Official reprint from UpToDate www.uptodate.

com 2013 UpToDate

What's new in drug therapy Authors Diane MF Savarese, MD Jonathan M Zand, PharmD BCPS Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Nov 2013. | This topic last updated: .. 12, 2556. 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 for online users at this time, and can be accessed from the New Search tab or in the Drug Interactions section of the individual monographs in the Lexicomp reference when using UpToDate online. DRUG INTERACTIONS Coprescription of clarithromycin and calcium channel blockers (November 2013) In a population-based study of older adults, coprescribing clarithromycin with a calcium channel blocker (compared with azithromycin plus a calcium channel blocker) was associated with a small but statistically significant increase in risk of hospitalization with acute kidney injury [1]. Coprescription with clarithromycin was also associated with a higher risk of hospitalization with hypotension and all-cause mortality. Although the risks associated with the combined use of clarithromycin and calcium channel blockers appear to be small, they should be considered when deciding whether to use these agents in combination in older patients or other patients at risk for acute kidney injury. (See "Azithromycin, clarithromycin, and telithromycin", section on 'Drug interactions'.) Interactions during treatment of HCV-1 with newer antivirals (November 2013) Boceprevir and telaprevir are orally available inhibitors of hepatitis C virus NS 3/4A protease that have substantially improved virologic response rates in treatment of HCV genotype-1 (HCV-1) infection when combined with pegylated-interferon and ribavirin. Boceprevir and telaprevir are cleared by and are also strong inhibitors of CYP3A; numerous drug interactions have been noted. In 2013 additional data became available clarifying several interactions and the lists of major interactions with suggestions for management have been updated (table 1 and table 2) [2-4]. These drugs should not be coadministered with medications that are CYP3A4/5 inducers or with drugs that are highly dependent on CYP3A4/5 for clearance and associated with serious and/or life-threatening events when plasma concentrations are elevated. (See "Treatment regimens for chronic hepatitis C virus genotype 1", section on 'Drug interactions with protease inhibitors'.) Nilotinib and proton pump inhibitors (July 2013) Nilotinib is a potent selective Bcr-Abl tyrosine kinase inhibitor (TKI) that is useful for the treatment of chronic myeloid leukemia. Dissolution and absorption of the orally-administered capsule is dependent upon the presence of gastric acidity, and a pharmacokinetic study showed that systemic concentrations are decreased among individuals receiving proton pump inhibitors [5]. Although H2 antagonists and antacids may be used with nilotinib if there is adequate separation of dosing, the concomitant use of proton pump inhibitors and

nilotinib should be avoided. The prescribing information in the US for nilotinib has been updated accordingly [6]. (See "Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia", section on 'Dosing and drug interactions'.) NEW DRUGS AND US DRUG APPROVALS Posaconazole delayed release tablets for antifungal prophylaxis (December 2013) Posaconazole, an azole antifungal agent with activity against yeasts and molds, was previously available only as an oral suspension requiring oral intake, optimally with a high-fat meal, for effective absorption. The US Food and Drug Administration has approved delayed release tablets for the prophylaxis of invasive Aspergillus and Candida infections in patients at high risk for these infections, such as those with hematologic malignancies with prolonged chemotherapy induced neutropenia and hematopoietic cell transplant recipients with graft-versushost disease [7]. The delayed release tablets are especially useful in patients who cannot eat a full meal, since they result in higher plasma drug concentrations than the oral suspension under fasting conditions. (See "Pharmacology of azoles", section on 'Posaconazole'.) Telavancin receives expanded approval for HAP and VAP (October 2013) Telavancin, a glycopeptide antibiotic with activity against methicillin-resistant Staphylococcus aureus (MRSA), was first approved by US FDA in 2009 for treatment of complicated skin and skin structure infections. In 2013 telavancin became available again, following its unavailability due to unspecified manufacturing problems in 2012 and 2013. Telavancin has also received expanded approval by FDA for the treatment of hospital-acquired and ventilator-acquired pneumonia (HAP and VAP) caused by Staphylococcus aureus, but not for other bacterial causes of HAP or VAP [8]. The licensing information in the US has been revised to include boxed warnings of increased mortality in patients with renal insufficiency who were treated with telavancin for HAP or VAP compared with vancomycin, risk of new onset nephrotoxicity, and potential teratogenicity [9]. Telavancin is recommended only when alternative agents cannot be used. (See "Treatment of hospital-acquired, ventilatorassociated, and healthcare-associated pneumonia in adults", section on 'Telavancin'.) Approval of topical brimonidine for persistent facial erythema in rosacea (August 2013) Pharmacologic treatment options for persistent facial erythema in rosacea are limited. In August 2013, the US Food and Drug Administration approved the use of brimonidine 0.33% gel, a vasoconstrictive alpha-2 adrenergic receptor agonist, for the treatment of persistent (nontransient) facial erythema of rosacea in adults based upon two randomized trials that demonstrated superiority of brimonidine gel over placebo [10]. Topical brimonidine offers an alternative to laser and intense pulsed light therapy for facial erythema of rosacea. Brimonidine gel is expected to become commercially available in the United States later in 2013. (See "Management of rosacea", section on 'Topical brimonidine'.) Afatinib for advanced non-small cell lung cancer with a mutation in the epidermal growth factor receptor (August 2013) Epidermal growth factor receptor (EGFR) inhibitors are active in patients with advanced non-small cell lung cancer when the tumor contains an activating mutation in the EGFR. Afatinib (Gilotrif), an irreversible inhibitor of EGFR, was approved by the US Food and Drug Administration in July 2013 for use in patients with EGFRmutation positive advanced lung cancer. Approval was based upon the results of a phase III clinical trial that demonstrated a significant prolongation of progression free and overall survival compared with chemotherapy [11,12]. (See "Systemic therapy for advanced non-small cell lung cancer with an activating mutation in the epidermal growth factor receptor", section on 'Afatinib'.) Recombinant human factor IX for routine prophylaxis in hemophilia B (July 2013) Replacement of a deficient clotting factor is the cornerstone of treatment for hemophilia. The US Food and Drug Administration has approved a second recombinant human factor IX product (Rixubis), for the treatment and prevention of bleeding, perioperative management, and routine prophylaxis against bleeding for individuals with hemophilia B [13]. It is not licensed for immune tolerance induction (ie, inhibitor eradication) in those with inhibitors to factor IX. Studies comparing the efficacy of this product with the other recombinant human factor IX (BeneFIX) or with plasma-derived factor IX products are not available. (See "Treatment of hemophilia", section on

'Recombinant factor IX'.) Ibrutinib for mantle cell lymphoma (June 2013) Ibrutinib has been approved by the US Food and Drug Administration for the treatment of patients with recurrent or refractory mantle cell lymphoma (MCL). Approval was based on a phase II trial of ibrutinib in 111 patients with relapsed or refractory MCL [14]. The treatment was well tolerated and the overall response rate was 68 percent (21 percent complete) with an estimated median duration of response of 17.5 months. The high response rate and good tolerability of ibrutinib support ibrutinib as another treatment option for patients with MCL, many of whom are unable to tolerate other therapies. (See "Treatment of relapsed or refractory mantle cell lymphoma", section on 'Other regimens'.) Lenalidomide in relapsed mantle cell lymphoma (June 2013) The US Food and Drug Administration has approved lenalidomide for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib [15]. Approval was largely based upon an international phase II trial of single agent lenalidomide in 134 patients with relapsed or refractory MCL who had received prior therapy with bortezomib [16]. Responses were seen in 28 percent with a median duration of response of 17 months. The treatment was well tolerated and the most common severe toxicities were hematologic. Lenalidomide may be preferred for the treatment of older or frail patients with relapsed or refractory MCL who are unlikely to tolerate conventional chemoimmunotherapy. (See "Treatment of relapsed or refractory mantle cell lymphoma", section on 'Lenalidomide'.) DRUG WITHDRAWALS Marketing and sales of ponatinib suspended (November 2013) Ponatinib was approved by the US FDA in 2012 for the treatment of chronic myeloid leukemia (CML) in adults with resistance or intolerance to prior tyrosine kinase inhibitor therapy and is the only TKI that has demonstrated activity against the CML T3151 BCR-ABL type mutation [17]. Approval was accompanied by a boxed warning of vascular events and liver toxicity. Subsequent reports suggest higher rates of treatment-related complications than initially reported, including life-threatening arterial and venous thromboembolic events in 20 percent of patients receiving ponatinib and severe narrowing of blood vessels [18]. At the suggestion of FDA, the manufacturer suspended marketing and sales in October 2013. The drug remains available from the manufacturer through a registry program for select patients [19]. Enrollment information may be found at http://www.ariadpass.com/healthcare-professional/ or by calling 1-855-447-7277. (See "Treatment of chronic myeloid leukemia in chronic phase after failure of initial therapy", section on 'Ponatinib' and "Ponatinib: Drug information".) Withdrawal of ganciclovir ocular implants (August 2013) Ganciclovir ocular implants (Vitrasert), which were used in conjunction with systemic therapy for treatment of sight-threatening cytomegalovirus (CMV) retinitis in HIV-infected individuals, are no longer marketed. In absence of this option, we recommend oral valganciclovir for most patients due to its ease of administration and better tolerability compared with intravenous agents. This is consistent with recommendations from the Centers for Disease Control and Prevention, the National Institutes of Health, and HIV Medicine Association guidelines [20]. However, for patients with immediately sight-threatening lesions we also recommend initial therapy with local (intravitreal injection) ganciclovir or foscarnet in conjunction with oral valganciclovir as soon as possible [20]. (See "Treatment of AIDS-related cytomegalovirus retinitis", section on 'Overview'.) ADVERSE REACTIONS AND WARNINGS Rosiglitazone (December 2013) The US Food and Drug Administration has reversed restrictions placed in 2010 on the use of rosiglitazone for the treatment of type 2 diabetes [21]. There had been concerns about cardiovascular safety with this drug. However, the RECORD study, published in 2009, and designed as a noninferiority study comparing rosiglitazone with metformin or sulfonylurea with the premise that rosiglitazone would be beneficial for cardiovascular disease,

found no difference in cardiovascular hospitalizations or mortality. Reevaluation of the cardiovascular outcomes data by an independent group showed similar results [22]. Sales of rosiglitazone remain suspended in Europe. (See "Thiazolidinediones in the treatment of diabetes mellitus", section on 'RECORD study'.) Adverse outcomes with combined ACE-ARB treatment of diabetic nephropathy (November 2013) Combination therapy with an angiotensin converting enzyme (ACE) inhibitor plus an angiotensin II receptor blocker (ARB) should not be used in patients with diabetic nephropathy. The VA NEPHRON-D trial randomly assigned 1448 patients with diabetic nephropathy to lisinopril or placebo; all patients also received losartan [23]. The trial was discontinued early (after a median of 2.2 years) because of safety concerns. The primary event rate (a 50 percent or 30 mL/min/1.73m2 decline in estimated glomerular filtration rate [GFR], endstage renal disease, or death) occurred with similar frequency in both groups, while acute kidney injury requiring hospitalization or occurring during hospitalization was significantly more common with combination therapy (18.0 versus 11.0 percent), as was severe hyperkalemia (9.9 versus 4.4 percent). (See "Treatment of diabetic nephropathy", section on 'Combination ACE inhibitor and ARB therapy'.) Retinal and skin discoloration and vision loss associated with ezogabine (November 2013) Ezogabine is an antiepileptic drug approved by the US Food and Drug Administration (FDA) in 2011 for adjunctive treatment of partial seizures in adults. In October 2013, the FDA issued a boxed warning to underscore risks of retinal pigment abnormalities, potential vision loss, and blue skin discoloration that may occur with use of ezogabine [24]. It is not yet known whether these changes are reversible. The FDA recommends that all patients taking ezogabine have baseline and periodic eye exams that include visual acuity testing and dilated fundus photography. (See "Pharmacology of antiepileptic drugs", section on 'Ezogabine'.) Ketoconazole (October 2013) In 2013, the US Food and Drug Administration (FDA) revised the box warning for ketoconazole, stating that oral ketoconazole should not be used as first-line treatment for any fungal infection and that it should be used for the treatment of endemic mycoses (eg, histoplasmosis, blastomycosis) only when alternative antifungal therapies are not available or tolerated [25]. In addition, Candida and dermatophyte infections have been removed as indications. Oral ketoconazole is now contraindicated in patients with acute or chronic liver disease. The FDA has issued guidance regarding monitoring for hepatotoxicity, adrenal insufficiency, and drug interactions. (See "Pharmacology of azoles", section on 'Ketoconazole' and "Ketoconazole: Drug information".) Although the warning was primarily issued for the use of ketoconazole as an antifungal agent, guidance regarding monitoring, drug interactions, and contraindications in chronic liver disease is also relevant to use of oral ketoconazole for treatment of Cushings syndrome. (See "Ketoconazole (systemic): Drug information" and "Medical therapy of hypercortisolism (Cushings syndrome)", section on 'Ketoconazole'.) FDA boxed warning regarding tigecycline (October 2013) Tigecycline is a broad-spectrum antibiotic, which has been approved by the US Food and Drug administration (FDA) for community-acquired pneumonia, but not for hospital-acquired pneumonia. In September 2010, the FDA issued a safety announcement regarding increased mortality with use of tigecycline in patients with hospital-acquired pneumonia (HAP); tigecycline is not FDA-approved for HAP [26]. A recent analysis of 10 clinical trials showing an increased risk of death in patients receiving tigecycline for FDA-approved uses, including community-acquired bacterial pneumonia, complicated skin and skin structure infections, and complicated intraabdominal infections (2.5 versus 1.8 percent, adjusted risk difference 0.6 percent) [27]. In 2013, the FDA added a boxed warning stating that tigecycline should be reserved for use in situations when alternative agents are not suitable. (See "Treatment of community-acquired pneumonia in adults who require hospitalization", section on 'Tigecycline' and "Treatment of hospital-acquired, ventilator-associated, and healthcare-associated pneumonia in adults", section on 'Other agents'.) Varenicline in patients with stable depression (October 2013) Based primarily on post-marketing surveillance data and case reports, there have been concerns that varenicline, an aid to smoking cessation, may have serious neuropsychiatric side effects, and varenicline has therefore been avoided in patients being treated for depression. Previous randomized trials of varenicline have

excluded smokers with a history of major depression or other serious psychiatric conditions. The safety of varenicline in depressed patients was addressed in a multicenter trial in which adult smokers with stable treated current or past major depression were randomly assigned to varenicline or placebo [28]. Both groups had similar rates of suicidal ideation and suicidal behavior, and neither group showed overall worsening of depression or anxiety. (See "Pharmacotherapy for smoking cessation in adults", section on 'Neuropsychiatric effects'.) Timing of prasugrel administration in patients with NSTEACS affects safety (October 2013) For most patients with non-ST elevation acute coronary syndrome (NSTEACS) scheduled to undergo an invasive procedure (eg, percutaneous coronary intervention, [PCI]) a P2Y12 receptor blocker (either ticagrelor or clopidogrel) is given at the time of diagnosis rather than following diagnostic angiography. A third P2Y12 receptor blocker, prasugrel, was found to be superior to clopidogrel when given following angiography in the TRITON-TIMI 38 trial. However, in the ACCOAST trial, in which 4000 patients with NSTEACS were randomly assigned to receive prasugrel either before or after angiography, major bleeding occurred more frequently in patients who received preprocedural prasugrel. [29]. Therefore, we do not recommend early initiation of prasugrel in patients with NSTEACS who are to be managed invasively. (See "Antiplatelet agents in acute non-ST elevation acute coronary syndromes", section on 'Timing'.) Hepatitis B reactivation with rituximab and ofatumumab (September 2013) The US Food and Drug Administration has issued boxed warnings for the monoclonal anti-CD20 monoclonal antibodies rituximab and ofatumumab regarding an increased risk of hepatitis B reactivation among patients positive for hepatitis B surface antigen (HBsAg) or antibodies against hepatitis B core antigen (anti-HBc) [30]. All patients should be screened with these tests prior to starting treatment. Patients with evidence of prior hepatitis B infection should be monitored for clinical and laboratory signs of reactivation during therapy and for several months after completion of therapy. Rituximab and ofatumumab should be discontinued in patients with hepatitis reactivation. (See "Treatment of relapsed or refractory chronic lymphocytic leukemia", section on 'Ofatumumab' and "Rituximab and other B cell targeted therapies for rheumatoid arthritis", section on 'Opportunistic infections and viral reactivation'.) Dabigatran not indicated with mechanical heart valves (September 2013) Dabigatran is an oral direct thrombin inhibitor used as an anticoagulant for atrial fibrillation and venous thromboembolism treatment and prophylaxis. In the RE-ALIGN trial, patients who had undergone mechanical heart valve replacement were randomly assigned to receive dabigatran or warfarin postoperatively [31]. The trial was stopped early because of an excess of thromboembolic and bleeding events in the dabigatran group. We recommend not using dabigatran in patients with mechanical heart valves. Warfarin or another vitamin K antagonist is the preferred anticoagulant in such patients. (See "Antithrombotic therapy in patients with prosthetic heart valves", section on 'Oral direct thrombin inhibitors and factor Xa inhibitors'.) Rare but serious skin reactions with acetaminophen (September 2013) In August 2013, the US Food and Drug Administration (FDA) issued a safety communication about serious and potentially fatal acetaminophen-associated skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, and acute generalized exanthematous pustulosis that can occur with the first exposure to acetaminophen or at any time during use [32]. These reactions are rare (the FDA review found a total of only 107 cases between 1969 and 2012) and may also occur with other antipyretics. Individuals who develop skin lesions while using acetaminophen should discontinue acetaminophen and seek prompt medical attention. (See "Pathophysiology and management of fever in infants and children", section on 'Acetaminophen'.) Medication adjustments in cirrhosis (August 2013) Patients with cirrhosis and other types of advanced chronic liver disease are at increased risk of adverse events with many medications because of impaired hepatic metabolism and/or renal excretion. Many medications require dose adjustments or should be avoided altogether; however, specific recommendations are often lacking. A comprehensive review of managing medications in patients with chronic liver disease became available in 2013 that includes suggestions for dose adjustment of medications used for treatment of frequently encountered chronic diseases, infections, and pain (table 3 and table 4) [33]. (See "Cirrhosis in adults: Overview

of complications, general management, and prognosis", section on 'Medication adjustments'.) Safety of fluconazole during pregnancy (September 2013) Case reports have noted an association between prolonged fluconazole use in pregnant women and craniofacial and other abnormalities in their newborns. However, several studies that focused on low-dose, short-course therapy with fluconazole did not detect an increased risk of congenital malformations among the offspring of women who took fluconazole during pregnancy. In the largest of these studies, first trimester use of fluconazole (most commonly a single dose of 150 mg) in 7352 pregnancies was not associated with an increased risk of birth defects overall [34]. However, a small but statistically-significant increased risk of tetralogy of Fallot was observed (0.10 percent versus 0.03 percent in unexposed pregnancies). Although these data are reassuring, an increased risk of specific anomalies (in addition to tetralogy of Fallot) cannot be definitively excluded. (See "Pharmacology of azoles", section on 'Pregnancy' and "Candida vulvovaginitis", section on 'Pregnancy'.) Fluoroquinolones (August 2013) The popular fluoroquinolone class of antibiotics are generally well-tolerated but have some side effects that have been previously under-recognized. In 2013, the US Food and Drug Administration (FDA) required label changes to better describe the risk of peripheral neuropathy associated with fluoroquinolones [35]. These label changes state that if a patient develops symptoms of peripheral neuropathy, which can occur rapidly and be persistent, the fluoroquinolone should be stopped and the patient switched to an alternative antibiotic from a different class, unless the benefit of continuing the fluoroquinolone outweighs the risk. (See "Fluoroquinolones", section on 'Nervous system'.) Fluoroquinolones have also been associated with both hypoglycemia and hyperglycemia, which led to the withdrawal of gatifloxacin in 2006. In a population-based cohort study, the absolute risk for hyperglycemia per 1000 treated patients was 6.9 for moxifloxacin, 3.9 for levofloxacin, and 4.0 for ciprofloxacin, compared with 1.6 for macrolides [36]. The risk of dysglycemia should be considered when prescribing fluoroquinolones, particularly in diabetic patients. (See "Fluoroquinolones", section on 'Hypoglycemia and hyperglycemia'.) Cardiovascular risk of NSAIDs (August 2013) Most nonsteroidal antiinflammatory drugs (NSAIDs) increase the risks of major cardiovascular events. The magnitude of risk is best illustrated by a meta-analysis of data from over 300,000 participants in over 700 trials that compared nonselective NSAIDs (used at the upper end of their dose range) or coxibs with either placebo or another nonselective NSAID or coxib [37]. Compared with placebo, use of high-dose diclofenac or a coxib increased major cardiovascular events (nonfatal MI, nonfatal stroke, or vascular death) by about 40 percent. High-dose ibuprofen increased the risk of major coronary events but not major vascular events. High-dose naproxen did not increase major cardiovascular events, major coronary events, or vascular death. The estimated excess absolute risk of a major vascular event or death with use of diclofenac, coxib, and possibly ibuprofen was two events per 1000 persons per year in patients at low baseline cardiovascular risk and seven to eight events per 1000 persons per year, including two fatal events, in patients at high baseline cardiovascular risk. Naproxen is therefore the preferred nonselective NSAID when long-term use is needed in patients at increased risk for cardiovascular disease. (See "Nonselective NSAIDs: Adverse cardiovascular effects", section on 'Risk of MI, stroke, and death'.) Isoniazid shortage (July 2013) Since November 2012, there have been generalized interruptions in the supply of oral isoniazid in the United States necessitating treatment with more costly and potentially more toxic alternatives and resulting in delayed or missed opportunities for treatment of latent tuberculosis infection (LTBI) [38]. The Centers for Disease control has issued a health advisory with recommendations for prevention and treatment of tuberculosis during isoniazid shortages [39]. Additional information may be found at the CDC website for the Division of Tuberculosis Elimination [40]. (See "Isoniazid: An overview", section on 'Isoniazid shortage'.) Antimicrobial prophylaxis in surgery (July 2013) Traditional prophylactic dosing of cefazolin (1 to 2 g) used in surgical patients may not be adequate to exceed microbial resistance breakpoints in some circumstances. New guidelines addressing antimicrobial prophylaxis

for prevention of surgical site infections published in February 2013 advocate a minimum 2 g dose of cefazolin, and administration of 3 g for patients 120 kg [41]. Other important issues addressed in the guidelines include timing of preoperative antibiotic dosing, intervals for repeat antibiotic during surgery, and role of preoperative S. aureus decolonization. (See "Antimicrobial prophylaxis for prevention of surgical site infection in adults", section on 'Initial dosing' and "Adjunctive measures for prevention of surgical site infection in adults".) Enteropathy with olmesartan (July 2013) In 2013, the United States Food and Drug Administration reported that olmesartan can produce a sprue-like enteropathy characterized by severe chronic diarrhea and weight loss, occurring months to years after initiation of the drug [42]. In some cases, intestinal biopsy revealed villous atrophy, which resolved after discontinuation of olmesartan. In nearly half of the reported cases, rechallenge with the drug reproduced the symptoms [42]. Thus, patients starting olmesartan should be cautioned about the possibility of developing diarrhea and weight loss. The drug should be stopped if these symptoms occur and another cause is not found. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Enteropathy with olmesartan'.) Concern about bleeding with dabigatran (June 2013) Concerns have been raised about a potential for a higher rate of major bleeding with dabigatran than warfarin, based on post-marketing reports in patients taking dabigatran. In a registry study, which compared 8936 patients taking warfarin to 4987 taking dabigatran, rates of major bleeding were comparable and the risk of intracranial hemorrhage was lower in the dabigatran group at dabigatran doses of 110 or 150 mg twice daily [43]. Based on all available evidence, we believe the risk of major bleeding is comparable between dabigatran 150 mg and warfarin and is less with dabigatran 110 mg compared to warfarin. Selection of the dose of dabigatran should take into account efficacy as well as bleeding risk. (See "Antithrombotic therapy to prevent embolization in atrial fibrillation", section on 'Dabigatran'.) Fatalities following long-acting injectable olanzapine (June 2013) The US Food and Drug Administration reported in June 2013 that it was investigating two deaths occurring three to four days after the patients were injected with olanzapine long-acting intramuscular (olanzapine-LAI) preparation [44]. Both patients were found to have very high blood levels of olanzapine post mortem. The olanzapine-LAI label warns about the risk of a post injection delirium and sedation syndrome (PDSS) when the drug enters the blood too quickly following injection of an appropriate dose. However, previously reported cases of PDSS occurred within three hours of injection and were not fatal. The causes of these deaths have not been determined; they raise concerns that PDSS might have been missed during the three-hour prescribed observation period or occurred after that period. (See "Pharmacotherapy for schizophrenia: Long-acting injectable antipsychotic drugs", section on 'Post-injection delirium sedation syndrome'.) Thrombotic complications with immune globulin (June 2013) In June 2013, the US Food and Drug Administration (FDA) required that further information about an increased risk of thromboembolic events with immune globulin be added to the existing boxed warning on intravenous products, and that a warning be added to subcutaneous and intramuscular products [45]. Trace amounts of an activated clotting factor were identified in earlier product releases, and production methods were modified subsequently. Although an increased rate of thrombotic events has not been identified after the modified production, it is unclear if the presence of clotting factors was entirely responsible for the excess thrombotic events. Therefore, for patients with one or more risk factors for thrombosis (eg, advanced age, history of thrombosis, hypercoagulable state, use of procoagulant medications, or cardiovascular risks), immune globulin should be infused using the lowest concentration available and at the minimum rate of infusion, and the patient should be adequately hydrated prior to starting the infusion. (See "Intravenous immune globulin: Adverse effects", section on 'Thrombotic complications'.) Cardiac and vascular events in patients taking nilotinib (June 2013) Most patients with newly-diagnosed chronic myeloid leukemia (CML) in chronic phase are treated with a BCRABL tyrosine kinase inhibitor (TKI), which is largely selected based upon side effect profile. While the second-

generation TKIs (nilotinib and dasatinib) demonstrate faster and deeper responses than those seen with imatinib, further follow-up is needed to better define toxicity and confirm whether this will translate into a survival benefit. At a median follow-up of four years, analysis of the randomized ENESTnd trial, which compared nilotinib with imatinib in patients with previously untreated CML suggests that nilotinib therapy results in an increased incidence of cardiac and vascular events (6.5 versus 1.4 percent with imatinib) [46]. Nilotinib should be permanently discontinued in patients diagnosed with vascular events including peripheral artery occlusive disease. (See "Clinical use of tyrosine kinase inhibitors for chronic myeloid leukemia", section on 'Vascular disease'.) Prolonged exposure to magnesium affects fetal bones (June 2013) Retrospective epidemiologic studies have reported a significant increase in radiographic bone abnormalities in neonates with in utero exposure to magnesium sulfate for more than seven days, and a significant difference in the serum values of magnesium, calcium, phosphorus, and osteocalcin (a marker of bone formation) at birth between neonates exposed to magnesium sulfate and those who were not. Based on these and other data, in May 2013, the US Food and Drug Administration advised healthcare professionals in the United States against using magnesium sulfate injection for more than five to seven days to stop preterm labor [47]. We agree with this recommendation, given the potential for adverse fetal effects and because tocolytic therapy is generally less effective after 48 hours. (See "Inhibition of acute preterm labor", section on 'Maternal and fetal side effects'.) VACCINES Japanese encephalitis (JE) vaccine available in US approved for use in children (November 2013) Japanese encephalitis (JE) is the most important cause of viral encephalitis in Asia and different types of JE vaccine have been used. The only JE vaccine available in the United States is an inactivated Vero cell culturederived vaccine (JE-VC; Ixiaro, IC-51). This vaccine, originally approved in 2009 for use in individuals 17 years, has now been licensed for use in children 2 months through 16 years of age [48]. Recommendations for use of JE vaccine in travelers are summarized in a table (table 5). (See "Japanese encephalitis: Epidemiology, diagnosis, treatment and prevention", section on 'Vaccination'.) Risk of seizures with delayed administration of MMR (November 2013) Young children have an increased risk of febrile seizures one to two weeks after they receive the first dose of the measles, mumps, rubella (MMR) vaccine. The risk appears to be greater among children who receive the first dose after the age when it is routinely recommended (12 to 15 months). In a large cohort study, the risk of seizures was increased among children who received the first dose of MMR between 16 and 23 months of age compared with those who received it between 12 and 15 months [49]. These findings highlight the importance of timely administration of the first dose of MMR. (See "Standard immunizations for children and adolescents", section on 'MMR adverse reactions'.) ACIP recommendations for seasonal influenza vaccination (September 2013) The United States Advisory Committee on Immunization Practices (ACIP) has published recommendations for seasonal influenza vaccination for the 2013 to 2014 influenza season [50]. As in past years, all individuals six months of age or older should be vaccinated. Both trivalent and quadrivalent vaccines are available for the 2013 to 2014 influenza season (table 6). New vaccines include a trivalent inactivated influenza vaccine produced in cultured mammalian cells (Flucelvax) and a trivalent recombinant hemagglutinin influenza vaccine (Flublok). The choice of vaccine formulation depends upon several factors, including age, comorbidities, pregnancy, and risk of adverse reactions. (See "Seasonal influenza vaccination in adults", section on 'Antigenic composition' and "Seasonal influenza vaccination in adults", section on 'Vaccine formulations' and "Seasonal influenza vaccination in children", section on 'Choice of vaccine'.) FDA approval of a meningococcal conjugate vaccine (Menveo) for infants (August 2013) In August 2013, the US Food and Drug Administration (FDA) approved a quadrivalent conjugate vaccine against meningococcus serogroups A, C, Y, and W135 (Menveo) for use in infants as young as 2 months of age [51]. The FDA had previously approved Menveo only for use in individuals between 2 and 55 years of age. In October 2013, the United States Advisory Committee on Immunization Practices voted to recommend Menveo for infants

2 months of age at increased risk for meningococcal disease [52]. Formal recommendations have not yet been released. (See "Meningococcal vaccines", section on 'In infants and toddlers'.) Measles postexposure prophylaxis (July 2013) Guidelines on prevention of measles, mumps, and rubella were issues by the Advisory Committee on Immunization Practices in June 2013 [53]. These guidelines expand recommendations for use of immune globulin administered intramuscularly (IGIM) to include infants aged birth to six months exposed to measles, increase the recommended dose of IGIM for immunocompetent individuals, and recommend use of immune globulin administered intravenously (IGIV) for severely immunocompromised individuals and pregnant women without evidence of measles immunity who are exposed to measles. (See "Prevention and treatment of measles", section on 'Immune globulin'.) PCV13 for immunocompromised children ages 6 through 18 (July 2013) In June 2013, the United States Advisory Committee on Immunization Practices recommended one dose of the 13-valent pneumococcal conjugate vaccine (PCV13) for PCV13-nave children 6 through 18 years of age in the United States with immunocompromising conditions (eg, human immunodeficiency virus, chronic renal failure, nephrotic syndrome, malignancy, etc.), anatomic or functional asplenia (including sickle cell disease), cochlear implant, or cerebrospinal fluid leak. PCV13 is recommended regardless of whether a child received the 7-valent pneumococcal conjugate vaccine (PCV7) or the 23-valent pneumococcal polysaccharide vaccine (PPSV23) [54]. PCV13 should be administered at least eight weeks after the last dose of PCV7 or PPSV23 (if the child received these vaccines). (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children", section on 'Indications'.) MMR for children with HIV infection (June 2013) In June 2013, the Advisory Committee on Immunization Practices updated its recommendations for prevention of measles, mumps, and rubella in the United States [53]. Two updated recommendations apply to individuals with human immunodeficiency virus (HIV) infection: Two doses of measles, mumps, rubella (MMR) vaccine, at least 28 days apart, should be administered to HIV-infected persons 12 months of age who are not severely immunocompromised (table 7) and have no evidence of immunity to measles, mumps, or rubella. Individuals with perinatal HIV infection who received MMR vaccine before establishment of effective antiretroviral therapy (ART) who do not have evidence of immunity to measles, mumps, and rubella should receive two doses of MMR vaccine, at least 28 days apart, once effective ART has been established. Effective ART is defined by receiving ART for 6 months and lack of severe immunosuppression. (See "Standard immunizations for children and adolescents", section on 'HIV infection'.) Use of UpToDate is subject to the Subscription and License Agreement. Topic 8360 Version 2997.0