Vaxzevria suspension for injection *

4.2     Posology and method of administration

Posology

[...]

Elderly population

No dose adjustment is required. See also section 5.1.

Paediatric population

The safety and efficacy of Vaxzevria in children and adolescents (less than 18 years of age) have not yet been established. No data are available.

Elderly population

No dose adjustment is required. See also sections 4.4 and 5.1.

4.4     Special warnings and precautions for use

[...]

Limitations of vaccine effectiveness

Protection starts from approximately 3 weeks after the first dose of Vaxzevria. Individuals may not be fully protected until 15 days after the second dose is administered.  As with all vaccines, vaccination with Vaxzevria may not protect all vaccine recipients (see section 5.1).

Currently available clinical trial data do not allow an estimate of vaccine efficacy in subjects over 55 years of age.

[...]

4.8     Undesirable effects

Summary of the safety profile

The overall safety of Vaxzevria is based on an analysis of pooled data from four clinical trials phase I/II, II/III and III conducted in the United Kingdom, Brazil, and South Africa., and of data from an additional phase III clinical trial conducted in the United States, Peru and Chile. At the time of the analysis, 24,244a total of 56,124 participants ≥18 years old had been randomised and received either Vaxzevria or control. Out of these, 12,28233,869 received at least one dose of Vaxzevria and 10,44831,217 received two doses. The median duration of follow-up was 81 days post-dose 2, with 7,158 participants completing >2 months follow-up post-dose 2.

The most frequently reported adverse reactions wereare injection site tenderness (63.868%), injection site pain (54.358%), headache (52.753%), fatigue (53.0%), myalgia (43.944%), malaise (44.4%), pyrexia (includes feverishness ([33.5%)%] and fever ≥38°C (7.6%)),[8%]), chills (32.2%), arthralgia (26.627%) and nausea (22.2%). The majority of these adverse reactions were mild to moderate in severity and usually resolved within a few days of vaccination.

Very rare cases of thrombosis with thrombocytopenia syndrome have been reported post‑marketing within the first three weeks following vaccination (see section 4.4).

Following vaccination with Vaxzevria, recipients may experience multiple adverse reactions occurring at the same time (for example, myalgia/arthralgia, headache, chills, pyrexia and malaise).

When compared with the first dose, adverse reactions reported after the second dose were milder and less frequent.

Reactogenicity was generally milder and reported less frequently in the population of older adults (≥65 years old) studied (2,274 individuals [9.4%]).).

The safety profile was consistent across participants with or without prior evidence of SARS-CoV-2 infection at baseline; the number of seropositive participants at baseline was 753 (3.1%)..

Tabulated list of adverse reactions

The safety profile presented below is based on an analysis of data from five clinical trials which included participants ≥18 years old (pooled data from four clinical trials conducted in the United Kingdom, Brazil and South Africa, and data from one clinical trial conducted in the United States, Peru and Chile) and on data from post-authorisation experience.

[...]

Update to table 1 adverse drug reactions

5.       PHARMACOLOGICAL PROPERTIES

Updated as a result of Study D8110C00001

2.       What you need to know before you are given Vaxzevria

Warnings and precautions

[...]

As with any vaccine, the 2-dose vaccination course of Vaxzevria may not fully protect all those who receive it. It is not known how long you will be protected for. Currently there are limited data on the efficacy of Vaxzevria in individuals aged 55 and older.

[...]

4.       Possible side effects

[...]

Uncommon (may affect up to 1 in 100 people)

• sleepiness or, feeling dizzy, or deep unresponsiveness and inactivity
• abdominal pain or decreased appetite
• enlarged lymph nodes
• excessive sweating, itchy skin, rash or hives
• sleepiness or deep unresponsiveness and inactivity
• muscle spasms

Rare (may affect up to 1 in 1,000 people)

• one-sided facial drooping

​​​​​​​[...]

4.4     Special warnings and precautions for use

[..]

Thrombosis with thrombocytopenia syndrome and cCoagulation disorders

Thrombosis with thrombocytopenia syndrome

Thrombosis with thrombocytopenia syndrome (TTS), in some cases accompanied by bleeding, has been observed very rarely following vaccination with Vaxzevria. This includes severe cases presenting as venous thrombosis, including unusual sites such as cerebral venous sinus thrombosis, splanchnic vein thrombosis, as well as arterial thrombosis, concomitant with thrombocytopenia. Some cases had a fatal outcome. The majority of these cases occurred within the first three weeks following vaccination.

Thrombocytopenia

Cases of thrombocytopenia, including immune thrombocytopenia (ITP), have been reported after receiving Vaxzevria, typically within the first four weeks after vaccination. Very rarely, these presented with very low platelet levels (<20,000 per µL) and/or were associated with bleeding. Some of these cases occurred in individuals with a history of immune thrombocytopenia. Cases with fatal outcome have been reported. If an individual has a history of a thrombocytopenic disorder, such as immune thrombocytopenia, the risk of developing low platelet levels should be considered before administering the vaccine and platelet monitoring is recommended after vaccination.

Healthcare professionals should be alert to the signs and symptoms of thromboembolism and/or thrombocytopenia. Those vaccinated should be instructed to seek immediate medical attention if they develop symptoms such as shortness of breath, chest pain, leg swelling, leg pain, persistent abdominal pain following vaccination. Additionally, anyone with neurological symptoms including severe or persistent headaches, blurred vision, confusion or seizures after vaccination, or who experiences spontaneous bleeding, skin bruising (petechia) beyond the site of vaccination after a few days, should seek prompt medical attention.

[..]

4.8     Undesirable effects

Update to the Adverse reactions table to include Thrombocytopenia with a frequency of 'not known'

10.     DATE OF REVISION OF THE TEXT

0910/2021

2.       What you need to know before you are given Vaxzevria

[..]

Warnings and precautions

[..]

Blood disorders

Very rare blood clots in combination with low level of blood platelets, in some cases together with bleeding, has been observed following vaccination with Vaxzevria. This included some severe cases with blood clots in different or unusual locations (e.g. brain, bowel, liver, spleen) and excessive clotting or bleeding throughout the body. The majority of these cases occurred within the first three weeks following vaccination. Some cases had a fatal outcome.

Very low levels of blood platelets (immune thrombocytopenia), that can be associated with bleeding, have been reported very rarely, usually within the first four weeks following vaccination with Vaxzevria.

Seek immediate medical attention if you develop shortness of breath, chest pain, leg swelling, leg pain or persistent abdominal pain following vaccination (see section 4).

Also, seek immediate medical attention if you experience after a few days following vaccination severe or persistent headaches, blurred vision, confusion or seizures (fits) after vaccination, or experience unexplained bleeding or skin bruising or pinpoint round spots beyond the site of vaccination which appears after a few days (see section 4).

4.       Possible side effects

[..]

Common (may affect up to 1 in 10 people)

• swelling or redness where the injection is given
• fever (≥38°C)
• being sick (vomiting) or diarrhoea
• lowmild and transient decreased level of blood platelets (laboratory findings)
• pain in legs or arms
• flu-like symptoms, such as high temperature, sore throat, runny nose, cough and chills
• physical weakness or lack of energy

[..]

Not known (cannot be estimated from the available data)

• severe allergic reaction (anaphylaxis)
• hypersensitivity
• rapid swelling under the skin in areas such as the face, lips, mouth and throat (which may cause difficulty in swallowing or breathing)
• capillary leak syndrome (a condition causing fluid leakage from small blood vessels)
• very low levels of blood platelets (immune thrombocytopenia) that can be associated with bleeding (see section 2, Blood disorders)

6.       Contents of the pack and other information

[..]

This leaflet was last revised in 0910/2021

4.4     Special warnings and precautions for use

[..]

Thrombosis with thrombocytopenia syndrome and coagulation disorders

Thrombosis with thrombocytopenia syndrome (TTS), in some cases accompanied by bleeding, has been observed very rarely following vaccination with Vaxzevria. This includes severe cases presenting as venous thrombosis, including unusual sites such as cerebral venous sinus thrombosis, splanchnic vein thrombosis, as well as arterial thrombosis, concomitant with thrombocytopenia. Some cases had a fatal outcome. The majority of these cases occurred within the first three weeks following vaccination and occurred mostly in women under 60 years of age..

4.8     Undesirable effects

[..]

10.     DATE OF REVISION OF THE TEXT

0709/2021

2.       What you need to know before you are given Vaxzevria

[..]

Warnings and precautions

Talk to your doctor, pharmacist or nurse before you are given Vaxzevria:

• If you have ever had a severe allergic reaction after any other vaccine injection or after you were given Vaxzevria in the past;
• If you have ever fainted following any needle injection;
• If you have a severe infection with a high temperature (over 38°C). However, you can have your vaccination if you have a mild fever or upper airway infection like a cold;
• If you have a problem with bleeding or bruising, or if you are taking an anticoagulant medicine (to prevent blood clots);
• If your immune system does not work properly (immunodeficiency) or you are taking medicines that weaken the immune system (such as highdose corticosteroids, immunosuppressants or cancer medicines).);
• If you previously had GuillainBarré syndrome (temporary loss of feeling and movement) after being given Vaxzevria.

[..]

Blood disorders

Very rare blood clots in combination with low level of blood platelets, in some cases together with bleeding, has been observed following vaccination with Vaxzevria. This included some severe cases with blood clots in different or unusual locations (e.g. brain, bowel, liver, spleen) and excessive clotting or bleeding throughout the body. The majority of these cases occurred within the first three weeks following vaccination and occurred mostly in women under 60 years of age.. Some cases had a fatal outcome.

4.       Possible side effects

[..]

Very Rare (may affect up to 1 in 10,000 people)

• blood clots often in unusual locations (e.g. brain, bowel, liver, spleen) in combination with low level of blood platelets
• serious nerve inflammation, which may cause paralysis and difficulty breathing (Guillain-Barré syndrome [GBS])

6.       Contents of the pack and other information

[..]

This leaflet was last revised in 0709/2021

(Inserted text/Deleted text)

4.6     Fertility, pregnancy and lactation

Pregnancy

There is limited experience with use of Vaxzevria in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryo/foetal development, parturition or post-natal development (see section 5.3). Animal reproductive toxicity studies have not been completed. Based upon results from the preliminary study, no effects are expected on development of the fetus (see section 5.3).

Administration of Vaxzevria during pregnancy should only be considered when the potential benefits outweigh any potential risks for the mother and fetus.

Breastfeeding

It is unknown whether Vaxzevria is excreted in human milk.

In animal studies, lactational transfer of anti-SARS-CoV-2 S antibodies from maternal female mice to pups was observed (see section 5.3).

Fertility

Animal studies do not indicate direct or indirect harmful effects with respect to fertility reproductive toxicity (see section 5.3).

5.3     Preclinical safety data

In a repeat-dose toxicity study in mice, IM administration of Vaxzevria was well tolerated. Non-adverse, mixed and/or mononuclear cell inflammation was observed in the subcutaneous tissues and skeletal muscle of the administration sites and adjacent sciatic nerve consistent with the anticipated findings after IM injection of vaccines. There were no findings in the administration sites or sciatic nerves at the end of the recovery period, indicating complete recovery of the Vaxzevria related inflammation.

Non-clinical data reveal no special hazard for humans based on a conventional study of repeat dose toxicity.

Genotoxicity/Carcinogenicity

Neither genotoxicity nor carcinogenicity studies were performed. The components of the vaccine are not expected to have genotoxic potential.

Reproductive toxicity

In a reproductive and development toxicity study, Vaxzevria did not induce maternal or developmental toxicity following maternal exposure during the pre-mating, gestation or lactating periods. In this study, vaccine elicited detectable anti-SARS-CoV-2 S-glycoprotein maternal antibodies were transferred to the foetuses and pups, indicating placental and lactational transfer, respectively. No Vaxzevria data are available on vaccine excretion in milk.Animal studies of potential toxicity to reproduction and development have not yet been completed. 

A preliminary reproductive toxicity study in mice does not show toxicity in dams or foetuses.

(Inserted Text; Deleted Text)

4.4     Special warnings and precautions for use

[...]

Neurological events

Guillain-Barré syndrome (GBS) has been reported very rarely following vaccination with Vaxzevria. Healthcare professionals should be alert of GBS signs and symptoms to ensure correct diagnosis, in order to initiate adequate supportive care and treatment, and to rule out other causes.

10.     DATE OF REVISION OF THE TEXT

0607/2021

(Inserted Text; Deleted Text)

2.       What you need to know before you are given Vaxzevria

[...]

Neurological events

Seek immediate medical attention if you develop weakness and paralysis in the extremities that can progress to the chest and face (Guillain-Barré syndrome). This has been reported very rarely after vaccination with Vaxzevria.

This leaflet was last revised in 0607/2021

SmPC updated to incorporate changes associated with a PRAC recommendation for Capillary Leak Syndrome.

(Inserted text)

2.       What you need to know before you are given Vaxzevria

The vaccine must not be given:

• If you are allergic to the active substance or any of the other ingredients of this vaccine (listed in section 6).
• If you have had a blood clot occurring at the same time as having low levels of blood platelets (thrombosis with thrombocytopenia syndrome, TTS) after receiving Vaxzevria.
• If you have a previous diagnosis of capillary leak syndrome (a condition causing fluid leakage from small blood vessels).

[...]

Warnings and precautions

[...]

Capillary leak syndrome

Very rare cases of capillary leak syndrome (CLS) have been reported following vaccination with Vaxzevria. Some affected patients had a previous diagnosis of CLS. CLS is a serious, potentially fatal condition causing fluid leakage from small blood vessels (capillaries) resulting in rapid swelling of the arms and legs, sudden weight gain and feeling faint (low blood pressure). Seek immediate medical attention if you develop these symptoms in the days following vaccination.

4.       Possible side effects

[...]

The following side effects may occur with Vaxzevria:

Not known (cannot be estimated from the available data)

• severe allergic reaction (anaphylaxis)
• hypersensitivity
• rapid swelling under the skin in areas such as the face, lips, mouth and throat (which may cause difficulty in swallowing or breathing)
• capillary leak syndrome (a condition causing fluid leakage from small blood vessels)

2.       What you need to know before you are given Vaxzevria

[...]

Warnings and precautions

[...]

Blood disorders

Very rare blood clots, often in unusual locations (e.g. brain, bowel, liver, spleen), in combination with low level of blood platelets, in some cases together with bleeding, has been observed following vaccination with Vaxzevria. This included some severe cases with blood clots in different or unusual locations (e.g. brain, bowel, liver, spleen) and excessive clotting or bleeding throughout the body. The majority of these cases occurred within the first three weeks following vaccination and occurred mostly in women under 60 years of age. Some cases had a fatal outcome.

[...]

4.       Possible side effects

Like all medicines, this vaccine can cause side effects, although not everybody gets them.

In clinical studies, most side effects were mild to moderate in nature and resolved within a few days. Fewer side effects were reported after the second dose.

After vaccination, you may have more than one side effect at the same time (for example, muscle/joint aches, headaches, chills and generally feeling unwell). If any of your symptoms are persistent, please seek advice from your doctor, pharmacist or nurse.

[...]

Common (may affect up to 1 in 10 people)

• swelling or redness where the injection is given
• fever (≥>38°C)
• being sick (vomiting) or diarrhoea
• low level of blood platelets
• pain in legs or arms
• flu-like symptoms, such as high temperature, sore throat, runny nose, cough and chills
• physical weakness or lack of energy

Uncommon (may affect up to 1 in 100 people)

• sleepiness or feeling dizzy
• abdominal pain or decreased appetite
• enlarged lymph nodes
• excessive sweating, itchy skin, or rash or hives
• sleepiness or deep unresponsiveness and inactivity

Very Rare (may affect up to 1 in 10,000 people)

• blood clots often in unusual locations (e.g. brain, bowel, liver, spleen) in combination with low level of blood platelets

Not known (cannot be estimated from the available data)

• severe allergic reaction (anaphylaxis)
• hypersensitivity
• rapid swelling under the skin in areas such as the face, lips, mouth and throat (which may cause difficulty in swallowing or breathing)

[...]

5.       How to store Vaxzevria

[...]

From the time of vial opening (first needle puncture) use within 6 hours when stored at temperatures up to 30°C. After this time, the vial must be discarded. Do not return it to the refrigerator. Alternatively, an opened vial may be stored in a refrigerator (2°C – 8°C) for a maximum of 48 hours if it is immediately returned to the refrigerator following each puncture.From the time of vial opening (first needle puncture) to administration store the vial for no more than 48 hours in a refrigerator (2°C–8°C). Within this time period the product may be kept and used at temperatures up to 30°C for a single period of up to 6 hours. After this time period, the product must be discarded. Do not return it to the refrigerator.

Discard the vial if the suspension is discoloured or particles are observed. Do not shake.

Vaxzevria contains genetically modified organisms (GMOs). Any unused vaccine or waste material should be disposed of in compliance with the local guidance for genetically modified organisms or biohazardous waste. Spills should be disinfected using agents with activity against adenovirus.

6.       Contents of the pack and other information

[...]

This leaflet was last revised in 06/202105/2021

[...]

Disposal

Any unused vaccine or waste material should be disposed of in compliance with the local guidance for pharmaceutical waste. Potential spills should be disinfected with agents with viricidal activity against adenovirus.

Type IB variation (Temporary temperature excursion for unopened vials) and type II variation (Oxford data cut off information) including addition of adverse events

(Inserted Text; Deleted Text)

2.       What you need to know before you are given Vaxzevria

The vaccine must not be given:

• If you are allergic to the active substance or any of the other ingredients of this vaccine (listed in section 6).
• If you have had a blood clot occurring at the same time as having low levels of blood platelets (thrombosis with thrombocytopenia syndrome, TTS) after receiving Vaxzevria.

[...]

Blood disorders

Very rare blood clots, often in unusual locations (e.g. brain, bowel, liver, spleen), in combination with low level of blood platelets, in some cases together with bleeding, has been observed following vaccination with Vaxzevria. This included some severe cases with blood clots in different or unusual locations and excessive clotting or bleeding throughout the body. The majority of these cases occurred within the first  fourteen days three weeks following vaccination and occurred mostly in women under 60 years of age. Some cases had a fatal outcome.

Seek immediate medical attention if you develop shortness of breath, chest pain, leg swelling, leg pain or persistent abdominal pain following vaccination (see section 4).

Also, seek immediate medical attention if you experience after a few days severe or persistent headaches or, blurred vision, confusion or seizures (fits) after vaccination, or experience skin bruising or pinpoint round spots beyond the site of vaccination which appears after a few days (see section 4).

[...]

4.       Possible side effects

Like all medicines, this vaccine can cause side effects, although not everybody gets them. If you notice any side effects not mentioned in this package leaflet, please tell your doctor, pharmacist or nurse.

Blood clots in combination with low levels of blood platelets (thrombosis with thrombocytopenia syndrome, TTS) have been reported very rarely, see section 2.

Get medical attention immediately if within three weeks of vaccination you get any of the following symptoms:

• experience a severe or persistent headache, blurred vision, confusion or seizures (fits)
• develop shortness of breath, chest pain, leg swelling, leg pain or persistent abdominal pain
• notice unusual skin bruising or pinpoint round spots beyond the site of vaccination

[...]

6.       Contents of the pack and other information

[...]

This leaflet was last revised in 0405/2021

Addition of Anaphylaxis as a result of a PRAC recommendation.

4.       Possible side effects

[...]

The following side effects may occur with Vaxzevria:

[...]

Not known (cannot be estimated from the available data)

• severe allergic reaction (anaphylaxis)
• hypersensitivity

Change in the Nijmegen legal entity from MedImmune to AstraZeneca

6.       Contents of the pack and other information

[...]

Manufacturer

MedImmune Pharma B.V., NijmegenAstraZeneca Nijmegen B.V.

Lagelandseweg 78

Nijmegen, 6545CG

Netherlands

Change in the brand name from Covid-19 Vaccine AstraZeneca to Vaxzevria.

Change in the brand name of the product from COVID-19 Vaccine AstraZeneca to Vaxzevria.

Inserted text - green

4.4 Special warnings and precautions for use

.....

Thrombocytopenia and coagulation disorders

A combination of thrombosis and thrombocytopenia, in some cases accompanied by bleeding, has been observed very rarely following vaccination with COVID-19 Vaccine AstraZeneca. This includes severe cases presenting as venous thrombosis, including unusual sites such as cerebral venous sinus thrombosis, mesenteric vein thrombosis, as well as arterial thrombosis, concomitant with thrombocytopenia. The majority of these cases occurred within the first seven to fourteen days following vaccination and occurred in women under 55 years of age, however this may reflect the increased use of the vaccine in this population. Some cases had a fatal outcome.

Healthcare professionals should be alert to the signs and symptoms of thromboembolism and/or thrombocytopenia. Those vaccinated should be instructed to seek immediate medical attention if they develop symptoms such as shortness of breath, chest pain, leg swelling, persistent abdominal pain following vaccination. Additionally, anyone with neurological symptoms including severe or persistent headaches or blurred vision after vaccination, or who experiences skin bruising (petechia) beyond the site of vaccination after a few days, should seek prompt medical attention.

Risk of bleeding with intramuscular administration

As with other intramuscular injections, the vaccine should be given with caution in individuals receiving anticoagulant therapy or those with thrombocytopenia or any coagulation disorder (such as haemophilia) because bleeding or bruising may occur following an intramuscular administration in these individuals.

.....

10. DATE OF REVISION OF THE TEXT

19 March 2021

Inserted text - green

2. What you need to know before you are given COVID-19 Vaccine AstraZeneca

....

Warnings and precautions

....

If you are not sure if any of the above applies to you, talk to your doctor, pharmacist or nurse before you are given the vaccine.

Blood disorders

A combination of blood clots and low level of platelets, in some cases together with bleeding, has been observed very rarely following vaccination with COVID-19 Vaccine AstraZeneca. This included some severe cases with blood clots in different or unusual locations and excessive clotting or bleeding throughout the body. The majority of these cases occurred within the first seven to fourteen days following vaccination and mostly occurred in women under 55 years of age, however more women under 55 received the vaccine than other people. Some cases had a fatal outcome.

Seek immediate medical attention if you develop shortness of breath, chest pain, leg swelling, or persistent abdominal pain following vaccination.

Also, seek immediate medical attention if you experience after a few days severe or persistent headaches or blurred vision after vaccination, or experience skin bruising or pinpoint round spots beyond the site of vaccination which appears after a few days.