Consumer medicine information

Bavencio

Avelumab

BRAND INFORMATION

Brand name

Bavencio

Active ingredient

Avelumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Bavencio.

SUMMARY CMI

BAVENCIO®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using BAVENCIO?

BAVENCIO contains the active ingredient, avelumab. BAVENCIO is used to treat certain types of cancer.

For more information, see Section 1. Why am I using BAVENCIO? in the full CMI.

2. What should I know before I use BAVENCIO?

Do not use if you have ever had an allergic reaction to BAVENCIO or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use BAVENCIO? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with BAVENCIO and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use BAVENCIO?

  • Prior to the first four infusions of BAVENCIO, you will be given paracetamol and an antihistamine. For subsequent infusions, these medicines will only be given if your doctor believe this is necessary.
  • You will receive BAVENCIO as an infusion (a drip) into a vein (intravenously) over a period of 60 minutes, once every 2 weeks.

More instructions can be found in Section 4. How do I use BAVENCIO? in the full CMI.

5. What should I know while using BAVENCIO?

Things you should do
  • Remind any doctor, nurse, dentist or pharmacist you visit that you are using BAVENCIO.
Driving or using machines
  • Treatment-related symptoms can affect your concentration and ability to react.

For more information, see Section 5. What should I know while using BAVENCIO? in the full CMI.

6. Are there any side effects?

Common side effects include feeling tired or weak; muscle, back, stomach area or joint pain; loose stools, vomiting, nausea, constipation; swelling in the arms, feet or legs; feeling less hungry, weight loss; cough; rash, itching, redness of the skin; fever, chills; shortness of breath; dizziness, headache; high blood pressure; low blood pressure; flushing; difficulty in speaking or breathing, hoarseness; urinary tract infection such as burning sensation when urinating, strong or frequent urge to urinate.

Serious side effects include infusion-related reactions; problems due to inflammation of your lungs (pneumonitis); problems with your liver (hepatitis or liver toxicity when used in combination with axitinib); problems with your intestines (colitis) or diarrhoea; problems with your hormone producing glands (including the thyroid, pituitary, and adrenal glands); problems with your pancreas (pancreatitis); Type 1 diabetes, including a serious, sometimes life-threatening problem due to increased acid in the blood produced from diabetes (diabetic ketoacidosis); problems with your kidneys; problems with your muscles (myositis, myasthenia gravis/myasthenic syndrome, polymyalgia rheumatica); problems with your bile ducts (sclerosing cholangitis); problems with your joints (arthritis); problems with your glands that make moisture for the body (Sjögren's syndrome); problems with your heart (myocarditis or major adverse cardiovascular events when used in combination with axitinib); problems with your eyes (uveitis); an immune system disorder that can cause nerve inflammation (Guillain-Barré Syndrome); low number of neutrophils (neutropenia).

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

BAVENCIO®

Active ingredient: avelumab (rch)

Consumer Medicine Information (CMI)

This leaflet provides important information about using BAVENCIO. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using BAVENCIO.

Where to find information in this leaflet:

1. Why am I using BAVENCIO?
2. What should I know before I use BAVENCIO?
3. What if I am taking other medicines?
4. How do I use BAVENCIO?
5. What should I know while using BAVENCIO?
6. Are there any side effects?
7. Product details

1. Why am I using BAVENCIO?

BAVENCIO contains the active ingredient, avelumab. BAVENCIO is a monoclonal antibody, which is a protein designed to recognise and attach to a specific target in the body to help the immune system attack and destroy cancer cells.

BAVENCIO is used to treat a rare type of skin cancer called metastatic Merkel cell carcinoma (mMCC) where the disease has spread; a type of cancer in the bladder or urinary tract called urothelial carcinoma, when the disease is advanced or metastatic but has not progressed with platinum-based chemotherapy; or a type of kidney cancer called renal cell carcinoma (RCC), when it is advanced, in combination with another medicine, axitinib. It is important that you also read the Consumer Medicine Information for axitinib. If you have any questions about axitinib, ask your doctor.

2. What should I know before I use BAVENCIO?

Warnings

Do not use BAVENCIO if:

  • you are allergic to avelumab, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • have any other medical conditions, including an autoimmune disease (a condition where the body attacks its own cells) like Crohn's, Guillain-Barré, ulcerative colitis or lupus. If you already have an autoimmune disease, your risk of immune-mediated side effects may be higher as BAVENCIO may cause inflammation in parts of your body. You may also experience frequent flares of your autoimmune disease, which in the majority of cases are mild; human immunodeficiency virus (HIV) infection or acquired immune deficiency syndrome (AIDS); hepatitis B or hepatitis C; have had an organ transplant
  • take any medicines for any other condition, including medicines that suppress your immune system

Once you are treated with BAVENCIO, your doctor may give you corticosteroids to reduce any possible side effects that you may have during your treatment.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Talk to your doctor or nurse before receiving BAVENCIO as it may cause:

  • problems due to inflammation of your lungs (pneumonitis)
  • problems with your liver (hepatitis or liver toxicity when used in combination with axitinib)
  • problems with your intestines (colitis) or diarrhoea
  • problems with your hormone producing glands (including the thyroid, pituitary, and adrenal glands)
  • problems with your pancreas (pancreatitis)
  • Type 1 diabetes, including a serious, sometimes life-threatening problem due to increased acid in the blood produced from diabetes (diabetic ketoacidosis).
  • problems with your kidneys
  • problems with your muscles (myositis, myasthenia gravis/myasthenic syndrome, polymyalgia rheumatica)
  • problems with your bile ducts (sclerosing cholangitis)
  • problems with your joints (arthritis)
  • problems with your glands that make moisture for the body such as tears and saliva (Sjögren's syndrome)
  • problems with your heart (myocarditis or major adverse cardiovascular events such as trouble breathing, chest discomfort, or swelling of lower legs or hands when used in combination with axitinib)
  • problems with your eyes (uveitis)
  • an immune system disorder that can cause nerve inflammation (Guillain-Barré Syndrome)
  • low number of neutrophils (neutropenia)
  • infusion-related reactions

In addition, autoimmune haemolytic anaemia (headaches, short of breath, looking pale, and yellowing of the skin and/or eyes) and systemic inflammatory response syndrome (redness and swelling in the affected parts of your body, pain, loss of function of parts of your body, fatigue, fast heart rate, abnormal breathing, fever or low body temperature, shaking or chills, warm or clammy/sweaty skin, rash, confusion, agitation or other mental changes, loss of consciousness) have been reported with BAVENCIO or other products in this class (PD-1/PD-L1 blocking antibodies).

Should any of the above occur, your doctor may give you other medicines in order to prevent complications and reduce your symptoms; withhold the next dose of BAVENCIO; or stop your treatment with BAVENCIO altogether.

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

BAVENCIO must not be used during pregnancy as it may cause harm to your unborn baby.

Make sure you maintain adequate contraception during treatment and for at least one month after your last dose.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

It is unknown if BAVENCIO is passed into your breast milk. A risk to the breast-fed infant cannot be excluded.

You should not breastfeed during treatment and for at least one month after your last dose.

Use in children

For mMCC, the effectiveness of BAVENCIO in children under the age of 12 years has not been established.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with BAVENCIO and affect how it works.

These include medicines that make your immune system weak, such as steroids.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect BAVENCIO.

4. How do I use BAVENCIO?

Prior to the first four infusions of BAVENCIO, you will be given paracetamol and an antihistamine. For subsequent infusions, these medicines will only be given if your doctor believe this is necessary. These premedications are given to help minimise potential reactions to the BAVENCIO infusion.

How much to use

  • A doctor experienced in the use of medicines for cancer will supervise your treatment with BAVENCIO.
  • Depending on your cancer, the recommended dose is either 10 mg per kg of your body weight or 800 mg of BAVENCIO.
  • BAVENCIO has to be diluted with 0.9% or 0.45% saline solution before use.
  • Your doctor will calculate the correct dose and dilution for you.

When to use BAVENCIO

  • You will receive BAVENCIO as an infusion (a drip) into a vein (intravenously) over a period of 60 minutes, once every 2 weeks.
  • Your doctor will decide how long you will receive BAVENCIO based on your response to the medicine and the type of cancer you have.

If you use too much BAVENCIO

As BAVENCIO is given to you under the supervision of your doctor, it is very unlikely that you will receive too much.

However, if you think that you have used too much BAVENCIO, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using BAVENCIO?

Things you should do

Keep all appointments with your doctor so that your progress can be checked. Your doctor may do blood tests or other laboratory tests from time to time to prevent unwanted side effects during your treatment with BAVENCIO.

If you miss an appointment, talk to your doctor or nurse and arrange another visit as soon as possible.

Call your doctor straight away if you:

  • Become pregnant while you are being treated with BAVENCIO

Remind any doctor, nurse, dentist or pharmacist you visit that you are using BAVENCIO.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how BAVENCIO affects you.

Treatment-related symptoms can affect your concentration and ability to react.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Be aware of important symptoms of inflammation. BAVENCIO acts on your immune system and may cause inflammation in parts of your body. Inflammation may cause serious damage to your body and some inflammatory conditions may be life-threatening and need treatment or withdrawal of BAVENCIO.

Less serious side effects

Less serious side effectsWhat to do
  • feeling tired or weak
  • muscle or back pain, stomach area pain, joint pain
  • loose stools, vomiting, nausea, constipation
  • swelling in the arms, feet or legs
  • feeling less hungry, weight loss
  • cough
  • rash, itching, redness of the skin
  • fever, chills
  • shortness of breath
  • dizziness, headache
  • high blood pressure
  • low blood pressure
  • flushing
  • difficulty in speaking or breathing, hoarseness
  • urinary tract infection (UTI) such as burning sensation when urinating, strong or frequent or urge to urinate
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Signs of problems with your liver:
  • yellowing of the whites of the eyes or skin (jaundice), severe nausea or vomiting, pain on the right side of your stomach area (abdomen), drowsiness, dark urine (tea coloured), bleeding or bruising more easily than normal, feeling less hungry than usual, tiredness or abnormal liver function tests
Signs of problems with your thyroid, adrenal or pituitary glands (hormone producing glands):
  • extreme tiredness, rapid heartbeat, increased sweating, weight changes, changes in mood or behaviour, such as irritability or forgetfulness, feeling cold, very low blood pressure (fainting, dizziness, fatigue, nausea), headache
Signs of problem with your intestines:
  • diarrhoea (loose stools), more bowel movements than usual, blood in your stools or dark, tarry, sticky stools, severe stomach area (abdomen) pain or tenderness
Signs of problems with your lungs:
  • breathing difficulties, coughing
Signs of problems with your endocrine pancreas gland (Type 1 diabetes including a serious, sometimes life-threatening problem due to increase acid in the blood produced from diabetes (diabetic ketoacidosis)):
  • feeling more hungry or thirsty than usual, needing to urinate more often, weight loss, and feeling tired, having difficulty thinking clearly, breath that smells sweet or fruity, feeling sick or being sick, stomach pain, deep or fast breathing
Signs of problems with your kidneys:
  • abnormal kidney function tests, needing to urinate less than usual, blood in your urine, or swelling in your ankles
Signs of problems with your heart:
  • trouble breathing, dizziness or fainting, fever, chest pain, chest tightness, swelling in lower legs or hands, or flu-like symptoms
Signs of problems with your muscles:
  • muscle pain, stiffness, or weakness
Signs of problems with your pancreas:
  • abdominal pain, nausea, vomiting
Signs of problems with your eyes:
  • eye pain, eye redness, sensitivity to light, blurred or cloudy vision, small shapes moving across your field of vision (floaters), loss of peripheral vision (the ability to see objects at the side of your field of vision)
Signs of problems with your bile ducts:
  • pain in the upper right part of the stomach
  • swelling of the liver or spleen
  • fatigue
  • itching
  • yellowing of the skin or the whites of the eyes
Signs of problems with your joints:
  • joint pain, stiffness or swelling
Signs of problems with your glands that make moisture for the body:
  • dry eyes
  • dry mouth
Guillain-Barré Syndrome (an immune system disorder that can cause nerve inflammation):
  • pain, numbness, muscle weakness, difficulty walking
Changes in laboratory test results:
  • low number of neutrophils, a type of white blood cells that help fight infections
Signs of an allergic reaction (anaphylactic reaction and/or hypersensitivity):
  • shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin
Infusion-related:
  • fever
  • back and/or abdominal pain
  • chills or shaking
  • shortness of breath or wheezing
  • bumpy rash or skin wheals (hives)
  • flushing
  • low blood pressure (dizziness, fatigue, nausea)
Sometimes these symptoms may occur up to several hours later. To recognise early signs of these side effects, you will be monitored closely while you are receiving each infusion.
Your doctor may consider reducing the infusion rate, stop the infusion temporarily or permanently in order to manage these symptoms.		Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.
Please note that these signs and symptoms are sometimes delayed, and may develop weeks or months after your last dose.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What BAVENCIO contains

Active ingredient
(main ingredient)		avelumab (rch)
Other ingredients
(inactive ingredients)		Mannitol, glacial acetic acid, polysorbate 20, sodium hydroxide, water for injections
Potential allergensN/A

Do not take this medicine if you are allergic to any of these ingredients.

What BAVENCIO looks like

BAVENCIO is a clear, colourless, to slightly yellow solution. It is supplied in 10 mL colourless glass vials with a rubber stopper and aluminium seal. Each pack contains 1 vial. (Aust R 282729).

Who distributes BAVENCIO

Merck Healthcare Pty Ltd
Suite 1, Level 1
Building B
11 Talavera Road
Macquarie Park NSW 2113
Medical Information: 1800 633 463

This leaflet was prepared in January 2025.

® Registered trademark of Merck KGaA, Darmstadt, Germany

Published by MIMS March 2025

BRAND INFORMATION

Brand name

Bavencio

Active ingredient

Avelumab

Schedule

S4

 

1 Name of Medicine

Avelumab.

2 Qualitative and Quantitative Composition

Each 10 mL vial contains 200 mg of avelumab.
Each mL of concentrate contains 20 mg of avelumab.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Concentrate for solution for infusion (sterile concentrate).
Clear, colourless to slightly yellow solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Bavencio is indicated for the treatment of adults and paediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC). This indication is approved based on tumour response rate, duration of response in a single-arm study.
Bavencio is indicated for the first-line maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) whose disease has not progressed with first-line platinum-based induction chemotherapy.
Bavencio in combination with axitinib is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

4.2 Dose and Method of Administration

Treatment should be initiated and supervised by a physician experienced in the treatment of cancer.

Premedication.

Patients have to be premedicated with an antihistamine and with paracetamol prior to the first 4 infusions of Bavencio. If the fourth infusion is completed without an infusion-related reaction, premedication for subsequent doses should be administered at the discretion of the physician.

Dosage.

Merkel cell carcinoma.

The recommended dose of Bavencio as monotherapy is either 10 mg/kg body weight or 800 mg administered intravenously over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

Urothelial carcinoma.

The recommended dose of Bavencio as monotherapy is 800 mg administered intravenously over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.

Renal cell carcinoma.

The recommended dose of Bavencio in combination with axitinib is 800 mg administered intravenously over 60 minutes every 2 weeks and axitinib 5 mg orally taken twice daily (12 hours apart) with or without food until disease progression or unacceptable toxicity.

Treatment modifications.

Dose escalation or reduction is not recommended. Dosing delay or discontinuation may be required based on individual safety and tolerability. See Table 1.
Detailed guidelines for the management of immune-mediated adverse reactions are described in Section 4.4.

Treatment modifications when Bavencio is used in combination with axitinib.

If ALT or AST ≥ 3 times ULN but < 5 times ULN or total bilirubin ≥ 1.5 times ULN but < 3 times ULN, both Bavencio and axitinib should be withheld until these adverse reactions recover to Grades 0-1. If persistent (greater than 5 days), corticosteroid therapy with prednisone or equivalent followed by a taper should be considered. Rechallenge with Bavencio or axitinib or sequential rechallenge with both Bavencio and axitinib after recovery should be considered.
Dose reduction according to the axitinib product information should be considered if rechallenging with axitinib.
If ALT or AST ≥ 5 times ULN or > 3 times ULN with concurrent total bilirubin ≥ 2 times ULN or total bilirubin ≥ 3 times ULN, both Bavencio and axitinib should be permanently discontinued and corticosteroid therapy should be considered.

Special populations.

Renal impairment.

No dose adjustment is needed for patients with mild or moderate renal impairment. There are insufficient data in patients with severe renal impairment for dosing recommendations.

Hepatic impairment.

No dose adjustment is needed for patients with mild hepatic impairment. There are insufficient data in patients with moderate or severe hepatic impairment for dosing recommendations.

Administration.

Bavencio is administered over 60 minutes as an intravenous infusion using a sterile, non-pyrogenic, low-protein binding 0.2 micrometre in-line or add-on filter.
Bavencio has to be diluted with either 0.9% or 0.45% sodium chloride solution prior to infusion.
Bavencio infusion must not be administered as an intravenous push or bolus injection.

Compatibilities.

Bavencio is compatible with either 0.9% or 0.45% sodium chloride solution.
Bavencio is compatible with polypropylene, and ethylene vinyl acetate infusion bags, glass bottles, polyvinyl chloride infusion sets and in line filters with polyethersulfone membranes with pore sizes of 0.2 micrometre.
Bavencio must not be mixed with other medicinal products except those mentioned above.

Handling instructions.

An aseptic technique for the preparation of the solution for infusion has to be used.
The vial should be visually inspected for particulate matter and discolouration. Bavencio is a clear, colourless to slightly yellow solution. If the solution is cloudy, discoloured, or contains particulate matter, the vial has to be discarded.
An infusion bag of appropriate size (preferable 250 mL) containing either 0.9% or 0.45% sodium chloride solution should be used. The required volume of Bavencio should be withdrawn from the vial(s) and transferred to the infusion bag. Any partially used or empty vials have to be discarded.
The diluted solution should be mixed by gently inverting the bag in order to avoid foaming or excessive shearing of the solution.
The solution should be inspected to ensure it is clear, colourless, and free of visible particles. The diluted solution should be used immediately once prepared.
Do not co-administer other drugs through the same intravenous line.
Administer the infusion as described above.
After administration of Bavencio, the line should be flushed with either 0.9% or 0.45% sodium chloride solution.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Infusion-related reactions.

Infusion-related reactions, which might be severe, have been reported in patients receiving avelumab, see Section 4.8 Adverse Effects (Undesirable Effects).
Patients should be monitored for signs and symptoms of infusion-related reactions including pyrexia, chills, flushing, hypotension, dyspnoea, wheezing, back pain, abdominal pain, and urticaria.
For Grade 3 or Grade 4 infusion-related reactions, the infusion should be stopped and avelumab should be permanently discontinued.
For Grade 1 infusion-related reactions, the infusion rate should be slowed by 50% for the current infusion. For patients with Grade 2 infusion-related reactions, the infusion should be temporarily discontinued until Grade 1 or resolved, then the infusion will restart with a 50% slower infusion rate, see Section 4.2 Dose and Method of Administration.
In case of recurrence of Grade 1 or Grade 2 infusion-related reaction, the patient may continue to receive avelumab under close monitoring, after appropriate infusion rate modification and premedication with paracetamol and antihistamine, see Section 4.2 Dose and Method of Administration.

Immune-mediated adverse reactions.

Most immune-mediated adverse reactions occurring during treatment with avelumab as a single agent or in combination with axitinib were reversible and managed with temporary or permanent discontinuation of avelumab, administration of corticosteroids and/or supportive care. Immune-mediated adverse reactions have also occurred after the last dose of avelumab.
For suspected immune-mediated adverse reactions, adequate evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, avelumab should be withheld and corticosteroids administered. If corticosteroids are used to treat an adverse reaction, a taper of at least 1 month duration should be initiated upon improvement. In patients, whose immune-mediated adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants may be considered.
Patients with pre-existing autoimmune disease (AID). In patients with pre-existing autoimmune disease (AID), data from observational studies suggest that the risk of immune-mediated adverse reactions following immune-checkpoint inhibitor therapy may be increased compared to the risk in patients without pre-existing AID. In addition, flares of the underlying AID were frequent, but the majority were mild and manageable. Close monitoring of AID flares in patients with pre-existing AID is recommended during avelumab therapy.
Immune-mediated pneumonitis. Immune-mediated pneumonitis including fatal outcome has been reported in patients receiving avelumab, see Section 4.8 Adverse Effects (Undesirable Effects).
Patients should be monitored for signs and symptoms of pneumonitis and causes other than immune-mediated pneumonitis should be ruled out. Suspected pneumonitis should be confirmed with radiographic imaging.
Corticosteroids should be administered for Grade ≥ 2 events (initial dose of 1 - 2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper).
Avelumab should be withheld for Grade 2 immune-mediated pneumonitis until resolution, and permanently discontinued for Grade 3 or Grade 4 or recurrent Grade 2 immune-mediated pneumonitis, see Section 4.2 Dose and Method of Administration.
Immune-mediated hepatitis. Immune-mediated hepatitis including fatal outcome has been reported in patients receiving avelumab, see Section 4.8 Adverse Effects (Undesirable Effects).
Patients should be monitored for changes in liver function and symptoms of immune-mediated hepatitis. Causes other than immune-mediated hepatitis should be ruled out. Corticosteroids should be administered for Grade ≥ 2 events (initial dose 1 - 2 mg/kg/day prednisone or equivalent, followed by a corticosteroid taper).
Avelumab should be withheld for Grade 2 immune-mediated hepatitis until resolution and permanently discontinued for Grade 3 or Grade 4 immune-mediated hepatitis, see Section 4.2 Dose and Method of Administration.
Hepatotoxicity (in combination with axitinib). Hepatotoxicity occurred in patients treated with avelumab in combination with axitinib with higher than expected frequencies of Grade 3 and Grade 4 ALT and AST elevation compared to avelumab alone.
Patients should be more frequently monitored for changes in liver function and symptoms as compared to when avelumab is used as monotherapy.
Avelumab should be withheld for Grade 2 hepatotoxicity until resolution and permanently discontinued for Grade 3 or Grade 4 hepatotoxicity. Corticosteroids should be considered for Grade ≥ 2 events.
Immune-mediated colitis. Immune-mediated colitis has been reported in patients receiving avelumab, see Section 4.8 Adverse Effects (Undesirable Effects).
Patients should be monitored for signs and symptoms of immune-mediated colitis and causes other than immune-mediated colitis should be ruled out. Corticosteroids should be administered for Grade ≥ 2 events (initial dose of 1 - 2 mg/kg/day prednisone or equivalent followed by a corticosteroid taper).
Avelumab should be withheld for Grade 2 or Grade 3 immune-mediated colitis until resolution, and permanently discontinued for Grade 4 or recurrent Grade 3 immune-mediated colitis, see Section 4.2 Dose and Method of Administration.
Immune-mediated pancreatitis. Immune-mediated pancreatitis including fatal outcome has been reported in patients receiving avelumab, see Section 4.8 Adverse Effects (Undesirable Effects).
Patients should be monitored for signs and symptoms of immune-mediated pancreatitis. In symptomatic patients, obtain gastroenterology consultation and laboratory investigations (including imaging) to ensure the initiation of appropriate measures at an early stage. Corticosteroids should be administered for immune-mediated pancreatitis (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid taper).
Avelumab should be withheld in the event of suspected immune-mediated pancreatitis. Avelumab should be permanently discontinued if immune-mediated pancreatitis is confirmed, see Section 4.2 Dose and Method of Administration.
Immune-mediated myocarditis. Immune-mediated myocarditis including fatal outcome has been reported in patients receiving avelumab, see Section 4.8 Adverse Effects (Undesirable Effects).
Patients should be monitored for signs and symptoms of immune-mediated myocarditis. In symptomatic patients, obtain cardiologic consultation and laboratory investigations to ensure the initiation of appropriate measures at an early stage. Corticosteroids should be administered for immune-mediated myocarditis (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid taper). If no improvement within 24 hours on corticosteroids, additional immunosuppression (e.g. mycophenolate, infliximab, anti-thymocyte globulin) should be considered.
Avelumab should be withheld in the event of suspected immune-mediated myocarditis. Avelumab should be permanently discontinued if immune-mediated myocarditis is confirmed, see Section 4.2 Dose and Method of Administration.
Immune-mediated endocrinopathies. Immune-mediated thyroid disorders and immune-mediated adrenal insufficiency, and Type 1 diabetes mellitus have been reported in patients receiving avelumab, see Section 4.8 Adverse Effects (Undesirable Effects). Patients should be monitored for clinical signs and symptoms of endocrinopathies. Avelumab should be withheld for Grade 3 or Grade 4 endocrinopathies until resolution.

Thyroid disorders (hypothyroidism/hyperthyroidism).

Thyroid disorders can occur at any time during treatment. Patients should be monitored for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Hypothyroidism should be managed with replacement therapy and hyperthyroidism with anti-thyroid drug as needed.
For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm aetiology or to rule out other causes. Based on the severity of the adverse reaction, avelumab should be withheld and corticosteroids to be administered. Avelumab should be resumed when the immune-mediated adverse reaction remains at Grade 1 or less following corticosteroid taper. Avelumab should be withheld for any Grade 3 immune-mediated adverse reaction that recurs and for Grade 4 immune-mediated adverse reaction, see Section 4.2 Dose and Method of Administration.

Adrenal insufficiency.

Patients should be monitored for signs and symptoms of adrenal insufficiency during and after treatment. Corticosteroids should be administered (1 - 2 mg/kg/day prednisone i.v. or oral equivalent) for Grade ≥ 3 adrenal insufficiency followed by a taper until a dose of less than or equal to 10 mg/day has been reached.
Avelumab should be withheld for Grade 3 or Grade 4 symptomatic adrenal insufficiency, see Section 4.2 Dose and Method of Administration.

Type 1 diabetes mellitus.

Avelumab can cause Type 1 diabetes mellitus, including diabetic ketoacidosis, see Section 4.8 Adverse Effects (Undesirable Effects).
Patients should be monitored for hyperglycaemia or other signs and symptoms of diabetes. Initiate treatment with insulin for Type 1 diabetes mellitus. Avelumab should be withheld and anti-hyperglycaemics or insulin in patients with Grade ≥ 3 hyperglycaemia should be administered. Treatment with avelumab should be resumed when metabolic control is achieved on insulin replacement therapy or anti-hyperglycaemics.
Immune-mediated nephritis and renal dysfunction. Avelumab can cause immune-mediated nephritis, see Section 4.8 Adverse Effects (Undesirable Effects).
Patients should be monitored for elevated serum creatinine prior to and periodically during treatment. Corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a corticosteroid taper) should be administered for Grade ≥ 2 nephritis. Avelumab should be withheld for Grade 2 or Grade 3 nephritis until resolution to ≤ Grade 1 and permanently discontinued for Grade 4 nephritis.

Major adverse cardiovascular events (MACE).

Bavencio in combination with axitinib can cause severe and fatal cardiovascular events. Consider baseline and periodic evaluations of left ventricular ejection fraction. Monitor for signs and symptoms of cardiovascular events. Discontinue Bavencio and axitinib for Grade 3-4 cardiovascular events.
MACE occurred in 7% of patients with advanced RCC treated with Bavencio in combination with axitinib compared to 3.4% treated with sunitinib in JAVELIN Renal 101. These events included death due to cardiac events (1.4%), Grade 3-4 myocardial infarction (2.8%), and Grade 3-4 congestive heart failure (1.8%). Median time to onset of MACE was 4.2 months (range: 2 days to 24.5 months).

Other immune-mediated adverse reactions.

Other clinically important immune-mediated adverse reactions were reported in less than 1% of patients: myositis, hypopituitarism, uveitis, myasthenia gravis, myasthenic syndrome, Guillain-Barré syndrome, sclerosing cholangitis, arthritis, polymyalgia rheumatica, Sjogren's syndrome, and neutropenia, see Section 4.8 Adverse Effects (Undesirable Effects).
The following clinically significant, immune-mediated adverse reactions have been reported with avelumab or other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: autoimmune haemolytic anaemia (AIHA), systemic inflammatory response syndrome (SIRS).
For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm aetiology or to rule out other causes. Based on the severity of the adverse reaction, avelumab should be withheld and corticosteroids to be administered. Avelumab should be resumed when the immune-mediated adverse reaction remains at Grade 1 or less following corticosteroid taper.
Avelumab should be permanently discontinued for any other Grade 3 immune-mediated adverse reactions that recur and for any Grade 4 treatment related adverse reactions except for endocrinopathies controlled with hormone replacement, see Section 4.2 Dose and Method of Administration.

Patients excluded from clinical studies.

Patients with the following conditions were excluded from clinical trials: active central nervous system (CNS) metastasis or treated within 2 months; active or a history of autoimmune disease; a history of other malignancies within the last 5 years except basal or squamous cell carcinoma of the skin or cervical carcinoma in situ; organ transplant; conditions requiring therapeutic immune suppression or active infection with HIV, or hepatitis B or C.

Paediatric use.

Merkel cell carcinoma.

The safety and efficacy of Bavencio have been established in paediatric patients age 12 years and older. Use of Bavencio in this age group is supported by evidence from adequate and well-controlled studies of Bavencio in adults with additional population pharmacokinetic data demonstrating that age and body weight had no clinically meaningful effect on the steady-state exposure of avelumab, that drug exposure is generally similar between adults and paediatric patients age 12 years and older for monoclonal antibodies, and that the course of MCC is sufficiently similar in adults and paediatric patients to allow extrapolation of data in adults to paediatric patients. The recommended dose in paediatric patients 12 years of age or greater is the same as that in adults.
The safety and efficacy of Bavencio in children less than 12 years of age have not been established.

Urothelial carcinoma.

The safety and efficacy of Bavencio in children and adolescents below 18 years of age have not been established.

Renal cell carcinoma.

The safety and efficacy of Bavencio in combination with axitinib in children and adolescents below 18 years of age have not been established.

Use in the elderly.

Merkel cell carcinoma.

Clinical studies of Bavencio in MCC did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

Urothelial carcinoma.

Of the 350 patients randomised to Bavencio 10 mg/kg plus BSC in the JAVELIN Bladder 100 trial, 63% were 65 years or older and 24% were 75 years or older. No overall differences in safety or efficacy were reported between elderly patients and younger patients.

Renal cell carcinoma.

Of the 434 patients who received Bavencio 10 mg/kg administered in combination with axitinib 5 mg twice daily in the JAVELIN Renal 101 trial, 38% were 65 years or older and 8% were 75 years or older. No overall difference in safety or efficacy were reported between elderly patients and younger patients.

Immunosuppressed/organ transplant patients.

Efficacy and safety have not been studied in immunosuppressed patients or in patients with a history of organ transplantation.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been conducted with avelumab in humans.
Avelumab is primarily metabolised through catabolic pathways. Therefore, it is not expected that avelumab will have drug-drug interactions with other medicinal products.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effect of avelumab on male and female fertility is unknown.
Although studies to evaluate the effect of avelumab on fertility have not been conducted, there were no notable effects in the male and female reproductive organs in monkeys following IV administration at up to 140 mg/kg weekly for 3 months (yielding 25 times the serum AUC in patients at the recommended clinical dose of 10 mg/kg or 800 mg every two weeks).
(Category D)
There are no or limited data from the use of avelumab in pregnant women.
Animal reproduction studies have not been conducted with avelumab. However, in murine models of pregnancy, blockade of PD-L1 signalling has been shown to disrupt tolerance to the foetus and to result in an increased foetal loss. These results indicate a potential risk, based on its mechanism of action, that administration of avelumab during pregnancy could cause foetal harm, including increased rates of abortion or stillbirth.
Human IgG1 immunoglobulins are known to cross the placental barrier. Therefore, avelumab has the potential to be transmitted from the mother to the developing foetus. It is not recommended to use avelumab during pregnancy unless the clinical condition of the woman requires treatment with avelumab.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving avelumab and should use effective contraception during treatment with avelumab and for at least 1 month after the last dose of avelumab.
 It is unknown whether avelumab is excreted in human milk. Since it is known that antibodies can be secreted in human milk, a risk to the newborns/infants cannot be excluded.
Breast-feeding women should be advised not to breastfeed during treatment and for 1 month after the last dose of avelumab due to the potential for serious adverse reactions in breastfed infants.

4.7 Effects on Ability to Drive and Use Machines

Avelumab has no or negligible influence on the ability to drive and use machines. Fatigue has been reported following administration of avelumab, see Section 4.8 Adverse Effects (Undesirable Effects).

4.8 Adverse Effects (Undesirable Effects)

Avelumab is associated with immune-mediated adverse reactions. Most of these, including severe reactions, resolved following initiation of appropriate medical therapy or withdrawal of avelumab, see Description of selected adverse reactions.
For immune-mediated adverse reactions and infusion-related reactions, see Section 4.4 Special Warnings and Precautions for Use.
All tables in Section 4.8 are presented by system organ class, preferred term, frequency, and grade of severity. Frequencies 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 < 1/1,000); very rare (< 1/10,000).

Merkel cell carcinoma.

Summary of the safety profile.

The safety of avelumab as monotherapy has been evaluated in patients with solid tumours including metastatic MCC receiving 10 mg/kg every 2 weeks of avelumab in clinical studies.
In this patient population, the most common adverse reactions with avelumab were fatigue (32.4%), nausea (25.1%), diarrhoea (18.9%), decreased appetite (18.4%), constipation (18.4%), infusion-related reactions (17.1%), weight decrease (16.6%), and vomiting (16.2%). The most common Grade ≥ 3 adverse reactions were anaemia (6.0%), dyspnoea (3.9%), and abdominal pain (3.0%).

Tabulated list of adverse reactions.

Adverse reactions reported for 88 patients with mMCC treated with avelumab 10 mg/kg in study EMR100070-003 and adverse reactions reported for 1,650 patients in a phase I study (EMR100070-001) in other solid tumours are presented in Table 2.

Urothelial carcinoma.

Summary of the safety profile.

In study B9991001 (N = 344), the most common adverse reactions (preferred term/composite term) with avelumab were fatigue (35.5%), musculoskeletal pain (23.5%), urinary tract infection (20.3%), rash (20.1%), pruritus (17.2%), diarrhoea (16.6%), constipation (16.3%), arthralgia (16.3%), nausea (15.7%), pyrexia (14.8%), cough (14.0%), decreased appetite (13.7%), vomiting (12.5%), hypothyroidism (11.6%), and infusion-related reactions (10.2%). The most common Grade ≥ 3 adverse reaction was urinary tract infection (5.8%).

Tabulated list of adverse reactions.

Table 3 and Table 4 describe the adverse reactions reported in 344 patients with locally advanced or metastatic UC receiving avelumab 10 mg/kg every 2 weeks plus best supportive care (BSC) in study B9991001.

Renal cell carcinoma.

Summary of the safety profile.

The safety of avelumab in combination with axitinib has been evaluated in a total of 434 patients in study B9991003, a randomised, open-label study in which 873 patients with treatment-naïve advanced RCC received avelumab 10 mg/kg intravenously every 2 weeks in combination with axitinib 5 mg orally twice daily (n = 434) or sunitinib 50 mg orally once daily for 4 weeks followed by 2 weeks off (n = 439).

Tabulated list of adverse reactions.

The adverse reactions presented in Table 5 and Table 6 describe the safety profile for avelumab in combination with axitinib in 434 patients with RCC.
Drug eruption was reported in one patient receiving avelumab in combination with axitinib in study B9991002.

Description of selected adverse reactions.

Data for the following adverse reactions for avelumab as monotherapy are based on 1650 patients in study EMR100070-001 in other solid tumours and 88 patients in study EMR100070-003, and for avelumab in combination with axitinib are based on 489 patients in studies B9991002 and B9991003 (see Section 5.1 Pharmacodynamic Properties).
The management guidelines for these adverse reactions are described in Section 4.4 Special Warnings and Precautions for Use.
Infusion-related reactions. In patients treated with avelumab as monotherapy, 25.3% (439/1738) of patients experienced infusion-related reactions. Of these, 98.6% (433/439) of patients with infusion-related reactions had a first infusion-related reaction during the first 4 infusions of which 2.7% (12/439) were Grade ≥ 3. In the remaining 1.4% (6/439) of patients, infusion-related reactions occurred after the first 4 infusions and all were of Grade 1 or Grade 2.
Immune-mediated pneumonitis. In patients treated with avelumab as monotherapy, 1.2% (21/1738) of patients developed immune-mediated pneumonitis. Of these patients, there was 1 (0.1%) patient with a fatal outcome, 1 (0.1%) patient with Grade 4, 5 (0.3%) patients with Grade 3, immune-mediated pneumonitis.
The median time to onset of immune-mediated pneumonitis was 2.5 months (range: 3 days to 11 months). The median duration was 7 weeks (range: 4 days to more than 4 months).
Avelumab was discontinued in 0.3% (6/1,738) of patients due to immune-mediated pneumonitis. All 21 patients with immune-mediated pneumonitis were treated with corticosteroids and 17 (81%) of the 21 patients were treated with high-dose corticosteroids for a median of 8 days (range: 1 day to 2.3 months). Immune-mediated pneumonitis resolved in 12 (57%) of the 21 patients at the time of data cut-off.
In patients treated with avelumab in combination with axitinib, 0.6% (3/489) of patients developed immune-mediated pneumonitis. Of these patients, none experienced immune-mediated pneumonitis Grade ≥ 3.
The median time to onset of immune-mediated pneumonitis was 3.7 months (range: 2.7 months to 8.6 months). The median duration was 2.6 months (range: 3.3 weeks to more than 7.9 months).
Immune-mediated pneumonitis did not lead to discontinuation of avelumab in any patient. All 3 patients with immune-mediated pneumonitis were treated with high-dose corticosteroids for a median of 3.3 months (range: 3 weeks to 22.3 months). Immune-mediated pneumonitis resolved in 2 (66.7%) of the 3 patients at the time of data cut-off.
Immune-mediated hepatitis. In patients treated with avelumab as monotherapy, 0.9% (16/1738) of patients developed immune-mediated hepatitis. Of these patients there were 2 (0.1%) patients with a fatal outcome, 11 (0.6%) patients with Grade 3 immune-mediated hepatitis.
The median time to onset of immune-mediated hepatitis was 3.2 months (range: 1 week to 15 months). The median duration was 2.5 months (range: 1 day to more than 7.4 months).
Avelumab was discontinued in 0.5% (9/1,738) of patients due to immune-mediated hepatitis. All 16 patients with immune-mediated hepatitis treated with corticosteroids and 15 (94%) of the 16 patients received high dose corticosteroids for a median of 14 days (range: 1 day to 2.5 months). Immune-mediated hepatitis resolved in 9 (56%) of 16 patients at the time of data cut-off.
In patients treated with avelumab in combination with axitinib, 6.3% (31/489) of patients developed immune-mediated hepatitis. Of these patients, there were 18 (3.7%) patients with Grade 3 and 3 (0.6%) patients with Grade 4 immune-mediated hepatitis.
The median time to onset of immune-mediated hepatitis was 2.3 months (range: 2.1 weeks to 14.5 months). The median duration was 2.1 weeks (range: 2 days to 8.9 months).
Avelumab was discontinued in 4.7% (23/489) of patients due to immune-mediated hepatitis. All 31 patients with immune-mediated hepatitis were treated for hepatitis including 30 (96.8%) patients treated with corticosteroids and 1 patient with a non-steroidal immunosuppressant. Twenty-eight (90.3%) of the 31 patients received high dose corticosteroids for a median of 2.4 weeks (range: 1 day to 10.2 months). Immune-mediated hepatitis resolved in 27 (87.1%) of the 31 patients at the time of data cut-off.
Immune-mediated pancreatitis. In patients treated with avelumab as monotherapy, immune-mediated pancreatitis occurred in less than 1% (1/4,000) of patients across clinical trials in multiple tumour types and in 0.6% (3/489) of patients receiving avelumab in combination with axitinib including 2 (0.4%) patients with fatal outcome.
Immune-mediated myocarditis. In patients treated with avelumab as monotherapy, immune-mediated myocarditis occurred in less than 1% (5/4,000) of patients across clinical trials in multiple tumour types and in 0.6% (3/489) of patients receiving avelumab in combination with axitinib including 2 (0.4%) patients with fatal outcome.
Immune-mediated colitis. In patients treated with avelumab as monotherapy, 1.5% (26/1738) of patients developed immune-mediated colitis. Of these patients, there were 7 (0.4%) patients with Grade 3 immune-mediated colitis.
The median time to onset of immune-mediated colitis was 2.1 months (range: 2 days to 11 months). The median duration was 6 weeks (range: 1 day to more than 14 months).
Avelumab was discontinued in 0.5% (9/1,738) patients due to immune-mediated colitis. All 26 patients with immune-mediated colitis were treated with corticosteroids and 15 (58%) of the 26 patients received high-dose corticosteroids for a median of 19 days (range: 1 day to 2.3 months). Immune-mediated colitis resolved in 18 (70%) of 26 patients at the time of data cut-off.
In patients treated with avelumab in combination with axitinib, 2.7% (13/489) of patients developed immune-mediated colitis. Of these patients, there were 9 (1.8%) patients with Grade 3 immune-mediated colitis.
The median time to onset of immune-mediated colitis was 5.1 months (range: 2.3 weeks to 14 months). The median duration was 1.6 weeks (range: 1 day to more than 9 months).
Avelumab was discontinued in 0.4% (2/489) of patients due to immune-mediated colitis. All 13 patients with immune-mediated colitis were treated with corticosteroids and 12 (92.3%) of the 13 patients received high-dose corticosteroids for a median of 2.3 weeks (range: 5 days to 4.6 months). Immune-mediated colitis resolved in 10 (76.9%) of 13 patients at the time of data cut-off.
Immune-mediated endocrinopathies.

Thyroid disorders.

In patients treated with avelumab as monotherapy, 5.6% (98/1738) of patients developed immune-mediated thyroid disorders. Of these patients, there were 90 (5%) patients with hypothyroidism, 7 (0.4%) with hyperthyroidism, and 4 (0.2%) with thyroiditis. Of these patients there were 3 (0.2%) patients with Grade 3 immune-mediated thyroid disorders. The median time to onset of thyroid disorders was 2.8 months (range: 2 weeks to 13 months). The median duration was not estimable (range: 1 day to more than 26 months).
Avelumab was discontinued in 0.1% (2/1,738) of patients due to immune-mediated thyroid disorders. Thyroid disorders resolved in 7 (7%) of the 98 patients at the time of data cut-off.
In patients treated with avelumab in combination with axitinib, 24.7% (121/489) of patients developed immune-mediated thyroid disorders, including 111 (22.7%) patients with hypothyroidism, 17 (3.5%) with hyperthyroidism, and 7 (1.4%) with thyroiditis. Of these patients, there were 2 (0.4%) patients with Grade 3 immune-mediated thyroid disorders. The median time to onset of thyroid disorders was 2.8 months (range: 3.6 weeks to 19.3 months).
The median duration was not estimable (range: 8 days to more than 23.9 months).
Avelumab was discontinued in 0.2% (1/489) of patients due to immune-mediated thyroid disorders.
Thyroid disorders resolved in 15 (12.4%) of the 121 patients at the time of data cut-off.

Adrenal insufficiency.

In patients treated with avelumab as monotherapy, 0.5% (8/1738) of patients developed immune-mediated adrenal insufficiency. Of these patients, there was 1 (0.1%) patient with Grade 3 immune-mediated adrenal insufficiency.
The median time to onset of immune-mediated adrenal insufficiency was 2.5 months (range: 1 day to 8 months). The median duration was not estimable (range: 2 days to more than 6 months).
Avelumab was discontinued in 0.1% (2/1738) patients due to immune-mediated adrenal insufficiency. All 8 patients with immune-mediated adrenal insufficiency were treated with corticosteroids, 4 (50%) of the 8 patients received high-dose systemic corticosteroids (≥ 40 mg prednisone or equivalent) followed by a taper for a median of 1 day (range: 1 day to 24 days). Adrenal insufficiency resolved in 1 patient with corticoid treatment at the time of data cut-off.
In patients treated with avelumab in combination with axitinib, 1.8% (9/489) of patients developed immune-mediated adrenal insufficiency. Of these patients, there were 2 (0.4%) patients with Grade 3 immune-mediated adrenal insufficiency.
The median time to onset of immune-mediated adrenal insufficiency was 5.5 months (range: 3.6 weeks to 8.7 months). The median duration was 2.8 months (range: 3 days to more than 15.5 months).
Immune-mediated adrenal insufficiency did not lead to discontinuation of avelumab in any patient. Eight (88.9%) patients with immune-mediated adrenal insufficiency were treated with corticosteroids and 2 (25%) of the 8 patients received high-dose corticosteroids (≥ 40 mg prednisone or equivalent) for a median of 8 days (range: 5 days to 11 days). Adrenal insufficiency resolved in 4 (44.4%) of the 9 patients at the time of data cut-off.

Type 1 diabetes mellitus.

Type 1 diabetes mellitus without an alternative aetiology occurred in 0.1% (2/1,738) of patients including two Grade 3 reactions that led to permanent discontinuation of avelumab.
In patients treated with avelumab in combination with axitinib, Type 1 diabetes mellitus without an alternative aetiology occurred in 1.0% (5/489) of patients. Of these patients, there was 1 (0.2%) patient with Grade 3 Type 1 diabetes mellitus.
The median time to onset of Type 1 diabetes mellitus was 1.9 months (range: 1.1 months to 7.3 months).
Avelumab was discontinued in 0.2% (1/489) of patients due to Type 1 diabetes mellitus. All 5 patients with Type 1 diabetes mellitus were treated with insulin. Type 1 diabetes mellitus did not resolve in any of the patients at the time of data cut-off.
Immune-mediated nephritis and renal dysfunction. Immune-mediated nephritis occurred in 0.1% (1/1,738) of patients receiving avelumab leading to permanent discontinuation of avelumab.
In patients treated with avelumab in combination with axitinib, immune-mediated nephritis occurred in 0.4% (2/489) of patients. Of these patients, there were 2 (0.4%) patients with Grade 3 immune-mediated nephritis.
The median time to onset of immune-mediated nephritis was 1.2 months (range: 2.9 weeks to 1.8 months). The median duration was 1.3 weeks (range: more than 4 days to 1.3 weeks).
Immune-mediated nephritis did not lead to discontinuation of avelumab in any patient. The 2 patients with immune-mediated nephritis were treated with high-dose corticosteroids for a median of 1.1 weeks (range: 3 days to 1.9 weeks). Immune-mediated nephritis resolved in 1 (50%) of the 2 patients at the time of data cut-off.
Hepatotoxicity (in combination with axitinib). In patients treated with avelumab in combination with axitinib, Grade 3 and Grade 4 increased ALT and increased AST were reported in 9% and 7% of patients, respectively. In patients with ALT ≥ 3 times ULN (Grades 2-4, n = 82), ALT resolved to Grades 0-1 in 92%.
Among the 73 patients who were rechallenged with either avelumab (59%) or axitinib (85%) monotherapy or with both (55%), 66% had no recurrence of ALT ≥ 3 times ULN.
Immunogenicity. Of 1,738 patients treated with avelumab 10 mg/kg as an intravenous infusion every 2 weeks, 1,627 were evaluable for treatment-emergent anti-drug antibodies (ADA) and 96 (5.9%) tested positive. In ADA positive patients, there may be an increased risk for infusion-related reactions (about 40% and 25% in ADA ever-positive and ADA never-positive patients, respectively).
An ADA method with improved sensitivity for evaluating treatment-emergent ADA in patients treated with avelumab as a single agent was used for study B9991001. Of the 344 patients treated with avelumab 10 mg/kg as an intravenous infusion every 2 weeks plus BSC, 325 were evaluable for treatment-emergent ADA and 62 (19.1%) tested positive in study B9991001.
Based on data available, including the low incidence of immunogenicity, the impact of ADA on pharmacokinetics, safety, and efficacy is uncertain, while the impact of neutralising antibodies (nAb) is unknown. The development of treatment-emergent ADA against avelumab did not appear to alter the risk of infusion-related reactions.
The ADA method with improved sensitivity and drug tolerance was used in the RCC population. Of the 480 patients with at least one valid ADA result at any time point treated with avelumab 10 mg/kg as an intravenous infusion every 2 weeks in combination with axitinib 5 mg twice daily (studies B9991002 and B9991003), 453 were evaluable for treatment-emergent ADA and 66 (14.6%) tested positive. Overall, there was no evidence of altered pharmacokinetic profile, increased incidence of infusion reactions or effects on efficacy with anti-avelumab antibody development.

Post-marketing experience.

Blood and lymphatic system disorders.

Neutropenia.

Hepatobiliary disorders.

Sclerosing cholangitis.

Musculoskeletal and connective tissue disorders.

Arthritis (including immune-mediated arthritis), Sjogren's syndrome, tenosynovitis, polymyalgia rheumatica, and myositis (including polymyositis).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There are limited experiences with overdose with avelumab in clinical studies.
In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions. The treatment is directed to the management of symptoms.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Other antineoplastic agents, monoclonal antibodies.
ATC code: L01FF04.

Mechanism of action.

PD-L1 may be expressed on tumour cells and/or tumour-infiltrating immune cells and can contribute to the inhibition of the anti-tumour immune response in the tumour microenvironment. Binding of PD-L1 to the PD-1 and B7.1 receptors found on T-cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation and cytokine production.
Avelumab is a fully human immunoglobulin G1 (IgG1) monoclonal antibody directed against programmed death ligand 1 (PD-L1). Avelumab binds PD-L1 and blocks the interaction between PD-L1 and the programmed death 1 (PD-1) and B7.1 receptors. This removes the suppressive effects of PD-L1 on cytotoxic CD8+ T-cells, resulting in the restoration of anti-tumour T-cell responses. In syngeneic mouse tumour models, blocking PD-L1 activity resulted in decreased tumour growth.
Avelumab has also been shown to induce NK cell-mediated direct tumour cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.
Avelumab (anti-PD-L1) and axitinib (a receptor tyrosine kinase inhibitor of the vascular endothelial growth factor receptors (VEGFR-1, VEGFR-2, and VEGFR-3) target different immunomodulatory pathways. Axitinib reduced the proliferation of immune suppressive cells and enhanced tumour infiltration of immune effector cells in mouse models. Axitinib also inhibited VEGF-mediated endothelial cell proliferation and survival, and tumour growth, in vitro and in mouse tumour xenograft models. Compared to either drug alone, co-administration of a PD-1 pathway inhibitor and a VEGF pathway blocker resulted in enhanced biological activity and improved anti-tumour responses in mouse models and patients with advanced RCC.

Clinical trials.

Merkel cell carcinoma (study EMR100070-003). The efficacy and safety of avelumab was investigated in the study EMR100070-003 with two parts. Part A was a single arm, multi-centre study conducted in patients with histologically confirmed metastatic MCC, whose disease had progressed on or after chemotherapy administered for distant metastatic disease, with a life expectancy of more than 3 months. Part B included patients with histologically confirmed metastatic MCC who were treatment-naïve to systemic therapy in the metastatic setting.
Patients with active central nervous system (CNS) metastasis or treated less than 2 months prior to enrolment, active or a history of any autoimmune disease, a history of other malignancies within the last 5 years, organ transplant, conditions requiring therapeutic immune suppression or active infection with HIV or hepatitis B or C, were excluded.
Patients received avelumab at a dose of 10 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Patients with radiological disease progression not associated with significant clinical deterioration, defined as no new or worsening symptoms, no change in performance status for greater than two weeks, and no need for salvage therapy could continue treatment.
Tumour response assessments were performed every 6 weeks, as assessed by an Independent Endpoint Review Committee (IERC) using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1.

Study 003 part A - previously treated patients.

For Part A, the major efficacy outcome measure was confirmed best overall response (BOR); secondary efficacy outcome measures included duration of response (DOR), progression-free survival (PFS), and overall survival (OS).
An efficacy analysis was evaluated in all 88 patients after a minimum of 36 months follow-up after the last patient initiated treatment. Patients received a median of 7 doses of avelumab (range: 1 dose to 95 doses), and the median duration of treatment was 17 weeks (range: 2 weeks to 208 weeks).
Of the 88 patients, 65 (73.9%) were male, the median age was 72.5 years (range 33 years to 88 years), 81 (92.0%) patients were Caucasian, and 49 (55.7%) patients and 39 (44.3%) patients with an ECOG performance status 0 and 1, respectively.
Overall, 52 (59.1%) of the patients were reported to have had 1 prior anti-cancer therapy for MCC, 26 (29.5%) with 2 prior therapies, 10 (11%) with 3 or more prior therapies. Forty-seven (53.4%) of the patients had visceral metastases.
The median time to response was 6 weeks (range: 6 weeks to 36 weeks) after the first dose of avelumab. Twenty-two out of 29 (75.9%) patients with a response responded within 7 weeks after the first dose of avelumab.
Responses were observed in patients regardless of PD-L1 expression and/or Merkel cell polyomavirus status.
Table 7 summarises efficacy endpoints in patients receiving avelumab at the recommended dose for study EMR100070-003 Part A, with a minimum follow-up of 36 months. Overall survival was evaluated in an analysis with a minimum follow-up of 44 months. The median OS was 12.6 months (95% CI: 7.5, 17.1).

Study 003 part B - patients who have not received systemic therapy in the metastatic setting.

For Part B, the major efficacy outcome measure was durable response, defined as objective response (complete response [CR] or partial response [PR]) with a duration of at least 6 months; secondary outcome measures included BOR, DOR, PFS, and OS.
The primary analysis for Part B included 116 patients who received at least one dose of avelumab with a minimum follow-up of 15 months at the time of the data cut-off (cut-off date 2 May 2019).
Of the 116 patients, 81 (70%) were male, the median age was 74 years (range: 41 to 93 years), 75 (65%) were Caucasian, and 72 (62%) and 44 (38%) had an ECOG performance status of 0 and 1, respectively.
Responses were observed in patients regardless of PD L1 expression and/or Merkel cell polyomavirus status.
Table 8 summarises the primary analysis of efficacy endpoints including an estimate of the 24-month rates by Kaplan-Meier for DOR and PFS in patients receiving avelumab at the recommended dose for study EMR100070-003, Part B.
Urothelial carcinoma (study B9991001). The efficacy and safety of Bavencio was demonstrated in study B9991001, a randomised, multi-centre, open label study conducted in 700 patients with unresectable, locally advanced or metastatic urothelial carcinoma whose disease had not progressed with first-line platinum-based induction chemotherapy. Patients with autoimmune disease or a medical condition that required immunosuppression were excluded.
Randomisation was stratified by best response to chemotherapy (CR/PR vs. stable disease [SD]) and site of metastasis (visceral vs. non-visceral) at the time of initiating first-line induction chemotherapy. Patients were randomised (1:1) to receive either Bavencio 10 mg/kg intravenous infusion every 2 weeks plus best supportive care (BSC) or BSC alone.
Treatment with Bavencio continued until RECIST v1.1 defined progression of disease by Blinded Independent Central Review (BICR) assessment or unacceptable toxicity. Administration of Bavencio was permitted beyond RECIST defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumour status was performed at baseline, 8 weeks after randomisation, then every 8 weeks up to 12 months after randomisation, and every 12 weeks thereafter until documented confirmed disease progression based on BICR assessment per RECIST v1.1.
Demographic and baseline characteristics were generally well balanced between the Bavencio plus BSC and the BSC alone arm. Baseline characteristics were a median age of 69 years (range: 32 to 90), 66% of patients were 65 years or older, 77% were male, 67% were White, and the ECOG PS was 0 (61%) or 1 (39%) for both arms.
For first-line induction chemotherapy, 56% of patients received cisplatin plus gemcitabine, 38% of patients received carboplatin plus gemcitabine and 6% of patients received cisplatin plus gemcitabine and carboplatin plus gemcitabine (i.e. these patients received one or more cycles of each combination). Best response to first-line induction chemotherapy was CR or PR (72%) or SD (28%). Sites of metastasis prior to chemotherapy were visceral (55%) or non-visceral (45%). Fifty one percent of patients had PD-L1-positive tumours. Six percent of patients in the Bavencio plus BSC arm and 44% of patients in the BSC alone received another PD-1/PD-L1 checkpoint inhibitor after discontinuation of treatment.
The primary efficacy outcome measure was overall survival (OS) in all randomised patients and in patients with PD-L1-positive tumours.
Progression-free survival (PFS) based on BICR assessment per RECIST v1.1 was an additional efficacy outcome measure.
Efficacy outcomes were measured from time of randomisation after 4 to 6 cycles of platinum-based induction chemotherapy.
Efficacy results from study B9991001 are presented in Table 9. Also see Figures 1 and 2.
In addition, a statistically significant improvement in OS was demonstrated in patients with PD-L1 positive tumours for Bavencio plus BSC compared to BSC alone (HR 0.56; 95% CI: 0.40, 0.79; 2 sided p-value 0.0007). The median OS was not reached (95% CI: 20.3 months, not reached) in the Bavencio plus BSC arm, and 17.1 months (95% CI: 13.5, 23.7) in the BSC alone arm. Consistent results were observed across pre-specified subgroups, including best response to first line induction chemotherapy, and sites of metastasis as shown in Figure 3.

Patient reported outcomes (PRO).

Patient reported outcomes of physical and emotional disease-related symptoms, treatment side effects, and function and well-being were collected using the FACT/NCCN Bladder Symptom Index (FBlSI-18). No detrimental effects were observed when adding Bavencio maintenance therapy to BSC compared to BSC alone as measured by FBlSI-18 during the treatment period.
Renal cell carcinoma (study B9991003). The efficacy and safety of avelumab in combination with axitinib was demonstrated in study B9991003 (NCT02684006), a randomised (1:1), multi-centre, open-label study of avelumab in combination with axitinib in patients with untreated advanced RCC. Patients were included irrespective of tumour PD-L1 expression.
Patients with prior systemic therapy directed at advanced or metastatic RCC; prior systemic immunotherapy treatment with IL-2, IFN-α, anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies; or active brain metastasis were ineligible.
Randomisation was stratified according to Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (0 vs. 1) and region (United States vs. Canada/Western Europe vs. the rest of the world). Patients were randomised to receive avelumab 10 mg/kg intravenous infusion every 2 weeks in combination with axitinib 5 mg twice daily until disease progression or unacceptable toxicity.
A total of 886 patients were randomised: 442 to the avelumab in combination with axitinib arm and 444 to the sunitinib arm.
The primary efficacy endpoints were progression-free survival (PFS), as assessed by a Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 and overall survival (OS) in the first-line treatment of patients with advanced RCC who have PD-L1-positive tumours (PD-L1 expression level ≥ 1%). The key secondary endpoints were PFS based on a BICR assessment per RECIST v.1.1 and OS irrespective of PD-L1 expression. PD-L1 status was determined by immunohistochemistry. Additional secondary endpoints included objective response (OR), time to response (TTR) and duration of response (DOR).
The study population characteristics were: median age of 61 years (range: 27.0 to 88.0), 38% of patients were 65 years or older, 75% were male, 75% were White, and the ECOG performance score was 0 (63%) or 1 (37%), respectively.
Patient distribution by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk groups was 21% favourable, 62% intermediate, and 16% poor. Patient distribution by Memorial Sloan-Kettering Cancer Center (MSKCC) risk groups was 22% favourable, 65% intermediate, and 11% poor.
The first tumour assessments were conducted 6 weeks after randomisation and continued every 6 weeks up to 18 months after randomisation, and every 12 weeks thereafter until confirmed disease progression.
Efficacy results in patients irrespective of PD-L1 expression are presented in Table 10 and Figure 4.
At the time of the first interim analysis, the OS data were still immature. The observed HR was 0.78 (95% CI: 0.554, 1.084) in favour of avelumab in combination with axitinib. Median OS was not yet reached in either treatment arms. The probability of being alive at 12 months was 86.3% (95%CI: 82.2%, 89.5%) for the avelumab plus axitinib arm and 83.0% (95% CI: 78.8%, 86.5%) for the sunitinib arm.
A statistically significant improvement in PFS was observed in both patients with PD-L1-positive tumours and all patients irrespective of PD-L1 expression who received the combination of avelumab with axitinib, with a 39% and 31% reduction of the risk of progression or death as compared to patients treated with sunitinib, respectively. Improvement of PFS was observed across all risk groups based on IMDC and MSKCC.

5.2 Pharmacokinetic Properties

The pharmacokinetics of avelumab as monotherapy have been determined by non-compartmental analyses and a population PK analysis in which patients received avelumab up to 20 mg/kg were studied while the majority of them received dose of 10 mg/kg every 2 weeks, which equates to the recommended avelumab dose. The pharmacokinetics of avelumab in combination with axitinib were also assessed using a population PK approach.
Based on a population PK analysis for avelumab as a single agent and in combination with axitinib, there are no expected clinically meaningful differences in avelumab exposure of avelumab administered every 2 weeks at 800 mg or 10 mg/kg as a single agent and in combination with axitinib.

Distribution.

Avelumab is expected to be distributed in the systemic circulation and to a lesser extent in the extracellular space. The volume of distribution at steady-state was 4.12 L.
Consistent with a limited extravascular distribution, the volume of distribution of avelumab at steady-state is small. As an antibody, avelumab is not expected to bind to plasma proteins in a specific manner.

Elimination.

Based on a population pharmacokinetic analysis from 2171 patients treated with avelumab monotherapy, the value of total systemic clearance (CL) is 0.66 L/day.
Steady-state concentrations of avelumab were reached after approximately 4 to 6 weeks (2 to 3 cycles) of repeated dosing at 10 mg/kg every 2 weeks, and systemic accumulation was approximately 1.25-fold.
The elimination half-life (t1/2) at the recommended dose is 6.1 days based on the population PK analysis.

Linearity/non-linearity.

The exposure of avelumab increased dose-proportionally in the dose range of 10 mg/kg to 20 mg/kg every 2 weeks.
Based on a population PK analysis, there are no expected clinically meaningful differences in exposure of avelumab administered every 2 weeks at 800 mg or 10 mg/kg.
When avelumab 10 mg/kg was administered in combination with axitinib 5 mg, the respective exposures of avelumab and axitinib were unchanged compared to the single agents. There was no evidence to suggest a clinically relevant change of avelumab clearance over time in patients with advanced RCC.

Special populations.

A population pharmacokinetic analysis suggested no difference in the total systemic clearance of avelumab based on age, gender, race, PD-L1 status, tumour burden, renal impairment and mild or moderate hepatic impairment.
Total systemic clearance increases with body weight.

Renal impairment.

No clinically important differences in the clearance of avelumab were found between patients with mild (glomerular filtration rate [GFR] 60 to 89 mL/min, n = 623), moderate (GFR 30 to 59 mL/min, n = 320) and patients with normal (GFR greater than or equal to 90 mL/min, n = 671) renal function.
Avelumab has not been studied in patients with severe renal impairment (GFR 15 to 29 mL/min).

Hepatic impairment.

No clinically important differences in the clearance of avelumab were found between patients with mild hepatic impairment (bilirubin less than or equal to the ULN and AST greater than ULN or bilirubin between 1 and 1.5 times ULN, n = 217), or moderate hepatic impairment (bilirubin between 1.5 and 3 times ULN, n = 4), and normal hepatic function (bilirubin and AST less than or equal to ULN, n = 1,388) in a population PK analysis.
Avelumab has not been studied in patients with severe hepatic impairment (bilirubin greater than 3 times ULN).

Paediatric population.

The pharmacokinetics of avelumab at a dose of 10 mg/kg intravenously was evaluated in 3 adolescents (12 - 17 years old) in study MS100070-0306. The exposures in these patients appeared to be similar to those in adults receiving 10 mg/kg or 800 mg avelumab.

5.3 Preclinical Safety Data

Genotoxicity.

No studies have been conducted to assess the genotoxic potential of avelumab. As a large protein molecule, avelumab is not expected to interact directly with DNA or other chromosomal material.

Carcinogenicity.

No studies have been conducted to assess the carcinogenic potential of avelumab.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, glacial acetic acid, polysorbate 20, sodium hydroxide, and water for injections.

6.2 Incompatibilities

This medicine must not be mixed with other medicines except those mentioned in Section 4.2 Dose and Method of Administration.

6.3 Shelf Life

Unopened vial.

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

After opening.

Bavencio should be diluted and infused immediately.

After preparation of infusion.

Bavencio does not contain a preservative. The diluted solution should be infused immediately, unless dilution has taken place in controlled and validated aseptic conditions.
If Bavencio is not used immediately, store the diluted solution of Bavencio, either:
at room temperature and room light for up to 8 hours. This includes room temperature storage of the infusion in the infusion bag and the duration of infusion;
at 2°C to 8°C (Refrigerate. Do not freeze) for up to 24 hours at the time of dilution. If refrigerated, allow the diluted solution to come to room temperature prior to administration.
Do not freeze or shake the diluted solution.

6.4 Special Precautions for Storage

Store in a refrigerator (2°C - 8°C). Do not freeze.
Store in the original package in order to protect from light.
Product is for single use in one patient only. Discard any residue.
For storage conditions after dilution of the medicine, see Section 6.3 Shelf Life.

6.5 Nature and Contents of Container

10 mL of concentrated solution for intravenous infusion in a 16 mL vial (Type I glass) with a halobutyl rubber stopper and an aluminium seal fitted with a removable plastic cap.
Pack size of 1 vial.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

The solution pH is in the range of 5.0 - 5.6 and the osmolality is between 285 and 350 mOsm/kg.

Chemical structure.


Avelumab is a human monoclonal IgG1 antibody directed against the immunomodulatory cell surface ligand protein PD-L1 and produced in Chinese hamster ovary cells by recombinant DNA technology.

CAS number.

1537032-82-8.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes