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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/.
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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 . (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 . 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
Confirmatory data on idarucizumab for dabigatran reversal (July 2017)
Idarucizumab (pronounced "I-dare-you-cizumab") is a monoclonal antibody fragment against dabigatran that can reverse the anticoagulant effect within minutes. A preliminary report suggested good efficacy in patients with dabigatran-associated bleeding or those undergoing emergency surgery. In a new report of over 500 patients treated with idarucizumab, most had cessation of bleeding or underwent surgery without abnormal bleeding . We continue to suggest idarucizumab for clinically significant bleeding or truly emergent surgery in patients on dabigatran with a history or laboratory testing that suggest they are actively anticoagulated. (See "Management of bleeding in patients receiving direct oral anticoagulants", section on 'Dabigatran reversal'.)
Lenvatinib for advanced hepatocellular cancer (July 2017)
The benefits of first-line sorafenib for advanced hepatocellular cancer (HCC) are modest. A randomized noninferiority trial (the REFLECT study) compared lenvatinib versus sorafenib in over 900 patients with unresectable HCC and no prior systemic therapy . In a preliminary report presented at the 2017 annual meeting of the American Society of Clinical Oncology (ASCO), lenvatinib was noninferior in terms of median overall survival, and both the objective response rate and time to tumor progression were significantly better. Rates of grade 3 or 4 hypertension were higher with lenvatinib, while hand-foot skin reaction was more frequent with sorafenib. Lenvatinib represents a reasonable first-line treatment alternative to sorafenib, especially for patients who cannot tolerate sorafenib. (See "Systemic treatment for advanced hepatocellular carcinoma", section on 'Lenvatinib'.)
Delafloxacin for treatment of skin and soft tissue infections (July 2017)
Delafloxacin, a fluoroquinolone, has been approved by the US Food and Drug Administration for treatment of bacterial skin and soft tissue infections. It has activity against staphylococci (including methicillin-resistant strains), gram-negative bacteria (including Pseudomonas aeruginosa and Enterobacteriaceae), and some anaerobes (including Clostridium difficile) but does not have activity against enterococci. In two phase III clinical trials, the drug was statistically noninferior to the combination of vancomycin and aztreonam at the endpoint of early clinical response at 48 to 72 hours [6,7]. Given limited clinical experience with delafloxacin, at this time its use should be reserved for patients who do not respond to or do not tolerate first-line antimicrobial agents. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections", section on 'Delafloxacin'.)
New oral direct factor Xa inhibitor betrixaban approved (June 2017)
The US Food and Drug administration has approved a new oral direct factor Xa inhibitor, betrixaban, for venous thromboembolism prophylaxis in acutely ill medical patients . Betrixaban (brand name Bevyxxa) is taken at a dose of 160 mg on day 1 followed by 80 mg once daily for the duration of thromboprophylaxis. In a trial in which over 7500 patients hospitalized for an acute medical illness were randomly assigned to receive betrixaban or the low molecular weight heparin enoxaparin for 35 to 42 days, betrixaban was associated with a trend towards greater efficacy and a similar risk of bleeding compared with enoxaparin. (See "Direct oral anticoagulants and parenteral direct thrombin inhibitors: Dosing and adverse effects" and "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults".)
Subcutaneous formulation of rituximab for certain lymphomas (June 2017)
Most studies evaluating the efficacy of the anti-CD20 monoclonal antibody rituximab in the treatment of B-cell lymphomas have utilized intravenous administration. A subcutaneous formulation (rituximab-hyaluronidase) has been developed, which can be administered over a shorter time and uses a fixed dose that varies with histology and chemotherapy regimen. Randomized trials have demonstrated comparable efficacy and safety of the two formulations in patients with follicular lymphoma, diffuse large B cell lymphoma, or chronic lymphocytic leukemia [9-11]. The subcutaneous formulation (rituximab-hyaluronidase) is now an option for patients with these lymphoma subtypes who have tolerated at least one full dose of intravenous rituximab . (See "Initial treatment of advanced stage (III/IV) follicular lymphoma", section on 'Immunotherapy-based treatment'.)
Dupilumab for moderate to severe atopic dermatitis (June 2017)
Dupilumab is an interleukin (IL)-4 receptor alpha antagonist approved by the US Food and Drug Administration (FDA) for adults with moderate to severe atopic dermatitis not adequately controlled with topical therapies. In a phase III trial of over 700 patients with moderate to severe atopic dermatitis and inadequate response to topical corticosteroids, one year of treatment with dupilumab improved symptoms relative to placebo . All patients received topical corticosteroids or topical calcineurin inhibitors. These results support the use of dupilumab for the long-term treatment of moderate to severe atopic dermatitis when topical therapies alone are insufficient and other systemic treatments are contraindicated. (See "Treatment of atopic dermatitis (eczema)", section on 'Dupilumab'.)
Countering the high cost of epinephrine autoinjectors (June 2017)
Physicians and patients in the United States have been struggling with the high cost of epinephrine autoinjectors, and alternatives, as well as ways to maximize the utility of expensive devices, have begun to appear:
●A prefilled syringe (Symjepi) containing 0.3 mg epinephrine per dose was approved by the US Food and Drug Administration (FDA) in June 2017 and should offer a more affordable alternative to autoinjectors . It will be available in upcoming months in just one dose, labeled for use in patients weighing ≥30 kg (66 lbs). (See "Prescribing epinephrine for anaphylaxis self-treatment", section on 'Prefilled syringes'.)
●A study of 31 expired autoinjectors (EpiPens) found that devices as much as four years past the expiration date still contained 84 to 88 percent of the intended epinephrine dose . Thus, patients should understand that expired devices retain most of their potency and that if anaphylaxis develops, using an outdated device is preferable to not injecting epinephrine at all. (See "Prescribing epinephrine for anaphylaxis self-treatment", section on 'Use of expired autoinjectors'.)
Adjuvant pertuzumab for HER2-positive breast cancer (June 2017)
While pertuzumab has shown benefit in the neoadjuvant setting for high-risk HER2-positive breast cancer, its role in the adjuvant setting is just now emerging. In the phase III APHINITY trial, over 4800 patients with HER2-positive breast cancer who were treated with adjuvant chemotherapy and trastuzumab were randomly assigned to pertuzumab (concurrent with trastuzumab) or placebo . At a median follow-up of approximately 45 months, patients receiving pertuzumab had higher three-year invasive disease-free survival rates (94 versus 93 percent), with the greatest benefit for those with node-positive disease. Given this trial, we now suggest the addition of adjuvant pertuzumab for women with node-positive disease or larger, node-negative tumors (>2 cm). However, some patients may reasonably choose against additional treatment, given the added toxicities of pertuzumab and lack of demonstrated overall survival benefit. (See "Adjuvant systemic therapy for HER2-positive breast cancer", section on 'Addition of pertuzumab for high-risk disease'.)
New once-daily raltegravir formulation (June 2017)
For patients with HIV infection, the most effective antiretroviral therapy regimens contain two different nucleoside reverse transcriptase inhibitors and an integrase strand transfer inhibitor (INSTI). Raltegravir, the first available INSTI, has traditionally required twice-daily dosing. In the United States, a new raltegravir formulation that allows once-daily dosing (two 600 mg tablets once daily) has recently been approved for treatment-naïve patients . This approval continues to expand the treatment options for patients with newly diagnosed HIV infection, particularly when drug interactions limit the use of other once-daily INSTIs. (See "Selecting antiretroviral regimens for the treatment-naïve HIV-infected patient", section on 'Commonly used agents'.)
Ivacaftor for treatment of cystic fibrosis (June 2017)
Ivacaftor is an effective therapy for patients with cystic fibrosis caused by certain types of cystic fibrosis transmembrane regulator (CFTR) mutations. It is used in patients with G551D and nine other mutations. Now, the US Food and Drug Administration (FDA) has expanded the indications for ivacaftor treatment to include 23 additional mutations, based primarily on in vitro testing of responsiveness to ivacaftor [18,19]. We recommend treatment with ivacaftor for patients two years and older who carry at least one copy of G551D or another mutation listed in the table (table 1). (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Ivacaftor for G551D, other gating mutations, and residual function mutations'.)
Next-generation ALK-inhibitors in crizotinib-naive ALK-positive NSCLC (June 2017)
For patients with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), crizotinib has been administered as frontline therapy. However, newer agents have shown promising efficacy in advanced ALK-positive NSCLC:
●In a global trial of 303 patients randomly assigned to frontline crizotinib versus the next-generation inhibitor alectinib (ALEX), those receiving alectinib experienced a longer progression-free survival (PFS, not reached versus 11.1 months), with fewer toxicities, at a median follow-up of approximately 18 months . These results are consistent with an earlier Japanese trial .
●In a phase III trial of 376 patients comparing ceritinib, another next-generation ALK inhibitor, with pemetrexed and a platinum agent, ceritinib improved progression-free survival (17 versus 8 months) . Ceritinib has not been compared with crizotinib in the frontline setting.
For patients with newly diagnosed, ALK-positive NSCLC, we now recommend frontline therapy with alectinib. For those without access to alectinib, appropriate alternatives include crizotinib or ceritinib. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer".)
Subcutaneous C1 inhibitor for hereditary angioedema (April 2017, Modified June 2017)
Patients with hereditary angioedema (C1 inhibitor deficiency) develop attacks of angioedema affecting the skin, gastrointestinal tract, and airway, which can be prevented with intravenous infusions of C1 inhibitor, typically given twice weekly. Subcutaneous administration should significantly facilitate self-treatment. In a randomized multicenter trial of 90 children and adults, participants injected a subcutaneous formulation of C1 inhibitor or placebo twice weekly for 16 weeks . Therapy was well tolerated and participants receiving active drug had fewer attacks per month (mean 0.5 versus 4.0 attacks). This formulation was approved by the US Food and Drug Administration (FDA) in June 2017, and approval in Europe is anticipated in the near future. However, it is not yet available for clinical use. (See "Hereditary angioedema: General care and long-term prophylaxis".)
Brigatinib in crizotinib-refractory ALK-positive NSCLC (May 2017)
While the first generation anaplastic lymphoma kinase (ALK) inhibitor crizotinib is highly active in patients with ALK-positive non-small cell lung cancer (NSCLC), almost all patients develop resistance to the drug. In a phase II study of 222 patients with crizotinib-refractory, ALK-positive NSCLC receiving the next generation ALK inhibitor brigatinib, progression-free survival was 9.2 and 12.9 months, respectively, among those receiving a lower and higher dose of the agent . Although it has been associated with early pulmonary toxicity in approximately 9 percent of cases, brigatinib is now approved by the US Food and Drug Administration (FDA) for patients with ALK-positive metastatic NSCLC who have progressed on or are intolerant to crizotinib . We consider brigatinib or another next generation ALK inhibitor, ceritinib or alectinib, to be appropriate therapy in this setting. (See "Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section on 'Brigatinib'.)
Edaravone for amyotrophic lateral sclerosis (May 2017)
Edaravone is a free radical scavenger that is thought to reduce oxidative stress, which has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Edaravone may slow functional deterioration in some patients with ALS. An earlier trial found no benefit for edaravone compared with placebo, but a post-hoc analysis showed a possible treatment effect in a subgroup of individuals with early-stage ALS. A subsequent trial enrolled 137 Japanese patients within two years of ALS diagnosis who were living independently and had a forced vital capacity (FVC) of ≥80 percent . Compared with placebo, functional decline at 24 weeks was smaller in the edaravone group, and the difference was considered clinically meaningful. Edaravone was approved in 2015 for the treatment of ALS in Japan and Korea and has now received regulatory approval to treat patients with ALS in the United States . We now suggest edaravone for patients with early-stage disease as well as for those with more advanced disease, although the data are less compelling for the latter group. (See "Disease modifying treatment of amyotrophic lateral sclerosis", section on 'Edaravone'.)
Pembrolizumab immunotherapy for advanced non-small cell lung cancer (NSCLC) (May 2017)
Based upon the results of two randomized phase III trials, the US Food and Drug Administration (FDA) has approved pembrolizumab monotherapy as initial treatment for patients with advanced non-small cell lung cancer (NSCLC) lacking a driver mutation if programmed death ligand 1 (PD-L1) is expressed on at least 50 percent of tumor cells [28,29]. Pembrolizumab has also been approved for first line therapy of nonsquamous advanced NSCLC, in combination with carboplatin and pemetrexed, irrespective of PD-L1 expression. However, this regimen has not been compared with other platinum-based combinations incorporating concurrent and maintenance bevacizumab, which remain another option for such patients. Although we continue to prefer pembrolizumab monotherapy for patients whose tumors have ≥50 percent staining for PD-L1, and targeted agents for those with specific driver mutations (eg, in EGFR or ALK), we now offer the combination of carboplatin, pemetrexed, and pembrolizumab as one frontline treatment option for other patients with nonsquamous NSCLC. (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'Pembrolizumab' and "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'First-line setting'.)
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 . Overall mortality was not reduced. We now recommend administration of tranexamic acid as a component of the treatment for postpartum hemorrhage. (See "Postpartum hemorrhage: Medical and minimally invasive management".)
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 . 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 . 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 initial therapy of advanced urothelial carcinoma (April 2017, Modified May 2017)
The role of checkpoint inhibition immunotherapy for patients with advanced urothelial carcinoma is evolving. Pembrolizumab, an agent targeting the programmed cell death-1 (PD-1) protein, previously had been shown to prolong overall survival in patients who relapsed following chemotherapy and was approved in the United States for this indication. In an expanded phase II study of pembrolizumab as initial therapy for patients who were not candidates for cisplatin chemotherapy, the objective response rate was 29 percent and the median duration of response had not been reached . Based upon these results, pembrolizumab is now approved for first-line therapy in this setting. Atezolizumab had previously been approved for this indication. (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. In a phase III trial of over 700 patients, the multitargeted small molecule FLT3 inhibitor midostaurin improved 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 , 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 . 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 . 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) . 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 . 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 . 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 . 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 used to treat advanced Merkel cell carcinoma (MCC), although it has not been shown to prolong survival and has been associated with significant toxicity. 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 in patients who had received prior chemotherapy 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 [42,43]. Based upon these results, avelumab is our preferred treatment for the initial treatment of 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 . 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 . However, efficacy has also been shown for treatment of OIC in cancer patients , 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 . (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 . Based on these results, the US Food and Drug Administration (FDA) has approved niraparib for the maintenance treatment of such patients . 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 ; 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 ; 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 . 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 . 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 . The recommended dose is 250 mg three times daily . (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 . 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 [57,58]. 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) . 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'.)
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) . 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 [61,62]. 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'.)
ADVERSE REACTIONS AND WARNINGS
Psychiatric side effects of finasteride and dutasteride therapy (June 2017)
Concerns have been raised about possible psychiatric side effects of 5-alpha-reductase inhibitors for the management of benign prostatic hyperplasia. In a retrospective cohort study of over 90,000 men prescribed finasteride or dutasteride between 2003 and 2010, there was no increased risk of suicide compared with matched controls . However, 5-alpha-reductase inhibitors were associated with an increased risk of self-harm and depression during the initial 18 months of therapy. Discontinuation of these medications may be appropriate if depression develops. (See "Medical treatment of benign prostatic hyperplasia", section on 'Side effects'.)
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 . 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 2). 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 . 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 . 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) . 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 . 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 . 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 . 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 . 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 . 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 . 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'.)
Recombinant hemagglutinin influenza vaccine in older adults (June 2017)
Recombinant hemagglutinin influenza vaccines (Flublok and Flublok Quadrivalent) are produced using recombinant DNA technology and a baculovirus expression system rather than the traditional egg-based methods. In a randomized trial that included adults ≥50 years of age, Flublok Quadrivalent was more effective than the quadrivalent standard-dose inactivated vaccine for preventing influenza . Flublok Quadrivalent has not been compared directly with the high-dose inactivated vaccine, which has been found to be more effective than the standard dose inactivated vaccine in older adults (including a mortality benefit). Flublok Quadrivalent is a reasonable alternative to the high-dose vaccine for older adults. (See "Seasonal influenza vaccination in adults", section on 'Recombinant hemagglutinin vaccine'.)
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 . 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 . (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 . 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 . 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 [79,80]. 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 3). 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'.)
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