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Breast cancer screening combined with follow-up and treatment reduces breast cancer mortality. However, in the study clinic, only 12 % of eligible women ≥40 years received a mammogram in the previous year. The objective of this project was to implement patient navigation, in our partner health clinic to (1) identify women overdue for a mammogram; and (2) increase mammography utilization in this population over a 2-year period. Women overdue for a mammogram were identified. One patient navigator made navigation attempts over a 2-year period (2009–2011). Navigation included working around systems- and individual-level barriers to receive a mammogram as well as the appropriate follow-up post screening. Women were contacted up to three times to initiate navigation. The proportion of women navigated and who received a mammogram during the study period were compared to women who did not receive a mammogram using Chi square tests for categorical variables and t tests for continuous variables with an α = 0.05. Barriers to previous mammography were also assessed. With 94.8 % of eligible women navigated and 94 % of these women completing mammography, the implementation project reached 89 % of the target population. This project was a successful implementation of an evidence-based patient navigation program that continues to provide significant impact in a high-need area. Cost was the most commonly cite barrier to mammography. Increasing awareness of resources in the community for mammography and follow-up care remains a necessary adjunct to removing structural and financial barriers to accessing preventive services.

Mirabegron (Betmiga™), a β3-adrenergic receptor agonist, is a useful option for the treatment of overactive bladder syndrome. In clinical trials in this patient population, oral mirabegron 50 mg once daily significantly reduced incontinence and micturition episodes, consistently reduced urgency episodes and increased the volume of urine voided per micturition, and was associated with improvements in health-related quality of life and treatment satisfaction. Mirabegron is generally well tolerated and is associated with less dry mouth than extended-release tolterodine.

Simeprevir (Olysio™; Galexos™; Sovriad®) is an orally-administered NS3/4A protease inhibitor for use in combined drug regimens against chronic hepatitis C virus (HCV) infection. This article reviews studies relevant to the EU simeprevir label. In proof-of-concept studies, simeprevir had potent antiviral activity against all HCV genotypes, except genotype 3. In trials in patients with chronic HCV genotype 1 infection, week-12 sustained virological response (SVR12) rates in treatment-naïve patients and prior relapsers were significantly higher with simeprevir plus peginterferon-α/ribavirin (PR) [79-89 %] than with placebo plus PR (36-62 %). In prior partial/null responders, the SVR12 rate with simeprevir plus PR (54 %) was noninferior to that with telaprevir plus PR (55 %). Simeprevir plus PR was also efficacious in patients with HCV genotype 1/HIV-1 co-infection. In prior null responders without severe liver fibrosis (cohort 1) and treatment-naïve patients with severe liver fibrosis (cohort 2) treated with simeprevir plus sofosbuvir, the SVR12 rate for the two cohorts combined was 92 %. In patients with chronic HCV genotype 4 infection, the SVR12 rates with simeprevir plus PR were 83, 87 and 40 % in treatment-naïve patients, prior relapsers and prior null responders, respectively. Grade 3-4 adverse event, serious adverse event and treatment withdrawal rates with simeprevir plus PR were similar to those with placebo plus PR. Skin rashes with simeprevir were mostly mild or moderate; serious photosensitivity reactions occur, but are rare. Simeprevir is efficacious and generally well tolerated in patients with chronic HCV genotypes 1 and 4 infection. Studies of simeprevir in interferon-free regimens and in other subpopulations with HCV infections will be of interest.

Dulaglutide (Trulicity™) is a long-acting, glucagon-like peptide-1 (GLP-1) receptor agonist that has been developed by Eli Lilly and Company for the treatment of type 2 diabetes mellitus. It consists of a dipeptidyl peptidase-IV-protected GLP-1 analogue covalently linked to a human IgG4-Fc heavy chain by a small peptide linker. The subcutaneous formulation is approved for use in type 2 diabetes in the US, has been recommended for approval in the EU in this indication, and is under regulatory review in other countries. This article summarizes the milestones in the development of subcutaneous dulaglutide leading to this first approval for type 2 diabetes.

Fingolimod (Gilenya(®)) is an orally administered disease modifying agent (DMA) for use in relapsing-remitting multiple sclerosis (RRMS). In placebo-controlled trials in patients with RRMS with active disease, fingolimod 0.5 mg/day significantly reduced the annualized relapse rate (ARR) by approximately one-half over 2-year trial periods. It also significantly increased the proportion of patients with no disability progression, reduced deterioration from baseline in the Extended Disability Status Scale score and reduced MRI markers of disease progression (new/newly enlarging brain lesions and percentage change in brain volume). In a 12-month, comparison with intramuscular interferon β-1a (IFNβ- 1a) 30 μg/week, the ARR in fingolimod 0.5 mg/day recipients was significantly lower than in IFNβ-1a recipients by one-half; fingolimod recipients also had significantly lower MRI markers of disease progression. In extensions to the pivotal clinical trials, fingolimod exposure for up to 4 years was associated with low relapse rates and continuing benefits in terms of disability and disease progression. In clinical trials, adverse events in fingolimod recipients were generally mild to moderate in severity. In the pivotal placebo-controlled trial, serious adverse events occurred in similar proportions of fingolimod 0.5 mg/day and placebo recipients. First-dose bradycardia and atrioventricular block, which are generally asymptomatic, were clinically important adverse events associated with fingolimod in placebo-controlled trials. The risk for serious cardiovascular adverse events at the approved fingolimod dosage appears to be low in patients without pre-existing cardiac conditions. Fingolimod is an efficacious therapy for RRMS that reduces relapses, disability progression, new brain lesions and loss of brain volume. It has an acceptable tolerability profile and provides a useful alternative treatment in patients with RRMS who have responded poorly to other DMAs.

OnabotulinumtoxinA (BOTOX(®)) is a type A neurotoxin derived from Clostridium botulinum bacteria that is approved as treatment for urinary incontinence (UI) in patients with neurogenic detrusor overactivity resulting from multiple sclerosis (MS) or subcervical spinal cord injury (SCI) who are not adequately treated by antimuscarinics. This article reviews the pharmacology of intradetrusor onabotulinumtoxinA in this indication. The presumed mode of action of onabotulinumtoxinA in bladder disorders is by interfering with efferent innervation of the detrusor muscle and afferent pathways involved in the micturition reflex. In phase III trials in adult patients with MS or SCI with UI who were not adequately treated with antimuscarinics, intradetrusor onabotulinumtoxinA 200 U produced significantly greater mean changes (reductions) from baseline in UI episodes/week at week 6 than placebo (primary endpoint). Similar significant benefits of intradetrusor onabotulinumtoxinA 200 U over placebo were observed on other UI, urodynamic, health-related quality of life and treatment satisfaction endpoints. Intradetrusor onabotulinumtoxinA 200 U was generally well tolerated, with the most frequent adverse events being urinary tract infections and urinary retention. Few patients discontinued treatment because of adverse events. Based on interim analyses of an extension study of the phase III trials, repeat injections of onabotulinumtoxinA 200 U were similarly efficacious and well tolerated. Intradetrusor onabotulinumtoxinA represents a clinically important advance in the therapy of UI in patients with MS or SCI who have not responded to antimuscarinics or who are unable to tolerate antimuscarinics.

Elosulfase alfa (Vimizim™) is a recombinant form of N-acetylgalactosamine-6-sulfatase (GALNS) that was developed by BioMarin Pharmaceutical Inc. as an enzyme replacement therapy for patients with mucopolysaccharidosis type IVA (MPS IVA), also known as Morquio A syndrome. Patients with MPS IVA have a GALNS deficiency, which results in serious musculoskeletal, cardiorespiratory and other system disturbances. Elosulfase alfa was approved by the US FDA on 14 February 2014 for the treatment of MPS IVA. The European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) has recently recommended that elosulfase alfa be approved for use in the EU in the same indication. Within the last year, the manufacturer has also filed applications for approval for the use of elosulfase alfa in MPS IVA in Brazil, Australia, Canada and Mexico. This article summarizes the milestones in the development of elosulfase alfa leading to its first global approval in MPS IVA.

Ibrutinib (Imbruvica™) is a small molecule, first-in-class, once-daily, orally available, Bruton's tyrosine kinase inhibitor that is under development for the treatment of B cell malignancies, including chronic lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL) and diffuse large B cell lymphoma (DLBCL), as well as multiple myeloma (MM), follicular lymphoma (FL) and Waldenstrom's macroglobulinemia (WM). It has been developed by Pharmacyclics, Inc. and Janssen Biotech, Inc. Ibrutinib acts by blocking B-cell antigen receptor signalling, thereby reducing malignant proliferation of B cells and inducing cell death. Based chiefly on findings from a phase Ib/II study, ibrutinib has been approved in the USA for the treatment of MCL in previously treated patients and is one of the first approvals through the US FDA's Breakthrough Therapy Designation Pathway. An application has been filed in the EU seeking regulatory approval in this indication. In both the USA and EU, further applications have been filed with regulatory bodies seeking approval for the use of ibrutinib in patients with previously treated CLL/small lymphocytic lymphoma (SLL). Phase III trials are underway worldwide to evaluate ibrutinib in the treatment of patients with CLL/SLL, DLBCL and MCL, and the agent is in phase II development for use in WM, FL and MM. This article summarizes the milestones in the development of ibrutinib leading to its first approval in MCL.

Enzalutamide (MDV3100, XTANDI(®)) is an androgen receptor inhibitor that is indicated for the treatment of metastatic, castration-resistant, prostate cancer (mCRPC) that has progressed despite treatment with docetaxel. This article reviews the pharmacology, efficacy and tolerability of enzalutamide relevant to this indication. In a randomized, double-blind, placebo-controlled, multinational, phase III trial in patients with mCRPC progressing after docetaxel therapy, enzalutamide significantly prolonged overall survival (OS), delayed prostate specific antigen progression and prolonged radiographic progression-free survival and time to the first skeletal event. The median OS was 18.4 months in the enzalutamide group and 13.6 months in the placebo group, which represents a 37 % reduction in the mortality risk in the enzalutamide group. Enzalutamide was also associated with significant benefits in health-related quality of life and in pain palliation. Enzalutamide was generally as well tolerated as placebo during the trial, with most adverse events at a mild or moderate level of severity. Enzalutamide carries a small increased risk of seizures that appears to be dose-dependent. Enzalutamide is an efficacious and well tolerated treatment for this severe, rapidly progressive disease.

Trastuzumab (Herceptin(®)) is a humanized monoclonal antibody that binds selectively to human epidermal growth factor 2 (HER2), interfering with its downstream cancer-promoting effects. This article focuses on the efficacy and tolerability of trastuzumab in HER2-positive advanced gastric cancer. The potential of trastuzumab as a cytotoxic for use in gastric cancer was confirmed by in vitro studies in HER2-positive gastric cancer cell lines and gastric cancer xenograft models. In a randomized, controlled, open-label, multinational trial in patients with HER2-positive advanced gastric cancer, trastuzumab plus chemotherapy (cisplatin plus capecitabine or 5-fluorouracil) was significantly more efficacious than chemotherapy alone, in terms of a longer median overall survival (13.8 vs. 11.1 months in the chemotherapy alone group) [primary endpoint], a longer median progression-free survival, and a higher response rate. Trastuzumab was efficacious across patient subgroups, although stronger effects were observed in a subgroup with high HER2 overexpression (immunohistochemistry 2+/fluorescence in-situ hybridization positive or immunohistochemistry 3+). There was a slightly higher tolerability burden in the trastuzumab plus chemotherapy group than with chemotherapy alone, based on small between-group numerical differences in rates of common gastrointestinal and general adverse events. Most individual adverse events reported in this trial were at a grade 1 or 2 level of severity. However, in both treatment groups approximately half of the haematological adverse were at a grade 3 or 4 level of severity, with no marked between-group differences. Trastuzumab in combination with cisplatin and a fluoropyrimidine is an effective regimen for patients with HER2-positive advanced gastric cancer, has acceptable tolerability and represents an important advance in the treatment of gastric cancer.

Avanafil (STENDRA™, SPEDRA™, Zepeeed™) is an oral phosphodiesterase type 5 inhibitor indicated for the treatment of erectile dysfunction. Avanafil is rapidly absorbed after oral administration, with a median time to maximum plasma concentration of 30 to 45 min. In a 12-week, randomized, double-blind, placebo-controlled, multicentre trial in patients with erectile dysfunction, avanafil 50, 100 and 200 mg recipients had significantly greater improvements from baseline than placebo recipients in mean international index of erectile dysfunction-erectile function domain scores and in successful vaginal penetration and sexual intercourse attempts (coprimary endpoints). Treatment effects were significantly larger in avanafil 100 and 200 mg recipients than 50 mg recipients. For avanafil recipients, approximately two-thirds of attempts at sexual intercourse that were made prior to 15 min, or more than 6 h, after drug administration were successful, compared with approximately one-quarter of attempts made during these time periods by placebo recipients. In trials in patients with erectile dysfunction in association with diabetes mellitus, and after nerve-sparing radical prostatectomy, avanafil 100 or 200 mg was significantly more efficacious than placebo for primary and most secondary endpoints. Avanafil was generally well tolerated in the above-mentioned studies. In a pooled analysis of three clinical trials, ≤2 % of avanafil and placebo recipients discontinued treatment because of adverse events. During extended treatment with avanafil for >52 weeks, 2.8 % of patients discontinued treatment because of adverse reactions and there were no drug-related serious adverse events.

Mirabegron (YM178, Myrbetriq™, Betanis(®), Betmiga™) is a β3-adrenergic receptor agonist approved in several countries for the symptomatic treatment of adults with overactive bladder syndrome. In three 12-week, randomized, double-blind, placebo-controlled, multinational trials in patients with overactive bladder syndrome, oral mirabegron 25 or 50 mg once daily significantly reduced the adjusted mean number of incontinence episodes per 24 h (in patients with incontinence at baseline) and the adjusted mean number of micturition episodes per 24 h (in full trial populations) [coprimary endpoints]. Across trials, mirabegron 50 mg once daily also consistently significantly reduced urgency episodes and increased the volume of urine voided per micturition, generally in association with improved health-related quality of life (HR-QOL) and treatment satisfaction. Based on descriptive analyses from a 12-month trial, once-daily mirabegron 50 mg and tolterodine extended-release (ER) 4 mg were both efficacious in reducing urinary symptoms and improving HR-QOL. Mirabegron was generally well tolerated in the trials. Over 12 weeks, the adverse event rate with mirabegron 50 mg once daily was similar to that with placebo. During 12 months of treatment, 2.8 % of mirabegron 50 mg once daily recipients reported dry mouth compared with 8.6 % with tolterodine ER 4 mg once daily recipients. Mirabegron 50 mg once daily carries a low risk of QT interval prolongation. Thus, mirabegron is an efficacious new treatment for overactive bladder syndrome with a favourable tolerability profile.

Once-daily administration of the rotigotine transdermal patch (Neupro®) is effective in treating patients with early Parkinson’s disease (as monotherapy), advanced Parkinson’s disease (in combination with levodopa), inadequate morning motor control despite antiparkinsonian treatment (mostly in combination with levodopa), and moderate to severe idiopathic restless legs syndrome. Rotigotine is generally well tolerated, with the most common treatment-emergent adverse events being application-site reactions, gastrointestinal disturbances, somnolence and headache.

This review focuses on the efficacy and tolerability of lurasidone, which is approved in the USA, Puerto Rico and Canada for the treatment of schizophrenia. In two placebo-controlled, phase II trials, lurasidone 40-120 mg/day was efficacious in reducing the acute symptoms of schizophrenia. In a third phase II trial, the lurasidone groups and haloperidol control group failed to separate from placebo on key endpoints. In two placebo- and active treatment-controlled, phase III trials, lurasidone at dosages of 40-160 mg/day, olanzapine 15 mg/day and quetiapine extended-release (XR) 600 mg/day were efficacious in reducing the symptoms of schizophrenia. In a 12-month, double-blind extension trial, the relapse rate in lurasidone recipients was noninferior to that in quetiapine XR recipients. In a third phase III trial, lurasidone 80 mg/day, but not 40 or 120 mg/day, was more efficacious than placebo for the primary endpoint. In an unpublished trial, there were no significant differences between lurasidone, active comparator and placebo groups on the primary endpoint. Lurasidone was generally well tolerated over the short and longer term. Extrapyramidal symptoms and akathisia occurred in ≈10-13 % of patients. Lurasidone was associated with a low risk of QT interval prolongation, weight gain, metabolic disturbances and hyperprolactinaemia. Further trials against other antipsychotics are needed to fully evaluate its efficacy and tolerability.

Ipilimumab (Yervoy™), a recombinant monoclonal antibody targeted at cytotoxic T-lymphocyte-associated antigen 4, is approved for the treatment of advanced melanoma. In a placebo-controlled trial in previously treated patients with advanced melanoma, ipilimumab, without or with an investigational glycoprotein (gp) 100 peptide vaccine, was associated with significantly longer median overall survival than gp100 peptide vaccine monotherapy. The risk of death relative to the gp100 peptide vaccine was reduced by 34% with ipilimumab monotherapy and by 32% with ipilimumab plus gp100 peptide vaccine. Overall survival did not differ significantly between treatment with ipilimumab monotherapy and ipilimumab plus gp100 peptide vaccine. Novel immune-related events that are not typical of other anticancer agents, most commonly dermatologic and gastrointestinal disorders, can occur with ipilimumab, necessitating specific monitoring and management protocols.

Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) (PCV13; Prevenar 13(®); Prevnar 13(®)) is approved in adults aged ≥50 years (focus of review) and in children aged 6 weeks to 5 years for protection against pneumococcal diseases caused by Streptococcus pneumoniae in numerous countries worldwide, including the US and those in the EU; specific indications may vary between individual countries. Polysaccharide conjugated vaccines such as PCV13 may have an immunological advantage over unconjugated vaccines [e.g. 23-valent pneumococcal polysaccharide vaccine (PPV23)], since immunization with conjugated vaccines results in the development of T-cell-dependent immune responses, whereas unconjugated vaccines do not lead to booster responses on revaccination. In clinical trials in adults aged ≥50 years, PCV13 elicited a functional immune response and, overall, was shown to be noninferior to PPV23 for all 12 serotypes common to the two vaccines. Furthermore, PCV13 elicited significantly greater functional immune responses than PPV23 for the majority of serotypes common to both vaccines. PCV13 administered concomitantly with trivalent inactivated influenza vaccine generally produced antibody responses that were noninferior to those following sequential administration of the vaccines. The PCV13 vaccine was generally well tolerated in older adults participating in these trials.

Pneumococcal polysaccharide conjugate vaccine (13-valent, adsorbed) [PCV13] is approved for protection against pneumococcal disease in children aged 6 weeks to 5 years and adults aged ≥50 years. In randomized trials in adults aged 60–64 years (not previously vaccinated with 23-valent pneumococcal polysaccharide vaccine [PPV23]) and ≥70 years (previously vaccinated with PPV23), PCV13 was non-inferior to PPV23 in opsonophagocytic assay (OPA) geometric mean titres (GMTs) for all 12 serotypes common to the two vaccines. More PCV13 than PPV23 recipients had ≥4-fold increases in serotype 6A OPA GMTs (serotype 6A is not included in PPV23). PCV13 recipients also had higher OPA GMTs and met superiority criteria for most serotypes. Adults aged 50–59 years had antibody responses to PCV13 that were noninferior to those in adults aged 60–64 years for all included serotypes. PCV13 administered concomitantly with trivalent inactivated influenza vaccine in adults aged 50–59 or ≥65 years produced antibody responses that were noninferior to those following sequential administration, except for influenza strain A/H3N2 and pneumococcal serotype 19F in those aged ≥65 years. Antibody responses were numerically higher with sequential administration, although the clinical significance of this is unknown. Adverse events within 14 days of vaccination were mostly of mild-to-moderate severity, with serious events occurring in 0.2–1.4% of PCV13 and 0.4–1.7% of PPV23 recipients.

The CD20 monoclonal antibody ofatumumab is effective in the treatment of patients with chronic lymphocytic leukaemia refractory to fludarabine and alemtuzumab. Although adverse events such as infection and neutropenia are common, intravenous ofatumumab has an acceptable tolerability profile in this heavily pre-treated population.

Quetiapine (Seroquel®) is an orally administered atypical antipsychotic that is indicated for the treatment of schizophrenia and bipolar disorder, including bipolar depression. An extended-release (XR) formulation of quetiapine is also available. This review summarizes the pharmacological properties, efficacy and tolerability of quetiapine and quetiapine XR in patients with bipolar depression. Quetiapine is an antagonist at both serotonin 5-HT2 and dopamine D2 receptors, and its antipsychotic effects are thought to stem from interactions at these receptors. The antidepressant effects of quetiapine are poorly understood, but may be related to antagonism of 5-HT2A receptors in cortical regions, partial agonism of 5-HT1A in the prefrontal cortex in association with increased extracellular dopamine release in the region, or to reduced synaptic reuptake of noradrenaline resulting from inhibition of the noradrenaline reuptake transporter by the quetiapine metabolite norquetiapine. The efficacy and tolerability of quetiapine was evaluated in five 8-week, randomized, double-blind, placebo-controlled, multicentre or multinational trials in patients with a major depressive episode (MDE) associated with bipolar disorder. Across trials, monotherapy with oral quetiapine 300 or 600 mg/day (or quetiapine XR 300 mg/day) produced significantly greater improvements than placebo in depressive symptoms (primary endpoint), according to the change in the Montgomery-Asberg Depression Rating Scale total score. In general, quetiapine and quetiapine XR were also associated with significantly higher MDE response and remission rates than placebo. Across trials, quetiapine and quetiapine XR produced significantly greater improvements in global severity of illness scores than placebo, according to changes in the Clinical Global Impressions scale score. There were no differences in treatment outcomes between quetiapine 300 mg/day and 600 mg/day dosage groups. Patients with bipolar depression who responded to quetiapine during two 8-week acute treatment trials also benefited from continuing quetiapine therapy for up to 52 weeks. Compared with quetiapine responders randomized to placebo, quetiapine responders who continued quetiapine 300 or 600 mg/day had a significantly reduced risk of recurrence of any mood events and of depression mood events, but not of hypomanic/manic events. In a randomized, double-blind, placebo-controlled trial, quetiapine maintenance therapy for up to 104 weeks was more efficacious than placebo or lithium in prolonging the time to recurrence of any mood event (primary endpoint). Patients in this trial had bipolar I disorder with mania, depression or a mixed episode as the index episode, and the trial included only patients who were responsive to acute phase quetiapine, which may have introduced a positive bias in favour of quetiapine over lithium during maintenance therapy. Quetiapine 300 or 600 mg/day and quetiapine XR 300 mg/day was generally well tolerated in patients with bipolar depression, with most treatment-emergent adverse events being of mild to moderate severity. The most frequent adverse events occurring during the acute treatment phase were dry mouth, sedation, somnolence, dizziness (quetiapine and quetiapine XR), constipation (quetiapine) and increased appetite (quetiapine XR). Extrapyramidal symptoms (EPS) occurred across quetiapine and placebo groups, but there were no significant differences between quetiapine and placebo recipients on objective measures of EPS and akathisia. In some trials, quetiapine recipients experienced significantly greater weight gain than placebo recipients. Across trials, some quetiapine recipients had clinically relevant increases in blood glucose or lipid parameters, although these also occurred in patients from other treatment groups. The clinical significance of these changes is uncertain. In conclusion, quetiapine and quetiapine XR are valuable additions to the first-line treatments for bipolar depression. Further head-to-head trials of quetiapine versus other drug regimens that are effective in bipolar depression would be of considerable interest.

Vardenafil orodispersible tablet (ODT) is a supralingual formulation of vardenafil that is available for the on-demand treatment of erectile dysfunction. The pharmacokinetics of vardenafil ODT are not equivalent to those of the vardenafil film-coated tablet in that the ODT formulation provides consistently greater vardenafil systemic exposure. Therefore, the two formulations are not interchangeable. The efficacy of on-demand vardenafil ODT 10 mg was established in the POTENT I and II studies, which were 6-week, randomized, double-blind, multinational trials in men with erectile dysfunction of at least 6 months duration. In both trials, vardenafil ODT improved erectile function significantly more than placebo, as indicated by International Index of Erectile Function-Erectile Function subscale scores at week 12 and overall erection success rates during treatment according to responses to questions 2 and 3 of the Sexual Encounter Profile (coprimary endpoints). In a pooled analysis of both trials, vardenafil ODT improved erectile function regardless of age, severity of erectile dysfunction at baseline or the presence or absence of underlying medical conditions. Vardenafil ODT was generally well tolerated in clinical trials, including in men aged ≥65 years, and adverse events were mostly mild or moderate in severity.

Subcutaneous recombinant interferon-β-1a (Rebif®) 22 or 44μg three times weekly is a valuable option in the first-line treatment in patients with relapsing-remitting multiple sclerosis (RRMS). It has shown benefits on outcome measures related to relapses, progression of disability and magnetic resonance imaging (MRI) in clinical trials. A significant efficacy advantage for subcutaneous interferon-β-1a three times weekly over intramuscular interferon-β-1a 30μg once weekly was shown at 24 and 48 weeks. The most common adverse events are generally mild and clinically manageable. Considering both direct and indirect comparative clinical trial data, an assessment suggests that subcutaneous interferon-β-1a 44μg three times weekly has the best benefit-to-risk values of the available disease-modifying drugs used to treat RRMS. Glycosylated recombinant interferon-β-1a has the same primary structure and biological effects in the body as endogenous human interferon-β. Immunomodulatory activity, the principal pharmacodynamic property of interferon-β-1a, most likely results from interferon-stimulated gene products mediating biological activities. The long-term clinical significance of the development of neutralising antibodies (NABs) to interferon-β-1a is currently unclear; therefore, it is recommended that treatment decisions are based on clinical efficacy and not on the presence of NABs alone. In healthy volunteers, subcutaneous interferon-β-1a has a long apparent elimination half-life and appears to accumulate after repeated doses. In a randomised 2-year trial, subcutaneous interferon-β-1a 22 or 44μg three times weekly for 2 years was more effective than placebo as assessed by a number of clinical (e.g. relapse rate per patient, proportion of patients without clinical relapse and changes from baseline in Kurtzke Expanded Disability Status Scale [EDSS] scores) and MRI (total burden of disease and numbers of active lesions per patient per scan) endpoints. Significant dose-response effects in favour of the higher dosage were evident when the study period was extended for another 2 years. Extension data for a total follow-up period of 7–8 years in the original cohort showed sustained clinical benefits with subcutaneous interferon-β-1a therapy. In a 48-week comparative trial, patients randomised to subcutaneous interferon-β-1a 44μg three times weekly were more likely to remain free of relapses and have significantly more favourable measures of MRI lesion activity at weeks 24 and 48 weeks, and a longer time to first relapse, than those randomised to intramuscular interferon-β-1a 30μg once weekly. In the crossover extension phase (median treatment duration 34 weeks), clinical and MRI outcomes improved in patients who crossed over from treatment with intramuscular interferon-β-1a 30μg once weekly to subcutaneous interferon-β-1a 44μg three times weekly. In clinical trials of subcutaneous interferon-β-1a, the most commonly reported adverse events (e.g. injection-site reactions, headache and influenza-like symptoms) were generally mild, manageable and reversible. Mild, asymptomatic and reversible haematological disorders and alterations in liver function tests may occur. A few patients experience serious effects on liver function. Subcutaneous interferon-β-1a 44μg three times weekly was associated with a significantly higher incidence of injection-site disorders and liver function or haematological abnormalities than intramuscular interferon-β-1a 30μg once weekly. No between-group differences were noted regarding the proportions of patients experiencing serious adverse events. In an assessment that evaluated the four available RRMS disease-modifying treatments based on the numbers of patients needed to treat to obtain benefit or harm, subcutaneous interferon-β-1a 44μg three times weekly had the best benefit-to-risk values. Based on data from pivotal directly comparative trials, subcutaneous interferon-β-1a 44μg three times weekly had favourable benefit-to-risk values relative to subcutaneous interferon-β-1a 22μg three times weekly and intramuscular interferon-β-1a 30μg once weekly. Based on indirect comparative data from published clinical trials, subcutaneous interferon-β-1a appeared to have favourable efficacy values relative to interferon-β-1b every other day, and interferon-β formulations appeared to have favourable benefit-to-risk ratios relative to placebo and also subcutaneous glatiramer acetate 20gmg once daily. In pharmacoeconomic analyses from a healthcare payer perspective, subcutaneous interferon-β-1a 44μg three times weekly was predicted to be increasingly more cost effective than placebo over the mid-(10 years) and long-(20 years) term with regard to preventing EDSS-months of disability in the UK and France, and cost saving relative to intramuscular interferon-β-1a 30μg once weekly over 48 weeks in the US.

Eldecalcitol (1α,25[OH](2)-2β-(3-hydroxypropyloxy)vitamin D(3); ED-71; Edirol®) is an orally administered analogue of active vitamin D (calcitriol) that is available in Japan for the treatment of osteoporosis. Two randomized, double-blind, multicentre trials were conducted in patients with osteoporosis. In a placebo-controlled, dose-ranging trial, eldecalcitol significantly reduced serum bone-specific alkaline phosphatase (BALP) and serum osteocalcin, markers of bone formation, more than placebo. Eldecalcitol at a 1.0 μg/day dosage, but not at lower dosages, also significantly reduced urinary type I collagen N-telopeptide (NTX), a marker of bone resorption, more than placebo. In a comparison with alfacalcidol (a prodrug of calcitriol), eldecalcitol produced significantly greater reductions in serum BALP and urinary NTX, and had a positive effect on CT markers of femoral biomechanical properties. In the comparison with alfacalcidol, eldecalcitol 0.75 μg/day significantly reduced the 3-year incidence of vertebral fractures, with an absolute risk reduction of 4.1% over this period, representing a relative risk reduction of 26%. There was no significant difference in the rate of non-vertebral fractures. In both trials, eldecalcitol treatment was also associated with an increase in bone mineral density, whereas patients who received the comparators generally had a reduction in bone mineral density. Increases in blood calcium (to >2.6 mmol/L) and urinary calcium (to >0.1 mmol/L glomerular filtrate) were the most clinically important treatment-emergent adverse events. In the placebo-controlled, dose-ranging trial, 23% and 25% of patients in the eldecalcitol 1 μg/day group had increased blood and urinary calcium compared with 7% and 7%, 6% [corrected] and 9%, and 0% and 1.9% in the eldecalcitol 0.5 and 0.75 μg/day, and placebo groups, respectively. In the comparison with alfacalcidol, 21.0% and 13.5% of eldecalcitol 0.75 μg/day and alfacalcidol 1.0 μg/day recipients had increased blood calcium, whereas hypercalcaemia (defined as a serum calcium >2.9 mmol/L) occurred in 0.4% and urolithiasis in 1.3% of eldecalcitol recipients over 36 months of treatment. Eldecalcitol is an efficacious treatment for patients with osteoporosis that should be further investigated in head-to-head trials with other recommended first-line pharmacological treatments.

Quetiapine extended release (XR) is a once-daily oral formulation of the atypical antipsychotic quetiapine that is available for use as adjunctive therapy in major depressive disorder (MDD). Systemic quetiapine exposure after orally administered quetiapine XR is similar to that of quetiapine immediate release at the same dosage, although quetiapine XR is absorbed more slowly and plasma concentrations are more stable over time. In two 6-week, randomized, double-blind, placebo-controlled, multinational trials in patients with MDD with an inadequate response to antidepressants, quetiapine XR 300 mg/day adjunctive to antidepressant reduced depressive symptoms significantly more than antidepressant plus placebo, according to changes in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores. In one trial, adjunctive quetiapine XR 150 mg/day also led to significantly greater reductions in MADRS total scores than antidepressant plus placebo. MDD response rates were significantly higher with adjunctive quetiapine XR 300 mg/day (but not 150 mg/day) than with antidepressant plus placebo. The numbers needed to treat to achieve an additional response over antidepressant plus placebo were 11-18 and 8-9 in the quetiapine XR 150 and 300 mg/day dosage groups, respectively. Treatment-emergent adverse events were mostly of mild to moderate severity; 1% of adjunctive quetiapine XR and 1.3% of antidepressant plus placebo recipients reported serious adverse events.

A transdermal patch formulation of the non-ergolinic dopamine agonist rotigotine (Neupro®) is indicated as monotherapy for the treatment of early Parkinson's disease and as combination therapy with levodopa throughout the course of the disease. Daily application of the rotigotine transdermal patch (referred to here as rotigotine) provided predictable release and absorption of rotigotine, with steady-state rotigotine concentrations reached within 1-2 days. In six large, well designed clinical trials, rotigotine was an efficacious treatment for Parkinson's disease. In early Parkinson's disease, rotigotine initiated without levodopa produced significantly greater improvements than placebo in the Unified Parkinson's Disease Rating Scale (UPDRS) summed motor and activities of daily living (ADL) scores, as well as significantly higher response rates. In a comparison with oral ropinirole, rotigotine did not meet a prespecified response-rate noninferiority criterion, although this may reflect the dosages used, which may not have been directly comparable. In advanced Parkinson's disease, rotigotine in combination with levodopa reduced 'off' time and improved motor functioning and ADL significantly more than levodopa plus placebo. Rotigotine was noninferior to oral pramipexole in reducing 'off' time, although it did not meet a response-rate noninferiority criterion. A recent trial focused on both motor and non-motor endpoints in patients with inadequate early morning motor control despite antiparkinsonian treatment (most received levodopa). Rotigotine improved morning motor functioning and reduced sleep disturbances, night-time motor symptoms, depressive symptoms, pain and functioning, and quality of life to a significantly greater extent than placebo. Rotigotine was generally well tolerated across the trials and in longer-term extension studies, with the most common treatment-emergent adverse events being application-site reactions, gastrointestinal disturbances, somnolence and headache. Application-site reactions were generally mild to moderate in severity; where reported, up to 3% of patients had severe skin reactions. Thus, rotigotine offers a novel approach to the treatment of Parkinson's disease and, given its ease of administration, efficacy in reducing disabling motor and non-motor symptoms, and acceptable tolerability profile, it has the potential to be an attractive treatment option for this highly debilitating disease.

Imatinib is a protein-tyrosine kinase inhibitor with antitumour effects in patients with gastrointestinal stromal tumour (GIST) that is indicated for the treatment of unresectable and/or metastatic GIST and as adjuvant therapy in patients with KIT-positive GIST. Imatinib binds to and inhibits KIT and platelet-derived growth factor receptor (PDGFR)-α tyrosine kinases, interfering with their downstream tumourogenic processes. Cell lines with KIT mutations that are common in patients with GIST were sensitive to imatinib at low in vitro concentrations. Patients with exon 11 KIT mutations were significantly more likely to have partial tumour responses and longer overall survival (OS) and were significantly less likely to have progression of disease than patients with exon 9 KIT mutations or no detectable KIT or PDGFR mutations. In a large (n > 700) randomized, double-blind, placebo-controlled, multinational trial (ACOSOG [American College of Surgeons Oncology Group] Z9001), patients who received 1 year of adjuvant treatment with oral imatinib 400 mg/day after surgical resection of GIST had significantly longer recurrence-free survival than placebo recipients, with an overall hazard ratio of 0.35 (95% CI 0.22, 0.53) [primary endpoint]. At the time of reporting, there was no significant between-group difference in OS. In patients with GIST who received adjuvant imatinib in this trial, adverse events were mostly of mild or moderate severity; the imatinib treatment group had an almost 2-fold higher rate of US National Cancer Institute Common Toxicity Criteria grade 3 or 4 adverse events than the placebo group.

Levobupivacaine (Chirocaine ® ) is a long-acting amide local anaesthetic that is effective when administered as an epidural, spinal, peripheral nerve or ocular block, or by topical application or local infiltration. In comparative trials, its clinical effects were not generally significantly different from those of bupivacaine or ropivacaine, although there was some variability in efficacy findings in different clinical populations. Levobupivacaine was generally well tolerated. Levobupivacaine provides effective anaesthesia and analgesia for a wide range of clinical populations and is a useful alternative to bupivacaine.

Gefitinib (Iressa™) is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that offers treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC), in particular in those who are harbouring EGFR mutations. In a large phase III trial (IPASS) in chemotherapy-naive Asian patients with adenocarcinoma who were never smokers or former light smokers, oral gefitinib was more effective than carboplatin plus paclitaxel in prolonging progression-free survival (PFS). In a prespecified subgroup analysis, EGFR-mutation-positive status was associated with a positive response to gefitinib treatment. Furthermore, a trial in chemotherapy-naive patients with NSCLC that was restricted to those with EGFR mutations found that gefitinib recipients had significantly longer PFS than carboplatin plus paclitaxel recipients. In large phase III trials (INTEREST, V-15-32) in unselected, previously treated patients, the overall survival (OS) in gefitinib recipients was noninferior to, or not significantly different from, that of docetaxel recipients. In a placebo-controlled trial in previously treated patients (ISEL), pre-planned subgroup analyses in Asian patients and non-smokers showed that in these subgroups gefitinib prolonged OS, and that EGFR biomarkers predicted a positive response to gefitinib. Gefitinib was also associated with greater improvements in quality of life (QOL) in both chemotherapy-naive and previously treated patients. A head-to-head trial of gefitinib versus erlotinib in EGFR-mutation-positive patients would help position gefitinib relative to erlotinib in this population. Further research is also required to identify factors associated with non-response to EGFR-tyrosine-kinase inhibitors in EGFR-mutation-positive patients. Gefitinib was a generally well tolerated treatment, with rash and diarrhoea being the most common treatment-emergent adverse events. Interstitial lung disease (ILD) is a serious co-morbidity of NSCLC associated with gefitinib and other cancer treatments; ILD-type events occurred with an overall incidence of ≈1% in gefitinib recipients participating in clinical trials, and were more common in Asian patients. Notably, gefitinib was associated with significantly fewer haematological and neurological adverse effects than comparator chemotherapy regimens. Gefitinib as monotherapy is an effective treatment for patients with locally advanced or metastatic NSCLC with EGFR mutations. Pharmacological The presumed mechanism of action of gefitinib is through inhibition of EGFR Properties tyrosine kinase, thereby blocking EGFR downstream signalling processes that activate cell proliferation, cell migration, angiogenesis and cell survival. Inhibitory effects on downstream EGFR processes occur at concentrations well below those achieved at the recommended clinical dosage. Mutations in the kinase domain of EGFR are correlated with sensitivity to gefitinib and other EGFR-tyrosine-kinase inhibitors. After oral administration, gefitinib is relatively slowly absorbed, with a time to peak concentration of 3-7 hours. In healthy adults, for single doses up to and including 250 mg, increases in systemic exposure to gefitinib are dose-proportional. The oral bioavailability of gefitinib in patients with solid tumours is 59%. Gefitinib also penetrates tumour tissues, reaching high concentrations 42- to 60-fold those in plasma.

Niacin extended-release (ER)/simvastatin is a once-daily, fixed-dose combination of the HMG-CoA reductase inhibitor simvastatin and an ER formulation of niacin (a B-complex vitamin). In healthy volunteers who were given niacin ER/simvastatin 2000 mg/40 mg, niacin exposure was similar to that with niacin ER 2000 mg, while simvastatin exposure was increased compared to that with simvastatin 40 mg. In patients with elevated non-high-density lipoprotein cholesterol (non-HDL-C) but with low-density lipoprotein cholesterol (LDL-C) at or below the National Cholesterol Education Program (NCEP) goal after a > or = 2-week simvastatin 20 mg/day run-in period (SEACOAST I), 24 weeks of niacin ER/simvastatin 1000 mg/20 mg or 2000 mg/20 mg per day reduced median plasma non-HDL-C levels to a significantly greater extent than simvastatin 20 mg/day. In patients with elevated non-HDL-C and LDL-C at any level after a > or = 2-week simvastatin 40 mg/day run-in period (SEACOAST II), 24 weeks of niacin ER/simvastatin 1000 mg/40 mg or 2000 mg/40 mg per day was noninferior to simvastatin 80 mg/day in reducing median plasma non-HDL-C levels. Compared with simvastatin monotherapy, there was no significant difference in reduction in plasma LDL-C levels with niacin ER/simvastatin in SEACOAST I, and the noninferiority criterion for LDL-C was not met in SEACOAST II. However, plasma HDL-C levels increased more and triglyceride levels were lowered more than with simvastatin monotherapy (SEACOAST I and II). Niacin ER/simvastatin was generally well tolerated, with flushing being the most common adverse reaction.

Anastrozole (Arimidex) is an aromatase inhibitor approved in the EU, the US and in other countries worldwide for use as an adjuvant treatment in postmenopausal women with early-stage, hormone receptor-positive breast cancer. It is also approved in the EU and other countries worldwide for continuing adjuvant treatment in women who have already had 2-3 years of adjuvant tamoxifen treatment for breast cancer. Anastrozole is an effective primary adjuvant treatment for postmenopausal women with early-stage breast cancer. In patients with hormone receptor-positive tumours, 5 years of anastrozole treatment was more efficacious in reducing breast cancer recurrence than 5 years of tamoxifen, both in a head-to-head comparison and in switching trials when given after 2-3 years of tamoxifen treatment. The treatment benefits have now been shown to extend to 100 months following breast surgery. To date, overall survival was better in anastrozole than tamoxifen recipients in one switching trial and in a meta-analysis of three switching trials. There was no increased benefit in health-related quality of life with anastrozole over tamoxifen. In women who had received 5 years of tamoxifen treatment, continuation of treatment with anastrozole further reduced the risk of breast cancer recurrence. Ongoing head-to-head trials against other third-generation aromatase inhibitors will provide data as to its relative efficacy against these agents. Anastrozole is a generally well tolerated treatment for early-stage breast cancer. Like other aromatase inhibitors, its most important adverse effect was an increased risk of bone fractures, which for anastrozole was restricted to the treatment period. It is still unclear whether primary adjuvant treatment extended beyond 5 years is of benefit and whether primary adjuvant treatment with anastrozole for 5 years is preferable to switching to anastrozole after 2-3 years of tamoxifen treatment. However, the evidence to date establishes anastrozole as a valuable adjuvant and extended adjuvant treatment for postmenopausal women with hormone receptor-positive, early-stage breast cancer.

▲ Dabigatran etexilate is an orally administered prodrug of dabigatran, which is a potent, concentration-dependent inhibitor of thrombus formation and thrombin-induced platelet aggregation. ▲ Dabigatran etexilate pharmacokinetics were linear across a wide dosage range. There were no clinically important pharmacokinetic interactions with digoxin (a P-glycoprotein substrate), pantoprazole (a proton-pump inhibitor) or drugs that are substrates and/or inhibitors of hepatic cytochrome P450 enzymes. ▲ In two large, randomized, double-blind trials of the prevention of venous thromboembolism (VTE) in patients undergoing total hip or total knee replacement surgery, orally administered dabigatran etexilate 220 mg/day was noninferior to subcutaneous enoxaparin sodium 40 mg/day for the primary composite endpoint of total VTE events or all-cause mortality during the treatment period. ▲ There were no significant differences between dabigatran etexilate and enoxaparin sodium in major VTE events and VTE-related mortality. Across trials, ≤0.5% of patients experienced a symptomatic pulmonary embolus or died. ▲ Dabigatran etexilate was generally well tolerated. In patients undergoing total hip or total knee replacement surgery, there was no significant difference between dabigatran etexilate and enoxaparin sodium recipients in the incidence of major or minor bleeding.

Aripiprazole is a novel atypical antipsychotic that is approved in the US for use in adolescents with schizophrenia. In adolescents with schizophrenia, oral aripiprazole 10 or 30 mg/day lead to significantly greater reductions than placebo in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to 6 weeks, according to findings from a randomized, double-blind, multicenter trial (n = 302). In addition, aripiprazole 10 or 30 mg/day recipients had significantly greater improvements in the PANSS positive subscale and Clinical global Impression-Severity and -Improvement scale scores than placebo recipients, and a significantly greater improvement in the PANSS negative subscale score was seen with aripiprazole 10 mg/day than with placebo. Aripiprazole was generally well tolerated in adolescents with schizophrenia, with most adverse events being of mild to moderate severity. Clinically significant weight gain (> or = 7% as defined by the US FDA) occurred in 4.0% of aripiprazole 10 mg/day recipients, 5.2% of aripiprazole 30 mg/day recipients, and 1% of placebo recipients. The mean weight change was significantly different in aripiprazole and placebo recipients (0, +2, and -0.8 kg in aripiprazole 10 mg/day, aripiprazole 30 mg/day, and placebo recipients, respectively).

Secukinumab (Cosentyx™) is a fully human monoclonal antibody against interleukin-17A, formulated for intravenous and subcutaneous administration. It received its first global approval in Japan on 26 December 2014 for the treatment of psoriasis and psoriatic arthritis in adults who are not adequately responding to systemic therapies (except for biologic agents). In the USA and the EU, secukinumab was approved in early 2015 for the treatment of patients with moderate-to-severe plaque psoriasis. Secukinumab is also being investigated in patients with ankylosing spondylitis and rheumatoid arthritis. This article summarizes the milestones in the development of secukinumab leading to its first approval for the treatment of adult patients with psoriasis and psoriatic arthritis.

Blinatumomab (BLINCYTO™) is a novel, bispecific T-cell engaging antibody that binds cluster of differentiation (CD) 19 antigens on blast cells while also binding and activating the CD3/T cell receptor complex, causing cell lysis. The antibody is being developed by Amgen as a treatment for haematological cancers that originate from B cell lines. Blinatumomab was approved by the US FDA in December 2014 for the treatment of adults with Philadelphia chromosome (Ph)-negative relapsed/refractory B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). It is awaiting approval for this indication in the EU and is in phase III development in various countries. This article summarizes the milestones in the development of blinatumomab leading to its first approval for the treatment of Ph-negative BCP-ALL.

Eldecalcitol (1α,25[OH](2)-2β-(3-hydroxypropyloxy)vitamin D(3); ED-71; Edirol®) is an orally administered analogue of active vitamin D (calcitriol) that is available in Japan for the treatment of osteoporosis at a dosage of 0.75 μg/day. In a randomized, double-blind, placebo-controlled, dose-ranging trial, eldecalcitol reduced markers of bone turnover significantly more than placebo. Similarly, in a randomized, double-blind comparison with the calcitriol prodrug, alfacalcidol 1.0 μg/day, eldecalcitol 0.75 μg/day produced significantly greater reductions in markers of bone turnover and had a positive effect on femoral biomechanical properties. In both trials, eldecalcitol treatment was associated with an increase in bone mineral density (BMD), whereas patients who received the comparators generally had a reduction in BMD. In the comparison with alfacalcidol, eldecalcitol significantly reduced the 3-year incidence of vertebral fractures (primary endpoint), with an absolute risk reduction of 4.1% over this period, representing a relative risk reduction of 26%. There was no significant difference in the rate of non-vertebral fractures. In both trials, increases in blood calcium (to2.6 mmol/L) and urinary calcium (to0.1 mmol/L glomerular filtrate) were the most clinically important treatment-emergent adverse events. In the comparison with alfacalcidol over 36 months of treatment, 21.0% and 13.5% of eldecalcitol 0.75 μg/day and alfacalcidol 1.0 μg/day recipients had increased blood calcium, whereas hypercalcaemia (defined as a serum calcium2.9 mmol/L) occurred in 0.4% and urolithiasis in 1.3% of eldecalcitol recipients. Eldecalcitol is an efficacious treatment for patients with osteoporosis that should be further investigated in head-to-head trials with other recommended first-line pharmacological treatments.

Human immunoglobulin is an established replacement therapy for patients with primary immunodeficiency disorders (PIDs). Recombinant human hyaluronidase (rHuPH20) is a spreading factor that temporarily digests hyaluronan in the skin interstitium enabling large volumes of fluid or drug solutions to be infused and absorbed subcutaneously. HyQvia® (IGHy) is a new combination product whereby rHuPH20 is injected subcutaneously, followed by human immunoglobulin 10 % infused through the same needle. Thus, IGHy can be administered at a reduced frequency compared with non-facilitated subcutaneous injection of human immunoglobulin, and with a lower frequency of infusion reactions than with intravenous administration. Home-based administration of IGHy is also feasible for adequately trained patients. IGHy was compared with intravenous human immunoglobulin 10 % in a non-randomized, open-label, phase 3 study in patients aged ≥2 years with PIDs who were receiving human immunoglobulin replacement therapy (n = 87). In this study, trough IgG concentrations, acute serious bacterial infection rates (primary endpoint) and occurrences of adverse events during the IGHy treatment period were generally similar to those observed during an intravenous treatment period. IGHy was associated with a numerically lower rate of systemic adverse events and a numerically higher rate of localized adverse events than those observed with intravenous treatment. Compared with intravenous administration, IGHy was administered at a significantly higher maximum flow rate and at a similar frequency. Most patients preferred IGHy over intravenous administration. IGHy offers a new method for subcutaneous delivery of human immunoglobulin replacement therapy in patients with PIDs.

Trastuzumab (Herceptin®) is a humanized IgG1 monoclonal antibody that is an efficacious treatment for HER2-positive breast and gastric cancers. Subcutaneous trastuzumab is a new formulation approved in the European Union for use in patients with early or metastatic breast cancer. In the randomized, open-label, multinational HannaH (enHANced treatment with NeoAdjuvant Herceptin) study of neoadjuvant/adjuvant trastuzumab in patients with early HER2-positive breast cancer, the pharmacokinetics of neoadjuvant subcutaneous trastuzumab were similar to those after intravenous administration, meeting the noninferiority criterion for mean predose trough concentrations, as assessed prior to surgery (primary pharmacokinetic endpoint). Trastuzumab blood concentrations throughout the dosing interval remained above those considered necessary for anticancer activity. In this study, the pathologic complete response rates (primary efficacy endpoint) were 45.4 and 40.7 % in the subcutaneous and intravenous administration groups, respectively, meeting a study noninferiority criterion. In the randomized, open-label, crossover, multinational PrefHer study of neoadjuvant/adjuvant or adjuvant trastuzumab in early HER2-positive breast cancer, subcutaneous administration of trastuzumab was preferred over intravenous administration by >85 % of patients, most commonly because it was time saving and induced less pain and discomfort. In the HannaH study, the tolerability profile of subcutaneous trastuzumab was similar to that of intravenous trastuzumab, except that the rate of serious adverse events was 21 % (vs. 12 % with intravenous administration), partly because of more infections with subcutaneous administration. Whether this finding is of any clinical significance should emerge from ongoing studies. On the evidence, subcutaneous trastuzumab is an effective and generally well-tolerated treatment option that is preferred by patients over intravenous administration.

Background : The St. Louis Komen Project was conceived to address disparities in breast cancer treatment and outcomes between African-American and White women in St. Louis, Missouri. Our goal was to apportion tasks and funding through a process to which all researcher partners had input and to which all could agree, thus eliminating institutionalized inequalities. Methods : This paper describes the collaborative process and resulting division of responsibilities, determination of costs, and ultimate allocation of funds and resources, as well as the documentation employed to achieve funding reciprocity and equal accountability. Results : Both communication and documentation are critical. Although the Memoranda of Understanding employed are not a panacea, they codify roles and expectations and promote trust. The process of developing financial transparency set the tone for subsequent steps in the research process. Conclusions : The exhaustive planning process and project-specific procedures developed by its partners have helped the project foster reciprocity, facilitate participation, and equitably distribute resources.

Ziconotide (Prialt(®)) is a synthetic conopeptide analgesic that acts by selectively antagonizing N-type voltage-gated calcium channels. Intrathecal ziconotide is the only non-opioid intrathecal analgesic that is FDA-approved for use in patients with treatment-refractory, chronic pain. The efficacy of intrathecal ziconotide was demonstrated in randomized, double-blind, placebo-controlled trials in patients with treatment-refractory noncancer-related pain or cancer- or AIDS-related pain. Across trials, ziconotide recipients had significantly greater reductions in pain intensity during ziconotide treatment than those receiving placebo (primary endpoint). At the end of the titration period, approximately one-sixth to one-third of patients with noncancer chronic pain and one-half with cancer- or AIDS-related pain who received ziconotide reached a pain response threshold (≥30 % reduction in the pain intensity score). In ziconotide responders, analgesic effects were enduring, with some patients continuing treatment over extended periods. Across trials, the chief tolerability concerns in ziconotide recipients during the titration phase and during extended treatment were related to CNS adverse events. These were mostly of mild to moderate intensity, although serious adverse events were commonly attributed to ziconotide treatment, especially in trials with rapid ziconotide titration and that permitted higher dosages. In general, clinically important non-CNS adverse events were infrequent, and during the ziconotide titration phase, relatively few patients discontinued treatment because of adverse events. Ongoing research will assess various strategies for selecting patients for ziconotide treatment and for enhancing its efficacy and tolerability. At the present time, intrathecal ziconotide provides a treatment option for patients with severe, unremitting pain who have failed to respond to other intensive analgesic regimens.

Fluocinolone acetonide intravitreal implant (Iluvien®) is an injectable, non-erodible, corticosteroid implant that is approved in several European countries for the treatment of chronic diabetic macular oedema (DMO). In analyses of two multinational trials in patients with DMO previously treated with macular laser photocoagulation, fluocinolone acetonide intravitreal implant 0.2 μg/day was significantly more efficacious than sham injection in improving visual acuity. At 24 months post injection, 29 % of fluocinolone acetonide intravitreal implant 0.2 μg/day recipients had an improvement in the best-corrected visual acuity (BCVA) letter score of ≥15 compared with 16 % in the sham injection group (p = 0.002) [primary endpoint]. Treatment benefit was most evident in the subgroup of patients whose duration of DMO was ≥3 years. In this subgroup at 36 months, 34 % of fluocinolone acetonide intravitreal implant 0.2 μg/day recipients had an increase in the BCVA score of ≥15, compared with 13 % of sham injection recipients (p < 0.001). Fluocinolone acetonide intravitreal implant recipients also had generally greater benefits than sham injection recipients on secondary endpoints. In patients who were phakic in the study eye at baseline, cataracts occurred in 82 % of fluocinolone acetonide intravitreal implant 0.2 μg/day recipients and 51 % of sham injection recipients. Overall, 37 % and 12 % of patients in the fluocinolone acetonide intravitreal implant and sham injection groups developed raised intraocular pressure (IOP), which was generally controlled with IOP-lowering drugs.

Ipilimumab is a recombinant, fully human, monoclonal antibody targeted at cytotoxic T-lymphocyte-associated antigen 4 that is available for the treatment of advanced melanoma. This review focuses on the efficacy and tolerability of ipilimumab in advanced melanoma and provides an overview of its pharmacology. In a randomized, double-blind, multinational, phase III trial in previously treated patients with advanced melanoma, median overall survival (OS) was significantly longer with ipilimumab 3 mg/kg plus glycoprotein (gp) 100 peptide vaccine or ipilimumab plus placebo than with gp100 peptide vaccine plus placebo (10.0 and 10.1 vs 6.4 months). Hazard ratios for death were 0.68 (p < 0.001) with ipilimumab plus gp100 peptide vaccine versus gp100 peptide vaccine plus placebo and 0.66 (p = 0.003) for ipilimumab plus placebo versus gp100 peptide vaccine plus placebo, with corresponding 32% and 34% relative reductions in the risk of death. There was no significant difference in OS between patients receiving ipilimumab plus gp100 peptide vaccine and those receiving ipilimumab plus placebo. Novel immune-related events that are not typical of other anticancer agents, most commonly dermatologic and gastrointestinal disorders, can occur with ipilimumab, necessitating specific monitoring and management protocols. In the phase III trial, grade 3/4 immune-related adverse events occurred in 10-15% of ipilimumab 3 mg/kg recipients versus 3% of gp100 peptide vaccine plus placebo recipients. In all, 2.1% of patients died as a result of treatment-related adverse events, with half of the deaths attributed to immune-related adverse events.

Rilpivirine is an orally administered, non-nucleoside reverse transcriptase inhibitor that is a component drug in combination therapy for antiretroviral-naive patients with HIV-1 infection. The randomized, double-blind, double-dummy, multinational ECHO and THRIVE trials in antiretroviral-naive adult patients with HIV-1 infection compared rilpivirine with efavirenz, administered with background nucleoside/nucleotide antiretroviral regimens. Rilpivirine 25 mg once daily recipients had a treatment response (confirmed plasma HIV-1 RNA level of50 copies/mL at 48 weeks; primary endpoint) that was noninferior to that of efavirenz 600 mg once daily recipients. The response rates in the rilpivirine and efavirenz groups were 83% and 84% (ECHO) and 87% and 83% (THRIVE). Virological failure rates in rilpivirine and efavirenz groups in the intent-to-treat analysis were 11% and 4% in the ECHO trial and 7% and 5% in the THRIVE trial. In a pooled analysis of both trials, in rilpivirine recipients with an HIV-1 RNA level of100,000 copies/mL at baseline, the virological failure rate at 48 weeks was 15% (vs 6% with efavirenz), whereas in those with a level of ≤100,000 copies/mL, the virological failure rate was 4% (vs 3% with efavirenz). In general, rilpivirine was better tolerated than efavirenz throughout treatment. Rilpivirine recipients had significantly fewer treatment-related adverse events, discontinuations because of adverse events, psychiatric-neurological adverse events and a significantly lower rate of blood lipid abnormalities.

Rotigotine transdermal patch (Neupro(®)) [referred to here as rotigotine] is a non-ergolinic dopamine agonist that is available in the EU as monotherapy for the treatment of early Parkinson's disease and as combination therapy with levodopa throughout the course of the disease. Daily application of the rotigotine patch provided predictable release and absorption of rotigotine, with steady-state rotigotine concentrations reached within 1-2 days. In early Parkinson's disease, compared with placebo, rotigotine monotherapy produced significantly greater improvements in the Unified Parkinson's Disease Rating Scale summed motor and activities of daily living (ADL) scores (primary endpoint), as well as significantly higher response rates. In advanced Parkinson's disease, rotigotine in combination with levodopa reduced 'off' time (primary endpoint) and improved motor functioning and ADL significantly more than levodopa plus placebo. In patients with inadequate early morning motor control despite antiparkinsonian treatment, rotigotine improved morning motor functioning and reduced sleep disturbances, night-time motor symptoms, depressive symptoms, pain and functioning, and quality of life to a significantly greater extent than placebo. The efficacy of rotigotine relative to other treatments requires further evaluation, as there were inconsistent results in noninferiority analyses that compared rotigotine to other dopamine agonists. Rotigotine was generally well tolerated across the trials, with the most common treatment-emergent adverse events being application-site reactions, gastrointestinal disturbances, somnolence and headache. No unexpected adverse effects were observed in extension studies of up to 6 years. Thus, rotigotine offers a novel approach to the treatment of Parkinson's disease and, given its ease of administration, efficacy in reducing disabling motor and non-motor symptoms, and acceptable tolerability profile, it has the potential to be an attractive treatment option for this highly debilitating disease.

Primary care providers deliver the majority of care for patients with diabetes. This article presents a qualitative analysis of systemic barriers to primary care diabetes management in the small office setting in Delaware. Grounded theory was used to identify key themes of focus group discussions with 25 Delaware physicians. A total of 6 systemic barriers were identified: (1) a persistent orientation toward acute care; (2) an inability to provide proactive, population-based patient management; (3) an inability to provide adequate self-management education; (4) poor integration of payer-driven disease management activities; (5) lack of universally available clinical information; and (6) lack of public health support. The results suggest that significant systemic barriers limit the ability of primary care providers, particularly those in small practices, to effectively manage diabetes in current practice. Future primary care reform should consider how to support providers, particularly those in small practices, to overcome these barriers.

Roflumilast is an orally administered, selective phosphodiesterase 4 inhibitor that is a novel treatment for patients with severe chronic obstructive pulmonary disease (COPD). Across four randomized, double-blind, multinational trials in patients with moderate to severe or severe COPD, roflumilast 500 microg/day produced significantly greater improvements from baseline than placebo in pre- and post-bronchodilator forced expiratory volume in 1 second (FEV(1)). While mean increases in FEV(1) in roflumilast groups were small, they were in marked contrast to the decreases or negligible increase in FEV(1) in the placebo groups. In three of four trials, roflumilast significantly reduced the COPD exacerbation rate; in a pooled analysis of two 52-week trials, roflumilast was associated with a 17% reduction over placebo. Further randomized, double-blind, multinational trials compared roflumilast 500 microg plus salmeterol with placebo plus salmeterol and roflumilast 500 microg plus tiotropium bromide with placebo plus tiotropium bromide. In both trials, roflumilast plus long-acting bronchodilator produced significantly greater increases in pre- and post-bronchodilator FEV(1) than placebo plus long-acting bronchodilator. Roflumilast had an acceptable tolerability profile. In a pooled analysis of two trials, 19% and 22% of roflumilast and placebo recipients had serious adverse events; in the corresponding groups, 14% and 11% discontinued medications because of adverse events.

Pazopanib is an orally administered, multi-tyrosine kinase inhibitor that interrupts tumor growth in renal cell carcinoma. In a randomized, double-blind, placebo-controlled, multinational trial in patients with locally advanced or metastatic renal cell carcinoma, the median progression-free survival (PFS) of patients who were treated with pazopanib 800 mg once daily was significantly longer than that of placebo recipients (9.2 vs 4.2 months; hazard ratio 0.46 [95% CI 0.34, 0.62]). In prespecified analyses in treatment-naive and cytokine-pretreated patients, grouped according to prior treatment history, age, sex, Memorial Sloan-Kettering Cancer Center risk category, and Eastern Cooperative Oncology Group performance status, median PFS was significantly longer in pazopanib than placebo recipients in all subgroups. Pazopanib recipients also had a significantly higher overall response rate than placebo recipients; in pazopanib recipients, the median time to response was 11.9 weeks and the median duration of response was 58.7 weeks. Oral pazopanib had an acceptable tolerability profile in patients with advanced renal cell carcinoma. Adverse events were common in pazopanib and placebo recipients and were mostly of mild to moderate severity.

Individuals who have been infected with varicella zoster virus (VZV) are at risk for developing herpes zoster and this risk appears to be related to a decline in VZV-specific cell-mediated immunity (CMI). Zostavax® (zoster vaccine) is a one-dose, high-potency, live, attenuated VZV vaccine that boosts VZV-specific CMI and this is its presumed mechanism of action. Zoster vaccine is registered in the EU for use in adults aged ≥50 years for the prevention of herpes zoster and herpes zoster-related postherpetic neuralgia. In the Shingles Prevention Study, a placebo-controlled trial in adults aged ≥60 years (n = 38 546), zoster vaccine led to a sustained boost of VZV-specific CMI. Over a mean herpes zoster surveillance period of 3.1 years, zoster vaccine reduced the herpes zoster-related burden of illness by 61%, reduced the incidence of herpes zoster by 51% and reduced the incidence of postherpetic neuralgia by 67%. Zoster vaccine recipients who developed herpes zoster had a shorter illness duration and severity than placebo recipients who developed herpes zoster. Zoster vaccine had continuing efficacy in a Shingles Prevention Study sub-population followed for 7 years post-vaccination. Zoster vaccine was generally well tolerated in older adults. While cost-effectiveness estimates in pharmaco-economic analyses varied widely according to vaccine and herpes zoster parameter cost/benefit estimates, an analysis from a UK perspective found a zoster vaccine immunization programme in adults aged 65 years to be cost effective. In older adults, the zoster vaccine has the potential to significantly reduce the herpes zoster burden of illness by decreasing the incidence of herpes zoster or reducing its severity.

black triangle Olmesartan medoxomil/amlodipine is a fixed-dose combination of olmesartan medoxomil and amlodipine, both established antihypertensive agents. Dose titration with the individual constituent drugs is recommended before switching to the equivalent fixed-dose combination. black triangle In a randomized, double-blind, factorial trial in patients with mild to severe hypertension, 8 weeks of olmesartan medoxomil/amlodipine was more effective in reducing diastolic BP (DBP) and systolic BP (SBP) than placebo or equivalent dosages of olmesartan medoxomil or amlodipine as monotherapy. black triangle In two randomized, double-blind trials in patients with moderate to severe hypertension not adequately treated with amlodipine or olmesartan medoxomil monotherapy, 8 weeks of olmesartan medoxomil/amlodipine 20 mg/5 mg, 40 mg/5 mg or 40 mg/10 mg per day was more effective in reducing DBP and SBP than continuing treatment with olmesartan medoxomil 20 mg/day or amlodipine 5 mg/day monotherapy. black triangle More patients receiving olmesartan medoxomil/amlodipine at approved dosages than monotherapy recipients at equivalent dosages reached BP goals (42.5-51.0% vs 21.1-36.3% in the factorial trial and 44.5-54% vs 28.5-30% in the monotherapy comparisons). black triangle In the comparison with amlodipine monotherapy,70% of olmesartan medoxomil/amlodipine recipients, some requiring upwards dosage adjustment, met BP goals. black triangle Olmesartan medoxomil/amlodipine was generally well tolerated in clinical trials. Peripheral oedema was significantly less common in olmesartan medoxomil/amlodipine 40 mg/10 mg per day than amlodipine monotherapy 10 mg/day recipients.

UNLABELLED Sapropterin dihydrochloride (Kuvan), hereafter referred to as sapropterin, is a synthetic formulation of the active 6R-isomer of tetrahydrobiopterin, a naturally occurring cofactor for phenylalanine hydroxylase. In the EU, sapropterin is approved for the treatment of hyperphenylalaninaemia in patients >or=4 years of age with tetrahydrobiopterin-responsive phenylketonuria (PKU) and in adults and children with tetrahydrobiopterin deficiency who have been shown to be responsive to such treatment. In the US, it is approved to reduce blood phenylalanine levels in patients with hyperphenylalaninaemia due to tetrahydrobiopterin-responsive PKU. Oral sapropterin effectively lowers blood phenylalanine levels in a proportion of patients with PKU; to date, there are no published efficacy trials of the specific sapropterin formulation under review in patients with tetrahydrobiopterin deficiency. Sapropterin was well tolerated in patients with PKU, although longer-term tolerability data are required. Sapropterin is the first non-dietary treatment for patients with PKU that has been shown in randomized, double-blind trials to be effective in lowering blood phenylalanine levels. Thus, sapropterin provides a promising treatment option for patients with PKU who are tetrahydrobiopterin-responsive. PHARMACOLOGICAL PROPERTIES: The mechanism of action of sapropterin in lowering blood phenylalanine levels in patients with PKU has not been fully elucidated, but appears to be related, in part, to its effect in augmenting and stabilizing mutant phenylalanine hydroxylases, resulting in increased clearance of phenylalanine from the body. In tetrahydrobiopterin deficiency, its mechanism of action is presumed to be secondary to replacement of endogenous tetrahydrobiopterin. In healthy adults, orally-administered sapropterin is absorbed into the bloodstream, reaching maximum concentrations in 3-4 hours. It has a mean elimination half-life of approximately 4 hours in healthy adults and, based on a population pharmacokinetic study, 6.7 hours in patients with tetrahydrobiopterin-responsive PKU. Age, from 9 to 49 years, had no effect on key pharmacokinetic parameters. THERAPEUTIC EFFICACY: In an 8-day screening study in patients aged >or=8 years with PKU, approximately 20% of patients responded to sapropterin 10 mg/kg/day (i.e. were tetrahydrobiopterin responsive). Tetrahydrobiopterin-responsive patients from this study were entered into a randomized, double-blind, placebo-controlled trial in which they received sapropterin 10 mg/kg/day or placebo. At the end of 6 weeks of treatment, sapropterin recipients experienced a significant 28% decrease from baseline in mean blood phenylalanine level, while there was no significant change in placebo recipients. The difference in mean blood phenylalanine level between sapropterin and placebo groups was statistically significant at -245 micromol/L. In an extension of this trial, significantly greater reductions in blood phenylalanine levels were observed with sapropterin dosages of 10 and 20 mg/kg/day than with sapropterin 5 mg/kg/day (each dose administered for 2 weeks), indicating a dose dependent effect. During 12 weeks of treatment with the sapropterin dosage individualized to the patient according to the earlier response to sapropterin 5, 10 or 20 mg/kg/day, reductions in plasma phenylalanine were observed in all dosage groups. In a randomized, double-blind trial in children aged 4-12 years with tetrahydrobiopterin-responsive PKU, patients treated with sapropterin 20 mg/kg/day had reduced blood phenylalanine levels after 3 weeks of treatment. Over the full 10-week trial, sapropterin and placebo recipients experienced a significantly increased tolerance to dietary phenylalanine (20.9 mg/kg/day in sapropterin and 2.9 mg/kg/day in placebo recipients). TOLERABILITY Sapropterin was well tolerated in patients with PKU. In clinical trials in patients with PKU, the following adverse events were identified: headache, rhinorrhoea (both at a frequency of >or=10%), pharyngolaryngeal pain, nasal congestion, cough, diarrhoea, vomiting, abdominal pain and hypophenylalaninaemia (all at a frequency of >or=1% to

Enteric-coated mycophenolate sodium (Myfortic®) is a reversible, noncompetitive inosine monophosphate dehydrogenase (IMPDH) inhibitor that is approved in the EU, the US and in other countries worldwide for immunosuppressive prophylaxis against graft rejection in adult renal transplant patients. Enteric-coated mycophenolate sodium has a delayed absorption from the gastrointestinal (GI) tract in comparison with mycophenolate mofetil, thereby potentially reducing GI adverse events. In randomized, double-blind trials of de novo and maintenance immunosuppressive therapy in renal transplant patients receiving ciclosporin emulsion-based regimens, enteric-coated mycophenolate sodium was as effective as mycophenolate mofetil in preventing renal graft rejection. Enteric-coated mycophenolate sodium provides an alternative to mycophenolate mofetil in the treatment of de novo renal transplant recipients and ongoing research should indicate whether an intensified dosage regimen can further improve clinical outcomes. Renal transplant patients receiving mycophenolate mofetil maintenance immunosuppressive therapy may be switched to enteric-coated mycophenolate sodium without compromising efficacy. The general tolerability profile of enteric-coated mycophenolate sodium was similar to that of mycophenolate mofetil. Patients selected for GI intolerance associated with mycophenolate mofetil treatment showed reductions in GI symptoms when switched to enteric-coated mycophenolate sodium, while in unselected patients in comparative trials, there was no difference between enteric-coated mycophenolate sodium and mycophenolate mofetil in GI tolerability. Enteric-coated mycophenolate sodium provides an alternative to mycophenolate mofetil in renal transplant patients receiving mycophenolate mofetil maintenance immunosuppressive therapy who have GI symptoms that have not responded to other management strategies, because they may experience improvement if switched to enteric-coated mycophenolate sodium. Thus, in association with ciclosporin-based regimens, enteric-coated mycophenolate sodium is a valuable treatment option for immunosuppressive prophylaxis in adult renal transplant recipients. In stable renal transplant patients, the inhibitory effect of enteric-coated mycophenolate sodium on IMPDH, T-cell proliferation, T-cell activation, lymphocyte subsets and cytokine expression was not significantly different from that of mycophenolate mofetil. Mycophenolic acid (MPA) is released from enteric-coated mycophenolate sodium in the small intestine. In renal transplant patients receiving maintenance immunosuppressive therapy, the exposure to MPA with enteric-coated mycophenolate sodium treatment was equivalent to that seen with mycophenolate mofetil treatment, although the time to maximum plasma concentration was longer, as expected with an enteric-coated formulation. As observed with mycophenolate mofetil, in de novo renal transplant recipients, MPA exposure with enteric-coated mycophenolate sodium was generally lower in the immediate post-transplant period than in the maintenance period, although an intensified dosage regimen early after transplantation increased exposure to MPA. There is considerable interindividual and intraindividual variability in MPA pharmacokinetics with enteric-coated mycophenolate sodium and mycophenolate mofetil. In paediatric patents, MPA exposure with a single dose of enteric-coated mycophenolate sodium was slightly higher than that observed in adult patients. In randomized, double-blind, double-dummy, multinational trials, at recommended dosages, enteric-coated mycophenolate sodium had equivalent efficacy to mycophenolate mofetil in de novo renal transplant recipients, and renal transplant patients receiving maintenance immunosuppressive therapy could be switched from mycophenolate mofetil to enteric-coated mycophenolate sodium without affecting efficacy. Extension studies demonstrated that the efficacy of mycophenolate sodium was maintained in the longer term. Large, prospective, noncomparative studies confirm that de novo renal transplant recipients can be effectively treated with enteric-coated mycophenolate sodium, with low rates of renal graft loss and the establishment of stable renal functioning; renal transplant patients receiving maintenance immunosuppressive therapy switched from mycophenolate mofetil to enteric-coated mycophenolate sodium had low treatment failure rates, with no patient experiencing graft loss, and continuing stable renal function. In randomized, double-blind, multinational trials in de novo renal transplant patients and renal transplant patients receiving maintenance immunosuppressive therapy, the most common adverse events associated with mycophenolate sodium treatment were infections and GI symptoms. There were no significant differences between enteric-coated mycophenolate sodium and mycophenolate mofetil treatment groups in the incidence of general or serious adverse events, except that enteric-coated mycophenolate sodium recipients had a lower rate of serious pneumonia in de novo renal transplant patients and serious infections in renal transplant patients receiving maintenance immunosuppressive therapy. The GI tolerability of enteric-coated mycophenolate sodium was no different to that of mycophenolate mofetil in de novo and renal transplant patients receiving maintenance immunosuppressive therapy in randomized, double-blind, multinational trials. In PROGIS and myTIME studies, in patients who had received renal transplants ≥1 month previously and who were experiencing GI symptoms while receiving mycophenolate mofetil, switching to enteric-coated mycophenolate sodium was associated with a significant reduction in GI symptom scores and an improvement in GI health-related quality of life.