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What's new in drug therapy
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What's new in drug therapy
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2017. | This topic last updated: May 24, 2017.

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 Lexi-Interact drug interactions program included with UpToDate. This program is available to online desktop and mobile web users and can be accessed from the Drug Interactions tab located in the top right corner of any screen and in the search results list after searching on a drug name. iOS and Android users may also purchase an installed app version of Lexi-Interact from the Clinical Drug Information online store.

DRUG INTERACTIONS

Risk of hypoglycemia if repaglinide is given with clopidogrel (February 2017)

Clopidogrel, an antiplatelet drug whose glucuronide metabolite inhibits CYP2C8 hepatic metabolism, can increase levels of repaglinide, a CYP2C8 substrate, and cause hypoglycemia [1,2]. The prescribing information in the United States was recently revised to recommend against concomitant use and, if the combination cannot be avoided, to limit the total daily dose of repaglinide to 4 mg or less. Characterizing this interaction has contributed to a growing appreciation of CYP2C8 as a clinically relevant drug metabolizing enzyme leading to potential drug interactions with strong CYP2C8 inhibitors or inducers [2]. (See "Sulfonylureas and meglitinides in the treatment of diabetes mellitus", section on 'Precautions and side effects'.)

Dabigatran combined with certain statins associated with increased risk of major bleeding (February 2017)

An analysis of health records of nearly 46,000 Canadian patients showed that older adults (age ≥66) with atrial fibrillation taking dabigatran who also received simvastatin or lovastatin had approximately a 50 percent greater risk of hospitalization for major hemorrhage relative to those who used other statins [3]. Although the mechanism for this interaction is uncertain, until additional information becomes available, it may be prudent to choose a statin other than lovastatin or simvastatin for older patients receiving dabigatran, and for those with an elevated risk for serious bleeding. (See "Statins: Actions, side effects, and administration", section on 'Drug interactions'.)

NEW DRUGS AND US DRUG APPROVALS

Tranexamic acid for management of postpartum hemorrhage (May 2017)

Tranexamic acid, an antifibrinolytic drug, reduces bleeding in surgical and trauma patients. In a pragmatic randomized trial involving over 20,000 women with postpartum hemorrhage in over 20 countries (the World Maternal Antifibrinolytic Randomized Trial [WOMAN]), tranexamic acid, compared with placebo, reduced the relative risk of death due to bleeding by 20 to 30 percent, reduced the incidence of laparotomy to control bleeding, and was not associated with an increase in adverse effects [4]. Overall mortality was not reduced. We now recommend administration of tranexamic acid as a component of the treatment for postpartum hemorrhage. (See "Management of postpartum hemorrhage at vaginal delivery".)

Valbenazine for tardive dyskinesia (May 2017)

Tetrabenazine and valbenazine are vesicular monoamine transporter 2 inhibitors that deplete presynaptic dopamine and may be useful therapeutic agents for tardive dyskinesia (TD). Data from old, small studies supported the utility of tetrabenazine for this indication. Now there is evidence from the placebo-controlled KINECT 3 trial that valbenazine 40 mg once daily reduces dyskinesia in patients with TD [5]. For patients who have disturbing and intrusive tardive dyskinesia or tardive dystonia not amenable to treatment with botulinum toxin, we suggest treatment with tetrabenazine or valbenazine. (See "Tardive dyskinesia: Prevention and treatment", section on 'Valbenazine'.)

Eltrombopag for adults with acquired severe aplastic anemia unable to undergo HCT (May 2017)

Acquired aplastic anemia (AA) has a high morbidity, and allogeneic hematopoietic cell transplantation (HCT) is suggested as therapy for patients healthy enough to tolerate HCT who have a suitable donor. Immunosuppressive therapy (IST) is offered to those for whom HCT is not an option but is often ineffective in improving outcomes over the long term. A prospective cohort study in adults with acquired severe AA evaluated the effectiveness of IST plus eltrombopag, a thrombopoietin receptor agonist that acts on platelet precursors and hematopoietic stem cells [6]. Eltrombopag plus IST produced higher rates of overall hematologic response at six months compared with responses in a historical cohort (80 to 94 percent versus 66 percent for the historical group). Based on these findings, we now suggest administration of eltrombopag plus IST for individuals with acquired severe AA who are not candidates for allogeneic HCT. (See "Treatment of aplastic anemia in adults", section on 'Evidence for efficacy'.)

Checkpoint inhibition immunotherapy for advanced urothelial carcinoma (April 2017, Modified May 2017)

The role of checkpoint inhibition immunotherapy for patients with advanced urothelial carcinoma is expanding. Pembrolizumab, an agent targeting the programmed cell death-1 (PD-1) protein, has been shown to prolong survival in patients who relapse and is approved in the US for this indication. Based upon expanded phase I or phase II studies, four other anti-PD-1 or anti-PD-L1 checkpoint inhibitors (atezolizumab, nivolumab, durvalumab, avelumab) have also been approved by the US Food and Drug Administration (FDA) for patients who progressed during or within 12 months after cisplatin-based chemotherapy.

In a multicenter, single-arm phase II study, atezolizumab was used as first-line therapy in patients who were not eligible for treatment with a cisplatin-based regimen [7]. In this study, the objective response rate was 23 percent, and the majority of those patients continued to respond at the time of analysis. Based upon these results, the FDA approved atezolizumab as initial therapy for patients who are not candidates for a cisplatin-based chemotherapy regimen. We suggest using atezolizumab, nivolumab, durvalumab, or avelumab for patients who have relapsed after initial treatment with a cisplatin regimen, and using atezolizumab as initial therapy for patients who are unable to undergo treatment with cisplatin. (See "Treatment of metastatic urothelial cancer of the bladder and urinary tract", section on 'Immunotherapy'.)

Midostaurin approved for induction therapy of AML with FLT3 mutations (April 2017)

Mutations of the FLT3 gene are found in approximately one-third of adults with acute myeloid leukemia (AML) and are associated with worse outcomes in patients undergoing induction therapy with cytarabine and daunorubicin. The multitargeted small molecule FLT3 inhibitor midostaurin improves event-free and overall survival when added to standard induction therapy in adults with AML demonstrating FLT3 mutations. Midostaurin is now approved by the US Food and Drug Administration in this setting [8], and we suggest the addition of midostaurin to induction therapy for treatment of adults with newly diagnosed AML who are FLT3 mutation-positive. (See "Induction therapy for acute myeloid leukemia in younger adults", section on 'FLT3 mutation positive AML'.)

Ocrelizumab for treatment of multiple sclerosis in adults (April 2017)

Ocrelizumab, a recombinant anti-CD20 monoclonal antibody, is the first drug to reduce the risk of disability progression among patients with primary progressive multiple sclerosis (PPMS), as shown by the multicenter ORATORIO randomized trial [9]. Compared with placebo, ocrelizumab modestly reduced the proportion of patients with disability progression at 24 weeks (30 versus 36 percent). In addition, ocrelizumab slowed deterioration from baseline to week 120 on the timed 25-foot walk and led to improvements on other endpoints. While the long-term risks of infection and neoplasm with ocrelizumab are uncertain, there are no other disease-modifying therapies for PPMS. Therefore, we suggest treatment with ocrelizumab for most patients with PPMS. (See "Treatment of progressive multiple sclerosis in adults", section on 'Ocrelizumab'.)

Ocrelizumab has also been approved by the US Food and Drug Administration for use in relapsing-remitting multiple sclerosis (RRMS). In two clinical trials, ocrelizumab significantly reduced the relapse rate and mean number of gadolinium-enhancing brain lesions on magnetic resonance imaging and reduced the proportion of subjects with confirmed disability progression at 24 weeks [10]. The role of this agent in the treatment of RRMS remains to be clarified pending further safety data on rates of infection and neoplasm. (See "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults", section on 'Ocrelizumab'.)

Sublingual immunotherapy tablet for house dust mite allergy (April 2017)

A house dust mite (HDM) sublingual immunotherapy tablet was approved in the United States by the US Food and Drug Administration (FDA) for treatment of HDM-induced allergic rhinitis with or without conjunctivitis (AR/C) in adults (ages 18 to 65) [11]. HDM tablet immunotherapy is available in Europe, Australia, and Asia. Approval was based on several studies, including a recent randomized trial of over 1400 subjects with HDM-induced AR/C with or without asthma, who received HDM tablets or placebo daily for 52 weeks [12]. The total combined rhinitis score improved by 17 percent compared with placebo, with no serious treatment-related adverse events. Treatment is given daily for at least one year. Further study is needed to define the optimal duration of therapy and to what extent the effect persists after therapy is stopped. (See "Sublingual immunotherapy for allergic rhinoconjunctivitis and asthma", section on 'Availability'.)

Dupilumab for moderate to severe atopic dermatitis (April 2017)

Dupilumab is an interleukin-4 receptor alpha antagonist being evaluated in atopic dermatitis. In two 16-week clinical trials (SOLO1 and SOLO2), dupilumab was more effective than placebo in improving the signs and symptoms of atopic dermatitis [13]. Based on these results, the US Food and Drug Administration has approved dupilumab for the treatment of adult patients with moderate to severe atopic dermatitis not adequately controlled with topical prescription therapies [14]. While the role for dupilumab is still evolving, it appears to be a reasonable option for adult patients with severe disease who have failed other systemic therapies. (See "Treatment of atopic dermatitis (eczema)", section on 'Dupilumab'.)

Avelumab immunotherapy for metastatic Merkel cell carcinoma (March 2017)

Chemotherapy historically has been the standard approach to treating advanced Merkel cell carcinoma (MCC). Avelumab, a monoclonal antibody that blocks the PD-1 ligand (PD-L1), was approved by the US Food and Drug Administration based on a phase II study demonstrating a 32 percent response rate (23 percent partial and 9 percent complete), relatively durable remissions (six-month progression-free survival 40 percent), and a favorable side effect profile [15,16]. Based upon these results, avelumab is our preferred treatment for patients with metastatic MCC. (See "Staging and treatment of Merkel cell carcinoma", section on 'Avelumab'.)

Naldemedine for opioid-induced constipation (March 2017)

The benefit of naldemedine, an oral peripherally acting opioid receptor antagonist, for opioid-induced constipation (OIC) was shown in two identically designed 12-week phase III randomized trials conducted in patients with noncancer chronic pain and OIC [17]. In a preliminary report, naldemedine, compared with placebo, decreased constipation and was well tolerated with no signs or symptoms of opioid withdrawal or decrease in opioid analgesic efficacy. Naldemedine has been approved in the United States for OIC in adult patients with chronic noncancer pain [18]. However, efficacy has also been shown for treatment of OIC in cancer patients [19], and naldemedine can be used off label in this population. The European Medicines Agency has approved naldemedine for treatment of OIC without restriction to noncancer pain [20]. (See "Cancer pain management with opioids: Prevention and management of side effects", section on 'Other oral agents'.)

Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer (March 2017)

In a phase III trial, enrolling approximately 550 patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have responded to platinum-based chemotherapy, niraparib maintenance improved progression-free survival relative to placebo, although over a third experienced severe hematologic toxicity [21]. Based on these results, the US Food and Drug Administration (FDA) has approved niraparib for the maintenance treatment of such patients [22]. However, overall survival data are still immature and niraparib has not been compared with bevacizumab, which is better studied in the maintenance setting. Pending further data, we reserve use of niraparib maintenance for patients with relapsed ovarian cancer who are not candidates for bevacizumab and who are in a complete or partial response to platinum-based chemotherapy. (See "Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinum-sensitive disease".)

Baricitinib, an oral JAK-1/JAK-2 inhibitor for the treatment of rheumatoid arthritis (March 2017)

A series of recent randomized trials have documented the efficacy and relative safety of baricitinib, a small molecule, orally administered, Janus kinase (JAK)-1 and JAK-2 inhibitor, as a treatment for rheumatoid arthritis (RA). These include a trial involving almost 600 patients with active RA who were naïve (or had minimal exposure) to both conventional nonbiologic disease-modifying antirheumatic drugs (DMARDs) and biologic DMARDs, in which baricitinib was superior to methotrexate as monotherapy [23]; a trial involving almost 700 patients with inadequate responses to prior DMARD therapy, in which responses were greater with the addition of baricitinib compared with placebo [24]; and a trial involving over 1300 patients with active RA and an inadequate response to methotrexate (MTX), in which the addition of baricitinib was more effective than adalimumab and placebo [25]. Baricitinib was associated with minor increases in serum creatinine and LDL cholesterol and small reductions in blood neutrophil counts. Baricitinib has been approved in Europe for use either alone or in combination with MTX and is undergoing regulatory review in the United States. (See "Cytokine networks in rheumatic diseases: Implications for therapy", section on 'Baricitinib'.)

Telotristat for refractory carcinoid syndrome diarrhea (March 2017)

Telotristat inhibits the production of serotonin by carcinoid tumors and reduces the frequency of carcinoid syndrome diarrhea. The randomized TELESTAR trial compared two doses of oral telotristat (250 mg and 500 mg, each taken three times daily) against placebo in 135 patients who had uncontrolled symptoms from carcinoid syndrome despite treatment with a somatostatin analog [26]. Treatment with telotristat at either dose was associated with a reduction in bowel movement frequency compared with placebo, and the drug was well tolerated. Based upon these results, telotristat has been approved in the United States, in combination with somatostatin analog therapy, for the treatment of adults with diarrhea related to carcinoid syndrome that is inadequately controlled by somatostatin analog therapy alone [27]. The recommended dose is 250 mg three times daily [28]. (See "Treatment of the carcinoid syndrome", section on 'Telotristat'.)

Brodalumab for moderate to severe plaque psoriasis (February 2017)

Brodalumab, an anti-IL-17 receptor A monoclonal antibody, is a new addition to the armamentarium of highly effective biologic therapies for psoriasis. In February 2017, the US Food and Drug Administration approved brodalumab for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy and have failed to respond or have lost response to other systemic therapies [29]. Approval of brodalumab was based upon data from three randomized trials (AMAGINE-1, AMAGINE-2, and AMAGINE-3) that found brodalumab more effective than placebo [30,31]. However, suicidal ideation and behavior occurred in a small number of patients treated with brodalumab. As a result, the drug will only be available in the United States through a Risk Evaluation and Mitigation Strategy program designed to identify patients who develop new or worsening symptoms of depression or suicidality. (See "Treatment of psoriasis", section on 'Brodalumab'.)

Bezlotoxumab for secondary prevention of C. difficile infection (February 2017)

Bezlotoxumab is a monoclonal antibody against Clostridium difficile toxin B (which is essential for the virulence of the organism) that received US Food and Drug Administration approval in 2016 for secondary prevention of C. difficile infection in patients at high risk for recurrence. In two randomized trials including more than 2500 patients with C. difficile infection, the addition of bezlotoxumab to standard oral antibiotic therapy lowered the rate of recurrence (16 to 17 versus 26 to 28 percent with antibiotics alone) [32]. However, further evaluation to identify those who would be most likely to benefit is needed to define the optimal role of bezlotoxumab relative to other approaches to C. difficile infection treatment, including fecal microbiota transplant. (See "Clostridium difficile in adults: Treatment", section on 'Alternative therapies'.)

Nusinersen for spinal muscular atrophy (January 2017)

Nusinersen, an antisense oligonucleotide, is the first drug approved to treat spinal muscular atrophy (SMA) by the US Food and Drug Administration (FDA). In an interim analysis of the double-blind ENDEAR trial, which enrolled 82 infants with SMA, improvement in motor milestones was observed in 40 percent of patients treated with intrathecal nusinersen, versus none for those who received the sham procedure [33]. The FDA based its approval upon data from this trial and open-label studies in older patients with SMA [34,35]. We recommend nusinersen for most infants with SMA and select children ages 2 to 12 years with SMA. (See "Spinal muscular atrophy", section on 'Nusinersen'.)

Dosing interval for zoledronic acid in patients with bone metastases (January 2017)

For patients with bone metastases from a solid tumor, the approved dose and schedule of administration for zoledronic acid to reduce the frequency of skeletal-related events (SREs) is 4 mg every three to four weeks. Less frequent dosing is supported by data from CALGB (Alliance) trial 70604, which randomly assigned 1822 patients with bone metastases from breast or prostate cancer or multiple myeloma to the same dose of zoledronic acid every 4 or every 12 weeks for two years, starting with the first dose. There was no difference in the proportion of patients who developed at least one SRE (29.5 versus 28.6 percent) [36]. There are now sufficient data in breast and castration-resistant prostate cancer to support dosing of zoledronic acid every 12 rather than every 4 weeks, and we suggest this approach for most patients. We still prefer every-four-week dosing, at least initially, for patients who have extensive or highly symptomatic bone metastases. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Dosing interval'.)

Rucaparib in BRCA mutation-associated advanced ovarian cancer (January 2017)

Poly-ADP ribose polymerase (PARP) inhibitors have activity against BRCA mutation-associated epithelial ovarian cancer. The PARP inhibitor rucaparib is now approved by the US Food and Drug Administration for BRCA mutation-associated advanced ovarian cancer that has been treated with two or more lines of chemotherapy, based on response rates of over 50 percent in such cancers [37,38]. We now offer rucaparib as an option in this setting. (See "Medical treatment for relapsed epithelial ovarian, fallopian tubal, or peritoneal cancer: Platinum-resistant disease", section on 'Patients with a BRCA mutation'.)

Tenofovir alafenamide for the treatment of chronic hepatitis B virus infection (December 2016)

Tenofovir disoproxil fumarate is a first-line therapy for chronic hepatitis B virus (HBV) infection. A newer formulation of tenofovir, tenofovir alafenamide, was approved by the US Food and Drug Administration in November 2016 for the treatment of chronic HBV in patients with compensated liver disease [39]. In two large randomized noninferiority trials among patients with chronic HBV infection (both treatment-naive and experienced, and including patients positive or negative for HBV e antigen), tenofovir alafenamide resulted in similar rates of HBV suppression and fewer adverse effects on renal function and bone density at 48 weeks compared with tenofovir disoproxil fumarate [40,41]. Given these findings, tenofovir alafenamide is our preferred formulation for patients with chronic HBV who initiate therapy with tenofovir. We also favor switching those initially started on tenofovir disoproxil fumarate to tenofovir alafenamide. Given limited available safety data, we do not currently use tenofovir alafenamide in pregnant women. (See "Hepatitis B virus: Overview of management", section on 'Nucleos(t)ide analogues'.)

Topical crisaborole for atopic dermatitis (December 2016)

A topical preparation containing 2% crisaborole, an investigational boron-based, small-molecule, phosphodiesterase-4 inhibitor, was approved by the US Food and Drug Administration in December 2016 for the treatment of mild to moderate atopic dermatitis in patients two years of age and older [42]. In four-week clinical trials, topical crisaborole was more effective than placebo in reducing pruritus, skin inflammation, excoriation, and lichenification. However, trials comparing topical crisaborole with other topical treatments for atopic dermatitis are lacking. (See "Treatment of atopic dermatitis (eczema)", section on 'Crisaborole'.)

Iloprost therapy for severe frostbite (December 2016)

For years, no effective therapy was available to prevent tissue necrosis and subsequent amputation in patients with severe frostbite, but an increasing body of evidence suggests that treatment with iloprost, a prostacyclin analog (IV formulation not available in the United States) can prevent such injury in appropriately selected patients. According to one open-label randomized trial [43], a growing number of case reports [44], and revised management recommendations from wilderness medicine experts [45], treatment with iloprost is effective and safe. We suggest treatment with iloprost (where available), with or without tPA, for patients with severe frostbite (Grade 2-4) if given within 48 hours of the initial insult. (See "Frostbite", section on 'Prostacyclin therapy for severe injury presenting within 48 hours'.)

Vaginal prasterone for dyspareunia in postmenopausal women (November 2016)

In November 2016, the US Food and Drug Administration approved the use of prasterone (also known as dehydroepiandrosterone [DHEA]) for treatment of dyspareunia in women with vulvovaginal atrophy (VVA) due to menopause [46]. In an earlier randomized trial of women with VVA and moderate to severe dyspareunia, 12 weeks of daily intravaginal DHEA resulted in improved scores for pain during sexual activity and other key domains of female sexual function (desire, arousal, lubrication, orgasm, satisfaction) compared with placebo [47]. However, patients may find daily dosing more cumbersome than twice-weekly dosing with vaginal estrogen preparations. (See "Treatment of genitourinary syndrome of menopause (vulvovaginal atrophy)", section on 'Dehydroepiandrosterone (prasterone)'.)

Ustekinumab for anti-TNF refractory Crohn disease (November 2016)

Ustekinumab is approved for use in adult patients with moderate to severely active Crohn disease who have failed conventional therapy, but efficacy in inducing clinical remission in patients with disease refractory to anti-tumor necrosis factor (anti-TNF) therapy had not been previously established. In two randomized induction trials, approximately 1300 patients with Crohn disease and nonresponse or intolerable side effects to anti-TNF therapy were assigned to eight weeks of intravenous ustekinumab or placebo [48]. Those who responded to ustekinumab were assigned to 44 weeks of subcutaneous maintenance with ustekinumab or placebo. Patients assigned to ustekinumab had significantly higher clinical response rates at week six and rates of remission at week 44 as compared with placebo, demonstrating a role for ustekinumab in patients who have failed anti-TNF therapy. (See "Overview of the medical management of severe or refractory Crohn disease in adults", section on 'Ustekinumab'.)

Adalimumab for noninfectious uveitis (November 2016)

Patients with noninfectious uveitis can benefit from effective and safe glucocorticoid-sparing therapy. Two well-designed, randomized trials showed that adalimumab was effective in the treatment of noninfectious intermediate, posterior, and pan-uveitis [49,50]. In these trials, adalimumab improved the time-to-treatment failure in patients with uveitis who followed a tapering schedule for oral glucocorticoids. Both the European Medicines Agency and the US Food and Drug Administration recommended approval of adalimumab for adults with these forms of uveitis. (See "Uveitis: Treatment", section on 'Anti-tumor necrosis factor-alpha'.)

ADVERSE REACTIONS AND WARNINGS

HBV reactivation during HCV antiviral therapy (May 2017)

Reactivation of hepatitis B virus (HBV) can occur during direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection. Among 29 cases reported to the US Food and Drug Administration (FDA) or described in the literature between 2013 and 2016, reactivation occurred at an average of 53 days into DAA treatment and was not associated with a particular HCV genotype or DAA regimen [51]. Two cases were fatal, and one patient required liver transplant. Patients should be tested for HBV coinfection prior to initiation of HCV therapy, with HBV treatment initiated for those who meet criteria (table 1). HBV coinfected patients who do not initially meet HBV treatment criteria should be monitored for reactivation during HCV treatment. (See "Patient evaluation and selection for antiviral therapy for chronic hepatitis C virus infection", section on 'HBV coinfection' and "Overview of the management of chronic hepatitis C virus infection", section on 'Monitoring during antiviral therapy'.)

Safety warnings issued for codeine and tramadol in breastfeeding women and children under age 12 years (April 2017)

The US Food and Drug Administration (FDA) issued a strong warning to restrict use of codeine and tramadol in breastfeeding women and children <12 years old because of increasing reports of life-threatening respiratory depression in young children exposed to these drugs [52]. Children who are ultra-rapid metabolizers metabolize these drugs faster than normal, leading to dangerously high levels of active drug. We suggest avoiding codeine and tramadol in breastfeeding women and children <12 years old. (See "Evaluation and management of pain in children", section on 'Agents not recommended'.)

Adverse events with short-term oral glucocorticoid use in adults (April 2017)

Chronic steroid use is associated with a wide spectrum of adverse effects. However, there is a paucity of clinical data on the adverse effects associated with short-term use. A retrospective cohort study and self-controlled case series assessed the risk of three adverse events (sepsis, venous thromboembolism [VTE], and fracture) in over 300,000 adults younger than 65 who received at least one short-term (<30 days) outpatient prescription for oral glucocorticoids over a three-year period [53]. The most common indications for use were upper respiratory tract infections, spinal conditions, and allergies. Within 30 days of drug initiation, there was a two- to fivefold increase in the rates of sepsis, VTE, and fracture, which then decreased over the subsequent 31 to 90 days. These findings suggest that even short courses of oral steroids are associated with adverse effects that should be considered before prescribing. (See "Major side effects of systemic glucocorticoids", section on 'Dose effects'.)

2011 shortage of norepinephrine in the United States and septic shock outcome (April 2017)

The impact of a shortage of norepinephrine in the United States in 2011 on vasopressor agent selection was recently highlighted in a study of 28,000 patients with sepsis. When norepinephrine (first-line agent) was in short supply, phenylephrine was the most frequent alternative agent chosen, during which time mortality rates from septic shock also rose (36 to 40 percent) [54]. While there is little guidance for selecting a second-line vasopressor agent in patients with sepsis, phenylephrine should continue to be avoided, when feasible. (See "Evaluation and management of suspected sepsis and septic shock in adults", section on 'Vasopressors'.)

Concurrent benzodiazepines in opioid-using patients and overdose risk (April 2017)

Benzodiazepines can potentiate the respiratory depressant effects of opioid medication, and concurrent use may be a factor in the rising rate of opioid overdose. In an analysis of a large sample of patients prescribed an opioid, the proportion who concurrently received a benzodiazepine nearly doubled over 12 years [55]. Concurrent use of both medications was associated with an increased risk of opioid overdose compared with patients receiving only the opioid. Avoiding this medication combination may prevent some overdoses. (See "Prevention of lethal opioid overdose in the community", section on 'Risk factors'.)

Switching MI patients from ticagrelor to clopidogrel (March 2017)

The potent platelet P2Y12 receptor blocker ticagrelor, rather than clopidogrel, is initiated in hospital for many patients with myocardial infarction. However, some of these individuals will need to switch to clopidogrel either before or after hospital discharge for a variety of reasons, including cost, bleeding risk, and nonbleeding side effects (eg, dyspnea). The optimal strategy to make the switch while avoiding a subtherapeutic antiplatelet effect is not known. This issue was addressed in a randomized trial comparing the pharmacodynamic effects of switching from ticagrelor to clopidogrel with or without a loading dose of clopidogrel [56]. The study identified a period of time after the first dose of clopidogrel (12 hours after the last dose of ticagrelor) when there was greater antiplatelet effect with the loading dose than without. Based on this pharmacodynamic study, we give a clopidogrel loading dose of 600 mg at 12 hours when switching from ticagrelor to clopidogrel therapy. (See "Antiplatelet agents in acute non-ST elevation acute coronary syndromes", section on 'Switching from a P2Y12 agent to clopidogrel' and "Antiplatelet agents in acute ST elevation myocardial infarction", section on 'Switching from a P2Y12 agent to clopidogrel'.)

Antipsychotic drugs and risk of falls and fracture (March 2017)

In a large, population-based sample of Finnish people with Alzheimer disease, new users of antipsychotic medication had an increased risk of hip fractures from the first days of use [57]. Subsequent to multiple similar reports in patients with varied disorders, the US Food and Drug Administration (FDA) issued a warning that antipsychotic drugs may cause falls and fractures as a result of somnolence, postural hypotension, and/or motor and sensory instability, and recommended that a fall risk assessment be completed when initiating antipsychotic treatment and recurrently for patients continuing on long-term antipsychotics. (See "Second-generation antipsychotic medications: Pharmacology, administration, and side effects", section on 'Falls'.)

Differences in anaphylaxis treatment by age (February 2017)

Epinephrine given by intramuscular (IM) injection is the treatment of choice for anaphylaxis, but clinicians are sometimes reluctant to administer it, particularly to older adults. In a retrospective study of nearly 500 children and adults with anaphylaxis presenting to the emergency department, patients >50 years of age were less likely to receive epinephrine (36 versus 61 percent) compared with younger patients [58]. In addition, among patients who were given epinephrine, older adults were more likely to receive excessive doses when epinephrine was administered intravenously (IV). IM epinephrine was well-tolerated by patients of all ages, while IV administration was associated with a higher rate of cardiovascular complications. These findings support our recommendations to administer epinephrine by IM injection whenever possible and reserve IV administration for refractory cases. (See "Anaphylaxis: Emergency treatment", section on 'Situations requiring caution'.)

High-risk drug prescribing in adults with dementia (February 2017)

Older adults with dementia are at heightened risk for adverse drug effects from anticholinergic drugs, benzodiazepines, and opioids, among many others. Despite these risks, polypharmacy remains common in this population. In a study that included over 75,000 adults with dementia, 44 percent of patients were prescribed at least one potentially unsafe medication (mostly drugs with high anticholinergic activity), and rates were consistently higher in patients receiving care from multiple providers [59]. These results highlight the need for careful monitoring of drug therapy in patients with dementia and the importance of communication among providers before starting new therapies. (See "Safety and societal issues related to dementia", section on 'Polypharmacy'.)

Metformin use in patients with diabetes and renal impairment, heart failure, or chronic liver disease (January 2017)

In a systematic review of 17 observational studies comparing diabetes regimens with and without metformin, metformin use was associated with lower all-cause mortality among patients with heart failure, renal impairment, or chronic liver disease with hepatic impairment [60]. In addition, metformin use in patients with renal impairment or heart failure was associated with fewer heart failure readmissions. This study supports a recent US Food and Drug Administration (FDA) labeling revision for metformin, which will increase use in patients with renal impairment. Metformin remains contraindicated in patients with estimated glomerular filtration rate (eGFR) <30 mL/min, concurrent active or progressive liver disease, or unstable or acute heart failure with risk of hypoperfusion and hypoxemia. Recommendations regarding metformin use in patients with an eGFR between 30 and 45 mL/min vary and UpToDate authors individualize decisions about metformin use in such patients. (See "Metformin in the treatment of adults with type 2 diabetes mellitus", section on 'Contraindications'.)

Relative cardiovascular safety of celecoxib, naproxen, and ibuprofen (December 2016)

The cardiovascular (CV) safety of celecoxib, the COX-2 selective nonsteroidal anti-inflammatory drug (NSAID), compared with other NSAIDs, is a matter of debate. In a randomized trial (PRECISION) involving over 24,000 patients with arthritis and either known CV disease or CV risk factors, the CV safety of celecoxib was noninferior to both naproxen and ibuprofen, two nonselective NSAIDs [61]. Depending upon the analysis, about 2 to 5 percent of subjects experienced a CV event during follow-up, which was slightly lower than the expected event rate. Despite some limitations, this trial suggests that celecoxib in moderate doses can be administered, when indicated, without concern about increased CV risk compared with the nonselective nonsteroidal agents naproxen and ibuprofen. (See "COX-2 selective inhibitors: Adverse cardiovascular effects", section on 'Celecoxib' and "Nonselective NSAIDs: Adverse cardiovascular effects", section on 'Risk of myocardial infarction, stroke, and death'.)

FDA issues warning about anesthesia for pregnant patients and children under three years of age (December 2016)

The US Food and Drug Administration has warned about potential negative effects on the developing brain from administration of anesthetics and sedatives to pregnant women and children under age three, especially for repeated exposures or procedures lasting more than three hours [62]. However, the degree of risk remains unclear. A single, brief exposure to anesthesia probably does not cause neurotoxicity in healthy young children. Further study is required to determine the effects of prolonged or repeated anesthetics, variability among anesthetic agents and combinations of drugs, and patient factors that may confer vulnerability to anesthetic neurotoxicity. At present, there is no compelling evidence that any specific anesthetic agent should be avoided during pregnancy or in young children, or that necessary surgery should be delayed because of concerns about neurotoxicity. (See "Management of the pregnant patient undergoing nonobstetric surgery", section on 'Fetal brain development'.)

FDA warning removed from varenicline for smoking cessation (December 2016)

In 2009, the US Food and Drug Administration (FDA) required varenicline packaging to include a boxed warning about potential neuropsychiatric side effects, but this warning has been removed in 2016 [63], based on results of a randomized trial that found no difference in adverse neuropsychiatric events comparing varenicline with nicotine patch or placebo in patients with or without a coexisting psychiatric disorder [64]. As with any medication, we advise that patients should be told to contact their clinician if they or their family notice any unusual behavior or mood symptoms as well as any new or worsening symptoms of cardiovascular disease. (See "Pharmacotherapy for smoking cessation in adults", section on 'Safety'.)

Ibrutinib and Pneumocystis pneumonia (December 2016)

The Bruton tyrosine kinase inhibitor ibrutinib has not clearly been associated with an increased risk of opportunistic infections, but cases have been reported. In a series of 96 patients receiving ibrutinib as the sole agent for chronic lymphocytic leukemia (CLL), five were reported to have Pneumocystis pneumonia [65]. All of the infections were grade ≤2 and resolved with oral trimethoprim-sulfamethoxazole. A limitation is that the diagnoses were made by polymerase chain reaction (PCR) of bronchoalveolar lavage fluid, which could represent a false positive in the setting of colonization with Pneumocystis. Nevertheless, clinicians should have a high index of suspicion for Pneumocystis pneumonia in patients receiving ibrutinib, and the diagnosis should be sought in those with compatible signs and symptoms. (See "Risk of infections in patients with chronic lymphocytic leukemia", section on 'Ibrutinib' and "Prevention of infections in patients with chronic lymphocytic leukemia", section on 'Ibrutinib and idelalisib'.)

Type 1 diabetes mellitus and anti-PD-1 immunotherapy (December 2016)

Checkpoint inhibitor immunotherapy with an anti-programmed cell death 1 (PD-1) receptor antibody, often in conjunction with ipilimumab, has resulted in the acute onset of type 1 diabetes mellitus in rare cases. This may be manifested by severe hyperglycemia or diabetic ketoacidosis [66]. These patients have remained insulin-dependent for diabetic control following management of their acute episode. Blood glucose is typically monitored weekly during the first 12 weeks of therapy with the combination of nivolumab plus ipilimumab. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Type 1 diabetes mellitus'.)

Combination antiretroviral treatment in pregnancy (November 2016)

Combination antiretroviral treatment (ART) has become the worldwide standard of care for HIV-infected pregnant women, both for their own health and for prevention of HIV transmission to their infants. In a large randomized trial of HIV-infected pregnant women in Africa and India, antepartum ART (with one of two different protease inhibitor-based regimens) resulted in lower transmission rates compared with zidovudine plus single-dose nevirapine (0.5 versus 1.8 percent) [67]. Rates of preterm birth at <37 weeks were higher with the ART regimens than with zidovudine, but more significant prematurity (<34 weeks) and neonatal deaths were not increased. Clinicians should discuss with patients the potential risk for adverse pregnancy outcome with certain ART regimens. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Preterm birth'.)

Cardiotoxicity of checkpoint inhibitor immunotherapy (November 2016)

Checkpoint inhibitor immunotherapy for melanoma and other cancers may result in severe or fatal cardiotoxicity, even in the absence of a history of significant cardiac risk factors [68]. High-dose steroids are indicated to treat myositis and other cardiac complications, but symptoms may progress in some cases despite steroids. The early institution of more aggressive immunosuppressive therapy and monitoring should be considered for patients without an immediate response to high-dose steroids. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Cardiotoxicity'.)

VACCINES

Missed opportunity for MMR vaccination during pretravel consultation (May 2017)

Measles is a highly contagious viral illness spread by respiratory droplets; complications include pneumonia, otitis media, and encephalitis. Travelers are at risk for measles infection, and measles, mumps, and rubella (MMR) vaccination is recommended for all international travelers without evidence of immunity. However, in a retrospective review including more than 6600 adults who visited a United States pretravel clinic and were eligible for MMR vaccine, fewer than half of these individuals received it during the consultation [69]. The pretravel visit provides an important opportunity to reduce the likelihood of importation and transmission of measles by ensuring that MMR vaccination (in addition to other routine immunizations) is current. (See "Immunizations for travel", section on 'Measles, mumps, and rubella'.)

Maternal Tdap vaccination and prevention of infant pertussis (May 2017)

Immunization with the tetanus, diphtheria, and acellular pertussis (Tdap) vaccine is recommended for women during each pregnancy in order to provide passive protection against pertussis to their infants. Although passive transfer of maternal antibodies can blunt the infant's own immune response to infant doses of the diphtheria, tetanus toxoids, and acellular pertussis (DTaP) vaccine, it does not appear to interfere with clinical vaccine efficacy. In a retrospective study of nearly 150,000 infants at every level of DTaP vaccine exposure, infants exposed in utero to Tdap vaccine were better protected against pertussis during the first year of life than infants not exposed in utero [70]. (See "Immunizations during pregnancy", section on 'Rationale, efficacy, and safety'.)

Pregnancy outcomes with HPV vaccination (March 2017)

Human papillomavirus (HPV) vaccination during pregnancy is not recommended, but mounting evidence suggests that it is safe. In a large cohort study from Denmark, the risks of spontaneous abortion, major birth defects, preterm birth, and low birth weight were comparable among women who received quadrivalent HPV vaccine during pregnancy (mostly during the first trimester) and matched controls who did not [71]. Women who inadvertently receive HPV vaccine during pregnancy can be reassured that it does not increase their risk of adverse pregnancy or fetal outcomes. (See "Immunizations during pregnancy", section on 'Human papillomavirus'.)

High-dose influenza vaccine in older adults (March 2017)

For influenza vaccination of adults ≥65 years of age, we recommend the high-dose inactivated influenza vaccine, which has previously been shown to be more immunogenic and modestly more effective at preventing influenza infection than the standard-dose vaccine. In a study of United States Medicare beneficiaries ≥65 years of age, the high-dose vaccine was more effective than the standard-dose vaccine for preventing postinfluenza death during the 2012-2013 influenza season, a season when circulation of H3N2 influenza A (a strain associated with severe disease) was common [72]. In contrast, it was not more effective for preventing postinfluenza death during the following season, when H1N1 influenza A (a strain associated with mild disease) predominated. This difference was likely due to the difficulty in demonstrating benefit during a mild influenza season, when death is a rare outcome. The high-dose vaccine was associated with a reduced risk of hospitalization during both seasons. (See "Seasonal influenza vaccination in adults", section on 'High-dose vaccine'.)

Recommended immunization schedule—United States, 2017 (March 2017)

The Advisory Committee on Immunization Practices has released the 2017 recommended immunization schedule for children and adolescents in the United States [73,74]. New recommendations include the following:

All infants should now receive monovalent hepatitis B vaccine within 24 hours of birth; earlier recommendations allowed some infants born to hepatitis B surface antigen-negative mothers to receive the vaccine after discharge. (See "Hepatitis B virus immunization in infants, children, and adolescents", section on 'Mother's HBsAg status unknown, birth weight ≥2 kg'.)

When administered during pregnancy, the tetanus and diphtheria toxoids and acellular pertussis (Tdap) vaccine should be given as early as possible between 27 and 36 weeks of gestation. (See "Immunizations during pregnancy", section on 'Tetanus, diphtheria, and pertussis vaccination'.)

For individuals receiving the meningococcal serogroup B vaccine MenBFHbp (Trumenba), two doses are recommended for healthy adolescents and young adults who are not at increased risk for meningococcal disease. Three doses are recommended for individuals ≥10 years of age at increased risk for meningococcal disease and for use during serogroup B meningococcal disease outbreaks (table 2). Previously, three doses were recommended for all recipients. The dosing frequency and interval for the other serogroup B vaccine, MenB-4C (Bexsero), have not changed. (See "Meningococcal vaccines", section on 'Serogroup B meningococcus vaccines'.)

Meningococcal conjugate vaccination for HIV-infected patients (November 2016)

Growing evidence has suggested that HIV-infected individuals have a disproportionate incidence of invasive meningococcal disease, with an estimated risk 5 to 13 times that of the general population. Because of this, the Centers for Disease Control and Prevention in the United States now recommends meningococcal conjugate vaccination (with MenACWY-CRM [Menveo] or MenACWY-D [Menactra]) for all HIV-infected individuals older than two months [75]. This includes a primary vaccine series for those who have not previously received it and interval booster doses every several years; the precise schedule depends on the age of the patient (table 2). Individuals may also have separate indications for serogroup B meningococcal vaccination. Evidence of vaccine efficacy in HIV-infected patients is limited to immunologic outcomes. (See "Immunizations in HIV-infected patients", section on 'Meningococcal vaccine' and "Meningococcal vaccines".)

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