Low-dose doxepin: in the treatment of insomnia.

Doxepin binds with high specificity and affinity to the histamine H(1) receptor compared with other receptors. Therefore, at low doses, doxepin selectively antagonises H(1) receptors, which is believed to promote the initiation and maintenance of sleep. In three large, well designed, phase III trials in adult or elderly patients with chronic primary insomnia, oral, low-dose doxepin 3 or 6 mg once daily improved wake time after sleep onset, total sleep time and sleep efficiency to a significantly greater extent than placebo. Significant between-group differences in polysomnographic sleep recordings that favoured low-dose doxepin were evident after a single administration of the drug. Other efficacy measures, including patient-reported sleep quality, also favoured low-dose doxepin over placebo. Symptom control was maintained for up to 12 weeks of low-dose doxepin administration and there was no evidence of physical dependence or worsening insomnia after doxepin withdrawal. Oral, low-dose doxepin 6 mg was also significantly more effective than placebo in a large, well designed trial modelling transient insomnia in healthy adults, according to polysomnographic recordings (e.g. in latency to persistent sleep). Oral, low-dose doxepin was generally well tolerated in clinical trials.

Bevacizumab plus platinum-based chemotherapy: in advanced non-small cell lung cancer.

black triangle Bevacizumab is a recombinant, humanized vascular endothelial growth factor (VEGF) monoclonal antibody that inhibits tumor growth and tumor metastases. VEGF stimulates angiogenesis in tumors, is involved in early metastatic processes, and is overexpressed in non-small cell lung cancer (NSCLC). black triangle The addition of bevacizumab to standard chemotherapy significantly delayed disease progression in two large, randomized, phase III trials in chemotherapy-naive patients with advanced, nonsquamous NSCLC. In the open-label E4599 trial, median overall survival duration was significantly extended by 2 months and median progression-free survival was significantly increased by 1.7 months when intravenous bevacizumab 15 mg/kg once every 3 weeks was added to first-line carboplatin/paclitaxel therapy compared with carboplatin/paclitaxel alone. black triangle In the double-blind AVAiL trial, median progression-free survival was significantly increased (by 0.6 and 0.4 months) by the addition of intravenous bevacizumab 7.5 or 15 mg/kg once every 3 weeks to first-line cisplatin/gemcitabine therapy compared with placebo plus cisplatin/gemcitabine. However, median overall survival duration was not significantly improved (13.6 and 13.4 months vs 13.1 months). black triangle Response rates in the E4599 and AVAiL trials were 30-35% in patients receiving bevacizumab plus platinum-based chemotherapy compared with 15% and 20% without bevacizumab. black triangle The safety and tolerability profile of bevacizumab-containing treatment regimens in patients with advanced NSCLC was generally manageable in the E4599 and AVAiL trials, and in two large, ongoing, trials (the open-label SAiL and the observational ARIES studies).

Plerixafor: in patients with non-Hodgkin's lymphoma or multiple myeloma.

*The bicyclam plerixafor mobilizes haematopoietic stem cells (HSCs) from the bone marrow into the peripheral blood circulation and augments the effects of granulocyte colony-stimulating factor (G-CSF). *More patients requiring autologous HSC transplantation for non-Hodgkin's lymphoma or multiple myeloma in first or second remission achieved goal increases in mobilized CD34+ cells after subcutaneous plerixafor 240 microg/kg/day for up to four apheresis days in conjunction with a G-CSF treatment regimen than after placebo plus G-CSF. *Sufficient CD34+ cells for transplantation were collected earlier for recipients of plerixafor plus G-CSF (often after one apheresis) than for patients receiving placebo plus G-CSF. *Time to engraftment and durability of grafts after 12 months were similar for both plerixafor plus G-CSF and placebo plus G-CSF. *In a compassionate-use trial in patients with non-Hodgkin's lymphoma, multiple myeloma or Hodgkin's disease in whom prior mobilization attempts were unable to stimulate sufficient cells, therapy with the plerixafor/G-CSF combination regimen was successful in > or = 60% of patients. *Plerixafor appears to be generally well tolerated; most adverse effects in clinical trials were mild and transient.

Sodium picosulfate/magnesium citrate: a review of its use as a colorectal cleanser.

Oral sodium picosulfate/magnesium citrate (CitraFleet; Picolax), consisting of sodium picosulfate (a stimulant laxative) and magnesium citrate (an osmotic laxative), is approved for use in adults (CitraFleet; Picolax) and/or adolescents and children (Picolax) as a colorectal cleansing agent prior to any diagnostic procedure (e.g. colonoscopy or x-ray examination) requiring a clean bowel and/or surgery. It is dispensed in powder form (sodium picosulfate 0.01 g, magnesium oxide 3.5 g, citric acid 12.0 g per sachet), with the magnesium oxide and citric acid components forming magnesium citrate when the powder is dissolved in water. In adult patients, two sachets of sodium picosulfate/magnesium citrate was at least as effective and well tolerated as oral magnesium citrate 17.7 or 35.4 g, or oral polyethylene glycol 236 g in adult patients undergoing a double-contrast barium enema procedure in three large, randomized, comparative clinical studies. In contrast, sodium picosulfate/magnesium citrate was less effective than a sodium phosphate enema preparation in two studies in patients undergoing flexible sigmoidoscopy. A similar number of patients receiving two sachets of sodium picosulfate/magnesium citrate or two 45 mL doses of oral sodium phosphate the day before a double-contrast barium enema procedure achieved satisfactory barium coating and none/minimal faecal residue in one study. However, the data from three of these studies should be interpreted with caution because the administrative regimens used differed from that recommended. Sodium picosulfate/magnesium citrate is also an effective and generally well tolerated colorectal cleansing agent in children and adolescents; the preparation was more effective than oral bisacodyl 0.01 or 0.02 g plus a sodium phosphate enema preparation in this population. Further research is thus required to accurately position sodium picosulfate/magnesium citrate and fully establish its efficacy and tolerability prior to various exploratory or surgical procedures. Nevertheless, oral sodium picosulfate/magnesium citrate provides a useful option in the preparation of the colon and rectum in adults, adolescents and children undergoing any diagnostic procedure (e.g. colonoscopy or x-ray examination) requiring a clean bowel and/or surgery. Oral sodium picosulfate/magnesium citrate acts locally in the colon as both a stimulant laxative, by increasing the frequency and the force of peristalsis (sodium picosulfate component), and an osmotic laxative, by retaining fluids in the colon (magnesium citrate component), to clear the colon and rectum of faecal contents. It is not absorbed in any detectable quantities. Sodium picosulfate is a prodrug: it is hydrolyzed by bacteria in the colon to the active metabolite 4,4'-dihydroxydiphenyl-(2-pyridyl)methane. Sodium picosulfate/magnesium citrate may be associated with a dehydrating effect, as evidenced by a reduction in bodyweight and increased haemoglobin levels; some at-risk patients may experience postural hypotension and older patients may require additional electrolytes. In three large (n >100), randomized, single-blind clinical studies, two sachets of oral sodium picosulfate/magnesium citrate was at least as effective as oral magnesium citrate 17.7 or 35.4 g, or oral polyethylene glycol 236 g as a colorectal cleansing agent in adult patients undergoing a double-contrast barium enema procedure. In contrast, sodium picosulfate/magnesium citrate was less effective than a sodium phosphate enema preparation in two studies in patients undergoing flexible sigmoidoscopy. A similar number of patients receiving two sachets of sodium picosulfate/magnesium citrate or two 45 mL doses of oral sodium phosphate the day before a double-contrast barium enema procedure achieved satisfactory barium coating and none/minimal faecal residue in one study. However, the data from three of these studies should be interpreted with caution because the administrative regimens used differed from that recommended. In children and adolescents, sodium picosulfate/magnesium citrate was significantly more effective as a colorectal cleansing agent than oral bisacodyl 0.01 or 0.02 g plus a sodium phosphate enema preparation in a randomized, single-blind study; dosages were adjusted for age in this study. Oral sodium picosulfate/magnesium citrate is generally well tolerated in adult patients undergoing various investigational colorectal procedures. Adverse events were generally mild to moderate in intensity and mainly gastrointestinal in nature (e.g. abdominal cramps/pain, nausea); other common treatment-emergent adverse events included disturbance of daily activity, headache and sleep disturbance. This combination is at least as well tolerated as oral sodium phosphate or oral polyethylene glycol, with moderate/severe nausea and vomiting occurring less frequently in sodium picosulfate/magnesium citrate recipients than in those receiving oral sodium phosphate, and abdominal bloating/pain and nausea developing less often with sodium picosulfate/magnesium citrate than polyethylene glycol therapy. The incidence of abdominal pain and sleep disturbance in sodium picosulfate/magnesium citrate versus oral magnesium citrate recipients was similar in one study, but significantly lower with sodium picosulfate/magnesium citrate in another. While the incidence of most adverse events was similar in recipients of sodium picosulfate/magnesium citrate and a sodium phosphate enema preparation, more patients receiving sodium picosulfate/magnesium citrate reported moderate/severe flatulence, incontinence and sleep disturbance, and more patients receiving the enema preparation reported rectal soreness. The tolerability profile of sodium picosulfate/magnesium citrate in patients aged >70 years is reportedly similar to that in patients aged <70 years. Abdominal pain also occurred less frequently with sodium picosulfate/magnesium citrate than with oral bisacodyl plus a sodium phosphate enema preparation in children and adolescents.

Spotlight on fondaparinux sodium in acute coronary syndromes.

Fondaparinux sodium (Arixtra) is a synthetic, sulfated pentasaccharide, selective factor Xa inhibitor that is indicated in Europe for preventing thrombus formation in patients with acute coronary syndromes (ACS; the focus of this review), including those with ST-segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), or unstable angina. The large (n = 20,078), well designed OASIS-5 trial showed that subcutaneous fondaparinux 2.5 mg/day for < or =8 days was noninferior to subcutaneous enoxaparin 1 mg/kg twice daily (once daily in those with renal dysfunction) in reducing death or ischemic events at 9 days and the efficacy was maintained for up to 6 months (study end) in patients with unstable angina or NSTEMI. During this time, major bleeding occurred in fewer fondaparinux than enoxaparin recipients, resulting in a benefit : risk balance favoring fondaparinux. The incidence of death or reinfarction at 30 days was significantly lower in recipients of subcutaneous fondaparinux 2.5 mg/day than in those who received usual care (including unfractionated heparin treatment as indicated) in patients with STEMI in the large (n > 12,000) OASIS-6 trial. There were no differences in the incidence of major bleeding between these groups, resulting in a benefit : risk balance favoring fondaparinux. The specificity and selectivity of fondaparinux, combined with its long half-life and 100% bioavailability, allows once-daily anticoagulation without the need for monitoring activated clotting time. Subcutaneous fondaparinux was noninferior to enoxaparin treatment in patients with unstable angina or NSTEMI, and was more effective than usual care in those with STEMI. Fondaparinux has a favorable tolerability profile, particularly with regard to the risk of major bleeding, and limited data suggest that it is more cost effective than enoxaparin in the short term. Thus, overall, clinical evidence suggests that fondaparinux has a valuable place in the treatment of patients with ACS.

Sucrose-formulated octocog alfa: a review of its use in patients with haemophilia A.

Sucrose-formulated octocog alfa (Kogenate Bayer, Kogenate FS, Helixate FS, Helixate nexgen) is a full-length recombinant human coagulation factor VIII (FVIII) product that is purified and formulated without the addition of human serum albumin and is stabilized with sucrose. The purification process of this formulation includes a solvent/detergent viral inactivation step. Sucrose-formulated octocog alfa is approved in the EU and US for the treatment of bleeding in patients with haemophilia A (congenital FVIII deficiency). Additionally, it is approved in the EU for the prophylaxis of bleeding in patients with haemophilia A and as a continuous infusion treatment in patients undergoing major surgery. Sucrose-formulated octocog alfa is effective and well tolerated as a FVIII replacement therapy in patients with haemophilia A, including those with severe disease undergoing major surgery. The therapeutic profile of this sucrose-formulated product cannot be compared with that of other octocog alfa or moroctocog alfa products because of a lack of head-to-head comparative studies. Pathogen transmission has not been reported with use of sucrose-formulated octocog alfa. Available data indicate that sucrose-formulated octocog alfa is an appropriate alternative to other recombinant FVIII products for the treatment and prophylaxis of bleeding episodes in adults and children with haemophilia A.

Ciclesonide nasal spray: in allergic rhinitis.

Ciclesonide nasal spray delivers the corticosteroid ciclesonide as a hypotonic spray via a metered-dose manual pump. Systemic exposure to ciclesonide and its active metabolite desisobutyryl-ciclesonide is low after intranasal administration. High protein binding (approximately 99%) and rapid first-pass clearance further reduce systemic exposure to the drug. In well designed trials, intranasal ciclesonide 200 microg once daily for 2-4 weeks was more effective than placebo in terms of improving nasal symptoms in adolescents and adults with moderate to severe seasonal allergic rhinitis. Quality of life measures were statistically significantly improved in ciclesonide relative to placebo recipients during the first 2 weeks of therapy. Similarly, in adolescents and adults with moderately severe perennial allergic rhinitis, ciclesonide 200 microg once daily was more effective than placebo in terms of reducing nasal symptoms in well designed trials of 6 weeks' and 1 year's duration. Improvements relative to placebo in quality of life measures were not considered clinically relevant. Ciclesonide nasal spray was generally well tolerated in these clinical trials; most adverse events were mild to moderate in intensity.

Fondaparinux sodium: a review of its use in the management of acute coronary syndromes.

Fondaparinux sodium (Arixtra) is a synthetic, sulfated pentasaccharide, selective factor Xa inhibitor that is indicated in Europe for preventing thrombus formation in patients with acute coronary syndromes (ACS; the focus of this review), including those with ST-segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), or unstable angina.The large (n = 20,078), well designed OASIS-5 trial showed that subcutaneous fondaparinux 2.5 mg/day for 12,000) OASIS-6 trial. There were no differences in the incidence of major bleeding between these groups, resulting in a benefit : risk balance favoring fondaparinux. The specificity and selectivity of fondaparinux, combined with its long half-life and 100% bioavailability, allows once-daily anticoagulation without the need for monitoring activated clotting time. Subcutaneous fondaparinux was noninferior to enoxaparin treatment in patients with unstable angina or NSTEMI, and was more effective than usual care in those with STEMI. Fondaparinux has a favorable tolerability profile, particularly with regard to the risk of major bleeding, and limited data suggest that it is more cost effective than enoxaparin in the short term. Thus, overall, clinical evidence suggests that fondaparinux has a valuable place in the treatment of patients with ACS.

Continuous-use ethinylestradiol/levonorgestrel 20microg/90microg: as an oral contraceptive.

The continuous-use combination oral contraceptive ethinylestradiol/levonorgestrel 20microg/90microg suppresses gonadotropins, and subsequently ovulation and endometrial thickening, and suppresses breakthrough bleeding. Amenorrhoea and absence of breakthrough bleeding increase in incidence with extended administration. The pregnancy rate attributable to method failure in a large noncomparative trial of healthy, sexually active (aged 18-49 years) women during treatment with ethinylestradiol/levonorgestrel 20microg/90microg for 12 months was 15 per 2134 women (adjusted Pearl Index 1.26 per 100 women-years of use). There were no differences in pregnancy rates over 12 months between continuous-use ethinylestradiol/levonorgestrel 20microg/90microg and cyclical ethinylestradiol/levonorgestrel 20microg/100microg in a smaller, randomised, nonblind trial. Adverse menstrual cycle-related symptoms were significantly improved with administration of continuous-use ethinylestradiol/levonorgestrel 20microg/90microg in a noncomparative trial. In small trials, hormonal and ultrasound changes indicative of reinstated ovulation occurred within a month of discontinuation of the drug, and menstruation began again in most women within 90 days. The incidence of adverse effects was similar in continuous-use and cyclical regimens of ethinylestradiol/levonorgestrel (20microg/90microg vs 20microg/100microg).

Topical imiquimod: a review of its use in the management of anogenital warts, actinic keratoses, basal cell carcinoma and other skin lesions.

Topical imiquimod 5% cream (Aldara) is an immune response modulator that is indicated for the treatment of external anogenital warts, superficial basal cell carcinoma and actinic keratoses. The cream is applied two to five times per week for varying periods, depending on the indication. Topical imiquimod cream has also been evaluated in the treatment of several other skin conditions. Immunomodulatory therapy with topical imiquimod 5% is an effective option for the approved indications. The drug appears to be relatively well tolerated, with the option of breaks from treatment as required for local skin reactions (which are common). Systemic reactions have been reported. Treatment of human papillomavirus- and UV-associated skin lesions with topical imiquimod offers a noninvasive, tissue-sparing alternative to ablative treatment options. However, well designed trials of the sustained, long-term efficacy and tolerability of topical imiquimod versus those of common treatment approaches including surgery and other topical alternatives are required before the place of the drug in the management of these lesions can be finalised. Nonetheless, while other treatments for anogenital warts, superficial basal cell carcinoma or actinic keratoses are available, the advantages of self treatment linked with the demonstrated efficacy of topical imiquimod offer an attractive alternative for many patients.

Subcutaneous interferon-beta-1a : new formulation.

The new formulation of subcutaneous interferon-beta-1a was developed without serum-derived components with the aim of improving immunogenicity and injection tolerability in patients with relapsing forms of multiple sclerosis (MS). In a prospectively defined interim analysis at 48 weeks of an ongoing, single-arm, phase IIIb trial, 13.9% of MS patients receiving the new formulation of subcutaneous interferon-beta-1a 44 microg three times weekly had developed neutralising antibodies (NAbs). In the EVIDENCE trial, which served as an historical control, 24.4% of patients receiving the same dosage of the current formulation had developed NAbs at 48 weeks. The new formulation demonstrated similar pharmacokinetic activity to that of the current formulation in a phase I, double-blind, placebo-controlled study in healthy volunteers. About two-thirds of patients with MS who received the new formulation of subcutaneous interferon-beta-1a were relapse free in the interim, 48-week analysis of the single-arm trial; this is similar to results for the current formulation from historical data. A comparison of results from the interim, 48-week analysis with historical-control data from the EVIDENCE trial indicates that the new formulation of interferon-beta-1a may be associated with a lower incidence of injection-site reactions and a higher incidence of influenza-like symptoms than the current formulation. Adverse events associated with the new formulation were mostly mild to moderate in severity

Ranibizumab.

Ranibizumab is the antigen-binding fragment of a recombinant, humanised monoclonal antibody, which binds with high affinity to, and inhibits the activity of, all active forms of vascular endothelial growth factor A, an important mediator in the development of choroidal neovascularisation. Well designed, phase III trials in patients with neovascular (wet) age-related macular degeneration (AMD) indicated that monthly intravitreal injections of ranibizumab 0.3 or 0.5 mg for up to 2 years maintained or improved visual acuity to a greater extent than sham injection, verteporfin photodynamic therapy or sham photodynamic therapy. In patients with predominantly classic wet AMD who received ranibizumab in combination with verteporfin therapy, preliminary results indicate that combination therapy is superior to that of verteporfin therapy alone. Most serious ocular adverse events, which were uncommon, were associated with either the injection procedure or ranibizumab.

Sorafenib: in advanced renal cancer.

black triangle Sorafenib is an oral multikinase inhibitor that targets the mitogen-activated protein kinase signalling pathway and receptor tyrosine kinases involved in tumour proliferation and angiogenesis.black triangle In the large, phase III, randomised, double-blind, multicentre Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) of patients with advanced clear-cell renal cell cancer in whom previous systemic therapy had failed, median progression-free survival was doubled in patients receiving sorafenib compared with those receiving placebo (5.9 vs 2.8mo).black triangle Significantly more patients receiving sorafenib than those receiving placebo in the phase III trial experienced complete or partial responses or stable disease.black triangle Age, risk-assessment score, prior treatment, metastasis in lung or liver, or time from diagnosis did not affect the improved progression-free survival in sorafenib recipients.black triangle In a randomised, phase II discontinuation trial of patients with advanced renal cancer, in which only those showing stable disease with sorafenib were randomised to further sorafenib or placebo, more patients receiving sorafenib were free of progressive disease 12 weeks after randomisation than were those receiving placebo, and median progression-free survival was longer in sorafenib recipients.black triangle In clinical trials, most drug-related adverse events were mild to moderate in severity. Grade 3/4 hand-foot skin reaction and hypertension occurred more often with sorafenib than with placebo.

Fentanyl buccal tablet: in breakthrough pain in opioid-tolerant patients with cancer.

The fentanyl buccal tablet (FBT) is a new formulation of fentanyl that uses an effervescent drug delivery system to enhance penetration across the buccal mucosa for the treatment of breakthrough pain in opioid-tolerant patients with cancer. Fentanyl is rapidly absorbed from FBT across the buccal mucosa and into the bloodstream. Fentanyl is more rapidly absorbed and bioavailability is higher from FBT than from the oral transmucosal fentanyl citrate formulation. In a well designed phase III trial in opioid-tolerant patients with cancer, a single dose of FBT 100-800 microg provided clinically significant improvements in pain intensity from 15 to 60 minutes after the dose. Single FBT doses of 100-800 microg were generally well tolerated; the majority of adverse events were mild to moderate in nature and typical of those associated with opioids.

Intravenous droperidol: a review of its use in the management of postoperative nausea and vomiting.

Droperidol (Dehydrobenzperidol, Dehidrobenzoperidol, Dridol, Droleptan, Inapsine) is a dopamine D(2) receptor antagonist that has been widely used in adults and children for the prevention and treatment of postoperative nausea and vomiting (PONV) over several decades and, more recently, for the prevention of opioid-induced PONV during patient-controlled analgesia (PCA) in adults. In well controlled clinical trials of patients undergoing surgery, the efficacy of single-dose intravenous (IV) droperidol in preventing PONV was similar to that of ondansetron and dexamethasone. Droperidol significantly reduced opioid-induced PONV in adults during PCA and had a morphine-sparing effect. Droperidol is generally well tolerated and the incidence of adverse effects is similar to that observed with placebo and the serotonin 5-HT(3) receptor antagonists (setrons). Guidelines recommend that, in adults, droperidol monotherapy be considered for those at moderate risk of PONV, and droperidol in combination with a setron and/or dexamethasone be considered for patients at moderate or high risk of PONV. In children with moderate or high risk of PONV, droperidol is recommended for first-line use in some countries, and second-line use in others.

Panitumumab: in the treatment of metastatic colorectal cancer.

Panitumumab is a fully human immunoglobulin G2 monoclonal antibody highly selective for the epidermal growth factor receptor (EGFR), which is overexpressed in 25-77% of colorectal cancers. This overexpression is frequently associated with a poor prognosis. In a large, randomised, nonblind, multicentre phase III study in pretreated adult patients with metastatic colorectal cancer and EGFR staining in >or=1% tumour cells, panitumumab 6 mg/kg every 2 weeks plus best supportive care (BSC) was significantly (p < 0.0001) more effective in improving progression-free survival than BSC alone; recipients of panitumumab plus BSC had a 46% lower disease progression rate than those receiving BSC alone after a median follow-up of 19 weeks. Panitumumab 6 mg/kg every 2 weeks or 2.5 mg/kg/week, administered as monotherapy, produced partial response rates of 8-13% and stable disease rates of 21-30% in pretreated patients with metastatic colorectal cancer in three noncomparative, multicentre phase II studies. Preliminary phase II results also suggest a potential role for panitumumab as first-line therapy in combination with fluorouracil, folinic acid and irinotecan in patients with metastatic colorectal cancer. Panitumumab was generally well tolerated. Grade 3/4 skin-related toxicities were reported in 14% of patients receiving panitumumab plus BSC in the phase III study (versus 0% of patients receiving BSC alone). An analysis of pooled data found that high-affinity binding antibodies to panitumumab were detected in <1% of patients.

Valsartan/hydrochlorothiazide: a review of its use in the management of hypertension.

Valsartan/hydrochlorothiazide is a fixed-dose (valsartan 80, 160 or 320mg plus hydrochlorothiazide 12.5 or 25mg) angiotensin II receptor blocker/diuretic drug combination indicated for the treatment of patients with essential hypertension not adequately controlled by monotherapy.There is ample evidence that valsartan/hydrochlorothiazide is an effective fixed-dose combination antihypertensive agent. However, efficacy and tolerability data pertaining to the 320mg dose of valsartan in the combination are currently relatively few. There is also some evidence of potential benefits associated with the relatively favourable tolerability profile of the combination, the low occurrence of new-onset diabetes mellitus versus amlodipine and the valsartan-associated improvements in cardiac and endothelial function.