Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETERO LETROZOLE 2,5 mg  
Dosage form and strength: Film coated tablet contains 2,5 mg letrozole  
PROFESSIONAL INFORMATION FOR HETERO LETROZOLE 2,5 mg  
SCHEDULING STATUS  
S4  
1 NAME OF THE MEDICINE  
HETERO LETROZOLE 2,5 mg (film coated tablets)  
2 QUALITATIIVE AND QUANTITATIVE COMPOSITION  
Each film coated tablet contains 2,5 mg letrozole.  
Contains sugar: 32,5 mg lactose monohydrate.  
For the full list of excipients, see section 6.1.  
3 PHARMACEUTICAL FORM  
Film coated tablets.  
HETERO LETROZOLE 2,5 mg tablets are dark yellow colored, round shaped, slightly biconvex  
bevel-edged film coated tablets debossed with '5' on one side and 'H' on the other side.  
4 CLINICAL PARTICULARS  
4.1 Therapeutic indications  
•
•
•
•
Adjuvant treatment of postmenopausal women with hormone receptor positive early breast  
cancer.  
Extended adjuvant treatment of early breast cancer in postmenopausal women who have  
received prior standard adjuvant tamoxifen therapy  
First-line treatment in postmenopausal women with hormone-dependent advanced breast  
cancer.  
Treatment of advanced breast cancer in women with natural or artificially induced  
postmenopausal status, who have previously been treated with antioestrogens.  
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Product proprietary name: HETERO LETROZOLE 2,5 mg  
Dosage form and strength: Film coated tablet contains 2,5 mg letrozole  
•
Pre-operative therapy in postmenopausal women with localised hormone receptor positive  
breast cancer, to allow subsequent breast-conserving surgery in women not originally  
considered candidates for this type of surgery. Subsequent treatment after surgery should  
be in accordance with standard of care.  
4.2 Posology and method of administration  
Posology  
Adults and elderly patients:  
The recommended dose of HETERO LETROZOLE 2,5 mg is 2,5 mg once daily. In the adjuvant and  
extended adjuvant setting, treatment with HETERO LETROZOLE 2,5 mg should continue for 5 years  
or until tumour relapse occurs, whichever comes first.In patients with metastatic disease treatment  
with HETERO LETROZOLE 2,5 mg should continue until tumour progression is evident.  
Special populations  
Elderly patients:  
No dose adjustment is required for elderly patients.  
Children:  
Not applicable.  
Patients with hepatic and/or renal impairment:  
No dosage adjustment is required for patients with mild to moderate hepatic impairment (Child Pugh  
grade A and B) or renal impairment (creatinine clearance ≥ 10 ml/min).  
Insufficient data are available to establish dosage recommendations for patients with a creatinine  
clearance of < 10 ml/min (see Section 4.3).  
However, HETERO LETROZOLE 2,5 mg should not be used in patients with severe hepatic  
impairment (Child-Pugh score C).  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETERO LETROZOLE 2,5 mg  
Dosage form and strength: Film coated tablet contains 2,5 mg letrozole  
Method of administration  
HETERO LETROZOLE 2,5 mg should be taken orally and can be taken with or without food.  
4.3 Contraindications  
•
•
•
•
•
Hypersensitivity to letrozole or any of the of HETERO LETROZOLE 2,5 mg (see Section 6.1).  
Pregnancy and lactation (see Section 4.6).  
Premenopausal endocrine status.  
Severe impairment of hepatic function (Child-Pugh grade C).  
Severe  
impairment  
of  
renal  
function  
(creatinine  
clearance  
<
10  
ml/min).  
4.4 Special warnings and precautions for use  
Menopausal status  
In patients whose menopausal status is unclear, luteinising hormone (LH), follicle-stimulating  
hormone (FSH) and/or oestradiol levels should be measured before initiating treatment with  
HETERO LETROZOLE 2,5 mg Only women of postmenopausal endocrine status should receive  
HETERO LETROZOLE 2,5 mg.  
Renal impairment  
HETERO LETROZOLE 2,5 mg has not been investigated in a sufficient number of patients with a  
creatinine clearance lower than 10 ml/min (see Section 4.3).  
Hepatic impairment  
In patients with severe hepatic impairment (Child-Pugh C), systemic exposure and terminal half-  
life were approximately doubled compared to healthy volunteers (see Section 4.3).  
Bone effects  
HETERO LETROZOLE 2,5 mg is a potent oestrogen-lowering medicine. Women with a history of  
osteoporosis and/or fractures, or who are at increased risk of osteoporosis, should have their bone  
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Product proprietary name: HETERO LETROZOLE 2,5 mg  
Dosage form and strength: Film coated tablet contains 2,5 mg letrozole  
mineral density formally assessed prior to the commencement of adjuvant and extended adjuvant  
treatment and monitored during and following treatment with HETERO LETROZOLE 2,5 mg.  
Treatment or prophylaxis for osteoporosis should be initiated as appropriate and carefully  
monitored. In the adjuvant setting a sequential treatment schedule (letrozole 2 years followed by  
tamoxifen 3 years) could also be considered depending on the patient’s safety profile (see Sections  
4.2, 4.8 and 5.1).  
Tendonitis and tendon rupture  
Tendonitis and tendon ruptures (less frequent) may occur. Close monitoring of the patients and  
appropriate measures (e.g. immobilisation) must be initiated for the affected tendon (see section  
4.8).  
Other warnings  
Co-administration of HETERO LETROZOLE 2,5 mg with tamoxifen, other anti-oestrogens or  
oestrogen-containing therapies should be avoided as these medicines may diminish the  
pharmacological action of letrozole (see Section 4.5).  
Lactose  
HETERO LETROZOLE 2.5 mg contains lactose. Patients with rare hereditary problems of  
galactose intolerance, total lactase deficiency or glucose galactose malabsorption should not take  
HETERO LETROZOLE 2,5 mg.  
4.5 Interaction with other medicines and other forms of interaction  
Metabolism of letrozole is partly mediated via CYP2A6 and CYP3A4. Cimetidine, a weak,  
unspecific inhibitor of CYP450 enzymes, did not affect the plasma concentrations of letrozole. The  
effect of potent CYP450 inhibitors is unknown. Clinical interaction studies with warfarin indicated  
that the co-administration of letrozole with warfarin did not result in clinically significant interactions.  
It was reported that, in a large clinical trial there was no evidence of clinically relevant interaction in  
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Product proprietary name: HETERO LETROZOLE 2,5 mg  
Dosage form and strength: Film coated tablet contains 2,5 mg letrozole  
patients receiving other commonly prescribed medicines (e.g. benzodiazepines; barbiturates;  
NSAIDs (Nonsteroidal Anti-Inflammatory Drugs) such as diclofenac sodium, ibuprofen;  
paracetamol; furosemide; omeprazole).  
There is no clinical experience to date on the use of letrozole in combination with oestrogens or  
other anticancer medicines other than tamoxifen. Tamoxifen, other anti-oestrogens or oestrogen-  
containing therapies may diminish the pharmacological action of letrozole. Co-administration of  
HETERO LETROZOLE 2,5 mg with tamoxifen, other anti-oestrogens or oestrogens should be  
avoided (see Section 4.3).  
In in vitro experiments letrozole, was not able to substantially inhibit the metabolism of diazepam (a  
substrate of CYP2Cl9) at concentrations approximately 100-fold higher than those observed in  
plasma at steady state. Thus, clinically relevant interactions with CYP2C19 are unlikely to occur.  
However, caution should be used in the concomitant administration of drugs whose disposition is  
mainly dependent on these isoenzymes and whose therapeutic index is narrow.  
4.6 Fertility, pregnancy and lactation  
Women of perimenopausal status or child-bearing potential  
HETERO LETROZOLE 2,5 mg should only be used in women with a clearly established  
postmenopausal status (see Section 4.4). As there are reports of women regaining ovarian  
function during treatment with letrozole as in HETERO LETROZOLE 2,5 mg despite a clear  
postmenopausal status at start of therapy, the medical practitioner needs to discuss adequate  
contraception when necessary.  
Pregnancy  
Based on human experience in which there have been isolated cases of birth defects (labial  
fusion, ambiguous genitalia), letrozole as in HETERO LETROZOLE 2,5 mg may cause congenital  
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Product proprietary name: HETERO LETROZOLE 2,5 mg  
Dosage form and strength: Film coated tablet contains 2,5 mg letrozole  
malformations when administered during pregnancy. Studies in animals have shown reproductive  
toxicity (see Section 5.3).  
HETERO LETROZOLE 2,5 mg is contraindicated during pregnancy (see Section 4.3).  
Breastfeeding  
It is unknown whether letrozole and its metabolites are excreted in human milk. A risk to the  
newborns/infants cannot be excluded.  
HETERO LETROZOLE 2,5 mg is contraindicated during breastfeeding (see Section 4.3).  
Fertility  
The pharmacological action of letrozole is to reduce oestrogen production by aromatase inhibition.  
In premenopausal women, the inhibition of oestrogen synthesis leads to feedback increases in  
gonadotropin (LH, FSH) levels. Increased FSH levels in turn stimulate follicular growth and can  
induce ovulation.  
4.7 Effects on ability to drive and use machines  
HETERO LETROZOLE 2,5 mg may cause side effects such as dizziness, fatigue and somnolence  
which may affect the ability of the patients to drive and use machines. Patients should be advised  
not to drive or operate machines until it is established that their ability to perform such activities is  
not affected.  
4.8 Undesirable effects  
a) Summary of the safety profile  
The frequencies of adverse reactions for letrozole are mainly based on data collected from clinical  
trials.  
Up to approximately one third of the patients treated with letrozole in the metastatic setting and  
approximately 80% of the patients in the adjuvant setting as well as in the extended adjuvant  
setting experienced adverse reactions. The majority of the adverse reactions occurred during the  
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Product proprietary name: HETERO LETROZOLE 2,5 mg  
Dosage form and strength: Film coated tablet contains 2,5 mg letrozole  
first few weeks of treatment.  
The most frequently reported adverse reactions in clinical studies were hot flushes,  
hypercholesterolaemia, arthralgia, fatigue, increased sweating and nausea.  
Important additional adverse reactions that may occur with letrozole are: skeletal events such as  
osteoporosis and/or bone fractures and cardiovascular events (including cerebrovascular and  
thromboembolic events). The frequency category for these adverse reactions is described in Table  
1.  
b) Tabulated list of adverse reactions  
The frequencies of adverse reactions for letrozole are mainly based on data collected from clinical  
trials.  
The following adverse drug reactions, listed in Table 1, were reported from clinical studies and from  
post-marketing experience with letrozole:  
Table 1  
Infections and infestations  
Less frequent:  
Urinary tract infection  
Neoplasms benign, malignant and unspecified (including cysts and polyps):  
Less frequent:  
Tumour pain  
Blood and lymphatic system disorders:  
Less frequent:  
Leukopenia  
Immune system disorders:  
Frequency unknown  
Anaphylactic reaction, Angioedema  
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Product proprietary name: HETERO LETROZOLE 2,5 mg  
Dosage form and strength: Film coated tablet contains 2,5 mg letrozole  
Metabolism and nutrition disorders:  
Frequent:  
Decreased appetite, increased appetite,  
hypercholesterolemia  
Psychiatric disorders:  
Frequent:  
Depression  
Less frequent:  
Anxiety, nervousness, irritability  
Nervous system disorders:  
Frequent:  
Headache, dizziness  
Less frequent:  
Somnolence, insomnia, memory impairment, dysaesthesia  
(including paraesthesia and hypoesthesia), dysgeusia,  
cerebrovascular accident, carpal tunnel syndrome.  
Eye disorders:  
Less frequent:  
Cardiac disorders:  
Frequent  
Cataract, eye irritation, blurred vision  
Palpitations  
Less frequent:  
Tachycardia, ischaemic cardiac events (including new or  
worsening angina, angina requiring surgery, myocardial  
infarction and myocardial ischaemia), cardiac failure.  
Vascular disorders:  
Frequent  
Hot flushes, hypertension  
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Applicant/PHRC: Hetero Drugs South Africa (Pty) Ltd  
Product proprietary name: HETERO LETROZOLE 2,5 mg  
Dosage form and strength: Film coated tablet contains 2,5 mg letrozole  
Less frequent:  
Thrombophlebitis (including superficial and deep  
thrombophlebitis), ischemic cardiac events, pulmonary  
embolism, arterial thrombosis, cerebrovascular infarction,  
transient ischaemic attack  
Respiratory, thoracic and mediastinal disorders:  
Less frequent  
Dyspnoea, cough  
Gastrointestinal disorders:  
Frequent:  
Nausea, vomiting, dyspepsia, constipation, diarrhoea,  
Abdominal pain  
Less frequent:  
Stomatitis, dry mouth  
Hepato-biliary disorders:  
Less frequent:  
Increased hepatic enzymes, Hyperbilirubinemia, jaundice  
hepatitis  
Frequency unknown  
Skin and subcutaneous tissue disorders:  
Frequent  
Hyperhidrosis, alopecia, rash (including erythematous,  
maculopapular, psoriaform and vesicular rash), dry skin  
Pruritus, urticaria  
Less frequent  
Frequency unknown  
Toxic epidermal necrolysis, erythema multiforme  
Musculoskeletal and connective tissue frequent:  
Frequent  
Arthralgia, myalgia, bone pain, osteoporosis, bone  
fractures, arthritis,  
Less frequent  
Tendonitis, tendon rupture.  
Frequency unknown  
Trigger finger  
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Product proprietary name: HETERO LETROZOLE 2,5 mg  
Dosage form and strength: Film coated tablet contains 2,5 mg letrozole  
Renal and urinary disorders:  
Less frequent:  
Increased urinary frequency  
Reproductive system and breast disorders:  
Frequent  
Vaginal haemorrhage  
Less frequent:  
Vaginal discharge, vaginal dryness, breast pain,  
endometrial proliferative disorders (endometrial  
hyperplasia/endometrial cancer)  
General disorders and administration site conditions:  
Frequent:  
Fatigue, asthenia, malaise, peripheral oedema, chest pain  
Less frequent:  
Investigations:  
Frequent  
Pyrexia, general oedema, mucosal dryness, thirst  
Weight increased  
Weight decreased  
Less frequent  
Reporting of suspected adverse reactions  
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows  
continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to  
report any suspected adverse reactions via the “6.04 Adverse Drug Reactions Reporting Form”,  
found online under SAHPRA’s publications: https://www.sahpra.org.za/publications/Index/8 and to  
the Holder of certificate of registration through the mail: pvg.cdma@heterogroups.com  
4.9 Overdose  
Isolated cases of overdosage with letrozole have been reported.  
No specific treatment for overdosage is known; treatment should be symptomatic and supportive. In  
overdose, side effects can be precipitated and/or be of increased severity (see section 4.8).  
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Product proprietary name: HETERO LETROZOLE 2,5 mg  
Dosage form and strength: Film coated tablet contains 2,5 mg letrozole  
5 PHARMOCOLOGICAL PROPERTIES  
5.1 Pharmacodynamic properties  
A 21.12 Hormone Inhibitors  
Mechanism of action:  
The elimination of oestrogen-mediated stimulatory effects is a prerequisite for tumour response in  
cases where the growth of tumour tissue depends on the presence of oestrogens. In postmenopausal  
women, oestrogens are mainly derived from the action of the aromatase enzyme, which converts  
adrenal androgens primarily androstenedione and testosterone to estrone (E1) and oestradiol (E2).  
The suppression of oestrogen biosynthesis in peripheral tissues and the cancer tissue itself can  
therefore be achieved by specifically inhibiting the aromatase enzyme.  
Letrozole is a non-steroidal aromatase inhibitor. It inhibits the aromatase enzyme by competitively  
binding to the haem of the cytochrome P450 subunit of the enzyme, resulting in a reduction of  
oestrogen biosynthesis in all tissues.  
In healthy postmenopausal women, single doses of 0,1 mg, 0,5 mg and 2,5 mg letrozole suppress  
serum oestrone and oestradiol by 75 to 78 % and 78 % from baseline respectively. Maximum  
suppression is achieved in 48 to 78 hours.  
In postmenopausal patients with advanced breast cancer, daily doses of 0,1 to 5 mg suppress plasma  
concentration of oestradiol, oestrone, and oestrone sulphate by 75 to 95 % from baseline in all  
patients treated. With doses of 0,5 mg and higher, many values of oestrone and oestrone sulphate  
are below the limit of detection in the assays, indicating that higher oestrogen suppression is achieved  
with these doses. Oestrogen suppression was maintained throughout treatment in all these patients.  
Letrozole is specific in inhibiting aromatase activity. Impairment of adrenal steroidogenesis has not  
been observed. No clinically relevant changes were found in the plasma concentrations of cortisol,  
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Product proprietary name: HETERO LETROZOLE 2,5 mg  
Dosage form and strength: Film coated tablet contains 2,5 mg letrozole  
aldosterone, 11-deoxycortisol, 17-hydroxy-progesterone, and ACTH or in plasma renin activity among  
postmenopausal patients treated with a daily dose of letrozole, 0,1 to 5 mg. The ACTH stimulation  
test performed after 6 and 12 weeks of treatment with daily doses of 0,1 mg, 0,25 mg, 0,5 mg, 1 mg,  
2,5 mg and 5 mg did not indicate any attenuation of aldosterone or cortisol production. Thus,  
glucocorticoid and mineralocorticoid supplementation is not necessary.  
No changes were noted in plasma concentrations of androgens (androstenedione and testosterone)  
among healthy postmenopausal women after 0,1 mg, 0,5 mg and 2,5 mg single doses of letrozole or  
in plasma concentrations of androstenedione among postmenopausal patients treated with daily  
doses of 0,1 to 5 mg, indicating that the blockade of oestrogen biosynthesis does not lead to  
accumulation of androgenic precursors. Plasma levels of LH and FSH are not affected by letrozole in  
patients, nor are thyroid function as evaluated by TSH, T4 and T3 uptake.  
5.2 Pharmacokinetic properties:  
Absorption  
Letrozole is rapidly and completely absorbed from the gastrointestinal tract (mean absolute  
bioavailability: 99,9 %). Food slightly decreases the rate of absorption but the extent of absorption  
(AUC) is not changed. The minor effect on the absorption rate is not considered to be of clinical  
relevance and therefore letrozole may be taken without regard to mealtimes.  
Distribution  
Plasma protein binding of letrozole is approximately 60 %, mainly to albumin (55 %). The  
concentration of letrozole in erythrocytes is about 80 % of that in plasma. After administration of 2,5  
mg 14C-Iabelled letrozole, approximately 82 % of the radioactivity in plasma was unchanged  
compound. Systemic exposure to metabolites is therefore low. Letrozole is rapidly and extensively  
distributed to tissues. Its apparent volume of distribution at steady state is about 1,87 ± 0,47 ℓ/kg.  
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Product proprietary name: HETERO LETROZOLE 2,5 mg  
Dosage form and strength: Film coated tablet contains 2,5 mg letrozole  
Biotransformation  
Metabolic clearance to a pharmacologically inactive carbinol metabolite is the major elimination  
pathway of letrozole (Clm= 2,1 ℓ/h) but is relatively slow when compared to hepatic blood flow (about  
90 ℓ/h). The cytochrome P450 isoenzymes 3A4 and 2A6 were found to be capable of converting  
letrozole to this metabolite. Formation of minor unidentified metabolites and direct renal and faecal  
excretion play only a minor role in the overall elimination of letrozole. Within 2 weeks after  
administration of 2,5 mg 14C-Iabelled letrozole to healthy postmenopausal volunteers, 88,2 ± 7,6 % of  
the radioactivity was recovered in urine and 3,8 ± 0,9 % in faeces. At least 75 % of the radioactivity  
recovered in urine up to 216 hours (84,7 ± 7,8 % of the dose) was attributed to the glucuronide of the  
carbinol metabolite, about 9 % to two unidentified metabolites, and 6 % to unchanged letrozole.  
Elimination  
The apparent terminal elimination half-life in plasma is about 2 days. After daily administration of 2,5  
mg steady-state levels are reached within 2 to 6 weeks. Plasma concentrations at steady state are  
approximately 7 times higher than concentrations measured after a single dose of 2,5 mg, while they  
are 1,5 to 2 times higher than the steady-state values predicted from the concentrations measured  
after a single dose, indicating a slight non-linearity in the pharmacokinetics of letrozole upon daily  
administration of 2,5 mg. Since steady-state levels are maintained over time, it can be concluded that  
no continuous accumulation of letrozole occurs.  
Special populations:  
Elderly:  
Age had no effect on the pharmacokinetics of letrozole.  
Renal impairment  
It was reported that in a study involving volunteers with varying degrees of renal function (24-hour  
creatinine clearance 9 to 116 ml/ min) no effect on the pharmacokinetics of letrozole was found after a  
single dose of 2,5 mg. In a similar study involving subjects with varying degrees of hepatic function,  
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Product proprietary name: HETERO LETROZOLE 2,5 mg  
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the mean AUC values of the volunteers with moderate hepatic impairment (Child-Pugh score B) was  
37 % higher than in normal subjects, but still within the range seen in subjects without impaired  
function.  
Hepatic impairment  
It was reported that in a study comparing the pharmacokinetics of letrozole after a single oral dose in  
eight subjects with liver cirrhosis and severe hepatic impairment (Child-Pugh score C) to those in  
healthy volunteers (N=8), AUC and t1/2 increased by 95 and 187 %, respectively. Breast cancer  
patients with severe hepatic impairment are thus exposed to higher levels of letrozole than patients  
without severe hepatic dysfunction.  
5.3 Preclinical safety data;  
In a variety of preclinical safety studies conducted in standard animal species, there was no  
evidence of systemic or target organ toxicity.  
Letrozole showed a low degree of acute toxicity in rodents exposed up to 2000 mg/kg. In dogs  
letrozole caused signs of moderate toxicity at 100 mg/kg.  
In repeated-dose toxicity studies in rats and dogs up to 12 months, the main findings observed can  
be attributed to the pharmacological action of the compound. The no-adverse-effect level was 0,3  
mg/kg in both species.  
Oral administration of letrozole to female rats resulted in decreases in mating and pregnancy ratios  
and increases in pre-implantation loss.  
Both in vitro and in vivo investigations of letrozole's mutagenic potential revealed no indications of  
any genotoxicity.  
Letrozole was embryotoxic and fetotoxic in pregnant rats and rabbits following oral administration  
at clinically relevant doses. An increased incidence of foetal malformations was not seen in the  
rabbit. It is not known whether this was an indirect consequence of the pharmacological properties  
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Product proprietary name: HETERO LETROZOLE 2,5 mg  
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(inhibition of oestrogen biosynthesis) or a direct drug effect (see sections 4.3 and 4.6).  
Preclinical observations were confined to those associated with the recognised pharmacological  
action, which is the only safety concern for human use derived from animal studies.  
6 PHARMACEUTICAL PARTICULARS  
6.1 List of excipients  
•
•
•
•
Croscarmellose sodium (Ac-di-sol),  
lactose monohydrate (Pharmatose 200M),  
magnesium stearate,  
Opadry yellow (containing hypromellose, iron oxide yellow, macrogol, talc, titanium dioxide)  
(03B82401),  
•
•
Povidone (K-29/32),  
silica colloidal anhydrous (Aerosil 200).  
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 blisters in the outer carton until required for use.  
KEEP OUT OF REACH OF CHILDREN.  
6.5 Nature and contents of container  
• Plain silver aluminium/aluminium blister strips containing 10 tablets per blister packed in an  
outer cardboard carton.  
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Product proprietary name: HETERO LETROZOLE 2,5 mg  
Dosage form and strength: Film coated tablet contains 2,5 mg letrozole  
• Plain silver aluminium/clear PVC blister strips containing 10 tablets per blister packed in an  
outer cardboard carton.  
• Plain silver aluminium/clear PVC blister strips containing 14 tablets per blister packed in an  
outer cardboard carton  
• Pack sizes: 10 (1x10), 28 (2x14), 30 (3x10) 56 (4x14) or 60 (6x10) film coated tablets per pack.  
Not all packs may be marketed.  
6.6 Special precautions for disposal and other handling  
No special requirements  
7 HOLDERS OF CERTIFICATE OF RIGISTRATION  
Hetero Drugs South Africa (Pty) Ltd,  
Waterfall Corporate Campus,  
Building No 2, First Floor  
74 Waterfall Drive,  
Midrand, 2066.  
8 REGISTRATION NUMBER(S)  
47/21.12/0505.  
9 DATE OF FIRST AUTHORISATION/ RENEWAL OF AUTHORISATION  
10 August 2021  
10 DATE OF REVISION OF THE TEXT  
05 June 2022  
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