Correction to: Fostamatinib in chronic immune thrombocytopenia: a profile of its use in the USA.

[This corrects the article DOI: 10.1007/s40267-018-0551-x.].

Ginkgo biloba extract EGb 761® in the symptomatic treatment of mild-to-moderate dementia: a profile of its use.

EGb 761® (Tanakan®) is a standardized extract of Ginkgo biloba leaves that has demonstrated protective properties against neuronal and vascular damage. Overall, in randomized, placebo-controlled clinical trials and meta-analyses in adults with mild-to-moderate dementia, EGb 761® displayed positive effects, with changes from baseline in outcomes related to cognition, behaviour and global change that are generally better than those shown with placebo. EGb 761® is generally well tolerated, with no safety issues being identified during its many years of widespread use.

Fostamatinib in chronic immune thrombocytopenia: a profile of its use in the USA.

Oral fostamatinib is an orally administered small molecule spleen tyrosine kinase (SYK) inhibitor approved for the treatment of adults with chronic immune thrombocytopenia (ITP) who have an inadequate response to a previous treatment. Fostamatinib has a unique mechanism of action, whereby its active metabolite targets the SYK-mediated pathway of platelet destruction. In clinical trials, fostamatinib provided durable responses in adults with chronic ITP who had not responded or had relapsed following treatment with one or more prior ITP therapies, including corticosteroids, thrombopoietin receptor agonists, rituximab, and/or splenectomy. Most patients who respond to fostamatinib maintain platelet counts of > 50 × 109/L for periods of ≥ 12 months. The most common adverse events reported with fostamatinib in clinical trials were diarrhea, hypertension, nausea, and increased transaminase levels.

Doxycycline 40 mg capsules (30 mg immediate-release/10 mg delayed-release beads): anti-inflammatory dose in rosacea.

Anti-inflammatory dose doxycycline 40 mg capsules (30 mg immediate-release and 10 mg delayed-release beads) provide a sub-antimicrobial dose that reduces the inflammatory response in patients with rosacea without producing drug concentrations required to treat bacterial diseases. The efficacy of oral, anti-inflammatory dose doxycycline 40 mg capsules once daily in the treatment of adults with rosacea was demonstrated in two pivotal large, randomized, double-blind, placebo-controlled, multicenter trials. After 16 weeks' therapy, anti-inflammatory dose doxycycline 40 mg was significantly more effective in improving rosacea than placebo, providing a greater reduction in the total inflammatory lesion count (primary endpoint) than placebo. Anti-inflammatory dose doxycycline 40 mg was associated with a rapid onset of action, achieving a significantly greater decrease in total inflammatory lesion count than placebo by the first follow-up visit at week 3 in both studies. Maximum anti-inflammatory efficacy appears to be achieved with doxycycline 40 mg capsules once daily, as no additional improvement in rosacea symptoms was achieved with oral doxycycline 100 mg once daily (usual antibacterial dosage) in a small, randomized, double-blind trial. Anti-inflammatory dose doxycycline 40 mg was generally well tolerated in clinical trials, with most adverse events being of mild to moderate intensity.

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.

Bortezomib: a review of its use in patients with multiple myeloma.

Bortezomib (VELCADE) is a proteasome inhibitor that not only targets the myeloma cell, but also acts in the bone marrow micro-environment, inhibiting the binding of myeloma cells to bone marrow stromal cells, as well as demonstrating anabolic effects on bone. Intravenous bortezomib, with or without dexamethasone, is effective and well tolerated in patients with relapsed/refractory multiple myeloma, as demonstrated in the phase II CREST and SUMMIT trials, and the phase III APEX trial, and is a recommended treatment for this patient group. Based on the results of another phase III trial, the combination of bortezomib plus pegylated liposomal doxorubicin is also a recommended treatment for patients with relapsed/refractory multiple myeloma. Other bortezomib-combination regimens have demonstrated promising response data in phase II trials in patients with relapsed/refractory disease, although response and survival data for these combinations need to be confirmed in larger phase III trials. Bortezomib was effective and well tolerated when used as part of a first-line regimen in previously untreated patients with multiple myeloma. In the phase III VISTA trial in elderly patients with previously untreated multiple myeloma not eligible for transplantation, bortezomib in combination with melphalan and prednisone was effective and well tolerated and is a recommended treatment regimen for this group of patients. Preliminary data from phase II/III trials in patients with previously untreated multiple myeloma indicate a promising role for the use of bortezomib combined with various other chemotherapeutic agents as induction therapy prior to transplantation.

Darunavir: a review of its use in the management of HIV infection in adults.

UNLABELLED: Darunavir is an oral nonpeptidic HIV-1 protease inhibitor (PI) that is used, together with a low boosting dose of ritonavir, as part of an antiretroviral therapy (ART) regimen in treatment-experienced and -naive patients with HIV-1 infection. Compared with early-generation PIs, boosted darunavir has a high genetic barrier to resistance and is active against multidrug-resistant HIV isolates. In clinical trials in treatment-experienced patients with HIV-1 infection receiving an optimized background regimen (OBR), twice-daily boosted darunavir was more effective than investigator-selected ritonavir-boosted control PIs (CPIs) or ritonavir-boosted lopinavir. In clinical trials in treatment-naive patients with HIV-1 infection receiving a fixed background regimen, once-daily boosted darunavir was noninferior to boosted lopinavir at 48 weeks and more effective than boosted lopinavir at 96weeks. Boosted darunavir was generally well tolerated in patients with HIV-1 infection in clinical trials. It was associated with a lower incidence of diarrhoea than CPIs or lopinavir in treatment-experienced or -naive patients, and fewer lipid abnormalities than lopinavir in treatment-naive patients. Thus, for the management of treatment-experienced or -naive patients with HIV-1 infection, a ritonavir-boosted darunavir-based ART regimen is a valuable treatment option. PHARMACOLOGICAL PROPERTIES: Darunavir is an oral nonpeptidic HIV-1 PI that selectively inhibits the cleavage of HIV gag and gag-pol polyproteins, thereby preventing viral maturation. Darunavir is highly potent against laboratory strains and clinical isolates of wild-type and multidrug-resistant HIV and has limited cytotoxicity. In an in vitro study in MT-2 cells, the potency of darunavir was greater than that of saquinavir, amprenavir, nelfinavir, indinavir, lopinavir and ritonavir. Darunavir binds with high affinity to HIV-1 protease, including multidrug-resistant proteases, and retains potency against multidrug-resistant HIV-1 strains. Although some potential may exist for cross-resistance with amprenavir, darunavir did not display cross-resistance with other PIs in vitro. In a 24-week analysis of pooled data from the POWER 1 and 2 studies in treatment-experienced patients, 11 protease mutations associated with a reduced response to boosted darunavir were identified (V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V and L89V). The presence of at least three darunavir resistance-associated mutations (prevalent in approximately 7-9% of treatment-experienced patients) together with a high number of protease resistance-associated mutations were required to confer darunavir resistance. In the 48-week analysis of treatment-experienced patients with virological failure in the the TITAN study, fewer in the boosted darunavir group than in the boosted lopinavir group developed additional mutations or lost susceptibility to PIs compared with baseline. In treatment-naive patients, no primary PI-resistance-associated mutations developed in patients with an available genotype at baseline and endpoint during 96 weeks of treatment with boosted darunavir or boosted lopinavir. Oral darunavir, boosted with low-dose ritonavir, is rapidly absorbed, generally reaching peak plasma concentrations within 2.5-4 hours. The bioavailability of oral darunavir is increased by about 30% when taken with food. Darunavir is primarily metabolized by the hepatic cytochrome P450 (CYP) enzymes, primarily CYP3A. The 'boosting' dose of ritonavir acts an an inhibitor of CYP3A, thereby increasing darunavir bioavailability. Drug interactions can result when darunavir is coadministered with other drugs that are inducers or inhibitors of, or act as substrates for, CYP3A. The mean elimination half-life of boosted darunavir is approximately 15 hours. THERAPEUTIC EFFICACY: In treatment-experienced patients with HIV-1 infection, the therapeutic efficacy of oral twice-daily darunavir 600 mg, boosted with ritonavir 100 mg, versus that of investigator selected boosted CPIs (POWER studies) or versus twice-daily boosted lopinavir (administered as a fixed dose combination of lopinavir/ritonavir 400/100 mg) [TITAN study] has been evaluated in phase IIb and III studies. All patients received concurrent treatment with an OBR. Significantly more patients receiving boosted darunavir achieved a viral load reduction from baseline of >or=1 log(10) copies/mL (primary endpoint) than boosted CPI recipients at all timepoints, up to and including the final efficacy analysis at 144 weeks, in the combined analyses of POWER 1 and 2. The efficacy of boosted darunavir was noninferior to that of boosted lopinavir at 48 weeks, and was significantly better than boosted lopinavir at 48 and 96 weeks in the TITAN study, as determined by significantly more patients in the darunavir group than in the lopinavir group achieving a viral load of <400 copies/mL (primary endpoint). In the ARTEMIS study in treatment-naive patients with HIV-1 infection receiving a fixed background regimen of tenofovir and emtricitabine, once-daily boosted darunavir 800 mg was noninferior to boosted lopinavir 800 mg/day at 48 weeks. At 96 weeks, boosted darunavir was found to be more effective than boosted lopinavir, as determined by significantly more patients in the darunavir group than in the lopinavir group achieving a confirmed plasma viral load of <50 copies/mL (primary endpoint). TOLERABILITY: Boosted darunavir was generally well tolerated in patients with HIV-1 infection in clinical trials, with most events being mild to moderate in severity. At 48-week analyses, the most common adverse events associated with once- or twice-daily boosted darunavir in treatment-experienced or -naive patients were diarrhoea, nausea, headache, upper respiratory tract infection and nasopharyngitis. The most common boosted darunavir-related grade 2-4 laboratory abnormalities in treatment-experienced patients included increased triglycerides and increased total cholesterol. Overall, boosted darunavir was associated with less diarrhoea than CPIs or boosted lopinavir in treatment-experienced and -naive patients, and a lower incidence of grade 2-4 elevations in triglycerides and total cholesterol than boosted lopinavir in treatment-naive patients. Treatment discontinuation because of adverse events occurred in 3% of boosted darunavir recipients and 7% of boosted lopinavir recipients during 48 weeks of therapy in treatment-naive patients. PHARMACOECONOMIC CONSIDERATIONS: Healthcare costs in the UK and US were estimated to be lower with boosted darunavir than with investigator-selected CPIs in treatment-experienced patients with HIV-1 infection in two 1-year cost analyses conducted from the perspective of a healthcare provider and using predicted costs based on CD4+ cell counts and clinical data from the POWER studies. The higher acquisition cost of boosted darunavir compared with CPIs was more than offset by the better efficacy of darunavir. In modelled cost-effectiveness analyses, boosted darunavir was predicted to be cost effective compared with other boosted CPIs in heavily pretreated adults from a healthcare payer perspective in Europe and from a societal perspective in the US. In a further model of a subgroup of patients with at least one primary International AIDS Society-USA PI mutation, boosted darunavir was predicted to be cost effective compared with boosted lopinavir from a healthcare payer perspective in Europe. The incremental costs per quality-adjusted life-year gained were within commonly accepted thresholds in all cost-effectiveness analyses.

Ravulizumab: First Global Approval.

Ravulizumab (ravulizumab-cwvz; ULTOMIRIS™), a humanized monoclonal antibody, is a complement C5 inhibitor developed by Alexion Pharmaceuticals for the treatment of paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS). Like the first-generation C5 inhibitor, eculizumab, ravulizumab binds specifically and with high affinity to the complement protein C5, thereby preventing formation of the terminal complement complex C5b-9, which mediates cell lysis. In December 2018, intravenous ravulizumab received its first global approval in the USA for the treatment of adults with PNH, and is under regulatory review in the European Union and Japan in this indication. Phase 3 development of intravenous ravulizumab for the treatment of aHUS is underway worldwide. The use of ravulizumab in myasthenia gravis and IgA nephropathy is also being evaluated in the USA in early-phase and preclinical studies, respectively. Clinical development of a subcutaneous formulation for PNH and aHUS is also underway. Ravulizumab has been developed using Xencor's antibody half-life prolongation technology (Xtend™), which utilises antibody Fc variants to prolong half-life. Alexion is also evaluating the coadministration of subcutaneous ravulizumab with Halozyme's ENHANZE® drug-delivery technology (rHuPH20), which may have the potential to further extend the dosing interval. This article summarizes the milestones in the development of ravulizumab leading to this first approval for PNH.

Risankizumab: First Global Approval.

Risankizumab (Skyrizi®), a humanised IgG monoclonal antibody that targets the p19 subunit of IL-23, was developed by AbbVie in collaboration with Boehringer Ingelheim for the treatment of immunological and inflammatory disorders. In March 2019, risankizumab received its first global approval in Japan for the treatment of adults with psoriasis vulgaris, psoriatic arthritis, generalized pustular psoriasis and erythrodermic psoriasis. Risankizumab has also received approval in the USA, Canada and the EU for the treatment of moderate-to-severe plaque psoriasis, and is in phase 3 development for this indication as well as psoriatic arthritis in several countries worldwide. Phase 2 and 3 clinical evaluation of risankizumab is ongoing in several countries in the treatment of Crohn's disease and ulcerative colitis. Risankizumab is also in phase 2 development for the treatment of atopic dermatitis globally. This article summarizes the milestones in the development of risankizumab leading to this first approval for psoriasis vulgaris, psoriatic arthritis, generalized pustular psoriasis and erythrodermic psoriasis.

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.

Tigecycline: in community-acquired pneumonia.

Tigecycline is a first-in-class glycylcycline, broad-spectrum, intravenous antibacterial developed to overcome the two major mechanisms of tetracycline resistance (ribosomal protection and efflux). The drug has been in use since 2005 for complicated intra-abdominal infections, and complicated skin and soft tissue structure infections, but is currently being assessed in the US for community-acquired pneumonia (CAP) in adults. In vitro, tigecycline had good activity against a range of Gram-positive, Gram-negative and atypical community-acquired respiratory tract pathogens implicated in CAP. Compared with other antibacterials, tigecycline has a prolonged post-antibiotic effect against key bacteria and a long serum elimination half-life in humans. The drug effectively penetrates lung tissue. The combined results of two well designed, phase III studies demonstrated that tigecycline 100 mg initially, followed by 50 mg every 12 hours for 7-14 days was not inferior to recommended dosages of levofloxacin in the treatment of hospitalized patients with CAP. Clinical cure rates were 89.7% versus 86.3% in the clinically evaluable population and 81.0% versus 79.7% in the clinical modified intent-to-treat population. Tigecycline was generally well tolerated in patients with CAP.

Transdermal matrix fentanyl membrane patch (matrifen): in severe cancer-related chronic pain.

The matrix fentanyl membrane patch is a new transdermal patch designed with a reduced drug load compared with established reservoir and matrix fentanyl patches. The drug is contained within a silicone matrix with a rate-controlling membrane designed to maintain constant serum fentanyl concentrations over the 72-hour application period. The matrix fentanyl membrane patch was equivalent to the reservoir fentanyl patch in terms of transdermal delivery of fentanyl, as demonstrated after both single (100 microg/h) and multiple (50 microg/h) applications by the peak serum fentanyl concentration and the area under the serum concentration-time curve over 72 hours. In a randomized, nonblind, multicentre trial, the transdermal matrix fentanyl membrane patch was noninferior to standard opioid therapy (transdermal reservoir or matrix fentanyl patch or an oral opioid) in terms of analgesic efficacy over 30 days in patients with cancer-related chronic pain requiring long-term opioid use. The transdermal matrix fentanyl membrane patch was as well tolerated as standard opioid therapy; patient-rated tolerability scores for constipation, nausea, daytime drowsiness and sleep disturbance were similar between treatments.

Esomeprazole: a review of its use in the management of gastric acid-related diseases in adults.

Esomeprazole (Nexium); S-omeprazole) is a single optical isomer proton-pump inhibitor (PPI) approved for the management of reflux oesophagitis, the symptomatic treatment of gastro-oesophageal reflux disease (GORD), the prevention and healing of NSAID-associated gastric ulcer disease (and the prevention of NSAID-associated duodenal ulcers in the UK), the treatment of Helicobacter pylori infection and associated duodenal ulcer disease (and prevention of relapse of H. pylori-associated peptic ulcers in the UK), and the treatment of Zollinger-Ellison syndrome (and other hypersecretory syndromes in the US).Once-daily oral esomeprazole 40 mg demonstrates greater antisecretory activity than other PPIs. Overall, in well designed clinical studies of 4 weeks' to 6 months' duration in patients with GORD, esomeprazole had similar or better efficacy than other agents. In patients requiring ongoing treatment with NSAIDs, co-therapy with once-daily esomeprazole 20 or 40 mg achieved relief of gastrointestinal symptoms or prevented ulcer occurrence, more effectively than placebo. Esomeprazole was also better than ranitidine 150 mg twice daily in healing NSAID-associated gastric ulcers. In addition, the drug has demonstrated efficacy as part of a triple-therapy regimen for the eradication of H. pylori infection, the healing of H. pylori associated duodenal ulcers and the prevention of relapse of gastric ulcers. Esomeprazole also effectively treated patients with Zollinger-Ellison syndrome. Esomeprazole is generally well tolerated with an adverse-event profile similar to that of other PPIs. Thus, the efficacy and tolerability of esomeprazole for the management of GORD and H. pylori eradication remains undisputed, and the data support its use for the first-line treatment of NSAID-associated gastric ulcer disease and Zollinger-Ellison syndrome.

Interferon-beta-1b: in newly emerging multiple sclerosis.

The mechanism of action of interferon-[beta]-1b in multiple sclerosis (MS) is not clearly understood, but is thought to involve immunoregulatory activities, including enhancing the suppressor activity of peripheral blood mononuclear cells. In the planned 3-year analysis of the BENEFIT study in patients with a single clinical event suggestive of MS, the relative risk of clinically definite (CD) MS was reduced by 41% in those receiving interferon-[beta]-1b 250 [micro]g every other day for 3 years (early-treatment group) compared with patients who were initially randomized to placebo then switched to interferon-[beta]-1b 250 [micro]g every other day at the end of 2 years or at the onset of CDMS (delayed-treatment group) [p < 0.01]. The relative risk of confirmed progression of the expanded disability status scale (EDSS) was reduced by 40% in the early-treatment group compared with the delayed-treatment group over 3 years (p < 0.05). At the end of the 2-year, randomized, placebo-controlled period of the BENEFIT study, the risk of developing CDMS (p < 0.0001) and McDonald-defined MS (p < 0.00001) was significantly lower in the interferon-[beta]-1b group than in the placebo group, and in the magnetic resonance imaging analysis, fewer newly active lesions developed in the interferon-[beta]-1b group (p < 0.001). Interferon-[beta]-1b was generally well tolerated. In the 3-year BENEFIT study, neutralizing activity, which was reported in about one-third of the early-treatment group, had no effect on outcome.

Clindamycin/benzoyl peroxide gel (BenzaClin): a review of its use in the management of acne.

Clindamycin 1%/benzoyl peroxide 5% (BenzaClin) is a combination gel indicated for use twice daily, or as directed by a physician, for the topical treatment of inflammatory and noninflammatory lesions of acne vulgaris. In well designed clinical trials in patients with mild to moderately severe acne, the efficacy of once- or twice-daily clindamycin/benzoyl peroxide in the reduction of inflammatory lesion counts was greater than that of benzoyl peroxide alone, clindamycin alone, or tretinoin plus clindamycin, and not significantly different from that of erythromycin/benzoyl peroxide. In the reduction of noninflammatory lesion counts, the efficacy of once- or twice-daily clindamycin/benzoyl peroxide was greater than that of clindamycin alone, but not significantly different to that observed with benzoyl peroxide, tretinoin plus clindamycin, or erythromycin/benzoyl peroxide. Clindamycin/benzoyl peroxide has a fairly rapid onset of action, with acne improvement usually recorded within 2-4 weeks. Despite widespread use, bacterial resistance is not associated with clindamycin/benzoyl peroxide. The product is generally well tolerated, and the main treatment-related adverse events in clinical trials were application-site dryness, irritation, peeling, and erythema. Thus, clindamycin/benzoyl peroxide is an effective and well tolerated option for the management of mild to moderately severe acne.

Amlodipine/atorvastatin fixed-dose combination: a review of its use in the prevention of cardiovascular disease and in the treatment of hypertension and dyslipidemia.

Amlodipine/atorvastatin (Caduet) is a once-daily fixed-dose combination of the dihydropyridine calcium channel antagonist amlodipine and the HMG-CoA reductase inhibitor atorvastatin. In Europe, the combination is indicated for the prevention of cardiovascular events in hypertensive patients with three concomitant cardiovascular risk factors and, in the US, it is indicated for the management of hypertension and dyslipidemia in patients for whom treatment with both agents is appropriate. In clinical trials, the fixed-dose combination of amlodipine/atorvastatin effectively managed two important risk factors simultaneously in hypertensive patients at risk of cardiovascular disease or in those with concomitant hypertension and dyslipidemia. The combination is bioequivalent to amlodipine and atorvastatin given alone and does not modify the efficacy of either single agent. Amlodipine/atorvastatin is generally well tolerated, with a tolerability profile consistent with that of each single agent. Compared with the coadministration of each single agent, the convenience of single-pill amlodipine/atorvastatin has the potential to improve patient adherence and the management of cardiovascular risk in selected patients, thereby improving clinical outcomes.

Trastuzumab: a pharmacoeconomic review of its use in early breast cancer.

Trastuzumab (Herceptin) is a monoclonal antibody approved for the treatment of breast cancer that overexpresses human epidermal growth factor receptor 2 (HER2). Well designed clinical trials in women with early breast cancer have demonstrated that 1 years' therapy with adjuvant intravenous trastuzumab (a loading dose followed by 6 mg/kg every 3 weeks or 2 mg/kg weekly) significantly improves disease-free survival and overall survival compared with observation (subsequent to chemotherapy) or chemotherapy alone in women with HER2-positive disease. In the HERA trial, disease-free survival was estimated to improve by 6.3% at 3 years in the trastuzumab group compared with the observation group. Trastuzumab is generally well tolerated. The most common adverse events are infusion-related symptoms, such as fever and chills, which usually occur with administration of the first dose. Cardiotoxicity occurs in a small proportion of patients receiving trastuzumab, particularly when coadministered with anthracyclines, and cardiac assessment is recommended for all patients at baseline and at 3-monthly intervals. In modelled cost-effectiveness analyses based on data from clinical trials in patients with HER2-positive early breast cancer, adjuvant trastuzumab was predicted to be cost effective from a healthcare payer or societal perspective in several countries. Incremental costs per QALY or life-year gained with trastuzumab administered subsequent to or concurrent with chemotherapy compared with chemotherapy alone were consistently within accepted local thresholds for cost effectiveness. Sensitivity analyses demonstrated that these results remained generally robust to plausible changes in key model assumptions. In conclusion, in patients with HER2-positive early breast cancer, the addition of adjuvant trastuzumab is clinically effective in improving disease-free survival. Available pharmacoeconomic data from several countries, despite some inherent limitations, support the use of adjuvant trastuzumab for 1 year as a cost-effective treatment relative to chemotherapy alone in this patient population.

Zoledronic acid: a pharmacoeconomic review of its use in the management of bone metastases.

Zoledronic acid (Zometa is a third-generation nitrogen-containing parenteral bisphosphonate indicated for the treatment of bone metastases due to solid tumours or multiple myeloma and for hypercalcaemia of malignancy (HCM). In patients with advanced breast or prostate cancer, zoledronic acid 4 mg every 3-4 weeks for up to 15 months significantly reduced the proportion of patients with > or =1 skeletal-related event (SRE), excluding HCM, compared with placebo. In patients with advanced breast cancer or multiple myeloma, the incidence of SREs was similar in patients treated with zoledronic acid 4 mg or pamidronic acid 90 mg every 3-4 weeks for up to 25 months but, in breast cancer patients, zoledronic acid reduced the risk of SREs, including HCM, by an additional 20% compared with pamidronic acid. In modelled cost-utility studies comparing direct costs based on efficacy and resource-use data from these and/or other trials, results have varied. In the most recent study performed from the perspective of the UK NHS and modelled over a 10-year treatment period in women with advanced breast cancer, intravenous zoledronic acid and oral ibandronic acid were dominant over no treatment. Intravenous zoledronic acid was the most cost effective, in terms of incremental costs per QALY gained, followed by oral ibandronic acid, intravenous pamidronic acid and intravenous ibandronic acid. Two other modelled analyses in patients with advanced breast cancer, also conducted from the perspective of the NHS, evaluated the cost utility of three bisphosphonate therapies in patients receiving hormonal therapy or intravenous chemotherapy. Analyses were modelled over 14.3 months (i.e. expected survival) and assumptions varied markedly from results in clinical breast cancer trials. Also, efficacy assumptions for zoledronic acid were not based on clinical trials with the drug. The results of these analyses suggest that oral ibandronic acid is more cost effective than intravenous zoledronic acid and intravenous pamidronic acid in terms of incremental cost per QALY gained. In a global, 15-month modelled cost-effectiveness analysis of patients with advanced prostate cancer, conducted from a third-party perspective, the incremental cost per QALY gained for zoledronic acid versus no treatment was $US159 200 (year 2000 value), which is about 3-fold greater than commonly accepted thresholds for cost effectiveness. In conclusion, a recent modelled economic analysis suggests that intravenous zoledronic acid 4 mg is dominant relative to no treatment in the management of bone metastases in patients with advanced breast cancer. In contrast, in patients with advanced prostate cancer, the incremental cost per QALY gained for zoledronic acid 4 mg versus no treatment was predicted to be higher than commonly accepted thresholds. Compared with other bisphosphonates in the setting of advanced breast cancer, intravenous zoledronic acid was more cost effective than oral or intravenous ibandronic acid and intravenous pamidronic acid in one study, but less cost effective than oral ibandronic acid in another. Further efficacy and economic data comparing intravenous zoledronic acid with oral ibandronic acid are needed. Meanwhile, zoledronic acid appears to be the most cost effective intravenous bisphosphonate for the management of bone metastases in patients with advanced breast cancer and possibly in patients with different types of advanced solid tumours.

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.

Imatinib: a review of its use in chronic myeloid leukaemia.

Imatinib (Gleevec, Glivec) is a synthetic tyrosine kinase inhibitor used in the treatment of chronic myeloid leukaemia (CML). It is specifically designed to inhibit the breakpoint cluster region (BCR)-Abelson (ABL) fusion protein that results from the chromosomal abnormality known as the Philadelphia chromosome. CML is characterised by this abnormality, which leads to abnormalities of the peripheral blood and bone marrow including an increase in the number of granular leukocytes. Imatinib is approved in numerous countries worldwide for the treatment of newly diagnosed Philadelphia chromosome-positive (Ph+) chronic-phase CML, Ph+ accelerated-phase or blast-crisis CML, and in patients with Ph+ chronic-phase CML who have failed to respond to interferon-alpha therapy. It is also indicated in paediatric patients with newly diagnosed Ph+ chronic-phase CML, in accelerated-phase or blast-crisis CML, or in chronic-phase CML after failure of interferon-alpha therapy or when the disease has recurred after haematopoietic stem cell transplantation (HSCT). Approved indications, however, may vary by country. Imatinib is effective and generally well tolerated in patients with Ph+ CML. In patients with newly diagnosed chronic-phase CML, imatinib was more effective than interferon-alpha plus cytarabine in preventing progression of the disease and in achieving haematological and cytogenetic responses. Overall survival rates remain high after 5 years of follow-up, and historical comparisons with other treatments demonstrate improved overall survival with imatinib in the long term. Patients with accelerated-phase or blast-crisis CML, or those who have not responded to prior interferon-alpha therapy also benefit from imatinib treatment. Some patients become resistant or intolerant to imatinib therapy; management strategies to overcome these problems include dosage adjustment, other treatments, or combination therapy with imatinib and other agents. Allogeneic HSCT is currently the only potentially curative treatment, but it is associated with high rates of morbidity and mortality and is not suitable for all patients. The introduction of imatinib has had a marked impact on outcomes in patients with CML. It remains a valuable treatment for all stages of the disease, especially initial treatment of newly diagnosed Ph+ chronic-phase CML, and is endorsed by European and US treatment guidelines as a first-line option.