ARTESUNAT AMIVAS 110mg powder + solvent for injection medication leaflet

Artesunate Amivas 110 mg powder and solvent for solution for injection

Each vial of powder contains 110 mg of artesunate.

Each vial of solvent for reconstitution contains 12 mL of 0.3 M sodium phosphate buffer.

After reconstitution, the solution for injection contains 10 mg of artesunate per mL.

After reconstitution, the solution for injection contains 13.4 mg sodium per mL.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection

Powder: white or almost white, fine crystalline powder.

Solvent: clear and colourless solution.

Artesunate Amivas is indicated for the initial treatment of severe malaria in adults and children (seesections 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 onlyafter consultation with a physician with appropriate experience in the management of malaria.

Initial treatment of severe malaria with artesunate should always be followed by a complete treatmentcourse 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 bodyweight) by intravenous (IV) 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 oraltreatment may continue to receive intravenous treatment with 2.4 mg/kg once every 24 hours (from 48hours after start of treatment).

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

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

No dose adjustment is required (see section 5.2).

No dose adjustment is required (see section 5.2).

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

Artesunate Amivas is for IV administration only. The reconstituted solution should be administered asa 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 usedwithin 1.5 hours of preparation. Therefore, the required dose of artesunate should be calculated (dosein mg = patient’s weight in kg x 2.4) and the number of vials of artesunate needed should bedetermined prior to reconstituting the artesunate powder.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

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

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

Post-artesunate delayed haemolysis

Post-artesunate delayed haemolysis (PADH) is characterised by decreased haemoglobin withlaboratory evidence of haemolysis (such as decreased haptoglobin and increased lactatedehydrogenase) with onset at least 7 days and sometimes several weeks after initiating artesunatetreatment. PADH has been reported to occur very commonly after successful treatment of severemalaria that commenced with IV artesunate in returning travellers. The risk of PADH may be highestin patients with hyperparasitaemia and in younger children. Patients should be monitored for evidenceof 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 anaemiasevere enough to require transfusion have been reported. Since a subset of patients with delayedhaemolysis after artesunate therapy have evidence of immune haemolytic anaemia, performing a directantiglobulin 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 in vitro andinhibit bone marrow responses (especially red blood cell precursors) in animal models. Both animalpreclinical data and human data from clinical trials have suggested that reversible reticulocytopeniaoccurs 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 Plasmodiumvivax, Plasmodium malariae or Plasmodium ovale. Available data indicates that it is effective againstall 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.

Infants aged less than 6 months

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

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

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. Asthe first and second doses are recommended 12 hours apart, on days when two doses are given in a24 hour period, then the dose would be 386 mg sodium per day, equivalent to 19.2 % of the WHOrecommended 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. DHAis 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 shouldbe avoided if possible.

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.

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 artesunateand/or oral DHA have indicated that DHA induces CYP3A and inhibits CYP1A2. Caution is advisedwhen co-administering intravenous artesunate with substrates of CYP3A4 or CYP1A2 that havenarrow therapeutic windows.

There is limited clinical experience with the use of Artesunate Amivas in the first trimester ofpregnancy. 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 recommendedunless 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 IV in their second or thirdtrimester. As a precautionary measure, it is preferable to avoid the use of Artesunate Amivas duringthe second or third trimester of pregnancy.

Pregnancy registry

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

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

No fertility data are available in humans.

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

No studies on the effects on the ability to drive and use machines have been performed. Patientsshould be warned not to drive or use machines if they feel tired or dizzy.

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

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

Reticulocytopenia that resolves after completion of treatment with IV artesunate occurs commonly orvery commonly (see section 4.4).

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 (1/1000-1/100) 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 Rhinitis

Infestations

Blood and Anaemia Immune

Lymphatic System Reduced haemolytic

Disorders reticulocyte count anaemia

Post-artesunatedelayed haemolysis

Metabolism And Anorexia

Nutrition Disorders

Nervous System Dizziness,

Disorders Dysgeusia,

Cardiac Disorders Bradycardia Electrocardiogram

QT prolonged

Vascular Disorders Hypotension, Flushing

Phlebitis

Respiratory, Cough

Thoracic and

Mediastinal

Disorders

Gastrointestinal Abdominal Pain, Nausea,

Disorders Diarrhoea, Vomiting Constipation

Hepatobiliary Hyperbilirubinaemia

Disorders Jaundice

Skin and Stevens-

Subcutaneous Johnson

Tissue Disorders Syndrome,

Pruritus, Rash,

Urticaria

Organ Systems Very Common Common Uncommon Not known

Renal and Urinary Haemoglobinuria

Disorders Acute renal failure

General Disorders Pyrexia Fatigue, Pain atand Administration injection site

Site Conditions

Immune System Anaphylaxis

Disorders

Investigations ALT increased,

AST increased

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

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

In-vitro activity

Available in-vitro data indicate that artesunate 50% inhibitory concentrations (IC50 values) are broadlycomparable 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 ofparasite clearance is associated with mutation in the K13 gene, which encodes the parasite’s Kelchpropeller protein Kelch13.

In SEAQUAMAT (South East Asian Quinine Artesunate Malaria Trial), an open-label, multicentretrial conducted in Bangladesh, India, Indonesia and Myanmar, 1461 patients (1259 adults and 202children <15 years) with severe falciparum malaria were randomised to initial intravenous treatmentwith artesunate or quinine until oral medication could be tolerated. Artesunate was administered at2.4 mg/kg IV at 0, 12 and 24 hours and then every 24 hours. Quinine was given IV at 20 mg/kg over 4hours, followed by 10 mg/kg thrice daily over 2-8 hours. Mortality in the intention to treat populationwas 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 to28.1% (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 toparenteral artesunate or parenteral quinine using the same dose as in SEAQUAMAT. Mortality in theintent to treat population was 8.5% (230 of 2712) in the artesunate group compared to 10.9% (297 of2713) 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 deathadjusted by study site of 23% (95% CI: 7%, 36%; (p=0.0055).

Following intravenous administration of artesunate as a bolus injection over 1-2 minutes, thepharmacokinetics 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) 1.3 0.75 (median value)

CL (L/kg/h) 3.4 1.1t½ (min) 15 80

AUC (ng-h/mL) 727-750 2017-3492

Artesunate and DHA distribute into the extracellular body fluid. DHA is approximately 93 %protein-bound in patients with uncomplicated malaria infection. Erythrocytes infected with Plasmodiahave been reported to contain very high DHA concentrations compared to plasma levels (e.g. 300-foldvs. mean plasma concentrations).

Artesunate is converted to DHA by cytochrome 2A6 and blood esterases. In human liver microsomalincubations of DHA, DHA-glucuronide was the only metabolite found. In urine from patients, α-

DHA-β-glucuronide (α-DHA-G) and a variable amount of the tetrahydrofuran isomer of α-DHA-Gwas identified. DHA itself was present only in very small amounts.

Artesunate is very rapidly eliminated from blood (within a few minutes) via conversion to DHA. DHAis eliminated from blood within a few hours after an intravenous dose, mainly via urinary excretion ofglucuronides.

There are no pharmacokinetic data available after intravenous artesunate dosing in patients aged 65years or older with severe malaria (see sections 4.2 and 4.4).

No pharmacokinetic data are available for patients with impaired renal function. Clinical trial datafrom patients with severe malaria and accompanying renal impairment at start of treatment indicatethat no dose modifications are necessary.

No pharmacokinetic data are available for patients with impaired hepatic function. Clinical trial datafrom patients with severe malaria and accompanying hepatic impairment at start of treatment indicatethat no dose modifications are necessary.

There are limited PK data on the use of IV artesunate in neonates and infants. Physiologically-based

PK modelling and simulations predict that plasma exposures are likely to be higher in infants below6 months of age compared to infants aged more than 6 months (see section 4.4).

Artesunate was negative in an in vitro bacterial reverse mutation assay, an in vitro Chinese hamsterovary chromosome aberration assay, an in vivo mouse bone marrow micronucleus assay using oraladministration, and in an in vivo micronucleus assay in rats when administered intravenously.

Carcinogenicity studies have not been conducted with artesunate.

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar toclinical exposure levels and with possible relevance to clinical use were as follows:

In a fertility and early embryonic development study IV administration of artesunate to rats at between1-2 times the clinical dose (based on body surface area comparisons) did not affect female fertility, orearly embryonic development. Oral administration of artesunate during organogenesis in rats, rabbits,and monkeys induces a dose-dependent increase in embryolethality and fetal malformations (includingcardiovascular, brain, and/or skeletal) at 0.3 to 1.6-times the clinical dose based on body surface area(BSA) comparisons. Although animal reproduction studies in several species have demonstrated fetalharm from oral and IV administered artesunate and other artemisinin class drugs, the clinical relevanceof the animal data is uncertain.

Studies in the literature indicate that artesunate oral administration in the male rat can cause a dose andduration dependent effect on the epididymis and testes with reversible decreases in the production ofviable sperm at near clinical doses. No such effects were noted in rats or dogs in 28-day Good

Laboratory Practice (GLP) studies conducted using IV dosing.

Monosodium phosphate monohydrate

Disodium phosphate dihydrate

Phosphoric acid, concentrated (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

4 years

Chemical and physical in-use stability has been demonstrated for 1.5 hours at 25°C.

From a microbiological point of view, unless the method of opening/reconstituting/dilution precludesthe risks of microbial contamination, the product should be used immediately.

If not used immediately, in-use storage times and conditions are the responsibility of the user.

This medicinal product does not require any special storage conditions.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

The powder is supplied in a Type I glass vial capped with a latex-free bromobutyl rubber stopper andaluminium seal, containing 110 mg of artesunate.

The solvent is supplied in a Type I glass vial capped with a latex-free bromobutyl rubber stopper andaluminium seal, containing 12 mL of sterile 0.3 M sodium phosphate buffer for reconstitution.

Each pack contains 2 or 4 vials of artesunate powder and 2 or 4 vials of sodium phosphate buffersolvent.

Not all pack sizes may be marketed.

Withdraw 11 mL of the supplied 0.3 M sodium phosphate buffer with a needle and syringe and injectinto the vial containing Amivas Artesunate powder for injection (the final concentration of artesunateis 10 mg/mL when reconstituted). Swirl gently (do not shake) for up to 5 to 6 minutes until the powderis fully dissolved and no visible particles remain.

Instructions for use and disposal

Visually inspect the solution within the vial to ensure that no visible particles remain and there is nodiscolouration of the solution. Do not administer if the solution is discoloured or contains particulatematter.

Inject the reconstituted solution IV as a slow bolus over 1-2 minutes. Do not administer via continuous

IV infusion.

Discard the vial and any unused portion of the medicinal product after use.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Amivas Ireland Ltd

Suite 5, Second Floor

Station House

Railway Square

Waterford

Ireland

EU/1/21/1582/001

EU/1/21/1582/002

Date of first authorisation: 22/11/2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.