Decitabine: a review of its use in older patients with acute myeloid leukaemia.

Decitabine (Dacogen(®)) is a deoxynucleoside analogue of cytidine that selectively inhibits DNA methyltransferases. Decitabine administered at a dose of 20 mg/m(2) by a 1-h intravenous infusion for 5 consecutive days of a 4-week cycle has been approved by the European Medicines Agency (EMA) for use in adult patients aged ≥65 years with de novo or secondary acute myeloid leukaemia (AML) who are not candidates for standard induction therapy. Decitabine, compared with treatment choice (cytarabine or supportive care), did not result in a statistically significant improvement in median overall survival (OS) in older patients with AML at the pre-specified primary endpoint of a pivotal phase III trial. However, the improvement in OS was considered by the EMA to be clinically meaningful. After a further year of follow-up, an analysis of the mature survival data demonstrated a statistical significance in median OS in favour of decitabine over treatment choice. Complete remission (CR) rates in the phase III trial were significantly improved with decitabine versus treatment choice. The overall safety profile of decitabine in older patients with AML was generally similar to that of cytarabine, with pyrexia, thrombocytopenia and anaemia being the most commonly reported adverse events. In conclusion, low-dose decitabine may be considered as an effective and generally well tolerated alternative treatment to cytarabine or supportive care in older patients with AML who are not candidates for standard induction therapy.

Tadalafil: in the treatment of signs and symptoms of benign prostatic hyperplasia with or without erectile dysfunction.

Tadalafil is a selective cyclic guanosine monophosphate-specific phosphodiesterase type 5 inhibitor. Once-daily tadalafil 5 mg was effective in treating the signs and symptoms of benign prostatic hyperplasia (BPH). In phase III trials in men with BPH, the mean change from baseline to week 12 in the total International Prostate Symptom Score (IPSS; primary endpoint) was significantly greater in those treated with once-daily tadalafil 5 mg than with placebo. Improvements in total IPSS that occurred over the initial 12 weeks of tadalafil treatment were maintained with continued treatment over a 1-year period in an open-label extension study. Moreover, tadalafil was effective in treating both erectile dysfunction (ED) and the signs and symptoms of BPH in a phase III trial that specifically enrolled men with both indications. Both the International Index of Erectile Function-Erectile Function domain score and the total IPSS (co-primary endpoints) were significantly improved from baseline to week 12 after treatment with once-daily tadalafil 5 mg compared with placebo. Tadalafil was generally well tolerated (for a period of up to 1 year) in patients with BPH, including those with ED, with adverse events being of mild to moderate intensity.

Transdermal granisetron: a guide to its use in preventing nausea and vomiting induced by chemotherapy.

Transdermal granisetron (Sancuso®) is effective in the prevention of nausea and vomiting in patients with cancer who are receiving moderately or highly emetogenic chemotherapy for 3-5 days. Transdermal granisetron is noninferior to oral granisetron in this indication, and is generally well tolerated in this indication. Thus, transdermal granisetron provides a convenient option for the prevention of chemotherapy-induced nausea and vomiting, with the potential to improve patient compliance.

Live attenuated influenza vaccine (Fluenz™): a guide to its use in the prevention of seasonal influenza in children in the EU.

Live attenuated influenza vaccine (LAIV).[Fluenz™] has a convenient intranasal route of administration. In the EU, it is indicated for the prevention of influenza disease caused by the influenza virus strains contained in the vaccine in children and adolescents aged 2 years to <18 years. The vaccine elicits a high immunogenic response, is protective against seasonal influenza infection and is associated with the development of herd immunity. LAIV is generally well tolerated, with the safety of the vaccine in the approved pediatric population generally considered to be similar to that of placebo based on clinical trials and extensive experience involving more than 39 million vaccine doses.

Canakinumab: in patients with cryopyrin-associated periodic syndromes.

Canakinumab is a recombinant, fully human, monoclonal, anti-human interleukin-1ß (IL-1ß) antibody that binds with high affinity and specificity to human IL-1ß, preventing its interaction with IL-1 receptors. Canakinumab (150 mg in patients weighing >40 kg or 2 mg/kg in those weighing 15-40 kg) administered once every 8 weeks as a single dose via subcutaneous injection provided a rapid and sustained response in patients with cryopyrin-associated periodic syndromes (CAPS). During the initial 8-week phase of a three-part, phase III trial, a complete response to a single dose of canakinumab occurred in 97% of the 35 patients with CAPS, with 71% of responses occurring within 8 days. After 8 weeks, 31 responders entered a 24-week, randomized, double-blind, withdrawal phase; there was a significant between-group difference in this phase in that none of the canakinumab recipients relapsed compared with 81% of placebo recipients. All patients from the second phase of the trial entered a third, 16-week phase of open-label treatment with canakinumab once every 8 weeks; clinical and biochemical remission was maintained in 28 of 29 patients who completed the trial. In a 2-year, open-label, phase III trial, subcutaneous canakinumab once every 8 weeks provided sustained disease control in the majority of patients with CAPS. Canakinumab was generally well tolerated in all trials, with the predominant adverse events being mild to moderate infections that were responsive to standard treatment.

Crizotinib: in locally advanced or metastatic non-small cell lung cancer.

Crizotinib is an inhibitor of receptor tyrosine kinases (including anaplastic lymphoma kinase [ALK]). Oral crizotinib 250 mg twice daily was associated with clinically meaningful response rates in two noncomparative trials (phase I and phase II) in patients with locally advanced or metastatic ALK-positive non-small cell lung cancer (NSCLC). In the phase I trial (median duration of treatment of 32 weeks) and phase II trial (median duration of treatment of 22 weeks), the objective response rate in crizotinib recipients was 61% and 50%, respectively, and the median duration of response was 48.1 and 41.9 weeks, respectively. Responses were rapid, with the majority of patients achieving an objective response within the first 8 weeks of treatment. Crizotinib was generally well tolerated, with most adverse reactions being grade 1 or 2. The most commonly reported treatment-related adverse reactions were vision disorder, gastrointestinal disorders and oedema.

Everolimus: in patients with subependymal giant cell astrocytoma associated with tuberous sclerosis complex.

Everolimus is an orally administered inhibitor of the mammalian target of rapamycin (mTOR). Everolimus (starting dosage 3.0 mg/m(2)) was associated with a significant reduction in the volume of the largest subependymal giant cell astrocytoma (SEGA) in 28 patients aged ≥3 years with tuberous sclerosis complex (TSC) in a phase II trial (C2485). At 6 months, 32% of patients treated with everolimus had a ≥50% reduction in the volume of their largest SEGA lesion (assessed via an independent central radiology review); 75% had a ≥30% reduction. No patients developed new lesions. During the extension phase of this trial (median duration 34 months), the reduction in SEGA volume was maintained, with no everolimus recipient requiring surgery or other therapy for SEGA or hydrocephalus. In a phase III trial (EXIST-1) in 117 patients with SEGA associated with TSC, 35% of everolimus recipients (starting dosage 4.5 mg/m(2)) versus none of the placebo recipients (p < 0.0001) had an overall response (a reduction in the sum of all target SEGA volumes of ≥50% relative to baseline, nonworsening of non-target SEGA lesions, no new SEGA lesions, and no new/worsening hydrocephalus). Everolimus was generally well tolerated in patients with SEGA associated with TSC; most drug-related adverse reactions were mild to moderate in severity.

Live attenuated influenza vaccine (FluMist®; Fluenz™): a review of its use in the prevention of seasonal influenza in children and adults.

Live attenuated influenza vaccine (LAIV) is an intranasally administered trivalent, seasonal influenza vaccine that contains three live influenza viruses (two type A [H1N1 and H3N2 subtypes] and one type B). LAIV was effective in protecting against culture-confirmed influenza caused by antigenically matched and/or distinct viral strains in children aged ≤71 months enrolled in three phase III trials. LAIV was superior to trivalent inactivated influenza vaccine (TIV) in protecting against influenza caused by antigenically-matching viral strains in a multinational phase III trial in children aged 6-59 months. LAIV was also significantly more effective than TIV in decreasing the incidence of culture-confirmed influenza illness in two open-label studies (in children with recurrent respiratory tract illnesses aged 6-71 months and in children and adolescents with asthma aged 6-17 years). LAIV did not differ significantly from placebo in preventing febrile illnesses in adults (primary endpoint) enrolled in a phase III trial. However, LAIV significantly reduced the incidence of febrile upper respiratory tract illnesses (URTI), severe febrile illnesses, febrile URTI-related work absenteeism and healthcare provider use. In another well designed trial in adults, LAIV significantly reduced the incidence of symptomatic, laboratory-confirmed influenza compared with placebo (but not intramuscular TIV). LAIV was generally well tolerated in most age groups, with the majority of adverse events being mild to moderate in severity, and runny nose/nasal congestion being the most common. In a large phase III trial, LAIV, compared with TIV, was associated with an increased incidence of medically significant wheezing in vaccine-naive children aged <24 months and an increased incidence of hospitalization in children aged 6-11 months; LAIV is not approved for use in children <24 months. LAIV was not always associated with high rates of seroconversion/seroresponse, particularly in older children and adults, or in subjects with detectable levels of haemagglutination-inhibiting antibodies at baseline. However, LAIV did elicit mucosal (nasal) IgA antibody responses and strong cell-mediated immunity responses. Only one confirmed case of LAIV virus transmission to a placebo recipient (who did not become ill) occurred in a transmission study conducted in young children. The immunogenic response to LAIV in young healthy children was not affected by concomitant administration with other commonly administered childhood vaccines. In conclusion, intranasal LAIV seasonal influenza vaccine is effective and well tolerated in children, adolescents and adults. LAIV was more effective than TIV in children, although this advantage was not seen in adults. In the US, LAIV is indicated for the active immunization of healthy subjects aged 2-49 years against influenza disease caused by virus subtypes A and type B contained in the vaccine.

Silodosin: treatment of the signs and symptoms of benign prostatic hyperplasia.

Silodosin is an α-adrenoceptor antagonist with high selectivity for α(1A)- relative to α(1B)- adrenoceptors. In men aged >50 years with benign prostatic hyperplasia (BPH), silodosin 8 mg once daily, compared with placebo, was associated with a significantly more rapid and effective improvement in the total International Prostate Symptom Score (IPSS) and the storage and voiding IPSS subscores in three 12-week, phase III trials conducted in Europe and the US. In the European trial, silodosin was at least as effective as tamsulosin 0.4 mg once daily in improving the total IPSS. Silodosin was significantly more effective than placebo (all three phase III trials) and tamsulosin (European phase III trial) in simultaneously improving nocturia, frequency and incomplete emptying, according to a post hoc analysis. Long-term, open-label extension trials demonstrated that silodosin provided sustained relief of the signs and symptoms of BPH for up to 1 year. Silodosin was generally well tolerated, and was associated with minimal cardiovascular adverse effects. Abnormal ejaculation, a class effect of α(1A)-adrenoceptor antagonists, was the most common silodosin-associated adverse reaction, but resulted in treatment withdrawal of only a limited number of patients.

Aripiprazole: in the treatment of irritability associated with autistic disorder in pediatric patients.

Aripiprazole is an atypical antipsychotic approved for the treatment of irritability associated with autistic disorder in pediatric patients aged 6-17 years. In two, randomized, double-blind, placebo-controlled studies in pediatric patients aged 6-17 years with irritability associated with autistic disorder, 8 weeks of treatment with aripiprazole 2-15 mg/day, compared with placebo, resulted in significant improvements in the Aberrant Behavior Checklist Irritability subscale score at endpoint (primary endpoint), and the mean Clinical Global Impression-Improvement score. Aripiprazole was generally well tolerated in this patient population in the two 8-week studies and a 52-week study, with most adverse events being mild to moderate in severity. Aripiprazole was associated with weight gain in both the short- and long-term studies; data from the long-term study indicated that the increase in bodyweight reached a plateau at 3-6 months.

Aliskiren: a review of its use as monotherapy and as combination therapy in the management of hypertension.

Aliskiren is an orally administered, nonpeptide direct renin inhibitor indicated for the management of hypertension. Aliskiren was effective in controlling blood pressure (BP) as monotherapy and in combination with other antihypertensives, in large, randomized trials. Aliskiren 150-300 mg/day as monotherapy was effective in lowering BP across short- (≤12 weeks) and longer-term (up to 54 weeks) periods, providing sustained and consistent effects with 24-hour BP control. Compared with other antihypertensives, aliskiren was generally as effective as hydrochlorothiazide (HCTZ), valsartan, losartan, irbesartan and lisinopril in reducing BP. Furthermore, short-term aliskiren was noninferior to ramipril in reducing BP, but with a longer treatment duration, a greater efficacy of aliskiren-based therapy over ramipril-based therapy was demonstrated. Additional BP-lowering effects occurred when aliskiren was coadministered (as a fixed-dose combination or separate tablets) with other antihypertensives, including HCTZ, valsartan and amlodipine, according to large, randomized trials of short- (≤12 weeks) and longer-term (up to 54 weeks) duration. Combination therapy with aliskiren plus HCTZ was effective in hypertensive patients when administered as initial therapy or to patients previously treated with HCTZ or aliskiren monotherapy. Aliskiren-based therapy was also effective in lowering BP in obese patients, patients with type 1 or 2 diabetes mellitus, patients with metabolic syndrome and the elderly. Aliskiren efficacy was observed irrespective of patient age, sex or ethnicity. Aliskiren monotherapy or combination therapy was generally well tolerated over short- and longer-term study durations in large, randomized clinical trials. Clinical trials to evaluate the effects of aliskiren on clinical outcomes, including renoprotective and cardioprotective effects, are currently ongoing. Thus, aliskiren is a useful option for the treatment of patients with stage 1 to stage 2 (mild to moderate) hypertension, alone or in combination with other antihypertensives, including HCTZ, valsartan or amlodipine.

Hyaluronic acid (Supartz®): a review of its use in osteoarthritis of the knee.

Hyaluronic acid (Supartz®; molecular weight 620-1170 kDa) is a sterile, viscoelastic, non-pyogenic solution that is indicated as a medical device for the treatment of pain in patients with osteoarthritis of the knee who have failed to respond adequately to conservative nonpharmacological therapy and simple analgesics. Intra-articular injections of Supartz® were significantly more effective than control injections, according to an integrated longitudinal analysis of pooled data from five randomized, double-blind, vehicle-controlled, multicentre trials in patients with osteoarthritis of the knee. Supartz®, compared with the phosphate-buffered saline control, significantly reduced the total Lesquésne Index score in the post-injection period. Data from the individual trials demonstrated that the reduction in the total Lesquésne Index score was significantly greater than the control in two of the five studies. According to another efficacy endpoint (the mean reduction in the Western Ontario and McMaster Universities Osteoarthritis Index), which was assessed in only one of these trials, Supartz® was significantly more effective than the control in reducing the pain and stiffness subscale scores. Clinical scores of pain/inflammation and visual analogue scale (VAS) scores of pain during walking improved from baseline values for up to 6 months after treatment with Supartz® or a corticosteroid, with no significant between-group differences, in a small, randomized, open-label, multicentre trial in patients with osteoarthritis of the knee. Intra-articular injections of both Supartz® and Synvisc®, as well as a phosphate-buffered saline control, significantly reduced VAS scores of weight-bearing pain versus baseline after 26 weeks of therapy in a well designed trial; however, there were no significant differences between the three treatment groups. Neither hyaluronic acid formulation had a longer duration of clinical benefit than the saline control. Supartz® was well tolerated in patients with osteoarthritis of the knee. An integrated analysis of the five, well designed clinical trials demonstrated no significant difference between the Supartz® or control groups in the incidence of adverse events. The most common adverse events reported in Supartz® recipients were arthralgia, arthropathy/arthrosis/arthritis, back pain, nonspecific pain, injection-site reaction, headache and injection-site pain.

Inactivated split-virion seasonal influenza vaccine (Fluarix): a review of its use in the prevention of seasonal influenza in adults and the elderly.

Fluarix is a trivalent, inactivated, split-virion influenza vaccine containing 15 microg haemagglutinin from each of the three influenza virus strains (including an H1N1 influenza A virus subtype, an H3N2 influenza A virus subtype and an influenza B virus) that are expected to be circulating in the up-coming influenza season. Fluarix is highly immunogenic in healthy adults and elderly, and exceeds the criteria that make it acceptable for licensure in various regions (including the US and Europe). In a large, phase III, placebo-controlled, double-blind trial conducted in the US (2004/2005) in subjects aged 18-64 years, postvaccination seroconversion rates against the H1N1, H3N2 and B antigens were 60-78% and respective postvaccination seroprotection rates were 97-99% in Fluarix recipients. Another phase III trial conducted in the US (2005/2006) established the noninferiority of Fluarix versus another trivalent inactivated influenza virus vaccine in subjects aged >or=18 years, including a subgroup of elderly subjects. In annual European registration trials, Fluarix has consistently exceeded the immunogenicity criteria set by the EU Committee for Medicinal Products for Human Use for adults and the elderly. Fluarix demonstrated immunogenicity in small, open-label studies in at-risk subjects. During a year when the vaccine was well matched to the circulating strain, Fluarix demonstrated efficacy against culture-confirmed influenza A and/or B in a placebo-controlled trial in adults aged 18-64 years. In addition, Fluarix vaccination of pregnant women demonstrated efficacy in reducing the rate of laboratory-confirmed influenza in the infants and reducing febrile respiratory illnesses in the mothers and their new-born infants in a randomized trial. Fluarix was generally well tolerated in adults and the elderly in well designed clinical trials and in the annual European registration trials, with most local and general adverse events being transient and mild to moderate in intensity. The most common adverse reactions in recipients of Fluarix were pain, redness or swelling at the injection site, muscle aches, fatigue, headache and arthralgia. In conclusion, Fluarix is an important means of decreasing the impact of seasonal influenza viruses on adults and the elderly.

Lapatinib: in postmenopausal women with hormone receptor-positive, HER2-positive metastatic breast cancer.

Lapatinib is an orally active, low molecular weight, reversible inhibitor of the intracellular tyrosine kinase domains of both human epidermal growth factor receptor (HER) type 1 (HER1) and type 2 (HER2). In a large phase III trial (EGF30008) in 1286 postmenopausal women with hormone receptor (HR)-positive, metastatic breast cancer who had not received previous therapy for advanced or metastatic disease, the primary endpoint of median progression-free survival in a HER2-positive population of 219 women was significantly longer with lapatinib plus letrozole than with letrozole plus placebo (8.2 vs 3.0 months). Overall response rates (28% vs 15%) and clinical benefit rates (responsive or stable disease for >or=6 months; 48% vs 29%) were also significantly higher with lapatinib plus letrozole than with letrozole plus placebo. Most adverse events associated with lapatinib when administered in combination with letrozole were mild to moderate in severity in the EGF30008 phase III trial.

Spotlight on topical pimecrolimus in pediatric atopic dermatitis.

Topical pimecrolimus 1% cream (Elidel) [hereafter referred to as topical pimecrolimus] is a nonsteroidal alternative in the treatment of pediatric atopic dermatitis. In vehicle-controlled, short-term, continuous-use trials in pediatric patients with mild to moderate atopic dermatitis, topical pimecrolimus was effective in treating disease symptoms. Topical pimecrolimus was effective in preventing disease flares and reducing the need for topical corticosteroids in longer term, intermittent-use trials. In addition, topical pimecrolimus was associated with improvements in the health-related quality of life of pediatric patients with atopic dermatitis and their parents. In vehicle-controlled trials, topical pimecrolimus was generally as well tolerated as vehicle. Topical pimecrolimus showed similar efficacy to topical tacrolimus 0.03% ointment in a short-term, continuous-use trial and the two agents had a generally similar tolerability profile. Although comparative data between topical pimecrolimus and topical corticosteroids are lacking in pediatric patients, and the long-term tolerability (beyond 1-2 years) of topical pimecrolimus is yet to be established, topical pimecrolimus is a useful agent in the management of pediatric patients with mild to moderate atopic dermatitis who do not achieve satisfactory treatment with other topical pharmacologic treatments, including topical corticosteroids.

Bivalirudin: in patients with ST-segment elevation myocardial infarction.

Bivalirudin is a synthetic 20 amino acid polypeptide that directly inhibits both fibrin-bound and soluble thrombin. In the randomized, open-label, multicentre HORIZONS-AMI trial in patients with ST-segment elevation myocardial infarction (STEMI) who were undergoing primary percutaneous coronary intervention (PCI), compared with unfractionated heparin (UFH) plus a glycoprotein (GP) IIb/IIIa inhibitor, bivalirudin was associated with a significantly lower 30-day rate of net adverse clinical events that was largely due to the significantly lower 30-day rate of non-coronary-artery bypass grafting major bleeding. There was no significant between-group difference in the 30-day rate of major adverse cardiovascular events. These 30-day clinical outcomes were maintained at the 1- and 2-year follow-up. Bivalirudin, compared with UFH plus a GP IIb/IIIa inhibitor, was associated with lower short- (30-day) and long- (1- and 2-year) term overall and cardiac mortality rates. Although there was an increased risk of acute stent thrombosis within 24 hours in recipients of bivalirudin compared with UFH plus a GP IIb/IIIa inhibitor, there was no significant between-group difference between 24 hours and 30 days,

Pramipexole extended release: in Parkinson's disease.

Pramipexole extended release (ER) is a non-ergolinic dopamine receptor agonist available for use as a once-daily oral treatment for the signs and symptoms of early and advanced idiopathic Parkinson's disease. Once-daily pramipexole ER and three times-daily pramipexole immediate release (IR) have similar exposure over 24 hours. The ER formulation is associated with fewer fluctuations in plasma pramipexole concentrations over this period. Pramipexole ER improved the symptoms of Parkinson's disease in three well designed trials in adults with early or advanced disease, as measured by changes from baseline in the sum of the Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III subtotal scores. In a 9-week study, the majority of patients with early Parkinson's disease who were receiving stable pramipexole IR treatment were successfully switched to pramipexole ER. Relative to placebo at week 18, pramipexole ER 0.375-4.5 mg (of the salt) once daily significantly decreased the sum of the UPDRS parts II and III subtotal scores from baseline in two trials in patients with early or advanced Parkinson's disease, and also reduced the percentage of off-time during waking hours in patients with advanced disease. The efficacy of pramipexole ER was maintained after 33 weeks of treatment in the trials in patients with early or advanced Parkinson's disease. Pramipexole ER was generally well tolerated in patients with Parkinson's disease, with the rate of adverse events being generally similar to that with pramipexole IR.