Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd.  
Product proprietary name: Hetovanil 62,5/25 mg and Hetovanil 250/100 mg  
Dosage form and strength: Film coated tablets. Each contains 62,5 mg or 250 mg of Atovaquone and 25  
mg or 100 mg of Proguanil HCl.  
CLEAN PROFESSIONAL INFORMATION FOR HETOVANIL  
SCHEDULING STATUS  
S2  
1. NAME OF THE MEDICINE  
HETOVANIL 62,5/25 mg (FILM-COATED TABLETS)  
HETOVANIL 250/100 mg (FILM-COATED TABLETS)  
2 QUALITATIVE AND QUANTITATIVE COMPOSITION  
HETOVANIL 62,5/25 mg  
Each tablet contains 62,5 mg of atovaquone and 25 mg of proguanil HCI  
Sugar-free and contains 2.03 mg of Sodium  
HETOVANIL 250/100 mg  
Each tablet contains 250 mg of atovaquone and 100 mg of proguanil HCI  
Sugar-free and contains 8.13 mg of Sodium  
‘for full list of excipients, see section 6.1’  
3. PHARMACEUTICAL FORM  
HETOVANIL 62,5/25 mg  
Pink, round, biconvex film coated tablets, debossed with 'I' on one side and '11' on the other side.  
HETOVANIL 250/100 mg  
Pink, round, biconvex film coated tablets debossed with 'H' on one side and '175' on the other side.  
4. CLINICAL PARTICULARS  
4.1 Therapeutic indications  
HETOVANIL is indicated for the prophylaxis of drug sensitive and drug resistant Plasmodium  
falciparum malaria.  
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Product proprietary name: Hetovanil 62,5/25 mg and Hetovanil 250/100 mg  
Dosage form and strength: Film coated tablets. Each contains 62,5 mg or 250 mg of Atovaquone and 25  
mg or 100 mg of Proguanil HCl.  
Official guidelines and local information on the prevalence of resistance to antimalarial drugs should be  
taken into consideration.  
4.2 Posology and method of administration  
Prophylaxis:  
Prophylaxis should start 1 to 2 days before entering a malaria-endemic area, and be continued daily  
until 7 days after leaving the area.  
Dosage in adults:  
One HETOVANIL 250/100 mg tablet daily.  
Dosage in Children:  
Weight (kg)  
Dosage Regimen  
11 to 20 kg body weight  
21 to 30 kg body weight  
31 to 40 kg body weight  
Special populations  
One HETOVANIL 62,5/25 mg tablet daily  
Two HETOVANIL 62,5/25 mg tablets as a single dose daily.  
Three HETOVANIL 62,5/25 mg tablets as a single dose daily.  
Dosage in the elderly:  
A pharmacokinetic study indicates that no dosage adjustments are needed in the elderly (see  
section 5.2).  
Dosage in hepatic impairment:  
A pharmacokinetic study indicates that no dosage adjustments are needed in patients with mild to  
moderate hepatic impairment. No studies have been conducted in patients with severe hepatic  
impairment (see section 5.2 in hepatic impairment).  
Dosage in renal impairment:  
Pharmacokinetic studies indicate that no dosage adjustments are needed in patients with mild to  
moderate renal impairment.  
For prophylaxis of P. falciparum malaria in patients with severe renal impairment (see section 4.3).  
May 2022  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd.  
Product proprietary name: Hetovanil 62,5/25 mg and Hetovanil 250/100 mg  
Dosage form and strength: Film coated tablets. Each contains 62,5 mg or 250 mg of Atovaquone and 25  
mg or 100 mg of Proguanil HCl.  
Method of administration  
The daily dose should be taken with food or milk at the same time each day. In the event of vomiting  
within 1 hour of dosing, a repeat dose should be taken.  
4.3 Contraindications  
HETOVANIL is contra-indicated in individuals with known hypersensitivity to atovaquone or  
proguanil hydrochloride or any of the excipients listed in section 6.1  
HETOVANIL is contra-indicated for prophylaxis of P. falciparum malaria in patients with severe renal  
impairment (creatinine clearance < 30 mL/min).  
4.4 Special warnings and precautions for use  
The safety and effectiveness of HETOVANIL 250/100 mg for prophylaxis of malaria in adult patients  
who weigh less than 40 kg, or HETOVANIL 62.4/25 mg for prophylaxis of malaria in paediatric  
patients who weigh less than 11kg has not been established.  
Persons taking HETOVANIL for prophylaxis of malaria should take a repeat dose if they vomit within  
1 hour of dosing. In the event of diarrhoea, normal dosing should be continued.  
Absorption of atovaquone may be reduced in patients with diarrhoea or vomiting, but diarrhoea  
or vomiting was not associated with reduced efficacy in clinical trials of a HETOVANIL for malaria  
prophylaxis. However, patients with diarrhoea or vomiting should be advised to continue with  
malaria prevention measures by complying with personal protection measures (repellants,  
impregnated bednets).  
Occasionally, severe allergic reactions (including anaphylaxis) have been reported in patients taking  
HETOVANIL. If patients experience an allergic reaction (see section 4.8) HETOVANIL  
should be discontinued promptly and appropriate treatment initiated.  
In the event of recrudescent infections due to P. falciparum or failure of chemoprophylaxis with  
HETOVANIL, patients should be treated with a different blood schizonticide as such events can  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd.  
Product proprietary name: Hetovanil 62,5/25 mg and Hetovanil 250/100 mg  
Dosage form and strength: Film coated tablets. Each contains 62,5 mg or 250 mg of Atovaquone and 25  
mg or 100 mg of Proguanil HCl.  
reflect a resistance of the parasite.  
Parasitaemia should be closely monitored in patients receiving concurrent tetracycline (see section  
4.5).  
The concomitant administration of HETOVANIL and efavirenz or boosted protease-inhibitors should  
be avoided whenever possible (see section 4.5)  
The concomitant administration of HETOVANIL and rifampicin or rifabutin is not recommended (see  
section 4.5). Concurrent use of metoclopramide is not recommended. Another antiemetic treatment  
should be given (see section 4.5).  
Caution is advised when initiating or withdrawing malaria prophylaxis with HETOVANIL in patients  
on continuous treatment with warfarin and other coumarin based anticoagulants (see section 4.5).  
Atovaquone can increase the levels of etoposide and its metabolite (see section 4.5).  
In patients with severe renal impairment (creatinine clearance <30 mL/min) alternatives to  
HETOVANIL for treatment of acute P. falciparum malaria should be recommended whenever  
possible (see sections 4.2, 4.3 and 5.2).  
Skin rashes ranging from photosensitivity rashes and urticaria to Stevens-Johnson syndrome have  
been reported. HETOVANIL must be stopped immediately at the first sign of a serious skin rash  
or where there is blistering or mucosal involvement. HETOVANIL should be taken with caution in  
patients with a history of epilepsy (see section 4.8)  
4.5 Interaction with other medicines and other forms of interaction  
Concomitant administration of rifampicin or rifabutin is not recommended as it is known to reduce  
plasma concentrations of atovaquone levels by approximately 50% and 34%, respectively  
(see section 4.4).  
Concomitant treatment with metoclopramide has been associated with a significant decrease (about  
50%) in plasma concentrations of atovaquone (see section 4.4). Another antiemetic treatment  
May 2022  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd.  
Product proprietary name: Hetovanil 62,5/25 mg and Hetovanil 250/100 mg  
Dosage form and strength: Film coated tablets. Each contains 62,5 mg or 250 mg of Atovaquone and 25  
mg or 100 mg of Proguanil HCl.  
should be given.  
When given with efavirenz or boosted protease-inhibitors, atovaquone concentrations have been  
observed to decrease as much as 75%. This combination should be avoided whenever  
possible (see section 4.4)  
Proguanil may potentiate the anticoagulant effect of warfarin and other coumarin based  
anticoagulants which may lead to an increase in the risk of haemorrhage. The mechanism of this  
potential drug interaction has not been established. Caution is advised when initiating or withdrawing  
malaria prophylaxis or treatment with atovaquone/proguanil in patients on continuous with oral  
anticoagulants.  
Concomitant treatment with tetracycline has been associated with decreases in plasma  
concentrations of atovaquone.  
The co-administration of atovaquone at doses of 45 mg/kg/day in children with acute lymphoblastic  
leukaemia for prophylaxis of PCP was found to increase the plasma concentrations (AUC) of  
etoposide and its metabolite etoposide catechol by a median of 8,6% (P=0,055) and 28,4%  
(P=0,031) (respectively compared to the co-administration of etoposide and sulfamethoxazole-  
trimethoprim). Caution should be advised in patients receiving concomitant therapy with etoposide  
(see section 4.4).  
Proguanil is primarily metabolised by CYP2C19. However, potential pharmacokinetic interactions  
with other substrates, inhibitors (e.g.moclobemide, fluvoxamine) or inducers (e.g. artemisinin,  
carbamazepine) of CYP2C19 are unknown (see section 5.2).  
4.6 Fertility, pregnancy and lactation  
Pregnancy  
The proguanil component of HETOVANIL acts by inhibiting parasitic dihydrofolate reductase. There  
are no clinical data indicating that folate supplementation diminishes drug efficacy.  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd.  
Product proprietary name: Hetovanil 62,5/25 mg and Hetovanil 250/100 mg  
Dosage form and strength: Film coated tablets. Each contains 62,5 mg or 250 mg of Atovaquone and 25  
mg or 100 mg of Proguanil HCl.  
For women of childbearing age receiving folate supplements to prevent neural tube birth defects,  
such supplements should be continued while taking HETOVANIL.  
The safety of atovaquone and proguanil hydrochloride when administered concurrently for use in  
human pregnancy has not been established.  
Breastfeeding  
The atovaquone concentrations in milk, in a rat study, were 30% of the concurrent atovaquone  
concentrations in maternal plasma. It is not known whether atovaquone is excreted in human milk.  
Proguanil is excreted in human milk in small quantities. HETOVANIL should not be taken by  
breastfeeding women.  
Fertility  
There is no data regarding the potential effects of HETOVANIL on fertility.  
4.7 Effects on ability to drive and use machines  
Dizziness has been reported. Patients should be warned that if affected they should not drive,  
operate machinery or take part in activities where this may put themselves or others at risk.  
4.8 Undesirable effects  
In clinical trials of atovaquone/proguanil for prophylaxis of malaria, the most commonly reported  
adverse reactions were headache, abdominal pain and diarrhoea.  
There are limited long-term safety data in children. In particular, the long-term effects of  
HETOVANIL on growth, puberty and general development have not been studied.  
Tabulated summary of adverse reactions  
System Organ Class  
Blood and lymphatic  
system disorders  
Frequency  
Adverse reaction  
Frequent  
Anaemia  
Neutropenia1  
Frequency unknown  
Pancytopenia in patients with severe renal  
May 2022  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd.  
Product proprietary name: Hetovanil 62,5/25 mg and Hetovanil 250/100 mg  
Dosage form and strength: Film coated tablets. Each contains 62,5 mg or 250 mg of Atovaquone and 25  
mg or 100 mg of Proguanil HCl.  
impairment  
Immune system disorders  
Frequent  
Allergic reactions  
urticaria  
Less frequent  
Frequency unknown  
Angioedema3,  
Anaphylaxis (see section 4.4) Vasculitis3  
Hyponatraemia1  
Anorexia  
Metabolism and nutrition  
disorders  
Frequent  
Less frequent  
Frequent  
Elevated amylase levels1  
Abnormal dreams Depression  
Anxiety  
Psychiatric disorders  
Less frequent  
Hallucinations  
Panic attack  
Frequency unknown  
Crying  
Psychotic disorder  
Headache  
Nervous system disorders Frequent  
Insomnia  
Dizziness  
Frequency unknown  
Seizure  
Cardiac disorders  
Less frequent  
Frequency unknown  
Frequent  
Palpitations  
Tachycardia  
Respiratory, thoracic and  
mediastinal disorders  
Cough  
Gastrointestinal disorders  
Frequent  
Nausea1  
Vomiting  
Diarrhoea  
Abdominal pain  
Stomatitis  
Less frequent  
Frequency unknown  
Gastric intolerance3 Oral ulceration3  
May 2022  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd.  
Product proprietary name: Hetovanil 62,5/25 mg and Hetovanil 250/100 mg  
Dosage form and strength: Film coated tablets. Each contains 62,5 mg or 250 mg of Atovaquone and 25  
mg or 100 mg of Proguanil HCl.  
Hepatobiliary disorders  
Frequent  
Elevated liver enzymes1  
Hepatitis Cholestasis3  
Pruritus  
Frequency unknown  
Frequent  
Skin and subcutaneous  
tissue disorders  
Rash  
Hair loss  
Urticaria  
Frequency unknown  
Stevens-Johnson Syndrome  
Erythema multiforme2  
Blister  
Skin exfoliation  
Photosensitivity reactions  
Fever  
General disorders and  
administration site  
conditions  
Frequent  
1. Frequency taken from atovaquone label. Patients participating in clinical trials with atovaquone  
have received higher doses and have often had complications of advanced Human  
Immunodeficiency Virus (HIV) disease. These events may have been seen at a lower frequency or  
not at all in clinical trials with atovaquone/proguanil.  
2. Observed from post-marketing spontaneous reports and the frequency is therefore unknown.  
3. Observed with proguanil. Clinical trial data indicated that abnormalities in liver function tests were  
reversible and not associated with untoward clinical events  
Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorisation of HETOVANIL is important. It allows  
continued monitoring of the benefit/risk balance of the HETOVANIL. Healthcare professionals  
are asked to report any suspected adverse to report any suspected adverse reactions to SAHPRA  
via the “6.04 Adverse Drug Reactions Reporting Form”, found online under SAHPRA’s  
publications: https://www.sahpra.org.za/publications/Index/8 or to the Holder of certificate of  
registration through the mail:pvg.cdma@heterogroups.com  
May 2022  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd.  
Product proprietary name: Hetovanil 62,5/25 mg and Hetovanil 250/100 mg  
Dosage form and strength: Film coated tablets. Each contains 62,5 mg or 250 mg of Atovaquone and 25  
mg or 100 mg of Proguanil HCl.  
4.9 Overdose  
There is insufficient experience to predict the consequences or suggest specific management of  
atovaquone/proguanil overdose. However, in the reported cases of atovaquone overdose, the  
observed effects were consistent with known undesirable effects of the medicine. If overdose  
occurs, the patient should be monitored and standard supportive treatment applied.  
5 PHARMACOLOGICAL PROPERTIES  
5.1 Pharmacodynamic properties  
Pharmacotherapeutic group: Antiprotozoals, antimalarials,  
ATC code: P01B B51  
PHARMACOLOGICAL CLASSIFICATION:  
A 20.2.6 Medicines against protozoa  
Mechanism of Action  
The constituents of HETOVANIL, atovaquone and proguanil hydrochloride, interfere with two  
different pathways involved in the biosynthesis of pyrimidines required for nucleic acid replication.  
The mechanism of action of atovaquone against P. falciparum is via inhibition of mitochondrial  
electron transport, at the level of the cytochrome bc1 complex, and collapse of mitochondrial  
membrane potential. One mechanism of action of proguanil, via its metabolite cycloguanil, is  
inhibition of dihydrofolate reductase, which disrupts deoxythymidylate synthesis. Proguanil also has  
antimalarial activity independent of its metabolism to cycloguanil, and proguanil, but not  
cycloguanil, is able to potentiate the ability of atovaquone to collapse mitochondrial membrane  
potential in malaria parasites. This latter mechanism may explain the synergy seen when  
atovaquone and proguanil are used in combination.  
Microbiology  
Atovaquone has potent activity against Plasmodium spp (in vitro IC50 against P. falciparum 0,23-  
1,43 ng/mL).  
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Product proprietary name: Hetovanil 62,5/25 mg and Hetovanil 250/100 mg  
Dosage form and strength: Film coated tablets. Each contains 62,5 mg or 250 mg of Atovaquone and 25  
mg or 100 mg of Proguanil HCl.  
Resistance  
Atovaquone is not cross-resistant with any other antimalarial medicines in current use. In in-vitro  
studies with more than 30 P.falciparum isolates, resistance had been detected against  
chloroquine (41 % of isolates), quinine (32 % of isolates), mefloquine (29 % of isolates), and  
halofantrine (48 % of isolates) and not against atovaquone (0 % of isolates).  
The antimalarial activity of proguanil is exerted via the primary metabolite cycloguanil (in vitro IC50  
against various P. falciparum strains of 4-20 ng/mL; some activity of proguanil and another  
metabolite, 4-chlorophenylbiguanide, is seen in vitro at 600-3000 ng/mL).  
In in vitro studies of P. falciparum the combination of atovaquone and proguanil was shown to be  
synergistic. This enhanced efficacy was also demonstrated in clinical studies in both immune and  
non-immune patients.  
5.2 Pharmacokinetic properties  
There are no pharmacokinetic interactions between atovaquone and proguanil at the recommended  
dose.  
Absorption  
Atovaquone is a highly lipophilic compound with low aqueous solubility. The pharmacokinetics of  
atovaquone are comparable between healthy and HIV-infected patients, In HIV-infected  
patients the absolute bioavailability of a 750 mg single dose of atovaquone tablets taken with food is  
21 % (90 % Cl: 17-27 %)  
Dietary fat taken with atovaquone increases the rate and extent of absorption, increasing AUC 2-3  
times and Cmax 5 times over fasting.  
Patients are recommended to take HETOVANIL with food or a milky drink (see section 4.2).  
Proguanil hydrochloride is rapidly and extensively absorbed regardless of food intake.  
Distribution  
Apparent volume of distribution of atovaquone and proguanil is a function of bodyweight.  
Atovaquone is highly protein bound (>99 %) but does not displace other highly protein bound drugs  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd.  
Product proprietary name: Hetovanil 62,5/25 mg and Hetovanil 250/100 mg  
Dosage form and strength: Film coated tablets. Each contains 62,5 mg or 250 mg of Atovaquone and 25  
mg or 100 mg of Proguanil HCl.  
in vitro, indicating significant drug interactions arising from displacement are unlikely.  
Following oral administration, the volume of distribution of atovaquone in adults and children is  
approximately 8,8 L/kg.  
Proguanil is 75 % protein bound. Following oral administration, the volume of distribution of  
proguanil in adults weighing 41 to 80 kg is 42 t0 27 L/kg. The volume of distribution is 42 to 20L/kg in  
children weighing 11 to 40 kg and is 79 to 45 L/kg in children weighing 5 to 10kg.  
In human plasma the binding of atovaquone and proguanil was unaffected by the presence of the  
other.  
Biotransformation  
There is no evidence that atovaquone is metabolised and there is negligible excretion of atovaquone  
in urine with the parent drug being predominantly (>90%) eliminated unchanged in faeces.  
Proguanil hydrochloride is partially metabolised, primarily by the polymorphic cytochrome P450  
isoenzyme 2C19, with less than 40 % being excreted unchanged in the urine. Its metabolites,  
cycloguanil and 4-chlorophenylbiguanide, are also excreted in the urine.  
During administration of HETOVANIL film-coated tablets at recommended doses proguanil  
metabolism status appears to have no implications for treatment or prophylaxis of malaria.  
Elimination  
The elimination half-life of atovaquone is about 2-3 days in adults and 1-2 days in children. Following  
oral administration, the clearance of atovaquone in adults and children weighing 41 to 80kg is  
approximately 0,16 to 0,05L/h/kg  
The elimination half-lives of proguanil and cycloguanil are about 12-15 hours in both adults and  
children.  
Pharmacokinetics in the elderly  
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Product proprietary name: Hetovanil 62,5/25 mg and Hetovanil 250/100 mg  
Dosage form and strength: Film coated tablets. Each contains 62,5 mg or 250 mg of Atovaquone and 25  
mg or 100 mg of Proguanil HCl.  
There is no clinically significant change in the average rate or extent of absorption of atovaquone or  
proguanil between elderly and young patients. Systemic availability of cycloguanil is higher in the  
elderly compared to the young patients (AUC is increased by 140 % and Cmax is increased by 80%),  
but there is no clinically significant change in its elimination half-life (see section 4.2).  
Pharmacokinetics in renal impairment  
In patients with mild to moderate renal impairment, oral clearance and/or AUC data for atovaquone,  
proguanil and cycloguanil are within the range of values observed in patients with normal renal  
function.  
Atovaquone Cmax and AUC are reduced in patients with severe renal impairment.  
In patients with severe renal impairment, the elimination half lives for proguanil and cycloguanil are  
prolonged,resulting in the potential for drug accumulation with repeated dosing (see sections 4.2 and  
4.4).  
Pharmacokinetics in hepatic impairment  
In patients with mild to moderate hepatic impairment there is no clinically significant change in  
exposure to atovaquone when compared to patients with normal hepatic function.  
In patients with mild to moderate hepatic impairment there is an increase in proguanil AUC with no  
change in elimination half life and there is a decrease in Cmax and AUC for cycloguanil.  
No data are available in patients with severe hepatic impairment (see section 4.2).  
Paediatric population  
Not applicable  
6 PHARMACEUTICAL PARTICULARS  
6.1 List of excipients  
•
•
Atovaquone  
Proguanil HCL  
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Product proprietary name: Hetovanil 62,5/25 mg and Hetovanil 250/100 mg  
Dosage form and strength: Film coated tablets. Each contains 62,5 mg or 250 mg of Atovaquone and 25  
mg or 100 mg of Proguanil HCl.  
•
•
•
•
•
•
•
Cellulose microcrystalline  
Low-substituted hydroxyl propyl cellulose  
Sodium starch glycolate  
Silica colloidal anhydrous  
Povidone  
Poloxamers  
Magnesium Stearate  
Composition of opadry pink 06G540000  
•
•
Hypromellose 3cP E464  
Titanium dioxide E171  
•
•
•
•
•
Hypromellose 15cP E464  
Hypromellose 50cP E464  
MA Rogol/PEG 800 E1521  
MA Rogol/PEG 400 E1521  
Iron oxide red E172  
6.2 Incompatibilities  
Not applicable.  
6.3 Shelf life  
36 months  
6.4 Special precautions for storage  
Store at or below 25 °C. Protect from light and moisture.  
Keep the tablets in the carton until required for use  
KEEP OUT OF REACH OF CHILDREN.  
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Product proprietary name: Hetovanil 62,5/25 mg and Hetovanil 250/100 mg  
Dosage form and strength: Film coated tablets. Each contains 62,5 mg or 250 mg of Atovaquone and 25  
mg or 100 mg of Proguanil HCl.  
6.5 Nature and contents of container  
30’s count  
Round white opaque HDPE container 40 cc - 33 mm neck with 33 mm, PP child resistant closures  
with pulp liners  
100’s count  
High Density Polyethylene container 40 cc - 33 mm neck with 33 mm, PP child resistant closures  
with pulp liners  
10’s PVC Alu Blister  
100 mm clear PVC film 250 microns with 0,025 x96 mm plain aluminium foil (hard tempered) with  
7GSM HSL coating on bright a side  
10’s Alu / Alu Blister  
Cold form foil 108mm (60microns PVC/45microns Aluminum foil/ 25 microns OPA) with 0,025 x108  
mm plain Aluminium foil (hard tempered) with 7GSM HSL coating on bright side  
6.6 Special precautions for disposal and other handling  
‘No special requirements’  
7 HOLDER OF CERTIFICATE OF REGISTRATION  
Hetero Drugs South Africa (Pty) Ltd  
Waterfall Corporate Campus  
Building No. 2, First floor  
74 Waterfall Drive  
Midrand, 2066  
Telephone: 012 644 1220  
Fax number: 012 644 1564  
e-mail address: nokuthula.n@heterodrugs.com  
May 2022  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd.  
Product proprietary name: Hetovanil 62,5/25 mg and Hetovanil 250/100 mg  
Dosage form and strength: Film coated tablets. Each contains 62,5 mg or 250 mg of Atovaquone and 25  
mg or 100 mg of Proguanil HCl.  
8 REGISTRATION NUMBER (S)  
HETOVANIL 62,5/25 mg: 48/20.2.6/0526  
HETOVANIL 250/2100 mg: 48/20.2.6/0526  
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE  
AUTHORISATION  
30 AUGUST 2022  
10 DATE OF REVISION OF THE NEXT  
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