Abstract: 
Chemotherapy-induced anaemia can be treated using erythropoiesis-stimulating agents (ESAs), but these can cause serious side-effects including tumour progression, venous thromboembolism, and shorter survival. Following extensive review of recent literature, the American Society of Clinical Oncology and the American Society of Hematology have updated their guidelines on the use of ESAs. New recommendations include minimising the use of ESA in patients receiving chemotherapy with curative intent.

Cancer patients with chemotherapy-induced anaemia have two treatment options for boosting their haemoglobin (Hb) levels: blood transfusion or the use of erythropoiesis-stimulating agents (ESAs). Both have advantages and disadvantages, so to help physicians navigate their way through treatment decisions, the American Society of Clinical Oncology and the American Society of Hematology have collaborated to update an earlier Clinical Practice Guideline on the use of epoetin and darbepoetin in adult patients with cancer [1].

The original publication of 2002 was updated in 2007 following the availability of more information on risks associated with ESAs. The latest (2010) update gives recommendations for the use of ESAs, and also summarises evidence on their effectiveness at reducing transfusions and increasing Hb and reviews the latest evidence on ESA-associated tumour progression, venous thromboembolism, and/or survival. It involved a literature review with one new individual patient data analysis, four meta-analyses, two systematic reviews, and 13 new reports of randomised controlled trials, including through searching MEDLINE and the Cochrane Collaboration Library.

The 2010 update is available, together with a patient guide and other clinical tools and resources at www.asco.org/guidelines/esa and www.hematology.org/guidelines/esa

Overall, the 2010 guideline confirms that ESA therapy is associated with shorter survival and/or increased risk of tumour progression and recurrence—in addition to the previously highlighted increased risk of thromboembolism. The 2010 guideline recommends that for patients receiving myelotoxic chemotherapy with an Hb level of less than 10g/dL, physicians should discuss with them the potential risks and benefits of ESAs compared to the potential harms and benefits of transfusion. Transfusion carries a risk of serious infections and immune-mediated adverse events, but offers the benefit of a rapid rise in Hb levels. Patient preference should be taken into account in the final decision on treatment, the updated guideline cautions against using ESA under all other circumstances.

Specific recommendations are:

I General recommendation
The 2010 update includes the general recommendation that alternative causes of anaemia aside from chemotherapy or other underlying haemopoietic malignancy be explored before ESA treatment commences. Physicians should also aim to minimize the use of ESA in order to reduce the risk of thromboembolism, ‘particularly in patients with malignancy being treated with curative intent.’

FDA labelling indicates the use of ESAs in patients receiving chemotherapy for palliative intent, in order to reduce the need for transfusions. FDA does not recommend treatment with ESAs for patients receiving curative chemotherapy because of an increased risk of mortality and thromboembolism. The 2010 update notes, however, that because the evaluation of risks versus benefits has not been done according to subgroups with different chemotherapy intent, i.e. curative versus palliative, clinical judgement is required to determine the goal of treatment for individual patients. The update states, ‘Clinicians are urged to exercise caution in considering ESA use in patients with malignancy being treated with curative intent. The Update Committee stresses the importance of including a detailed discussion between healthcare providers and their patients about the potential harms and benefits of ESA therapy.’

The 2010 update gives examples of diseases for which the treatment goal should be curative: testicular cancer, first-line therapy of Hodgkin’s disease, and early stage breast, lung, or colon cancer.

The 2010 update also summarises the evidence showing both a statistically significant increased risk of mortality and thromboembolism, and the reduced need for transfusions, with ESA treatment. 

II Special commentary on the comparative effectiveness of epoetin and darbepoetin 
Regarding the comparative effectiveness of epoetin and darbepoetin, the position remains unchanged since 2007 that these agents are considered to be equivalent with respect to safety and efficacy.

IIIa Chemotherapy-induced anaemia: threshold for initiating ESA therapy 
The 2010 update recommends, in accordance with FDA-approved labelling, the use of epoetin or darbepoetin in patients with chemotherapy-induced anaemia and whose Hb concentration has fallen to below 10g/dL, in order to decrease the requirement for transfusions. The question of threshold, however, ‘merits further investigation’, as the 2010 Update Committee found evidence insufficient for recommending ESA treatment for patients with Hb concentrations higher than 10g/dL, or any associated increase in harms associated with doing so.

IIIb Chemotherapy-induced anaemia: initiating when Hb is > 10 g/dL but < 12 g/dL 
Clinical judgement is needed to decide when to commence ESA treatment in patients with anaemia whose Hb concentration is between 10 and 12 g/dL, as well as consideration of the risks, benefits, and goals of ESA treatment. The goal of such treatment remains the reduction of transfusions, rather than to improve quality of life, for which the evidence remains insufficient.

IV Thromboembolytic risk 
The 2010 update confirms the 2007 guideline that the use of ESAs leads to a statistically significant increased risk for thromboembolism. The 2010 update, therefore, recommends that clinicians should carefully weigh the risk of thromboembolism in patients when prescribing ESAs. 

V Starting and modifying doses 
The 2010 update recommends following FDA guidelines, for example, starting epoetin at a dose of 150 U/g three times a week or 40,000 U weekly subcutaneously, and increasing or reducing the dose, or discontinuing, according to the outcome in terms of reduction of transfusions and Hb levels achieved. 

VI Discontinuing therapy for no response 
The 2010 update repeats the recommendations of 2007 that ESA treatment be discontinued in patients who do not respond within 6 to 8 weeks.

VII Hb target 
Given the evidence that ESA treatment leads to an increased risk in mortality, which has become more apparent since 2007, the 2010 update recommends that treatment aims to increase Hb to ‘the lowest concentration needed to avoid transfusions, which may vary by patient and by condition’. The available data do not identify a specific target Hb concentration for ESA therapy that is free from an increased risk of mortality.

VIII Iron monitoring and supplementation 
As in 2007, the 2010 update suggestions that patients should be monitored for iron status, including iron levels and iron-binding capacity, and treated with iron supplements where necessary. There is insufficient evidence to support intravenous iron therapy.

IX Anaemia in patients not receiving concurrent chemotherapy 
As for the 2007 guideline, the 2010 update continues to recommend that ESA treatment should be limited to patients undergoing concurrent chemotherapy, and that treatment should be discontinued when patients complete their chemotherapy course.

X Treatment of anaemia in patients with non-myeloid haematologic malignancies who are receiving concurrent chemotherapy 
As in 2007, the 2010 update recommends that before considering use of ESAs, physicians should first observe the outcomes of chemotherapy and/or corticosteroids in patients with myeloma, non-Hodgkin’s lymphoma, or chronic lymphocytic leukaemia. Treatment with ESAs should commence only if there is no increase in Hb in these patients.

In its conclusions, the 2010 update calls for additional research to ‘clarify the mechanisms of harm and, particularly, the groups of patients or circumstances of clinical use that are least associated with these risks’. The authors add, ‘This understanding is paramount to the ability of clinicians to extend the benefit of these drugs while reducing the risks.’

Competing interests: None.

Provenance and peer review: Article prepared based on published scientific or research papers recommended by members of Editorial Board; internally peer reviewed.

Editor’s comments

The guideline is based on a comprehensive literature review, concludes that of erythropoiesis-stimulating agents are considered therapeutic equivalent choices.

Reference

1. Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Somerfield MR, Temin S. American Society of Clinical Oncology/American Society of Hematology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. J Oncol Pract. 2010 Nov;6(6):317-20. doi: 10.1200/JOP.2010.000132

Julie Clayton, PhD, GaBI Journal Editor

Disclosure of Conflict of Interest Statement is available upon request.

Introduction: Childhood obesity is associated with morbidity and premature death. The worldwide prevalence of childhood obesity is increasing and, in some countries, occurs in 15% of children. Obesity-related changes in physiology and body composition may affect drug pharmacokinetics and dosing. Antibiotics are the most commonly prescribed medications in children. This review summarizes pharmacokinetic information for antibiotics in obese children and implications for dosing. 
Methods: We searched PubMed, EMBASE, and International Pharmaceutical Abstracts for pharmacokinetic studies of antimicrobial agents in obese children. We used combined search  terms including obesity, pharmacokinetics, pharmacodynamics, drug toxicity, dosing, anti-infective agents, antiviral agents, and antifungal agents. 
Results: We identified four pharmacokinetic studies of antibiotics in obese children: one for cefazolin and tobramycin, one for gentamicin, and two for vancomycin. These drugs have variable tissue and body water distribution. Two the studies (tobramycin and gentamicin) reported pharmacokinetic differences that required dosing modifications in obese children relative to their non-obese peers. 
Discussion: The lack of pharmacokinetic studies in obese children is pronounced. The scarcity of pharmacokinetic data limits the ability to predict drug disposition using drug physicochemical properties and impedes a rational approach to selection of appropriate body size measures for dosing. Given this knowledge gap, prospective trials in obese children are needed. 
Conclusion: Prospective studies of antimicrobials in obese children should be prioritized based on clinical importance and evidence of suboptimal dosing.

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Abstract:
Although Liposomal Amphotericin B injectable (LAMB) is the WHO-recommended drug for Visceral Leishmaniasis (VL), it is still difficult for patients to access in many countries. Price is a major obstacle, but not the only one: despite the development and marketing of generic liposomal amphotericin B formulations, the lack of clear regulatory guidance remains a key bottleneck. Given this context, recent approval of the first generic liposomal formulation (pegylated liposomal doxorubicin) by the US Food and Drug Administration (US FDA) in February 2013 could be a turning point, and could serve as a basis for WHO to develop guidance for the evaluation of generic liposomal formulations.

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Abstract:
Solid organ transplant recipients are treated with immunosuppressive drugs in order to prevent rejection of their grafts. The most frequently used maintenance immunosuppressive drugs in Europe are the calcineurin inhibitors (tacrolimus and cyclosporine), and mycophenolic acid (mycophenolate mofetil). For all three drugs patents have expired and generic formulations have been registered. In 2010 the Council of the  European Society for Organ Transplantation (ESOT) formed an Advisory Committee to formulate recommendations on the use of generic drugs in solid organ transplant recipients1. The initiative was taken as a result of concerns regarding generic substitution of immunosuppressive drugs. Health insurance companies stimulate the prescription of generic drugs, as they have substantially lower prices compared to the original brand name product. In some countries this led to substitutions by pharmacists, even in patients who had a prescription for brand name drug. Prescribers felt that they were no longer in control of what drug their patients were taking. Uncontrolled substitutions by pharmacists have been linked to graft dysfunction and the transplant community sent signals to ESOT, as well as to the national transplant societies, that mobilized working groups and advisory committees to formulate guidelines on how to deal with generic substitution. In this manuscript the contents of the ESOT guideline are summarized, as well as some recent developments in this field. For the full text the reader is referred to the original publication.

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Abstract:
In Japan, a biosimilar product is defined as a biotechnological drug product developed by a different company which is comparable to the approved biotechnology-derived product (reference product) of an innovator company [1].

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Aim: To explain the components of pharmaceutical expenditure in order to illustrate the strengths and limitations of this indicator. Particularly, the influence of policies applied in European countries, which impact both price and volume of medicines will be explored.
Methodology: This article is based on a presentation held at the EuroDURG/ISPE meeting in Antwerp on 1 December 2011. The presentation had the teaching goal to raise awareness about limitations, and it aimed to build capacity on how to interpret pharmaceutical expenditure data. The information about pharmaceutical policies in European countries has been updated based on a survey by the Vienna WHO Collaborating Centre for Pharmaceutical Pricing and Reimbursement Policies.
Results: Pharmaceutical expenditure consists of price and volume components. Prices may be indicated at different levels: Key price types are the ex-factory price (manufacturer level), the pharmacy purchasing price (wholesale) and the pharmacy retail price (pharmacy). Taxes, such as the value-added tax, are likely to be added. In the hospital sector different price types (official hospital price and actual hospital price) apply. Volume may be expressed in sales units (e.g. Standard Units), prescriptions, or Defined Daily Doses. Pharmaceutical policies (e.g. reference price system, prescription monitoring, discounts and rebates) influence prices or volume and thus pharmaceutical expenditure.
Conclusions: For analyses based on pharmaceutical expenditure data it is advised to critically check which components are included and which markets the data refer to. Particular attention should be paid to the limitation that total pharmaceutical expenditure data frequently only cover the out-patient sector.

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Background: Increase in the treatment cost has influenced the consumer’s interest towards generic medicines. Many developed nations have modified National Drug Policies to promote the use of generic medicines. However, a key point that affects the goals National drug Policies is whether the consumers will accept to choose generic medicines for their ailments.
Objective: The current study aims to assess the patient’s knowledge and attitudes toward the generic medicines in Hospital Seberang Jaya (HSJ), which is a second biggest public hospital in the State of Penang, Malaysia.
Methodology: A cross-sectional survey was conducted using a 26-item questionnaire.  The minimum effective sample size needed for this study was 460.  All the patients who came for their refill were invited to give their feedback for the survey. Data was analyzed using appropriate descriptive statistics using Statistical Package for Social Science (SPSS®) version 16.
Results: A total N= 420 responded to the study (Response rate 91.3%). Mean age of the respondents was 36 ±9.3. Most of the participants were Malay followed by Chinese and Indians. Overall, 232(55.7%) of patients were aware of the cheaper bands in Malaysia. About 122(29.3%) of the respondents believe that generic medicines are less in quality than the brand medicines. Gender was the only variable that was found significantly associated with the respondent perceptions about the quality of generic medicines. In terms of selection of generic medicines, it is seen that about 313 (75.6%) of the respondents were purchasing the medicine based on physician’s advice and 219 (52.9%) were purchasing the medicines in consultation with the pharmacist. However, if the cost saving is about 50.0% or more on the purchase of generic medicines, then 303 (73.2%) of the respondents have shown willingness to ask the physician and pharmacist for the generic medicines.
Conclusion: Overall, in this study patients were found to have poor knowledge towards generic medicines availability and efficacy. Patient’s negative views about the safety, efficacy and quality were found to be the main barriers for improving utilization of generics in the Malaysian public health system.

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Abstract:
For generic approval of small molecule (chemical) drug products, the United States Food and Drug Administration (FDA) requires evidence of equivalence in average bioavailability be provided through the conduct of bioavailability/bioequivalence study. To address drug interchangeability, the concept of population bioequivalence (PBE) for drug prescribability and individual bioequivalence (IBE) for drug switchability under replicated crossover design are also proposed. In practice, it is recognized that standard methods for bioequivalence assessment of small molecule drug products cannot be directly applied to assessing biosimilarity of biosimilar products due to some fundamental differences between small molecule generics and large molecule biosimilar products. In this article, we consider assessing biosimilarity of biosimilar products by constructing a 95% upper confidence bound for the IBE criterion recommended by FDA based on the method of the generalized pivotal quantities (GPQs) under a 2×3 extra-reference crossover design proposed by Chow et al. (2002). A simulation study is conducted to evaluate the performance of the proposed method under various scenarios.

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Abstract: 
Italy is the third largest national pharmaceutical market in Europe [1]. Health care is mainly delivered through the National Health Service (NHS), a public service funded by general taxation which provides universal coverage and comprehensive healthcare free at the point of delivery. The system is highly decentralized and 20 Regional Health Authorities (RHA) are responsible for planning healthcare services and allocating financial resources. In principle, local autonomy also implies stronger financial accountability, which leads regions to develop different economic strategies. To control and rationalise expenditure, each Italian RHA can establish a central organisation for purchasing goods and services [2]. The regions differ widely among in size, with residential populations ranging from around 130,000 (Valle d’Aosta) to 10,000,000 inhabitants (Lombardy) (Figure 1) [3]. Eight large regions are divided in so called “Vast Areas” (VA), although only two of them (Emilia-Romagna and Tuscany) committed these organizations for drugs purchasing.

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Abstract: 
The European Organisation for Research and Treatment of Cancer (EORTC) has updated its 2006 guideline on the use of granulocyte colony-stimulating factor (G-CSF) for the prevention of febrile neutropenia (FN), a sometimes fatal condition in which a loss of neutrophils in patients receiving chemotherapy leads to infections and fever. The guideline provides recommendations on the assessment of risk factors for FN, and the choice of G-CSF formulation.

Background

Patients undergoing chemotherapy for cancer are at risk of developing Febrile Neutropenia (FN), a condition in which a loss of neutrophils leads to infection, fever and sepsis, and is fatal in 9.5 to 12.5 per cent of cases. Patients aged over 65, and those undergoing myelosuppressive therapy appear to be most at risk, and may have their chemotherapy delayed, or treatment doses reduced, to minimize the effects of FN. As a consequence, they are then more prone to treatment failure and poorer clinical outcome with regard to their cancer, particularly solid tumours and lymphoma.