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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: Nov 2016. | This topic last updated: Nov 29, 2016.

The following material represents a subset of new drugs, drug approvals, drug warnings, and drugs removed from the market from the past six months. This is not a complete list; it includes those topics considered by the authors and editors to be of particular interest or importance. For a complete list of new drug approvals, see http://www.lexi.com/home/newdrugs/.

You can check drug interactions by going to the Lexi-Interact drug interactions program included with UpToDate. This program is only available to online web users (ie, not in content downloaded when off-line or on a mobile device) and can be accessed from the Drug Interactions tab located in the top right corner of any screen and in the search results list after searching on a drug name.

DRUG INTERACTIONS

Potential interaction between high-dose methotrexate and levetiracetam (November 2016)

Levetiracetam is sometimes used for prophylaxis and treatment of seizures in patients undergoing high-dose methotrexate (MTX) treatment for brain or other central nervous system (CNS) cancers, including lymphomas. Health Canada has issued a safety review describing a potential interaction between the two drugs, noting 13 reports received by the levetiracetam manufacturer and concluding that concurrent use can lead to significantly elevated levels of MTX and increased risk of toxicity [1]. The labeling is being revised to recommend careful MTX blood level monitoring. Additional details are available from Lexi-Interact, the drug interactions tool included within UpToDate. (See "Therapeutic use and toxicity of high-dose methotrexate", section on 'Coadministered drugs that may interfere with excretion'.)

Proton pump inhibitors may diminish capecitabine efficacy (October 2016)

Two recent studies suggest that proton pump inhibitors diminish the effectiveness of capecitabine in the treatment of colorectal and gastroesophageal cancer [2,3]. It is hypothesized that higher gastric pH levels may inhibit dissolution and absorption of capecitabine. Patients who are receiving a capecitabine-containing regimen for adjuvant treatment of colon cancer or other malignancies should, when possible, avoid taking concurrent proton pump inhibitors. (See "Adjuvant therapy for resected stage III (node-positive) colon cancer", section on 'Capecitabine'.)

NEW DRUGS AND US DRUG APPROVALS

Vaginal prasterone for dyspareunia in postmenopausal women (November 2016)

In November 2016, the US Food and Drug Administration approved the use of prasterone (also known as dehydroepiandrosterone [DHEA]) for treatment of dyspareunia in women with vulvovaginal atrophy (VVA) due to menopause [4]. In an earlier randomized trial of women with VVA and moderate to severe dyspareunia, 12 weeks of daily intravaginal DHEA resulted in improved scores for pain during sexual activity and other key domains of female sexual function (desire, arousal, lubrication, orgasm, satisfaction) compared with placebo [5]. However, patients may find daily dosing more cumbersome than twice weekly dosing with vaginal estrogen preparations. (See "Treatment of genitourinary syndrome of menopause (vulvovaginal atrophy)", section on 'Dehydroepiandrosterone (prasterone)'.)

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

Ustekinumab is approved for use in adult patients with moderate to severely active Crohn disease who have failed conventional therapy, but efficacy in inducing clinical remission in patients with disease refractory to anti-tumor necrosis factor (anti-TNF) therapy had not been previously established. In two randomized induction trials, approximately 1300 patients with Crohn disease and nonresponse or intolerable side effects to anti-TNF therapy were assigned to eight weeks of intravenous ustekinumab or placebo [6]. Those who responded to ustekinumab were assigned to 44 weeks of subcutaneous maintenance with ustekinumab or placebo. Patients assigned to ustekinumab had significantly higher clinical response rates at week six and rates of remission at week 44 as compared with placebo, demonstrating a role for ustekinumab in patients who have failed anti-TNF therapy. (See "Overview of the medical management of severe or refractory Crohn disease in adults", section on 'Ustekinumab'.)

Adalimumab for noninfectious uveitis (November 2016)

Patients with noninfectious uveitis can benefit from effective and safe glucocorticoid-sparing therapy. Two well-designed, randomized trials showed that adalimumab was effective in the treatment of noninfectious intermediate, posterior, and pan-uveitis [7,8]. In these trials, adalimumab improved the time-to-treatment failure in patients with uveitis who followed a tapering schedule for oral glucocorticoids. Both the European Medicines Agency and the US Food and Drug Administration recommended approval of adalimumab for adults with these forms of uveitis. (See "Uveitis: Treatment", section on 'Anti-tumor necrosis factor-alpha'.)

Olaratumab in combination for advanced soft-tissue sarcoma (November 2016)

Olaratumab is a monoclonal antibody that binds to the platelet-derived growth factor receptor alpha (PDGFRA) and blocks binding of PDGF ligands. In a randomized phase II study comparing doxorubicin with or without olaratumab in previously untreated patients with locally advanced or metastatic soft tissue sarcoma (STS) from a variety of histologic subtypes, initial combination therapy was associated with improved median overall survival (27 versus 15 months) [9]. Grade 3 or 4 neutropenia, mucositis, nausea, vomiting, and diarrhea were all more common with combined therapy. Based upon these results, and consistent with the recent approval of olaratumab in the United States for this indication [10], we suggest doxorubicin plus olaratumab rather than doxorubicin alone for first-line treatment of patients who cannot be cured with radiation or surgery and who have a type of STS for which anthracyclines represent appropriate chemotherapy. (See "Systemic treatment of metastatic soft tissue sarcoma", section on 'Doxorubicin plus olaratumab'.)

Intravenous carbamazepine approved for use in adults (November 2016)

An intravenous (IV) preparation of carbamazepine has been approved by the US Food and Drug Administration for use as short-term replacement therapy in adult patients on stable doses of oral carbamazepine who are transiently unable to ingest oral preparations [11]. The recommended IV conversion dose is 70 percent of the total daily oral dose, divided into four equal doses and given every six hours. (See "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects", section on 'Carbamazepine'.)

Daratumumab-based regimens in relapsed multiple myeloma (October 2016, Modified October 2016)

Two recent multicenter randomized trials including over 1000 patients have demonstrated large improvements in progression-free survival (PFS) when the anti-CD38 monoclonal antibody daratumumab is added to standard regimens in relapsed multiple myeloma. The addition of daratumumab to either lenalidomide plus dexamethasone (POLLUX trial) or to bortezomib plus dexamethasone (CASTOR trial) resulted in substantially improved response rates and PFS with a mild to moderate increase in toxicity [12,13]. Mostly mild infusion reactions were common with the first infusion, but rarely resulted in drug discontinuation. Overall survival data are not yet mature. Based on these results we now recommend a daratumumab-based regimen for the treatment of first relapse in myeloma. (See "Treatment of relapsed or refractory multiple myeloma", section on 'Daratumumab'.)

Eteplirsen for Duchenne muscular dystrophy (September 2016)

Small studies of eteplirsen, an exon 51 skipping drug, suggest that it can increase dystrophin production in skeletal muscle without drug-related adverse effects in patients with Duchenne muscular dystrophy (DMD) with an amenable dystrophin gene mutation. Based upon this finding, the US Food and Drug Administration granted accelerated approval of eteplirsen in September 2016 for the treatment patients with DMD who have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping [14]. The mutation is present in approximately 13 percent of patients with DMD. (See "Treatment of Duchenne and Becker muscular dystrophy", section on 'Eteplirsen'.)

Nivolumab dose regimen (September 2016)

Nivolumab is an IgG4 monoclonal antagonist antibody to PD-1 that is US Food and Drug Administration (FDA)-approved for the treatment of several types of malignancies. The FDA has modified the approved dose regimen for advanced renal cell carcinoma, melanoma, and non-small cell lung cancer to 240 mg intravenously every two weeks until disease progression or intolerable toxicity [15]. This new dose replaces the previous regimen of 3 mg/kg and is based on population pharmacokinetic analyses demonstrating comparable efficacy and safety in patients with these cancers. For patients with Hodgkin lymphoma, or for those with melanoma being treated concurrently with ipilimumab, the recommended dose of nivolumab remains unchanged (3 mg/kg and 1 mg/kg, respectively). (See "Immunotherapy of non-small cell lung cancer with immune checkpoint inhibition", section on 'Nivolumab' and "Immunotherapy of renal cell carcinoma" and "Immunotherapy of advanced melanoma with immune checkpoint inhibition".)

Biosimilars for tumor necrosis factor inhibitors (August 2016)

Copies of biologic agents, termed biosimilars, including several of the tumor necrosis factor (TNF) inhibitors and other medications, have been marketed or are under development for use in the rheumatic diseases. A recent systematic review of 19 observational studies and clinical trials compared biosimilar TNF-alpha inhibitors with their reference biologic products, including infliximab, etanercept, and adalimumab, with testing done in healthy volunteers and in patients with rheumatoid arthritis, inflammatory bowel disease, and ankylosing spondylitis [16]. Pharmacokinetic measurements were within defined equivalence margins, and similar clinical responses and adverse events were found for the tested products and their reference drugs. Additionally, similar efficacy and safety were observed in four cohort studies in which patients were switched from the reference product to a biosimilar medication. Limitations for many of the studies included small sample size and short trial duration, but collectively these data illustrate the potential utility of these agents. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases", section on 'Biosimilars for biologic agents'.)

Sofosbuvir-velpatasvir for all genotypes of chronic HCV infection (July 2016)

All-oral, direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have proliferated over the past two years. Sofosbuvir-velpatasvir, a coformulated combination of an NS5B and an NS5A inhibitor, is the first such regimen that has high, well-established efficacy for all genotypes, even in patients with cirrhosis or prior treatment failure with interferon-based regimens [17-19]. This agent was approved by the US Food and Drug Administration in June 2016 and is now our preferred or one of our preferred regimens for adults with chronic HCV infection of any genotype because of its efficacy, simplicity of administration, and limited drug interactions (algorithm 1 and algorithm 2 and algorithm 3 and algorithm 4). Sofosbuvir-velpatasvir is given for 12 weeks for all genotypes. For genotype 3 infection, the addition of ribavirin may be warranted, depending on the presence of cirrhosis, the prior treatment history, and the presence of mutations associated with NS5A resistance. (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'.)

Omalizumab for allergic asthma in children 6 to 11 years of age (July 2016)

Omalizumab, a monoclonal antibody to immunoglobulin E (IgE), is an option for patients with moderate to severe persistent asthma and sensitization to perennial aeroallergens who are inadequately controlled on inhaled glucocorticoids. The US Food and Drug Administration (FDA) has now lowered the approved age range from 12 to 6 years of age, expanding the therapeutic options in step 5 asthma management in children [20]. (See "Asthma in children younger than 12 years: Treatment of persistent asthma with controller medications", section on 'Step-up therapy' and "Asthma in children younger than 12 years: Treatment of persistent asthma with controller medications", section on 'Anti-IgE therapy' and "Anti-IgE therapy", section on 'Omalizumab therapy in asthma'.)

Glycopyrronium-indacaterol versus fluticasone-salmeterol for moderate-to-severe COPD (June 2016)

Current guidelines suggest use of an inhaled glucocorticoid (ICS)-long-acting beta agonist (LABA) in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) who are at increased risk of exacerbations. New data suggest that long-acting anticholinergic (LAMA)-LABA combinations, which improve pulmonary function and variably reduce symptoms in patients with COPD at low risk of exacerbations, may also benefit patients at increased risk of exacerbation. In a multicenter trial, glycopyrronium-indacaterol once daily was compared with fluticasone-salmeterol twice daily in over 3000 patients with moderate-to-severe COPD and at least one moderate-severe exacerbation in the previous year [21]. Over the 52-week trial, glycopyrronium-indacaterol reduced exacerbations by 11 percent and was associated with slightly fewer episodes of pneumonia compared with fluticasone-salmeterol. The use of LAMA-LABA combinations in these patients, in preference to an ICS-LABA combination, requires further study to determine the generalizability and durability of these findings. (See "Management of stable chronic obstructive pulmonary disease", section on 'Comparison with LAMA-LABA'.)

Ixekizumab for moderate to severe plaque psoriasis (June 2016)

Similar to the previously published UNCOVER-2 and UNCOVER-3 trials, high efficacy of ixekizumab (a humanized monoclonal antibody against IL-17A) for moderate to severe plaque psoriasis was demonstrated in the UNCOVER-1 trial, which compared every-two-week and every-four-week regimens of ixekizumab with placebo [22]. In addition, data from long-term extension periods of the UNCOVER trials supports efficacy of ixekizumab through 60 weeks of treatment. Adverse effects reported during ixekizumab treatment included candidal infections, neutropenia, and inflammatory bowel disease. These data support the inclusion of ixekizumab in the therapeutic armamentarium for psoriasis. (See "Treatment of psoriasis", section on 'Ixekizumab'.)

Daclizumab approved in the US for treating relapsing-remitting multiple sclerosis (June 2016)

Daclizumab, a humanized monoclonal antibody, was recently approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis [23]. The approval was based upon evidence from two randomized controlled trials that daclizumab is effective for reducing relapse rates, and evidence from one trial that it may be effective for reducing disability progression. However, the clinical utility of daclizumab is likely to be limited by the risk of serious adverse events, including hepatotoxicity and infection, making it a second- or third-line agent for patients who have had an inadequate response to two or more disease-modifying agents for relapsing-remitting multiple sclerosis. Daclizumab will be available in the United States only through a restricted distribution program. (See "Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults", section on 'Daclizumab'.)

68-Ga DOTATATE approved for imaging of neuroendocrine tumors (June 2016)

Most well-differentiated neuroendocrine tumors arising in the gastrointestinal tract, pancreas, bronchus, and other sites express somatostatin receptors, and they can be imaged using radiolabeled somatostatin analogs. Uptake of radiolabeled somatostatin analogs is predictive of a clinical response to somatostatin analogs such as octreotide, and a positive scan can also identify an otherwise occult primary site in patients presenting with metastatic disease. Newer positron-emitting somatostatin analogs such as Gallium 68-Ga DOTATATE (68-Ga DOTATATE) have emerged which, when combined with high-resolution positron emission tomography (PET) scanning, are more sensitive than conventional 111-In pentetreotide imaging (OctreoScan) for detection of small lesions [24]. A kit for preparation of 68-Ga DOTATATE injection as a radioactive diagnostic agent for PET imaging (Netspot) was approved by the US Food and Drug Administration in June 2016 [25]. Due to its greater sensitivity, 68-Ga DOTATATE PET may be preferred over conventional 111-In pentetreotide scanning in certain clinical settings (eg, small volume disease), where available. (See "Neuroendocrine neoplasms of unknown primary site", section on 'Initial workup' and "Metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors: Presentation, prognosis, imaging, and biochemical monitoring", section on 'Somatostatin receptor-based imaging techniques'.)

ADVERSE REACTIONS AND WARNINGS

Combination antiretroviral treatment in pregnancy (November 2016)

Combination antiretroviral treatment (ART) has become the worldwide standard of care for HIV-infected pregnant women, both for their own health and for prevention of HIV transmission to their infants. In a large randomized trial of HIV-infected pregnant women in Africa and India, antepartum ART (with one of two different protease inhibitor-based regimens) resulted in lower transmission rates compared with zidovudine plus single-dose nevirapine (0.5 versus 1.8 percent) [26]. Rates of preterm birth at <37 weeks were higher with the ART regimens than with zidovudine, but more significant prematurity (<34 weeks) and neonatal deaths were not increased. Clinicians should discuss with patients the potential risk for adverse pregnancy outcome with certain ART regimens. (See "Safety and dosing of antiretroviral medications in pregnancy", section on 'Preterm birth'.)

Cardiotoxicity of checkpoint inhibitor immunotherapy (November 2016)

Checkpoint inhibitor immunotherapy for melanoma and other cancers may result in severe or fatal cardiotoxicity, even in the absence of a history of significant cardiac risk factors [27]. High-dose steroids are indicated to treat myositis and other cardiac complications, but symptoms may progress in some cases despite steroids. The early institution of more aggressive immunosuppressive therapy and monitoring should be considered for patients without an immediate response to high-dose steroids. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Cardiotoxicity'.)

HBV reactivation during HCV antiviral therapy (October 2016)

Reactivation of hepatitis B virus (HBV) infection, including cases with fatal fulminant hepatitis, has been reported in several patients receiving direct-acting antiviral therapy for hepatitis C virus (HCV) infection [28]. Patients should be tested for HBV coinfection prior to initiation of HCV therapy, with HBV treatment initiated for those who meet criteria (table 1). HBV surface antigen (HBsAg) positive patients who do not initially meet HBV treatment criteria should be monitored with HBV DNA testing during HCV treatment. In patients with a positive HBV core antibody (HBcAb) but negative HBsAg, we check liver enzymes during HCV treatment and perform reflex HBsAg and HBV DNA testing for unexplained elevations. (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 'Other laboratory testing'.)

Updated MASCC/ESMO guidelines for nausea and emesis related to cancer treatment (October 2016)

Updated guidelines for prevention and management of cancer therapy-associated nausea and vomiting are available from the Multinational Association of Supportive Care in Cancer and the European Society of Medical Oncology (table 2), the consensus panel also provides guidance on the use of prophylactic antiemetics in patients undergoing radiation therapy. (See "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults", section on 'Recommendations for specific groups'.)

Thrombotic microangiopathy from interferon (October 2016)

Drug-induced thrombotic microangiopathy (DITMA) has been described with a number of chemotherapeutic, immunosuppressive, and other drugs. Unlike thrombotic thrombocytopenic purpura (TTP), DITMA is not associated with severely reduced ADAMTS13 activity, and the principal treatment is drug discontinuation rather than plasma exchange. A new report has provided strong evidence for interferon as a cause of TMA [30]. Patients receiving interferon who develop signs of a TMA should have the drug discontinued promptly before organ failure develops. (See "Drug-induced thrombotic microangiopathy", section on 'Immunosuppressive agents'.)

Pharmacotherapy for antipsychotic-induced akathisia in schizophrenia (October 2016)

Benzodiazepines, beta blockers, and the anticholinergic drug benztropine are believed to be comparably effective in the treatment of akathisia in schizophrenia patients, based upon limited data from small clinical trials. Until recently, we favored benzodiazepines for first line treatment of akathisia. Earlier in 2016, however, a large retrospective analysis of claims and mortality data reported an increased mortality risk associated with benzodiazepine use in patients with schizophrenia [31]. Subsequently, a dose-related relationship between cumulative benzodiazepine use and increased mortality was found in a national registry study of over 20,000 Swedish adults with schizophrenia [32]. Although the study designs do not allow causality to be determined, based upon these findings, we now suggest that a beta blocker, such as propranolol, be used as first-line treatment for akathisia. Benzodiazepines remain an option, particularly in patients who do not respond to a beta blocker or benztropine. (See "Pharmacotherapy for schizophrenia: Side effect management", section on 'Akathisia'.)

Pulmonary toxicity of anti-PD-1 and anti-PD-L1 antibodies (September 2016)

Pulmonary toxicity is an uncommon but potentially fatal complication of treatment with checkpoint inhibitor immunotherapy targeting programmed cell death-1 (PD-1) or its ligand (PD-L1). The incidence of pneumonitis was 5 percent in a series of 915 patients treated with one of these agents [33]. All patients had immunotherapy withheld until toxicity resolved, and this was sufficient to reverse toxicity in most patients with grade 1 pneumonitis (table 3). For those with more severe toxicity, corticosteroids were indicated. Five out of 43 patients worsened and died despite therapy, mostly attributed to infectious complications or tumor progression. (See "Toxicities associated with checkpoint inhibitor immunotherapy", section on 'Pneumonitis'.)

Medication modification following fracture in older adults (September 2016)

Adverse drug effects are a particularly important issue for geriatric patients and may be unrecognized as a cause of illness or injury. A study reviewed data from a sample of 168,000 Medicare patients seen for treatment of hip, shoulder, or wrist fractures [34]. In the four months prior to presentation, three-quarters of the patients had been taking a nonopioid drug associated with increased fracture risk (eg sedatives, atypical antipsychotics, tricyclic antidepressants, or antihypertensives). In the four months after the fracture, such drugs were discontinued for 7 percent but were newly prescribed for another 7 percent. Review of drug therapy, with assessment of the need for ongoing therapy and discontinuation of nonessential medications, is indicated when patients present with an injury or illness that might relate to an adverse effect of a medication. (See "Drug prescribing for older adults", section on 'Review current drug therapy'.)

Safety of inhaled glucocorticoid-LABA combination therapy in asthma (September 2016)

In early studies, a small increase in asthma-related deaths associated with salmeterol led the US Food and Drug Administration to place a boxed warning on the use of long-acting beta agonists (LABAs) in asthma. While concerning, the number of events was small, and it could not be determined if the potential risk of salmeterol could be mitigated by combining LABAs with inhaled glucocorticoids. Three large randomized trials including 30,000 children and adults found no increase in asthma-related adverse events or deaths among patients who used combination inhalers with salmeterol or formoterol plus an inhaled glucocorticoid versus glucocorticoid monotherapy [35-37]. These studies support the safety of these fixed-dose combination inhalers in patients with moderate-to-severe asthma. (See "Beta agonists in asthma: Controversy regarding chronic use", section on 'Potential risk mitigation'.)

Lack of association between acetaminophen and asthma in children (September 2016)

More frequent use of acetaminophen was associated with increased asthma-related complications in children in observational studies, leading to the recommendation by some for children with asthma to avoid acetaminophen. However, these findings were not replicated in a prospective, randomized trial comparing acetaminophen and ibuprofen use [38]. In this trial, 300 children with mild persistent asthma were randomly assigned to as-needed treatment with acetaminophen or ibuprofen for fever or pain over a 48-week period. All children received standard controller therapy for asthma. There was no significant difference between the two groups in the number of asthma exacerbations requiring treatment with systemic glucocorticoids or in the number of asthma exacerbations. Thus, we do not advise restricting the use of acetaminophen in children with asthma. (See "Virus-induced wheezing and asthma: An overview", section on 'Acetaminophen use for febrile illnesses'.)

Screening and prevention of hydroxychloroquine retinopathy (August 2016)

Antimalarial agents hydroxychloroquine (HCQ) and chloroquine are widely used for the treatment of systemic lupus erythematosus, rheumatoid arthritis, and other inflammatory and dermatologic conditions, and are generally thought to be safe. Retinal toxicity is a known risk, however, and measures to minimize this potential toxicity are necessary. Recently, the American Academy of Ophthalmology issued revised recommendations for screening and prevention of retinopathy [39]. Key changes include the following:

The maximum daily dose of HCQ should not exceed 5 mg/kg (previously 6.5 mg/kg), and the maximum daily dose of chloroquine should not exceed 2.3 mg/kg (previously 3 mg/kg).

Real body weight should be used to calculate dose limits instead of ideal body weight.

In addition to exceeding the recommended daily dose, major risk factors for retinal toxicity include antimalarial use for greater than five years, renal disease, concomitant tamoxifen use, and the presence of macular disease. All patients should undergo a baseline eye examination before or within a year of beginning treatment with an antimalarial drug and, if normal, at least annually after five years of exposure for patients without major risk factors. For the treatment of rheumatic diseases, we typically use standard daily doses of HCQ (non-weight-based, eg, up to 400 mg) in individuals weighing 80 kg or more. In patients weighing less than 80 kg, we use a lower daily dose of HCQ up to the maximum of 5 mg/kg of real body weight. (See "Antimalarial drugs in the treatment of rheumatic disease", section on 'Ocular health'.)

Complications of dopaminergic therapy for restless legs syndrome (August 2016)

The main complication of long-term dopaminergic therapy for restless legs syndrome/Willis-Ekbom disease (RLS/WED) is “augmentation,” or an increase in symptom severity with increasing doses of medication. This may present as earlier onset of symptoms during the day, increased intensity of symptoms, or spread to previously uninvolved body parts (eg, arms, trunk). New consensus-based guidelines on the identification and management of augmentation recommend avoiding dopaminergic drugs as first-line therapy for RLS/WED when possible, screening patients on dopaminergic therapy for augmentation as part of routine clinical follow-up (table 4), and using the lowest doses possible to control symptoms [40]. Treatment options for augmentation reviewed in the guideline include altering the dopaminergic dosing schedule, switching to an extended release preparation, and transitioning to an alpha-2-delta calcium channel ligand (eg, gabapentin enacarbil, pregabalin). In addition, alternative causes of worsening symptoms should be sought, such as low iron stores, sleep deprivation, and certain drugs such as serotonergic antidepressants. (See "Treatment of restless legs syndrome/Willis-Ekbom disease and periodic limb movement disorder in adults", section on 'Augmentation'.)

New guidelines for the management of Stevens-Johnson/toxic epidermal necrolysis syndrome (August 2016)

The British Association of Dermatologists released new guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), a severe and potentially fatal mucocutaneous drug reaction [41]. The guidelines provide evidence-based recommendations for the diagnosis, severity assessment, and management of SJS/TEN. Specific areas covered include initial management, supportive care, and therapies intended to reduce mortality, such as intravenous immune globulins, systemic corticosteroids, and cyclosporine. The treatment of eye involvement, including systemic therapies and amniotic membrane transplantation to prevent permanent ocular sequelae, as well as the management of oral, urogenital, and airway mucosal involvement are also addressed. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Management, prognosis, and long-term sequelae", section on 'General principles'.)

Safety of intranasal triamcinolone for allergic rhinitis in pregnancy (July 2016)

Intranasal glucocorticoid sprays are highly effective for treatment of allergic rhinitis, but concerns remain about their use in pregnancy. The overall safety of intranasal glucocorticoids in pregnancy was supported by an observational cohort study of over 140,000 pregnant women, of whom 2502 were exposed to these medications during the first trimester [42]. Exposure was not associated with increased rates of miscarriage or overall rates of major congenital malformations compared with non-exposure. Triamcinolone was the only intranasal glucocorticoid of potential concern; first trimester use was associated with abnormalities of the respiratory system and choanal atresia. Although these findings are not conclusive, we prefer to use other intranasal glucocorticoids in the first trimester, such as intranasal mometasone, fluticasone, or budesonide, pending further data [43]. (See "Recognition and management of allergic disease during pregnancy", section on 'Glucocorticoid nasal sprays'.)

Outbreak of Burkholderia cepacia infection associated with contaminated oral liquid docusate (June 2016)

In June 2016, a multistate outbreak of Burkholderia cepacia infection was reported in the United States [44]. B. cepacia typically causes lung colonization and infection in patients with cystic fibrosis (CF), but most cases in this outbreak have involved mechanically ventilated intensive care unit patients without CF. The types of infections involved have not yet been reported. Because cases in one state have been associated with contaminated oral liquid docusate, the United States Centers for Disease Control and Prevention (CDC) recommends that facilities not use liquid docusate products for any patient. PharmaTech LLC, the manufacturer of the contaminated product, Diocto Liquid, has voluntarily recalled all non-expired lots [45]. Updated information about the outbreak and public health reporting can be found on the CDC’s website. (See "Epidemiology, pathogenesis, microbiology, and diagnosis of hospital-acquired and ventilator-associated pneumonia in adults", section on 'Outbreak of Burkholderia cepacia infection'.)

Mild skin-limited allergic reactions to antibiotics in children (June 2016)

It is not uncommon for young children to develop mild skin-limited reactions (eg, rash, hives) to antibiotics, particularly amoxicillin, during treatment for routine infections. Most of these reactions do not represent serious drug allergy, but IgE-mediated anaphylaxis can first present in this manner, so caution is necessary. In a new study of over 800 young children referred to an allergy clinic with past mild cutaneous reactions to amoxicillin, all children underwent a two-step challenge [46]. Ninety-four percent had no reaction, 2 percent had mild immediate reactions (isolated hives), and 4 percent had mild delayed reactions. Skin testing was later performed on the subset with immediate initial reactions, and only 1 of 17 children had a positive result, indicating that skin testing would not have been useful in identifying these children before challenge. At present, we do not advocate this approach unless there is no alternative antibiotic and allergy referral is not available. However, this study provides valuable information about the pathophysiology of this common type of reaction and may allow for safe rechallenge protocols to be developed in the future for use in the primary care setting. (See "Penicillin allergy: Delayed hypersensitivity reactions", section on 'Children'.)

Vascular disease in patients with CML taking tyrosine kinase inhibitors (June 2016)

For the initial treatment of chronic myeloid leukemia (CML), the second-generation tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib are able to achieve faster and deeper responses than imatinib, but have a different toxicity profile, including increased cardiovascular toxicity. A retrospective cohort study used a Swedish population-based registry to analyze the risk of vascular events in 896 patients with chronic-phase CML treated with imatinib, dasatinib, or nilotinib [47]. When compared with age- and sex-matched controls, patients treated with any TKI had an increased risk of vascular events, but the association was greater with the second-generation agents. Event rates for myocardial infarction among patients treated with nilotinib, dasatinib and imatinib were 29, 19, and 8 per 1000 person-years, respectively. These findings underscore the importance of screening for and optimal management of traditional cardiac risk factors. Although it is not known whether anticoagulation helps, many clinicians offer low-dose aspirin for general cardiovascular prophylaxis in patients taking TKIs. (See "Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia", section on 'Vascular disease'.)

Dosing of direct oral anticoagulants in obese patients (June 2016)

Limited data are available to guide dosing of direct oral anticoagulants (DOACs; dabigatran, apixaban, edoxaban, rivaroxaban) in patients with obesity. The International Society of Thrombosis and Hemostasis (ISTH) has issued guidance on this subject [48]. The major recommendations include use of DOACs at standard doses for those with a body mass index (BMI) ≤40 kg/m2 or weight <120 kg, and avoidance of DOACs in individuals with a BMI >40 kg/m2 or weight ≥120 kg. (See "Direct oral anticoagulants: Dosing and adverse effects".)

Restriction of fluoroquinolone use in uncomplicated infections (May 2016)

The US Food and Drug Administration (FDA) has stated that the serious adverse effects associated with fluoroquinolones generally outweigh the benefits for patients with uncomplicated acute sinusitis, acute bronchitis, and urinary tract infections who have other treatment options [49]. For patients with these infections, fluoroquinolones should be reserved for those who have no alternative treatment options. This announcement was based on an FDA safety review showing that systemic fluoroquinolone use is associated with disabling and potentially permanent serious side effects, including those involving the tendons, muscles, joints, nerves, and central nervous system. (See "Fluoroquinolones", section on 'Restriction of use for uncomplicated infections'.)

VACCINES

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

Growing evidence has suggested that HIV-infected individuals have a disproportionate incidence of invasive meningococcal disease, with an estimated risk 5 to 13 times that of the general population. Because of this, the Centers for Disease Control and Prevention in the United States now recommends meningococcal conjugate vaccination (with MenACWY-CRM [Menveo] or MenACWY-D [Menactra]) for all HIV-infected individuals older than two months [50]. This includes a primary vaccine series for those who have not previously received it and interval booster doses every several years; the precise schedule depends on the age of the patient (table 5). Individuals may also have separate indications for serogroup B meningococcal vaccination. Evidence of vaccine efficacy in HIV-infected patients is limited to immunologic outcomes. (See "Immunizations in HIV-infected patients", section on 'Meningococcal vaccine' and "Meningococcal vaccines".)

HPV vaccine dosing for individuals younger than 15 years (November 2016)

For individuals younger than 15 years receiving human papillomavirus (HPV) vaccination, two vaccine doses administered at least six months apart are now recommended by the Centers for Disease Control and Prevention in the United States [51]. This new vaccine schedule is similar to schedules used in other countries and is supported by data demonstrating that two vaccine doses in young females have similar immunogenicity to three doses. However, the efficacy of fewer than three doses for prevention of cervical neoplastic disease has not been directly established. Three doses are still recommended for individuals older than 15 years because they have lower immunologic responses to HPV vaccination. (See "Recommendations for the use of human papillomavirus vaccines", section on 'Immunization schedule'.)

Complement-mediated HUS, eculizumab, meningococcal group B vaccine, and risk for hemolytic anemia (September 2016)

The introduction of eculizumab (a monoclonal antibody that blocks activation of the terminal complement cascade) has significantly improved the outcome of patients with complement-mediated hemolytic uremic syndrome (HUS), a rare, potentially life-threatening disease. Eculizumab therapy increases the risk of meningococcal infection, and vaccination against Neisseria meningitidis (with a quadrivalent vaccine and, for patients older than 10 years, a serogroup B vaccine) has been recommended in treated patients. However, a review from Health Canada reported an increased risk of hemolytic anemia following receipt of the multicomponent meningococcal serogroup B vaccine (Bexsero, MenB-4C) among patients who were already being treated with eculizumab [52]. To minimize the risk of hemolysis, serogroup B meningococcal vaccination should be performed prior to the initiation of eculizumab therapy, if possible. In cases where prior vaccination is not possible, the manufacturer of eculizumab recommends that serogroup B meningococcal vaccination should be administered when patients are stable and their disease is well controlled and it is assumed that the blood level of eculizumab is high. (See "Complement-mediated hemolytic uremic syndrome", section on 'Adverse effects'.)

Investigational inactivated vaccine to prevent zoster and postherpetic neuralgia (September 2016)

The live attenuated zoster vaccine reduces the risk of herpes zoster with a reported vaccine efficacy of 60 to 70 percent in adults 50 years and older but appears to have decreased efficacy in adults 70 years and older. In an initial trial of the experimental recombinant inactivated zoster vaccine (HZ/su), administered in two doses, overall vaccine efficacy was 97 percent in adults 50 years and older. In a subsequent randomized, placebo-controlled trial of 13,900 patients aged 70 and older, vaccine efficacy for preventing herpes zoster and postherpetic neuralgia was each approximately 90 percent after a mean 3.7-year follow-up [53]. No serious adverse events were reported in either trial; however, reactions such as pain at the injection site and myalgias were more common among those who received the vaccine. If approved, this inactivated vaccine may be particularly useful for such older individuals and immunocompromised individuals who cannot receive live vaccines, but it requires two doses for initial protection. (See "Vaccination for the prevention of shingles (herpes zoster)", section on 'Investigational vaccines'.)

Inactivated influenza vaccine for 2016-2017 season in the northern hemisphere (August 2016)

The effectiveness of seasonal influenza vaccines varies from season to season and is determined by a number of factors, including the match between circulating influenza strains and influenza strains in the vaccine. During the 2015-2016 influenza season, data from the United States Influenza Vaccine Effectiveness Network indicated that inactivated influenza vaccine (IIV) was 63 percent effective in preventing influenza in children, but live attenuated influenza vaccine (LAIV) was not effective [54]. Findings of poor or lower than expected LAIV effectiveness were also noted during the 2013-2014 and 2014-2015 seasons in the United States. These findings are inconsistent with studies sponsored by the manufacturer and studies from other countries that found LAIV was effective (ranging from 46 to 58 percent) during the 2015-2016 season [55-58]; however, LAIV was less effective than IIV in all of these studies [59]. In August 2016, the United States Centers for Disease Control and Prevention recommended that LAIV not be used during the 2016-2017 influenza season [60]. While some countries have elected to continue using LAIV [55], we suggest IIV rather than LAIV for the 2016-2017 influenza season in the northern hemisphere. (See "Seasonal influenza in children: Prevention with vaccines", section on 'IIV versus LAIV' and "Seasonal influenza vaccination in adults", section on 'Choice of vaccine formulation'.)

Oral vaccine to prevent cholera in high-risk travelers (June 2016)

Cholera, caused by infection with the bacterium Vibrio cholerae, is characterized by severe watery diarrhea, which can rapidly lead to dehydration. In June 2016, a live attenuated oral cholera vaccine (Vaxchora) was approved by the US Food and Drug Administration for prevention of cholera caused by serogroup O1 in adults 18 through 64 years of age traveling to affected areas [61]. Most travelers are at low risk for cholera infection; those who warrant vaccination include aid, refugee, and health care workers planning to work among or near displaced populations (eg, in crowded camps and urban slums) in endemic or epidemic settings. Long-stay travelers in very high-risk countries are also appropriate vaccine recipients. In a trial of healthy volunteers, a single dose of vaccine given prior to an oral challenge with a V. cholerae O1 strain was 80 to 90 percent effective in preventing moderate to severe cholera [62]. The effectiveness of Vaxchora for populations living in cholera-affected areas has not been established. (See "Immunizations for travel", section on 'Cholera vaccine'.)

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