Eltrombopag as frontline treatment of aplastic anaemia in routine practice: implications on cost and efficacy.

The thrombopoietin mimetic eltrombopag (EPAG) is efficacious in clinical trials of newly diagnosed moderate (M), severe (S) and very severe (vS) aplastic anaemia (AA). Its use in routine practice and resource-constrained settings is not well described. Twenty-five men and 38 women at a median age of 54 (18-86) years with newly diagnosed AA treated consecutively in a 7-year period with EPAG (N = 6), EPAG/cyclosporine (CsA) (N = 33) and EPAG/CsA/anti-thymocyte globulin (ATG) (N = 24) were analyzed. Because EPAG was not reimbursed, peak doses ranged from 25 to 200 mg/day depending on affordability. EPAG/CsA-treated patients were older (median age: 61 years) with less severe AA (MAA, N = 15; SAA, N = 14; vSAA, N = 4), whereas EPAG/CsA/ATG-treated patients were younger (median age: 44 years) with more severe AA (MAA, N = 2; SAA, N = 12, vSAA, N = 10). The overall/trilineage response rates were 83%/50% for EPAG-treated patients; 79%/42% for EPAG/CsA-treated patients and 75%/63% for EPAG/CsA/ATG-treated patients. Adverse events included grade 1 liver derangement (N = 7) and grade 1 dyspepsia (N = 3). The 5-year overall survivals/failure-free survivals were 62%/80% for the entire cohort; 55%/75% for EPAG/CsA-treated patients and 82%/78% for EPAG/CsA/ATG-treated patients. EPAG showed robust efficacy in AA in routine practice. However, EPAG dosage and combinations remain to be optimized for AA of different severities.

Risk factors for endocrine complications in transfusion-dependent thalassemia patients on chelation therapy with deferasirox: a risk assessment study from a multi-center nation-wide cohort.

Transfusion-dependent patients typically develop iron-induced cardiomyopathy, liver disease, and endocrine complications. We aimed to estimate the incidence of endocrine disorders in transfusiondependent thalassemia (TDT) patients during long-term iron-chelation therapy with deferasirox (DFX). We developed a multi-center follow-up study of 426 TDT patients treated with once-daily DFX for a median duration of 8 years, up to 18.5 years. At baseline, 118, 121, and 187 patients had 0, 1, or ≥2 endocrine diseases respectively. 104 additional endocrine diseases were developed during the follow-up. The overall risk of developing a new endocrine complication within 5 years was 9.7% (95% Confidence Interval [CI]: 6.3-13.1). Multiple Cox regression analysis identified three key predictors: age showed a positive log-linear effect (adjusted hazard ratio [HR] for 50% increase 1.2, 95% CI: 1.1-1.3, P=0.005), the serum concentration of thyrotropin showed a positive linear effect (adjusted HR for 1 mIU/L increase 1.3, 95% CI: 1.1-1.4, P<0.001) regardless the kind of disease incident, while the number of previous endocrine diseases showed a negative linear effect: the higher the number of diseases at baseline the lower the chance of developing further diseasess (adjusted HR for unit increase 0.5, 95% CI: 0.4-0.7, P<0.001). Age and thyrotropin had similar effect sizes across the categories of baseline diseases. The administration of levothyroxine as a covariate did not change the estimates. Although in DFX-treated TDT patients the risk of developing an endocrine complication is generally lower than the previously reported risk, there is considerable risk variation and the burden of these complications remains high. We developed a simple risk score chart enabling clinicians to estimate their patients' risk. Future research will look at increasing the amount of variation explained from our model and testing further clinical and laboratory predictors, including the assessment of direct endocrine magnetic resonance imaging.

The Cost-effectiveness of Eltrombopag for the Treatment of Immune Thrombocytopenia in the United States.

PURPOSE: Eltrombopag was evaluated as a second-line treatment for adult chronic immune thrombocytopenia (ITP) in the 2006 Phase III RAISE (Eltrombopag for Management of Chronic Immune Thrombocytopenia) randomized, placebo-controlled trial. More than 80% of patients reached satisfactory platelet counts within 2 weeks. However, the economic value of eltrombopag as a second-line treatment for ITP remains to be formally assessed. This study aimed to estimate the cost-effectiveness of treating ITP with a comparable thrombopoietin receptor agonist (eltrombopag vs romiplostim). METHODS: A Markov model was implemented over a lifetime time horizon to estimate the benefits and costs of each treatment. The model featured 3 health states based on current guidelines: (1) on treatment; (2) treatment failure/discontinuation; and (3) mortality. In line with therapeutic goals in ITP, model patients could experience 3 events: no bleeding, mild/moderate bleeding, or severe bleeding. Data on eltrombopag use were obtained from an open-label extension of previous Phase II/III trials, including RAISE. Romiplostim data were obtained from Phase III trials and an extension study. Lifetime overall survival was extrapolated by using treatment-specific mortality rates derived from severe bleeding and natural mortality rates. The costs of drugs, routine care, bleeding episodes, adverse events, and mortality were represented in the model. FINDINGS: Eltrombopag-treated patients gained 17.58 life years and 14.68 quality-adjusted life years, whereas romiplostim-treated patients gained 17.52 life years and 14.67 quality-adjusted life years. The total lifetime cost of eltrombopag treatment was estimated at $1.58 million versus $2.13 million for romiplostim. Sensitivity analyses supported base case findings. Deterministic sensitivity analysis predicted the greatest sensitivity to the rates of severe bleeding, discontinuation, and natural mortality. Probabilistic sensitivity analysis showed that eltrombopag would be an efficient use of resources at a $50,000 threshold in 52.8% of cases. In all probabilistic iterations, the total cost of eltrombopag treatment was lower than with romiplostim, primarily because of lower drug costs. IMPLICATIONS: Clinical data were applied in an economic analysis, and eltrombopag exhibited economic dominance compared with romiplostim, driven largely by the reduced costs of primary therapy. This model was limited by a lack of specific patient-level data and robust data on the duration of secondary therapy, as well as by the fact that utilization values are likely conservative estimates for routine care use.

A decision framework for treating chronic immune thrombocytopenia with thrombopoietin receptor agonists.

Aim: Eltrombopag and romiplostim are comparable second-line therapies in chronic immune thrombocytopenia. Treatment decisions are made in different contexts. A framework was created to outline decision pathways for physicians and payers. Materials & methods: The costs of drugs, administration, routine care, bleeding, other adverse events and mortality were included in the year-long calculation of total costs from a US private payer perspective. Treatment parameters and outcome data were obtained from relevant clinical trials. Results: The total cost per year, per patient of eltrombopag was US$51,000 versus US$76,000 for romiplostim. Drug costs and costs associated with bleeding-related events were the main drivers of cost difference. Conclusion: This framework facilitates decision-making in the management of chronic immune thrombocytopenia with eltrombopag and romiplostim.

Assessment of preclinical pharmacokinetics and acute toxicity of pioglitazone and telmisartan combination.

The prevalence of hypertension is very common amongst the diabetic patients and is reported as the major cause of mortality in diabetes. Pioglitazone reported to have an ability to alter the blood cholesterol level and cardioprotective efficiency along with its antidiabetic activity. Telmisartan, through activation of PPAR-γ receptor exerts insulin sensitizing property in addition to its primary cardioprotective efficiency. Theoretically, a combination of pioglitazone and telmisartan may be beneficial to effectively control the high blood glucose level and management of coexisting cardiovascular complication in diabetes. The aim of this research was to experimentally evaluate the pharmacokinetic interaction of pioglitazone and telmisartan when are coadministered in rat. Pioglitazone and telmisartan were administered orally as a single dose individually and in combination to the rats. The plasma samples of the pharmacokinetic study were analyzed using a validated LCMS method. The acute toxicity of the combination with a high dose in rats was also evaluated as a part of the determination of its safety profile. There was no significant change in pharmacokinetic parameters were resulted due to the coadministration of pioglitazone and telmisartan in rat. Absence of major toxicological effect supports the in vivosafety of the combination.

Comparative treatment-related adverse event cost burden in immune thrombocytopenic purpura.

AIMS: Real-world evidence on the safety profile and costs associated with immune thrombocytopenic purpura (ITP) treatment in adults is lacking. This study quantifies and compares adverse event (AE) crude rates and costs associated with ITP treatments as found in claims data. MATERIALS AND METHODS: A retrospective claims-based analysis was conducted using IMS Pharmetrics Plus database. Included patients were ≥18 years old, with a diagnosis of ITP (2007-2012); an ITP-related claim for anti-D, intravenous immunoglobulin (IVIG), rituximab, romiplostim, or eltrombopag; and 1-year continuous enrollment (3-years for rituximab) during follow-up. AEs and event costs were identified during active treatment, defined from the first claim of each drug to a pre-defined treatment gap or end of study period. Descriptive statistics were reported with Wilcoxon rank-sum significance tests. RESULTS: A total of 2,518 patients were identified (mean age = 50.8 (±16.3 years); 55.8% male). Of all patients, 22.8% experienced any AE. Significantly fewer anti-D patients had any AE (13.8% vs IVIG: 21.1%, rituximab: 29.4%, romiplostim: 28.1%, eltrombopag: 22.4%). Nausea/vomiting and arthralgia/musculoskeletal pain were most common across treatments, and hemolytic events did not differ significantly across treatments. Most costly AEs were urinary tract infection, aseptic meningitis, and fever ($5000+/case); headache, nasal congestion, and hemolytic event were $4,000-5,000/case. Cost per AE did not differ by treatment. LIMITATIONS AND CONCLUSIONS: Although lower than trial-based AE rates, claims for ITP treatment-related AEs are common, with higher numbers for rituximab and lower numbers for anti-D. This disparity suggests a possible differential cost burden overall that future analysis should explore.

Are adverse drug reaction patterns different between romiplostim and eltrombopag? 2009-2013 French PharmacoVigilance assessment.

BACKGROUND: Romiplostim and eltrombopag, the two marketed thrombopoietin receptor agonists (TPO-RAs), have distinct binding sites and might have distinct pharmacodynamic mechanisms. The aim of this study was to compare their adverse drug reaction (ADR) patterns. METHODS: We selected in the French PharmacoVigilance Database all ADRs associated with TPO-RAs from TPO-RA marketing until the 31st of December 2013. Medical charts were reviewed. We conducted disproportionality analyses comparing romiplostim exposure in the reports of a given ADR pattern (thrombosis, neurological, cutaneous, gastrointestinal or hematological) to romiplostim exposure in all other TPO-RA-related ADR reports. Reporting Odds Ratios (RORs) were adjusted for age and gender. We also compared the number of reports of a given ADR pattern per million daily defined doses (DDDs) dispensed in France during the study period. RESULTS: We described 45 reports (53 ADRs) with romiplostim and 26 reports (37 ADRs) with eltrombopag. There were 19 venous thromboses. At least one other risk factor was present in 83.3% of the cases. Ten (55.6%) patients had been splenectomized previously. There were eight arterial thromboses. Another risk factor was noticed in all cases. There was no signal for an excess risk of thrombosis with romiplostim versus eltrombopag (ROR: 1.45, 95% CI [0.48-4.45]). There was a signal for a higher risk of gastrointestinal ADRs with eltrombopag (ROR: 30.28, 95% CI [3.23-383.86]) and of hematological ADRs with romiplostim (ROR: 14.36, 95% CI [1.73-119.08]). Dispensing data-adjusted comparisons led to similar results. CONCLUSIONS: This study suggests different ADR patterns between romiplostim and eltrombopag.

[Economic evaluation of Thrombopoietin Receptor Agonists in the treatment of chronic primary immune thrombocytopenia]. / Evaluación económica del tratamiento de la trombocitopenia inmune primaria crónica refractaria con agonistas del receptor de la trombopoyetina.

PURPOSE: To develop a tool to assist the decision-making for selection of Thrombopoyetin Receptor Agonists of adult patients with chronic immune primary thrombocytopenia (PTI). METHODS: Stochastic cost-effectiveness analysis with a 6-Health- States Markov model: stable, bleeding type 2, 3 or 4, post-type 4 bleeding and death. Each simulation analyzes a randomly generated scenario that describes patients characteristics, results measured in quality adjusted life years (QALYs) and costs (in ?2011). Distributions were obtained from the Spanish data of the European health survey of 2009, the INE estimate of population for 2011 and the 6-months clinical studies for Eltrombopag and Romiplostim. Utility values were obtained from the literature and the costs from Spanish official rates lists. A set of 10.000 random scenarios were generated and the patients evolution of each scenario was simulated during a time horizon of five years (in 2-weeks cycles). National Health System Perspective was used and the annual discount rate was set at 3%. RESULTS: Eltrombopag showed more effectiveness in 9.983 scenarios and there was no difference in 17. In 7.048 scenarios the alternative Eltombopag was dominant. It was cost-effective in another 19 (threshold 30,000 ??/AVAC). CONCLUSIONS: Eltrombopag was the most cost-effective alternative in 70,67% of the simulated scenarios and its use could produce lower costs to the NHS.

Objetivo: Desarrollar una herramienta de apoyo a la decisión en la selección de agonistas del receptor de trombopoyetina en el tratamiento de pacientes adultos con trombocitopenia inmune primaria crónica (PTI) refractaria. Métodos: Análisis coste-efectividad estocástico con un modelo de Markov de seis estados: estable, sangrado tipo 2, 3 ó 4, post-sangrado 4 y muerte. Cada simulación analiza un escenario aleatoriamente generado que describe las características del paciente, los resultados medidos en años de vida ajustados a calidad (AVACs) y los costes (en ?2011). Se obtuvieron distribuciones a partir de los datos para España de la Encuesta Europea de Salud de 2009, de la estimación de población para 2011 del INE, de los estudios a 6 meses de Eltrombopag y Romiplostim, de las utilidades obtenidas de la bibliografía y de las tarifas oficiales en España para procesos y actividad. Se generaron 10.000 escenarios aleatorios y se simuló la evolución de los pacientes de cada escenario durante un horizonte temporal de cinco años (ciclos de dos semanas). Perspectiva del Sistema Nacional de Salud (SNS). Tasa de descuento anual del 3% para costes y efectos. Resultados: En 9.983 escenarios Eltrombopag mostró mayor efectividad y en 17 no hubo diferencias. Eltombopag fue la alternativa dominante en 7.048 escenarios y la más coste efectiva en otros 19 (umbral 30.000 ?/AVAC). Conclusiones: Eltrombopag es la alternativa más coste-efectiva en el 70,67% de los escenarios simulados, por lo que su uso podría producir menores costes al SNS.

Eltrombopag for the treatment of chronic immune or idiopathic thrombocytopenic purpura: a NICE single technology appraisal.

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of eltrombopag (GlaxoSmithKline) to submit evidence for the clinical and cost effectiveness of this drug for the treatment of patients with chronic immune or idiopathic thrombocytopenic purpura (ITP), as part of the their Single Technology Appraisal (STA) process. The Aberdeen Technology Assessment Review (TAR) Group, commissioned to act as the evidence review group (ERG), critically reviewed and supplemented the submitted evidence. This paper describes the company submission, the ERG review and NICE's subsequent decisions. The ERG critically appraised the clinical and cost-effectiveness evidence submitted by the manufacturer, independently searched for relevant literature, conducted a critical appraisal of the submitted economic models and explored the impact of altering some of the key model assumptions as well as combining relevant sensitivity analyses. Three trials were used to inform the safety and efficacy aspects of this submission; however, one high-quality randomized controlled trial (RAISE study) was the principal source of evidence and was used to inform the economic model. Eltrombopag had greater odds of achieving the primary outcome of a platelet count between 50 × 10^9/L and 400 × 10^9/L during the 6-month treatment period than placebo (odds ratio [OR] 8.2, 99% CI 3.6, 18.7). In the eltrombopag group, 50/83 (60%) of non-splenectomized patients and 18/49 (37%) of splenectomized patients achieved this outcome. The median duration of response was 10.9 weeks for eltrombopag (splenectomized 6 and non-splenectomized 13.4) compared with 0 for placebo. Eltrombopag patients required less rescue medication and had lower odds of bleeding events for both the splenectomized and the non-splenectomized patients. For a watch-and-rescue strategy of care, the comparator was placebo and the ERG found that substantial reductions in the cost of eltrombopag are needed before the incremental cost per QALY is less than £30,000. There was significant uncertainty, with the incremental cost-effectiveness ratio (ICER) reported varying from £33,561 to £103,500 per QALY (splenectomized) and £39,657 to £150,245 per QALY (non-splenectomized). All costs are presented in £, year 2008 values, as this was the costing year for the manufacturer's model. Other than bleeding, no adverse events were modelled. In relation to the long-term treatment model, the ERG questioned the robustness of the use of non-randomized non-comparative data. The base-case results restricting the time horizon to 2 years and prescribing eltrombopag as second-line treatment post-rituximab were found to be favourable towards eltrombopag. As rituximab is not a licensed treatment for ITP, the ERG were concerned that its inclusion may not be reflective of clinical practice. None of the treatment sequences resulted in an ICER approaching the recommended threshold of £30,000 per QALY gained. Eltrombopag appears to be a safe treatment for ITP (although long-term follow-up studies are awaited) and has short-term efficacy. However, NICE found based on the evidence submitted and reviewed that there was no robust evidence on the long-term efficacy or cost effectiveness of eltrombopag and a lack of direct evidence for eltrombopag tested against other relevant comparators.

Assessment of the pharmacokinetic interaction between eltrombopag and lopinavir-ritonavir in healthy adult subjects.

Eltrombopag is an orally bioavailable thrombopoietin receptor agonist that is approved for the treatment of chronic idiopathic thrombocytopenic purpura. It is being developed for other medical disorders that are associated with thrombocytopenia. Patients with human immunodeficiency virus (HIV) may suffer from thrombocytopenia as a result of their HIV disease or coinfection with hepatitis C virus (HCV). HIV medications, particularly ritonavir (RTV)-boosted HIV protease inhibitors, are involved in many drug interactions. This study evaluated the potential drug-drug interaction between eltrombopag and lopinavir (LPV)/RTV. Forty healthy adult subjects enrolled in this open-label, three-period, single-sequence crossover study received a single 100-mg dose of eltrombopag (period 1), LPV/RTV at 400/100 mg twice daily (BID) for 14 days (period 2), and LPV/RTV at 400/100 mg BID (2 doses) with a single 100-mg dose of eltrombopag administered with the morning LPV/RTV dose (period 3). There was a 3-day washout between periods 1 and 2 and no washout between periods 2 and 3. Serial pharmacokinetic samples were collected during 72 h in periods 1 and 3 and during 12 h in period 2. The coadministration of 400/100 mg LPV/RTV BID with a single dose of 100 mg eltrombopag decreased the plasma eltrombopag area under the plasma concentration-time curve from time zero extrapolated to infinity (AUC(0-∞)) by 17%, on average, with no change in plasma LPV/RTV exposure. Adverse events (AEs) reported in period 2 were consistent with known LPV/RTV AEs, such as diarrhea, abdominal pain, nausea, vomiting, rash, and fatigue. No subjects withdrew due to AEs, and no serious AEs were reported. These study results suggest that platelet counts should be monitored and the eltrombopag dose adjusted accordingly if LPV/RTV therapy is initiated or discontinued.

Telmisartan for the management of patients at high cardiovascular risk.

BACKGROUND: Cardiovascular disease (CVD) places a significant burden on healthcare providers. High blood pressure (BP) is the single most prevalent risk factor for CVD worldwide and is responsible for more deaths than any other risk factor. 'Cardiovascular (CV) high-risk patients' make up the broad cross-section of patients in the middle of the risk spectrum for CVD progression that is referred to as the CV continuum and includes those with atherothrombotic disease, those with target organ damage associated with type 2 diabetes and those with multiple risk factors. Angiotensin II is involved in CVD progression at every stage of the CV continuum, making the renin-angiotensin system a rational target for pharmacologic intervention. Angiotensin II receptor blockers (ARBs) offer a better tolerated alternative to angiotensin converting enzyme inhibitors, with greater long-term adherence. The ARB telmisartan recently received an indication for CV prevention. SCOPE: A PubMed literature search was conducted to identify evidence on the use of telmisartan for preventing CV events. FINDINGS: Telmisartan has a favourable safety and tolerability profile, and has demonstrated efficacious and long-lasting 24-hour BP reductions, whether as monotherapy or in combination with hydrochlorothiazide or amlodipine. In the largest CV prevention trial program undertaken with an ARB (the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial; ONTARGET), telmisartan 80 mg/day alone was as effective as ramipril in reducing the composite primary endpoint of CV mortality, non-fatal myocardial infarction, non-fatal stroke and hospitalization for heart failure in CV high-risk patients. However, patients were significantly more likely to adhere to treatment with telmisartan than ramipril due to its better tolerability. CONCLUSION: To date, telmisartan is the only ARB indicated to reduce CV morbidity in a broad CV high-risk population.

The European Medicines Agency review of eltrombopag (Revolade) for the treatment of adult chronic immune (idiopathic) thrombocytopenic purpura: summary of the scientific assessment of the Committee for Medicinal Products for Human Use.

On 11(th) March 2010, the European Commission issued a marketing authorization valid throughout the European Union for Revolade for the treatment of adult chronic immune (idiopathic) thrombocytopenic purpura. Revolade is an orphan medicinal product indicated for splenectomized patients with immune (idiopathic) thrombocytopenic purpura who are refractory to other treatments (e.g. corticosteroids, immunoglobulins) and as second-line treatment for non-splenectomized patients where surgery is contraindicated. The active substance of Revolade is eltrombopag (ATC code B02BX05). Eltrombopag increases platelet production through activation of the thrombopoietin receptor. The recommended oral dose is 50 mg once daily to achieve and maintain a platelet count of the 50×10(9)/L or more necessary to reduce or prevent the risk of bleeding. The benefit of Revolade is a durable response in maintaining platelet levels. The most common side effects include headache, nausea, hepatobiliary toxicity, diarrhea, fatigue, paresthesia, constipation, rash, pruritus, cataract, arthralgia and myalgia. The decision to grant the marketing authorization was based on the favorable recommendation of the Committee for Medicinal Products for Human Use of the European Medicines Agency. The objective of this paper is to describe the data submitted to the European Medicines Agency and to summarize the scientific review of the application. The detailed scientific assessment report and product information, including the summary of product characteristics, are available on the European Medicines Agency website (www.ema.europa.eu).

[Clinical- functional assessment of organoprotective efficacy of enalapril and telmisartan in patients with arterial hypertension].

Effect of enalapril and telmisartan on hemodynamic indices, structural-functional parameters of the left ventricle, and vasomotor function of arterial endothelium was studied in 49 patients (mean age 48.3+/-3.2 years) with 1-2 degree arterial hypertension (AH) and abnormal relaxation type of left ventricular diastolic dysfunction. Enalapril was given to 24 and telmisartan to 25 patients. Examination included 24-hour arterial pressure monitoring, echocardiography, duplex scanning of the left brachial artery. At the background of therapy with enalapril target levels of systolic and diastolic arterial pressure (AP) were achieved in 79.2 and 70.85% of patients. This was associated with 54.2% reduction of number of non-dippers and night peakers. Therapy with telmisartan (30 weeks) besides effective AP control provided normalization of 24-hour AP profile in 90% of patients with pathological circadian rhythm. This was accompanied by improvement of vasomotor endothelial function of arteries, positive dynamics of structural-functional parameters of the left heart chambers, improvement of indices of left ventricular diastolic function.

Prospective assessment of effects on iron-overload parameters of deferasirox therapy in patients with myelodysplastic syndromes.

We report the first prospective study evaluating the effects of deferasirox on liver iron concentration (LIC), labile plasma iron (LPI) and pharmacokinetics (PK) along with serum ferritin values in patients with IPSS Low- and Intermediate-1 risk myelodysplastic syndromes (MDS) and evidence of iron overload. Twenty-four heavily transfused MDS patients were enrolled in a planned 52 weeks of therapy. PK studies showed dose-proportional total drug exposure. Data demonstrated that deferasirox was well tolerated and effectively reduced LIC, LPI and serum ferritin in the iron-overloaded patients with MDS who completed 24 and 52 weeks of therapy despite ongoing receipt of red blood cell transfusions.

Update on toxicity and efficacy aspects of treatment with deferasirox and its implication on the morbidity and mortality of transfused iron loaded patients.

There are major concerns regarding the toxicity, efficacy and costs of deferasirox in transfused iron loaded patients. Marketing policies resulted in its indiscriminate use and have overtaken safety issues. Renal, hepatic and pancytopenia fatal episodes have been reported. However, despite these fatalities it would appear that there is no regular monitoring of such toxicities or of effects such as the accumulation of toxic metals. The safety of some patients can also be compromised by the low efficacy of deferasirox in the removal of excess iron, especially from the heart, which in the long term can also result in an overall increase in morbidity and mortality. Safer, less costly and more effective treatments are available by using deferoxamine, deferiprone and their combination.

Ethical issues and risk/benefit assessment of iron chelation therapy: advances with deferiprone/deferoxamine combinations and concerns about the safety, efficacy and costs of deferasirox.

New developments in the area of iron and other metal metabolism and toxicity and the effects and uses of chelators have been presented at the 16th International Conference on Chelation (ICOC), Limassol, Cyprus in October 2006. Marketing practices by pharmaceutical companies, contradictory policies by regulatory authorities and ineffective policies by health authorities deprive thousands of thalassemia and other transfused patients of life saving iron chelating drugs and of efficacious chelation treatments. Thousands of patients were using deferasirox (DFRA) worldwide a few months after the European Union (EU) authorities, and about 1 year after the Food and Drugs Administration (FDA), proceeded to its accelerated approval with no sufficient evidence that the drug was efficacious, especially for clearing excess cardiac iron, and also safe. Cases of fatal, acute, irreversible renal and liver failure, fatal agranulocytosis and other toxicities have recently been reported with DFRA. The FDA has not yet approved deferiprone (L1) depriving thousands of patients of potentially life saving treatment. The high cost of DFRA at 60 euros/g, L1 at 5.5 euros/g and deferoxamine (DFO) at 8.3 euros/g, diminishes the prospects of universal chelation therapy, especially for patients in developing countries. The safety and efficacy record of L1, DFO, and their combination in particular, appear to provide universal solutions in the treatment of transfusional iron overload, and also in reducing mortality because of their ability to clear rapidly and effectively excess cardiac iron.

Results of a comparative, phase III, 12-week, multicenter, prospective, randomized, double-blind assessment of the efficacy and tolerability of a fixed-dose combination of telmisartan and amlodipine versus amlodipine monotherapy in Indian adults with stage II hypertension.

OBJECTIVE: The aim of this study was to evaluate the efficacy and tolerability of a new fixed-dose combination (FDC) of telmisartan 40 mg + amlodipine 5 mg (T+A) compared with amlodipine 5-mg monotherapy (A) in adult Indian patients with stage II hypertension. METHODS: This comparative, Phase III, 12-week, multicenter, prospective, randomized, double-blind study was conducted in Indian patients aged 18 to 65 years with established stage II hypertension. Patients were treated with oral FDC of T+A or A QD before breakfast for 12 weeks; blood pressure (BP) and heart rate were measured in the sitting position. Primary efficacy end points were reduction in clinical systolic BP (SBP)/ diastolic BP (DBP) from baseline to study end and number of responders (ie, patients who achieved target SBP/ DBP <130/<80 mm Hg) at end of study. Tolerability was assessed by treatment-emergent adverse events, identified using physical examination, laboratory analysis, and electrocardiography. RESULTS: A total of 210 patients were enrolled in the study; 203 patients (143 men, 60 women) completed the study while 7 were lost to follow-up (4 patients in the T+A group and 3 in the A group) and considered with-drawn. At study end, statistically significant percentage reductions from baseline within groups and between groups were observed in SBP (T+A [-27.4%]; A [-16.6%]) and DBP (T+A [-20.1%]; A [-13.3%]) (all, P < 0.05). Response rates were 87.3% (89/102) in the T+A group and 69.3% (70/101) in the A group (P < 0.05). The prevalences of adverse events were not significantly different between the 2 treatment groups (T+A, 16.0% [17/106]; A, 15.4% [16/104]). Peripheral edema was reported in 8.5% patients (9/106) in the T+A group compared with 13.5% (14/104) in the A group, and cough was reported in 3.8% patients (4/106) in the T+A group and 1.0% (1/104) patients in the A group; these differences did not reach statistical significance. The incidences of headache, dizziness, and diarrhea were similar between the 2 groups. CONCLUSIONS: Among these Indian patients with stage II hypertension, the FDC of T+A was found to be significantly more effective, with regard to BP reductions, than A, and both treatments were well tolerated.