benefit was less in patients with blood cancer compared with those with solid tumors [17]. These data support administering a third dose of mRNA vaccine for patients with active cancer; such patients are also eligible subsequently for a booster dose. (See "COVID-19: Considerations in patients with cancer".)

ITP after COVID-19 vaccination (January 2022)

Exacerbations of immune thrombocytopenia (ITP) as well as new-onset ITP have been reported after COVID-19 vaccination [18,19]. Individuals with ITP who receive any COVID-19 vaccine should be advised about this risk, and platelet counts should be monitored before and after vaccination. The benefits of vaccination outweigh the risks in almost all patients with ITP. Those in the midst of a flare can delay vaccination until the flare is controlled; flares that occur following vaccination tend to be transient and respond well to standard ITP therapy. ITP is distinct from the exceedingly rare syndrome of vaccine-induced immune thrombotic thrombocytopenia (VITT). (See "Initial treatment of immune thrombocytopenia (ITP) in adults", section on 'COVID-19 vaccination'.)

Immunogenicity of available vaccines against SARS-CoV-2 in patients with cancer (January 2022)

Patients with cancer are considered to be at high risk for SARS-CoV-2 infection, but there are limited studies directly comparing available COVID-19 vaccines. In an observational cohort study (CANVAX) of over 700 patients with solid organ or hematologic cancers, two doses of an mRNA vaccine (either BNT162b2/Pfizer-BioNTech or mRNA-1273/Moderna) were associated with higher protective immune responses compared with one dose of the adenoviral vector vaccine Ad26.COV2.S/Janssen [20]. Although clinical outcomes were not measured, other studies in the general population suggest that mRNA vaccines may have greater effectiveness against severe disease. In patients with cancer receiving COVID-19 vaccination, as for the general population, we suggest an mRNA COVID vaccine, rather than an adenoviral vector vaccine. (See "COVID-19: Considerations in patients with cancer", section on 'Safety and efficacy' and "COVID-19: Vaccines", section on 'Indications and vaccine selection'.)

Neutralization of SARS-CoV-2 variants in transplant recipients after three doses of mRNA vaccine (December 2021)

In transplant recipients, administration of a third COVID-19 mRNA vaccine dose has been shown to improve the immune response without causing short-term adverse events; however, data on vaccine immunogenicity against SARS-CoV-2 variants are limited. In a secondary analysis of a recent randomized trial, sera obtained from participants after receipt of the third vaccine dose had greater ability to neutralize wild-type SARS-CoV-2 and Alpha, Beta, and Delta variants when compared with sera obtained after the second dose and sera from participants who received placebo [21]. The third dose was well tolerated; no cases of rejection were reported, and graft function remained stable in all patients for three months after the third dose. These findings support administering a three-dose primary vaccine series among transplant recipients and other immunocompromised patients. (See "COVID-19: Issues related to solid organ transplantation", section on 'Vaccination'.)

COVID-19 vaccination and hematopoietic cell transplant or CAR-T therapy (November 2021)

Immunocompromised individuals who are recipients of hematopoietic cell transplantation (HCT) or chimeric antigen receptor (CAR)-T-cell therapies are at risk for a suboptimal immune response to COVID-19 vaccination. Updated guidance from the United States Centers for Disease Control and Prevention (CDC) now recommends revaccination with a full primary series for patients who were vaccinated prior to receiving HCT or CAR-T-cell therapy and who are at least three months post-HCT or CAR-T-cell therapy. Our recommendations are in agreement with this guidance [22]. (See 'COVID-19: Considerations in patients with cancer', section on 'COVID-19 vaccination' and 'Immunizations in hematopoietic cell transplant candidates and recipients', section on 'COVID-19 vaccine'.)

Evaluation and management of immediate allergic reactions to SARS-CoV-2 vaccines (November 2021)

An international panel of experts in allergy, infectious disease, and emergency medicine released recommendations for the evaluation and management of immediate allergic reactions to SARS-CoV-2 vaccines, based on a systematic review and meta-analysis [23]. These recommendations, which include not performing empiric testing in patients with past anaphylaxis to polyethylene glycol (PEG) or polysorbates, and referring patients who experienced anaphylaxis to the first dose of an mRNA vaccine to an allergist or completing vaccination with a different vaccine, are consistent with our approach. Most patients are able to complete the vaccination process. (See "COVID-19: Allergic reactions to SARS-CoV-2 vaccines", section on 'Immediate reactions to an initial dose'.)

COVID-19 vaccination in children 5 years and older (November 2021)

In October 2021, the US Food and Drug Administration authorized BNT162b2 (Pfizer vaccine) for individuals 5 to 11 years old based on data from randomized trials in over 2000 children in this age group, which demonstrated 91 percent vaccine efficacy against symptomatic COVID-19 and immunogenicity similar to that in adolescents and young adults [24]. There were no cases of vaccine-associated myocarditis in the trials; although the precise risk is uncertain, it is expected to be lower than that seen in older individuals. We agree with recommendations from the Centers for Disease Control and Prevention to give BNT162b2 to children ages 5 to 11 years. Clinicians should be aware that the dose and formulation used for children are different than those for adolescents and adults. (See "COVID-19: Vaccines", section on 'Summary and recommendations'.)

COVID-19 vaccination does not increase risk for miscarriage (September 2021)

Evidence of the safety of COVID-19 vaccination in pregnancy continues to accrue. In one study involving nearly 2500 pregnancies, the age-standardized cumulative risk of miscarriage was 12.8 percent individuals who received a mRNA COVID-19 vaccine preconception or prior to 20 weeks of gestation, which is similar to the expected miscarriage rate in the general obstetric population [25]. In another study including over 105,000 pregnancies, individuals who experienced miscarriage had similar odds of exposure to a COVID-19 vaccine in the prior 28 days as those with ongoing pregnancies [26]. Results were consistent with either mRNA-1273 or BNT162b2 vaccine exposure; risks specific to Ad26.COV.2.S vaccine could not be assessed due to a small number of exposures. We recommend COVID-19 vaccination regardless of pregnancy status. (See "COVID-19: Overview of pregnancy issues", section on 'Vaccination in people planning pregnancy and pregnant or recently pregnant people'.)

Updated guidance for COVID-19 vaccine use in patients with rheumatic disease (September 2021)

The American College of Rheumatology (ACR) COVID-19 Vaccine Clinical Guidance Task Force has updated their recommendations regarding use of COVID-19 vaccines in patients with rheumatic disease [27]. These now emphasize that a third dose of either of the mRNA vaccines is appropriate for most patients with systemic rheumatic diseases. The ACR also noted a preference for a mRNA vaccine for patients not yet vaccinated, based on the potential benefits and regulatory approval of a three-dose series. The guidance addresses the timing of the vaccination, administration of immunosuppressive agents, and the use of postexposure prophylaxis with monoclonal antibodies in certain patients. (See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'Timing of vaccine'.)

GENERAL DRUG THERAPY

New naming convention for therapeutic monoclonal antibodies (January 2022)

The number of therapeutic monoclonal antibodies (mAbs) continues to increase. In order to reduce sound-alikes and specify structural components of the immunoglobulins, the World Health Organization International Nonproprietary Names (INN) Programme has developed four new suffixes to be used instead of "mab" for antibodies developed from 2022 onward [28]. Unmodified immunoglobulins will end in "tug"; mAbs with an engineered constant region will end in "bart"; bifunctional mAbs will end in "mig"; and variable region fragments will end in "ment." (See "Overview of therapeutic monoclonal antibodies", section on 'Naming convention for therapeutic mAbs'.)

RECENT APPROVALS - DERMATOLOGIC AND ALLERGY THERAPIES

Tralokinumab for atopic dermatitis (February 2022)

Adults with persistent, moderate-to-severe atopic dermatitis (AD) despite optimal topical therapy may require systemic immunomodulatory therapy to achieve adequate disease control. In a recent randomized trial of 380 adults with moderate-to-severe AD, more patients assigned to subcutaneous tralokinumab, a fully human monoclonal anti-interleukin-13 antibody, achieved a 75 percent improvement in the Eczema Area and Severity Index at 16 weeks compared with placebo (56 versus 36 percent, respectively) [29]. All patients were allowed to use a midpotency topical corticosteroid as needed. Treatment was general well tolerated. Conjunctivitis was more common in patients receiving tralokinumab than in those receiving placebo. These findings support the efficacy of tralokinumab for adults with AD; this and other studies were the basis for US Food and Drug Administration approval of tralokinumab for this indication. However, long-term studies are needed before its use becomes routine. (See "Treatment of atopic dermatitis (eczema)", section on 'Tralokinumab'.)

Topical ruxolitinib for atopic dermatitis (October 2021)

Topical ruxolitinib, a Janus kinase (JAK) inhibitor, is a new short-term therapy for atopic dermatitis (AD). In two randomized trials that enrolled over 1200 adolescents and adults with mild to moderate AD (<20 percent of body surface area affected) not controlled by topical prescription medications, more individuals assigned to ruxolitinib cream (0.75% or 1.5%) achieved clear or almost clear skin and reduced pruritis with no increase in adverse effects compared with vehicle [30]. Based on these findings, topical ruxolitinib has been approved by the US Food and Drug Administration for the short-term treatment of mild to moderate AD in immunocompetent individuals with the characteristics of the study participants. Although topical ruxolitinib appears promising, more data are needed regarding its systemic absorption and long-term safety before its use becomes routine. (See "Treatment of atopic dermatitis (eczema)", section on 'Topical ruxolitinib'.)

RECENT APPROVALS - HEMATOLOGIC AND ANTICOAGULANT

Belumosudil for steroid-refractory chronic graft-versus-host disease (GVHD) (December 2021)

More than two-thirds of patients with chronic graft-versus-host disease (cGVHD) require treatment beyond systemic corticosteroids, but there is no consensus treatment for steroid-refractory (SR) cGVHD and current approaches have limited efficacy and/or substantial toxicity. Belumosudil, a novel oral inhibitor of ROCK2, was associated with objective responses and significant symptomatic improvement in more than two-thirds of patients with SR-cGVHD, with mostly modest adverse effects [31]. Belumosudil was recently approved by the US Food and Drug Administration (FDA) for treatment of SR-cGVHD in patients who received two to five prior therapies. We consider belumosudil an acceptable later-line treatment for SR-cGVHD as we await studies that compare it with other available therapies. (See "Treatment of chronic graft-versus-host disease", section on 'Belumosudil'.)

Direct oral anticoagulants for venous thromboembolism in children ≥2 years (August 2021)

In 2021, the US Food and Drug Administration approved two direct oral anticoagulants (DOACs), dabigatran and rivaroxaban, for treatment of venous thrombosis and thromboembolism (VTE) in children [32,33]. These regulatory approvals were based upon two large multicenter pediatric trials demonstrating that dabigatran and rivaroxaban have similar efficacy and bleeding risk compared with low molecular weight heparin (LMWH) and warfarin [34,35]. Adolescents made up most of the trial populations, and children <2 years were underrepresented. DOACs are an attractive option since they are orally administered and do not require drug monitoring. We now suggest one of the approved DOACs (dabigatran or rivaroxaban) for treatment of VTE in adolescents, after at least five days of initial parenteral therapy. For children ages 2 to 11 years, either a DOAC or LMWH is acceptable. For infants and children <2 years, the efficacy and safety of DOACs remain uncertain, and we continue to suggest LMWH. (See "Venous thrombosis and thromboembolism (VTE) in children: Treatment, prevention, and outcome", section on 'Direct oral anticoagulants'.)

RECENT APPROVALS - NEUROLOGIC AND PSYCHIATRIC

Efgartigimod alfa for treatment of myasthenia gravis (February 2022)

Efgartigimod alfa, a novel immunoglobulin G1 (IgG1) Fc fragment that inhibits the neonatal Fc receptor and reduces circulating IgG antibody levels, has been under investigation for myasthenia gravis (MG) and other autoimmune disorders associated with IgG autoantibodies. In a trial of 167 patients with generalized MG, weekly infusions of efgartigimod increased the rate of symptomatic improvement at four weeks compared with placebo (68 versus 30 percent) [36]. Adverse effects were mild and similar between groups with short-term follow-up. Based on these results, efgartigimod was approved by the US Food and Drug Administration for treatment of MG in patients with antiacetylcholine receptor antibodies. It will likely find use initially as an alternative steroid-sparing agent for patients unable to tolerate first-line therapies with slower time to effect (table 4). (See "Chronic immunosuppressive therapy for myasthenia gravis", section on 'AChR-positive and seronegative MG'.)

Oral atogepant for episodic migraine prevention (October 2021)

Small-molecule calcitonin gene-related peptide (CGRP) antagonists ("gepants") are orally administered medications formulated typically for the acute treatment of migraine. The effectiveness of a novel agent, atogepant, was evaluated in a preventive trial in 873 patients with migraine. After 12 weeks, patients assigned to atogepant had fewer migraine days per month than those assigned to placebo and were also likelier to achieve at least 50 percent reduction in the three-month mean number of monthly migraine days (58 versus 29 percent) [37]. These data support the addition of oral atogepant as an effective agent for the prevention of episodic migraine. (See "Preventive treatment of episodic migraine in adults", section on 'CGRP antagonists'.)

Mixed oxybate salts approved for idiopathic hypersomnia (August 2021)

Mixed oxybate salts (Xywav) have received US Food and Drug Administration (FDA) approval for treatment of adults with idiopathic hypersomnia [38]. Approval was based on results of a randomized discontinuation trial in 154 patients with idiopathic hypersomnia, in which mixed oxybate salts were more effective than placebo as measured by Epworth Sleepiness Scale (ESS) scores [39]. Side effects were consistent with those observed in patients with narcolepsy, most commonly nausea, headache, anxiety, and dizziness. Oxybates have potential for misuse and abuse and are regulated in the United States by the Risk Evaluation and Mitigation Strategies program. Although modafinil/armodafinil and stimulants remain our preferred first-line options based on safety, availability, and cost, oxybates are reasonable to offer as second-line therapy. (See "Idiopathic hypersomnia", section on 'Pharmacotherapy'.)

RECENT APPROVALS - ONCOLOGIC

Adjuvant pembrolizumab for high-risk node-negative melanoma (November 2021, Modified January 2022)

Although patients with resected, node-negative (Stage IIB and IIC) cutaneous melanoma are at risk for disease recurrence, there was previously no approved adjuvant therapy. In a phase III trial of almost 1000 patients with resected Stage IIB and IIC disease, one year of adjuvant pembrolizumab improved 18-month recurrence-free survival compared with placebo (86 versus 77 percent) [40,41]. Based on these data, the US Food and Drug Administration (FDA) approved adjuvant pembrolizumab for pediatric (12 years and older) and adult patients with Stage IIB and IIC melanoma after complete resection, and we suggest its use in these patients. (See "Adjuvant and neoadjuvant therapy for cutaneous melanoma", section on 'Pembrolizumab versus surveillance'.)

Adjuvant pembrolizumab in localized renal cell carcinoma (December 2021)

In patients with localized renal cell carcinoma (RCC) treated with nephrectomy, adjuvant immunotherapy is being evaluated. In a randomized trial of approximately 1000 patients with clear cell RCC treated with nephrectomy, one year of adjuvant pembrolizumab improved disease-free survival (DFS) compared with placebo (two-year DFS, 77 versus 68 percent), and was well tolerated [42]. Based on these data, the US Food and Drug Administration approved adjuvant pembrolizumab in patients with RCC at intermediate-high or high risk of disease recurrence following nephrectomy [43]. We suggest adjuvant pembrolizumab for those with resected RCC who have an estimated five-year recurrence risk of ≥30 percent. (See "Overview of the treatment of renal cell carcinoma", section on 'Approach to adjuvant therapy'.)

Pembrolizumab as initial therapy for metastatic urothelial carcinoma (November 2021)

The United States (US) Food and Drug Administration (FDA) previously conditionally approved the checkpoint inhibitor pembrolizumab for patients with treatment-naïve metastatic urothelial carcinoma (UC), but long-term follow-up data were limited. In extended follow-up of a phase II trial of almost 400 patients with treatment-naïve, platinum-ineligible metastatic UC, the objective response rate for pembrolizumab was 29 percent at a median follow-up of 56 months, and three-year overall survival was 22 percent [44]. Based on these data, the US FDA granted full regulatory approval to pembrolizumab for patients with locally advanced or metastatic UC who are not eligible for any platinum-containing chemotherapy [45], and it remains one of our preferred options in this patient population. (See "Treatment of metastatic urothelial cancer of the bladder and urinary tract", section on 'Pembrolizumab'.)

Adjuvant immunotherapy in resectable NSCLC (July 2021, Modified November 2021)

The role of immunotherapy in resectable non-small cell lung cancer (NSCLC) was previously undefined. In a randomized trial in almost 900 patients with stage II to IIIA NSCLC who had undergone surgery and adjuvant chemotherapy, those randomly assigned to atezolizumab had improved disease-free survival relative to the best supportive care group (42 versus 35 months, hazard ratio [HR] 0.79), with greater benefits among those with tumor PD-L1 ≥1 percent (not evaluable versus 35 months; HR 0.66) [46]. Based on these data, atezolizumab is approved by the US Food and Drug administration (FDA) as adjuvant treatment following resection and platinum-based chemotherapy for adults with stage II to IIIA NSCLC whose tumors have programmed cell death ligand 1 (PD-L1) expression on ≥1 percent of tumor cells, as determined by an FDA-approved test [47]. (See "Systemic therapy in resectable non-small cell lung cancer", section on 'Adjuvant immunotherapy for PD-L1-positive disease'.)

Adjuvant abemaciclib in high-risk, hormone receptor-positive, HER2-negative breast cancer (October 2021)

For patients with high-risk, hormone receptor (HR)-positive, HER2-negative breast cancer, previous data have shown benefits with adjuvant abemaciclib. Now, in longer follow-up of 27 months, benefits are maintained, both in regard to invasive disease-free survival (three-year rate of 89 versus 83 percent), and distant recurrence-free survival (90 versus 86 percent) [48]. A higher incidence of Grade ≥3 adverse events (AEs) was observed with versus without abemaciclib (50 versus 16 percent, respectively). These data led to US Food and Drug Administration approval of abemaciclib in patients with HR-positive, HER2-negative, node-positive breast cancer at high risk of recurrence and a Ki-67 score ≥20 percent [49], and we suggest the addition of adjuvant abemaciclib to endocrine therapy in this subset. High risk in this instance is defined as either ≥4 involved axillary lymph nodes; or 1 to 3 involved lymph nodes and either tumor grade 3 or size ≥5.0 cm. However, we note that it is also acceptable not to administer this additional treatment, given the toxicity and only short-term supporting data. (See "Adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Patient selection'.)

Adjuvant nivolumab for resected urothelial carcinoma (September 2021)

In a placebo-controlled phase III trial of over 700 patients with urothelial carcinoma (UC) and high-risk disease after radical cystectomy, one year of adjuvant nivolumab improved disease-free survival (median 21 versus 11 months) [50]. These data led to approval by the US Food and Drug Administration (FDA) for adjuvant nivolumab in patients at high risk for recurrence after undergoing radical resection of UC [51]. This includes patients with muscle-invasive or node-positive disease after receiving neoadjuvant chemotherapy, or those with extravesicular extension or node-positive disease who did not receive neoadjuvant chemotherapy and were ineligible for or refused adjuvant cisplatin-based chemotherapy. (See "Adjuvant therapy for muscle-invasive urothelial carcinoma of the bladder", section on 'Adjuvant nivolumab'.)

Tisotumab vedotin in metastatic cervical cancer progressive on chemotherapy (September 2021)

Tisotumab vedotin is a tissue factor-directed antibody and microtubule inhibitor drug conjugate. In a single arm, open-label study in 101 patients with metastatic or recurrent cervical cancer previously treated with chemotherapy, the agent was associated with a response rate of 24 percent, including 7 percent with complete responses [52]. Based on these results, tisotumab vedotin was approved by the US Food and Drug Administration for recurrent or metastatic cervical cancer that has progressed on chemotherapy [53], and we consider it to be one of several appropriate options in this setting. (See "Management of recurrent or metastatic cervical cancer", section on 'Second-line therapy'.)

Ivosidenib approved for advanced IDH1-mutated cholangiocarcinoma (August 2021)

Mutations in one of the isocitrate dehydrogenase (IDH) genes are present in up to 25 percent of advanced cholangiocarcinomas, particularly intrahepatic tumors. The oral IDH1 inhibitor ivosidenib has been approved by the US Food and Drug Administration (FDA) for treatment of adults with previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation, as detected by an FDA-approved test [54]. Approval was based on the randomized placebo-controlled Clar1DHy trial, which showed modestly prolonged survival and durable responses with ivosidenib [55]. Although adverse reactions (nausea, vomiting, fatigue) were common, they were mostly low-grade. (See "Systemic therapy for advanced cholangiocarcinoma", section on 'Ivosidenib for IDH-mutated cholangiocarcinoma'.)

Nab-sirolimus for malignant perivascular epithelioid cell differentiation (PEComa) (January 2021)

Mechanistic (mammalian) target of rapamycin (mTOR) inhibitors have shown promise for advanced perivascular epithelioid cell differentiation (PEComa). In an open-label phase II trial in approximately 30 patients with locally advanced unresectable or metastatic malignant PEComa, the mTOR inhibitor nab-sirolimus was associated with an overall response rate of 39 percent [56]. Based on these data, the US Food and Drug Administration (FDA) approved nab-sirolimus in adult patients with locally advanced unresectable or metastatic malignant PEComa. For those without access to nab-sirolimus, other mTOR inhibitors (sirolimus, everolimus, and temsirolimus) are reasonable alternatives. (See "Systemic treatment of metastatic soft tissue sarcoma", section on 'Nab-sirolimus'.)

RECENT APPROVALS - OTHER

Faricimab for treatment of wet age-related macular degeneration (AMD) (February 2022)

Faricimab, a bispecific antibody that inhibits vascular endothelial growth factor A (VEGF-A) and angiopoeitin-2, was approved by the US Food and Drug Administration (FDA) in 2022 for the treatment of wet (neovascular) age-related macular degeneration (AMD) and diabetic macular edema. The FDA approval for the treatment of wet AMD was based on the results of two randomized, double-masked, multicenter global studies [57]. In both studies, faricimab (with intravitreal dosing initially every four weeks for four doses and then less frequently up to every 16 weeks based upon disease activity) was found to be noninferior to aflibercept (with intravitreal dosing up to every eight weeks), with a comparable adverse event profile. Faricimab may offer similar efficacy and safety profile as compared with aflibercept but with the possibility of a significantly less burdensome treatment schedule. (See "Age-related macular degeneration: Treatment and prevention", section on 'Faricimab'.)

Dupilumab for children ≥6 years old with moderate-to-severe asthma (November 2021)

Dupilumab, a monoclonal antibody that blocks interleukin (IL)-4 and IL-13 signaling, is now approved by the US Food and Drug Administration (FDA) for children 6 years of age and older with moderate-to-severe persistent asthma and eosinophilia or dependency on oral glucocorticoids. Approval is based upon trials in adolescents and adults and a single randomized trial in 408 children 6 to 11 years of age with moderate-to-severe asthma that showed a significant reduction in the annual rate of severe exacerbations requiring treatment with systemic glucocorticoids in children treated with dupilumab compared with placebo (rate ratio 0.35, 95% CI 0.22-0.56) [58]. Because dupilumab is also approved for use in selected children with moderate-to-severe atopic dermatitis (AD), it may be particularly useful in children with comorbid refractory asthma and AD. (See "Asthma in children younger than 12 years: Management of persistent asthma with controller therapies", section on 'Add on a biologic agent'.)

DRUG OR INDICATION WITHDRAWALS

Withdrawal of panobinostat from United States market (January 2022)

Panobinostat, an orally available histone deacetylase inhibitor, was granted accelerated approval by the US Food & Drug Administration in 2015 for the treatment of relapsed or refractory multiple myeloma in combination with bortezomib and dexamethasone. It is being withdrawn from the US market beginning December 2021; the manufacturer was not able to complete the required postapproval clinical studies as part of the accelerated approval process [59]. (See "Multiple myeloma: Treatment of third or later relapse", section on 'Panobinostat'.)

PI3K inhibitors in follicular lymphoma (December 2021, Modified January 2022)

The landscape of phosphoinositide 3'-kinase (PI3K) inhibitors in follicular lymphoma (FL) is changing, with umbralisib and copanlisib used for multiply relapsed disease, and regulatory approval recently withdrawn for duvelisib and idelalisib for this indication. While direct comparisons are not available, indirect comparisons suggest that umbralisib is similarly effective and better tolerated than the others. In a pooled analysis of >370 patients treated with umbralisib for FL and other non-Hodgkin lymphomas, adverse events led to drug discontinuation in 14 percent [60]. The most common toxicities were diarrhea, nausea, vomiting, and fatigue. Umbralisib is our preferred PI3K inhibitor for treatment of relapsed or refractory FL due to its oral administration and favorable toxicity profile. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Umbralisib'.)

Melphalan flufenamide withdrawn from market (March 2021, Modified October 2021)

Melphalan flufenamide is a peptide-drug conjugate that showed promising outcomes in combination with dexamethasone among patients with relapsed refractory multiple myeloma (MM), which led to its accelerated approval by the US Food and Drug Administration (FDA) in combination with dexamethasone in heavily pretreated MM. However, following approval, the FDA raised concerns about its efficacy and safety based on a preliminary analysis of a randomized trial (OCEAN), which suggested inferior outcomes when compared with pomalidomide plus dexamethasone [61]. On October 22, the manufacturer announced its decision to withdraw melphalan flufenamide from the market, although it will provide access to the drug for patients who started treatment prior to its withdrawal. (See "Multiple myeloma: Treatment of first or second relapse".)

ADVERSE REACTIONS AND WARNINGS

Dental problems associated with oral dissolving buprenorphine (January 2022)

There are >300 reports of dental problems associated with use of buprenorphine formulations dissolved in the mouth, including the buccal formulation and sublingual tablets [62,63]. Reported problems include dental caries, abscesses, and damaged teeth, many of which have required tooth removal. The incidence of dental problems with buprenorphine is unknown. Patients who use orally dissolving buprenorphine should swish and swallow water after the drug has dissolved, see a dentist soon after starting the drug, and make sure the dentist knows they are taking the drug. The US Food and Drug Administration (FDA) has issued a related safety advisory and will mandate a label change. (See "Use of opioids in the management of chronic non-cancer pain", section on 'Buprenorphine for chronic pain'.)

Routine premedication for PEGylated asparaginase (January 2022)

Asparaginase, a polypeptide of bacterial origin, is an important component of treatment for acute lymphoblastic leukemia, and PEGylated products (eg, pegaspargase, calaspargase) are now preferred for newly diagnosed patients. While they are less immunogenic than nonpegylated E. coli-derived asparaginase, infusion reactions still occur in up to one-third of patients. In 2021, the pegaspargase United States prescribing information was updated to recommend routine premedication with acetaminophen, an H1-receptor blocker, and an H2-receptor blocker administered 30 to 60 minutes prior to each dose [64]. The prescribing information for calaspargase has also been similarly updated [65]. (See "Infusion reactions to systemic chemotherapy", section on 'Asparaginase'.)

Risk of GI bleeding with DOACs (October 2021)

Direct oral anticoagulants (DOACs) are generally preferred over warfarin in individuals with non-valvular atrial fibrillation or venous thromboembolism. A new study evaluated the risk of gastrointestinal (GI) bleeding in over 5000 individuals taking apixaban, rivaroxaban, or dabigatran [66]. Higher rates of GI bleeding were seen in individuals taking rivaroxaban (3.2 per 100 patient-years) than with the other agents (2.5 for apixaban and 1.9 for dabigatran). The once-daily dosing of rivaroxaban and higher peak levels may explain the higher bleeding risk; the other agents are dosed twice daily. These results may be a consideration when choosing among DOACs. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Differences between factor Xa inhibitors'.)

Cardiovascular and malignancy risk with Janus kinase inhibitors (September 2021)

The level of risk for cardiovascular (CV) events and malignancy with Janus kinase (JAK) inhibitors is uncertain. Unpublished data from a phase 4 open-label trial comparing tofacitinib with a tumor necrosis factor (TNF) inhibitor in over 4300 patients ≥50 years old on methotrexate for rheumatoid arthritis (RA) and with elevated CV risk showed a small, largely dose-dependent increased risk of nonfatal myocardial infarction, thrombosis, lymphoma, and lung cancer with tofacitinib [67,68]. These findings prompted the US Food and Drug Administration to advise screening for relevant risk factors in patients with serious inflammatory diseases, including RA and ulcerative colitis, and to limit use of tofacitinib, baricitinib, and upadacitinib to patients with an inadequate response or intolerance to TNF inhibitors [67]. European regulators issued a narrower advisory to limit use of tofacitinib in older patients (≥65 years), current or past smokers, and those with other CV and malignancy risk factors [68]. (See "Janus kinase inhibitors for rheumatologic and other inflammatory disorders: Biology, principles of use, and adverse effects", section on 'Overview of adverse effects'.)

VACCINES - OTHER

ACIP recommendations on dengue vaccination (February 2022)

Dengue is endemic to tropical regions of the world, including the US territories of Puerto Rico, American Samoa, the US Virgin Islands, the Federated States of Micronesia, and the Republic of Palau. In December 2021, the CDC Advisory Committee on Immunization Practices (ACIP) recommended the dengue vaccine CYD-TDV (Dengvaxia) for children aged 9 to 16 who live in those US territories and have serologic evidence of prior infection [69]. Serology for dengue must be performed prior to vaccination. In trials, breakthrough infection after vaccination was more likely to be severe in individuals who were seronegative at baseline, and thus such individuals should not receive the vaccine. It is not approved for travelers visiting dengue-endemic areas. (See "Dengue virus infection: Prevention and treatment", section on 'CYD-TDV (Dengvaxia)'.)

Herpes zoster vaccination for immunocompromised adults ≥19 years old (October 2021, Modified February 2022)

Herpes zoster vaccination is indicated for those ≥50 years of age to reduce the risk of herpes zoster and postherpetic neuralgia. The United States Advisory Committee on Immunization Practices recently expanded the indication for the recombinant zoster vaccine (RZV) to include immunocompromised adults ≥19 years of age [70]; RZV has been shown to reduce the incidence of herpes zoster in immunocompromised adults. Vaccination should ideally be administered prior to immunosuppression, but when this is not possible, it should be administered during periods of lower immunosuppression and stable disease.

Novel trivalent hepatitis B vaccine (January 2022)

Most available hepatitis B virus vaccines are recombinant vaccines using yeast-derived S protein of the surface antigen. In December 2021, the US Food and Drug Administration approved a trivalent mammalian cell-derived recombinant vaccine that contains two pre-S epitopes in addition to the S antigen [71]. Compared with conventional hepatitis B vaccines, this vaccine is more immunogenic in older adults [72]. However, its role remains uncertain since it causes side effects more frequently than conventional hepatitis B vaccines and requires more doses than the adjuvanted recombinant hepatitis B vaccine (HepB-CpG; three versus two doses). (See "Hepatitis B virus immunization in adults", section on 'Mammalian cell-derived'.)

Vaccination against human papillomavirus, especially at an early age, is associated with greater reductions in cervical cancer (December 2021)

Human papillomavirus (HPV) vaccination has been shown to decrease incidence of HPV infection and cervical intraepithelial neoplasia (CIN), but whether vaccinating females at an earlier age is associated with lower incidence of cervical cancer has not been well established. In a registry-based observational study of 13.7 million years of follow-up of females aged 20 to 30 years, females who received the bivalent HPV vaccine at a younger age had a greater relative reduction in the incidence of cervical cancer and CIN3 (34 percent for vaccination at age 16 to 18 years, 62 percent at age 14 to 16 years, and 87 percent at age 12 to 13 years) compared with the unvaccinated cohort [73]. This lends further support to vaccinating against HPV at a younger age. (See "Human papillomavirus vaccination", section on 'Cervical, vaginal, and vulvar disease'.)

Updated ACIP guidance on influenza vaccination in the United States (September 2021)

In August 2021, the United States Advisory Committee on Immunization Practices (ACIP) issued recommendations for prevention of seasonal influenza [74]. During the 2021-22 influenza season, the following vaccine types are expected to be available: inactivated influenza vaccines (IIV4s), recombinant influenza vaccine (RIV4), and live attenuated influenza vaccine (LAIV4) (table 5 and table 6); all vaccines are expected to be quadrivalent. For the IIV4s produced from cell culture, the approved age indication has been expanded from ≥4 years to ≥6 months of age [75,76]. Influenza vaccination may be co-administered with COVID-19 vaccination, at different anatomic sites. We agree with the ACIP guidance. (See "Seasonal influenza vaccination in adults", section on 'Available formulations' and "Seasonal influenza in children: Prevention with vaccines", section on 'Influenza vaccines'.)

REFERENCES

  1. Gupta A, Gonzalez-Rojas Y, Juarez E, et al. Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab. N Engl J Med 2021; 385:1941.
  2. Gottlieb RL, Vaca CE, Paredes R, et al. Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients. N Engl J Med 2022; 386:305.
  3. Hammond J, Leister-Tebbe H, Gardner A, et al. Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. N Engl J Med 2022.
  4. Sullivan DJ, Gebo KA, Shoham S, et al. Randomized Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma. medRxiv 2021.
  5. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med 2022; 386:509.
  6. US Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization for bebtelovimab. Available at: https://www.fda.gov/media/156152/download (Accessed on February 16, 2022).
  7. The COVID-19 Treatment Guidelines Panel’s Interim Statement on Patient Prioritization for Outpatient Anti-SARS-CoV-2 Therapies or Preventive Strategies When There Are Logistical or Supply Constraints https://www.covid19treatmentguidelines.nih.gov/therapies/statement-on-patient-prioritization-for-outpatient-therapies/ (Accessed on December 23, 2021).
  8. Halasa NB, Olson SM, Staat MA, et al. Effectiveness of Maternal Vaccination with mRNA COVID-19 Vaccine During Pregnancy Against COVID-19-Associated Hospitalization in Infants Aged <6 Months - 17 States, July 2021-January 2022. MMWR Morb Mortal Wkly Rep 2022; 71:264.
  9. Stock SJ, Carruthers J, Calvert C, et al. SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland. Nat Med 2022.
  10. Emergency Use Authorization (EUA) of the Pfizer-BioNTech COVID-19 Vaccine to Prevent Coronavirus. Fact sheet for healthcare providers administering vaccine. https://www.fda.gov/media/144413/download (Accessed on December 09, 2021).
  11. Emergency Use Authorization (EUA) of the Moderna COVID-19 Vaccine to prevent Coronavirus Disease 2019 (COVID-19). Factsheet for healthcare providers administering vaccine. https://www.fda.gov/media/144637/download?utm_medium=email&utm_source=govdelivery (Accessed on November 20, 2021).
  12. US Food and Drug Administration. Emergency use authorization (EUA) of the Janssen COVID-19 vaccine to prevent coronavirus disease 2019 (COVID-19). https://www.fda.gov/media/146304/download (Accessed on February 03, 2022).
  13. CDC Expands Eligibility for COVID-19 Booster Shots to All Adults https://www.cdc.gov/media/releases/2021/s1119-booster-shots.html (Accessed on November 20, 2021).
  14. CDC - An Additional Dose of mRNA COVID-19 Vaccine Following a Primary Series in Immunocompromised People. Available at: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-08-13/02-COVID-Dooling-508.pdf (Accessed on August 14, 2021).
  15. Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the United States. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html (Accessed on February 24, 2022).
  16. Aharon D, Lederman M, Ghofranian A, et al. In Vitro Fertilization and Early Pregnancy Outcomes After Coronavirus Disease 2019 (COVID-19) Vaccination. Obstet Gynecol 2022.
  17. Fendler A, Shepherd S, Au L, et al. Omicron neutralising antibodies after third COVID-19 vaccine dose in patients with cancer. Lancet 2022.
  18. Gardellini A, Guidotti F, Maino E, et al. Severe immune thrombocytopenia after COVID-19 vaccination: Report of four cases and review of the literature. Blood Cells Mol Dis 2021; 92:102615.
  19. Visser C, Swinkels M, van Werkhoven E, et al. COVID-19 vaccination in patients with immune thrombocytopenia. Blood Adv 2021.
  20. Naranbhai V, Pernat CA, Gavralidis A, et al. Immunogenicity and Reactogenicity of SARS-CoV-2 Vaccines in Patients With Cancer: The CANVAX Cohort Study. J Clin Oncol 2022; 40:12.
  21. Kumar D, Ferreira VH, Hall VG, et al. Neutralization of SARS-CoV-2 Variants in Transplant Recipients After Two and Three Doses of mRNA-1273 Vaccine : Secondary Analysis of a Randomized Trial. Ann Intern Med 2022; 175:226.
  22. Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the United States. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html (Accessed on November 04, 2021).
  23. Greenhawt M, Abrams EM, Shaker M, et al. The Risk of Allergic Reaction to SARS-CoV-2 Vaccines and Recommended Evaluation and Management: A Systematic Review, Meta-Analysis, GRADE Assessment, and International Consensus Approach. J Allergy Clin Immunol Pract 2021; 9:3546.
  24. US FDA. Emergency Use Authorization (EUA) of the Pfizer-BioNTech COVID-19 vaccine to prevent coronavirus disease 2019 (COVID-19) for 5 through 11 years of age. https://www.fda.gov/media/153714/download (Accessed on November 02, 2021).
  25. Zauche LH, Wallace B, Smoots AN, et al. Receipt of mRNA Covid-19 Vaccines and Risk of Spontaneous Abortion. N Engl J Med 2021; 385:1533.
  26. Kharbanda EO, Haapala J, DeSilva M, et al. Spontaneous Abortion Following COVID-19 Vaccination During Pregnancy. JAMA 2021; 326:1629.
  27. American College of Rheumatology COVID-19 Vaccine Clinical Guidance Summary for Patients with Rheumatic and Musculoskeletal Diseases (August 19,2021 update). https://www.rheumatology.org/Portals/0/Files/COVID-19-Vaccine-Clinical-Guidance-Rheumatic-Diseases-Summary.pdf (Accessed on August 21, 2021).
  28. Balocco R, De Sousa Guimaraes Koch S, Thorpe R, et al. New INN nomenclature for monoclonal antibodies. Lancet 2022; 399:24.
  29. Silverberg JI, Toth D, Bieber T, et al. Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: results from the double-blind, randomized, multicentre, placebo-controlled phase III ECZTRA 3 trial. Br J Dermatol 2021; 184:450.
  30. Papp K, Szepietowski JC, Kircik L, et al. Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: Results from 2 phase 3, randomized, double-blind studies. J Am Acad Dermatol 2021; 85:863.
  31. Cutler C, Lee SJ, Arai S, et al. Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study. Blood 2021; 138:2278.
  32. https://www.fda.gov/news-events/press-announcements/fda-approves-first-oral-blood-thinning-medication-children (Accessed on June 25, 2021).
  33. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-treat-help-prevent-types-blood-clots-certain-pediatric-populations (Accessed on January 14, 2022).
  34. Halton J, Brandão LR, Luciani M, et al. Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial. Lancet Haematol 2021; 8:e22.
  35. Male C, Lensing AWA, Palumbo JS, et al. Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial. Lancet Haematol 2020; 7:e18.
  36. Howard JF Jr, Bril V, Vu T, et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol 2021; 20:526.
  37. Ailani J, Lipton RB, Goadsby PJ, et al. Atogepant for the Preventive Treatment of Migraine. N Engl J Med 2021; 385:695.
  38. https://pp.jazzpharma.com/pi/xywav.en.USPI.pdf (Accessed on August 17, 2021).
  39. Dauvilliers Y, Arnulf I, Foldvary-Schaefer N, et al. Safety and efficacy of lower-sodium oxybate in adults with idiopathic hypersomnia: a phase 3, placebo-controlled, double-blind, randomised withdrawal study. Lancet Neurol 2022; 21:53.
  40. Luke JJ, Rutkowski P, Queirolo P, et al. Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: Efficacy and safety results from the KEYNOTE-716 double-blind phase III trial. Ann Oncol 2021; 32;5S.
  41. Luke JJ, Long GV, Khattak MA, de La Cruz Merino L, Del Vecchio M, et al. Pembrolizumab versus Placebo After Complete Resection of HIgh-Risk Stage II Melanoma: Updated Result from KEYNOTE-716. Presented at Society for Melanoma Research Congress, October 28-31, 2021.
  42. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med 2021; 385:683.
  43. Pembrolizumab: United States (US) Food and Drug Administration (FDA) Label https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s113lbl.pdf (Accessed on November 19, 2021).
  44. O'Donnell PH, Balar AJ, Vuky J, et al. First-line pembrolizumab (pembro) in cisplatin-ineligible patients with advanced urothelial cancer (UC): Response and survival results up to five years from the KEYNOTE-052 phase 2 study. J Clin Oncol 2021; 39;15S.
  45. Pembrolizumab: United States Food and Drug Administration Prescribing Label https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125514s117,s118lbl.pdf (Accessed on September 07, 2021).
  46. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet 2021; 398:1344.
  47. Atezolizumab injection. United States Prescribing Information. US National Library of Medicine. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761034Orig1s042lbl.pdf (Accessed on October 27, 2021).
  48. Harbeck N, Rastogi P, Martin M, et al. Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study. Ann Oncol 2021; 32:1571.
  49. Abemaciclib tablets. United States Prescribing Information. US National Library of Medicine. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208716s006s007s008lbl.pdf (Accessed on October 15, 2021).
  50. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med 2021; 384:2102.
  51. Nivolumab: United States Food and Drug Administration (FDA) Prescribing Label https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/125554s097lbl.pdf (Accessed on September 01, 2021).
  52. Coleman RL, Lorusso D, Gennigens C, et al. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol 2021; 22:609.
  53. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761208s000lbl.pdf (Accessed on September 22, 2021).
  54. US FDA approval letter for ivosidenib in advanced cholangiocarcinoma https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2021/211192Orig1s008ltr.pdf (Accessed on August 30, 2021).
  55. Zhu AX, Macarulla T, Javle MM, et al. Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial. JAMA Oncol 2021; 7:1669.
  56. Wagner AJ, Ravi V, Riedel RF, et al. Long-term follow-up for duration of response (DoR) after weekly nab-sirolimus in patients with advanced malignant perivascular epithelioid cell tumors (PEComa): Results from a registrational open-label phase II trial, AMPECT. J Clin Oncol 2020; 38S.
  57. Heier JS, Khanani AM, Quezada Ruiz C, et al. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet 2022; 399:729.
  58. Dupilumab https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761055s031lbl.pdf.
  59. Multiple Myeloma Hub; FDA withdrawal of panobinostat for the treatment of R/R MM https://multiplemyelomahub.com/medical-information/fda-withdrawal-of-panobinostat-for-the-treatment-of-rr-mm (Accessed on January 07, 2022).
  60. Davids MS, O'Connor OA, Jurczak W, et al. Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1ε inhibitor, in relapsed/refractory lymphoid malignancies. Blood Adv 2021; 5:5332.
  61. https://www.fda.gov/media/151080/download (Accessed on August 04, 2021).
  62. Suzuki J, Mittal L, Woo SB. Sublingual buprenorphine and dental problems: a case series. Prim Care Companion CNS Disord 2013; 15.
  63. https://www.fda.gov/media/155352/download.
  64. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/103411s5201lbl.pdf (Accessed on January 04, 2022).
  65. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761102s008lbl.pdf (Accessed on January 04, 2022).
  66. Ingason AB, Hreinsson JP, Ágústsson AS, et al. Rivaroxaban Is Associated With Higher Rates of Gastrointestinal Bleeding Than Other Direct Oral Anticoagulants : A Nationwide Propensity Score-Weighted Study. Ann Intern Med 2021; 174:1493.
  67. FDA Drug Safety Communication. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death (Accessed on September 06, 2021).
  68. EMA/PRAC Recommendations for update of the product information for tofacitinib. July 5, 2021. https://www.ema.europa.eu/en/documents/prac-recommendation/prac-recommendations-signals-adopted-7-10-june-2021-prac-meeting_en.pdf (Accessed on September 06, 2021).
  69. Paz-Bailey G, Adams L, Wong JM, et al. Dengue Vaccine: Recommendations of the Advisory Committee on Immunization Practices, United States, 2021. MMWR Recomm Rep 2021; 70:1.
  70. Anderson TC, Masters NB, Guo A, et al. Use of Recombinant Zoster Vaccine in Immunocompromised Adults Aged ≥19 Years: Recommendations of the Advisory Committee on Immunization Practices - United States, 2022. MMWR Morb Mortal Wkly Rep 2022; 71:80.
  71. Package insert. PREHEVBRIO. https://www.fda.gov/media/154561/download (Accessed on January 04, 2022).
  72. Vesikari T, Langley JM, Segall N, et al. Immunogenicity and safety of a tri-antigenic versus a mono-antigenic hepatitis B vaccine in adults (PROTECT): a randomised, double-blind, phase 3 trial. Lancet Infect Dis 2021; 21:1271.
  73. Falcaro M, Castañon A, Ndlela B, et al. The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study. Lancet 2021; 398:2084.
  74. Grohskopf LA, Alyanak E, Ferdinands JM, et al. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices, United States, 2021-22 Influenza Season. MMWR Recomm Rep 2021; 70:1.
  75. Nolan T, Fortanier AC, Leav B, et al. Efficacy of a Cell-Culture-Derived Quadrivalent Influenza Vaccine in Children. N Engl J Med 2021; 385:1485.
  76. US Food and Drug Administration. Flucelvax quadrivalent. https://www.fda.gov/vaccines-blood-biologics/vaccines/flucelvax-quadrivalent (Accessed on October 18, 2021).
Topic 8360 Version 10977.0

References

1 : Early Treatment for Covid-19 with SARS-CoV-2 Neutralizing Antibody Sotrovimab.

2 : Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients.

3 : Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19.

4 : Randomized Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma.

5 : Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients.

6 : Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients.

7 : Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients.

8 : Effectiveness of Maternal Vaccination with mRNA COVID-19 Vaccine During Pregnancy Against COVID-19-Associated Hospitalization in Infants Aged<6 Months - 17 States, July 2021-January 2022.

9 : SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland.

10 : SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland.

11 : SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland.

12 : SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland.

13 : SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland.

14 : SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland.

15 : SARS-CoV-2 infection and COVID-19 vaccination rates in pregnant women in Scotland.

16 : In Vitro Fertilization and Early Pregnancy Outcomes After Coronavirus Disease 2019 (COVID-19) Vaccination.

17 : Omicron neutralising antibodies after third COVID-19 vaccine dose in patients with cancer

18 : Severe immune thrombocytopenia after COVID-19 vaccination: Report of four cases and review of the literature.

19 : COVID-19 vaccination in patients with immune thrombocytopenia.

20 : Immunogenicity and Reactogenicity of SARS-CoV-2 Vaccines in Patients With Cancer: The CANVAX Cohort Study.

21 : Neutralization of SARS-CoV-2 Variants in Transplant Recipients After Two and Three Doses of mRNA-1273 Vaccine : Secondary Analysis of a Randomized Trial.

22 : Neutralization of SARS-CoV-2 Variants in Transplant Recipients After Two and Three Doses of mRNA-1273 Vaccine : Secondary Analysis of a Randomized Trial.

23 : The Risk of Allergic Reaction to SARS-CoV-2 Vaccines and Recommended Evaluation and Management: A Systematic Review, Meta-Analysis, GRADE Assessment, and International Consensus Approach.

24 : The Risk of Allergic Reaction to SARS-CoV-2 Vaccines and Recommended Evaluation and Management: A Systematic Review, Meta-Analysis, GRADE Assessment, and International Consensus Approach.

25 : Receipt of mRNA Covid-19 Vaccines and Risk of Spontaneous Abortion.

26 : Spontaneous Abortion Following COVID-19 Vaccination During Pregnancy.

27 : Spontaneous Abortion Following COVID-19 Vaccination During Pregnancy.

28 : New INN nomenclature for monoclonal antibodies.

29 : Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: results from the double-blind, randomized, multicentre, placebo-controlled phase III ECZTRA 3 trial.

30 : Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: Results from 2 phase 3, randomized, double-blind studies.

31 : Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study.

32 : Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study.

33 : Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar Study.

34 : Dabigatran etexilate for the treatment of acute venous thromboembolism in children (DIVERSITY): a randomised, controlled, open-label, phase 2b/3, non-inferiority trial.

35 : Rivaroxaban compared with standard anticoagulants for the treatment of acute venous thromboembolism in children: a randomised, controlled, phase 3 trial.

36 : Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial.

37 : Atogepant for the Preventive Treatment of Migraine.

38 : Atogepant for the Preventive Treatment of Migraine.

39 : Safety and efficacy of lower-sodium oxybate in adults with idiopathic hypersomnia: a phase 3, placebo-controlled, double-blind, randomised withdrawal study.

40 : Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: Efficacy and safety results from the KEYNOTE-716 double-blind phase III trial

41 : Pembrolizumab versus placebo after complete resection of high-risk stage II melanoma: Efficacy and safety results from the KEYNOTE-716 double-blind phase III trial

42 : Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma.

43 : Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma.

44 : First-line pembrolizumab (pembro) in cisplatin-ineligible patients with advanced urothelial cancer (UC): Response and survival results up to five years from the KEYNOTE-052 phase 2 study.

45 : First-line pembrolizumab (pembro) in cisplatin-ineligible patients with advanced urothelial cancer (UC): Response and survival results up to five years from the KEYNOTE-052 phase 2 study.

46 : Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.

47 : Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial.

48 : Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study.

49 : Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study.

50 : Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma.

51 : Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma.

52 : Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study.

53 : Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study.

54 : Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study.

55 : Final Overall Survival Efficacy Results of Ivosidenib for Patients With Advanced Cholangiocarcinoma With IDH1 Mutation: The Phase 3 Randomized Clinical ClarIDHy Trial.

56 : Long-term follow-up for duration of response (DoR) after weekly nab-sirolimus in patients with advanced malignant perivascular epithelioid cell tumors (PEComa): Results from a registrational open-label phase II trial, AMPECT.

57 : Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials.

58 : Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials.

59 : Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials.

60 : Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1εinhibitor, in relapsed/refractory lymphoid malignancies.

61 : Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1εinhibitor, in relapsed/refractory lymphoid malignancies.

62 : Sublingual buprenorphine and dental problems: a case series.

63 : Sublingual buprenorphine and dental problems: a case series.

64 : Sublingual buprenorphine and dental problems: a case series.

65 : Sublingual buprenorphine and dental problems: a case series.

66 : Rivaroxaban Is Associated With Higher Rates of Gastrointestinal Bleeding Than Other Direct Oral Anticoagulants : A Nationwide Propensity Score-Weighted Study.

67 : Rivaroxaban Is Associated With Higher Rates of Gastrointestinal Bleeding Than Other Direct Oral Anticoagulants : A Nationwide Propensity Score-Weighted Study.

68 : Rivaroxaban Is Associated With Higher Rates of Gastrointestinal Bleeding Than Other Direct Oral Anticoagulants : A Nationwide Propensity Score-Weighted Study.

69 : Dengue Vaccine: Recommendations of the Advisory Committee on Immunization Practices, United States, 2021.

70 : Use of Recombinant Zoster Vaccine in Immunocompromised Adults Aged≥19 Years: Recommendations of the Advisory Committee on Immunization Practices - United States, 2022.

71 : Use of Recombinant Zoster Vaccine in Immunocompromised Adults Aged≥19 Years: Recommendations of the Advisory Committee on Immunization Practices - United States, 2022.

72 : Immunogenicity and safety of a tri-antigenic versus a mono-antigenic hepatitis B vaccine in adults (PROTECT): a randomised, double-blind, phase 3 trial.

73 : The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study.

74 : Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices, United States, 2021-22 Influenza Season.

75 : Efficacy of a Cell-Culture-Derived Quadrivalent Influenza Vaccine in Children.