Comparison 4. Pyronaridine‐artesunate versus other antimalarials for all malaria subtypes (safety outcomes only).

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Serious adverse events	7	3941	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.54, 2.84]
2 Adverse events leading to withdrawal	6	3911	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.58, 1.94]
3 First treatment, ALT increase > 5 × ULN	14	6581	Risk Ratio (M‐H, Fixed, 95% CI)	3.34 [1.63, 6.84]
4 First treatment, AST increase > 5 × ULN	14	6581	Risk Ratio (M‐H, Fixed, 95% CI)	1.80 [0.89, 3.65]
5 First treatment, bilirubin increase > 2.5 × ULN	13	6384	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.49, 2.18]
6 Subsequent treatment(s), ALT increase > 5 × ULN	7	1649	Risk Ratio (M‐H, Fixed, 95% CI)	2.18 [0.76, 6.27]
7 Subsequent treatment(s), AST increase > 5 × ULN	7	1649	Risk Ratio (M‐H, Fixed, 95% CI)	1.82 [0.74, 4.44]
8 Subsequent treatment(s), bilirubin increase > 2.5 × ULN	7	1649	Risk Ratio (M‐H, Fixed, 95% CI)	1.13 [0.42, 3.01]
9 Sensitivity analysis: first treatment, ALT increase > 5 × ULN	10	5672	Risk Ratio (M‐H, Fixed, 95% CI)	4.07 [1.83, 9.05]
10 Other adverse events	10		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
10.1 Blood and lymphatic: anaemias	4	4517	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.86, 1.54]
10.2 Blood and lymphatic: eosinophilic disorders	2	2543	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.86, 1.93]
10.3 Blood and lymphatic: leukocytoses	2	2615	Risk Ratio (M‐H, Fixed, 95% CI)	0.76 [0.42, 1.37]
10.4 Blood and lymphatic: neutropaenias	2	2616	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.63, 1.10]
10.5 Cardiac: cardiac arrhythmias	1	180	Risk Ratio (M‐H, Fixed, 95% CI)	5.95 [0.25, 143.93]
10.6 Cardiac: cardiac signs and symptoms	5	2108	Risk Ratio (M‐H, Fixed, 95% CI)	0.57 [0.37, 0.89]
10.7 Cardiac: myocardial disorders	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.58]
10.8 Ear: ear disorders	1	197	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.01, 7.69]
10.9 Gastrointestinal: diarrhoea (excl infective)	4	411	Risk Ratio (M‐H, Fixed, 95% CI)	2.56 [1.10, 5.99]
10.10 Gastrointestinal: dyspeptic signs and symptoms	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.13, 68.26]
10.11 Gastrointestinal: GI and abdominal pains	7	4544	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.87, 1.45]
10.12 Gastrointestinal: nausea and vomiting symptoms	9	5534	Risk Ratio (M‐H, Fixed, 95% CI)	0.91 [0.71, 1.17]
10.13 General: asthenic conditions	2	653	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.64, 2.75]
10.14 General: general signs and symptoms	1	535	Risk Ratio (M‐H, Fixed, 95% CI)	1.20 [0.54, 2.70]
10.15 General: feelings and sensations	1	197	Risk Ratio (M‐H, Fixed, 95% CI)	4.75 [0.23, 97.79]
10.16 General: febrile disorders	2	715	Risk Ratio (M‐H, Fixed, 95% CI)	1.39 [0.65, 2.96]
10.17 General: pain and discomfort	1	197	Risk Ratio (M‐H, Fixed, 95% CI)	0.19 [0.01, 3.91]
10.18 Infections and infestations: eye and eyelid	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	3.0 [0.13, 68.26]
10.19 Infections and infestations: LRTI and lung	2	3216	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.83, 1.11]
10.20 Infections and infestations: URTI	7	5350	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.88, 1.20]
10.21 Investigations: ECG	4	3347	Risk Ratio (M‐H, Fixed, 95% CI)	0.46 [0.36, 0.58]
10.22 Investigations: skeletal/cardiac muscle analyses	2	636	Risk Ratio (M‐H, Fixed, 95% CI)	1.32 [0.55, 3.15]
10.23 Investigations: physical exam	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.58]
10.24 Investigations: platelet	2	565	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.55, 1.56]
10.25 Investigations: protein	1	535	Risk Ratio (M‐H, Fixed, 95% CI)	0.67 [0.36, 1.24]
10.26 Metabolism and nutrition: appetite disorders	3	683	Risk Ratio (M‐H, Fixed, 95% CI)	1.47 [0.80, 2.68]
10.27 Metabolism and nutrition: hypoglycaemia conditions	1	535	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.50, 1.46]
10.28 Metabolism and nutrition: metabolic disorders	1	2681	Risk Ratio (M‐H, Fixed, 95% CI)	0.88 [0.61, 1.29]
10.29 MSK and connective tissue: muscle pains	3	1924	Risk Ratio (M‐H, Fixed, 95% CI)	1.40 [0.97, 2.01]
10.30 MSK and connective tissue: pain and discomfort	1	197	Risk Ratio (M‐H, Fixed, 95% CI)	0.32 [0.01, 7.69]
10.31 Nervous system: headaches	9	6271	Risk Ratio (M‐H, Fixed, 95% CI)	1.09 [0.90, 1.32]
10.32 Nervous system: sleep disturbance	1	180	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.03, 15.99]
10.33 Nervous system: paraesthesias and dysasthesias	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.58]
10.34 Respiratory: coughing and assoc symptoms	6	6412	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.82, 1.19]
10.35 Respiratory: upper respiratory tract signs and symptoms	3	407	Risk Ratio (M‐H, Fixed, 95% CI)	1.80 [0.32, 10.07]
10.36 Renal and urinary: urinary abnormalities	1	197	Risk Ratio (M‐H, Fixed, 95% CI)	1.90 [0.18, 20.63]
10.37 Skin and subcutaneous tissue: dermatitis and eczema	2	276	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.15, 6.99]
10.38 Skin and subcutaneous tissue: pruritis	2	184	Risk Ratio (M‐H, Fixed, 95% CI)	0.25 [0.13, 0.49]
10.39 Skin and subcutaneous tissue: rashes, eruptions, exanthems	1	197	Risk Ratio (M‐H, Fixed, 95% CI)	1.90 [0.18, 20.63]
10.40 Skin and subcutaneous tissue: urticaria	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.58]
10.41 Vascular: vascular hypotensive disorders	1	30	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.01, 7.58]