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Innovation in malaria drug packaging: Coartem® and Coartem® Dispersible

therapeutic drug levels during the middle third of the life cycle, when they are most sensitive to treatment [17,18]. This anti-malarial has been an important component of the crusade to roll back malaria.

The development of a dispersible formulation of Coartem® adapted for use in infants and young children demonstrates a patient-centric approach. Ahead of a call from WHO for child-friendly medicines, Novartis, working in partnership with Medicines for Malaria Venture (MMV), started the development of a new formulation of Coartem® for infants and young children: Coartem® Dispersible. The choice of which paediatric formulation to develop was carefully considered. Both syrups and powder for reconstitution, which are used for existing paediatric anti-malarial formulations, have several disadvantages: they are bulky to supply and store, and once opened/reconstituted, the stability and hygiene of the formulations can no longer be guaranteed. Accurate dosing of syrups, which are typically delivered in a multi-dose format, is difficult in the field. Consequently, a report from the Expert Committee on Selection and Use of Essential Medicines hosted by WHO, recommends the avoidance of oral liquids [19]. Novartis recognised an unmet medical need and responded with the delivery of a child-friendly formulation specifically designed to meet the needs of these vulnerable patients, supported by a rigorous clinical development programme. The development of Coartem® Dispersible represents a significant advance in the successful treatment of this population.

Novartis also has an ongoing commitment to the education of healthcare workers and the communities they serve. Initiatives include training courses – for example, a malaria case-management programme for nurses in Zambia – and the development of educational materials for healthcare workers and mothers/caregivers. These have been translated into several different African languages, and are distributed free of charge to the countries that request them. In addition, Novartis

Malaria is highly preventable and treatable, yet it is still a major cause of disease and death worldwide, especially in tropical and sub-tropical regions where it stems from and causes poverty. There are approximately 881,000 malaria-related deaths every year [1], with nine out of ten deaths occurring in sub-Saharan Africa and 85% of deaths in children under five years old. This equates to a child dying of malaria in Africa every 30 seconds [2]. In 2008, it was reported that 109 countries were endemic for malaria, with 45 of these countries being within Africa [1]. There were an estimated 247 million episodes of malaria in 2006, with 86% of cases reported in the African region [3].

In addition to the human cost of malaria, the economic burden of the disease is vast. It is thought that malaria causes an average loss of 1.3% of annual economic growth in countries with intense transmission [4]. Malaria affects productivity – adults with malaria cannot work, and children with malaria cannot attend school. Up to 40% of African health budgets are spent on malaria each year [4].

Effective control and treatment of malaria also presents enormous logistical challenges. Many at-risk populations live in extreme poverty in remote rural areas. Poor and rural families are the least likely to have access to preventative measures such as insecticide-treated nets [5] that are fundamental to malaria control, and are less able to afford treatment once infection has occurred [5].

The key to reducing the burden of malaria is an integrated approach that combines preventative measures, such as long-lasting insecticide-treated bed nets and indoor residual spraying, with improved access to effective anti-malarial drugs.

Novartis’ commitment to the fight against malaria

The Novartis anti-malarial treatment Coartem® (Artemether/Lumefantrine) is the first fixed-dose artemisinin-based

combination therapy (ACT) prequalified by WHO [6], and the first ACT to be approved by the US Food and Drug Administration (FDA). The efficacy and safety of Coartem® has clearly been demonstrated in a clinical development programme spanning over 14 years and enrolling approximately 5000 patients [7,8]. Coartem® has consistently achieved 28-day PCR-corrected cure rates of over 95% in the evaluable populations, in randomised, controlled trials conducted in malaria-endemic areas [9–13]. It has demonstrated a favourable safety and tolerability profile [9–14], and when used first-line, in parallel with preventative measures, results in dramatic reductions in malaria-related deaths [15,16].

Coartem® has made a remarkable journey, from discovery of artemether in China to the delivery of a curative treatment to some of the world’s poorest communities, serving those most vulnerable to malaria – infants and children. From the outset, Novartis has worked in collaboration with government bodies, research institutes, and multilateral organisations to bring Coartem® to those who need it most. A landmark private-public agreement between Novartis and the World Health Organization (WHO) was unveiled in 2001, and in a ten-year pact, Novartis agreed to make Coartem® available without profit for distribution through WHO in malaria-endemic developing countries. This broad partnership has provided millions of children and adults with access to an effective high-quality treatment for malaria. Since 2001, Novartis has delivered more than 300 million treatments of Coartem®, without profit, helping to save an estimated 750,000 lives. Coartem® consistently achieves 28-day PCR-corrected cure rates of over 95% even in areas of multi-drug resistance; over 35 independent studies have confirmed the efficacy and safety of this anti-malarial in a wide range of geographical areas and in a variety of populations [7]. The simple, three-day regimen of Coartem®, means two asexual life cycles of P. falciparum are exposed to treatment (as recommended by WHO), while the twice-daily dosing helps to ensure that the parasites are exposed to

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During the development of the packaging for the new formulation of Coartem® – Coartem® Dispersible – Novartis commissioned several independent studies in African communities. Research in Kenya and Uganda was conducted by Dr. Ane Haaland (Communications Specialist, University of Oslo) and James Moloney (MPhil, University of Oslo), in partnership with the Kenyan and Ugandan Ministries of Health, and the Child Health and Development Centre (Makerere University, Uganda). Additional research was conducted in Malawi and Tanzania. All studies involved a variety of community members, including health workers, community health workers, caregivers and potential patients. The research in Kenya, Tanzania and Uganda

regularly brings together the managers of national malaria control programmes across Africa to share best practice in community awareness, health worker training, stock management and distribution, and health impact measurement.

The key role of packaging for malaria drugs

Packaging for anti-malarials must fulfil a number of criteria: it must protect the drug from humidity and physical damage under the conditions that prevail in malaria-endemic countries, be easy and hygienic to store, and be acceptable and understood by end users from a variety of cultural backgrounds who may have low levels of literacy.

Developing and testing Coartem® packaging

Drug packaging for anti-malarials has not traditionally been tested with end users in malaria-endemic countries. However, Ministries of Health and health workers appreciate testing, as it helps ensure that the packaging is practical in the environment in which it will be used and is understood by patients and rural health workers. Novartis invested in user testing of the Coartem® packaging for the public market over a period of several years, allowing the development of packaging for Coartem® that is relevant and accessible to health workers and patients in African countries.

Figure 1: Coartem® and Coartem® Dispersible packaging. The packs are colour-coded according to different body-weight groups.

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significance of completing the full treatment course. This is particularly important in areas where there are varying levels of education, illiteracy is common, and the disease is most prevalent. The Coartem® packaging is also colour-coded to denote the different dosing regimens recommended for different body-weight groups, which aids identification of the correct dose for each individual patient, and facilitates the recognition of the Coartem® product. By providing specific packs that contain a full three-day course of treatment for different body-weight groups, the need to score tablets or split packs is avoided.

The user-friendly packaging of Coartem® ensures proper dosing and patient compliance. Ensuring that a patient takes the full course of an anti-malarial drug is beneficial not just for the patient, but for society as a whole. If patients do not take anti-malarials correctly then this can present a major problem, as drug levels will potentially be sub-therapeutic and thus will not be adequate to cure the infection. Exposure of parasites to sub-therapeutic levels of anti-malarials could lead to the development of parasite resistance [21]. Appropriate dosing advice is vital for promoting compliance, reducing the emergence of resistance, and preserving the effectiveness of ACT.

Coartem® DispersibleThe majority of malaria deaths are in

children [1], but until recently there were no anti-malarials specifically formulated for this critical group. Novartis, working in partnership with Medicines for Malaria

was co-sponsored by Medicines for Malaria Venture.

Questionnaires, demonstrations and role-plays were employed to gather information on how health workers were using current Coartem® packaging and their impressions of the new packaging in development in partnership with WHO. Most participants were already familiar with Coartem® tablets, which they perceived to be effective and well packaged with clear instructions. During these sessions, a wide variety of feedback was obtained not only on the design of the packaging but also on the images used. For example, respondents felt it was important that a baby depicted on the pack intended for the smallest children looked ill, ‘so we believe that they have malaria’, but not so sick as to suggest that the mother had left it too long before getting medical help. In addition, respondents commented on hairstyles and head-dresses, style of dress, the colours used, and the way the mother was holding her baby. A middle ground had to be found to avoid cultural bias and make the images acceptable to different communities across Africa.

During field testing of the packaging, it became apparent that when educating patients on the need to complete the full course of Coartem®, health workers often failed to explain why this is important. Novartis responded to this by enhancing the educational features of the packaging and encouraging (in their training materials) health workers to use the pack as an

educational aid with mothers and patients. The usefulness of depicting a diminishing population of parasites with each dose – to explain why it is important to complete the course – was assessed by semi-structured questionnaires and observation in Tanzania and Uganda [20].

Coartem® – responding to the requirements for anti-malarial packaging

Coartem® supplied to the public market has an innovative packaging design that was developed in partnership with WHO to address the challenging requirements of anti-malarial packaging (Figure 1). The foil blister packs produced on stiff card protect the tablets from humidity and damage during transport, while the enclosure of each tablet in a separate blister provides hygienic storage. Clustering of tablets within the blister pack reminds the patient or caregiver how many tablets should be taken at each dose. Each pack contains one full three-day course of treatment, and different packs are produced for different body-weight groups, with a pictorial representation of the patient in each body-weight group. Consequently, each patient receives exactly the amount of medication required, reducing wastage and promoting correct dosing.

In addition to written instructions, the Coartem® packaging incorporates illustrations designed to increase the understanding of the treatment regimen, remind the patient of how many tablets to take at each time point, and to help explain the

Figure 2: Explanation of pictorial guides for health workers on the Coartem® Dispersible pack

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Venture, developed a dispersible formulation of Coartem® expressly tailored to the needs of children. Coartem® Dispersible is as efficacious as the crushed tablet formulation [10], with a similar safety profile. It is sweet tasting, easy to administer [10] and affordable. Coartem® Dispersible is the first dispersible ACT developed for children with uncomplicated P. falciparum malaria.

The Coartem® Dispersible packaging was created to further build on the legacy

Figure 3: Summary of levels of adherence to the three-day Coartem® regimen across different countries [18–21]

of the existing pack for standard Coartem® tablets. The packaging was enhanced on the basis of independent field testing with rural African health workers, patients and community members, including mothers. As literacy levels vary, the packaging was illustrated as much as possible. There are clear, three-step instructions on how to make up the dispersible formulation and give the dispersed tablet(s) to the child. Colour-coding of the different Coartem® packs according to the recommended dosing regimen for each body-weight range has been maintained with Coartem® Dispersible.

Key features of Coartem® Dispersible packaging include:

further development of the patient •illustrations to assist with the identification of the correct pack (Figure 2)images of malaria parasites decreasing •in number as the three-day course progresses, to indicate how the drug works and the reason why it is necessary to complete the full courseenhanced clarification of when to take •the tabletssimple instructions and illustrations to •indicate how to make up the dispersible formulation

The packaging serves as an educational tool that the health worker can use to teach

the caregiver how and when to administer the dispersible Coartem® tablets, and serves as a visual aid for the caregiver once at home. It is thought that educating the mother of a sick child may be the biggest factor in compliance with anti-malarial therapy. Ultimately, the packaging supports best practice in both local health service provision and patient use of Coartem®

Dispersible. Evidence for adherence and

acceptability of Coartem® packagingFeedback from the field testing was

utilised to create user-friendly packaging that promoted adherence to the three-day, twice-daily regimen. Several studies have confirmed excellent adherence to Coartem® under field conditions [22-25]; these data are summarised in Figure 3. In addition, data from a study in Tanzania indicate that the illustrations and design of the Coartem® packaging encourage patients to take their medication appropriately.

A study conducted in Malawi evaluated adherence to Coartem® using electronic containers that record the date and time of opening. Overall, 92% of study participants took all doses out of the electronic container, indicating excellent adherence [22]. Another study conducted in Bangladesh reported similarly high rates of adherence. In this study, adherence was assessed by counting remaining tablets and conducting interviews. Among the 160 study participants, 93.1% were judged to be adherent [23]. Examination of the 140 available blister packs revealed that the final sixth dose was missed most frequently; 64% of non-adherent patients missed their last dose [23]. The most frequent reason given for discontinuation of treatment was the improvement of condition. Once symptoms resolve, patient adherence to a treatment regimen can reduce. To try to counteract this possibility, illustrations were included on the Coartem® Dispersible packaging, which show a decrease in parasite numbers with each dose, to help explain to patients why it is so important to complete the full course of treatment. Adherence to the Coartem® regimen has also been examined in the context of home-based management of malaria in febrile children in Nigeria and Uganda [24]. Treatments were dispensed by community medicine distributors and administered by caregivers. Used at this community level, adherence to Coartem® was 81% in Uganda and 93% in Nigeria [24].

A further study, designed to prospectively examine the adherence to and acceptability of Coartem® administration in Tanzania, provides further evidence of excellent

adherence to the dosing schedule [25] and demonstrates that end users find the design of the Coartem® packaging useful in helping them to correctly adhere to the Coartem® regimen. Following microscopic confirmation of P. falciparum infection, the first dose of Coartem® was taken under supervision, with the remaining five doses taken unsupervised at home. Patients were randomised to receive a home-based assessment close to the scheduled time for one of the unsupervised doses, but were blinded to which follow-up visit they had been allocated. The full six-dose regimen was taken by 98% of patients, with 90% of doses being taken at the correct time. Only 1.7% of participants reported missing a dose [25]. Patient responses to a questionnaire indicated that the clustering of tablets for each dose of Coartem® within the blister packs was a helpful aid to remembering how many tablets to take at each dose. In addition, 91.8% of patients found the dosing pictogram useful. Illustrative instructions for the timing of drug administration provide a useful reminder of the dosing schedule in rural areas where few individuals have a clock or wristwatch [25].

Enhancing patient compliance by packaging solutions

The effort that Novartis has put in to the development of the Coartem® Dispersible pack was recently acknowledged by the Healthcare Compliance Packaging Council (HCPC) Europe.

The HCPC-Europe’s 2009 Conference involved an international forum of experts discussing the role of packaging in the context of patient adherence. Innovative packaging solutions containing elements that help and encourage patients to take their medication appropriately were presented, and the annual HCPC-Europe Compliance Pack Award was given to a pack that offered the most comprehensive support. Out of a large number of entries, the jury (HCPC-Europe’s Board and Advisory Board members) short-listed three outstanding packaging solutions for the award. The jury based their decision on the pack’s design (use of colours, icons, reminder aids and readability), ease of use (accessibility, compact, portable, longevity/re-closable, and life-time appeal), intuitiveness of use, leaflet presentation, practicality and sustainability.

Coartem® Dispersible was the winner of the 2009 HCPC-Europe’s Drug Packaging Design Award. This award symbolises an “innovative solution for what might appear to be a complex unsolvable problem”.

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Dr. Nadia elMasry PhD, MBA, is the Global Brand and Country Liaison Manager for the not-for-profit Novartis Malaria Initiatives, based in the company’s Headquarters in Switzerland. With over 14 years’ experience in the pharmaceutical industry, Dr. elMasry is currently responsible for the development and implementation of medical marketing activities and communication/education materials for healthcare professionals and patients across Africa.Email:nadia.elmasry@novartis.com

Dr. Chemtai Kipkeu, is the Medical Advisor for Novartis in Kenya. She is a medical doctor by training and has a clinical research background. Dr Kipkeu provides medical support for Novartis within the east and central African region.Email: chemtai.kipkeu@novartis.com

ConclusionsNovartis is a committed partner in the

fight against malaria. Coartem® consistently achieves 28-day PCR-corrected cure rates of over 95%, but however efficacious the anti-malarial, its impact will be diminished if not taken correctly. In order to facilitate adherence, Novartis has taken a patient-centric approach to developing the Coartem® and Coartem® Dispersible packaging. Faced with the considerable challenge of creating packaging suitable for use in rural Africa, which could be understood by and be acceptable to health workers, caregivers and patients from different cultural backgrounds and with variable levels of literacy, Novartis conducted extensive field tests of packaging concepts. The result is an innovative packaging solution that is fit for use in rural Africa.

Since 2001 Novartis has provided 300 million Coartem®/Coartem® Dispersible treatments on a not-for-profit basis to the public sector of malaria-endemic developing countries..

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