Correction to: Cladribine Tablets: In Relapsing-Remitting Multiple Sclerosis.

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Asenapine: A Review in Schizophrenia.

Asenapine (Saphris(®), Sycrest(®)) is an atypical antipsychotic that is administered sublingually twice daily and is approved for schizophrenia in the USA, Japan and other countries, but not in the EU. This article reviews the pharmacology, clinical efficacy and tolerability profile of asenapine in the treatment of adults with schizophrenia. Clinical trials with asenapine have demonstrated efficacy in terms of both positive and negative symptoms of schizophrenia, although findings have not always been consistent. Across three short-term (6-week) studies in acute schizophrenia (including one in Asian patients), asenapine was generally superior to placebo and had broadly similar efficacy to active controls in improving total scores on the Positive and Negative Syndrome Scale. A meta-analysis of four short-term trials with asenapine (that also included a negative study and a failed trial) also showed significant benefit with asenapine over placebo. In longer-term trials and extensions (up to ≈3 years' duration), asenapine was effective relative to placebo in preventing relapse in schizophrenia, but was less effective than olanzapine in patients with schizophrenia or schizoaffective disorder (according to intent-to-treat LOCF analysis). However, in two trials in patients with persistent negative symptoms of schizophrenia, asenapine and olanzapine were similarly effective in reducing negative symptoms at week 26, with asenapine providing better results than olanzapine at week 52 in one of the extensions. The most frequently reported adverse events with asenapine are somnolence, akathisia and oral hypoesthesia. Although potentially associated with more extrapyramidal symptoms, asenapine appears to have less weight gain and metabolic effects than some other antipsychotic agents, such as olanzapine.

AFREZZA® (insulin human) Inhalation Powder: A Review in Diabetes Mellitus.

Afrezza® (insulin human) inhalation powder is a rapid-acting Technosphere® insulin (TI) administered via a breath-powered oral inhaler to patients with diabetes requiring prandial insulin. TI, a dry powdered formulation of recombinant human insulin adsorbed onto a proprietary carrier, is designed to deliver insulin to the deep lung, at the level of the alveoli, where it is absorbed into the systemic circulation. In a randomized, open-label, multinational, phase III trial (trial 171) in type 1 diabetes (T1DM) patients, prandial TI via the Gen2 inhaler provided noninferior glycated haemoglobin (HbA1c) lowering compared with prandial subcutaneous insulin aspart. Although TI was associated with less HbA1c lowering, it provided significantly lower fasting plasma glucose levels and significantly less hypoglycaemia and bodyweight gain compared with insulin aspart. In a randomized, double-blind, placebo-controlled, multinational, phase III trial (trial 175) in type 2 diabetes (T2DM) patients, prandial TI via the Gen2 inhaler provided superior HbA1c lowering compared with inhaled placebo. Cough was the most commonly occurring non-hypoglycaemia adverse event across both studies. In a pooled analysis of tolerability data from phase II and III studies, the most commonly occurring non-hypoglycaemia adverse events in T1DM and T2DM patients were cough and throat pain/irritation. However, cough was generally mild, dry and decreased over time. In addition, treatment with TI was associated with positive patient-reported outcomes. Insulin human inhalation powder is an effective and generally well-tolerated agent for the prandial treatment of hyperglycaemia in T1DM and T2DM patients and may provide a solution to insulin initiation barriers such as injection phobia, concerns of bodyweight gain and concerns of hypoglycaemia.

13-Valent Pneumococcal Conjugate Vaccine: A Review of Its Use in Adults.

The 13-valent pneumococcal conjugate vaccine (Prevenar 13(®), Prevnar 13(®)) [PCV13] consists of 13 serotype-specific polysaccharides of Streptococcus pneumoniae (pneumococcus), each covalently conjugated to a non-toxic immunogenic carrier protein. PCV13 has a well established immunogenicity and tolerability profile in adults, particularly those ≥50 years of age. Results of CAPiTA, a randomized, double-blind, placebo-controlled trial in >84,000 older adults aged ≥65 years, showed that PCV13 was effective in preventing vaccine-type pneumococcal community-acquired pneumonia (CAP), vaccine-type pneumococcal nonbacteraemic (noninvasive) CAP and vaccine-type invasive pneumococcal disease (IPD). These findings, along with changes in pneumococcal serotype distribution and epidemiology of pneumococcal disease, prompted the US Advisory Committee on Immunization Practices (ACIP) to recommend PCV13 in series with 23-valent pneumococcal polysaccharide vaccine (PPVS23) for all adults aged ≥65 years. PCV13 also has a role in preventing pneumococcal disease (pneumonia and IPD) in younger adults with immunocompromising conditions and potentially in those with other underlying medical conditions that increase the risk of pneumococcal disease.

Acamprosate: A Review of Its Use in Alcohol Dependence.

Acamprosate (Campral(®), Aotal(®), Regtect(®)) is one of a limited number of pharmacological treatment options approved as an adjunct to psychosocial interventions to facilitate the maintenance of abstinence in alcohol-dependent patients. It has been used in Europe, the USA and other countries for many years and was recently approved for this indication in Japan. In several randomized, double-blind, placebo-controlled trials (without active comparators), acamprosate in conjunction with psychosocial therapy for 3-12 months was generally significantly better than placebo plus psychosocial interventions in improving various key outcomes, including the proportion of patients who maintained complete abstinence from alcohol (complete abstinence rate), the mean cumulative abstinence duration, the percentage of alcohol-free days and the median time to first drink. Acamprosate as an adjunct to psychosocial interventions also demonstrated efficacy in some randomized, active-comparator trials of similar duration. Although results were not always consistent across individual trials, overall findings were generally favourable for acamprosate in a recent meta-analysis, which showed that alcohol-consumption outcomes were similarly improved with acamprosate or naltrexone. Acamprosate is generally well tolerated, has a low propensity for drug interactions and may be used without dosage adjustment in patients with mild to moderate hepatic impairment, although dosage adjustments or contraindications are recommended in patients with renal impairment. Thus, the use of acamprosate as an adjunct to psychosocial interventions in alcohol-dependent patients provides modest but potentially valuable improvements in alcohol-consumption outcomes and is generally well tolerated.

Diclofenac sodium injection (akis(®), dicloin (®)): a review of its use in the management of pain.

A novel formulation of diclofenac sodium suitable for subcutaneous or intramuscular injection (Akis(®), Dicloin(®)) has been developed using the complexing agent hydroxypropyl-ß-cyclodextrin (HPßCD) as a solubility enhancer. Diclofenac HPßCD is available in several European countries, where it is indicated for use in adults with acute forms of pain, including postoperative pain. Clinical trials have demonstrated the analgesic efficacy of diclofenac HPßCD in terms of relieving moderate to severe postoperative pain in patients undergoing dental surgery or minor orthopaedic surgery. Subcutaneous diclofenac HPßCD also effectively relieved moderate to severe neuropathic pain, related to cancer or not. Diclofenac HPßCD was generally well tolerated in clinical trials, with injection-site reactions among the most commonly reported adverse events. The local tolerability of diclofenac HPßCD was consistently rated as 'good' or 'excellent' across all studies. Subcutaneous administration of diclofenac is a valid alternative to intramuscular delivery, with the advantages of easier administration, the availability of additional body sites suitable for injection and the potential for self-administration. Thus, diclofenac HPßCD 25, 50 or 75 mg/mL solution for subcutaneous or intramuscular injection extends the treatment options available for use in the management of pain in adults.

Memantine extended release (28 mg once daily): a review of its use in Alzheimer's disease.

Memantine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that is a well-established treatment option for moderate to severe dementia of the Alzheimer's type, either alone or in combination with cholinesterase inhibitors. The immediate-release (IR) formulations of memantine (tablets and oral solution) have been available in numerous countries, including the USA, for more than a decade and are administered orally twice daily at a maximum recommended total daily dosage of 20 mg/day. The memantine extended-release (ER) (Namenda XR(®)) 28 mg once-daily capsule formulation was approved in the USA in 2010 and became available more recently. The potential advantages of memantine ER over the IR formulation include a more convenient dosage regimen and lower pill burden that may improve adherence to therapy; also, memantine ER capsules may be opened and the contents sprinkled on applesauce for patients who have difficulty swallowing. Memantine ER provides a higher total daily dosage than the recommended memantine IR regimen and pharmacokinetic data indicate greater exposure with the ER formulation, but the clinical implications of this are unclear, as the two formulations have not been assessed in a comparative clinical trial. The efficacy of memantine ER 28 mg once daily was demonstrated in a large, multinational, phase III trial, which showed that the addition of memantine ER to ongoing oral cholinesterase inhibitors improved key outcomes compared with cholinesterase inhibitor monotherapy, including measures of cognition and global status, which were the co-primary endpoints of the study. The most common adverse events were headache, diarrhoea and dizziness.

Sorafenib: a review of its use in patients with radioactive iodine-refractory, metastatic differentiated thyroid carcinoma.

Sorafenib (Nexavar®) is the first tyrosine kinase inhibitor to be approved for the treatment of radioactive iodine (RAI)-refractory differentiated thyroid carcinoma (DTC). In the pivotal phase III DECISION trial in patients with RAI-refractory, locally advanced or metastatic DTC, oral sorafenib 400 mg twice daily significantly prolonged median progression-free survival (PFS) relative to placebo. The PFS benefit of sorafenib over placebo was evident in all pre-specified clinical and genetic biomarker subgroups, and neither BRAF nor RAS mutation status was predictive of sorafenib benefit for PFS. The objective response rate was significantly higher in patients receiving sorafenib than in those receiving placebo; all objective responses were partial responses. The overall survival benefit of sorafenib is as yet unclear, with no significant benefit observed at the time of primary analysis or at 9 months following the primary analysis. Overall survival was possibly confounded by the crossover of patients in the placebo group to sorafenib upon disease progression. The adverse events associated with sorafenib in the DECISION trial were consistent with the known tolerability profile of the drug, with hand-foot skin reaction, diarrhea, and alopecia reported most commonly. Most treatment-emergent adverse events were grade 1 or 2 in severity and occurred early in treatment. However, a high proportion of patients discontinued sorafenib therapy or required dose reductions or interruptions because of toxicity. Although final overall survival data are awaited, current evidence suggests that sorafenib is a promising new treatment option for patients with RAI-refractory, metastatic DTC.

Sucroferric oxyhydroxide: a review in hyperphosphataemia in chronic kidney disease patients undergoing dialysis.

Sucroferric oxyhydroxide (Velphoro®), an iron-based oral phosphate binder, is available for the control of serum phosphorus levels in patients with chronic kidney disease (CKD) on dialysis. In a pivotal phase III trial, sucroferric oxyhydroxide 1000-3000 mg/day for 24 weeks was noninferior to sevelamer carbonate 4800-14,400 mg/day with regard to lowering serum phosphorus levels. Additionally, sucroferric oxyhydroxide at maintenance dosages was significantly more effective than low dosage sucroferric oxyhydroxide (250 mg/day) with regard to maintaining controlled serum phosphorus levels during weeks 24-27 of treatment. Sucroferric oxyhydroxide had a numerically lower mean daily pill burden and better treatment adherence than sevelamer carbonate. Treatment with sucroferric oxyhydroxide was generally well tolerated over 24 weeks' treatment, with the most frequently reported treatment-emergent adverse events being mild, transient diarrhoea and discoloured faeces. In a 28-week extension study, the efficacy and tolerability profile of sucroferric oxyhydroxide remained similar to sevelamer carbonate for up to 52 weeks. In conclusion, sucroferric oxyhydroxide is a valuable treatment option for hyperphosphataemia in CKD patients on dialysis, providing an effective and generally well tolerated noncalcium-based phosphate binder therapy with a lower pill burden than sevelamer carbonate and the potential for improved treatment adherence.

Ruxolitinib: a review of its use in patients with myelofibrosis.

Ruxolitinib (Jakavi(®), Jakafi(®)) is an orally administered inhibitor of Janus kinases (JAK) 1 and 2 used in the management of patients with myelofibrosis. Clinical trials with ruxolitinib, notably the phase III COMFORT-I and -II studies and their extensions, have demonstrated marked and durable clinical benefits in terms of reductions in splenomegaly and disease-related symptoms in patients with intermediate-2 or high-risk myelofibrosis. Ruxolitinib was also associated with improvements in health-related quality of life and functioning. Despite the crossover of patients in control groups to ruxolitinib, results of the COMFORT studies and their extensions indicate a survival advantage for patients randomized to ruxolitinib. The beneficial effects of ruxolitinib were observed across subgroups of myelofibrosis patients, including those not harbouring the JAK2V617F mutation. Improvements in splenomegaly and disease-related symptoms were also observed in a trial in Japanese/Asian patients with myelofibrosis and in myelofibrosis patients with a low baseline platelet count. Dose-related anaemia and thrombocytopenia were common in clinical trials with ruxolitinib, but rarely led to discontinuation of therapy and were managed with dosage modifications and/or transfusions of packed red blood cells. In addition to the USA and EU, ruxolitinib is now approved in a number of other countries, including Japan, and remains the only approved drug for the treatment of myelofibrosis, although various other agents are undergoing investigation. Appropriate monitoring and dosage titration are important to achieve optimal clinical benefits of ruxolitinib. Further research, including studies evaluating ruxolitinib-based combination therapy, may also help to optimise treatment.

Dapagliflozin: a review of its use in patients with type 2 diabetes.

Dapagliflozin (Forxiga(®), Farxiga(®)) is an orally administered sodium-glucose co-transporter-2 (SGLT2) inhibitor used in the management of patients with type 2 diabetes. Dapagliflozin reduces renal glucose reabsorption by inhibiting the transporter protein SGLT2 in the renal proximal tubule, thereby increasing urinary glucose excretion and reducing blood glucose levels. Its mechanism of action is independent of insulin secretion or action; therefore, dapagliflozin provides complementary therapy when used in combination with other antihyperglycaemic drugs. This article updates an earlier review of dapagliflozin and focuses on longer-term efficacy and tolerability data (e.g. from extensions of earlier clinical trials), as well as data from studies in special patient populations (e.g. history of cardiovascular disease). Numerous well-designed clinical trials with dapagliflozin, primarily as add-on therapy for 24 weeks (but also as monotherapy or initial combination therapy), have consistently demonstrated reductions in glycosylated haemoglobin, fasting plasma glucose levels and bodyweight. Extensions of these trials show the effects are maintained over longer-term follow-up periods of ≈1-4 years and dapagliflozin is generally well tolerated. Dapagliflozin has a low risk of hypoglycaemia, although the incidence varies depending on background therapy, and genital mycotic infections (particularly in women) are the most common adverse events. Dapagliflozin is not recommended in patients with moderate or severe renal impairment. In view of its unique mechanism of action and now well-established efficacy and tolerability profile, dapagliflozin is a useful treatment option in the management of type 2 diabetes, although its effects on diabetic complications remain to be evaluated.

Epoprostenol (Veletri®, Caripul®): a review of its use in patients with pulmonary arterial hypertension.

A bioequivalent formulation of intravenous epoprostenol containing the excipients arginine and sucrose (epoprostenol AS) (Veletri®, Caripul®) is approved in the USA, UK, and other countries for the treatment of pulmonary arterial hypertension (PAH), and has improved thermal stability compared with epoprostenol containing glycine and mannitol (epoprostenol GM) (Flolan®). Epoprostenol, a synthetic prostacyclin, is a potent pulmonary vasodilator. Epoprostenol GM was originally approved for use as a long-term continuous infusion in patients with PAH nearly 20 years ago in the USA; however, this formulation has limited stability at room temperature, and requires the use of cooling or frequent medication changes during administration. The prolonged thermal stability of epoprostenol AS compared with epoprostenol GM allows for its extended administration at room temperature and/or refrigerated storage of prepared solutions. This article summarizes the pharmacology of epoprostenol AS and reviews its therapeutic use in adult patients with PAH. In clinical trials, epoprostenol AS provided sustained efficacy in terms of hemodynamic and symptomatic outcomes, and was generally well tolerated after transitioning from stable epoprostenol GM therapy and during an open-label extension study. Furthermore, there was a significant increase in the treatment convenience with epoprostenol AS compared with epoprostenol GM. Therefore, epoprostenol AS is a valuable therapeutic option that has the potential to overcome some of the limitations of long-term intravenous epoprostenol therapy in patients with PAH.

10-Valent pneumococcal non-typeable haemophilus influenzae protein D-conjugate vaccine: a review in infants and children.

The 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) (Synflorix™) includes ten serotype-specific polysaccharides of Streptococcus pneumoniae, eight of which are conjugated individually to a nonlipidated cell-surface lipoprotein (protein D) of non-typeable H. influenzae and two of which are conjugated to nontoxic tetanus or diphtheria toxoid carrier proteins. This article provides an overview of the well-established immunogenicity of PHiD-CV, including functional immune responses and immunologic memory, as well as immune responses in preterm infants and HIV-infected children. It also includes a brief discussion of cross-protection against vaccine-related serotypes (6A and 19A) and focuses on labelling in the EU, where PHiD-CV is approved for active immunization against invasive disease, pneumonia, and acute otitis media (AOM) caused by S. pneumoniae in infants and young children up to 5 years of age. Evidence of the protective efficacy and effectiveness of PHiD-CV against pneumococcal diseases is available from several studies, including the randomized, double-blind trials COMPAS (Clinical Otitis Media and Pneumonia Study) and FinIP (Finnish Invasive Pneumococcal disease), as well as postmarketing studies from various countries. As would be expected, protection against pneumonia or AOM is substantially lower than that against invasive pneumococcal disease, as many micro-organisms other than pneumococcal vaccine serotypes can cause pneumonia and AOM, thereby limiting the overall protection of PHiD-CV against these diseases. PHiD-CV has a safety and reactogenicity profile similar to that of other pneumococcal conjugate vaccines.

Deferasirox: a review of its use for chronic iron overload in patients with non-transfusion-dependent thalassaemia.

Deferasirox (Exjade(®)) is a once-daily orally administered iron chelator which has been approved for use in the treatment of transfusional-dependent chronic iron overload since 2005. Based primarily on the findings of the THALASSA (Assessment of Exjade(®) in Non-Transfusion-Dependent THALASSemiA) trial, the approval for deferasirox has recently been expanded to include the management of chronic iron overload in patients with non-transfusion-dependent thalassaemia (NTDT) syndromes. Despite the lack of regular blood transfusions, NTDT patients can still develop clinically relevant iron overload, primarily due to increased gastrointestinal absorption secondary to ineffective erythropoiesis, and may require chelation therapy. The THALASSA trial, the first placebo-controlled clinical trial of an iron chelator in NTDT patients, demonstrated that deferasirox was effective in reducing liver iron and serum ferritin levels in this population. Deferasirox has an acceptable tolerability profile, with the most common adverse events reported in the THALASSA trial being related to mild to moderate gastrointestinal disorders. Although further long-term studies will be required to clearly demonstrate the clinical benefit of chelation therapy in NTDT patients, deferasirox presents a useful tool in the management of iron overload in this population.

Sevelamer carbonate: a review in hyperphosphataemia in adults with chronic kidney disease.

Sevelamer carbonate (Renvela(®)), a buffered form of sevelamer hydrochloride (Renagel(®)), is an orally administered non-absorbed phosphate-binding anion exchange resin used in the treatment of hyperphosphataemia in chronic kidney disease (CKD). In the EU, sevelamer carbonate is approved in adult CKD patients who require dialysis and in those who do not require dialysis with serum phosphate levels ≥ 1.78 mmol/L, whereas in the USA sevelamer carbonate is approved in adult CKD patients who require dialysis. Sevelamer carbonate and sevelamer hydrochloride achieved similar reductions in serum phosphate levels in randomized comparative trials in patients with CKD receiving haemodialysis; sevelamer carbonate also reduced serum phosphate levels in noncomparative studies in CKD patients not requiring dialysis. The most common adverse events with sevelamer carbonate are gastrointestinal in nature. Sevelamer has pleiotropic effects, such as improving the serum lipid profile and attenuating endothelial and cardiovascular risk factors in CKD. All formulations of sevelamer have markedly higher acquisition costs than calcium-based phosphate binders. Cost-effectiveness analyses focusing specifically on sevelamer carbonate have not been conducted, and those based on clinical trial data with sevelamer hydrochloride have provided both favourable and unfavourable results compared with calcium-based phosphate binders, reflecting heterogeneity between modelled analyses in terms of data sources, assumptions, comparators, geographical regions, type of costs included and other factors. Although well-designed studies evaluating the impact of phosphate binders on hard clinical endpoints appear to be warranted, sevelamer carbonate may be particularly useful for the treatment of patients at risk of metabolic acidosis (offering advantages over sevelamer hydrochloride in this regard) and for individuals requiring treatment with a phosphate binding agent that does not contain aluminium or calcium.

Canagliflozin: a review of its use in patients with type 2 diabetes mellitus.

Canagliflozin (Invokana™) is an orally administered sodium-glucose co-transporter-2 (SGLT2) inhibitor used in the treatment of patients with type 2 diabetes. By inhibiting the transporter protein SGLT2 in the kidneys, canagliflozin reduces renal glucose reabsorption, thereby increasing urinary glucose excretion and reducing blood glucose levels. Several randomized placebo- or active comparator-controlled trials of 26-52 weeks' duration (plus extension phases) have shown that canagliflozin improves glycaemic control when used as monotherapy or as add-on therapy to metformin and/or other antihyperglycaemic agents, including insulin, in patients with type 2 diabetes. In addition to achieving reductions from baseline in glycosylated haemoglobin, canagliflozin also showed beneficial effects for other endpoints including reductions from baseline in fasting plasma glucose levels and bodyweight. Canagliflozin has a low risk of hypoglycaemia and was generally well tolerated in clinical trials. The most frequently reported adverse events with canagliflozin are female genital mycotic infections, urinary tract infections and increased urination. The pharmacodynamic response to canagliflozin declines with increasing severity of renal impairment, and prescribing information should be consulted regarding dosage adjustments or restrictions in moderate to severe renal dysfunction. Canagliflozin has modest effects on the serum lipid profile, some beneficial (increased high-density lipoprotein cholesterol and decreased triglycerides) and others not (increased low-density lipoprotein cholesterol). Most patients treated with canagliflozin also have a modest reduction in blood pressure. The overall effect of canagliflozin on the risk of cardiovascular disease is unknown and will be evaluated in the ongoing CANVAS trial; preliminary cardiovascular safety data suggest no increased risk. Thus, with its unique mechanism of action that is independent of insulin secretion and action, canagliflozin is a useful addition to the therapeutic options available for the management of type 2 diabetes, particularly by providing complementary treatment when used as add-on therapy.

Rivaroxaban: a review of its use in acute coronary syndromes.

Rivaroxaban (Xarelto(®)) is an orally administered highly selective direct inhibitor of factor Xa that has been approved in many countries to reduce the risk of stroke in patients with atrial fibrillation and for the treatment and prevention of venous thromboembolism. More recently, rivaroxaban at a low dosage of 2.5 mg twice daily, co-administered with aspirin alone or aspirin plus either clopidogrel or ticlopidine, was approved for use in the EU for patients with a recent acute coronary syndrome (ACS). The approval of rivaroxaban in ACS was primarily based on findings of the phase III ATLAS ACS 2-TIMI 51 trial, which showed that after a median of 13.1 months of treatment with rivaroxaban 2.5 mg twice daily (combined with aspirin or aspirin plus either clopidogrel or ticlopidine) there was a statistically significant reduction in the rate of the primary composite endpoint, which was death from cardiovascular causes, myocardial infarction or stroke, compared with placebo. Rivaroxaban 2.5 mg twice daily was also associated with a reduction in all-cause and cardiovascular mortality. There was an increase in the risk of major bleeding and intracranial haemorrhage with rivaroxaban 2.5 mg twice daily compared with placebo; however, there was no increase in the risk of fatal bleeding. Aspirin plus either ticagrelor or prasugrel was not evaluated as background dual antiplatelet therapy in ATLAS ACS 2-TIMI 51 and the safety implications of rivaroxaban used in combination with such therapy are unknown. In conclusion, results of the ATLAS ACS 2-TIMI 51 trial suggest a potentially important role for rivaroxaban 2.5 mg twice daily co-administered with aspirin alone or aspirin plus either clopidogrel or ticlopidine in patients with a recent ACS.

Sitagliptin: a review of its use in patients with type 2 diabetes mellitus.

Sitagliptin (Januvia(®), Xelevia™, Glactiv(®), Tesavel(®)) is an orally administered, potent and highly selective inhibitor of dipeptidyl peptidase-4 (DPP-4) and was the first agent of its class to be approved for use in the management of adults with type 2 diabetes. Numerous randomized placebo- or active comparator-controlled trials have demonstrated the efficacy of sitagliptin in terms of improving glycaemic control in patients with type 2 diabetes, including its use as monotherapy, initial combination therapy (usually with fixed-dose combinations of sitagliptin/metformin), or add-on therapy to metformin or to other antihyperglycaemic drugs, with or without metformin. The primary endpoint of the clinical trials was the reduction from baseline in glycosylated haemoglobin (HbA1c), although sitagliptin also showed beneficial effects for other endpoints, such as the proportion of patients who achieved target HbA1c, and reductions from baseline in fasting plasma glucose (FPG) levels and 2-h postprandial glucose (PPG) levels. Sitagliptin was generally well tolerated in clinical trials, had a low risk of hypoglycaemia (although this depends on background therapy) and had a neutral effect on body weight. Despite concerns regarding a possible increased risk of rare pancreatic adverse events (e.g. pancreatitis) with glucagon-like peptide-1 (GLP-1)-based therapies, such as GLP-1 receptor agonists and DPP-4 inhibitors, no causal association has been found; regulators in Europe recently conducted a review of available data, concluding that there is little evidence that these drugs could cause pancreatic inflammation or pancreatic cancer. A similar review is planned in the USA and postmarketing surveillance will continue. Thus, oral sitagliptin is an effective and generally well tolerated treatment option for the management of patients with type 2 diabetes.

Bosutinib: a review of its use in patients with Philadelphia chromosome-positive chronic myelogenous leukemia.

Bosutinib (Bosulif®) is an orally administered small molecule tyrosine kinase inhibitor (TKI) of BCR-ABL and SRC family kinases. It is indicated for the treatment of adult patients with chronic-, accelerated-, or blast-phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy (imatinib, dasatinib, or nilotinib) [USA] or for a small subpopulation of these patients for whom imatinib, nilotinib, and dasatinib are not considered appropriate treatment options (EU). In a multinational pivotal trial (n = 547), bosutinib treatment resulted in a major cytogenetic response (MCyR) at 24 weeks in one-third of all treated patients with imatinib-resistant chronic-phase CML who had no previous exposure to any TKIs other than imatinib (primary endpoint), with similar results observed in chronic-phase CML patients who were intolerant of imatinib and naïve to all other TKIs. MCyRs were also seen in more than one-quarter of evaluable patients with chronic-phase CML previously treated with multiple TKIs. Most of the patients with chronic-phase CML achieved a complete hematologic response with bosutinib and some patients with advanced phases of CML achieved an overall hematologic response. Responses were seen irrespective of the type of BCR-ABL mutation at baseline, except T315I. Bosutinib had a manageable tolerability profile in the pivotal trial, with ≤21 % of patients with chronic-phase CML discontinuing the treatment because of adverse events. Diarrhea was the most common adverse event but was generally manageable, with only few patients discontinuing the treatment because of diarrhea. Therefore, bosutinib is a useful TKI option for patients with Ph+ CML in second-line or greater settings.

13-valent pneumococcal conjugate vaccine: a review of its use in infants, children, and adolescents.

The 13-valent pneumococcal conjugate vaccine (Prevenar 13(®); Prevnar 13(®)) [PCV13] includes 13 serotype-specific polysaccharides of Streptococcus pneumoniae conjugated individually to non-toxic diphtheria CRM197 protein, thus providing wider coverage of pneumococcal serotypes than its 7-valent predecessor (PCV7). For pediatric populations, PCV13 was initially approved for use in infants and children up to 5 years of age, but recently received approval for expanded use (ages 6 weeks to 17 years) in the EU and the USA. This change in labeling was made primarily on the basis of results of Study 3011, which demonstrated the serotype-specific immunogenicity of a single dose of PCV13 in children ≥5 to <10 years of age who had previously received PCV7. Study 3011 also demonstrated functional immune responses after a single dose of PCV13 in a cohort ≥10 to <18 years of age who had not previously received PCV7. Importantly, prior to Study 3011, several randomized studies comparing PCV13 and PCV7 in infants and younger children demonstrated noninferiority of immune responses to the seven serotypes common to both vaccines after a two- or three-dose primary infant series and after the toddler booster dose; immunogenicity and functional immune responses were also demonstrated for the six additional serotypes. The safety and reactogenicity of PCV13 was generally similar to that of PCV7, and PCV13 did not interfere with the immune responses to coadministered routine pediatric vaccines. PCV13 is expected to substantially reduce the incidence of invasive pneumococcal diseases in a manner similar to that which occurred after PCV7 was introduced, and evidence of the protective effectiveness of PCV13 against pneumococcal diseases is emerging.