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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 2017. | This topic last updated: Dec 08, 2017.

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

You can check drug interactions by going to the Lexicomp drug interactions program included with UpToDate. This program is available to online desktop and mobile users and can be accessed from the Drug Interactions tab located in the top right corner of any screen and in the search results list after searching on a drug name.

DRUG INTERACTIONS

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'.)

RECENT APPROVALS - ANTIMICROBIALS

Letermovir for cytomegalovirus prophylaxis in allogeneic hematopoietic cell transplant recipients (November 2017)

Letermovir, a novel anti-cytomegalovirus (CMV) agent with intravenous and oral formulations, was approved by the US Food and Drug Administration and Health Canada in November 2017 for CMV prophylaxis in adult CMV-seropositive (CMV R+) allogeneic hematopoietic cell transplant (HCT) recipients [4-6]. Unlike ganciclovir and valganciclovir, letermovir is not myelosuppressive. In a phase III trial that has not yet been published, all-cause mortality among CMV-seropositive allogeneic HCT recipients was lower with letermovir than placebo [7]. In addition, fewer patients receiving letermovir developed clinically significant CMV or were considered to have failed prophylaxis. (See "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Primary prophylaxis'.)

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 [8]. 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 [9]; 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) [10-13]. 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 [14]. 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 [15,16]. 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 [17]. 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'.)

RECENT APPROVALS - DERMATOLOGIC AND ALLERGY THERAPIES

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 [18-20]. 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 [21]. 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 [22]. 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 [23]. 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'.)

RECENT APPROVALS - HEMATOLOGIC AND ANTICOAGULANT

Emicizumab for prophylaxis in hemophilia A with an inhibitor (November 2017)

Emicizumab, a bifunctional monoclonal antibody that can substitute for factor VIII (figure 1), was approved by the US Food and Drug Administration in November 2017 for prophylaxis against bleeding in individuals with hemophilia A who have an inhibitor [24]. It is administered subcutaneously once per week. In a randomized trial comparing emicizumab with standard therapy in 109 individuals with hemophilia and an inhibitor, emicizumab reduced the annualized bleeding rate from 23 to 3 events [25]. Three patients receiving emicizumab plus an activated prothrombin complex concentrate (aPCC) developed a thrombotic microangiopathy, and two had a thrombosis in an unusual site. Emicizumab cannot be used for acute bleeding. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab'.)

Letermovir for cytomegalovirus prophylaxis in allogeneic hematopoietic cell transplant recipients (November 2017)

Letermovir, a novel anti-cytomegalovirus (CMV) agent with intravenous and oral formulations, was approved by the US Food and Drug Administration and Health Canada in November 2017 for CMV prophylaxis in adult CMV-seropositive (CMV R+) allogeneic hematopoietic cell transplant (HCT) recipients [4-6]. Unlike ganciclovir and valganciclovir, letermovir is not myelosuppressive. In a phase III trial that has not yet been published, all-cause mortality among CMV-seropositive allogeneic HCT recipients was lower with letermovir than placebo [7]. In addition, fewer patients receiving letermovir developed clinically significant CMV or were considered to have failed prophylaxis. (See "Prevention of viral infections in hematopoietic cell transplant recipients", section on 'Primary prophylaxis'.)

CAR-T therapy for relapsed DLBCL after autologous transplantation (October 2017)

Optimal treatment is not well defined for patients with diffuse large B cell lymphoma (DLBCL) that relapses after autologous hematopoietic cell transplantation (HCT). Axicabtagene ciloleucel (axi-cel) is a CD19-directed, chimeric antigen receptor T (CAR-T) cell autologous immunotherapy that was recently approved by the US Food and Drug Administration (FDA) for treatment of adults with relapsed or refractory DLBCL after two or more lines of systemic therapy [26]. In a preliminary report, a single infusion of axi-cel achieved complete and partial remissions in 51 and 21 percent of patients, respectively, with an estimated median response duration of nine months. Treatment is associated with potentially life-threatening neurologic events and cytokine release syndrome, and axi-cel is only available under a Risk Evaluation and Mitigation Strategy (REMS) in the United States. (See "Treatment of relapsed or refractory diffuse large B cell lymphoma", section on 'Chimeric antigen receptor T (CAR-T) cells'.)

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 [27]. 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 [28]. 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 [29]. 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 [30]. Midostaurin has been approved by the US Food and Drug Administration (FDA) for this use [31] 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 [32], confirming results from an earlier trial [33]. 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) [34]. 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 [35]. 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 [36] 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 [37]. 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 [38]. 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 [39]. 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 [40]. 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 [41]. 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 [42-44]. 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 [45]. (See "Initial treatment of advanced stage (III/IV) follicular lymphoma", section on 'Immunotherapy-based treatment'.)

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 [46]. 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'.)

RECENT APPROVALS - ONCOLOGIC

Vaginal dehydroepiandrosterone for genitourinary symptoms in postmenopausal cancer survivors (October 2017)

Treatment of genitourinary syndrome of menopause (GSM) in survivors of estrogen-sensitive malignancies is challenging because vaginal estrogen may be contraindicated. In a randomized trial comparing two doses of vaginal dehydroepiandrosterone (DHEA) with a nonhormonal vaginal moisturizer in postmenopausal cancer survivors (primarily breast cancer), all three groups reported similar improvement in dyspareunia and vaginal dryness symptoms at 12 weeks, but only the higher dose DHEA group reported significant improvement in sexual function over baseline on a validated sexual health measure [47]. Vaginal DHEA holds promise as a GSM treatment for breast cancer survivors, but safety concerns remain because it increases serum estrogen levels. (See "Treatment of genitourinary syndrome of menopause (vulvovaginal atrophy)", section on 'Women with breast cancer'.)

Nivolumab for second-line treatment of advanced hepatocellular carcinoma (October 2017)

Nivolumab is a fully human monoclonal antibody that targets the programmed cell death-1 receptor, restoring T-cell immune activity directed against the tumor cell. In the Checkmate 040 trial, nivolumab was administered to 255 patients with advanced hepatocellular cancer (HCC) and Child Pugh A or B cirrhosis whose disease had either progressed on sorafenib or who refused or were intolerant of the drug [48]. An objective antitumor response was found in 49 patients (19 percent), including a complete response in six patients. Durable benefit was observed both in sorafenib-naïve and sorafenib-experienced patients [49]. Most adverse events were mild and transient. In September 2017, the US Food and Drug Administration expanded nivolumab indications to include treatment of HCC in patients who have been previously treated with sorafenib [50]. While regorafenib was also approved for this patient group in April 2017, we now suggest treatment with nivolumab given the potential for a higher objective response rate (including some complete responders) and a more favorable side effect profile compared with regorafenib. (See "Systemic treatment for advanced hepatocellular carcinoma", section on 'Checkpoint inhibitor immunotherapy'.)

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 [51], and in a nonrandomized phase II study abemaciclib showed single agent activity in patients with progression following chemotherapy [52]. 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'.)

Expanded indications for PD-1 inhibitors in advanced gastric cancer (September 2017)

Pembrolizumab is an immune checkpoint inhibitor that targets the programmed cell death 1 protein (PD-1), a key receptor in a pathway by which cancers evade immune surveillance. The efficacy of pembrolizumab in previously treated gastric and esophagogastric junction (EGJ) adenocarcinomas was shown in a cohort of 259 patients included in the KEYNOTE-059 trial, which showed a higher response rate in patients whose tumors overexpressed the ligand for PD-1 (PD-L1) [53]. Previously, pembrolizumab had been approved for treatment of refractory advanced tumors, including gastric/EGJ adenocarcinomas, that had high levels of microsatellite instability or deficient mismatch repair proteins. In September 2017, based largely upon the results of the KEYNOTE-059 study, pembrolizumab approval was extended to include patients with PD-L1-overexpressing gastric and EGJ adenocarcinomas who had received two or more lines of chemotherapy, and, if appropriate, HER2-targeted therapy [54]. In Japan, a second PD-1 inhibitor, nivolumab, has been approved for any unresectable advanced or recurrent gastric cancer that has progressed after conventional chemotherapy. (See "Systemic therapy for locally advanced unresectable and metastatic esophageal and gastric cancer", section on 'PD-1 and PD-L1 inhibitors'.)

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 [55-58]. These data have led to approvals by the US Food and Drug Administration of both niraparib and olaparib in this setting [59,60]. 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 [61]. 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 [62]. (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 [63]. 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".)

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 [64]. 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'.)

RECENT APPROVALS - OTHER

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 [65]. 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'.)

DRUG WITHDRAWALS

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) [66-68]. 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'.)

ADVERSE REACTIONS AND WARNINGS

Acetaminophen use in pregnancy and risk of attention-deficit/hyperactivity disorder (November 2017)

Epidemiologic studies have reported an association between in utero acetaminophen exposure and subsequent development of attention-deficit/hyperactivity disorder (ADHD)-like behaviors, but data are inconclusive. Now, a study from Norway that adjusted for maternal use of acetaminophen before pregnancy, familial risk of ADHD, and indications for using acetaminophen reported no association between ADHD and use <8 days, but an increased risk with use >29 days [69]. Moreover, paternal and maternal use of acetaminophen were similarly associated with ADHD risk. The authors hypothesized that paternal acetaminophen use before pregnancy may have male germ-line epigenetic effects. These data may reassure pregnant women with fever or pain who are considering short-term use of acetaminophen. (See "Prenatal care: Patient education, health promotion, and safety of commonly used drugs", section on 'Acetaminophen'.)

Selective androgen receptor modulators: Composition of products sold on the internet (November 2017)

Selective androgen receptor modulators (SARMs) are a class of compounds that have become popular as performance-enhancing drugs. None are approved for use, but many SARM products are sold via the internet, the majority with inaccurate labeling. In a study of 44 SARM products purchased from the internet and analyzed using procedures approved by the World Anti-Doping Agency, only 18 had accurate labeling (eg, they contained the correct SARM and dosage) [70]. Four products contained no active compounds at all, and the remainder were inaccurately labeled (most had at least one additional unapproved drug or substance [eg, growth hormone secretagogues and/or androgens]). (See "Use of androgens and other hormones by athletes", section on 'SARMs'.)

Acetylcysteine does not prevent contrast nephropathy (November 2017)

Radiocontrast media may cause acute kidney injury (AKI) among high-risk patients. Earlier studies have been inconsistent but indicated that the administration of oral acetylcysteine may decrease the risk of AKI, and led to our previous suggestion to administer acetylcysteine before and the day of angiography to patients at risk of contrast nephropathy. A recent randomized trial in over 5000 patients at increased risk for nephropathy who were undergoing scheduled angiography found that oral acetylcysteine, compared with placebo, did not prevent death, need for dialysis, or decline in kidney function [71]. The trial was a 2 by 2 factorial design and also compared intravenous sodium bicarbonate with isotonic saline, finding no benefit for sodium bicarbonate. UpToDate recommends giving isotonic saline rather than sodium bicarbonate and now suggests not giving acetylcysteine prior to angiography. (See "Prevention of contrast nephropathy associated with angiography", section on 'Acetylcysteine'.)

Frequency for dosing of oral iron (November 2017)

For many years, iron deficiency has been treated with oral iron given at least once per day, despite significant gastrointestinal side effects in the majority of individuals. A small, unblinded randomized trial has now demonstrated that giving oral iron every other day rather than every day resulted in greater iron absorption and fewer gastrointestinal side effects [72]. Alternate-day dosing is also supported by mechanistic studies that showed favorable effects on hepcidin, a negative regulator of intestinal iron absorption and iron release from macrophages. We now suggest that patients treated with oral iron for iron deficiency take the iron every other day rather than daily. (See "Treatment of iron deficiency anemia in adults", section on 'Dosing and administration (oral iron)'.)

Thrombotic microangiopathy due to quinine ingestion (October 2017)

Quinine is a common cause of drug-induced thrombotic microangiopathy (DITMA). A new report illustrates common features among the largest series of individuals (18 women and 1 man) with quinine-associated DITMA [73]. Most of the patients had a prior history of quinine-induced fever, nausea, headache, or confusion. Many reported symptoms within four hours of quinine ingestion. All had acute kidney injury. Eighteen required dialysis, and two underwent renal transplantation. Eighteen had quinine-dependent antibodies. Individuals presenting with thrombotic microangiopathy require specific questioning about quinine ingestion since the source may be a beverage or an over-the-counter tablet. (See "Drug-induced thrombotic microangiopathy", section on 'Quinine'.)

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 [74]. 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) [75]. 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 [76]. 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 [77]. 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 [78]. 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'.)

VACCINES

Low effectiveness of the influenza vaccine in Australia (December 2017)

During the 2017 influenza season in the southern hemisphere, Australia reported very high numbers of influenza cases, multiple institutional outbreaks, and increased numbers of hospitalizations and deaths [79]. Influenza A H3N2, which usually causes more severe disease than other strains, predominated. The overall adjusted vaccine effectiveness in Australia was estimated to be 33 percent, but only 10 percent for H3N2. Since the vaccine for the 2017-2018 influenza season in the northern hemisphere has the same composition as the vaccine used in the southern hemisphere during the 2017 season, there is concern that regions in the northern hemisphere could experience a severe influenza season, particularly if influenza A H3N2 virus circulates widely [80]. (See "Seasonal influenza vaccination in adults", section on 'Low effectiveness in the Southern Hemisphere during the 2017 season'.)

New adjuvanted recombinant hepatitis B vaccine (November 2017)

Hepatitis B vaccination is the best way to prevent hepatitis B virus transmission. Available nonadjuvanted recombinant vaccines are effective and extremely safe, although they require three doses and 5 to 10 percent of patients do not respond. In November 2017, the US Food and Drug Administration granted conditional approval of a new adjuvanted vaccine (HEPLISAV-B) for adults 18 years and older [81]. This vaccine, given in two doses, appears more immunogenic than the nonadjuvanted vaccines and is generally well tolerated. However, there are ongoing safety concerns regarding a potentially increased risk of acute myocardial infarction and immune mediated disorders, which will be further evaluated in a phase 4 study. The optimal use of this vaccine is thus still to be determined. (See "Hepatitis B virus vaccination", section on 'Single antigen vaccines'.)

Inactivated zoster vaccine in the United States (October 2017)

To date, only a live zoster vaccine has been available to prevent herpes zoster and postherpetic neuralgia; it is contraindicated in highly immunocompromised patients, and its efficacy is reduced in patients ≥70 years old. In October 2017, the US Food and Drug Administration approved an inactivated recombinant zoster vaccine that reduces the risk of herpes zoster by ≥90 percent, even among older individuals [82]. The Advisory Committee on Immunization Practices has recommended the recombinant (administered in two doses) rather than the live attenuated vaccine for all adults ≥50 years old, although not all committee members agreed given the lack of data in minority groups and on the long-term vaccine safety and effectiveness in real-world settings [83]. The optimal use of the inactivated vaccine continues to be assessed. Recommendations by the Centers for Disease Control and Prevention are forthcoming. (See "Vaccination for the prevention of shingles (herpes zoster)", section on 'Vaccine formulations'.)

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 [84,85]. Routine influenza immunization with a licensed, age-appropriate vaccine (table 2) 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 [86]. 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'.)

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