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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: Sep 2017. | This topic last updated: Oct 17, 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

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Thyroid hormone assay interference with biotin supplements (October 2017)

A growing number of reports have noted that ingestion of 5 to 10 mg of biotin (marketed over the counter to prevent hair loss) can cause artifactually low serum thyroid stimulating hormone (TSH) and high triiodothyronine (T3) and thyroxine (T4) in assays using biotin-streptavidin affinity systems in their design [1,2]. Thyroid tests should be repeated at least two days after discontinuation of biotin supplements. (See "Laboratory assessment of thyroid function", section on 'Assay interference with biotin ingestion'.)

Proton pump inhibitors may decrease absorption of capecitabine (July 2017)

Elevated gastric pH levels associated with use of proton pump inhibitors may alter dissolution and absorption of capecitabine and impair its efficacy. A secondary analysis of a large phase III study comparing capecitabine plus oxaliplatin with or without lapatinib for the treatment of advanced gastroesophageal cancer showed lower overall survival in patients who received concomitant proton pump inhibitors; a similar finding has been reported in patients receiving adjuvant capecitabine for colon cancer [3]. Patients who are receiving a capecitabine-containing regimen for any cancer should probably not take proton pump inhibitors concurrently. (See "Systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'Oral fluoropyrimidines' and "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Capecitabine'.)


Single-dose secnidazole for bacterial vaginosis (September 2017)

Metronidazole is a preferred treatment for bacterial vaginosis (BV) and is given topically or orally as a multi-day course. In September 2017, the US Food and Drug Administration approved secnidazole, a related oral antibiotic with a longer half-life, for the treatment of BV [4]. In an earlier study, a single dose of secnidazole was as effective as, but not superior to, metronidazole for seven days. Secnidazole is an option for BV when a single dose is desired (eg, to enhance adherence), but it is more expensive than other regimens. (See "Bacterial vaginosis: Treatment", section on 'Secnidazole'.)

Benznidazole approved for treatment of Chagas disease (September 2017)

Drugs with proven efficacy against Chagas disease in human trials are benznidazole and nifurtimox. Both drugs have been available in the United States through the Centers for Disease Control and Prevention (CDC) under investigational protocols. In August 2017 the US Food and Drug Administration (FDA) approved benznidazole for treatment of Chagas disease in children ages 2 to 12 years old [5]; use for other age groups is off-label. Benznidazole is expected to be commercially available in early 2018; until then, the CDC will continue to provide benznidazole under its existing investigational protocol. Nifurtimox has not received FDA approval but will continue to be available through the CDC. (See "Chagas disease: Antitrypanosomal drug therapy", section on 'Antitrypanosomal drugs'.)

Glecaprevir-pibrentasvir and sofosbuvir-velpatasvir-voxilaprevir for chronic HCV infection (August 2017)

Treatment options for patients with chronic hepatitis C virus (HCV) continue to grow. Two new combination therapies, glecaprevir-pibrentasvir and sofosbuvir-velpatasvir-voxilaprevir, were recently approved by the Food and Drug Administration in the United States and are expected to be approved in Europe this year. Glecaprevir-pibrentasvir is highly effective for patients with genotypes 1 through 6 infection, offers the possibility of an eight-week regimen for most patients without cirrhosis, and can be used in patients with renal impairment (including those on dialysis) [6-9]. It is now one of our preferred regimens for all genotypes; regimen duration depends on the genotype, the presence of cirrhosis, and the treatment history (algorithm 1 and algorithm 2 and algorithm 3 and algorithm 4). Sofosbuvir-velpatasvir-voxilaprevir is highly effective in patients with genotypes 1 through 6 infection who have failed a prior direct acting antiviral (DAA) regimen and is now the main treatment option for those who have failed an NS5A inhibitor-containing regimen [10]. Like other contemporary DAA regimens, these new combinations are well tolerated, with common but mild side effects. (See "Treatment regimens for chronic hepatitis C virus genotype 1 infection in adults", section on 'Selection of treatment regimens' and "Treatment regimens for chronic hepatitis C virus genotypes 2 and 3 infection in adults", section on 'Selection of treatment regimen' and "Treatment regimens for chronic hepatitis C virus genotypes 4, 5, and 6 infection in adults", section on 'Selection of treatment regimens'.)

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 [11,12]. 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 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 [13]. 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'.)


Subcutaneous C1 inhibitor for hereditary angioedema (April 2017, Modified September 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 [14]. 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 for prophylaxis by the US Food and Drug Administration (FDA) in June 2017 and is an appropriate option for patients who prefer this form of administration. Approval in Europe is anticipated in the near future. (See "Hereditary angioedema: General care and long-term prophylaxis", section on 'Subcutaneous C1 inhibitor'.)

Guselkumab and tildrakizumab for moderate to severe plaque psoriasis (July 2017)

New therapies targeting interleukin (IL)-23 are emerging for the treatment of moderate to severe plaque psoriasis and may be more effective than older biologic therapies, such as adalimumab and etanercept. Data from randomized trials support the superiority of IL-23 monoclonal antibodies guselkumab and tildrakizumab over adalimumab and etanercept, respectively [15-17]. The adverse effects were comparable. Based upon these data, the US Food and Drug Administration (FDA) approved guselkumab for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Tildrakizumab is not yet commercially available. Both represent additional highly effective treatments for moderate to severe plaque psoriasis. (See "Treatment of psoriasis in adults", section on 'Guselkumab' and "Treatment of psoriasis in adults", section on 'Future therapies'.)

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 [18]. 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 [19]. 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 [20]. 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'.)

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) [21]. 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 [22]. 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'.)


Copanlisib for relapsed follicular lymphoma (September 2017)

Most patients with follicular lymphoma (FL) are not cured with conventional therapies and will experience serial relapse requiring treatment with many different regimens over the disease course. The US Food and Drug Administration (FDA) has approved copanlisib for the treatment of patients with relapsed FL who have received at least two prior systemic therapies [23]. Copanlisib is an intravenous inhibitor of PI3K alpha and delta isoforms. In small, nonrandomized studies of patients with multiply relapsed FL treated with copanlisib, approximately half of patients achieved at least a partial response, but complete responses were uncommon [24]. Serious toxicities included opportunistic infections, hypertension, hyperglycemia, noninfectious pneumonitis, cutaneous reactions, and neutropenia. We reserve the use of copanlisib as one option for patients with multiply relapsed disease. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Copanlisib'.)

Tisagenlecleucel gene therapy for relapsed/refractory ALL (September 2017)

Relapsed/refractory lymphoblastic leukemia (ALL) generally requires achievement of complete remission prior to potentially curative allogeneic hematopoietic cell transplantation, but the optimal means of achieving remission is uncertain. Tisagenlecleucel is a novel immunotherapy in which the patient's own T cells are genetically modified to express a chimeric antigen receptor directed against CD19 on the leukemic cells. Based on an 83 percent response rate to a single treatment with tisagenlecleucel, it was approved by the US Food and Drug Administration (FDA) for treatment of patients up to 25 years old with relapsed/refractory B cell precursor ALL [25]. Tisagenlecleucel is associated with severe neurologic events and cytokine release syndrome (CRS), and is available only in specially certified facilities. Tisagenlecleucel is the first US FDA-approved gene therapy product, and it is an acceptable approach for achieving remission in children and young adults with relapsed or refractory B cell precursor ALL. (See "Treatment of relapsed or refractory acute lymphoblastic leukemia in adults", section on 'Chimeric antigen receptor T cells'.)

Midostaurin approved for therapy of FLT3 mutation-positive AML and systemic mastocytosis (September 2017)

Mutations of the FLT3 gene are found in approximately one-third of adults with acute myeloid leukemia (AML). In a phase III trial, the multitargeted small molecule FLT3 inhibitor midostaurin improved event-free and overall survival when added to standard induction therapy in adults with FLT3 mutation-positive AML [26]. Midostaurin has been approved by the US Food and Drug Administration (FDA) for this use [27] and we suggest addition of midostaurin to standard induction therapy for treatment of adults with newly diagnosed FLT3 mutation-positive AML. (See "Induction therapy for acute myeloid leukemia in younger adults", section on 'Midostaurin in AML with FLT3 mutation'.)

The US FDA also approved midostaurin for treatment of advanced systemic mastocytosis (SM), a group of disorders characterized by excessive mast cell accumulation in multiple tissues, based upon a trial demonstrating improvements in cytopenias and liver function in two-thirds of patients [28], confirming results from an earlier trial [29]. Midostaurin was well tolerated with primarily grade 1 to 2 nausea/vomiting and modest cytopenias. We suggest midostaurin for initial systemic therapy of advanced SM. (See "Systemic mastocytosis: Management and prognosis", section on 'Choice of therapy'.)

Gemtuzumab ozogamicin plus 7+3 induction therapy for AML (September 2017)

Addition of a third agent to anthracycline plus cytarabine induction therapy (so-called "7+3" regimens) for newly diagnosed acute myeloid leukemia (AML) has generally been disappointing. Gemtuzumab ozogamicin (GO) is a humanized anti-CD33 antibody linked to the cytotoxic agent calicheamicin. In a phase III study of adults with de novo CD33+ AML, addition of GO to 7+3 improved event-free survival, leading to its approval in this setting by the US Food and Drug Administration (FDA) [30]. It is also FDA approved as a single agent for relapsed or refractory AML in adults and in children ≥2 years old, irrespective of CD33+ status. GO has a boxed warning regarding hepatotoxicity (including potentially fatal sinusoidal obstructive syndrome) and may cause other severe adverse events (eg, infusion reactions, hemorrhage, teratogenicity). (See "Induction therapy for acute myeloid leukemia in younger adults", section on 'Adding a third agent'.)

Ibrutinib for treatment of chronic GVHD (August 2017)

Optimal management of patients with steroid-refractory (SR) chronic graft-versus-host disease (GVHD) is poorly defined. Preliminary results of a phase II trial of ibrutinib in 42 such patients reported multiorgan responses (eg, skin, mouth, gastrointestinal tract, liver) in two-thirds, which, for the majority of patients, permitted reduction in steroid dose and improved quality of life [31]. Reported side effects included fatigue, bruising, stomatitis, nausea, diarrhea, cytopenias, and infections. Ibrutinib was approved by the US Food and Drug Administration for treatment of chronic GVHD [32] and is an acceptable alternative to calcineurin inhibitors (eg, cyclosporin, tacrolimus) and other agents for treatment of SR-chronic GVHD. (See "Treatment of chronic graft-versus-host disease", section on 'Ibrutinib'.)

Liposomal daunorubicin-cytarabine for treatment-related AML (August 2017)

Optimal management of treatment-related acute myeloid leukemia (t-AML) is not well defined. Based on preliminary results of a phase III trial in which liposome-encapsulated daunorubicin-cytarabine improved median overall survival compared with conventional "7+3" administration of daunorubicin and cytarabine (10 versus 6 months), and had tolerable adverse effects (eg, bleeding, infections, mucositis), the US Food and Drug Administration approved this product for patients with newly diagnosed t-AML [33]. For patients with t-AML whose performance status permits an aggressive therapeutic approach, we offer liposome-encapsulated daunorubicin and cytarabine as an alternative to conventional 7+3 therapy. (See "Therapy-related myeloid neoplasms: Acute myeloid leukemia and myelodysplastic syndrome", section on 'Treatment'.)

Enasidenib is effective for relapsed or refractory acute myeloid leukemia (August 2017)

Relapsed or refractory acute myeloid leukemia (AML) is generally treated with intensive chemotherapy in order to achieve complete remission (CR) prior to hematopoietic cell transplantation. In a multicenter phase I/II trial, daily oral treatment with enasidenib, an inhibitor of IDH2 (isocitrate dehydrogenase-2), achieved responses in 40 percent of patients (19 percent with CR), with median overall survival of nine months [34]. Grade 3-4 differentiation syndrome (DS) occurred in <10 percent of patients, including two possible DS-related deaths. Other toxicities included elevated bilirubin and nausea, but hematologic toxicities were modest. For patients whose relapsed or refractory AML has a mutation of IDH2, treatment with enasidenib is an acceptable alternative to intensive chemotherapy, with careful monitoring and prompt intervention for potential DS. (See "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Remission re-induction' and "Differentiation (retinoic acid) syndrome".)

Daratumumab, pomalidomide, and dexamethasone for relapsed multiple myeloma (August 2017)

The anti-CD38 monoclonal antibody daratumumab is one of our preferred agents for the treatment of patients with relapsed or refractory multiple myeloma (MM). In a prospective trial of daratumumab, pomalidomide, and dexamethasone in multiply relapsed MM, this regimen had an overall response rate of 60 percent and a median progression-free survival of 8.8 months, and was well tolerated [35]. Based on this and other data, the US Food and Drug Administration has approved this regimen for patients with MM who have received at least two prior therapies including lenalidomide and a proteasome inhibitor. We reserve this regimen for patients with multiply relapsed disease unresponsive to lenalidomide (table 1). (See "Treatment of relapsed or refractory multiple myeloma", section on 'Efficacy'.)

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 [36]. We continue to suggest idarucizumab for clinically significant bleeding or emergency 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'.)

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 [37]. 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 [38-40]. 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 [41]. (See "Initial treatment of advanced stage (III/IV) follicular lymphoma", section on 'Immunotherapy-based treatment'.)

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 [42]. 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".)

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 [43]. 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'.)


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 [44]. 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 [45]. 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'.)

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 [46]. 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'.)

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 [47]. 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 [48]. 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'.)


Abemaciclib for hormone receptor-positive, HER2-negative advanced breast cancer (September 2017)

Abemaciclib is the third CDK 4/6 inhibitor to become available for use in women with hormone receptor-positive, HER2-negative advanced breast cancer. In a phase III trial, abemaciclib plus fulvestrant improved progression-free survival compared with fulvestrant alone [49], and in a nonrandomized phase II study abemaciclib showed single agent activity in patients with progression following chemotherapy [50]. Based upon these results, abemaciclib was approved by the US Food and Drug Administration in combination with fulvestrant for women with progressive disease after prior endocrine therapy and for use as a single agent for women with progressive disease after endocrine therapy and chemotherapy. (See "Treatment approach to metastatic hormone receptor-positive, HER2-negative breast cancer: Endocrine therapy", section on 'Abemaciclib'.)

PARP inhibitor maintenance therapy in platinum-sensitive, recurrent ovarian cancer (March 2017, Modified September 2017)

Inhibitors of poly-ADP ribose polymerase (PARP) are being actively evaluated as maintenance therapy in platinum-sensitive relapsed ovarian cancer. In phase III trials of women with recurrent ovarian cancer who achieved a response to their most recent platinum-based treatment, the PARP inhibitors niraparib, olaparib, and rucaparib have each demonstrated progression-free survival benefits as maintenance therapy compared with placebo [51-54]. These data have led to approvals by the US Food and Drug Administration of both niraparib and olaparib in this setting [55,56]. However, overall survival data for PARP inhibitors as maintenance therapy are immature, and these agents have not been compared with bevacizumab, which is better established in the maintenance setting. Pending further data, we reserve use of PARP inhibition as maintenance therapy 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".)

Nivolumab approval extended to mismatch repair-deficient metastatic colorectal cancer (August 2017)

Immunotherapy with checkpoint inhibitors, such as pembrolizumab, that block the programmed death receptor-1 (PD-1) benefits patients with metastatic colorectal cancer (mCRC) whose tumors are deficient in mismatch repair (dMMR). The benefit of nivolumab, a different PD-1 blocking antibody, was evaluated in a trial that reported an objective response in 23 of 74 patients treated with nivolumab alone, with response persisting at least 12 months in eight patients [57]. Largely based upon these data, in August 2017, the US Food and Drug Administration (FDA) extended the approval of nivolumab to dMMR mCRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin and irinotecan [58]. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Immune checkpoint inhibitors and mismatch repair deficient tumors'.)

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 [59]. 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'.)

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 [60]. 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'.)

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 [61]. These results are consistent with an earlier Japanese trial [62].

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) [63]. 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".)

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 [64,65]. 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'.)

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 [66]. 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 [67]. 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'.)

Pembrolizumab for advanced colorectal cancer and other refractory solid tumors with deficient DNA mismatch repair (May 2017)

In a small study comparing pembrolizumab administration in patients with mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC) or with MMR proficient (pMMR) mCRC, the objective response rate and disease control rate were 50 and 89 percent, respectively, for patients with dMMR mCRC and 0 and 16 percent for the pMMR group [68-70]. Largely based upon these data, the US Food and Drug Administration granted accelerated approval to pembrolizumab for the treatment of patients with advanced microsatellite instability-high (MSI-H) or dMMR mCRC that has progressed following conventional chemotherapy [71]. The approval of pembrolizumab also extended to a variety of other advanced solid tumors (including endometrial, other gastrointestinal, breast, prostate, bladder, and thyroid) that were MSI-H or dMMR, had progressed following prior treatment, and for which there were no satisfactory alternative treatment options. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Immune checkpoint inhibitors and mismatch repair deficient tumors' and see "Treatment of recurrent or metastatic endometrial cancer", section on 'Immune checkpoint inhibitors'.

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 [72]. 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'.)


Mepolizumab for eosinophilic granulomatosis with polyangiitis (August 2017)

Mepolizumab is a monoclonal anti-interleukin-5 antibody that is approved for use in severe eosinophilic asthma. In a multicenter trial, 136 patients with relapsing or refractory eosinophilic granulomatosis with polyangiitis (EGPA) were randomly assigned to receive mepolizumab 300 mg (three times the US Food and Drug Administration-approved dose of 100 mg) or placebo subcutaneously every four weeks for 52 weeks [73]. Mepolizumab led to significantly more accrued weeks of remission and a lower frequency of relapse than placebo. Among mepolizumab-treated subjects, 44 percent were able to taper prednisolone to ≤4 mg/day, compared with 7 percent on placebo. While not all patients respond, high-dose mepolizumab may be an additional option for selected patients with EGPA. (See "Treatment and prognosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)", section on 'Anti-IL-5 antibodies'.)

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 [74,75]. 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 2). (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'Ivacaftor for G551D, other gating mutations, and residual function mutations'.)


Opana ER withdrawn from the US market (July 2017)

A long-acting abuse-deterrent formulation of oxymorphone, Opana ER, is being voluntarily withdrawn from the United States (US) market at the request of the US Food and Drug Administration due to concerns related to injection abuse, including reports of thrombotic microangiopathy (TMA) when the oral formulation is injected intravenously (IV) [76-78]. The TMA is thought to be due to an inert component that was added to the formulation to make it crush-resistant and thus deter IV injection. Generic extended-release oxymorphone products remain on the US market. (See "Cancer pain management with opioids: Optimizing analgesia", section on 'Oxycodone, hydrocodone, hydromorphone, and oxymorphone' and "Drug-induced thrombotic microangiopathy", section on 'Drugs of abuse'.)


Mixed data regarding icatibant in ACE inhibitor-induced angioedema (August 2017)

Although the bradykinin receptor antagonist icatibant has proven efficacy in hereditary angioedema, particularly when given soon after onset of symptoms, evidence is mixed regarding its utility in angiotensin-converting enzyme inhibitor-associated angioedema (AceIA). In a randomized trial of 121 patients with AceIA of the head or neck, icatibant did not decrease the time to discharge relative to placebo [79]. Therefore, careful airway management, rather than icatibant, remains the primary intervention for most cases of AceIA, although icatibant may have a role in rare instances when patients present very early. (See "ACE inhibitor-induced angioedema", section on 'Icatibant'.)

Statin awareness and reported muscle-related adverse events (August 2017)

In clinical practice, side effects with statins are common, which could be related in part to a heightened awareness of adverse reactions traditionally attributed to the drugs. In a randomized double-blind, placebo-controlled trial involving over 10,000 patients, atorvastatin therapy did not increase the rate of muscle-related adverse events (AEs) [80]. By contrast, in the non-randomized, non-blinded extension of the study, muscle-related AEs were reported more often in patients taking atorvastatin compared with placebo. These results suggest that some muscle-related AEs attributed to atorvastatin are not causally linked to the drug. (See "Statins: Actions, side effects, and administration", section on 'Side effects'.)

Prevention of meningococcal infection in patients receiving eculizumab (August 2017)

Eculizumab is a monoclonal antibody used for treatment of complement-mediated hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria. It has been associated with a 1000 to 2000-fold increased incidence of meningococcal disease, including life-threatening and fatal infection. Therefore, patients should be immunized with meningococcal vaccines (both ACYW135 and serogroup B), if possible, at least two weeks prior to receiving a first dose of eculizumab. However, invasive meningococcal disease has occurred among patients receiving eculizumab despite receipt of meningococcal vaccine, including infections caused by non-typeable strains not included in the vaccines [81]. Accordingly, in addition to vaccination, we suggest daily antimicrobial prophylaxis (penicillin or, for penicillin-allergic patients, a macrolide) for prevention of meningococcal infection in all patients treated with eculizumab. In addition, patients should be monitored for signs of meningococcal infection and evaluated immediately if infection is suspected. (See "Treatment and prevention of meningococcal infection", section on 'Patients receiving eculizumab'.)

Risk of tympanic membrane perforation with topical quinolones after tympanostomy (August 2017)

An observational study reported that treatment with quinolone ear drops, with or without added topical corticosteroids, after tympanostomy tube (TT) placement was associated with increased risk of tympanic membrane (TM) perforation compared with treatment with neomycin plus hydrocortisone drops [82]. While the study raises concerns regarding the safety of quinolone ear drops, the findings should be viewed as preliminary given the observational design and source of the data (Medicaid encounter and pharmacy billing data). In addition, this study evaluated only the risk of TM perforation and did not address other adverse effects, including ototoxicity, which is a well-established side effect of neomycin (and other aminoglycosides). Until additional data are available, we continue to suggest fluoroquinolone-containing drops as our preferred treatment for uncomplicated acute TT otorrhea. (See "Tympanostomy tube otorrhea in children: Causes, prevention, and management", section on 'Uncomplicated acute TTO'.)

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 [83]. 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 [84]. 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 3). 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 [85]. 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 [86]. 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) [87]. 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 [88]. 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'.)


2017-2018 influenza immunization recommendations for the United States (September 2017)

The Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics (AAP) have released recommendations for influenza immunization for the 2017-2018 season in the United States [89,90]. Routine influenza immunization with a licensed, age-appropriate vaccine (table 4) is recommended for all persons ≥6 months of age. Live attenuated influenza vaccine is not recommended for the 2017-2018 season. Pregnant women and persons with egg allergy of any severity can receive any licensed, age-appropriate inactivated influenza vaccine with standard immunization precautions. Although neither the ACIP nor the AAP provide a preference for a particular formulation, we favor a quadrivalent vaccine when available for adults <65 years and we recommend the high-dose vaccine for those ≥65 years. (See "Seasonal influenza in children: Prevention with vaccines", section on 'Types of vaccine' and "Seasonal influenza vaccination in adults", section on 'Choice of vaccine formulation' and "Influenza and pregnancy", section on 'Vaccination' and "Influenza vaccination in individuals with egg allergy", section on 'Safety of vaccines in patients with egg allergy'.)

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 [91]. 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 [92]. 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 [93]. (See "Immunizations during pregnancy", section on 'Rationale, efficacy, and safety'.)

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