Artesun

Artesunate for injection: White crystalline powder.
Solvent (sodium bicarbonate injection): Clear, colourless liquid.
Diluent (sodium chloride injection): Clear, colourless liquid.
Each Artesun 60 mg box contains 1 vial of 60 mg artesunate powder for solution for injection, 1 ampoule of 1 ml sodium bicarbonate 50 mg/ml solution for injection and 1 ampoule of 5 ml sodium 9 mg/ml solution for injection.
Excipients/Inactive ingredients: Solvent: sodium bicarbonate.
Diluent: sodium chloride.

Pharmacotherapeutic group: Antimalarial. ATC code: P01BE03.
Pharmacology: Pharmacodynamics: Artesunate is a hemisuccinate derivative of dihydroartemisin, which itself formed by the reduction of artemisinin. Artemisinin is a sesquiterpene lactone endoperoxide extracted from qinghao (sweet wormwood, Artemisia annua L.), a plant which has been used for centuries in traditional Chinese medicine.
The mechanism of action of the artemisinin likely involves cleavage of the internal endoperoxide bridge through reaction with haeme within the infected erythrocyte, thereby generating free radicals which alkylate vital parasite proteins. However, artemisinins have also been reported to inhibit an essential parasite calcium adenosine triphosphatase.
The artemisinins are distinguished from other antimalarials by their ability to kill all erythrocytic stages of the malaria parasite, including the relatively inactive ring stage and late schizonts, as well as the gametocytes responsible for malaria transmission. Artesunate and the artemisinins are the most rapid acting of the antimalarials, and they have also been shown to enhance splenic clearance of infected erythrocytes by reducing cytoadherence.
In vitro, dyhydroartemisinin (DHA), the active metabolite of artesunate, exhibits similar potency against chloroquine-resistant and chloroquine-sensitive clones of P. falciparum. Artesunate and the other artemisinins are essentially inactive against extra-erythrocytic forms, sporozoites, liver schizontes or merozoites.
Clinical efficacy and safety: In the SEAQUAMAT (South East Asian Quinine Artesunate Malaria Trial), an international randomised, open-label, multicenter trial conducted in Bangladesh, India, Indonesia and Myanmar, 1461 patients with severe malaria (including 1259 adults) were treated intravenously with either artesunate or quinine. Artesunate was administered at 2.4 mg/kg IV at 0, 12 and 24 h and then every 24 h until the patient could tolerate oral medication. Quinine was given IV at 20 mg/kg over 4 hours, followed by 10 mg/kg over 2-8 hours, 3 times daily until oral therapy could be started. Mortality in the artesunate group was 15% versus 22% in the quinine group, for a reduction in risk of death of 34.7% (p=0.0002). Subgroup analysis suggested a greater benefit of artesunate versus quinine in patients with parasitemia >10%. The reduction in mortality observed in the 202 pediatric patients (<15 years of age) appeared consistent with the overall results, however the number of children was too small to demonstrate statistical significance. Post-treatment hypoglycaemia was more common in the quinine-treated group.
Paediatrics: The AQUAMAT (African Quinine Artesunate Malaria Trial) was an international, randomized open-label multicenter trial which sought to extend the results of the SEAQUAMAT study by comparing parenteral artesunate versus IV quinine for severe malaria in 5425 African children (<15 years) in 9 African countries (Mozambique, The Gambia, Ghana, Kenya, Tanzania, Nigeria, Uganda, Rwanda, and Democratic Republic of the Congo). Dosing was similar to SEAQUAMAT, except that both artesunate and quinine could be administered either intravenously or intramuscularly, using the same doses for IM and IV administered for each drug. Roughly one third of patients received study drug by intramuscular injection. Mortality in the artesunate group was 8.5% compared to the 10.9% in the quinine group, resulting in a relative risk reduction for death of 22.5% (p=0.0022); the risk reduction was similar for IV and IM administration. In addition, although the risk of neurological sequelae in survivors in both groups did not differ significantly by 28 days following treatment, in-hospital coma, convulsion, and deterioration of coma were all less frequent in the artesunate-treated patients. As in the SEAQUAMAT, post-treatment hypoglycaemia was more common in the quinine-treated group.
Pharmacokinetics: Intravenous: After intravenous injection artesunate is very rapidly biotransformed to its active metabolite, dihydroartemisinin (DHA). Consequently, artesunate half-life (t_½) is estimated to be less than following a single IV dose of 2.4 mg/kg, maximum artesunate plasma concentrations (C_max) were estimated to be 77 μmol/L in a study in Gabonese children with severe malaria, and 42 and 36 μmol/L in two studies in Vietnamese adults with uncomplicated malaria.
High concentrations of DHA are observed within 5 minutes of artesunate IV administration. In the previously mentioned studies (adult and paediatric), the ranges of values for the estimated to maximum concentration (t_max) and t_½ for DHA were 0.5-15 minutes and 21-64 minutes, respectively, while DHA C_max values ranged from 5.3-10.6 μmol/L.
Intramuscular: Artesunate is rapidly absorbed following intramuscular injection, and peak plasma levels are generally achieved within 30 minutes of administration. Thus, after IM injection of 2.4 mg/kg of artesunate, absorption was rapid in Gabonese children and Vietnamese adults, with T_max values of 8 and 12 minutes, respectively. The corresponding artesunate t_½ values were estimated to be 48 minutes in children and 41 minutes in adults, and C_max values were 1.7 and 2.3 μmol/L, for children and adults, respectively.
After IM injection artesunate C_max values were therefore lower by roughly 45-fold in children and 20-fold in adults when compared to IV injection. However, rates of artesunate elimination in children and adults were 32-fold and 13-fold slower, respectively, following IM injection, compared to IV administration.
Distribution: DHA has been shown to substantially accumulate in P. falciparum infected-erythrocytes. Plasma protein binding of dihydroartemisinin was determined to be 93% in patients and 88% in healthy volunteers.
Metabolism and elimination: Artesunate is extensively and rapidly hydrolysed by plasma esterases, with possible minimal contribution by CYP2A6. The main metabolite, dihydroartemisinin, accounts for most of the in vivo antimalarial activity of oral artesunate, however, following IV administration, artesunate may contribute more significantly. DHA is further metabolized in the liver via glucuronidation and is excreted in the urine; α-dihydroartemisinin-β-glucuronide has been identified as the major urinary product in patients with falciparum malaria.
Special population: No pharmacokinetic data are available for patients with impaired renal or hepatic function. However, based on the known mechanisms of metabolism and elimination of artesunate, combined with clinical data from patients with severe malaria and accompanying renal and/or hepatic compromise of various degrees, no dose modification are considered necessary in renal or hepatic impairment.
Toxicology: Preclinical safety data: General toxicity: Artesunate presents low acute toxicity. After repeated administration of 50 mg/kg/day in rats and 82.5 mg/kg/day in dogs, i.e. approximately 10 and 17 times the proposed maximal therapeutic dose in man, rare occurrences of moderate hepatotoxicity (4%) were reported, with regression in 100% of cases without sequelae. Hematopoietic toxicity on the red and white line is responsible for reticulocytopenia and leucopenia of central origin. The toxicity appears to be on the progenitors of the erythroid lineage. There is also a negative effect on the phagocytosis capacities of neutrophils and inhibition of lymphocyte proliferation (in vitro).
Genotoxicity: Artesunate did not show any mutagenic or clastogenic potential in in vitro or in vivo tests (Ames, mouse micronucleus).
Carcinogenesis: No studies of the carcinogenic potential of artesunate have been conducted.
Reproductive toxicology studies: Oral artesunate caused dose-dependent foetal toxicity in rats, rabbits and monkeys, resulting in foetal resorption and abortion, as well as low incidence of cardiac and skeletal defects. The no-observed-adverse-effect-level (NOAEL) was 12 mg/kg in pregnant monkeys (3 and 7 day exposures) and the no or low adverse effects level was 5-7 mg/kg in pregnant rats or rabbits (12 day exposures), both of which are above the therapeutic dose range (2.4-4.8 mg/kg) and expected duration of exposure for treatment of severe malaria in humans. In rats, the embryo-fetuses were most sensitive from gestational days 9-14; at other times embryotoxicity was significantly reduced.
Safety pharmacology studies: A slight sedative effect, decreased in body temperature, mild natriuretic effect and a decrease in creatinine clearance were observed with artesunate after single intravenous doses of 200 mg/kg (mice), 450 mg/kg (rats, rabbits and dogs) and following single oral doses of 180 mg/kg in male rats. Beagle dogs administered IV artesunate at 10, 20, 50, and 50 mg/kg for 14 days did not display significant clinical effects, including any signs of neurotoxicity, effects on body weight, ECG abnormalities (including QT interval changes), heart rate, blood pressure, or respiratory rate.

Artesun, administered intravenously or intramuscularly, is indicated for the treatment of severe malaria caused by Plasmodium falciparum, in adults and children.

Dose: Adults and children weighing 20 kg or more: Artesun is administered at a dose of 2.4 mg of artesunate/kg body weight, by intravenous (IV) or intramuscular (IM) injection, at 0, 12 and 24 hours, then once daily until oral treatment can be substituted.
Children weighing less than 20 kg: Artesun is administered at a dose of 3 mg of artesunate/kg body weight, by intravenous (IV) or intramuscular (IM) injection, at 0, 12 and 24 hours, then once daily until oral treatment can be substituted (see Pharmacology: Pharmacodynamics under Actions).
Method of administration: Artesun should be administered for a minimum of at least 24 hours (3 doses), regardless of the patient's ability to tolerate oral medication earlier. After at least 24 hours of Artesun, and when able to tolerate oral medication, the patient should be switched to a complete treatment course of an oral combination antimalarial regimen.
Preparation: Because of the instability of artesunate in aqueous solutions the reconstituted solution must be used within one hour of preparation. Therefore the required dose of artesunate should be calculated and the number of vials of artesunate needed should be determined prior to reconstituting the artesunate powder.
Reconstitution of the artesunate solution: Using a syringe, withdraw the supplied sodium bicarbonate solvent from the ampoule and inject into vial containing the artesunate powder. Shake the vial for several minutes to mix well until the powder is completely dissolved and the solution is clear. If the solution appears cloudy or a precipitate is present, it should be discarded. The reconstituted artesunate solution should always be used immediately, and discarded if not used within one hour.
Following reconstitution the solution must diluted according to the method of injection, as described as follows.
For intravenous (IV) injection: Using a syringe, add the supplied sodium chloride 0.9% for injection solvent to the vial containing the reconstituted artesunate solution. This will yield a solution containing artesunate 10 mg/ml. Shake to mix well, ensuring that the resulting solution is still clear. If the solution appears cloudy or a precipitate is present, it should be discarded.
The volume required will be equal to: (desired dose in mg)/10 ml.
Withdraw the required volume of artesunate solution from the vial with a syringe and then inject slowly intravenously, over 1-2 minutes.
Artesun should NOT be administered as an intravenous drip.
For intramuscular (IM) injection: Using a syringe, add to the vial containing the reconstituted artesunate solution the following volume of the supplied sodium chloride 0.9% for injection solvent: 2 ml for Artesun 60 mg. This will yield a solution containing artesunate 20 mg/ml. Shake to mix well, ensuring that the resulting solution is still clear. If the solution appears cloudy or a precipitate is present, it should be discarded.
The volume required will be equal to: (desired dose in mg)/20 ml.
Withdraw the required volume of artesunate solution from the vial with a syringe and then inject intramuscularly; the anterior thigh is usually the preferred site for injection. If the total volume of solution to be injected intramuscularly is large, it may be preferable to divide the volume and inject it at several sites, e.g. both thighs.
Do not use water for injection for reconstitution of the artesunate powder or for dilution of the resulting solution prior to injection.
Hepatic and renal impairment: Dose adjustment is not necessary in patients with hepatic or renal impairment (see Precautions and Pharmacology: Pharmacokinetics under Actions).

Experience of acute overdose with artesunate is limited. A case of overdose has been documented in 5-year-old child who was inadvertently administered rectal artesunate at a dose of 88 mg/kg/day over 4 days, representing a dose more than 7-fold higher than the highest recommended artesunate dose. The overdose was associated with pancytopenia, melena, seizures, multi-organ failure and death.

Artesun in contraindicated in patients with hypersensitivity to artesunate or other artemisinins.

Non-falciparum malaria: Artesunate has not been evaluated in the treatment of severe malaria due to Plasmodium vivax, Plasmodium malariae or Plasmodium ovale.
Resistance to antimalarials: Local inflammation on the prevalence of resistance to antimalarials should be considered in choosing the appropriate combination antimalarial regimen for use with Artesun (see Dosage & Administration).
Post-treatment haemolytic anaemia: Delayed haemolytic anemia following treatment with injectable artesunate has been observed in children in malaria endemic areas and in non-immune travelers presenting with severe falciparum malaria. The risk was most pronounced in patients with hyperparasitaemia and in younger children. Given the persistent uncertainties regarding the risk of delayed hemolysis, a minimum follow-up should be strictly observed until day 28 (see Adverse Reactions).
Hepatic/renal impairment: Data regarding artesunate pharmacokinetics in patients with hepatic and/or renal impairment are limited. Based on data from studies in patients with severe malaria, as well as the known metabolism of artesunate (see Pharmacology: Pharmacokinetics under Actions), dosage adjustment is not considered necessary in patients with hepatic or renal impairment.
Effects on ability to drive and use of machines: There is no information on the effect of artesunate on the ability to drive or use machines. The patient's clinical status should be considered when assessing ability to drive or operate machinery.
Use in Children: In clinical trials, the efficacy and safety of intravenous and intramuscular artesunate have been similar in adult and paediatric populations.
There is no clinical data available for infants weighing below 5 kg and adults weighing over 100 kg.

Pregnancy: Sever malaria is especially hazardous during pregnancy, therefore full dose parenteral artesunate treatment should be administered at any stage of pregnancy without delay. In animal studies, artesunate has been associated with fetal toxicity during the first trimester of pregnancy. Limited clinical experience with the use of artesunate in the first trimester of pregnancy as well as clinical data from pregnant women, predominantly treated with artesunate in the second and third trimester, do not indicate adverse effects of artesunate on pregnancy or on the health of the fetus/newborn child.
In addition, an observational study conducted in 1179 pregnant women with first-trimester falciparum malaria (of which 183 were treated with first line artemisinin derivatives) showed no differences in the risk of miscarriage or major congenital malformation in artemisinin derivatives versus quinine treatment.
Breastfeeding/lactation: Limited information indicates that dihydroartemisinin, the active metabolite of artesunate, is present at low levels in breast milk. The drug levels are not expected to cause any adverse effects in breastfed infants. The amount of drug present in breast milk does not protect the infant from malaria.

The most important reported side effect of artesunate is a rare severe allergic reaction (estimated risk approximately 1 in 3000 patients), which has involved urticarial rash as well as other symptoms, including hypotension, pruritus, oedema, and/or dyspnoea. A potentially serious delayed hemolysis (Post-Artesunate Delayed Hemolysis, PADH) has been reported frequently in travelers and in children. See following text.
More common minor side effects associated with IV administration have included dizziness, light-headedness, rash, and taste alteration (metallic/bitter taste). Transient elevation in liver transaminases, nausea, vomiting, anorexia and diarrhea have also been commonly reported, however it is uncertain whether such events have been symptoms of severe malaria.
Adverse events considered at least possibly related to artesunate are listed as follows by body system, organ class and absolute frequency. Frequencies are defined as very common (>1/10), common (1/100-1/10), uncommon (1/1,000-1/100), rare (1/10,000-1/1,000), and very rare (<1/10,000).
Blood and lymphatic systems disorders: Very common: Post-treatment haemolytic anaemia in travelers, mild and transient decrease in reticulocyte count.
Common to very common: Post-treatment haemolytic anaemia in endemic areas.
Uncommon: Neutropenia and anaemia (both occasionally severe), thrombocytopenia, agranulocytosis, reticulocytopenia, erythroblastopenia.
Very rare: Pure red cell aplasia.
Nervous system disorders: Common: Dizziness, light-headedness, headache, insomnia, tinnitus (with or without decrease in auditory function).
Very rare: Peripheral neuropathy (or paraesthesia).
Cardiovascular disorder: Uncommon: Rhythm and conduction disorders. Some cases of cardiac adverse events and particularly rhythm (bradycardia, sinus arrhythmia) and conduction disorders (QTc lengthening, abnormal sinoatrial conduction) have been recently described. One case of cardiac arrest has been reported in a context of severe malaria with multi-organ failure but the causality by Artesunate has not been established. Whether or not cardiovascular events should be attributed to artesunate or to severe malaria is not known, but considering that other artemisinin derivatives (arthemeter, arteether) have been associated with QT prolongation in pre-clinical data, EKG should be monitored before and during treatment, especially in patients with a history of cardiovascular impairment or having risk factors.
Rare: Arterial ischemia, hypertensive retinopathy.
Respiratory disorders: Common: Cough and/or nasal symptoms.
Gastrointestinal disorders: Common: Altered taste, nausea, vomiting, abdominal pain or cramps, diarrhoea.
Rare: Raised serum amylase, pancreatitis.
Hepatobiliary disorders: Uncommon: Transient rise in liver transaminases (AST, ALT).
Rare: Hepatitis, calculous cholecystitis.
Skin and subcutaneous tissue disorders: Common: Rash, alopecia.
Musculoskeletal and connective tissue disorders: Common: Arthralgia, muscle disorders.
General disorders and administration site conditions: Common: Fatigue, malaise, fever, pain at injection site.
Immune system disorders: Uncommon: Hypersensitivity.
*Post-Artesunate Delayed Hemolysis (PADH): A delayed hemolysis was detected in prospective studies with a frequency ranging from 7 to 27% of patients with artesunate. This adverse event has been observed both in travelers (15%) and among young African children (7-22%) in cases of severe malaria. The best-known cases of delayed haemolysis have been reported in travelers (including non-immune tourists and "visiting friends and relatives" persons). The pathophysiology of this phenomenon has not been fully elucidated but may include various combinations of delayed destruction of different subpopulations of erythrocytes and an immune-mediated etiology. All patients treated with parenteral artesunate should be followed for at least 4 weeks to detect signs of hemolysis and enable appropriate treatment.
Impact: PADH and other post-artesunate hemolytic episodes almost invariably resolve in less than a few weeks, often in a few days. Transfusion indication is per current standard of care. Whether long term sequelae occur in a small proportion of patients is not known. The overall risk/benefit remains highly favourable for injectable artesunate, with a large mortality advantage over quinine. WHO strongly recommends continued use of artesunate for severe malaria.
Paediatric population: The safety profile of injectable artesunate is similar in children and adults.

Artesunate is rapidly and extensively converted to dihydroartemisinin (DHA), the active metabolite, primarily by plasma and erythrocyte esterases. DHA elimination is also rapid (half-life approximately 45 min) and the potential for drug-drug interactions appears limited. In vitro drug-interaction studies have demonstrated minimal effects of artesunate on cytochrome P450 isoenzymes. Few clinical drug-drug interaction studies have been performed, however no clinically significant interactions have been identified.

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Special precautions for disposal: No special requirements.

Store below 30°C. Protect from light.
The reconstituted solution should be stored below 30°C and should be used within 1 hour.
Shelf life: 36 months.

Antimalarials

P01BE03 - artesunate ; Belongs to the class of artemisinin and derivative antimalarials.

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