Correction to: Afatinib in advanced NSCLC: a profile of its use.

[This corrects the article DOI: 10.1007/s40267-018-0482-6.].

Afatinib in advanced NSCLC: a profile of its use.

Afatinib [Giotrif® (EU); Gilotrif® (USA)] is an orally administered, irreversible inhibitor of the ErbB family of tyrosine kinases that provides an important first-line treatment option for advanced non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations (i.e. EGFRactMUT+), and an additional treatment option for squamous NSCLC that has progressed following first-line platinum-based chemotherapy. Relative to gefitinib in the first-line treatment of EGFRactMUT+ advanced lung adenocarcinoma, afatinib prolonged progression-free survival (PFS) and time to treatment failure (TTF), but not overall survival (OS). Afatinib also prolonged PFS, but not OS, versus cisplatin-based chemotherapy in this setting; however, afatinib improved OS versus chemotherapy in the subgroup of patients with deletions in exon 19. As a second-line treatment for advanced squamous NSCLC, afatinib prolonged PFS and OS compared with erlotinib, regardless of EGFR mutation status. Afatinib had a predictable and manageable tolerability profile.

Candesartan cilexetil: in children and adolescents aged 1 to <17 years with hypertension.

Candesartan cilexetil is the orally administered prodrug of candesartan, an angiotensin II subtype 1 receptor antagonist. The pharmacokinetics (area under the plasma concentration-time curve and maximum plasma concentration) of candesartan do not appear to be affected by age, sex, or weight, with a similar exposure observed in children aged 1 to <6 years or >6 years and adults. Therapy with candesartan cilexetil 0.05, 0.20, and 0.40 mg/kg/day for 4 weeks was effective in the treatment of hypertension in children aged 1 to <6 years, inducing significant dose-dependent reductions from baseline in sitting SBP (SSBP) [primary endpoint] and sitting DBP (SDBP) in the double-blind phase of a randomized, parallel-group, multinational, dose-ranging clinical study. The criteria for antihypertensive response (SBP and DBP values that were less than the 95th percentile) were met by 28-66% of patients. The beneficial antihypertensive effects of candesartan cilexetil therapy were sustained for up to 160 weeks. No significant difference from zero in the slope of the placebo-adjusted change in SSBP (primary endpoint) and SDBP was observed across the three candesartan cilexetil treatment groups (candesartan cilexetil 2, 8, or 16 mg/day in patients weighing <50 kg and candesartan cilexetil 4, 16, or 32 mg/day in patients weighing ≥50 kg) during the double-blind phase of a randomized, double-blind, parallel-group, placebo-controlled, multinational, dose-ranging study in children and adolescents aged 6 to <17 years. Nonetheless, candesartan cilexetil demonstrated significantly greater changes from baseline to the end of the double-blind phase than placebo in SSBP and SDBP, with a significantly higher proportion of patients receiving candesartan cilexetil meeting the criteria for antihypertensive response than those receiving placebo. Antihypertensive response rates were sustained for 52 weeks. Candesartan cilexetil therapy for up to 160 weeks was generally well tolerated in clinical studies in children and adolescents aged 1 to <17 years with hypertension.

Sorafenib: a review of its use in advanced hepatocellular carcinoma.

Sorafenib (Nexavar) is an orally active multikinase inhibitor that is approved in the EU for the treatment of hepatocellular carcinoma. Monotherapy with sorafenib prolongs overall survival and delays the time to progression in patients with advanced hepatocellular carcinoma who are not candidates for potentially curative treatment or transarterial chemoembolization. Sorafenib is generally well tolerated in patients with advanced hepatocellular carcinoma. Thus, sorafenib represents an important advance in the treatment of advanced hepatocellular carcinoma and is the new standard of care for this condition. The bi-aryl urea sorafenib is an oral multikinase inhibitor that inhibits cell surface tyrosine kinase receptors (e.g. vascular endothelial growth factor receptors and platelet-derived growth factor receptor-beta) and downstream intracellular serine/threonine kinases (e.g. Raf-1, wild-type B-Raf and mutant B-Raf); these kinases are involved in tumour cell proliferation and tumour angiogenesis. In vitro, dose-dependent inhibition of cell proliferation and induction of apoptosis was seen with sorafenib in human hepatocellular carcinoma cells lines. Sorafenib demonstrated dose-dependent antitumour activity in a murine xenograft model of human hepatocellular carcinoma. Steady-state plasma concentrations were reached within 7 days in patients with advanced, refractory solid tumours who received twice-daily oral sorafenib. Metabolism of sorafenib occurs primarily in the liver and is mediated via cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase 1A9. In advanced hepatocellular carcinoma, differences in sorafenib pharmacokinetics between Child-Pugh A and B patients were not considered clinically significant. Sorafenib may be associated with drug interactions. For example, sorafenib exposure was reduced by an average 37% with concomitant administration of the CYP3A4 inducer rifampicin (rifampin); sorafenib concentrations may also be decreased by other CYP3A4 inducers. Monotherapy with oral sorafenib 400 mg twice daily prolonged median overall survival and delayed the median time to progression in patients with advanced hepatocellular carcinoma, according to the results of two randomized, double-blind, placebo-controlled, multicentre, phase III trials (the SHARP trial and the Asia-Pacific trial). There was no significant difference between sorafenib and placebo recipients in the median time to symptomatic progression in either trial. The vast majority of patients included in these trials were Child-Pugh A. Combination therapy with sorafenib plus doxorubicin did not delay the median time to progression to a significant extent compared with doxorubicin alone in patients with advanced hepatocellular carcinoma, according to the results of a randomized, double-blind, phase II trial. However, the median durations of overall survival and progression-free survival were significantly longer in patients receiving sorafenib plus doxorubicin than in those receiving doxorubicin alone. Combination therapy with sorafenib plus tegafur/uracil or mitomycin also showed potential in advanced hepatocellular carcinoma, according to the results of noncomparative trials. Monotherapy with oral sorafenib was generally well tolerated in patients with advanced hepatocellular carcinoma, with a manageable adverse effect profile; diarrhoea and hand-foot skin reaction were consistently the most commonly occurring drug-related adverse events in clinical trials. In the SHARP trial, drug-related adverse events of any grade occurring in significantly more sorafenib than placebo recipients included diarrhoea, hand-foot skin reaction, anorexia, alopecia, weight loss, dry skin, abdominal pain, voice changes and 'other' dermatological events. A similar tolerability profile was seen in the Asia-Pacific trial. As expected given the addition of a chemotherapy agent, the adverse event profile in patients with advanced hepatocellular carcinoma who received combination therapy with sorafenib plus doxorubicin differed somewhat to that seen with sorafenib monotherapy in the SHARP trial. In patients receiving sorafenib plus doxorubicin, the most commonly occurring all-cause adverse events (all grades) included fatigue, neutropenia, diarrhoea, elevated bilirubin levels, abdominal pain, hand-foot skin reaction, left ventricular dysfunction, hypertension and febrile neutropenia.

Sapropterin: a review of its use in the treatment of primary hyperphenylalaninaemia.

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

Fesoterodine.

black triangle Fesoterodine is a muscarinic receptor antagonist that is rapidly and extensively converted to the active and more potent metabolite 5-hydroxymethyltolterodine. The drug is approved for once-daily oral administration in patients with overactive bladder syndrome (OAB). black triangle In two large, 12-week, randomized, double-blind, multicentre, phase III trials, oral fesoterodine 4 or 8 mg once daily improved the symptoms of OAB (frequency of micturition, urgency and urge incontinence) significantly more than placebo. black triangle Furthermore, significantly more patients receiving fesoterodine 4 or 8 mg once daily had a positive response to therapy than those receiving placebo, as determined by a treatment questionnaire. black triangle Health-related quality of life was improved to a significantly greater extent in patients with OAB who received fesoterodine 4 or 8 mg once daily than in those who received placebo in a post hoc analysis of pooled data from the phase III trials. black triangle Fesoterodine 4 or 8 mg once daily was generally well tolerated in patients with OAB; the most frequent adverse event was dry mouth, which was generally mild to moderate in severity.

Transdermal oxybutynin.

*Oxybutynin inhibits contraction of the detrusor muscle in the overactive bladder by binding to muscarinic M(3) receptors and blocking acetylcholinergic activation. *The transdermal oxybutynin system, applied twice weekly, delivers continuous oxybutynin over a 96-hour patch wear period. The transdermal route of administration avoids the extensive first-pass metabolism of oxybutynin to its active metabolite, N-desethyloxybutynin. *In two well designed trials in patients with overactive bladder, transdermal oxybutynin 3.9 mg/day decreased the number of incontinence episodes and increased average voided volume to a significantly greater extent than placebo. Urinary frequency was improved to a significantly greater extent with transdermal oxybutynin than with placebo in one trial but not the other. *There was no significant difference between transdermal oxybutynin and extended-release oral tolterodine for any of these endpoints. *Health-related quality-of-life improvements with transdermal oxybutynin were shown in patients with overactive bladder in the open-label MATRIX trial, as demonstrated by significant improvements in all domains of the King's Health Questionnaire. *Transdermal oxybutynin is generally well tolerated in patients with overactive bladder. The majority of patients who discontinued transdermal oxybutynin treatment in two pivotal trials did so because of application-site reactions. However, none discontinued treatment because of dry mouth.

Buprenorphine/naloxone: a review of its use in the treatment of opioid dependence.

Buprenorphine/naloxone (Suboxone) comprises the partial mu-opioid receptor agonist buprenorphine in combination with the opioid antagonist naloxone in a 4 : 1 ratio. When buprenorphine/naloxone is taken sublingually as prescribed, the naloxone exerts no clinically significant effect, leaving the opioid agonist effects of buprenorphine to predominate. However, when buprenorphine/naloxone is parenterally administered in patients physically dependent on full agonist opioids, the opioid antagonism of naloxone causes withdrawal effects, thus reducing the abuse potential of the drug combination. Buprenorphine/naloxone is an effective maintenance therapy for opioid dependence and has generally similar efficacy to methadone, although more data are needed. Less frequent dispensing of buprenorphine/naloxone (e.g. thrice weekly) does not appear to compromise efficacy and can improve patient satisfaction. Buprenorphine/naloxone is more effective than clonidine as a medically-supervised withdrawal therapy. Moreover, buprenorphine/naloxone is a generally well tolerated medically-supervised withdrawal and maintenance treatment. Thus, sublingual buprenorphine/naloxone is a valuable pharmacotherapy for the treatment of opioid dependence.

Ferric carboxymaltose: a review of its use in iron-deficiency anaemia.

Ferric carboxymaltose (Ferinject(R)), a novel iron complex that consists of a ferric hydroxide core stabilized by a carbohydrate shell, allows for controlled delivery of iron to target tissues. Administered intravenously, it is effective in the treatment of iron-deficiency anaemia, delivering a replenishment dose of up to 1000 mg of iron during a minimum administration time of

Ropinirole prolonged release: in advanced Parkinson's disease.

Ropinirole prolonged release is a non-ergoline dopamine receptor agonist that is indicated for the treatment of Parkinson's disease. * Once-daily ropinirole prolonged release and three-times-daily ropinirole immediate release have similar exposure over 24 hours. The prolonged-release formulation is associated with fewer fluctuations in plasma ropinirole concentrations. * Two well designed, placebo- or active comparator-controlled trials examined the efficacy of ropinirole prolonged release in patients with advanced Parkinson's disease suboptimally controlled by levodopa. In the placebo-controlled trial, 24 weeks' therapy with ropinirole prolonged release 6-24 mg once daily reduced hours of 'off' time (primary endpoint) to a significantly greater extent than placebo. In the active comparator-controlled trial, significantly more ropinirole prolonged-release recipients than ropinirole immediate-release recipients maintained a >or=20% reduction from baseline in 'off' time at week 24 (primary endpoint). *Ropinirole prolonged release 6-24 mg once daily was generally well tolerated in patients with advanced Parkinson's disease; adverse events were generally typical of non-ergoline dopamine receptor agonists.

Bosentan: a review of its use in the management of mildly symptomatic pulmonary arterial hypertension.

Bosentan (Tracleer) is an orally administered dual endothelin-1 (ET-1) receptor antagonist approved for use in patients with WHO class II (mildly symptomatic) pulmonary arterial hypertension (PAH). Oral bosentan therapy was beneficial and generally well tolerated in patients with mildly symptomatic PAH. In a well designed, placebo-controlled trial in adolescents and adults with mildly symptomatic PAH, pulmonary vascular resistance was significantly reduced with bosentan relative to placebo, but the 6-minute walk distance did not increase significantly. Similarly, pediatric patients (most of whom had mildly symptomatic PAH) in a small uncontrolled trial experienced some improvement in hemodynamic variables with bosentan, but did not experience a significant increase in exercise capacity. Adverse events associated with bosentan were consistent with those seen in other indications, with major concerns being the potential for teratogenicity and hepatotoxicity, for which regular liver function monitoring is recommended. Overall, considering the progressive nature of PAH, bosentan extends the treatment options available to patients with mildly symptomatic PAH.

Fenofibric acid: in combination therapy in the treatment of mixed dyslipidemia.

Fenofibric acid activates peroxisome proliferator-activated receptor alpha to modify fatty acid and lipid metabolism. Fenofibric acid is the first member of the fibric acid derivatives (fibrates) class approved for use as combination therapy with HMG-CoA reductase inhibitors (statins). In three randomized, double-blind, multicenter, phase III trials in adult patients with mixed dyslipidemia, up to 12 weeks' treatment with once-daily fenofibric acid 135 mg plus a low- or moderate-dose statin (atorvastatin 20 or 40 mg, rosuvastatin 10 or 20 mg, or simvastatin 20 or 40 mg) improved high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels to a significantly greater extent than statin monotherapy, and improved low-density lipoprotein cholesterol (LDL-C) levels to a significantly greater extent than fenofibric acid monotherapy. In a 52-week, open-label, multicenter, extension study, HDL-C, TG, and LDL-C levels continued to improve, or were maintained, during combination therapy with once-daily fenofibric acid 135 mg plus a moderate-dose statin (atorvastatin 40 mg, rosuvastatin 20 mg, or simvastatin 40 mg). Once-daily fenofibric acid 135 mg plus a statin was generally as well tolerated as monotherapy with fenofibric acid 135 mg/day or the corresponding statin dosage in the three phase III trials in patients with mixed dyslipidemia. The incidence of adverse events was similar between the combination therapy group and both monotherapy groups. In the extension trial, once-daily fenofibric acid 135 mg plus a moderate-dose statin (atorvastatin 40 mg, rosuvastatin 20 mg, or simvastatin 40 mg) for up to 52 weeks was generally well tolerated.

Clevidipine: a review of its use in the management of acute hypertension.

UNLABELLED: Clevidipine (Cleviprex), a late-generation dihydropyridine calcium channel antagonist available as a lipid emulsion for intravenous infusion, is approved in the US for the reduction of blood pressure (BP) when oral therapy is not feasible or desirable. Intravenous clevidipine is effective in the treatment of both acute preoperative and postoperative hypertension in adult cardiac surgery patients, and with a rapid onset and short duration of action the drug can be easily titrated for predictable BP control. Moreover, in terms of controlling acutely elevated BP in this patient population, clevidipine is more effective than sodium nitroprusside or nitroglycerin in the perioperative setting, and has an efficacy no different from that of nicardipine in the postoperative setting. Data from a noncomparative study also indicate that intravenous clevidipine is effective in the treatment of adults with acute severe hypertension. Clevidipine is generally well tolerated in these patient populations, and has a safety profile generally similar to that of sodium nitroprusside, nitroglycerin, or nicardipine in cardiac surgery patients. Additional comparative data are required to definitively position clevidipine with respect to other agents, particularly in patients with acute severe hypertension, and there is potential for its use to be investigated in other appropriate clinical settings requiring acute BP control. In the meantime, the clinical data currently available indicate that intravenous clevidipine has potential as an option for the treatment of acute perioperative hypertension during cardiac surgery and hypertensive emergencies in adults. PHARMACOLOGIC PROPERTIES: Clevidipine inhibits L-type calcium channels in a voltage-dependent manner and exhibits a high degree of vascular selectivity in vitro. The BP-lowering effects of the drug are rapid and dose dependent, and are achieved by decreasing systemic vascular resistance without affecting venous capacitance vessels or cardiac filling pressures, with offset of effect within 5-15 minutes. Clevidipine had greater effects on arterial vasodilation and lesser effects on venodilation compared with sodium nitroprusside in hypertensive post-coronary artery bypass graft (post-CABG) patients. Clevidipine was not associated with reflex increases in heart rate in normotensive post-CABG patients or post-cardiac surgery patients, although elevations in heart rate were seen in healthy volunteers, cardiac surgery patients who received the drug preoperatively, and patients with acute severe hypertension. Data from animal studies suggest that clevidipine may protect against myocardial and renal injury caused by ischemia and/or reperfusion. Steady-state concentrations of clevidipine in arterial and venous blood were rapidly attained (within approximately 2 or approximately 10 minutes) in healthy volunteers receiving infusions of 0.91 or 3.2 mug/kg/min. The relationship between intravenous clevidipine infusion dose and steady-state blood concentration was linear over wide dose ranges in patients with mild to moderate hypertension and in healthy volunteers. Clevidipine is highly plasma protein bound and rapidly distributed, and has a low volume of distribution at steady state. It is rapidly metabolized via hydrolysis by esterases in the blood and extravascular tissues to a major metabolite that is inactive as an antihypertensive. Concentrations of clevidipine in the blood fall rapidly in a multiphasic fashion after termination of infusion. The initial phase is rapid (half-life of approximately 1 minute) and accounts for the majority of clevidipine exposure after an intravenous bolus dose and for 85-90% of its elimination; the terminal elimination half-life is approximately 15 minutes. Clevidipine metabolites are excreted mainly via the urine and feces and the drug has a high mean total blood clearance. The clearance of clevidipine was significantly lower during hypothermic cardiopulmonary bypass than before the procedure. THERAPEUTIC EFFICACY: Intravenous clevidipine, administered by infusion, was effective in the treatment of both acute preoperative and postoperative hypertension in adult cardiac surgery patients in two large, well designed, phase III trials. Few clevidipine recipients had evidence of treatment failure, whereas most placebo recipients failed treatment (primary endpoint) and the between-group difference was significant. Clevidipine produced rapid reductions of >or=15% from baseline in systolic BP (SBP) in or=18 hours. TOLERABILITY: Intravenous clevidipine was safe and generally well tolerated in cardiac surgery patients with acute hypertension in large, randomized, clinical trials. Clevidipine was as safe as nitroglycerin, sodium nitroprusside, or nicardipine with regard to the incidence of myocardial infarction, stroke, or renal dysfunction (primary safety endpoints) in patients with perioperative or postoperative hypertension. Moreover, clevidipine recipients had an incidence of death (primary safety endpoint) not significantly different to that in nitroglycerin or nicardipine recipients and significantly lower than in sodium nitroprusside recipients, although this significant between-group difference was not confirmed by the findings of multiple logistic regression analysis after accounting for other factors. Clevidipine demonstrated a tolerability profile similar to that of placebo in patients with preoperative or postoperative hypertension, with the nature and incidence of treatment-emergent adverse events generally being similar between treatment groups. The most common treatment-emergent adverse events associated with clevidipine in the active comparator-controlled trials included atrial fibrillation and sinus tachycardia, although the incidence of such events did not differ from that seen with nitroglycerin, sodium nitroprusside, or nicardipine. Intravenous clevidipine was also generally well tolerated in patients with acute severe hypertension, regardless of infusion duration, in a large, noncomparative study. Most adverse events associated with clevidipine were mild or moderate in severity and considered unrelated to study drug, with the most commonly reported being headache, nausea, chest discomfort, and vomiting.

Pneumococcal polysaccharide protein D-conjugate vaccine (Synflorix; PHiD-CV).

The pneumococcal polysaccharide protein D-conjugate vaccine (PHiD-CV; Synflorix) contains ten capsular polysaccharide serotypes from the bacterium Streptococcus pneumoniae, eight of which are conjugated to a nonlipidated cell-surface liporotein (protein D) of non-typeable Haemophilus influenzae (NTHi) and two of which are conjugated to either tetanus or diphtheria toxoid. In a three-dose primary vaccination schedule in infants aged <6 months, PHiD-CV elicited high immune responses against all pneumococcal serotypes contained in the vaccine and was noninferior to an approved 7-valent pneumococcal conjugate vaccine (7vCRM) for eight of the ten serotypes (five of the seven common to both vaccines). Moreover, functional antibodies were elicited against all vaccine serotypes in an opsonophagocytic activity (OPA) assay. A fourth booster dose of PHiD-CV during the second year of life elicited an anamnestic response against all ten pneumococcal serotypes, as determined by both antibody concentrations and OPA titers. There were no clinically relevant changes in the immunogenicity of PHiD-CV when coadministered with meningococcal serogroup C conjugate or pentavalent whole cell pertussis combination vaccines, and polio vaccines using two different primary vaccination schedules. 11Pn-PD, an 11-valent prototype of PHiD-CV, demonstrated protection against episodes of acute otitis media (AOM) caused by S. pneumoniae and NTHi in infants aged <27 months. The first occurrence of an episode of AOM caused by pneumococcal vaccine serotypes was reduced by 52.6% in 11Pn-PD vaccinees compared with recipients of a control vaccine (primary endpoint). The tolerability profile of PHiD-CV was generally similar to that of 7vCRM.

Atomoxetine: a review of its use in attention-deficit hyperactivity disorder in children and adolescents.

Atomoxetine (Strattera(R)) is a selective norepinephrine (noradrenaline) reuptake inhibitor that is not classified as a stimulant, and is indicated for use in patients with attention-deficit hyperactivity disorder (ADHD). Atomoxetine is effective and generally well tolerated. It is significantly more effective than placebo and standard current therapy and does not differ significantly from or is noninferior to immediate-release methylphenidate; however, it is significantly less effective than the extended-release methylphenidate formulation OROS(R) methylphenidate (hereafter referred to as osmotically released methylphenidate) and extended-release mixed amfetamine salts. Atomoxetine can be administered either as a single daily dose or split into two evenly divided doses, has a negligible risk of abuse or misuse, and is not a controlled substance in the US. Atomoxetine is particularly useful for patients at risk of substance abuse, as well as those who have co-morbid anxiety or tics, or who do not wish to take a controlled substance. Thus, atomoxetine is a useful option in the treatment of ADHD in children and adolescents. The mechanism of action of atomoxetine is unclear, but is thought to be related to its selective inhibition of presynaptic norepinephrine reuptake in the prefrontal cortex. Atomoxetine has a high affinity and selectivity for norepinephrine transporters, but little or no affinity for various neurotransmitter receptors. Atomoxetine has a demonstrated ability to selectively inhibit norepinephrine uptake in humans and animals, and studies have shown that it preferentially binds to areas of known high distribution of noradrenergic neurons, such as the fronto-cortical subsystem. Atomoxetine was generally associated with statistically, but not clinically, significant increases in both heart rate and blood pressure in pediatric patients with ADHD. While there was an initial loss in expected height and weight among atomoxetine recipients, this eventually returned to normal in the longer term. Data suggest that atomoxetine is unlikely to have any abuse potential. Atomoxetine appeared less likely than methylphenidate to exacerbate disordered sleep in pediatric patients with ADHD. Atomoxetine is rapidly absorbed, and demonstrates dose-proportional increases in plasma exposure. It undergoes extensive biotransformation, which is affected by poor metabolism by cytochrome P450 (CYP) 2D6 in a small percentage of the population; these patients have greater exposure to and slower elimination of atomoxetine than extensive metabolizers. Patients with hepatic insufficiency show an increase in atomoxetine exposure. CYP2D6 inhibitors, such as paroxetine, are associated with changes in atomoxetine pharmacokinetics similar to those observed among poor CYP2D6 metabolizers. Once- or twice-daily atomoxetine was effective in the short-term treatment of ADHD in children and adolescents, as observed in several well designed placebo-controlled trials. Atomoxetine also demonstrated efficacy in the longer term treatment of these patients. A single morning dose was shown to be effective into the evening, and discontinuation of atomoxetine was not associated with symptom rebound. Atomoxetine efficacy did not appear to differ between children and adolescents. Stimulant-naive patients also responded well to atomoxetine treatment. Atomoxetine did not differ significantly from or was noninferior to immediate-release methylphenidate in children and adolescents with ADHD with regard to efficacy, and was significantly more effective than standard current therapy (any combination of medicines [excluding atomoxetine] and/or behavioral counseling, or no treatment). However, atomoxetine was significantly less effective than osmotically released methylphenidate and extended-release mixed amfetamine salts. The efficacy of atomoxetine did not appear to be affected by the presence of co-morbid disorders, and symptoms of the co-morbid disorders were not affected or were improved by atomoxetine administration. Health-related quality of life (HR-QOL) appeared to be positively affected by atomoxetine in both short- and long-term studies; atomoxetine also improved HR-QOL to a greater extent than standard current therapy. Atomoxetine was generally well tolerated in children and adolescents with ADHD. Common adverse events included headache, abdominal pain, decreased appetite, vomiting, somnolence, and nausea. The majority of adverse events were mild or moderate; there was a very low incidence of serious adverse events. Few patients discontinued atomoxetine treatment because of adverse events. Atomoxetine discontinuation appeared to be well tolerated, with a low incidence of discontinuation-emergent adverse events. Atomoxetine appeared better tolerated among extensive CYP2D6 metabolizers than among poor metabolizers. Slight differences were evident in the adverse event profiles of atomoxetine and stimulants, both immediate- and extended-release. Somnolence appeared more common among atomoxetine recipients and insomnia appeared more common among stimulant recipients. A black-box warning for suicidal ideation has been published in the US prescribing information, based on findings from a meta-analysis showing that atomoxetine is associated with a significantly higher incidence of suicidal ideation than placebo. Rarely, atomoxetine may also be associated with serious liver injury; postmarketing data show that three patients have had liver-related adverse events deemed probably related to atomoxetine treatment. Treatment algorithms involving the initial use of atomoxetine appear cost effective versus algorithms involving initial methylphenidate (immediate- or extended-release), dexamfetamine, tricyclic antidepressants, or no treatment in stimulant-naive, -failed, and -contraindicated children and adolescents with ADHD. The incremental cost per quality-adjusted life-year is below commonly accepted cost-effectiveness thresholds, as shown in several Markov model analyses conducted from the perspective of various European countries, with a time horizon of 1 year.

Micafungin: a review of its use in the prophylaxis and treatment of invasive Candida infections in pediatric patients.

Intravenous micafungin (Mycamine; Funguard) is an echinocandin indicated in Japan and the EU for the treatment of pediatric patients (including neonates) with invasive candidiasis and as prophylaxis against Candida infection in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). In the EU, micafungin is also indicated in pediatric patients who are expected to have neutropenia for >/=10 days. In Japan, children may also receive micafungin for the treatment of, or as prophylaxis against, invasive Aspergillus infection. Micafungin is not currently approved for use in pediatric patients in the US. Micafungin has very good antifungal activity against a wide range of Candida spp. in vitro. It has a favorable pharmacokinetic profile allowing for once-daily administration, has few drug-drug interactions, and reports of resistance are rare. The results of pediatric substudies indicate that intravenous micafungin is effective in a majority of patients for the treatment of candidemia and other types of invasive candidiasis, and provides effective prophylaxis against invasive fungal infections in pediatric patients undergoing HSCT. The tolerability profile of micafungin in pediatric patients was generally acceptable. In the EU, micafungin is indicated for use when other antifungal medications are not appropriate. Therefore, micafungin provides an alternative to other antifungal agents used in the management of candidemia and invasive candidiasis in pediatric patients, or as prophylaxis against fungal infections in pediatric patients undergoing HSCT.

Ranolazine: a review of its use in chronic stable angina pectoris.

Extended-release ranolazine (ranolazine ER) [Ranexa] is a piperazine derivative with a novel mechanism of action that was recently approved in the EU for use as add-on therapy in patients with stable angina pectoris. Ranolazine ER achieves its antianginal effect without affecting heart rate or blood pressure (BP) to a clinically significant extent. Results of well designed, placebo-controlled, short-term studies demonstrate that add-on therapy with ranolazine ER in patients with chronic stable angina improves exercise performance, and reduces anginal frequency and nitroglycerin use. Although longer-term therapy with ranolazine ER did not reduce the incidence of major cardiovascular events in patients with non-ST-elevation acute coronary syndromes, it did reduce the incidence of recurrent ischaemia. Ranolazine ER is a generally well tolerated antianginal agent. Although it is associated with modest dose-related increases in the corrected QT (QTc) interval, ranolazine ER does not appear to be associated with an excess of arrhythmias. Thus, ranolazine ER is a useful new option for patients with chronic stable angina whose symptoms are not controlled with first-line antianginal therapy or who do not tolerate first-line antianginal agents.

Parnaparin : a review of its use in the management of venous thromboembolism, chronic venous disease and other vascular disorders.

Parnaparin (Fluxum) is a low molecular weight heparin (LMWH) that is effective and generally well tolerated in the prevention of venous thrombosis, and in the treatment of chronic venous disease and venous and arterial thrombosis. Overall, the efficacy of parnaparin is at least as good as that of unfractionated heparin (UFH), but recent data indicate that parnaparin is more effective in preventing a triple composite endpoint of death, acute myocardial infarction (MI) and myocardial revascularisation in patients with unstable angina or acute ST-segment elevation myocardial infarction (STEMI). As with other LMWHs, parnaparin has a more convenient, once-daily, subcutaneous administration regimen and better local tolerability than UFH. Very little evidence comparing LMWHs is available but, because of similarities between these agents, very large studies would be needed to show significant differences. Meanwhile, data indicate that parnaparin is a useful option in the range of available LMWHs.

Dalbavancin.

Dalbavancin is a semisynthetic glycopeptide antibacterial agent that is active against Gram-positive bacteria associated with complicated skin and skin structure infections (cSSSIs). It is administered as a two-dose regimen intravenously infused over 30 minutes once weekly. The efficacy of dalbavancin (1000 mg on day 1 and 500 mg on day 8) has been examined in two randomized controlled trials in adults with cSSSIs. In each study, the primary efficacy measure was clinical success at the test-of-cure or follow-up visit in clinically evaluable patients. In a randomized, controlled, double-blind, multinational, phase III trial, dalbavancin was noninferior to linezolid, with clinical success rates of 88.9% and 91.2%. In a randomized, open-label, multicentre, phase II trial, clinical success rates were 94% with dalbavancin and 76% with comparator antibacterials. Dalbavancin was generally well tolerated by adult patients with cSSSIs, with most adverse events being of mild or moderate severity.

Sorafenib: in hepatocellular carcinoma.

Sorafenib is an orally active multikinase inhibitor with anti-tumour activity. It was recently approved in the US and the EU for the treatment of patients with hepatocellular carcinoma. Oral sorafenib 400 mg twice daily significantly improved survival in patients with advanced hepatocellular carcinoma in the randomized, double-blind, multicentre, phase III SHARP trial (n = 602); the median duration of survival was 10.7 months with sorafenib and 7.9 months with placebo. In addition, the median time to progression was significantly longer in patients receiving sorafenib than in those receiving placebo (5.5 vs 2.8 months). Combination therapy with oral sorafenib 400 mg twice daily and intravenous doxorubicin has potential in the treatment of patients with advanced hepatocellular carcinoma, according to the results of a randomized, double-blind, phase II study (n = 96). Although the addition of sorafenib to doxorubicin did not significantly delay the time to progression, the median durations of overall survival and progression-free survival were significantly longer with sorafenib plus doxorubicin than with doxorubicin alone. Monotherapy with oral sorafenib 400 mg twice daily was generally well tolerated in patients with advanced hepatocellular carcinoma, with a manageable adverse event profile.