Practical Info The pipeline for new antimalarial drugs is healthier than ever before, and several new compounds are in various stages of development. Some novel antimalarial agents are already registered in some countries. The decision to recommend antimalarial drugs for general use depends on the strength of the evidence for safety and efficacy and the context of use. In general, when there are no satisfactory alternatives, newly registered drugs may be recommended; however, for global or unrestricted recommendations, considerably more evidence than that submitted for registration is usually required, to provide sufficient confidence for their safety, efficacy and relative merits as compared with currently recommended treatments. Several new antimalarial drugs or new combinations have been introduced recently. Some are still in the preregistration phase and are not discussed here. Arterolane + piperaquine, artemisinin + piperaquine base and artemisinin + napththoquine are new ACTs, which are registered and used in some countries. In addition, there are several new generic formulations of existing drugs. None of these yet has a sufficient evidence base for general recommendation (i.e. unrestricted use). Artesunate + pyronaridine A systematic review of artesunate + pyronaridine included six trials with a total of 3718 patients. Artesunate + pyronaridine showed good efficacy as compared with artemether + lumefantrine and artesunate + mefloquine in adults and older children with P. falciparum malaria, but the current evidence for young children is insufficient to be confident that the drug is as effective as currently recommended options. In addition, regulatory authorities noted slightly higher hepatic transaminase concentrations in artesunate + pyronaridine recipients than in comparison groups and recommended further studies to characterize the risk for hepatotoxicity. Preliminary data from repeat-dosing studies are reassuring. In 2012, artesunate-pyronaridine was granted a positive scientific opinion under the European Medicines Agency (EMA) Article 58 procedure, but with a restricted label, mainly due to concerns over potential hepatotoxicity of the pyronaridine component, efficacy in children under 5 years of age, and safety, especially with repeat dosing (126). In 2015, an EMA Scientific Advisory Group concluded that cumulative safety data on hepatic events had provided sufficient evidence to alleviate concerns over hepatotoxicity and thus to allow recommendation of the use of artesunate pyronaridine for the treatment and re-treatment of uncomplicated malaria in patients without signs of hepatic injury (including children weighing 5 kg and over). The EMA therefore modified the product label to remove all restrictions on repeat dosing, on use only in areas of high antimalarial drug resistance and low malaria transmission, and on requirements to monitor liver function. In addition, it granted a positive scientific opinion for artesunatepyronaridine granules for the treatment of children with a body weight of 5–20 kg (125). Artesunate-pyronaridine was included in WHO’s list of prequalified medicines for malaria in April 2012, based on the EMA’s positive scientific opinion of this product in accordance with Article 58. Since labelling provisions are based on EMA conclusions, these provisions were updated as a result of the EMA’s 2015 review. Products included in the WHO prequalification list are those that have been assessed through the various mechanisms and found to comply with WHO-recommended regulatory standards and requirements for quality, safety and efficacy. In June 2017, artesunate-pyronaridine was also added to the WHO Model List of Essential Medicines and Model List of Essential Medicines for Children. Due to the hepatotoxicity concerns identified in 2012, the WHO Guidelines for the treatment of malaria (2015) did not recommend the use of artesunate-pyronaridine for general use. A further meeting in December 2017 resulted in the need for GMP to request, in 2018, the support of the WHO Advisory Committee on Safety of Medicinal Products to conduct an independent expert review of all available data and information. Having completed its review, the committee considered that the current safety restrictions on the use of artesunatepyronaridine (Pyramax®) for the treatment of uncomplicated malaria, as stated in the Guidelines for the treatment of malaria, are no longer justified (126). GMP will revise the Guidelines based on new information available in 2021. Arterolane + piperaquine is a combination of a synthetic ozonide and piperaquine phosphate that is registered in India. There are currently insufficient data to make general recommendations. Artemisinin + piperaquine base combines two wellestablished, well-tolerated compounds. It differs from previous treatments in that the piperaquine is in the base form, the artemisinin dose is relatively low, and the current recommendation is for only a 2-day regimen. There are insufficient data from clinical trials for a general recommendation, and there is concern that the artemisinin dose regimen provides insufficient protection against resistance to the piperaquine component. Artemisinin + naphthoquine is also a combination of two relatively old compounds that is currently being promoted as a single-dose regimen, contrary to WHO advice for 3 days of the artemisinin derivative. There are currently insufficient data from rigorously conducted randomized controlled trials to make general recommendations. Many ACTs are generics. The bioavailability of generics of currently recommended drugs must be comparable to that of the established, originally registered product, and the satisfactory pharmaceutical quality of the product must be maintained. Please refer to Good procurement practices for artemisininbased antimalaria medicines (127).