Decision

Information for Healthcare Professionals on COVID-19 Vaccine AstraZeneca

Updated 23 February 2021

Regulation 174 Information for UK healthcare professionals

This medicinal product has been given authorisation for temporary supply by the UK Department of Health and Social Care and the Medicines and Healthcare products Regulatory Agency. It does not have a marketing authorisation, but this temporary authorisation grants permission for the medicine to be used for active immunisation of individuals aged 18 years and older for the prevention of coronavirus disease 2019 (COVID-19).

As with any new medicine in the UK, this product will be closely monitored to allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

COVID-19 Vaccine AstraZeneca, solution for injection in multidose container

COVID-19 Vaccine (ChAdOx1 S [recombinant])

2. Qualitative and quantitative composition

One dose (0.5 ml) contains:

COVID-19 Vaccine (ChAdOx1-S* recombinant) 5 × 10^10 viral particles (vp)

*Recombinant, replication-deficient chimpanzee adenovirus vector encoding the SARS CoV 2 Spike (S) glycoprotein. Produced in genetically modified human embryonic kidney (HEK) 293 cells.

This product contains genetically modified organisms (GMOs).

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection.

The solution is colourless to slightly brown, clear to slightly opaque and particle free with a pH of 6.6.

4. Clinical particulars

4.1 Therapeutic indications

COVID-19 Vaccine AstraZeneca is indicated for active immunisation of individuals ≥18 years old for the prevention of coronavirus disease 2019 (COVID-19).

The use of COVID-19 Vaccine AstraZeneca should be in accordance with official guidance.

4.2 Posology and method of administration

Posology

The COVID-19 Vaccine AstraZeneca vaccination course consists of two separate doses of 0.5 ml each. The second dose should be administered between 4 and 12 weeks after the first dose (see section 5.1).

It is recommended that individuals who receive a first dose of COVID-19 Vaccine AstraZeneca complete the vaccination course with COVID-19 Vaccine AstraZeneca (see section 4.4).

Elderly population

Efficacy and safety data are currently limited in individuals ≥65 years of age (see sections 4.8 and 5.1). No dosage adjustment is required.

Paediatric population

The safety and efficacy of COVID-19 Vaccine AstraZeneca in children and adolescents (aged <18 years old) have not yet been established. No data are available.

Method of administration

COVID-19 Vaccine AstraZeneca is for intramuscular (IM) injection only, preferably in the deltoid muscle.

For instructions on administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

4.4 Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Hypersensitivity

As with all injectable vaccines, appropriate medical treatment and supervision should always be readily available in case of an anaphylactic event following the administration of the vaccine.

Concurrent illness

As with other vaccines, administration of COVID-19 Vaccine AstraZeneca should be postponed in individuals suffering from an acute severe febrile illness. However, the presence of a minor infection, such as cold, and/or low-grade fever should not delay vaccination.

Thrombocytopenia and coagulation disorders

As with other intramuscular injections, COVID-19 Vaccine AstraZeneca should be given with caution to individuals with thrombocytopenia, any coagulation disorder or to persons on anticoagulation therapy, because bleeding or bruising may occur following an intramuscular administration in these individuals.

Immunocompromised individuals

It is not known whether individuals with impaired immune responsiveness, including individuals receiving immunosuppressant therapy, will elicit the same response as immunocompetent individuals to the vaccine regimen.

Duration and level of protection

The duration of protection has not yet been established. As with any vaccine, vaccination with COVID-19 Vaccine AstraZeneca may not protect all vaccine recipients.

Interchangeability

No data are available on the use of COVID-19 Vaccine AstraZeneca in persons that have previously received a full or partial vaccine series with another COVID-19 vaccine.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, and is considered to be essentially sodium-free.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Concomitant administration of COVID-19Vaccine AstraZeneca with other vaccines has not been studied (see section 5.1).

4.6 Fertility, pregnancy and lactation

Pregnancy

There is a limited experience with the use of COVID-19 Vaccine AstraZeneca in pregnant women.

Preliminary animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryofetal development, parturition or post natal development; definitive animal studies have not been completed yet. The full relevance of animal studies to human risk with vaccines for COVID-19 remains to be established.

Administration of COVID-19 Vaccine AstraZeneca in pregnancy should only be considered when the potential benefits outweigh any potential risks for the mother and fetus.

Breastfeeding

It is unknown whether COVID-19 Vaccine AstraZeneca is excreted in human milk.

Fertility

Preliminary animal studies do not indicate direct or indirect harmful effects with respect to fertility.

4.7 Effects on ability to drive and use machines

COVID-19 Vaccine AstraZeneca has no or negligible influence on the ability to drive and use machines. However, some of the adverse reactions mentioned under section 4.8 may temporarily affect the ability to drive or use machines.

4.8 Undesirable effects

Summary of the safety profile

The overall safety of COVID-19 Vaccine AstraZeneca is based on an interim analysis of pooled data from four clinical trials conducted in the United Kingdom, Brazil, and South Africa. At the time of analysis, 23,745 participants ≥18 years old had been randomised and received either COVID-19 Vaccine AstraZeneca or control. Out of these, 12,021 received at least one dose of COVID-19 Vaccine AstraZeneca. The median duration of follow-up in the COVID-19 Vaccine AstraZeneca group was 105 days post dose 1, and 62 days post dose 2.

Demographic characteristics were generally similar among participants who received COVID-19 Vaccine AstraZeneca and those who received control. Overall, among the participants who received COVID-19 Vaccine AstraZeneca, 90.3% were aged 18 to 64 years and 9.7% were 65 years of age or older. The majority of recipients were White (75.5%), 10.1% were Black and 3.5% were Asian; 55.8% were female and 44.2% male.

The most frequently reported adverse reactions were injection site tenderness (63.7%); injection site pain (54.2%), headache (52.6%), fatigue (53.1%); myalgia (44.0%), malaise (44.2%); pyrexia (includes feverishness [33.6%] and fever ≥38°C [7.9%]), chills (31.9%), arthralgia (26.4%) and nausea (21.9%). The majority of adverse reactions were mild to moderate in severity and usually resolved within a few days of vaccination. By day 7 the incidence of subjects with at least one local or systemic reaction was 4% and 13% respectively. When compared with the first dose, adverse reactions reported after the second dose were milder and reported less frequently.

Reactogenicity events were generally milder and reported less frequently in older adults (≥65 years old).

If required, analgesic and/or anti-pyretic medicinal products (e.g. paracetamol-containing products) may be used to provide symptomatic relief from post-vaccination adverse reactions.

Tabulated list of adverse reactions

Adverse drug reactions (ADRs) are organised by MedDRA System Organ Class (SOC). Within each SOC, preferred terms are arranged by decreasing frequency and then by decreasing seriousness. Frequencies of occurrence of adverse reactions are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000) and not known (cannot be estimated from available data).

Adverse drug reactions

MedDRA SOC: Blood and lymphatic system disorders

• Frequency: Uncommon
• Adverse reactions: Lymphadenopathy (a)

MedDRA SOC: Immune system disorders

• Frequency: Not known
• Adverse reactions: Anaphylaxis (b)

MedDRA SOC: Metabolism and nutrition disorders

• Frequency: Uncommon
• Adverse reactions: Decreased appetite (a)

MedDRA SOC: Nervous system disorders

• Frequency: Very common
• Adverse reactions: Headache

MedDRA SOC: Nervous system disorders

• Frequency: Uncommon
• Adverse reactions: Dizziness (a)

MedDRA SOC: Gastrointestinal disorders

• Frequency: Very common
• Adverse reactions: Nausea

MedDRA SOC: Gastrointestinal disorders

• Frequency: Common
• Adverse reactions: Vomiting, diarrhoea (a)

MedDRA SOC: Gastrointestinal disorders

• Frequency: Uncommon
• Adverse reactions: Abdominal pain (a)

MedDRA SOC: Skin and subcutaneous tissue disorders

• Frequency: Uncommon
• Adverse reactions: Hyperhidrosis (a), pruritus (a), rash (a)

MedDRA SOC: Musculoskeletal and connective tissue disorders

• Frequency: Very common
• Adverse reactions: Myalgia, arthralgia

MedDRA SOC: General disorders and administration site conditions

• Frequency: Very common
• Adverse reactions: Injection site tenderness, injection site pain, injection site warmth, injection site pruritus, injection site bruising (c), fatigue, malaise, pyrexia (d), chills

MedDRA SOC: General disorders and administration site conditions

• Frequency: Common
• Adverse reactions: Injection site swelling, injection site erythema, injection site induration, influenza-like illness (a)(e)

(a) Unsolicited adverse reaction

(b) Identified from post-authorisation experience

(c) Injection site bruising includes injection site haematoma (uncommon, unsolicited adverse reaction)

(d) Pyrexia includes feverishness (very common) and fever ≥38°C (common)

(e) Post-authorisation reports of influenza-like illness: some recipients have reported chills, shivering (in some cases rigors), and increased body temperature possibly with sweating, headache (including migraine-like headaches), nausea, myalgia and malaise, starting within a day of vaccination. These effects usually last for a day or two. If a patient reports unusually high or prolonged fever, or other symptoms, alternative causes should be considered and appropriate advice should be provided for diagnostic investigation and medical management as required.

Very rare events of neuroinflammatory disorders have been reported following vaccination with COVID-19 Vaccine AstraZeneca. A causal relationship has not been established.

Reporting of suspected adverse reactions

If you are concerned about an adverse event, it should be reported on a Yellow Card. Reporting forms and information can be found at the Coronavirus Yellow Card reporting site search for MHRA Yellow Card in the Google Play or Apple App Store and include the vaccine brand and batch/Lot number if available.

Alternatively, adverse events of concern in association with COVID-19 Vaccine AstraZeneca can be reported to AstraZeneca on 08000541028 or via the AstraZeneca website.

Please do not report the same adverse event(s) to both systems as all reports will be shared between AstraZeneca and the MHRA (in an anonymised form) and dual reporting will create unnecessary duplicates.

4.9 Overdose

Experience of overdose is limited.

There is no specific treatment for an overdose with COVID-19 Vaccine AstraZeneca. In the event of an overdose, the individual should be monitored and provided with symptomatic treatment as appropriate.

5. Pharmacodynamic properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Vaccine, other viral vaccines, ATC code: J07BX03

Mechanism of action

COVID-19 Vaccine AstraZeneca is a monovalent vaccine composed of a single recombinant, replication-deficient chimpanzee adenovirus (ChAdOx1) vector encoding the S glycoprotein of SARS CoV 2. Following administration, the S glycoprotein of SARS CoV 2 is expressed locally stimulating neutralising antibody and cellular immune responses.

Clinical efficacy

COVID-19 Vaccine AstraZeneca has been evaluated based on an interim analysis of pooled data from four on-going randomised, blinded, controlled trials: a Phase I/II Study, COV001, in healthy adults 18 to 55 years of age in the UK; a Phase II/III Study, COV002, in adults ≥18 years of age (including the elderly) in the UK; a Phase III Study, COV003, in adults ≥18 years of age (including the elderly) in Brazil; and a Phase I/II study, COV005, in adults aged 18 to 65 years of age in South Africa. The studies excluded participants with history of anaphylaxis or angioedema; participants with severe and/or uncontrolled cardiovascular, gastrointestinal, liver, renal, endocrine/metabolic disease, and neurological illnesses; as well as those with immunosuppression. In studies COV001 and COV002, licensed seasonal influenza and pneumococcal vaccinations were permitted (at least 7 days before or after their study vaccine).

All participants are planned to be followed for up to 12 months, for assessments of safety and efficacy against COVID-19 disease.

Based on the pre-defined criteria for interim efficacy analysis, COV002 and COV003 exceeded the threshold of ≥5 virologically confirmed COVID-19 cases per study and therefore contributed to the efficacy analysis; COV001 and COV005 were excluded.

In the pooled analysis for efficacy (COV002 and COV003), participants ≥18 years of age and seronegative at baseline received two doses of COVID-19 Vaccine AstraZeneca (N=5,807) or control (meningococcal vaccine or saline) (N=5,829). Because of logistical constraints, the interval between dose 1 and dose 2 ranged from 4 to 26 weeks.

Baseline demographics were well balanced across COVID-19 Vaccine AstraZeneca and control treatment groups. Overall, among the participants who received COVID-19 Vaccine AstraZeneca, 94.1% of participants were 18 to 64 years old (with 5.9% aged 65 or older); 60.7% of subjects were female; 82.8% were White, 4.6% were Asian, and 4.4% were Black. A total of 2,070 (35.6%) participants had at least one pre-existing comorbidity (defined as a BMI ≥30 kg/m2, cardiovascular disorder, respiratory disease or diabetes). The median follow-up time post-dose 1 and post-dose 2 was 132 days and 63 days, respectively.

Final determination of COVID-19 cases were made by an adjudication committee, who also assigned disease severity according to the WHO clinical progression scale. A total of 131 participants had SARS CoV 2 virologically confirmed (by nucleic acid amplification tests) COVID-19 occurring ≥15 days post dose 2 with at least one COVID-19 symptom (objective fever (defined as ≥37.8°C), cough, shortness of breath, anosmia, or ageusia) and were without evidence of previous SARS CoV 2 infection. COVID-19 Vaccine AstraZeneca significantly decreased the incidence of COVID-19 compared to control.

An updated efficacy analysis included 17,178 participants from all four studies. Among the participants who received COVID-19 Vaccine AstraZeneca, 83.8% were 18 to 55 years old, 10.5% were 56 to 69 years old and 5.6% were aged 70 or older. The median follow-up time post-dose 1 and post-dose 2 was 143 days and 83 days, respectively. The results of these analyses, interim and updated efficacy analyses, are presented in Table 2.

COVID-19 Vaccine AstraZeneca efficacy against COVID-19

Population	COVID-19 Vaccine AstraZeneca	COVID-19 Vaccine AstraZeneca	Control	Control	Vaccine efficacy % (CI)
———	N	Number of COVID-19 cases, n (%)	N	Number of COVID-19 cases, n (%)	———
Interim analysis (cut-off date: 4 November 2020)
Primary (see above)	5,807	-	5,829	-	-
COVID-19 cases	-	30 (0.5)	-	101 (1.7)	70.4 (54.8, 80.6) (a)
Hospitalisations (b)	-	0	-	5 (0.1)	-
Severe disease (c)	-	0	-	1 (<0.1)	-
Updated analysis (cut-off date: 7 December 2020)
Primary (see above)	8,597	-	8,581	-	-
COVID-19 cases	-	84 (1.0)	-	248 (2.9)	66.7 (57.4, 74.0) (d)
Hospitalisations (b)	-	0	-	9 (0.1)	100 (50.2, NE)
Severe disease (c)	-	0	-	2 (<0.1)	-

N = Number of subjects included in each group

n = Number of subjects having a confirmed event

CI = Confidence Interval

NE = Not Evaluable

(a) 95.84% CI

(b) WHO severity grading ≥4

(c) WHO severity grading ≥6

(d) 95% CI

In the interim analysis, participants who had one or more comorbidities had a vaccine efficacy (VE) of 73.4% [95% CI: 48.5; 86.3]; 11 (0.5%) vs 43 (2.0%) cases of COVID-19 for COVID-19 Vaccine AstraZeneca (N=2,070) and control (N=2,113), respectively; which was similar to the VE observed in the overall population. In the updated analysis, the VE in this subgroup of participants with one or more comorbidities was 62.7% (95% CI: 44.8; 74.8 [COVID-19 Vaccine AstraZeneca 34/3,056 vs control 93/3,102]).

The number of COVID-19 cases in participants ≥65 years old were too few to draw conclusions on efficacy. However, in this subpopulation, immunogenicity data are available; see below. In the interim analysis there were 2 cases of COVID-19 in 660 participants. In the updated analysis, there were 12 cases in 1,383 participants (4 for COVID-19 Vaccine AstraZeneca vs 8 for control; VE = 51.9% [95% CI: -60.0, 85.5]). The majority of participants ≥65 years old received their doses with an interval shorter than 6 weeks.

The level of protection gained from a single dose of COVID-19 Vaccine AstraZeneca was assessed in an exploratory analysis that included participants who had received one dose. Participants were censored from the analysis at the earliest time point of when they received a second dose or at 12 weeks post dose 1. In this population, VE from 22 days post dose 1 was 73.0% (95% CI: 48.8; 85.8 [COVID-19 Vaccine AstraZeneca 12/7,998 vs control 44/7,982]). In the updated analysis, this was 69.2% (95% CI: 48.5; 82.4 [COVID-19 Vaccine AstraZeneca 20/11,044 vs control 65/11,015]).

Exploratory analyses showed that increased immunogenicity was associated with a longer dose interval (see Immunogenicity Table 4). Efficacy results from subgroup analyses using the updated dataset were consistent with the immunogenicity data (Table 3).

Table 3: COVID-19 Vaccine AstraZeneca efficacy by dosing interval (a)

Dosing interval	COVID-19 Vaccine AstraZeneca	COVID-19 Vaccine AstraZeneca	Control	Control	Vaccine efficacy % (95% CI)
———	N	Number of COVID-19 cases, n (%)	N	Number of COVID-19 cases, n (%)	———
<6 weeks	3,905	35 (0.9)	3,871	76 (2.0)	55.1 (33.0, 69.9)
6-8 weeks	1,124	20 (1.8)	1,023	44 (4.3)	59.7 (31.7, 76.3)
9-11 weeks	1,530	14 (0.9)	1,594	52 (3.3)	72.3 (50.0, 84.6)
≥12 weeks	2,038	15 (0.7)	2,093	76 (3.6)	80.0 (65.2, 88.5)

N = Number of subjects included in each group

n = Number of subjects having a confirmed event

CI = Confidence Interval

(a) Data from the updated analyses (7 December 2020 data cut off).

Immunogenicity

Following vaccination with COVID-19 Vaccine AstraZeneca, in participants who were seronegative at baseline, seroconversion (as measured by a ≥4 fold increase from baseline in S-binding antibodies) was demonstrated in ≥98% of participants at 28 days after the first dose and >99% at 28 days after the second. Higher S-binding antibodies were observed with increasing dose interval (Table 4).

Generally similar trends were observed between analyses of neutralising antibodies and S-binding antibodies. An immunological correlate of protection has not been established; therefore, the level of immune response that provides protection against COVID-19 is unknown.

SARS CoV-2 S-binding antibody response to COVID-19 Vaccine AstraZeneca (a), (b)

Population	Baseline	28 days after dose 1	28 days after dose 2
-	GMT (95% CI)	GMT (95% CI)	GMT (95% CI)
Overall	(N=1,538) 57.1	(N=1,466) 8,358.0	(N=1,511) 30,599.8
Population	Baseline	28 days after dose 1	28 days after dose 2
-	GMT (95% CI)	GMT (95% CI)	GMT (95% CI)
-	(53.8; 60.6)	(7,879.2; 8,866.0)	(29,137.1; 32,135.9)
Dose Interval	-	-	-
<6 weeks	(N=578) 61.4 (55.3; 68.0)	(N=578) 8,184.5 (7,423.9; 9023.1)	(N=564) 21,384.2 (19,750.7; 23,152.8)
6-8 weeks	(N=339) 56.1 (49.6; 63.3)	(N=290) 9,103.9 (8,063.1; 10,279.1)	(N=331) 28,764.8 (25,990.8; 31,834.9)
9-11 weeks	(N=331) 53.6 (47.5; 60.4)	(N=309) 8,120.9 (7,100.2; 9,288.4)	(N=327) 37,596.1 (34,494.2; 40,976.8)
≥12 weeks	(N=290) 54.3 (47.6; 61.9)	(N=289) 8,249.7 (7,254.5; 9,381.4)	(N=289) 52,360.9 (47,135.2; 58,165.9)

N = Number of subjects included in each group

GMT = Geometric mean titre

CI = Confidence interval

S = Spike

(a) Immune response evaluated using a multiplex immunoassay

(b) in seronegative individuals who received two recommended doses of vaccine

The immune response observed in participants with one or more comorbidities was consistent with the overall population.

High seroconversion rates were observed in older adults (≥65 years) after the first (97.3%; N=149) and second dose (100.0%; N=156). The increase in S-binding antibodies 28 days after second dose was lower for participants ≥65 years old (GMT=19,258.5 [N=161, 95% CI: 16,650.4; 22,275.1]) when compared to participants aged 18-64 years (GMT=32,337.1 [N=1,350, 95% CI: 30,720.8; 34,038.4]). The majority of participants ≥65 years old had a dose interval of <6 weeks, which may have contributed to the lower titres observed.

In participants with serological evidence of prior SARS-CoV-2 infection at baseline (GMT=10,979.1 [N=36; 95% CI: 6,452.7; 18,680.5]), S-antibody titres peaked 28 days after dose 1 (GMT=139,010.4 [N=35; 95% CI: 95,429.0; 202,495.1]) but did not increase further after the second dose.

Spike-specific T cell responses as measured by IFN ɣ enzyme-linked immunospot (ELISpot) assay were induced after a first dose of COVID-19 Vaccine AstraZeneca. These did not rise further after a second dose.

5.2 Pharmacokinetic properties

Not applicable.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on a conventional study of repeat dose toxicity. Animal studies into potential toxicity to reproduction and development have not yet been completed.

6. Pharmaceutical particulars

6.1 List of excipients

• L-Histidine
• L-Histidine hydrochloride monohydrate
• Magnesium chloride hexahydrate
• Polysorbate 80
• Ethanol
• Sucrose
• Sodium chloride
• Disodium edetate dihydrate
• Water for injections

6.2 Incompatibilities

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

6.3 Shelf life

Unopened multidose vial

6 months

After first use

Use as soon as practically possible and within 6 hours. The vaccine may be stored between 2°C and 25°C during the in-use period.

6.4 Special precautions for storage

• Unopened multidose vial
• Store in a refrigerator (2 to 8°C).
• Do not freeze.
• Keep vials in outer carton to protect from light.

After first use

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

6.5 Nature and contents of container

Multidose vial

• 5 ml of solution in a 10-dose vial (clear type I glass) with a halobutyl rubber stopper and an aluminium overseal with a plastic flip-off cap. Packs of 10 vials.
• 4 ml of solution in an 8-dose vial (clear type I glass) with a halobutyl rubber stopper and an aluminium overseal with a plastic flip-off cap. Packs of 10 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Administration

COVID-19 Vaccine AstraZeneca is a colourless to slightly brown, clear to slightly opaque solution. The vaccine should be inspected visually prior to administration and discarded if particulate matter or differences in the described appearance are observed. Do not shake the vial.

Each vaccine dose of 0.5 ml is withdrawn into a syringe for injection to be administered intramuscularly. Use a separate sterile needle and syringe for each individual. Each vial contains at least the number of doses stated. It is normal for liquid to remain in the vial after withdrawing the final dose. When low dead volume syringes and/or needles are used, the amount remaining in the vial may be sufficient for an additional dose. Care should be taken to ensure a full 0.5 ml dose is administered. Where a full 0.5 ml dose cannot be extracted, the remaining volume should be discarded.

The vaccine does not contain any preservative. Aseptic technique should be used for withdrawing the dose for administration.

After first dose withdrawal, use the vial as soon as practically possible and within 6 hours (stored at 2°C to 25°C). Discard any unused vaccine.

To facilitate the traceability of the vaccine, the name and the batch number of the administered product should be clearly recorded for each recipient.

Disposal

COVID-19 Vaccine AstraZeneca contains genetically modified organisms (GMOs). Any unused vaccine or waste material should be disposed of in accordance with local requirements. Spills should be disinfected with an appropriate antiviral disinfectant.

7. Marketing authorisation holder

Not applicable.

8. Marketing authorisation number(s)

Not applicable.

9. Date of first authorisation/renewal of the authorisation

Not applicable.

10. Date of revision of the text

22/02/2021