The following material represents a subset of new drugs, drug approvals, drug warnings, and drugs removed from the market since the last version of UpToDate. This is not a complete list; it includes those topics considered by the authors and editors to be of particular interest or importance.
DRUG INTERACTIONS — You can check interactions for multiple drugs simultaneously 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® drug reference when using UpToDate online.
Citalopram and CYP2C19 inhibitors — (See 'Citalopram cardiac effects' below.)
Lovastatin and CYP3A4 inhibitors — The drug interactions, contraindicated drug combinations, and dose limits listed in the US prescribing information for lovastatin have been revised; the US label now contraindicates or recommends against use of lovastatin in patients treated with most strong inhibitors of CYP3A4 (table 1), cyclosporine, or gemfibrozil. If co-administered with diltiazem or verapamil, a 20 mg daily dose limit of lovastatin is recommended [1]. (See "Muscle injury associated with lipid lowering drugs", section on 'Concurrent drug therapy'.)
HIV antiretroviral therapy and HCV protease inhibitors — Boceprevir and telaprevir are protease inhibitors that are used in the treatment of hepatitis C virus (HCV) genotype 1 infection. If boceprevir or telaprevir is used in combination with certain ritonavir-boosted HIV protease inhibitors (eg, lopinavir, darunavir [and atazanavir with boceprevir only]) in HIV-infected patients, the effectiveness of both medications may be decreased. Given the risk of virologic rebound and treatment failure, patients who are co-infected with HIV and HCV genotype 1 infections should be treated with specific highly-effective antiretroviral regimens that have not been associated with this drug interaction until further data are available [2,3]. (See "Treatment of hepatitis C virus infection in the HIV-infected patient", section on 'Potential drug interactions'.) HCV protease inhibitors are dependent on CYP3A4/5 for clearance and numerous other drug interactions have been noted as well (table 2 and table 3). (See "Treatment regimens for chronic hepatitis C virus genotype 1", section on 'Drug interactions with protease inhibitors'.)
Influenza vaccine in patients receiving rituximab — The anti-CD20 monoclonal antibody, rituximab, has become a standard component of treatment for CD20-positive B cell lymphomas. Since this agent depletes normal B cells, there is concern that it will attenuate the response to vaccines. In a study of lymphoma patients who had received a rituximab-containing treatment regimen within the previous six months, none of 67 patients developed seroprotective titers following administration of inactivated pandemic H1N1 influenza A vaccine [4]. In contrast, 82 percent of healthy controls developed seroprotective titers following vaccination. When feasible, the influenza vaccine (and other indicated vaccines) should be given to lymphoma patients before initiation of rituximab. (See "Immunizations in patients with cancer", section on 'Influenza vaccine' and "Immunizations in patients with cancer", section on 'General approach'.)
Proton pump inhibitors with high-dose methotrexate — The US Food and Drug Administration (FDA) has issued a warning about the use of proton pump inhibitors (PPIs) in patients receiving methotrexate, particularly high-dose methotrexate [5]. Concomitant use of PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high dose) appears to be a major risk factor for delayed elimination of methotrexate, which may increase toxicity [6-8]. PPIs should be avoided, if possible, during high-dose methotrexate treatment. (See "Therapeutic use of high-dose methotrexate", section on 'Use of proton pump inhibitors'.)
NSAID use with oral methotrexate — Nonsteroidal antiinflammatory drugs (NSAIDs) may decrease the renal excretion of methotrexate; however, a systematic review of randomized trials and large studies involving patients with rheumatoid arthritis found that NSAIDs could be safely given to patients receiving low-dose oral methotrexate, assuming that appropriate monitoring for drug toxicity is performed [9]. Given persisting concerns for renal and hepatic toxicity, higher (antiinflammatory) doses of salicylates, such as aspirin, salsalate, and choline magnesium trisalicylate, should probably be avoided in patients receiving methotrexate for inflammatory arthritis. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Pharmacology'.)
Newer oral anticoagulants — The drug interactions, management recommendations, and contraindicated drug combinations listed in licensed product information for dabigatran and rivaroxaban vary by country and have been revised (table 4 and table 5). We suggest avoiding the use of drugs that inhibit P-glycoprotein transporters with dabigatran in any patient aged ≥80 years or those with renal insufficiency. (See "Anticoagulants other than heparin and warfarin", section on 'Drug interactions' and "Anticoagulants other than heparin and warfarin", section on 'Dosing and safety issues' and 'Safety of dabigatran' below.)
NEW DRUGS/DRUG APPROVALS — For a complete list of new drug approvals see www.lexi.com/newdrugs.
Ivacaftor — Cystic fibrosis (CF) is a multisystem disorder that is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which regulates chloride and water transport in the lungs, digestive tract, and elsewhere. The G551D mutation, which is present in about 5 percent of CF patients, interferes with activation of the CFTR chloride channel.
Ivacaftor (Kalydeco™), an orally available CFTR modulator that is specific for the G551D mutation and restores functioning of the CFTR protein in patients who harbor this mutation, has received expedited approval by the FDA. In a clinical trial leading to its US approval, subjects with CF and a G551D mutation in at least one of their CFTR genes who were treated with ivacaftor experienced improved FEV1, less frequent pulmonary exacerbations, and greater weight gain compared with those receiving placebo [10]. All individuals with CF should undergo genotyping to determine whether they carry the G551D mutation. (See "Cystic fibrosis: Overview of the treatment of lung disease", section on 'CFTR modulators'.)
Erwinia asparaginase — Erwinia asparaginase (Erwinaze®), a form of L-asparaginase, has received approval by the FDA. For patients who develop an anaphylactic reaction to pegylated asparaginase (pegaspargase), which is derived from Escherichia coli (E coli), continued therapy is possible in over 80 percent by switching to Erwinia asparaginase. Cross reactivity is uncommon with the E coli and Erwinia derivatives because the two are antigenically distinct. Erwinia asparaginase was available in Canada and other countries prior to its US availability. (See "Infusion reactions to systemic chemotherapy", section on 'L-asparaginase'.)
Axitinib — Axitinib (Inlyta®), an orally available potent inhibitor of the vascular endothelial growth factor (VEGF) receptors 1, 2, and 3, has received FDA approval for treatment of advanced renal cell cancer after failure of one prior systemic therapy. Approval was based on a phase III trial comparing axitinib versus sorafenib in this population, which demonstrated improved outcomes with axitinib [11]. (See "Molecularly targeted therapy for advanced renal cell carcinoma", section on 'Axitinib'.)
Glucarpidase — High-dose methotrexate is used for central nervous system (CNS) prophylaxis in patients with leukemia and high-risk lymphoma, and for the treatment of leptomeningeal metastases, primary CNS lymphoma, and osteosarcoma. These otherwise lethal doses of methotrexate are followed by a two to three day period of leucovorin administration to terminate the toxic effects. Successful “rescue” by leucovorin depends on rapid elimination of methotrexate by the kidneys. Glucarpidase (recombinant carboxypeptidase G) is an enzyme that metabolizes antifolates such as methotrexate to inactive metabolites. The FDA has approved glucarpidase injection (Voraxaze®) for the treatment of toxic plasma methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function. (See "Therapeutic use of high-dose methotrexate", section on 'Glucarpidase (carboxypeptidase G2)'.)
Clobazam — Clobazam (Onfi™) is a long-acting benzodiazepine that recently became available in the United States. In two randomized trials of children with Lennox-Gastaut syndrome, adjunctive therapy with clobazam (0.5 to 1 mg/kg per day) was associated with a significant reduction in seizure frequency compared to patients taking placebo or low dose clobazam (0.25 mg/kg per day) [12,13]. Clobazam was available in Canada and other countries prior to its US availability. (See "Epilepsy syndromes in children", section on 'Lennox-Gastaut syndrome'.)
New testosterone preparations — Several new testosterone preparations are now available in the United States for androgen replacement therapy in hypogonadal men, including two higher concentrations of a testosterone gel, which permit a lower volume to be applied for each day’s dose (AndroGel® 1.62 percent, Fortesta® 2 percent) [14-16], and a topical testosterone solution that is applied to the axilla (Axiron® 2 percent) [17]. (See "Testosterone treatment of male hypogonadism", section on 'Testosterone gels'.)
Vismodegib — Vismodegib (Erivedge™), an inhibitor of the sonic hedgehog pathway, was approved by FDA for the treatment of metastatic and locally advanced basal cell carcinoma that is not amenable to treatment with surgery or radiation therapy. The approval was based upon clinically significant activity in a single arm phase II study of 104 patients [18]. (See "Systemic treatment of advanced cutaneous squamous and basal cell carcinomas", section on 'Vismodegib'.)
ADVERSE REACTIONS AND WARNINGS
Fibrates and renal function — Fibric acid derivatives are useful lipid-lowering agents but they have been associated with elevated creatinine levels in randomized trials. A population-based study also found an association between new fibrate use in older patients and nephrologist consultations and hospital admissions for a rise in creatinine level [19]. However, the clinical significance of these findings, in particular, whether the risk in creatinine reflects renal injury, is uncertain. In the placebo-controlled FIELD trial of fenofibrate in patients with type 2 diabetes mellitus, the increase in serum creatinine in patients treated with fenofibrate was reversible on discontinuation, and at the end of the trial, fenofibrate treatment appeared to have slowed loss of renal function and reduced proteinuria [20]. (See "Lipid lowering with fibric acid derivatives", section on 'Toxicity and drug interactions'.)
Fluoroquinolones and retinal detachment — A nested case-control study of patients who had visited an ophthalmologist found an increased rate of retinal detachment in patients who were currently receiving oral fluoroquinolones [21]. Past fluoroquinolone use, even if recent within the preceding week, was not associated with retinal detachment, indicating that retinal detachment may be an acute adverse effect. A possible reason for the increased risk of retinal detachment in patients taking a fluoroquinolone is the destructive effect of this class of agents on collagen and connective tissue. This adverse effect requires confirmation in an additional study. (See "Fluoroquinolones", section on 'Retinal detachment'.)
Citalopram cardiac effects — Citalopram causes dose-dependent QT interval prolongation, which can lead to a life-threatening abnormal heart rhythm, torsades de pointes (a form of polymorphic ventricular tachycardia) [22,23]. In August 2011, the FDA warned that doses of citalopram for all patients should not exceed 40 mg, and recommended avoiding the drug in patients with congenital long QT syndrome, bradycardia, hypokalemia, hypomagnesemia, recent acute myocardial infarction, uncompensated heart failure, or those taking other medications that prolong the QT interval [22]. A new warning, issued in March 2012, advises that the daily dose of citalopram be limited to 20 mg in patients at risk for increased serum concentrations of citalopram [23]. Risk factors include hepatic impairment, age >60 years, CYP2C19 variants that slowly metabolize citalopram, and concomitant medications that inhibit CYP2C19. (See "Unipolar depression in adults and selective serotonin reuptake inhibitors (SSRIs): Pharmacology, administration, and side effects", section on 'Cardiac'.)
Vasopressors in septic shock — A meta-analysis of six randomized trials (1408 patients) demonstrated that patients who receive dopamine pressor therapy during septic shock have higher mortality compared with patients who receive norepinephrine [24]. Although the causes of death in the two groups were not compared, arrhythmic events were twice as common with dopamine than with norepinephrine. The results indicate that norepinephrine is preferred over dopamine as a vasopressor in the management of septic shock. (See "Use of vasopressors and inotropes", section on 'Choice of agent in septic shock'.)
Sodium phosphate enemas — Sodium phosphate enemas (eg, Fleet® enema) are used in the treatment of constipation and for preparation for flexible sigmoidoscopy. In a retrospective series, sodium phosphate enema use in older adults (mean age 80 years, range 61 to 89 years) was associated with complications including hypotension and volume depletion, hyperphosphatemia, hypo- or hyperkalemia, metabolic acidosis, severe hypocalcemia, renal failure, and EKG changes (prolonged QT interval) [25]. Sodium phosphate enemas should be avoided for treatment of constipation in patients over the age of 70. (See "Management of chronic constipation in adults", section on 'Disimpaction' and "Constipation in the older adult", section on 'Stool softeners, suppositories, and enemas'.)
Revised Beers criteria — The Beers criteria, a list of medications categorized as inappropriate or requiring caution with use for older adults, are the most widely-cited criteria used to assess inappropriate geriatric drug prescribing. The criteria, initially developed in 1991 by an expert consensus panel and last revised in 2003, have been newly updated in 2012 [26]. The 2012 revised Beers criteria, which are available through the American Geriatrics Society website, include 53 medications designated in one of three categories: those that should always be avoided; those that are potentially inappropriate in older adults with particular health conditions or syndromes; and those that should be used with caution. New additions to the 34 potentially-inappropriate medications include sliding scale insulin, glyburide, and megestrol. Thiazolidinediones should be avoided in patients with heart failure and selective serotonin reuptake inhibitors (SSRIs) in patients with falls and fractures. (See "Drug prescribing for older adults", section on 'Beers criteria'.)
Revised monitoring of liver function tests with statin therapy — In 2012, the FDA revised its labeling information on statins to recommend liver function testing prior to initiation of therapy and to only repeat such testing as clinically indicated [1]. We agree that routine monitoring of liver function tests in patients receiving statin therapy is not necessary. (See "Statins: Actions, side effects, and administration", section on 'Hepatic dysfunction'.)
C. difficile and proton pump inhibitors — Proton pump inhibitors (PPIs) may be associated with an increased risk of Clostridium difficile (C. difficile)-associated disease (CDAD). FDA issued a drug safety communication in February 2012 following a review of published literature [27]. Most studies found that the risk of C. difficile infection or CDAD ranged from 1.4 to 2.75 times higher among patients with PPI exposure compared with those without PPI exposure. Providers should consider the diagnosis of CDAD in PPI users with persistent diarrhea.
The relationship between the risk of C. difficile infection and PPI dose or duration of use is uncertain. However, given the potential risk of CDAD, the FDA has recommended that providers prescribe the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. (See "Epidemiology, microbiology, and pathophysiology of Clostridium difficile infection in adults", section on 'Gastric acid suppression' and "Overview and comparison of the proton pump inhibitors for the treatment of acid-related disorders", section on 'Clostridium difficile and other enteric infections'.)
Iatrogenic IV acetaminophen overdose in children — Intravenous (IV) acetaminophen (paracetamol) in a concentration of 10 mg/mL has been available in the United Kingdom since 2003 and was approved for use in the United States in 2010 [28]. Iatrogenic overdoses involving ten-fold dosing errors have been described in hospitalized young children receiving IV acetaminophen for pain relief [29]. The typical error occurs when a prescribed dose in mg is mistakenly given as the volume of drug solution in mL. Other causes include human error when determining the volume to be infused via a pump, duplicated doses, and inadvertent IV injection of the oral liquid [28]. Treatment is controversial and consultation with a poison control center or medical toxicologist is strongly advised to guide management. (See "Management of acetaminophen (paracetamol) poisoning in children and adolescents".)
Fingolimod associated deaths — Fingolimod is an orally active sphingosine analog that is effective for reducing the relapse rate in patients with relapsing-remitting multiple sclerosis. Worldwide, 11 deaths have been linked to fingolimod as of late February 2012, including four patients who had cardiac events and seven with unexplained death [30]. Although these deaths may be coincidental and unrelated to the drug, we suggest not starting fingolimod treatment for patients with multiple sclerosis until the cause of death in these cases has been clarified. (See "Treatment of relapsing-remitting multiple sclerosis in adults", section on 'Clinical use of fingolimod'.)
Safety of dabigatran — Concerns have been raised about the safety of the orally active direct thrombin inhibitor dabigatran:
These observations, as well as reports of deaths among trauma victims who were receiving dabigatran [34], have called into question the safety of this agent in acutely injured patients, the elderly, and individuals with renal disease. (See "Anticoagulants other than heparin and warfarin", section on 'Bleeding and thrombotic events' and 'Newer oral anticoagulants' above.)
Clopidogrel hypersensitivity reactions — Hypersensitivity reactions develop in 1 to 4 percent of patients who receive clopidogrel following a coronary artery stenting procedure. Management options include switching to a different antiplatelet agent, embarking on a formal desensitization protocol, or simply continuing the drug with concomitant systemic glucocorticoids with or without antihistamines (ie, “treating through”). The safety of “treating through” with concomitant oral glucocorticoids was shown in an observational study in which 62 patients with mild to moderate clopidogrel reactions received a 20-day course of prednisone and continued clopidogrel [35]. Ninety-five percent had resolution of symptoms by a mean of five days, and all were able to complete the minimum desired period of clopidogrel treatment (ie, 1 to 12 months). (See "Antithrombotic therapy for intracoronary stent implantation: General use", section on 'Hypersensitivity'.)
Dronedarone and permanent atrial fibrillation — Dronedarone, a newer class III antiarrhythmic agent, has been contraindicated in patients with atrial fibrillation (AF) and New York Heart Association class III or IV heart failure (or a left ventricular ejection fraction <35 percent) because of poor efficacy and concerns about higher mortality rates. On the basis of recent findings, it is now recognized that dronedarone should not be used in any patient with permanent AF. The PALLAS trial of nearly 10,000 patients with permanent AF who were randomly assigned to receive dronedarone or placebo was stopped early after a significantly increased risk of cardiovascular events, hospitalization for heart failure, and death were observed in the dronedarone arm [36]. (See "Antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation: Recommendations", section on 'Concerns about dronedarone'.)
Uric acid monitoring during pegloticase treatment — For patients with recurrent gout who are receiving treatment with pegloticase, a recombinant form of urate oxidase, serum uric acid values should be checked prior to each infusion. A rise in the serum uric acid to >6 mg/dL (>357 micromol/L) after an initial response to pegloticase treatment should prompt discontinuation of the drug. Increasing serum uric acid levels, which result from high titer anti-pegloticase antibodies, are associated with an increased risk for infusion-related reactions, and they reflect loss of effectiveness of the drug. Because of this problem, other hypouricemic therapies, including allopurinol and febuxostat, should not be given to patients receiving pegloticase, as this may mask recognition of the increased uric acid levels [37]. (See "Prevention of recurrent gout", section on 'Pegloticase'.)
Drugs associated with development of nocturnal leg cramps — Anecdotal reports have linked the use of diuretics, statins, and inhaled long-acting beta agonists to an increased risk of nocturnal leg cramps. In an analysis of a population-derived pharmacy database involving over 24,000 individuals, patients initiating use of inhaled long-acting beta agonists, potassium-sparing diuretics, and thiazide-like diuretics were significantly more likely to receive a quinine prescription for nocturnal leg cramps during the year after starting a drug from one of these classes, compared with their likelihood during the year preceding such use [38]. Only small increased risks were seen for loop diuretics and statins. (See "Nocturnal leg cramps", section on 'Etiology'.)
Acetylcysteine for prevention of contrast nephropathy — Numerous prospective trials examining the prophylactic effect of acetylcysteine in contrast nephropathy have been performed, with substantial inconsistency in reported results. The Acetylcysteine for the prevention of Contrast-induced Nephropathy (ACT) trial showed NO benefit over placebo of acetylcysteine (1200 mg orally twice daily) on the incidence of contrast nephropathy among 2308 high-risk patients (at least one of the following risk factors: age greater than 70 years, chronic kidney disease, diabetes mellitus, heart failure or LVEF less than 45 percent, or shock) who were undergoing angiography [39]. Although data regarding the efficacy of acetylcysteine are conflicting, if it is to be used, the preferred dose is 1200 mg administered orally twice daily on the day before and the day of the procedure to patients at risk for contrast nephropathy. (See "Prevention of contrast-induced nephropathy", section on 'Acetylcysteine'.)
Relative safety and efficacy of anticholinergic medications for urinary incontinence — A systematic review of 86 randomized trials in patients with symptoms of an overactive bladder comparing differing doses and formulations of four anticholinergic drugs came to the following conclusions [40]:
Data were not available for other comparisons and data did not allow conclusions about comparative costs, long-term outcomes, or the impact on quality of life. (See "Treatment of urinary incontinence", section on 'Antimuscarinics'.)
Newer progestins associated with an increased risk of thrombosis — There have been concerns that newer third-generation progestins may be associated with a greater risk of venous thromboembolism when compared with older progestins. In a study that assessed the risk of cardiovascular events in over 800,000 women, the use of combined contraceptives containing drospirenone, norelgestromin, or etonogestrel (newer progestins used in oral contraceptive, transdermal patch, and vaginal ring, respectively) was associated with a significantly higher risk of venous thrombosis compared with use of older combined hormonal contraceptive pills containing second-generation progestins and similar low estrogen levels [41]. (See "Risks and side effects associated with estrogen-progestin contraceptives", section on 'Venous thromboembolic disease'.)
Antineoplastic agents and thyroid dysfunction — Newer antineoplastic agents, such as oral tyrosine kinase inhibitors (eg, sunitinib, sorafenib, imatinib) used for the treatment of gastrointestinal stromal tumors, renal cell carcinoma, hepatocellular cancer, chronic myeloid leukemia, and other cancers, can cause hypothyroidism in patients with previously normal thyroid function and increase thyroid hormone requirements in patients with hypothyroidism [42]. Hypophysitis and panhypopituitarism, including central hypothyroidism, may also occur as a complication of ipilimumab (anti-CTLA-4) immunotherapy used for the treatment of metastatic melanoma. Hyperthyroidism may occur after treatment with denileukin diftitox, ipilimumab, and alemtuzumab. Possible mechanisms include changes in thyroid hormone clearance, impaired iodine uptake, or destructive thyroiditis. (See "Drug interactions with thyroid hormones", section on 'Drugs that cause hypothyroidism' and "Drug interactions with thyroid hormones", section on 'Drugs that cause hyperthyroidism'.)
Brentuximab and progressive multifocal leukoencephalopathy — Brentuximab vedotin was granted accelerated approval by the FDA for treatment of patients with relapsed refractory Hodgkin lymphoma or relapsed systemic anaplastic large cell lymphoma. Rare reports of progressive multifocal leukoencephalopathy (PML) prompted the FDA to recently add a boxed warning about this risk to the licensed prescribing information [43]. PML typically presents with subacute neurologic deficits that may include altered mental status, visual symptoms, weakness, ataxia and seizures. (See "Neurologic complications of cancer treatment with biologic agents", section on 'Brentuximab'.)
Panitumumab and pulmonary toxicity — Initial reports suggested that pulmonary toxicity was rare with panitumumab; only 2 of 1467 patients enrolled in clinical trials (<1 percent) developed pulmonary fibrosis [44]. However, an increased number of cases of fatal interstitial lung disease and pulmonary fibrosis have been reported during postmarketing surveillance, prompting the FDA to issue a warning in December 2011. (See "Pulmonary toxicity associated with antineoplastic therapy: Molecularly targeted agents", section on 'Agents targeting the EGFR'.)
Safety of long-acting beta agonists in children — There is controversy regarding the safety of chronic treatment with long-acting beta agonists (LABA) in children with asthma. A meta-analysis of controlled clinical trials that included 60,954 patients found a significantly increased risk of serious asthma events (hospitalization, intubation, or death) associated with LABA therapy in the overall population particularly among the youngest patients aged 4 to 11 years [45]. However, this increased risk was not seen in children and adolescents who also received inhaled glucocorticoids as an assigned study treatment. (See "Beta agonists in asthma: Controversy regarding chronic use", section on 'Meta-analysis and clinical trial data'.)
ADHD pharmacotherapy and cardiovascular events — Stimulant drugs such as methylphenidate, dextroamphetamine, and mixed amphetamine salts are effective in improving behavior in children with attention deficit hyperactivity disorder (ADHD), but reports of unexpected deaths during therapy have led to concerns that these medications increase the risk of cardiovascular adverse events including sudden death. Analyses of data from four large health plans by the FDA and the Agency for Healthcare Research found no difference in the risk of serious cardiovascular events (ie, sudden cardiac death, acute myocardial infarction, or stroke) between patients (either pediatric or adult) receiving pharmacotherapy for ADHD and individuals not receiving ADHD therapy [46,47]. In an updated safety review based on these results, the FDA recommended clinicians continue to prescribe ADHD pharmacotherapy according to the professional prescribing label, and that patients continue to use prescribed therapy for the treatment of ADHD [48]. (See "Cardiac evaluation of patients receiving pharmacotherapy for attention deficit hyperactivity disorder", section on 'Risk of sudden unexpected deaths'.)
Prenatal SSRI exposure and newborn pulmonary hypertension — In a population-based study from Norway of more than 1.6 million live births, the use of a selective serotonin reuptake inhibitor (SSRI) antidepressant during the second half of pregnancy was associated with a twofold increase in the risk of persistent pulmonary hypertension of the newborn (PPHN) [49]. This elevated risk translated into only a small absolute increase of PPHN (2.9 cases per 1000 live births compared to 1.2 per 1000 births for the general population). In a 2011 review of their 2006 public health advisory regarding the possibility of an increased risk of PPHN in infants with late prenatal exposure to SSRIs, FDA concluded that it was not yet possible to establish a link between SSRI use in pregnancy and PPHN and recommended that health care professionals not alter their clinical management of depression during pregnancy based on a concern for PPHN in the offspring [50]. Of note, the FDA report did not include the Norwegian study, as it was published after the FDA review. However, the absolute increase in the incidence of PPHN is so small that we continue to suggest following the 2011 FDA recommendation of not altering effective SSRI therapy during pregnancy. (See "Infants with antenatal exposure to serotonin reuptake inhibitors", section on 'Persistent pulmonary hypertension'.)
VACCINES
(See 'Influenza vaccine in patients receiving rituximab' above.)
Varicella-zoster virus post exposure prophylaxis — Passive immunization with varicella-zoster immune globulin (VaraZIG™) was previously recommended within four days of exposure to varicella for nonimmune children and adults who are not candidates for varicella vaccine (eg, persons with malignancy, immunocompromise, or pregnant women). However, limited data suggest a comparable incidence of VZV infection among varicella-exposed persons who receive passive immunization within four as compared to 5 to 10 days of exposure [51,52]. FDA has extended the window for passive immunization to within 10 days of varicella exposure [53]. When postexposure prophylaxis for VZV is indicated and active immunization is contraindicated, varicella-zoster immune globulin should be offered as soon as possible. (See "Post-exposure prophylaxis against varicella-zoster virus infection", section on 'VariZIG'.)
Pneumococcal conjugate vaccine (PCV13)
Supplemental dose for children — A single “supplemental” dose of the 13-valent pneumococcal conjugate vaccine (PCV13) is recommended for healthy children aged 14 through 59 months who were previously fully vaccinated with the 7-valent pneumococcal conjugate vaccine (PCV7). The importance of the supplemental dose is highlighted by reports of invasive pneumococcal disease caused by one of the six serotypes unique to PCV13 among PCV7-vaccinated children who were eligible for, but did not receive, the supplemental dose of PCV13 [54]. (See "Pneumococcal (Streptococcus pneumoniae) conjugate vaccines in children", section on 'Supplemental dose'.)
Use of PCV13 in adults — In December 2011, PCV13, the formulation used routinely in children, was approved by FDA for use in adults ≥50 years of age based upon safety and immunogenicity data showing that PCV13-induced antibody responses were either comparable to or higher than the responses induced by the pneumococcal polysaccharide vaccine (PPSV23) [55,56]. PCV13 also appears to have a similar safety profile as PPSV23. Use of PCV13 in older adults has not yet been recommended by the United States Advisory Committee on Immunization Practices (ACIP). (See "Pneumococcal vaccination in adults", section on 'Conjugate vaccines'.)
Hepatitis B vaccination of patients with diabetes mellitus — The Advisory Committee on Immunization Practices (ACIP) now considers diabetes mellitus (both type 1 and type 2) to represent a high risk condition for hepatitis B virus (HBV) infection and recommends HBV vaccination for unvaccinated adults age 19 to 59 [57]. For older patients with diabetes, vaccination can be administered at the discretion of the treating clinician based upon the risk of acquiring HBV and the likelihood of an adequate immune response to vaccination. (See "Hepatitis B virus vaccination", section on 'Other high-risk groups'.)
Rotavirus vaccine contraindications — In October 2011, the Centers for Disease Control and Prevention added a history of intussusception as a contraindication to administration of rotavirus vaccine [58]. A history of intussusception previously had been considered only a precaution. (See "Rotavirus vaccines", section on 'RV5 contraindications' and "Rotavirus vaccines", section on 'RV1 contraindications'.)
HPV vaccine and prevention of anal intraepithelial neoplasia — A quadrivalent vaccine has been shown to be effective in preventing infection with human papillomavirus vaccine (HPV) types 6, 11, 16, and 18 and to prevent the development of external genital lesions [59]. A planned substudy of that trial analyzed the impact of the vaccine on the development of anal intraepithelial neoplasia in 602 men who have sex with men [60]. Study subjects were aged 16 to 26 years, had no history or evidence of anal lesions, had five or fewer lifetime sexual partners, and were HIV negative. Administration of the HPV vaccine was associated with a significant decrease in the incidence of anal intraepithelial neoplasia. (See "Anal intraepithelial neoplasia: Diagnosis, screening, prevention, and treatment", section on 'Prevention'.)
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