The CDC has updated its opioid prescribing guidelines (November 2022)
The Centers for Disease Control and Prevention (CDC) in the United States has issued an updated guideline for prescribing opioids for acute, subacute, and chronic pain (table 1). The guideline is intended for clinicians who prescribe opioids to outpatients under the age of 18, and it does not apply to pain caused by sickle cell disease, cancer, palliative care, or end-of-life care . (See “Use of Opioids in the Management of Chronic Non-Cancer Pain,” section on “Opioid Therapy in the Context of the Opioid Epidemic” for more information.)
Dosing of once-daily antihypertensive medications in the morning versus at bedtime (October 2022)
Previously, the best time of day to take once-daily antihypertensive medications was debatable, with some studies finding that bedtime dosing reduced nocturnal blood pressure and improved cardiovascular outcomes. More than 21,000 adults with hypertension were randomly assigned to take their antihypertensive medications in the morning or evening in the largest and most rigorous trial (the Treatment In the Morning or Evening [TIME] study) . After about five years, the rates of cardiovascular outcomes and adverse events were comparable between the groups. According to the findings of this study, patients can take their once-daily antihypertensive medications whenever they want. (See the section on ‘Bedtime versus morning dosing’ in “Choice of Drug Therapy in Primary (Essential) Hypertension.”)
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Endocarditis antibiotic prophylaxis before invasive dental procedures (September 2022)
Antibiotic prophylaxis has not been proven to be effective in preventing infective endocarditis (IE). A case-crossover analysis and cohort study of nearly 8 million people found an association between invasive dental procedures (particularly extractions and oral surgery) and subsequent IE in people at high IE risk . Antibiotic prophylaxis was associated with a lower risk of IE after these procedures.
Anticoagulation therapy for rheumatic mitral stenosis associated with atrial fibrillation (September 2022)
There has been limited data to guide anticoagulant choice in patients with rheumatic mitral stenosis and atrial fibrillation. A randomized trial enrolling over 4500 adults with rheumatic heart disease and atrial fibrillation discovered that the mortality and stroke rates were higher with rivaroxaban than with a vitamin K antagonist (VKA), but major bleeding rates were comparable .
Efficacy of a low-dose statin combined with ezetimibe in the secondary prevention of cardiovascular disease (September 2022)
The long-term efficacy of ezetimibe plus a moderate-dose statin for the secondary prevention of cardiovascular disease (CVD) has not been well studied. In the RACING trial, nearly 3800 patients with CVD were randomly assigned to combination therapy with moderate-dose rosuvastatin plus ezetimibe or high-dose rosuvastatin monotherapy. Rates of a composite of cardiovascular death, major cardiovascular events, or nonfatal stroke at three years were
WITHDRAWALS OF DRUG OR INDICATION
Atezolizumab as first-line therapy has no survival benefit in advanced urothelial carcinoma (January 2023)
The US Food and Drug Administration (FDA) previously approved atezolizumab, a programmed cell death ligand-1 (PD-L1) inhibitor, for patients with advanced or metastatic urothelial carcinoma (mUC) who were ineligible for any platinum-based chemotherapy and those with PD-L1 positive cancers who were ineligible for cisplatin-based chemotherapy. However, in a randomized phase III trial of over 1000 patients with treatment-naive
Belantamab mafodotin has been withdrawn from the market (December 2022)
Belantamab mafodotin will be withdrawn from the market in November 2022, though it will continue to be available through the manufacturer for patients who began treatment prior to its withdrawal . The antibody drug conjugate targeting B-cell maturation antigen (BCMA) was granted accelerated approval in the United States for patients with relapsed or refractory multiple myeloma (MM) based on response data from two uncontrolled open-label trials (DREAMM-1 and
WARNINGS AND ADVERSE REACTIONS
Tamoxifen and endometrial pathology are linked in breast cancer patients (January 2023)
Tamoxifen, a selective estrogen receptor modulator, is used as adjuvant therapy or chemoprevention for selected patients with hormone-sensitive breast cancer or at increased risk for breast cancer; however, it is linked to an increased risk of uterine pathology.
Overdoes are a risk in young people who are prescribed benzodiazepines for sleep disorders (December 2022)
Benzodiazepines are commonly prescribed for insomnia, despite risks and the availability of safer alternatives, according to prescription database studies. In a recent cohort study in the United States that included over 90,000 children and young adults (age 10 to 29 years) with a sleep disorder who were prescribed a new insomnia medication, benzodiazepines were associated with an increased risk of drug overdose in the next six months compared to alternative insomnia medications.
Progestogens and the risk of thromboembolism (September 2022)
Historically, estrogens but not progestogens were avoided in patients at increased risk of venous thromboembolism (VTE) who desired contraception or experienced abnormal uterine bleeding. However, current use of depot medroxyprogesterone acetate (DMPA), norethindrone acetate, or MPA was associated with an increased risk of VTE compared to non-use in a case-control study that matched >21,000 reproductive-age patients with acute
Delirium and dexmedetomidine in critically ill patients (August 2022)
Data on the clinical benefit of dexmedetomidine as a sedative in critically ill patients have been conflicting. A recent meta-analysis of 77 randomized trials (nearly 12,000 patients) reported that, when compared to other sedatives, dexmedetomidine reduced the risk of delirium (relative risk 0.67, 95% CI 0.55-0.81; moderate certainty) but increased the risk of bradycardia and hypotension .
ANTIMICROBIALS RECENT APPROVALS
Ibrexafungerp is used to treat recurrent vulvovaginal candidiasis (December 2022)
The treatment of recurrent vulvovaginal candidiasis (RVVC) has primarily consisted of long-term use of azole drugs such as fluconazole. However, in a phase 3 trial evaluating extended treatment with either ibrexafungerp, a novel triterpenoid antifungal, or placebo after initial fluconazole treatment in patients with RVVC, more patients receiving extended ibrexafungerp remained without evidence of RVVC
Recurrent vulvovaginal candidiasis treatment (July 2022)
Patients with recurrent vulvovaginal candidiasis (RVVC, defined as three culture-confirmed episodes in a 12-month period) who do not respond to oral fluconazole therapy have few other treatment options. In an industry-sponsored trial comparing treatment and maintenance with either oteseconazole (a novel azole) or fluconazole/placebo in 185 females with active RVVC, fewer patients receiving oteseconazole experienced (See “Candida vulvovaginitis: Treatment”.)
DERMATOLOGICAL AND ALLERGY THERAPIES RECENTLY APPROVED
Ruxolitinib topical for nonsegmental vitiligo (October 2022)
Vitiligo is a difficult-to-treat autoimmune skin disease characterized by depigmented patches. In two recent identical randomized trials involving 674 patients with nonsegmental vitiligo involving 10% of total body surface area, patients assigned to twice daily ruxolitinib 1.5% cream (a topical Janus kinase inhibitor) achieved a 75% reduction in the facial Vitiligo Area Scoring Index at 24 weeks, compared to vehicle (30
Deucravacitinib is an oral medication used to treat moderate to severe plaque psoriasis (October 2022)
Tyrosine kinase inhibition is a novel approach to psoriasis treatment, with two phase 3 trials supporting the efficacy of oral deucravacitinib, a selective tyrosine kinase 2 inhibitor, for moderate to severe plaque psoriasis [17,18]. In the POETYK PSO-1 and POETYK PSO-2 trials, adults with moderate to severe plaque psoriasis were randomly assigned
Alopecia areata treatment with oral baricitinib (August 2022)
Two phase 3 trials support the efficacy of baricitinib, an oral Janus kinase (JAK) 1 and JAK2 inhibitor . In BRAVE-AA1 (n = 654) and BRAVE-AA2 (n = 546), adults with severe alopecia areata were randomly assigned to baricitinib 4 mg per day, baricitinib 2 mg per day, or placebo. After 36 weeks, patients treated with either dose of
ENDOCRINE AND KIDNEY DISEASE THERAPIES RECENTLY APPROVED
Immunotherapy to postpone the onset of type 1 diabetes (December 2022)
Immunotherapies have been extensively studied as a means of preserving pancreatic beta cell function and thus delaying or preventing progression to type 1 diabetes in high-risk individuals . Teplizumab, administered as a single 14-day course of daily intravenous infusions, delays the diagnosis of type 1 diabetes by a median of two years.
Abaloparatide is prescribed for men who are at high risk of osteoporotic fracture (January 2022)
Abaloparatide is a synthetic analog of parathyroid hormone-related protein (PTHrP) that is administered as a daily subcutaneous injection to postmenopausal women to increase spine and hip bone mineral density (BMD) and reduce the risk of vertebral and nonvertebral fractures. It recently received regulatory approval in the United States to increase bone density in men at high risk for osteoporotic fracture based on the results of a 12-month trial comparing abalopa
HEMATOLOGIC AND ANTICOAGULANT RECENT APPROVALS
Mosunetuzumab is a treatment for multiple relapsed follicular lymphoma (August 2022, Modified January 2023)
Mosunetuzumab is a bispecific T cell engager (BiTE) monoclonal antibody that targets both CD20 on follicular lymphoma (FL) cells and CD3 on cytotoxic T cells. In a single-arm, multicenter phase 2 study of 90 patients with FL who had relapsed after at least two prior lines of treatment, there were high response rates (60 percent complete, 20% partial), with a median duration of response of 23 months .
Teclistamab, a bispecific T cell engager (BiTE), is used to treat multiple myeloma (November 2022)
For patients with penta-refractory multiple myeloma (MM), defined as disease resistant to an anti-CD38 monoclonal antibody, lenalidomide, pomalidomide, bortezomib, and carfilzomib (algorithm 1), therapies targeting the B cell maturation antigen (BCMA) are a preferred treatment option (algorithm 1). (See “Multiple myeloma: Treatment of third or later relapse”.)
NEUROLOGICAL AND PSYCHIATRIC RECENT APPROVALS
Ublituximab in Multiple Sclerosis Patients (January 2023)
Ublituximab, a recombinant monoclonal antibody that targets B cells, was approved by the US Food and Drug Administration in December 2022 for the treatment of adults with relapsing forms of multiple sclerosis (MS). Its efficacy was established in two identical randomized trials comparing intravenous ublituximab with oral teriflunomide .
Sodium phenylbutyrate-taurursodiol in the treatment of amyotrophic lateral sclerosis (October 2022)
Sodium phenylbutyrate-taurursodiol (PB-TURSO) is a combination of two orally available drugs that each reduce neuronal cell death in preclinical models of amyotrophic lateral sclerosis (ALS). By 24-week follow-up, patients assigned to PB-TURSO had a slower median rate of monthly functional decline than those assigned to placebo in a randomized trial of 137 patients with ALS (75 percent also taking ril
ONCOLOGIC RECENT APPROVALS
Atezolizumab is used to treat advanced alveolar soft part sarcoma (January 2023)
Treatment options for patients with metastatic alveolar soft part sarcoma (ASPS) are limited, and there is interest in investigating novel therapies. In a phase II trial (Study ML39345) of nearly 50 adult and pediatric patients with unresectable or metastatic ASPS, atezolizumab demonstrated an objective response rate of 24 percent and was well tolerated .
Futibatinib is a drug that is used to treat advanced intrahepatic cholangiocarcinoma that has a FGFR2 gene fusion or rearrangement (October 2022, Modified January 2023)
Futibatinib, a highly selective inhibitor of fibroblast growth factor receptor (FGFR) 1 to 4, has been approved by the US Food and Drug Administration for the treatment of locally advanced/metastatic intrahepatic cholangiocarcinoma with a FGFR2 gene fusion or rearrangement . Approval was based on the phase II FOENIX-CCA2 study, which demonstrated an objective response rate of 42%, a median duration of response of 10
In platinum-resistant epithelial ovarian cancer, mirvetuximab soravtansine (November 2022)
Mirvetuximab soravtansine is a folate receptor alpha-directed antibody and microtubule inhibitor conjugate that has been approved in the United States for the treatment of folate receptor-alpha positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer (EOC) that has previously been treated with one to three prior systemic treatment regimens .
Combinations of immune checkpoint inhibitors and chemotherapy in advanced NSCLC (November 2022)
In preliminary results of Study 16113, among 466 patients randomly assigned to chemotherapy with or without cemiplimab, the cemiplimab group experienced an improvement in median overall survival (22 versus 13 months), with low rates of serious adverse events . Similarly, in the POSEIDON trial, the addition of immune checkpoint inhibitors to chemotherapy improved survival in advanced non-small cell lung cancer (NSCLC), with new combinations being investigated.
Selpercatinib has received tissue-agnostic approval for RET fusion-positive solid tumors (November 2022)
Selpercatinib has been granted tissue-agnostic, accelerated approval by the US Food and Drug Administration for the treatment of adult patients with locally advanced or metastatic solid tumors and a rearranged during transfection (RET) gene fusion who have disease progression on or after prior systemic treatment, or who have no satisfactory alternative treatment options.
Durvalumab is used to treat advanced or metastatic biliary tract cancer (September 2022)
Durvalumab, an antiprogrammed cell death ligand 1 monoclonal antibody, has been approved by the US Food and Drug Administration in combination with cisplatin and gemcitabine for adults with previously untreated locally advanced or unresectable biliary tract cancer. The approval was based on the TOPAZ-1 trial, which directly compared cisplatin and gemcitabine with or without durvalumab for up to 24 weeks; those in the durvalumab group
Eflapegrastim is used to treat chemotherapy-induced neutropenia (September 2022)
The FDA approved eflapegrastim, a novel long-acting formulation of granulocyte colony stimulating factor (G-CSF), to reduce the incidence of infection in adult patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia . The approval was based on two separate trials of patients with early-stage breast cancer treated with docetaxel plus cyclopamine.
To reduce cisplatin ototoxicity in children with nonmetastatic solid tumors, sodium thiosulfate was used (September 2022)
The US Food and Drug Administration approved sodium thiosulfate (STS) to reduce the risk of cisplatin-related ototoxicity in pediatric patients aged 1 month or older with a localized, nonmetastatic solid malignancy . Approval was based on two randomized trials, the Children’s Oncology Group ACCL0431 trial and the SIOPEL-6 trial, which both demonstrated a lower incidence of ototoxicity among children treated with STS in the
Crizotinib is used to treat ALK-positive inflammatory myofibroblastic tumors (August 2022)
Inflammatory myofibroblastic tumor (IMT) is a rare chemotherapy-resistant sarcoma, and there is interest in novel targeted therapies for patients with advanced disease. Cricotinib demonstrated objective response rates of 86 percent among children (12 of 14 patients) and 71 percent among adults (5 of 7 patients) in two separate open-label phase I/II trials in patients with unresectable, recurrent, or refractory IMT harboring an ALK gene rearrangement.
PULMONARY AND CRITICAL CARE RECENT APPROVALS
Albuterol-budesonide has been approved for the treatment of asthma in the United States (January 2023)
International guidelines have increasingly endorsed the use of an as-needed inhaled glucocorticoid and a short-acting beta-agonist (SABA) as a therapeutic option for asthma, but combination inhalers are limited in availability. A combination inhaler (albuterol-budesonide) has now been approved by the US Food and Drug Administration (FDA) for as-needed therapy in patients 18 years of age with asthma .
OTHER RECENT APPROVALS
Trial of intravenous immune globulin for dermatomyositis (November 2022) (November 2022)
Intravenous immune globulin (IVIG) has been used in the treatment of dermatomyositis (DM) based on limited observational data and small randomized trials. In a new randomized trial of 95 patients with DM, the percentage of patients who achieved a response of at least minimal improvement based on a composite score of disease activity was higher among those who received IVIG compared with placebo (79 versus 44 percent) at 16 weeks . IVIG was associated with more adverse events, including thromboembolic events. Based on these results, the US Food and Drug Administration approved IVIG for the treatment of adults with dermatomyositis. More data are needed to help determine the potential role of IVIG as first-line therapy for patients with DM. (See “Treatment of recurrent and resistant dermatomyositis and polymyositis in adults”, section on ‘Intravenous immune globulin’.)
Risankizumab for moderate to severe Crohn disease (July 2022) (July 2022)
Therapeutic options for moderate to severe Crohn disease (CD) are expanding. In two induction trials comparing 600 and 1200 mg risankizumab (an anti-interleukin 23 antibody) with placebo in adults with moderate to severe CD, risankizumab resulted in higher rates of clinical remission at 12 weeks (40 to 45 percent in the treatment groups versus 20 to 25 percent in the placebo groups) . In a maintenance trial comparing risankizumab 180 or 360 mg with placebo, risankizumab resulted in higher rates of sustained remission after 52 weeks (52 and 55 percent in the treatment groups versus 41 percent in the placebo group) . No safety signals were detected. Based on these data, the US Food and Drug Administration approved risankizumab for adults with moderate to severe CD. We anticipate using risankizumab as an alternative to other first-line biologic therapies. (See “Overview of medical management of high-risk, adult patients with moderate to severe Crohn disease”, section on ‘Other biologic agents’.)
Nirmatrelvir-ritonavir in vaccinated individuals with COVID-19 (October 2022) (October 2022)
A large randomized trial previously demonstrated that nirmatrelvir-ritonavir (Paxlovid) substantively reduced hospitalization and death in unvaccinated individuals with COVID-19 and risk factors for severe disease; accumulating observational data suggest that high-risk vaccinated individuals also benefit. In a study of 1130 vaccinated adults who received nirmatrelvir-ritonavir within five days of COVID-19 diagnosis and 1130 controls matched for age, gender, race, and comorbidities, nirmatrelvir-ritonavir was associated with a lower rate of emergency department visits, hospitalization, and death (odds ratio 0.5) . All 10 deaths were among those who had not been treated. In another study, nirmatrelvir-ritonavir was associated with a reduction in hospitalization from 59 to 15 cases per 100,000 person-days among mostly vaccinated patients ≥65 years old . Despite the limitations of observational data, these data highlight the potential clinical impact of nirmatrelvir-ritonavir among vaccinated individuals with Omicron subvariant infection and support our recommendations to treat patients at risk for severe disease, including otherwise healthy individuals ≥65 years old, regardless of vaccination status (algorithm 2). (See “COVID-19: Management of adults with acute illness in the outpatient setting”, section on ‘Efficacy and rationale’.)
Booster doses with the bivalent COVID-19 mRNA vaccines (September 2022, Modified December 2022) (September 2022, Modified December 2022)
Booster doses of COVID-19 vaccines are a strategy to improve effectiveness in the setting of waning immunity and immune evasion from circulating SARS-CoV-2 variants. The US Food and Drug Administration authorized two bivalent mRNA booster vaccines that target the spike proteins of both the original SARS-CoV-2 strain and the Omicron B.4/B.5 variants (figure 1 and figure 2) [48,49]. The Centers for Disease Control and Prevention (CDC) now recommends that all individuals ≥5 years old who have completed a primary COVID-19 vaccine series (including those who already received booster doses with monovalent vaccines) receive a single booster dose with one of the bivalent vaccines at least two months after the last vaccine dose; bivalent booster recommendations for children younger than five years old depend on the primary series vaccine received (table 2) . Our approach is consistent with CDC recommendations. Although clinical data evaluating bivalent vaccines are limited, their use is supported by indirect evidence from trials and observational studies in which monovalent booster doses improved vaccine efficacy against infection and severe disease and by studies that indicate at least comparable immunogenicity with bivalent versus monovalent formulations. (See “COVID-19: Vaccines”, section on ‘Role of booster vaccinations’.)
Novavax COVID-19 vaccine in the United States (July 2022) (July 2022)
In July 2022, the US Food and Drug Administration issued an emergency use authorization for NVX-CoV2373 (Novavax COVID-19 vaccine) for individuals aged 12 years or older, and the Centers for Disease Control and Prevention subsequently recommended it as an option for COVID-19 vaccination . It is an adjuvanted recombinant protein vaccine, similar to other long-available non-COVID-19 vaccines. In trials conducted prior to the emergence of the Delta and Omicron variants, NVX-CoV2373 efficacy in preventing symptomatic COVID-19 was 90 percent in adults; rare cases of myocarditis were reported among vaccine recipients [52,53]. NVX-CoV2373 may be an attractive option for individuals who prefer a COVID-19 vaccine created with a more established vaccine platform. (See “COVID-19: Vaccines”, section on ‘Available vaccines’.)
VACCINES – OTHER
Expanded ACIP recommendations for oral cholera vaccine (October 2022) (October 2022)
CVD 103-HgR (Vaxchora) is a single-dose, live attenuated oral cholera vaccine derived from Vibrio cholerae serotype O1; it was licensed by the US Food and Drug Administration and recommended by the Advisory Committee on Immunization Practices (ACIP) in 2016 for adults age 18 to 64 years traveling to areas of active cholera transmission. In 2022, the ACIP expanded the age group to include individuals age 2 to 17 years who meet these criteria . Thus far, assessment of CVD 103-HgR vaccine benefit in children has been based on safety and immunogenicity data rather than direct assessment of vaccine efficacy. We are in agreement with this guidance. (See “Cholera: Clinical features, diagnosis, treatment, and prevention”, section on ‘For travelers to high-risk areas’.)
Updated recommendations for pneumococcal vaccination in children and adolescents (September 2022) (September 2022)
Updated guidance from the Advisory Committee on Immunization Practices (ACIP) permits interchangeable use of the recently licensed 15-valent pneumococcal conjugate vaccine (PCV15) and 13-valent PCV (PCV13) for routine infant immunization and immunization of high-risk children and adolescents (table 3) . PCV15 contains the 13 serotypes included in PCV13 plus serotypes 22F and 33F (table 4), which accounted for 15 to 23 percent of invasive pneumococcal disease cases in children <18 years in the United States during 2018 to 2019. In prelicensure randomized trials, PCV15 demonstrated immunogenicity and safety similar to those of PCV13. We agree with the ACIP recommendations for PCV15. Clinical trials of the 20-valent PCV in children are ongoing. (See "Pneumococcal vaccination in children", section on 'Conjugate vaccines'.) New ACIP recommendations for seasonal influenza vaccination (September 2022) (September 2022) In August 2022, the Advisory Committee on Immunization Practices (ACIP) issued new recommendations for seasonal influenza vaccination in the United States . The ACIP now recommends that adults aged ≥65 years preferentially receive any one of the following higher dose or adjuvanted influenza vaccines: quadrivalent high-dose inactivated influenza vaccine (HD-IIV4), quadrivalent recombinant influenza vaccine (RIV4), or quadrivalent adjuvanted inactivated influenza vaccine (aIIV4) (table 5). In addition, the approved age indication for the cell culture–based inactivated influenza vaccine has been changed from ≥2 years to ≥6 months. We are in agreement with this guidance. (See "Seasonal influenza vaccination in adults", section on 'Choice of vaccine formulation' and "Seasonal influenza in children: Prevention with vaccines", section on 'Influenza vaccines'.) Vaccine-derived poliovirus infection in Rockland County, New York (August 2022) (August 2022) In June 2022, poliovirus was confirmed in an unvaccinated, immunocompetent adult resident of Rockland County, New York hospitalized with acute flaccid lower limb weakness . Vaccine-derived poliovirus type 2 was detected in the patient's stool and was also identified from wastewater samples in two neighboring New York counties, reflecting community transmission. The patient had not traveled internationally during the presumed exposure period; therefore, these findings suggest transmission within the United States from a person who received a type 2-containing oral polio vaccine abroad. Unvaccinated individuals remain at risk for paralytic poliomyelitis if they are exposed to either wild or vaccine-derived poliovirus; all individuals should stay up to date on recommended poliovirus vaccination. (See "Poliomyelitis and post-polio syndrome", section on 'Epidemiology'.) Modified vaccinia Ankara vaccine for monkeypox postexposure prophylaxis (August 2022) (August 2022) During the 2022 monkeypox outbreak, a modified vaccinia Ankara (MVA) vaccine is being used for postexposure prophylaxis after known or likely exposure. In the United States, given limited vaccine supplies, emergency use authorization was granted for intradermal MVA administration in persons ≥18 years; younger individuals should continue to receive the vaccine subcutaneously . Intradermal administration uses a lower dose compared with the standard subcutaneous route, thus maximizing vaccine supply, and clinical trials suggest similar immunogenicity. However, data on the efficacy of postexposure prophylaxis and intradermal administration remain limited; patients who receive the vaccine should continue to monitor for symptoms after an exposure and reduce their risk of new exposures. (See "Vaccines to prevent smallpox, mpox (monkeypox), and other orthopoxviruses", section on 'Dose-sparing regimen'.)