Aripiprazole (ABILIFY MAINTENA®): a review of its use as maintenance treatment for adult patients with schizophrenia.

Aripiprazole (ABILIFY(®)) is an atypical antipsychotic drug that is proposed to act via partial agonism of dopamine D2 receptors. Trials with oral aripiprazole have shown that, compared with some other atypical antipsychotics, aripiprazole is associated with fewer metabolic disturbances and has a favourable cardiovascular tolerability profile. Recently, an intramuscular long-acting injectable (LAI) depot formulation of aripiprazole (ABILIFY MAINTENA(®)) (aripiprazole LAI) has been approved for use as a treatment for schizophrenia in adults. The efficacy of aripiprazole LAI as a maintenance treatment for schizophrenia has been demonstrated in randomized clinical trials. In the trials, aripiprazole LAI was more effective than placebo, and noninferior to oral aripiprazole, in delaying relapse and in reducing relapse rates in schizophrenia. Aripiprazole LAI was generally well tolerated, with a tolerability profile consistent with that of oral aripiprazole. Thus, aripiprazole LAI is a valuable new treatment option for adult patients with schizophrenia. It may be of particular use for patients stable on oral aripiprazole who would prefer, or are likely to benefit from, a long-acting formulation.

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.

Rivaroxaban: a review of its use in the treatment of deep vein thrombosis or pulmonary embolism and the prevention of recurrent venous thromboembolism.

Rivaroxaban (Xarelto(®)), an oral direct factor Xa inhibitor, is approved for the initial treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), as well as the prevention of recurrent DVT and PE. It is administered at a fixed oral dose and does not require routine coagulation monitoring. In the EINSTEIN-DVT and EINSTEIN-PE trials, in over 8,000 patients with DVT and/or PE, a single-drug approach with rivaroxaban was shown to be noninferior to standard therapy consisting of subcutaneous enoxaparin sodium overlapping with and followed by an oral dose-adjusted vitamin K antagonist (enoxaparin-VKA) with regard to the incidence of symptomatic recurrent venous thromboembolism (VTE) after 3, 6 or 12 months of treatment. Rivaroxaban was generally well tolerated in patients with DVT or PE, with no significant between-group differences in clinically relevant bleeding between the rivaroxaban and enoxaparin-VKA groups. Notably, rivaroxaban was associated with a significantly lower rate of major bleeding compared with enoxaparin-VKA when EINSTEIN-DVT and EINSTEIN-PE data were pooled. Pharmacoeconomic analyses indicated that rivaroxaban may be a cost-effective alternative to enoxaparin-VKA for the treatment of DVT or PE and prevention of recurrent VTE. Extended prophylaxis with rivaroxaban reduced the incidence of symptomatic recurrent VTE to a greater extent than placebo in the EINSTEIN-Extension trial, but was associated with a non-significant increase in the risk of clinically relevant bleeding compared with placebo. In conclusion, rivaroxaban is a reasonable alternative to standard therapy for the treatment of DVT and PE, and as extended thromboprophylaxis.

Raltegravir: a review of its use in the management of HIV-1 infection in children and adolescents.

Raltegravir (ISENTRESS(®)) is an HIV-1 integrase strand transfer inhibitor that is well established as a component of highly active antiretroviral therapy regimens for the treatment of adults with HIV-1 infection, and has recently been approved for the treatment of HIV-1-infected children and adolescents aged 2-18 years. A new chewable formulation has been introduced and results of a pharmacokinetic study have led to the establishment of dosages for this formulation for children. In a phase I/II, open-label, multicentre, clinical trial, raltegravir (administered as the chewable or the film-coated tablet) in combination with optimized background antiretroviral therapy was an effective treatment for treatment-experienced children and adolescents with HIV-1 infection, in terms of virologic measures of efficacy (i.e. a decrease of in HIV-1 RNA levels of ≥1 log(10), or an HIV-1 RNA level of <400 copies/mL at the 24-week primary efficacy assessment), with virologic efficacy sustained at the 48-week assessment. Immunologic improvements (increases from baseline in CD4+ cell counts) were also observed. As a component of combination therapy, raltegravir was generally well tolerated over a period of up to 48 weeks. Raltegravir is an important new option for the treatment of children and adolescents with HIV-1 infection, and the introduction of a new chewable formulation (allowing dosage flexibility) extends its benefits to the treatment of younger children.

Elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen (Stribild®): a review of its use in the management of HIV-1 infection in adults.

A new single-tablet, fixed-dose formulation consisting of elvitegravir, an HIV-1 integrase strand transfer inhibitor (INSTI); cobicistat, a pharmacokinetic enhancer; emtricitabine, a nucleoside reverse transcriptase inhibitor; and tenofovir disoproxil fumarate (tenofovir DF), a nucleotide reverse transcriptase inhibitor (elvitegravir/cobicistat/emtricitabine/tenofovir DF 150 mg/150 mg/200 mg/300 mg; Stribild®) is available in some countries for the once-daily treatment of HIV-1 infection in antiretroviral therapy-naïve adults. Elvitegravir/cobicistat/emtricitabine/tenofovir DF is the first INSTI-based single-tablet regimen available for the complete initial treatment of adults with HIV-1 infection. In two large, randomized, double-blind, phase III trials, once-daily treatment with elvitegravir/cobicistat/emtricitabine/tenofovir DF was effective in reducing plasma HIV-1 RNA levels to <50 copies/mL at the week 48 assessment and showed virological efficacy noninferior to that of the efavirenz/emtricitabine/tenofovir DF single-tablet regimen or a once-daily regimen of atazanavir plus ritonavir (ritonavir-boosted atazanavir) plus the fixed-dose combination of emtricitabine/tenofovir DF. Elvitegravir/cobicistat/emtricitabine/tenofovir DF also showed durable efficacy in terms of achieving sustained suppression of HIV-1 RNA levels to <50 copies/mL for up to 144 weeks in both of the phase III trials. Elvitegravir/cobicistat/emtricitabine/tenofovir DF is an important addition to the group of simplified once-daily single-tablet regimens currently available for the effective treatment of HIV-1 infection in antiretroviral therapy-naïve patients and is among the preferred regimens recommended for use as initial treatment. It offers advantages over more complex multiple-tablet regimens that may impair treatment adherence, which is fundamental to the successful management of HIV-1 infection.

Simeprevir: first global approval.

Simeprevir (Sovriad(TM)) is a new direct-acting antiviral drug and a second-generation small-molecule NS3/4A serine protease inhibitor developed by Janssen and Medivir for the oral treatment of adults with genotype 1 and/or genotype 4 chronic hepatitis C virus (HCV) infection (chronic hepatitis C). Simeprevir antiviral activity is achieved by its non-covalent binding to HCV protease, with a fast association and slow dissociation rate. The capsule formulation is approved in Japan and Canada for use in combination with pegylated interferon (peginterferon) and ribavirin for genotype 1 chronic hepatitis C, and has been filed for approval in the US in this indication. In addition, the capsule formulation has been filed for approval in the EU for use in combination with peginterferon and ribavirin for genotype 1 and 4 chronic hepatitis C. Phase III trials of the capsule formulation of simeprevir are underway in several other regions, including China. In the pivotal phase III trials, simeprevir was administered once daily for 12 weeks in combination with peginterferon and ribavirin for 24 or 48 weeks. This article summarizes the milestones in the development of simeprevir leading to this first approval for chronic hepatitis C.

Dolutegravir: first global approval.

Dolutegravir, an orally administered HIV-1 integrase strand transfer inhibitor (INSTI), is under development by ViiV Healthcare. Like other drugs belonging in the INSTI class of antiretroviral agents, dolutegravir binds to the integrase site of HIV-1 and blocks the strand transfer integration step, thereby preventing the replication of HIV-1. Dolutegravir is being developed as an unboosted once-daily therapy for use in combination with other antiretroviral agents for the treatment of both treatment-naïve and treatment-experienced patients with HIV-1 infection. Dolutegravir has been approved in the USA for the treatment of HIV-1 infection in combination with other antiretroviral agents and has been filed for approval in the EU and Canada. Phase III development is underway in North America, Europe, South Africa, South America, Australia and Taiwan. This article summarizes the milestones in the development of dolutegravir leading to this first approval for the treatment of HIV-1 infection in both therapy-naïve and -experienced patients.

Metreleptin: first global approval.

Metreleptin is an analogue of the human hormone leptin being developed by Amylin Pharmaceuticals (a subsidiary of Bristol-Myers Squibb) for the subcutaneous treatment of metabolic disorders including lipodystrophy. The compound is expected to improve insulin sensitivity, hypertriglyceridaemia and hyperglycaemia in patients with lipodystrophy who are unresponsive to conventional treatment. Metreleptin has been approved in Japan as a leptin therapy for the treatment of lipodystrophy. Amylin has also completed a submission for regulatory approval to the US FDA for metreleptin in the treatment of diabetes mellitus and/or hypertriglyceridaemia in patients with rare forms of lipodystrophy. Clinical development of the drug is also underway in the USA for the treatment of type 1 diabetes. Amgen was previously assessing the use of metreleptin as a treatment for amenorrhoea; however, it appears that development in this indication has been discontinued. This article summarizes the milestones in the development of metreleptin leading to this first approval for lipodystrophy.

Meningococcal groups C and Y and haemophilus B tetanus toxoid conjugate vaccine (HibMenCY-TT; MenHibrix(®)): a review.

The meningococcal groups C and Y and Haemophilus b (Hib) tetanus toxoid conjugate vaccine (HibMenCY-TT) contains Neisseria meningitidis serogroup C and Y capsular polysaccharide antigens, and Hib capsular polysaccharide [polyribosyl-ribitol-phosphate (PRP)]. The HibMenCY-TT vaccine is available in the USA for use as active immunization to prevent invasive disease caused by N. meningitidis serogroups C (MenC) and Y (MenY), and Hib in children 6 weeks-18 months of age. HibMenCY-TT is the first meningococcal vaccine available for use in the USA that can be administered to infants as young as 6 weeks of age. In a randomized, controlled, phase III clinical trial, the HibMenCY-TT vaccine, administered to infants at 2, 4, 6 and 12-15 months of age, was immunogenic against MenC and MenY, and met the prespecified criteria for immunogenicity. Anti-PRP antibodies, which have been shown to correlate with protection against Hib invasive disease, were also induced in the infants who received the HibMenCY-TT vaccine, with induced levels of this antibody noninferior to those occurring in the control group of infants who received a Hib tetanus toxoid conjugate vaccine at 2, 4, and 6 months and a single dose of Hib conjugated to N. meningitidis outer membrane protein at 12-15 months. In several randomized, controlled clinical trials, HibMenCY-TT was coadministered with vaccines that are routinely administered to infants and toddlers in the USA. These vaccines included: diphtheria and tetanus toxoids and acellular pertussis adsorbed, hepatitis B (recombinant) and inactivated poliovirus vaccine combined; 7-valent Streptococcus pneumoniae polysaccharide conjugate vaccine; measles, mumps and rubella vaccine; and varicella vaccine. Coadministration of these vaccines did not interfere with the immunogenicity of the HibMenCY-TT vaccine. Similarly, immune responses to the coadministered vaccines were not affected by the HibMenCY-TT vaccine. The tolerability profile of the HibMenCY-TT vaccine in infants and toddlers in the phase III trial was considered to be clinically acceptable and comparable to that of the Hib conjugate vaccines received by the control group.

Lomitapide: a review of its use in adults with homozygous familial hypercholesterolemia.

Lomitapide (Juxtapid(TM)), an orally administered inhibitor of the microsomal triglyceride transfer protein, inhibits the synthesis of chylomicrons and very low-density lipoprotein, thereby reducing plasma levels of low-density lipoprotein cholesterol (LDL-C). Lomitapide is used to lower lipid levels in adults with homozygous familial hypercholesterolemia, a rare, potentially life-threatening genetic disease that is commonly caused by mutations in the LDL receptor gene or other genes that affect the function of the LDL receptor. In a multinational single-arm, open-label, 78-week, phase III trial, lomitapide reduced mean plasma LDL-C levels by 50 % from baseline in 23 evaluable adults with homozygous familial hypercholesterolemia over a 26 week treatment period. Reductions from baseline in LDL-C levels were sustained for up to 78 weeks with continued lomitapide treatment. In this study, the initial dosage of lomitapide was 5 mg once daily for two weeks, with upward titration thereafter to 10, 20, 40, and 60 mg at weeks 2, 6, 10, and 14, respectively, or until an individually assessed maximum dosage was achieved. Prior to the start of treatment with lomitapide, other lipid-lowering therapy (including LDL apheresis) was stabilized over a 6-week period, and then continued throughout the lomitapide treatment phase. Lomitapide was generally well tolerated; the most common adverse events in the phase III trial were gastrointestinal events.

Ivabradine: in adults with chronic heart failure with reduced left ventricular ejection fraction.

Ivabradine (Procoralan®) is a pure heart rate-lowering drug that produces selective and specific inhibition of the cardiac pacemaker funny current (I(f)) in the sinus node that regulates heart rate. The drug acts directly on the sinus node and does not affect atrioventricular or intraventricular conduction times, myocardial contractility or ventricular repolarization. Ivabradine is used in the treatment of adults with New York Heart Association class II-IV chronic heart failure with systolic dysfunction, in sinus rhythm, with a heart rate of ≥75 beats per minute (bpm). This article reviews the pharmacology of ivabradine, and data on its clinical profile in adults with chronic heart failure. The large, randomized, double-blind, placebo-controlled, multicenter, SHIFT (Systolic Heart failure treatment with the I(f) inhibitor ivabradine Trial) study was conducted to evaluate the effect of reducing heart rate with ivabradine on outcomes in adults with symptomatic chronic heart failure and left ventricular systolic dysfunction, in sinus rhythm, and with a resting heart rate of ≥70 bpm, receiving stable background therapy. Study participants had reduced left ventricular ejection fraction of ≤35%. Results from the SHIFT study showed that compared with placebo (n = 3264), a clinically and statistically significant reduction of 18% in the relative risk of the primary composite endpoint (i.e. the composite of cardiovascular death or hospital admission for worsening heart failure) occurred in the ivabradine treatment group (n = 3241) within 3 months of the start of treatment. Study treatment was discontinued by significantly more ivabradine than placebo recipients in the SHIFT study; however, the incidence of serious adverse events was significantly higher in the placebo treatment group. Cardiovascular adverse events, including bradycardia, were the most common adverse events reported with ivabradine.

Paliperidone extended release: in adolescents with schizophrenia.

Paliperidone, the major active metabolite of risperidone, is an atypical antipsychotic agent formulated as an extended-release (ER) tablet suitable for once-daily oral administration. Paliperidone ER is approved for the treatment of adolescents aged 12-17 years with schizophrenia in the US (the focus of this review). It is also approved for the treatment of adults with schizophrenia or schizoaffective disorder. Paliperidone ER has shown efficacy in the treatment of patients aged 12-17 years with acutely symptomatic schizophrenia in a randomized, double-blind, parallel-group, placebo-controlled, multicenter, 6-week trial. The primary endpoint was the change from baseline in Positive and Negative Syndrome Scale (PANSS) total score to day 43 or the final assessment point post-baseline. Patients with a PANSS total score of 60-120 received one of three weight-based, fixed once-daily doses of paliperidone ER (patients weighing 29 kg to <51 kg: 1.5 mg [low-dose], 3 mg [medium], or 6 mg [high]; patients weighing ≥51 kg: 1.5 mg [low], 6 mg [medium], or 12 mg [high]), or placebo. Compared with placebo, significant improvements in mean PANSS total scores were reported for the medium-dose (3-6 mg) paliperidone ER treatment groups. There were no significant differences in mean PANSS total scores between the recipients of low-dose or high-dose paliperidone ER versus placebo. Mean PANSS total scores in the actual dose treatment groups (regardless of weight) decreased from baseline (i.e. improved) and were significantly lower for the 3, 6, and 12 mg groups than for the placebo group. Treatment-emergent adverse events were dose related in adolescents with schizophrenia who received weight-based fixed doses of paliperidone ER.

Azilsartan medoxomil: a review of its use in hypertension.

Azilsartan medoxomil (Edarbi®; Ipreziv™) is an orally administered angiotensin II receptor type 1 antagonist (blocker) used in the treatment of adults with essential hypertension. This article reviews data on the clinical efficacy and tolerability of azilsartan medoxomil in adults with essential hypertension and provides a summary of its pharmacological properties. Azilsartan medoxomil is a prodrug that undergoes rapid hydrolysis in the gastrointestinal tract after oral administration to the bioactive moiety azilsartan, before systemic absorption. Azilsartan medoxomil produces antihypertensive effects by selectively blocking the binding of angiotensin II to the angiotensin type 1 (AT(1)) receptor, thereby antagonizing the pressor response activity of angiotensin II. In vitro, azilsartan produced greater and more sustained AT(1) receptor binding/blockade activity than several comparator angiotensin II receptor antagonists. Azilsartan medoxomil reduces blood pressure (BP) in hypertensive adults. In addition, the drug has been shown to have pleiotropic effects (i.e. effects beyond AT(1) receptor blockade). In adults with essential hypertension, azilsartan medoxomil 20, 40 or 80 mg effectively reduced BP over a 24-hour period with once-daily administration in three major, randomized, controlled trials in which the primary endpoints were changes from baseline in 24-hour mean systolic BP (SBP) at week 6 (two trials) or week 24, assessed by ambulatory BP monitoring (ABPM). In the two 6-week trials, azilsartan medoxomil showed dose-dependent efficacy over all evaluated dosages and was more effective than placebo in lowering SBP. At the maximum approved dosage of 80 mg once daily, azilsartan medoxomil was significantly more effective than maximum dosages of olmesartan medoxomil (40 mg once daily) or valsartan (320 mg once daily), based on primary endpoint assessments. Mean reductions in clinic measurements of SBP and diastolic BP (DBP) measurements were also generally greater with azilsartan medoxomil 80 mg once daily than with the comparator drugs in these 6-week studies. Over a longer treatment period of 24 weeks, azilsartan medoxomil showed sustained BP-lowering efficacy, with the reduction in 24-hour mean SBP at week 24 significantly greater with azilsartan medoxomil 40 or 80 mg once daily than with valsartan 320 mg once daily. Mean reductions from baseline in mean clinic SBP and DBP as well as DBP by ABPM were also significantly greater with azilsartan medoxomil 40 or 80 mg once daily than with valsartan. Azilsartan medoxomil was generally well tolerated, with a tolerability profile similar to that of placebo in the 6-week trials. Across the three major trials, headache and dizziness were among the most common adverse events. Overall, rates of treatment discontinuation as a result of adverse events were low in the 6-week and 24-week trials. In conclusion, once-daily azilsartan medoxomil effectively lowers BP in adults with essential hypertension and has shown better antihypertensive efficacy than maximum therapeutic dosages of olmesartan medoxomil or valsartan in major trials of up to 24 weeks' duration. Azilsartan medoxomil is generally well tolerated and the low rates of discontinuation due to adverse events suggest that patients are likely to persist with long-term treatment. Azilsartan medoxomil is therefore a useful and attractive new option for lowering BP in patients with essential hypertension, particularly for those not able to tolerate other antihypertensive drugs. Further studies are required to evaluate the effects of azilsartan medoxomil on cardiovascular morbidity and mortality.

Telaprevir: a review of its use in the management of genotype 1 chronic hepatitis C.

Telaprevir (Incivo®, Incivek®), an orally administered inhibitor of the hepatitis C virus non-structural protein NS3-4A serine protease, is used in combination with pegylated interferon (peginterferon)-alpha and ribavirin in the treatment of adults with genotype 1 chronic hepatitis C virus (HCV) infection (chronic hepatitis C). This article reviews data on the clinical efficacy and tolerability of telaprevir in adults with genotype 1 chronic hepatitis C and provides a summary of its pharmacological properties. In in vitro studies, telaprevir shows good activity against genotype 1 HCV, including viral isolates from patients with chronic hepatitis C. Numerous resistant variants of HCV have been identified in clinical isolates from patients receiving treatment with telaprevir-based therapy. However, the clinical relevance of viral variants emerging during treatment requires further study. Telaprevir administered for 12 weeks in combination with peginterferon-alpha-2a and ribavirin for up to 48 weeks was effective in the treatment of previously untreated or previously treated adults with genotype 1 chronic hepatitis C in three major randomized phase III trials. Sustained virological response rates (i.e. percentages of patients with undetectable HCV RNA levels 24 weeks after the last planned dose of study medication: the primary endpoint) achieved with the telaprevir-based regimens were significantly higher than those produced with peginterferon-alpha-2a and ribavirin alone (the 'current standard of care'). In the largest trial (the ADVANCE trial) in previously untreated patients, 24 weeks after the last planned dose of study drug, recipients of 12 weeks' treatment with telaprevir in combination with peginterferon-alpha-2a and ribavirin followed by treatment with peginterferon-alpha-2a and ribavirin for a further 12 or 36 weeks experienced significantly (p < 0.001) higher sustained virological response rates than patients who received peginterferon-alpha-2a and ribavirin dual therapy for 48 weeks (75% vs 44%). Adverse events were reported more frequently with telaprevir-based regimens than with peginterferon-alpha-2a and ribavirin dual therapy in the major trials. The most common adverse events included fatigue, rash, pruritus, anaemia and nausea. In conclusion, telaprevir in combination with peginterferon-alpha and ribavirin is an effective treatment for treatment-naive and previously treated adults with genotype 1 chronic hepatitis C - patient groups in whom peginterferon-alpha and ribavirin dual therapy may not be successful. Thus, telaprevir is a valuable new treatment option for use in combination with peginterferon-alpha and ribavirin in treatment-naive or previously treated adults with genotype 1 chronic hepatitis C.

Liraglutide: a review of its use in the management of type 2 diabetes mellitus.

Liraglutide (Victoza®) is a subcutaneously administered glucagon-like peptide-1 (GLP-1) receptor agonist produced by recombinant DNA technology and used as an adjunct to diet and exercise in the treatment of adults with type 2 diabetes mellitus. This article reviews the clinical efficacy and tolerability of liraglutide in adults with type 2 diabetes, and provides a summary of its pharmacological properties. Recently published pharmacoeconomic studies of liraglutide are also reviewed. Administered subcutaneously, liraglutide (usually 1.2 or 1.8 mg once daily) generally produced greater improvements in glycaemic control than active comparators or placebo when administered as monotherapy or in combination with one or two oral antidiabetic drugs (OADs) to adults with type 2 diabetes in numerous randomized, controlled phase III trials. These included six trials in the LEAD trial programme that was designed to evaluate the efficacy and safety of liraglutide across a continuum of antihyperglycaemic management for patients with type 2 diabetes. Liraglutide was generally well tolerated, with a low risk of hypoglycaemia evident, in the phase III trials. The most common adverse events were gastrointestinal and included nausea and diarrhoea; most events were mild to moderate in severity and decreased in incidence over time. In conclusion, liraglutide has an important place in the management of adults with type 2 diabetes across a continuum of care. As well as providing effective glycaemic control, liraglutide improves pancreatic ß-cell function and leads to bodyweight loss, thereby addressing some of the unmet needs of patients treated with traditional OADs.

Eribulin.

Eribulin (eribulin mesylate) is a non-taxane microtubule dynamics inhibitor with tubulin-based antimitotic activity and chemotherapeutic effects. Eribulin is used in the treatment of patients with locally advanced or metastatic breast cancer who have previously been treated with at least two chemotherapeutic regimens, including an anthracycline and a taxane. In in vitro studies, eribulin displayed antiproliferative activity against human breast cancer cell lines. Regression and elimination of breast tumours were observed in human tumour xenograft models. In the randomized, open-label, multinational, phase III EMBRACE trial in patients with locally recurrent or metastatic breast cancer, median overall survival was significantly longer in patients who received intravenous eribulin (n = 508) [13.1 months] compared with that in patients who received a treatment of physician's choice (n = 254) [10.6 months; hazard ratio 0.81; 95% CI 0.66, 0.99; p = 0.041]. Prior to enrolment, study participants had received between two and five chemotherapeutic regimens, including an anthracycline and a taxane. Consistent with the findings of earlier phase I and II trials, eribulin was reported to have a manageable tolerability profile in the EMBRACE trial. Peripheral neuropathy (incidence 5%) was the most common adverse event resulting in the discontinuation of eribulin treatment. The most common grade 3/4 adverse events in the eribulin group were neutropenia, leukopenia and asthenia or fatigue.

Spotlight on histamine dihydrochloride in acute myeloid leukaemia.

Histamine dihydrochloride (Ceplene®) is a synthetic derivative of the biogenic amine histamine. Histamine dihydrochloride inhibits the formation of reactive oxygen species that suppress the activation of T cells and natural killer (NK) cells. When given in addition to the cytokine interleukin (IL)-2, histamine dihydrochloride enables the activation of T cells and NK cells by IL-2, resulting in the killing of cancer cells, including those of acute myeloid leukaemia (AML). In a large, 3-year, randomized, open-label, multicentre, phase III trial in adult patients with AML in first or subsequent remission, those who received subcutaneous histamine dihydrochloride and concomitant subcutaneous IL-2 as maintenance therapy had a significantly longer leukaemia-free survival (LFS; primary endpoint) than patients receiving no treatment. This difference was also shown for the subgroup of patients in first remission. The between-group difference in overall survival (OS) was not significant, although this trial was not powered to detect such a difference. Histamine dihydrochloride and IL-2 therapy had an acceptable tolerability profile in patients in the phase III trial. The majority of reported adverse events were of grade 1 or 2 severity. The most commonly reported grade 3 adverse events with active treatment were thrombocytopenia, headache, neutropenia, pyrexia, eosinophilia and diarrhoea; grade 4 adverse events were thrombocytopenia and leukopenia not otherwise specified. Serious adverse events were mostly relapse related. Histamine dihydrochloride and IL-2 as maintenance therapy significantly prolonged LFS compared with no treatment and had an acceptable tolerability profile in a large phase III trial in patients with AML. Although some issues remain to be addressed, most notably the effects of therapy on OS and the efficacy of treatment in older patients (who represent the majority of AML patients), histamine dihydrochloride in addition to IL-2 appears to be a useful maintenance therapy option for adult patients with AML in remission.

Histamine dihydrochloride: in the management of acute myeloid leukaemia.

Histamine dihydrochloride (Ceplene) is a synthetic derivative of the biogenic amine histamine. Histamine dihydrochloride inhibits the formation of reactive oxygen species that suppress the activation of T cells and natural killer cells. When administered in addition to the cytokine interleukin (IL)-2, histamine dihydrochloride enables the activation of T cells and natural killer cells by IL-2, resulting in the killing of tumour cells of various cancers, including acute myeloid leukaemia (AML). In a 3-year, randomized, multicentre, phase III trial in adult patients with AML in first or subsequent remission, those who received subcutaneous histamine dihydrochloride and concomitant subcutaneous IL-2 as maintenance therapy had a significantly longer leukaemia-free survival (LFS; primary endpoint) than recipients of no treatment. This difference was also shown for the subgroup of patients in first remission. The between-group difference in overall survival (OS) was not significant, although this trial was not powered to detect such a difference. Histamine dihydrochloride and IL-2 therapy had an acceptable tolerability profile in patients in the phase III trial. The majority of reported adverse events were grade 1 or 2 of the National Cancer Institute Common Toxicity Criteria. The most commonly reported grade 3 adverse events with active treatment were thrombocytopenia, headache, neutropenia, pyrexia, eosinophilia and diarrhoea; grade 4 adverse events were thrombocytopenia and leukopenia not otherwise specified. Serious adverse events were mostly relapse related. Histamine dihydrochloride and IL-2 as maintenance therapy significantly prolonged LFS compared with no treatment and had an acceptable tolerability profile in a large phase III trial in patients with AML. Although some issues remain to be addressed, most notably the effects of therapy on OS and the efficacy of treatment in older patients, histamine dihydrochloride in addition to IL-2 appears to be a useful maintenance therapy option for adult patients with AML in remission.

Efavirenz/emtricitabine/tenofovir disoproxil fumarate single-tablet regimen (Atripla®): a review of its use in the management of HIV infection.

The non-nucleoside reverse transcriptase inhibitor, efavirenz, and the two nucleoside reverse transcriptase inhibitors, emtricitabine and tenofovir disoproxil fumarate (tenofovir DF) are now available as a single-tablet regimen (efavirenz/emtricitabine/tenofovir DF 600 mg/200 mg/300 mg; Atripla®). The efavirenz/emtricitabine/tenofovir DF single-tablet regimen is the first once-daily, single-tablet, triple antiretroviral therapy (ART) formulation available for the treatment of HIV infection and, in the EU, is indicated for use in adults infected with HIV-1 who have been virologically suppressed for >3 months on their current ART regimen. In treatment-experienced adults with HIV-1 infection already virologically suppressed with ART, switching to once-daily triple combination therapy with efavirenz, emtricitabine and tenofovir DF (including the single-tablet regimen) is effective in maintaining virological suppression and is generally well tolerated, according to several randomized, open-label or noncomparative multicentre trials and an open-label extension study of up to 96 weeks' duration. Moreover, additional data from some of these studies indicate that adherence to treatment was maintained or improved after switching to the once-daily triple combination, with patients generally preferring the efavirenz/emtricitabine/tenofovir DF single-tablet regimen over their previous more complex regimen and (in one of two trials) finding it easier to follow. Thus, the efavirenz/emtricitabine/tenofovir DF single-tablet regimen provides a convenient once-daily regimen for use in treatment-experienced adults that may confer an advantage over more complex or frequently administered regimens for which adherence to treatment is an issue.

Lopinavir/Ritonavir: a review of its use in the management of HIV-1 infection.

Lopinavir/ritonavir (Kaletra®) is an orally administered coformulated ritonavir-boosted protease inhibitor (PI) comprising lopinavir and low-dose ritonavir. It is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection in adults, adolescents and children. Lopinavir/ritonavir is available as a tablet, soft-gel capsule and an oral solution for patients with difficulty swallowing. In well designed, randomized clinical trials, lopinavir/ritonavir, in combination with other antiretroviral therapies (ART), provided durable virological suppression and improved immunological outcomes in both ART-naive and -experienced adult patients with virological failure. Furthermore, lopinavir/ritonavir demonstrated a high barrier to the development of resistance in ART-naive patients. More limited data indicate that it is effective in reducing plasma HIV-1 RNA levels in paediatric patients. Lopinavir/ritonavir has served as a well established benchmark comparator for the noninferiority of other ritonavir-boosted PI regimens. Although generally well tolerated, lopinavir/ritonavir is associated with generally manageable adverse gastrointestinal side effects and hypertriglyceridaemia and hypercholesterolaemia, which may require coadministration of lipid-lowering agents to reduce the risk of coronary heart disease. Lopinavir/ritonavir, in combination with other ART agents, is a well established and cost-effective treatment for both ART-naive and -experienced patients with HIV-1 infection and, with successful management of adverse events, continues to have a role as an effective component of ART regimens for the control of HIV-1 infection.