Primaquine supply
Of the 51 manufacturers of primaquine identified, most were located in Asia. Sanofi and Remedica were the only producers of SRA-approved primaquine, and Ipca was identified as the main manufacturer of primaquine API. A few manufacturers of non SRA-approved primaquine were also interviewed.
Sanofi’s current primary customer is the United States Army, which places a single order of primaquine, usually on a yearly basis. Sanofi primaquine remains relatively expensive, with a current selling price of approximately $0.50 per 15 mg tablet as compared to Remedica tablets, which are approximately $0.03 per 7.5 mg tablet [9]. The high price is driven primarily by low demand and high quality of FDA-approved API. Sanofi FDA-approved primaquine is currently manufactured in Canada. A Sanofi plant in Colombia, GMP-certified by Colombian and Argentinean regulatory authorities, also produces 15 mg primaquine tablets, for regional markets, with greater capacity. Sanofi is working on optimizing production costs at both plants, and exploring various scenarios to register primaquine in malaria-endemic countries in which P. falciparum elimination could be considered.
Remedica tablets are SRA-approved by the Cyprus Ministry of Health-pharmaceutical services, a National competent authority listed by the SRA European Medicines Agency (EMA). Since 2011, Remedica has been the primary supplier of primaquine purchased through the GFATM, of which procurement has been growing rapidly over the past few years. In 2012, Remedica supplied approximately 34 million primaquine tablets to the GFATM [9], mostly for the radical cure of P. vivax malaria in southern and Southeast Asia. As SRA approval is often the minimum requirement for countries to procure drugs with international donor funding, Remedica supplies primaquine directly to countries, and also through donors, including UNICEF and the WHO/Roll Back Malaria Partnership.
Ipca is a major pharmaceutical manufacturer in India, producing approximately 2.4 million kg of assorted APIs per year, including approximately 48,000 kg of primaquine annually in two batches. Prices of primaquine phosphate API have increased over the past few years but this may change soon, as the US-based company Apicore LLC received an FDA Drug Master File for primaquine in July 2013, bringing more competition to the market.
Manufacturers that produce non SRA-approved primaquine stated a number of reasons for not seeking SRA approval for this drug. The most common reason was uncertainty around the commercial demand of an SRA-approved primaquine tablet. However, when told about growing interests in using SLD primaquine as a gametocytocide in African countries, manufacturers generally expressed an interest in developing a higher quality primaquine product and potentially seeking SRA approval or WHO prequalification. WHO prequalification is of particular interest for SLD primaquine, as most anti-malarials to date, including ACT, have undergone this route for use in sub-Saharan Africa. However, it is currently not possible for SLD primaquine to proceed through WHO prequalification, as SLD primaquine would first need to be listed on the WHO prequalification programme Expression of Interest (EOI) list, after which the WHO prequalification programme would be willing to accept a dossier for SLD primaquine.
Dosing
In-country interviews with key end users revealed that a major barrier to primaquine uptake is the lack of clarity of primaquine dosing in clinical settings. The current WHO recommendation is a weight-based 0.25 mg/kg dose, which is challenging to implement in actual field settings, where dosing is usually based on patient age. Age-based dosing bands are derived from the therapeutic dose range, a weight-based range spanning from the lowest efficacious dose to the highest safe dose, translated using weight-for-age data [13]. As primaquine safety depends on dose, there is a critical need to inform dosing practices by defining the therapeutic dose range of SLD primaquine for P. falciparum gametocytes.
The width of the therapeutic dose range of primaquine also has implications for dosing practices in clinical settings. Figure 1 illustrates several hypothetical therapeutic dose ranges of primaquine, and how these ranges may affect dosing practices, per the WHO recommendation. For example, if a 10 kg and a 20 kg child are dosed, and the therapeutic dose range is defined as 0.12 to 0.3 mg/kg, both children could be treated with a single 3 mg tablet of primaquine. However, if the therapeutic dose range were narrower, the dosing regimen becomes more complicated; the 10 kg child would require one 2.5 mg tablet while the 20 kg child would need two 2.5 mg tablets. Tablet strength becomes important, as bigger strengths may not afford weight-based coverage for paediatric patients, as highlighted in red (Fig. 1).
As the WHO recommends that SLD primaquine be used with an ACT, the dosing bands for commonly used types of ACT are also shown in Fig. 1. Dosing practices would be easier if the dosing bands for ACT and primaquine could be aligned, but this will unfortunately be challenging, as the dosing bands for artesunate-amodiaquine (AS-AQ) differ significantly from those for artemether–lumefantrine (AL) and dihydroartemisinin–piperaquine (DHA–PPQ).
To enable the use of SLD primaquine across the paediatric population, researchers and manufacturers agreed on a need for the development of a lower strength tablet for SRA approval or WHO prequalification. The current SRA-approved tablets, available from Remedica and Sanofi, are only available in 7.5 or 15 mg strengths, respectively, which do not allow for accurate dosing in sub-sections of the paediatric population. Although generic companies in India produce primaquine tablets at 2.5 mg strength, these are not SRA-approved and therefore do not meet the quality standards set out by international donors, and the therapeutic dose range is needed to determine whether 2.5 mg is a suitable tablet strength for SLD primaquine. Current SRA-approved primaquine tablets also do not have “splitting lines” or “break lines” which help facilitate pill-splitting for the administration of lower doses. Even if these lines were added, however, the tablets are already too small in size to split accurately; the 7.5 mg Remedica tablet is only 6 mm in diameter.
Manufacturers expressed an interest in developing lower strength primaquine tablets, but due to the complexity of these processes, the exact tablet strength needed to dose paediatric populations first needs to be established. Usually, tablets are made smaller using the same ratio of excipients to API, known as a “homothetic mix.” However, manufacturers stated that the primaquine tablets currently available are too small to be further reduced. Since the ratio of API to excipients determines the absorption and bioavailability of the API, seeking regulatory approval for changes to this ratio usually requires the submission of bioequivalence study data, which manufacturers expressed would both extend the amount of time required for regulatory approval, and furthermore add complexity to the process. It is possible to expedite the regulatory approval process by applying for a biowaiver, and although the properties of primaquine are likely to fulfill these biowaiver requirements [14], manufacturers expressed a general lack of understanding of this process. In the event that biowaiver requirements cannot be fulfilled, and furthermore the absorption and bioavailability of the API for homothetic mix(es) are not adequate for regulatory requirements, liquid-based formulations would need to be developed to allow for the availability of lower strength doses of primaquine.
Manufacturers also noted that small tablets are difficult to administer to paediatric patients, and dispersible tablets or liquid formulations are usually preferred. However, they also stated that new formulations are expensive and time consuming to develop, and may present additional regulatory hurdles since bioequivalence data would likely be required. Manufacturers also mentioned that it is possible to crush currently available primaquine tablets for paediatric use. At the time of study, the efficacy and reproducibility of this method in clinical practice had not been tested, but Sanofi has since released a Standard Operating Procedure for this practice [15]. Manufacturers expressed however, that the crushing of tablets is not an optimal solution to paediatric dosing, as the primaquine API is extremely bitter and is frequently found not to be palatable. Thus, they suggested that a child-friendly formulation would be preferred, and should furthermore strive to mask the bitter taste of primaquine API.
Country perspectives
African countries have little experience administering primaquine as part of routine malaria case management, and in-country interviews with key informants in National Malaria Control Programmes and their partner organizations revealed varying levels of understanding surrounding the use of primaquine. While some individuals were unaware that SLD primaquine could be used to clear mature P. falciparum gametocytes, others demonstrated a detailed understanding of primaquine as a gametocytocide. Despite varying degrees of knowledge, all countries in our case studies expressed interest in adopting primaquine as a transmission-blocking agent for P. falciparum malaria.
Respondents who were aware of primaquine and its use as an anti-malarial drug cited several benefits. Primarily, primaquine is an effective transmission-blocking tool for the control and elimination of P. falciparum malaria. In Ethiopia, the Ministry of Health (MoH) noted that the use of primaquine could help to achieve their ambitious goal of malaria elimination in low-transmission areas by 2015. In Senegal, where malaria transmission levels are higher and elimination is not the primary objective, experts from the NMCP agreed on the transmission-blocking potential of primaquine as a critical tool for reducing malaria transmission. In Zanzibar, health experts emphasized the need for primaquine to eliminate P. falciparum malaria.
Safety
Despite interest in adopting primaquine as a P. falciparum gametocytocide, all countries expressed safety concerns of the haemolytic potential of primaquine in G6PDd individuals. To facilitate the adoption of the WHO recommendation and to inform local deployment strategies, health experts requested that maps of the local prevalence of G6PD deficiency be made available. A second concern noted by academics, drug regulators, international organizations and national programmes arises from the potential risks that primaquine may cause in vulnerable patient groups, including small children and patients with other co-morbidities including HIV, sickle cell anaemia or malnutrition. Doctors and members of the NMCP in Swaziland, a country with the highest HIV prevalence at 26.5% [16], voiced unease about the use of primaquine among HIV-positive individuals because haematologic disorders, including anaemia, are particularly common in HIV-positive patients [17].
Regulatory issues
Countries explained a number of regulatory processes that may introduce delays and pose challenges to the adoption and implementation of SLD primaquine. Country anti-malarial drug guidelines are only reviewed, revised, and updated on a periodic basis potentially delaying anti-malarial policy changes at the national level. However, countries suggested the possibility of publishing a “circular” or interim recommendation, which can act as a standing recommendation until new guidelines are published. The process for policy change also varies between countries. In Zambia, a pre-requisite to drug registration is the inclusion of the product in existing malaria treatment policy guidelines whereas in Senegal, a drug is much more likely to be included in their guidelines if it is already registered for in-country use.
Regulatory requirements for primaquine registration presented additional obstacles and delays to the adoption of SLD primaquine as policy. The formal registration of drug products can take anywhere from one month, which is the case for Zanzibar, to up to two years, as is the case for Ethiopia and Zambia. Fortunately, most countries have an expedited review process, a process that generally takes anywhere between three to six months. In Ethiopia and Senegal, an expedited review is merited when the drug under consideration has demonstrated a clear public health need. In Zambia, an expedited review is possible if the drug is registered in another Southern African Development Community country. Swaziland does not currently have a drug regulatory authority, and generally follows South Africa’s recommendations.
Some countries also have additional regulations that pose further delays; in Senegal, manufacturers are required to submit product dossiers to make sure that products are safe and effective for use by local patients. Occasionally, in-country registration requires that the product be deemed as cost-effective.
Field deployment
Country programmes, international organizations and researchers expressed differing opinions on the best methods with which to deploy primaquine. They described three dominant strategies for the use of primaquine to interrupt malaria transmission: the treatment of confirmed clinical cases only, mass screen and treat (MSaT) strategies, and mass drug administration (MDA) campaigns. MSaT strategies aim to screen entire populations of interest, treating all individuals with detectable levels of malaria parasitaemia. MDA entails the administration of a curative regimen of anti-malarials to all individuals within a given locale, regardless of parasitaemia or the presence of symptoms [18].
Among those interviewed, the most widely accepted SLD primaquine deployment option was the treatment of confirmed clinical cases, noted by key opinion leaders, researchers, local doctors, and members of the NMCPs. However, there was interest in broader deployment strategies for primaquine as its use for clinical cases might have limited impact on the overall parasite reservoir. Some international organizations, governmental agencies, and researchers advocated for MSaT; in Ethiopia, the MoH recommended the use of MSaT during regional epidemics and MDA if the malaria slide positivity rate exceeds 50%. The NMCP in Swaziland was also open to targeted MSaT with primaquine. At the time of study, researchers in Zambia were considering the addition of primaquine to an MSaT study using ACT. Malaria researchers expressed a number of drawbacks to MSaT however, including operational challenges and high costs.
Other malaria researchers believed that MDA could best ensure malaria elimination within a population. However, the notion of deploying primaquine in an MDA campaign raised numerous concerns of safety in individuals with G6PD deficiency. Experts raised ethical questions about MDA, as to whether it is acceptable to pose potential risks to individuals in order to benefit entire populations. Furthermore, country programmes were hesitant to implement a strategy that is not currently recommended by the WHO.