The following material represents a subset of new available drugs, drug warnings, and drugs removed from the market since the last version of UpToDate. This is not a complete list; it includes those topics that were 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. This program is only available for online users at this time, and can be accessed from either the main search screen or in the drug interactions section of the drug database when using UpToDate online.

NEW DRUGS/DRUG APPROVALS

For a complete list of drug approvals see www.lexi.com/newdrugs.

The RE-LY trial, which evaluated the efficacy and safety of two different doses of dabigatran relative to warfarin in over 18,000 patients with atrial fibrillation, is the first trial to demonstrate that an alternative oral anticoagulant may be superior to adjusted-dose warfarin [1]. Dabigatran 110 mg was non-inferior to warfarin for the primary efficacy endpoint of stroke or systemic embolization, while dabigatran 150 mg was significantly more effective than warfarin or dabigatran 110 mg. Major bleeding, occurred significantly less often with dabigatran 110 mg than warfarin; dabigatran 150 mg had equal safety to warfarin. As of October 2009, dabigatran is available in Canada, United Kingdom and elsewhere, but is not yet available in United States. (See "Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation", section on 'Dabigatran'.)

In July 2009 the United States Food and Drug Administration (FDA) approved the oral antiplatelet agent prasugrel for use (along with aspirin) in patients with acute coronary syndromes (ACS) undergoing PCI. This was based upon the results of the TRITON-TIMI 38 trial in which over 13,000 patients with ACS who underwent PCI were randomly assigned to either prasugrel or clopidogrel [2]. Patients with non-ST elevation ACS received thienopyridine treatment after coronary angiography, while those with ST-elevation myocardial infarction generally received treatment before coronary angiography. At 15 months, the primary endpoint (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) occurred significantly less often with prasugrel (9.9 versus 12.1 percent). (See "Antiplatelet agents in unstable angina and acute non-ST elevation myocardial infarction", section on 'Summary and recommendations' and "Antiplatelet agents in acute ST elevation myocardial infarction", section on 'Summary and recommendations'.)

The randomized PLATO trial compared ticagrelor, an investigational oral antiplatelet agent, with clopidogrel in over 18,000 patients with an acute coronary syndrome [3]. At 12 months, the composite primary end point (death from vascular causes, MI, or stroke) occurred significantly less often in patients receiving ticagrelor (9.8 percent versus 11.7 percent with clopidogrel); there was no significant difference in major bleeding. (See "Antiplatelet agents in unstable angina and acute non-ST elevation myocardial infarction", section on 'Ticagrelor therapy'.)

Roflumilast is a phosphodiesterase-4 inhibitor that is being studied for use in COPD. A 52-week randomized trial of 3091 patients with COPD found that roflumilast improved the prebronchodilator forced expiratory volume in one second (FEV1) and decreased the rate of moderate to severe exacerbations [4]. Similarly, in two 24-week trials, roflumilast improved the prebronchodilator FEV1 in patients with moderate to severe COPD when added to either salmeterol or tiotropium [5]. (See "Management of stable chronic obstructive pulmonary disease", section on 'Future directions'.)

Saxagliptin, a newer dipeptidyl peptidase (DPP)-IV inhibitor that reduces hemoglobin A1C by aproximately 0.5 percentage points, can be used as initial pharmacologic therapy for the treatment of type 2 diabetes or as a second agent in those who do not respond to a single agent, such as a sulfonylurea, metformin, or a thiazolidinedione [6,7]. (See "GLP-1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Saxagliptin'.)

In the FREEDOM trial (7868 postmenopausal women with BMD T-scores between -2.5 and -4.0 at the LS or total hip), an investigational targeted human monoclonal antibody, denosumab, compared with placebo signficantly reduced the incidence of new vertebral (2.3 versus 7.2 percent), hip (0.7 versus 1.2 percent), and nonvertebral fractures (6.0 versus 8.5 percent) [8]. (See "Overview of the management of osteoporosis in postmenopausal women", section on 'Denosumab'.)

In a phase III trial in men treated with androgen deprivation therapy (ADT) for advanced prostate cancer without bone metastases, denosumab significantly decreased the incidence of new vertebral fractures [9]. (See "Managing the side effects of androgen deprivation therapy", section on 'Denosumab'.)

Pralatrexate was approved for use in relapsed or refractory peripheral T cell lymphoma (PTCL) by United States Food and Drug Administration (FDA) in the fall of 2009. Preliminary results from an international, open label phase II registration trial (the PROPEL trial) of pralatrexate in 115 heavily pretreated patients with PTCL noted an overall response rate of 27 percent with 10 percent complete responses [10]. The most common severe (grade 3/4) toxicities were thrombocytopenia (32 percent) and mucosal inflammation (21 percent). (See "Treatment of relapsed or refractory peripheral T cell lymphoma", section on Praletrexate.)

The United States FDA approved pemetrexed for maintenance treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer [11]. The approval was based upon a trial in which maintenance therapy with pemetrexed significantly increased both progression-free and overall survival [12]. (See "Sequential non-cross-resistant therapy for patients responding to initial treatment of advanced non-small cell lung cancer", section on 'Contemporary regimens'.)

Vistonuridine, an orally administered prodrug of uridine, is a specific pharmacologic antidote to fluorouracil (5-FU). It is a safe, effective, and potentially life-saving treatment for flurouracil overdose. In a preliminary study, recovery was reported in all 17 cases treated with vistonuridine for fluorouracil overexposure, compared to 2 of 13 who did not receive it [13]. (See "Enterotoxicity of chemotherapeutic agents", section on 'Predictive markers'.) Vistonuridine is not commercially available, but it has received orphan drug designation for treatment of fluorouracil overexposure from both United States FDA and European Medicines Agency. In United States, it is available from its manufacturer, Wellstat Therapeutics, under an emergency-use Investigational New Drug (IND) waiver.

A new parenteral iron preparation, ferumoxytol (Feraheme™), has been approved by United States FDA for the treatment of iron deficiency in patients with anemia due to chronic kidney disease [14]. (See "Use of iron preparations in hemodialysis patients", section on 'Ferumoxytol'.)

In September 2009, United States FDA approved ustekinumab, a human monoclonal antibody that targets IL-12 and IL-23 for the treatment of moderate to severe plaque psoriasis in patients who are candidates for phototherapy or systemic therapy. (See "Treatment of psoriasis", section on 'Ustekinumab'.)

Vigabatrin was approved by United States FDA in 2009 for the treatment of infantile spasms as well as for adjunctive treatment of adults with refractory partial seizures [15,16]. A boxed warning alerts clinicians to safety concerns regarding permanent vision loss with this medication. Physicians must be registered with the SHARE program in order to prescribed vigabatrin. (See "Pharmacology of antiepileptic drugs", section on 'Vigabatrin' and "Management and prognosis of infantile spasms", section on 'Vigabatrin'.)

The United States FDA has issued an Emergency Use Authorization to permit the use of oseltamivir for the treatment of influenza in infants younger than one year of age [17]. To avoid dosing errors, providers and pharmacists should counsel the caregiver(s) regarding proper administration and provide a dosing device with units of measure (mg or mL) that match the units of measure on the prescription [18-20]. (See "Antiviral drugs for the prevention and treatment of influenza in children", section on 'Treatment dosing'.)

ADVERSE REACTIONS

A subgroup analysis of over 1500 patients in the ACUITY trial who had an acute coronary syndrome and received CABG found that those who received clopidogrel, compared to those who did not, had significantly fewer adverse events (death, myocardial infarction, or unplanned revascularization) at 30 days, while rates of bleeding were not significantly different [21]. Thus, clopidogrel should not be withheld prior to coronary angiography due to concerns of excess bleeding in this population. (See "Antiplatelet agents in unstable angina and acute non-ST elevation myocardial infarction", section on Concerns about early CABG.)

A retrospective analysis of data from an earlier randomized trial found that the rate of serious bleeding events (intracranial hemorrhage, retinal hemorrhage, hemarthrosis, spinal hemorrhage, or other life threatening bleeding) was not increased among those who received heparin venous thromboembolism prophylaxis during recombinant human activated protein C (rhAPC) infusion, although total bleeding complications were increased [22]. (See "Management of severe sepsis and septic shock in adults", section on 'VTE prophylaxis during infusion'.)

Churg-Strauss syndrome (CSS) has been reported in patients receiving omalizumab for treatment of severe asthma. The timing of onset of symptoms suggests that CSS preceded treatment with omalizumab or coincided with tapering of glucocorticoids after initiation of omalizumab [23]. (See "Churg-Strauss syndrome (allergic granulomatosis and angiitis)", section on 'Association with medications'.)

The risk of pneumonia was not increased by inhaled budesonide in a meta-analysis of 7042 patients with COPD [24]. (See "Role of inhaled glucocorticoid therapy in stable COPD", section on 'Adverse effects'.)

The issue of worsened survival in cancer patients treated with erythropoietin (EPO) or darbepoetin has been raised. However, during long-term follow-up of a phase III ECOG trial, subjects with myelodysplastic syndrome (MDS) who were treated with EPO ± granulocyte colony-stimulating factor, when compared with those receiving supportive care only, had similar overall survival and a similar incidence of transformation to acute myeloid leukemia [25]. (See "Treatment and prognosis of the myelodysplastic syndromes", section on 'Effect on survival'.)

The United States Food and Drug Administration (FDA) has notified healthcare professionals of an Early Communication regarding an ongoing review of safety issues with the orally-active iron chelating agent deferasirox (Exjade®). New safety data suggest there may be a greater number of adverse events and deaths in patients using this agent who are >60 and have myelodysplastic syndrome [26]. (See "Treatment and prognosis of the myelodysplastic syndromes", section on 'Red cell transfusions and iron chelation'.)

In a meta-analysis of 11 clinical reports, nearly one out of every ten patients receiving cetuximab for treatment of advanced cancer developed hypokalemia, often severe, during therapy [27]. Periodic monitoring of serum potassium levels is warranted in patients receiving cetuximab. (See "Chemotherapy and renal insufficiency", section on 'EGFR pathway inhibitors'.)

Bevacizumab is increasingly used in patients with advanced breast and non-small cell lung cancer, in whom brain metastases are common. Given that bleeding is a known complication of bevacizumab therapy, concerns have been raised as to the risk of central nervous system (CNS) hemorrhage in patients who have nonhemorrhagic brain metastases. In a prospective study of 115 patients with brain metastases who were treated with a bevacizumab-containing regimen for advanced non-small cell lung cancer (NSCLC), there were no CNS hemorrhages [28]. Thus, patients with treated nonhemorrhagic brain metastases need not be excluded from systemic therapy with bevacizumab. (See "Systemic chemotherapy for brain metastases", section on 'Risk of CNS hemorrhage with bevacizumab'.)

For patients receiving oxaliplatin-based regimens (eg, FOLFOX) for treatment of metastatic colorectal cancer, dose-limiting sensory neuropathy can by mitigated by intermittent oxaliplatin-free intervals. Results from the OPTIMOX2 trial suggest that patients may have a worse outcome if courses of oxaliplatin-based chemotherapy are interspersed with entirely chemotherapy-free intervals [29]. Thus, for patients who develop neuropathy while receiving an oxaliplatin-based regimen (or who have received a cumulative oxaliplatin-dose of ≥680 mg/m2), it is reasonable to discontinue oxaliplatin temporarily while maintaining infusional 5-FU and leucovorin. (See "Systemic chemotherapy for metastatic colorectal cancer: Completed clinical trials", section on 'Intermittent versus continuous oxaliplatin'.)

There was a significant increase in all-cause mortality in men with preexisting heart failure or a history of myocardial infarction who received neoadjuvant androgen deprivation therapy (ADT) prior to brachytherapy for localized, node negative prostate cancer [30]. (See "Managing the side effects of androgen deprivation therapy", section on 'Cardiovascular disease' and "Brachytherapy for localized prostate cancer", section on 'Prostate gland size'.)

Data regarding use of insulin analogs and risk of cancer are conflicting with insulin glargine [31-35]. Until more data are available, there is insufficient evidence to make a recommendation against glargine. (See "General principles of insulin therapy in diabetes mellitus", section on 'Human versus analogs'.)

There have been 88 postmarketing case reports of acute pancreatitis in patients using sitagliptin [36]. Pancreatitis should be considered in patients with persistent severe abdominal pain (with or without nausea), and sitagliptin (or sitagliptin-metformin) should be discontinued in such patients. (See "GLP-1-based therapies for the treatment of type 2 diabetes mellitus", section on 'DPP-IV inhibitors'.)

A meta-analysis of eight randomized trials (3786 patients) found that patients taking eszopiclone for insomnia were at higher risk for infection than patients taking placebo (20 versus 11 percent, relative risk 1.48, 95% CI 1.25-1.74) [37]. A similar meta-analysis of ten randomized trials (2935 patients) found that patients taking zolpidem were also at higher risk for infection than patients taking placebo (5 versus 3 percent, relative risk 1.99, 95% CI 1.21-3.26) (see "Treatment of insomnia", section on 'Adverse effects'.

The United States FDA has required identical boxed warnings on bupropion and varenicline about the risk of serious neuropsychiatric symptoms (eg, behavior changes, agitation, depressed mood, suicidal thoughts, and attempted suicide) and noted the overlap with typical symptoms of nicotine withdrawal [38]. (See "Management of smoking cessation",)

Patients who had discontinued statin therapy because of myalgias tolerated red yeast rice and achieved significant reductions in LDL-C, in a placebo-controlled randomized trial [39]. There is a lack of standardization of red yeast rice products and it is not known if a lower dose of statin would have been tolerated and could achieve similar LDL-C reductions [40]. (See "Lipid lowering with diet or dietary supplements",)

A systematic review of second-generation antidepressants found that mirtazapine and paroxetine were associated with more weight gain than fluoxetine, sertraline, trazodone, and venlafaxine [41]. (See "Initial treatment of depression in adults".)

A cohort study of people 65 years and older found that depressed individuals were more than twice as likely to develop diabetes. compared to those without depression, regardless of antidepressant treatment [42]. In addition, specific antidepressants may be associated with an increased risk of diabetes. A nested case-control study in patients with depression found that long-term use (>24 months) of some antidepressants (amitriptyline, fluvoxamine, paroxetine, and venlafaxine) in moderate to high doses was associated with a significantly increased risk of diabetes [43]. (See "Initial treatment of depression in adults", section on Antidepressants, Side effects.)

Revised recommendations from the American Academy of Dermatology for monitoring for methotrexate-induced hepatotoxicity in patients with psoriasis suggest an individualized decision to perform liver biopsy based on a patient's risk factors, liver chemistry results, and cumulative dose [44]. Previous guidelines advocated performing liver biopsies after every 1 to 1.5 g of cumulative methotrexate. The new recommendations are dependent upon the presence or absence of patient risk factors for methotrexate-induced hepatotoxicity. (See "Treatment of psoriasis", section on 'Hepatotoxicity and liver biopsy'.)

Based upon a safety review of tumor necrosis factor (TNF) inhibitors, the United States FDA concluded that that there is an increased risk of lymphoma and other cancers associated with their use in children and adolescents [45]. This information has been included in a boxed warning for TNF inhibitors. Healthcare providers should review the risks and the potential benefits of these drugs, as well as the risks and benefits of alternative treatment. This FDA alert also reviewed 69 cases of new onset psoriasis in patients using TNF inhibitors for autoimmune and rheumatic diseases other than psoriasis and psoriatic arthritis. Drug discontinuation resulted in improvement of the psoriasis in the majority of patients. (See "Tumor necrosis factor-alpha inhibitors: Risk of malignancy", section on TNF inhibitor FDA warning.) (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Psoriatic skin lesions'.)

Since the reintroduction of natalizumab to the market in June 2006, more than 10 new cases of progressive multifocal leukoencephalopathy (PML) have been confirmed through June 2009 in patients with multiple sclerosis treated with natalizumab monotherapy [46-49]. The incidence of PML among patients on natalizumab for 18 months or longer approximates 1 in 1000. (See "Natalizumab for relapsing-remitting multiple sclerosis in adults", section on 'Risk of progressive multifocal leukoencephalopathy'.)

Use of postmenopausal hormone therapy increases breast density and interferes with the performance of screening mammography. Short-term (one to two months) cessation of hormone therapy in women prior to mammography, although advised by some clinicians, had no effect on mammography recall rates in a randomized trial [50]. (See "Breast imaging: Mammography and ultrasonography", section on 'The dense breast'.)

A retrospective study of over 220,000 women who underwent mifepristone/misoprostol abortion reported that rates of serious infection dropped significantly after the introduction of two protocol changes: routine use of doxycycline as a prophylactic antibiotic and administration of misoprostol buccally rather than vaginally [51]. The rate of serious infection declined from 0.93 to 0.06 per 1000 abortions. (See "Mifepristone for the medical termination of pregnancy", section on 'Infection' and "Mifepristone for the medical termination of pregnancy", section on 'Route of administration'.)

The benefit of iso-osmolal compared to low osmolal nonionic contrast agents in preventing contrast nephropathy is not known. A meta-analysis of 16 randomized trials showed that the iso-osmolal contrast agent, iodixanol, was associated with a reduction in risk of contrast nephropathy among patients with chronic kidney disease when compared to a single low osmolal agent, iohexol, but not when compared to other tested nonionic low osmolal contrast agents [52]. (See "Prevention of contrast-induced nephropathy", section on 'Nonionic iso-osmolal agents'.)

Although a retrospective study funded by United States Food and Drug Administration (FDA) reported an association between use of stimulant therapy for attention deficit hyperactivity disorder (ADHD) and sudden unexpected death (SUD) [53], the FDA concluded that this study was not able to verify a relationship between the use of stimulant therapy and SUD because of methodologic limitations [54].

An observational study suggests that evening administration of once-daily atomoxetine is associated with fewer adverse effects and may be better tolerated than morning administration when initiating atomoxetine therapy for attention deficit hyperactivity disorder [55]. (See "Attention deficit hyperactivity disorder in children and adolescents: Pharmacotherapy", section on 'Atomoxetine'.)

In children, the most commonly used anticholinergic agent for overactive bladder (OAB) is oxybutynin. In a study based on data from the United States Food and Drug Administration (FDA) Adverse Event Reporting System, central nervous system (CNS) side effects associated with oxybutynin appeared to occur more frequently in children than adults and included hallucination, agitation, sedation, confusion, amnesia, and nightmares. [56]. (See "Management of voiding dysfunction in children", section on 'Oxybutynin'.)

Due to reports of severe propylthiouracil (PTU)-related liver failure, the American Thyroid Association and United States FDA have published new recommendations (in preliminary form) for PTU use [57]. We agree with their recommendations and suggest that PTU not be prescribed as the first line drug in most children or adults. PTU is still preferred to methimazole during the first trimester of pregnancy and in patients with life-threatening thyrotoxicosis or thyroid storm. (See "Pharmacology and toxicity of thionamides" and "Diagnosis and treatment of hyperthyroidism during pregnancy" and "Treatment and prognosis of Graves' disease in children and adolescents".)

VACCINES

Seasonal influenza vaccine - Although in children the live attenuated (intranasal) influenza vaccine may be more effective than the inactivated (intramuscular) vaccine, studies in adults have shown that the inactivated vaccine is either equivalent to or more effective than the live attenuated vaccine. In a randomized trial that included 1952 adults vaccinated during the 2007 to 2008 influenza season, the inactivated vaccine was superior to the live attenuated vaccine in preventing influenza infection (68 versus 36 percent absolute efficacy, respectively) [58]. (See "Seasonal influenza vaccination in adults", section on 'Comparisons of inactivated and live-attenuated vaccines'.)

Pandemic H1N1 influenza ('swine influenza') vaccine - Vaccines against pandemic H1N1 influenza began being distributed in the United States in October 2009.

  Target groups - The recommended target groups for pandemic H1N1 influenza vaccination differ from those for seasonal influenza. The US Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) has recommended the following prioritization for administration of the pandemic H1N1 influenza vaccine [59]:

• Pregnant women
• Household contacts and caregivers of children younger than 6 months of age (eg, parents, siblings, and daycare providers)
• Healthcare and emergency medical services personnel
• Individuals from 6 months through 24 years of age
• Individuals from 25 through 64 years of age with health conditions associated with increased risk of influenza complications

(See "Prevention of pandemic H1N1 influenza ('swine influenza')", section on 'Target groups'.)

  Dosing schedule - Preliminary results from clinical trials have shown that a single dose of pandemic H1N1 vaccine is likely to be immunogenic in a substantial percentage of healthy adults and in children ≥10 years of age [60-62]. Children aged six months to nine years should receive two doses of the vaccine, separated by approximately four weeks; individuals ≥10 years of age should receive one dose [63]. (See "Prevention of pandemic H1N1 influenza ('swine influenza')", section on 'Dosing schedule'.)

Meningococcal vaccine - In September 2009, the United States Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) published updated recommendations regarding revaccination of individuals at prolonged increased risk for meningococcal disease [64]. Individuals who were previously vaccinated with either the quadrivalent meningococcal polysaccharide vaccine conjugated to diphtheria toxoid (Menactra, MCV4) or the meningococcal polysaccharide vaccine (Menomune, MPSV4) who remain at increased risk for meningococcal disease should be revaccinated with MCV4 according to the following schedule:

• Individuals who were vaccinated at 2 to 6 years of age should be revaccinated 3 years after receiving their previous meningococcal vaccine
• Individuals who were vaccinated at ≥7 years of age should be revaccinated 5 years after receiving their previous meningococcal vaccine and should continue to be revaccinated at 5 year intervals thereafter if the increased risk for meningococcal disease persists (see "Meningococcal vaccines", section on 'Revaccination'.

Haemophilus influenzae type b - The United States Food and Drug Administration (FDA) has licensed Hiberix, a Haemophilus influenzae type b (Hib) conjugate vaccine, for use as the booster dose in children aged 15 months through 4 years who have completed their primary series of Hib conjugate vaccines [65]. (See "Prevention of Haemophilus influenzae infection", section on Conjugate vaccines".)

Given the anticipated improvement in Hib conjugate vaccine supply, the Centers for Disease Control and Prevention (CDC) recommend Hib immunization (with any available Hib-containing vaccine) at the earliest opportunity for children aged 12 months through 4 years whose Hib booster was deferred because of the Hib vaccine shortage. The CDC also recommends provider-initiated recall of such children when office supply of Hib conjugate vaccine permits [65]. (See "Prevention of Haemophilus influenzae infection", section on 'Improvement in Hib conjugate vaccine supply'.)

Human papillomavirus vaccine - Adverse events following immunization were collected and analyzed within the Vaccine Adverse Event Reporting System (VAERS) from 2006-2008 after an estimated 23 million doses of quadrivalent HPV vaccine had been administered in the United States [66]. Most of the adverse event rates were not greater than background rates of other vaccines, although there was a disproportional reporting of syncope and venous thromboembolic events. The observation of increased thrombotic events was mainly noted in those with predisposing risk factors (eg, those on birth control pills or with a positive family history).

Typhoid prevention - Prevention of enteric fever in endemic areas would require implementing immunization for young children. In a study including more than 37,000 children 2 to 5 years of age, the parenteral Vi polysaccharide vaccine was useful for inducing both direct and indirect protection (overall protection 57 percent) [67]. These data should inform further efforts in prevention of typhoid in endemic areas. (See "Treatment and prevention of typhoid fever", section on Typhoid vaccine.)

Japanese encephalitis - In June 2009 the United States Advisory Committee on Immunization Practices (ACIP) approved revised recommendations for the use of Japenese encephalitis vaccine in travelers [68]. (See "Japanese encephalitis: Epidemiology, diagnosis, treatment and prevention".)

Rabies - The guidelines for rabies vaccine administration for post-exposure prophylaxis in unvaccinated persons changed in 2009. The Advisory Committee on Immunization Practices has advised that the five-dose schedule be changed to four doses, eliminating the last dose administered on day 28 [69].