artesunate: prescribing information – dosing, contraindications, interactions, side effects

Artesunate Amivas is indicated for the initial treatment of severe malaria in adults and children (see sections 4.2 and 5.1).

Consideration should be given to official guidance on the appropriate use of antimalarial agents.

It is recommended that Artesunate Amivas should be used to treat patients with severe malaria only after consultation with a physician with appropriate experience in the management of malaria.

Posology

Initial treatment of severe malaria with artesunate should always be followed by a complete treatment course with appropriate oral antimalarial therapy.

Adults and children (birth to less than 18 years)
The recommended dose is 2.4 mg/kg (0.24 mL of reconstituted solution for injection per kg body weight) by intravenous injection at 0, 12 and 24 hours (see sections 4.4 and 5.2).

After at least 24 hours (3 doses) treatment with Artesunate Amivas, patients unable to tolerate oral treatment may continue to receive intravenous treatment with 2.4 mg/kg once every 24 hours (from 48 hours after start of treatment).

Treatment with Artesunate Amivas should be stopped when patients can tolerate oral treatment. After stopping Artesunate Amivas, all patients should receive a complete treatment course of an appropriate oral combination antimalarial regimen.

Special populations

Elderly
No dose adjustment is required (see sections 4.4 and 5.2).

Renal impairment
No dose adjustment is required (see section 5.2).

Hepatic impairment
No dose adjustment is required (see section 5.2).

Paediatric population

No dose adjustment is recommended based on age or weight (see sections 4.4 and 5.2).

Method of administration

Artesunate Amivas is for intravenous administration only. The reconstituted solution should be administered as a slow bolus injection over 1-2 minutes.

Artesunate Amivas must be reconstituted with the supplied solvent prior to administration.
Because of the instability of artesunate in aqueous solutions the reconstituted solution must be used within 1.5 hours of preparation. Therefore, the required dose of artesunate should be calculated (dose in mg = patient’s weight in kg x 2.4) and the number of vials of artesunate needed should be determined prior to reconstituting the artesunate powder.

For instructions on reconstitution of the medicinal product before administration, see section 6.6. Post reconstitution the medicinal product should be a clear colourless solution with no visible particles.

Hypersensitivity to the active substance, to any other artemisinin antimalarial agent or to any of the excipients listed in section 6.1.

Summary of the safety profile

The most common adverse drug reaction reported in clinical trials has been anaemia. While anaemia occurs very commonly in patients with severe malaria as a result of the disease and effective treatment, anaemia that was not dose-related was also reported in healthy subjects in clinical pharmacology studies with intravenous artesunate.

Post-Artesunate Delayed Haemolysis (PADH) has been reported very commonly following effective treatment of severe malaria with intravenous artesunate in travellers and in children (see section 4.4).

Reticulocytopenia that resolves after completion of treatment with intravenous artesunate occurs commonly or very commonly (see section 4.4).

Tabulated list of adverse reactions

Adverse events considered at least possibly related to artesunate are listed below 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) and unknown (frequency cannot be determined) (Table 1).

Table 1. Summary of adverse drug reactions by organ system and frequency
Organ Systems
Very common
Common
Uncommon
Not known
Infections and infestations

Rhinitis

Blood and lymphatic system disorders
Anaemia
Reduced reticulocyte count
Post-artesunate delayed haemolysis

Immune haemolytic anaemia
Immune system disorders

Anaphylaxis
Metabolism and nutrition disorders

Anorexia

Nervous system disorders

Dizziness,
Dysgeusia,
Headache

Cardiac disorders

Bradycardia

Electrocardiogram
QT prolonged
Vascular disorders

Hypotension,
Phlebitis
Flushing

Respiratory, thoracic and mediastinal disorders

Cough

Gastrointestinal disorders

Abdominal Pain,
Diarrhoea, Vomiting
Nausea,
Constipation

Hepatobiliary disorders

Hyperbilirubinaemia
Jaundice

Organ Systems
Very common
Common
Uncommon
Not known
Skin and subcutaneous tissue disorders

Stevens-
Johnson
Syndrome,
Pruritus, Rash,
Urticaria

Renal and urinary disorders

Haemoglobinuria
Acute renal failure

General disorders and administration site conditions

Pyrexia
Fatigue, Pain at injection site

Investigations

ALT increased,
AST increased

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Hypersensitivity

Allergic reactions to intravenous artesunate, including anaphylaxis have been reported. Other reported allergic reactions include urticaria, rash and pruritus (see section 4.8).

Post-artesunate delayed haemolysis

Post-artesunate delayed haemolysis (PADH) is characterised by decreased haemoglobin with laboratory evidence of haemolysis (such as decreased haptoglobin and increased lactate dehydrogenase) with onset at least 7 days and sometimes several weeks after initiating artesunate treatment. PADH has been reported to occur very commonly after successful treatment of severe malaria that commenced with intravenous artesunate in returning travellers. The risk of PADH may be highest in patients with hyperparasitaemia and in younger children. Patients should be monitored for evidence of haemolytic anaemia for 4 weeks after starting artesunate treatment. Spontaneous recovery from PADH usually occurs within a few weeks. However, cases of post-artesunate haemolytic anaemia severe enough to require transfusion have been reported. Since a subset of patients with

delayed haemolysis after artesunate therapy have evidence of immune haemolytic anaemia, performing a direct antiglobulin test should be considered to determine if therapy, e.g. with corticosteroids, is necessary. See section 4.8.

Reticulocytopenia

The artemisinins have shown direct inhibitory effects on human erythroid precursors invitro and inhibit bone marrow responses (especially red blood cell precursors) in animal models. Both animal preclinical data and human data from clinical trials have suggested that reversible reticulocytopenia occurs at least commonly in association with treatment with intravenous artesunate (see section 4.8).
The reticulocyte count recovers after cessation of treatment.

Malaria due to Plasmodium vivax, Plasmodium malariae or Plasmodium ovale

Artesunate Amivas has not been evaluated in the treatment of severe malaria due to Plasmodium vivax, Plasmodium malariae or Plasmodium ovale. Available data indicates that it is effective against all Plasmodium species (see section 5.1). It does not treat the hypnozoite liver stage forms of Plasmodium and will therefore not prevent relapses of malaria due to Plasmodium vivax or Plasmodium ovale. Patients treated initially with artesunate for severe malaria due to P. vivax or P.
ovale should receive an antimalarial agent that is active against the hypnozoite liver stage forms of Plasmodium.

Co-administration of intravenous artesunate with strong inhibitors of UGT enzymes (e.g. axitinib, vandetanib, imatinib, diclofenac) may increase plasma exposures to DHA. Co-administration should be avoided if possible (see section 4.5).

Co-administration of Artesunate Amivas with UGT inducers (e.g. nevirapine, ritonavir, rifampicin, carbamazepine, phenytoin) may decrease DHA exposures, leading to a reduction in, or loss of, efficacy. Co-administration should be avoided (see section 4.5).

Pregnancy

The use of Artesunate Amivas in the first trimester is not recommended unless the benefit to the mother outweighs the risk to the fetus (see section 4.6).

Infants aged less than 6 months

There are insufficient clinical data to establish the safety and efficacy of Artesunate Amivas in infants below 6 months of age. Pharmacokinetic modelling and simulations indicate that after 2.4 mg/kg intravenous artesunate the dihydroartemisinin (DHA) plasma exposures in infants aged less than 6 months are likely to be higher than those in older infants and children (see section 5.2).

Elderly

There are insufficient clinical data to establish the safety and efficacy of intravenous artesunate in patients aged 65 years and older with severe malaria (see section 5.2).

Information about excipients

This medicinal product contains 193 mg sodium per the recommended single dose for a 60 kg adult, equivalent to 9.6 % of the WHO recommended maximum daily intake of 2 g sodium for an adult. As the first and second doses are recommended 12 hours apart, on days when two doses are given in a 24 hour period, then the dose would be 386 mg sodium per day, equivalent to 19.2 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

No clinical drug-drug interactions studies have been conducted with Artesunate Amivas.

Effect of other medicinal products on artesunate and/or dihydroartemisinin (DHA) After intravenous administration, artesunate is converted to DHA by esterases and by CYP2A6. DHA is converted to inactive glucuronide conjugates primarily by UGT1A9.

Co-administration of intravenous artesunate with strong inhibitors of UGT enzymes (e.g. axitinib, vandetanib, imatinib, diclofenac) may increase plasma exposures to DHA. Co-administration should be avoided if possible (see section 4.4).

Co-administration of Artesunate Amivas with UGT inducers (e.g. nevirapine, ritonavir, rifampicin, carbamazepine, phenytoin) may decrease DHA exposures, leading to a reduction in, or loss of, efficacy. Co-administration should be avoided (see section 4.4).

Effect of artesunate and/or DHA on other medicinal products
Limited data from in vitro studies and from clinical drug-drug interaction studies with oral artesunate and/or oral DHA have indicated that DHA induces CYP3A and inhibits CYP1A2. Caution is advised when co-administering intravenous artesunate with substrates of CYP3A4 or CYP1A2 that have narrow therapeutic windows.

Pregnancy

There is limited clinical experience with the use of Artesunate Amivas in the first trimester of pregnancy. A risk to the fetus cannot be excluded. Animal studies have shown reproductive toxicity (see section 5.3). The use of Artesunate Amivas in the first trimester is therefore not recommended unless the benefit to the mother outweighs the risk to the fetus.

A moderate amount of clinical data on pregnant women (between 300-1000 pregnancy outcomes) indicate no malformative or feto/neonatal toxicity of artesunate when given intravenous in their second or third trimester. As a precautionary measure, it is preferable to avoid the use of Artesunate Amivas during the second or third trimester of pregnancy.

Pregnancy registry
A pregnancy registry has been set up to monitor all pregnancies and their outcomes following treatment with Artesunate Amivas.

Breast-feeding

DHA, a metabolite of artesunate, is present in human milk. There are no data on the effects of artesunate or DHA on the breastfed infant or on milk production. The benefits of breastfeeding to mother and infant should be weighed against potential risk from infant exposure to DHA through breast milk.

Fertility

No fertility data are available in humans.

Animal studies have reported effects on the male reproductive organs, however studies on female rats show no effect on fertility (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed. Dizziness is common undesirable effect with Artesunate Amivas which may have a moderate influence on a patient’s ability to drive and use machines. Patients should be warned not to drive or use machines if they feel tired or dizzy.

In cases of suspected overdose symptomatic and supportive therapy should be given as appropriate.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antiprotozoals, artemisinin and derivatives, ATC code: P01BE03.

Mechanism of action

The antimalarial mechanism of action of artesunate is generally thought to depend upon activation involving iron-mediated cleavage of the endoperoxide bridge of DHA to generate an unstable organic free radical followed by alkylation, where the free radical binds to malarial proteins leading to destruction of parasite membranes.

In vitro activity

Available in vitro data indicate that artesunate 50% inhibitory concentrations (IC50 values) are broadly comparable for P. falciparum and for the other Plasmodium species that cause malaria in humans (P.
vivax, P. ovale, P. malariae, P. knowlesi).

Artemisinin resistance

Decreased susceptibility to artesunate and other artemisinins, manifesting clinically as slower rates of parasite clearance is associated with mutation in the K13 gene, which encodes the parasite’s Kelch propeller protein Kelch13.

Clinical efficacy

In SEAQUAMAT (South East Asian Quinine Artesunate Malaria Trial), an open-label, multicentre trial conducted in Bangladesh, India, Indonesia and Myanmar, 1461 patients (1259 adults and 202 children <15 years) with severe falciparum malaria were randomised to initial intravenous treatment with artesunate or quinine until oralmedicine could be tolerated. Artesunate was administered at

2.4 mg/kg intravenous at 0, 12 and 24 hours and then every 24 hours. Quinine was given intravenous at 20 mg/kg over 4 hours, followed by 10 mg/kg thrice daily over 2-8 hours. Mortality in the intention to treat population was 14.7% (107 of 730) in the artesunate group compared to 22.4% (164 of 731) in the quinine group, a reduction in the odds of death adjusted by study site of 40% (95% CI: 21%, 55%;
p=0.0002).

Mortality in patients with severe malaria in the artesunate group was 19.8% (101 of 509) compared to 28.1% (152 of 541), a reduction in the odds of death adjusted by study site of 35% (95% CI: 13%, 52%; p=0.003).

AQUAMAT (African Quinine Artesunate Malaria Trial) was an open-label multicentre trial in which African children aged < 15 years (n=5425) with severe falciparum malaria were randomised to parenteral artesunate or parenteral quinine using the same dose as in SEAQUAMAT. Mortality in the intent to treat population was 8.5% (230 of 2712) in the artesunate group compared to 10.9% (297 of 2713) in the quinine group, a reduction in the odds of death adjusted by study site of 25% (95% CI:
10%, 37%; p=0.0022). Mortality in children with severe malaria in the artesunate group was 9.9% (226 of 2280) compared to 12.4% (291 of 2338) in the quinine group, a reduction in the odds of death adjusted by study site of 23% (95% CI: 7%, 36%; (p=0.0055).

Absorption

Following intravenous administration of artesunate as a bolus injection over 1-2 minutes, the pharmacokinetics of artesunate and dihydroartemisinin in plasma are shown in Table 2.

Table 2: Summary of pharmacokinetic parameters in patients with severe malaria

Parameter
Artesunate
DHA
Cmax (ng/mL)
1020-3260
2060-3140
V (L/kg)