Consumer medicine information

Ocrevus

Ocrelizumab

BRAND INFORMATION

Brand name

Ocrevus

Active ingredient

Ocrelizumab

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ocrevus.

SUMMARY CMI

Ocrevus®

Consumer Medicine Information (CMI) summary

Ocrevus intravenous (IV): ocrelizumab 300 mg in 10 mL concentrate for solution for infusion
Ocrevus subcutaneous (SC): ocrelizumab 920 mg in 23 mL solution for subcutaneous injection

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

1. Why am I using Ocrevus?

Ocrevus contains the active ingredient ocrelizumab. Ocrevus is used for the treatment of patients with relapsing forms of multiple sclerosis and primary progressive multiple sclerosis. For more information, see Section 1. Why am I using Ocrevus? in the full CMI.

2. What should I know before I use Ocrevus?

Do not use if you have ever had an allergic reaction to Ocrevus 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 Ocrevus? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Ocrevus and affect how it works or Ocrevus may affect how other medicines work. 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 Ocrevus?

Your doctor or nurse will administer your Ocrevus dose as an intravenous infusion or as a subcutaneous injection. More information can be found in Section 4. How do I use Ocrevus? in the full CMI.

5. What should I know while using Ocrevus?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Ocrevus.
  • Tell your doctor or nurse if you have any signs and symptoms of infection or any signs or symptoms of infusion or injection related reaction or allergic reaction.
  • Tell your doctor or nurse if you have any stomach or bowel problems such as diarrhoea that does not go away, stomach pain, or blood in your stools.
  • Tell your doctor if you plan to receive or have received a vaccine.
  • Avoid becoming pregnant by using contraception during treatment with Ocrevus and for at least 6 months after your last infusion or injection. Discontinue breastfeeding while you are treated with Ocrevus.
  • Tell your doctor immediately if your condition worsens, or if you, your partner or caregivernotice any new symptoms like changes in movement or behaviour.
Things you should not do
  • Do not stop using this medicine without talking to your doctor first.
Driving or using machines
  • It is not known if Ocrevus will influence your ability to drive or use machines.
Looking after your medicine
  • It is unlikely that you will have to store Ocrevus at home. If necessary, refrigerate between 2°C and 8°C, do not freeze. Keep the vial in the carton to protect it from light and keep it out of reach of children.

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

6. Are there any side effects?

Common side effects include infusion related reactions or injection reactions and some types of infections, which can be seriousor less serious. Allergic reactions such as swelling of the face, lips, tongue or throat, trouble breathing, chest tightness, wheezing,coughing, and asthma that becomes worse, are serious side effects. Stomach and bowel problems such as diarrhoea that doesnot go away, stomach pain, or blood in your stools could be a serious side effect. 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.



FULL CMI

Ocrevus® (pronounced oak-rev-us)

Active ingredient: ocrelizumab

Consumer Medicine Information (CMI)

This leaflet provides important information about using Ocrevus. 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 Ocrevus.

Where to find information in this leaflet:

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

1. Why am I using Ocrevus?

Ocrevus contains the active ingredient ocrelizumab. Ocrevus is a monoclonal antibody. Antibodies are proteins, produced naturally in the body, which help the immune system by specifically recognising and binding to proteins found on target cells. Monoclonal antibodies are designed to work like natural antibodies so that they can target specific proteins involved in disease.

Ocrevus is used to treat patients with relapsing forms of multiple sclerosis (MS) and primary progressive multiple sclerosis.

Ocrevus works on a type cell of the immune system called B-cells, which play a role in multiple sclerosis. By targeting specific B cells, Ocrevus may reduce inflammation and attacks to the nervous system. Ocrevus can decrease the number of flare-ups (relapses) and slow the worsening of relapsing forms of multiple sclerosis. It can also reduce the worsening of primary progressive multiple sclerosis.

2. What should I know before I use Ocrevus?

Warnings

Do not use Ocrevus if:

  • you are allergic to ocrelizumab, 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 signs and symptoms of infection. You should not have your treatment until the infection is resolved.
  • have ever had hepatitis B or are a carrier of the hepatitis B virus. Before you start using Ocrevus, your doctor will check if you have or are at risk of having hepatitis B infection to decide if you can use Ocrevus and if they may need to monitor you during your treatment with Ocrevus.
  • have, or have ever had, cancer. Some type of medicines that work on the immune system may increase the risk of some cancers.
  • intend to have or have had immunisation with any vaccine. Some types of vaccines (called 'live' or 'live-attenuated') should not be given at the same time as Ocrevus and in the months after you receive Ocrevus. Your doctor will check if you should have any vaccines before you receive Ocrevus. Ocrevus may affect your normal response to a vaccine.
  • are allergic to any other medicines or substances.
  • have any other medical conditions.
  • take any medicines for any other condition.

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?

Pregnancy

Tell your doctor if you are pregnant or intend to become pregnant.

You should avoid becoming pregnant. If you are able to become pregnant, you should use effective contraceptive methods during treatment with Ocrevus and for at least 6 months after your last dose of Ocrevus.

Breastfeeding

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

You should avoid breastfeeding while you are using Ocrevus.

Children and Adolescents

It is not known whether Ocrevus is safe or effective in children and adolescents under 18 years of age, because it has not yet been studied in this age group.

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.

Ocrevus may affect how some medicines work:

  • vaccines. Speak to your doctor before you receive any vaccines. You should not have some types of vaccines (called 'live' or 'live-attenuated') while receiving Ocrevus and for several months after until your doctor advises that you can.

These medicines increase your risk of side effects with Ocrevus:

  • other treatments (including those for MS, or to treat other conditions) which could affect your immune system and so could affect your ability to fight infections. If you are currently using a different MS treatment or if you have used another MS treatment in the past, your doctor may ask you to stop the other medicine in advance of starting treatment with Ocrevus.
  • medicines that lower blood pressure. Ocrevus may lower your blood pressure. Your doctor may ask you to temporarily stop taking your blood pressure medicine before each infusion.

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

4. How do I use Ocrevus?

How much to use

Ocrevus intravenous (IV)

Ocrevus IV must be prepared by a healthcare professional and will be given in a hospital or clinic. You will have Ocrevus as an intravenous infusion. It will go slowly into your vein. This will be done by your doctor or nurse.

Before you receive Ocrevus, your doctor or nurse will give you other medicines to help reduce possible side effects such as infusion-related reactions.

  • The dose is 600 mg every 6 months.
  • Your first 600 mg will be given as 2 separate intravenous infusions (300 mg each), given 2 weeks apart by a doctor or nurse. Each infusion will take about 2 hours and 30 minutes.
  • Your next 600 mg doses of Ocrevus will be given as a single intravenous infusion every 6 months. These infusions will take either about 2 hours or 3 hours and 30 minutes depending on the infusion rate prescribed by your doctor.
  • Your doctor or nurse will closely monitor you during each infusion and may adjust your infusion rate depending on how well each dose is tolerated.
  • Follow the instructions provided and use Ocrevus until your doctor tells you to stop.

Ocrevus subcutaneous (SC)

Ocrevus SC must be administered under the supervision of a healthcare professional.

Before you receive Ocrevus you will be given other medicines to help reduce the risk of possible injection reactions.

  • The first injection: you will be given 920 mg of Ocrevus by SC injection in approximately 10 minutes. You will be closely monitored for at least one hour after the first injection to manage any possible injection reactions.
  • Subsequent injections: if the previous injection was well tolerated, you will be given 920 mg of Ocrevus by SC injection 6 months after the previous injection.

If you miss your dose

If you forget or miss your appointment for your treatment, do not wait until the next planned dose but make another appointment as soon as possible. Your doctor may need to change the timing of your later doses.

If you use too much Ocrevus

Your dose of Ocrevus is given to you by infusion or injection under the supervision of a doctor or nurse. However, if you think that you have received too much Ocrevus, you may need urgent medical care.

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 Ocrevus?

Things you should do

  • Tell your partner or caregiver about your Ocrevus treatment. They might notice symptoms that you do not, such as changes in movement or behaviour, which your doctor may need to investigate.
  • If you plan to become pregnant or you become pregnant during treatment with Ocrevus, tell the doctor right away. Tell your baby's doctor about your treatment with Ocrevus so that they can consider this in the timing of your baby's vaccinations.
  • Tell your doctor if you have any signs and symptoms of infection even if it has been some time (e.g. several weeks or months) since your last dose. Your doctor may need to do a blood test to check your white blood cell levels.
  • Tell your doctor if you have any stomach or bowel problems such as diarrhoea that does not go away, stomach pain, or blood in your stools.
  • Tell your doctor if you have any new medical conditions or plan to take any new medicines for any other condition.

Call your doctor straight away if you:

  • have any signs or symptoms of infusion or injection related reactions or allergic reactions.
  • think your multiple sclerosis is getting worse or if you or your partner or caregiver notice any new or unusual symptoms such as changes in movement or behaviour. There have been very rare reports of serious brain infection, called progressive multifocal leukoencephalopathy (PML) which can cause severe disability or be life-threatening. Symptoms of PML can be similar to those of MS.

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

Things you should not do

  • Do not stop using this medicine without talking to your doctor first.
  • Do not take any other medicines, whether they require a prescription or not without first telling your doctor or consulting with a pharmacist.

Driving or using machines

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

It is not known whether Ocrevus can affect you being able to drive or use any tools or machines.

Looking after your medicine

  • It is unlikely that you will have to store Ocrevus at home. If you have to store it: refrigerate, do not freeze. Store between 2°C and 8°C. Do not shake it.
  • Keep the vial in the carton to protect it from light.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are likely to be 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.

Less serious side effects

Less serious side effectsWhat to do
Infections such as:
  • viral infection (influenza)
  • respiratory tract infection (runny nose, sneezing, sore throat, cough, fever, fatigue, weakness, shortness of breath)
  • inflammation or infection of the sinuses - sinusitis (feeling of pressure or pain in the cheeks and forehead)
  • inflammation or infection of the lung - bronchitis (cough, chest pain, fever)
  • build up of mucus in the nose and throat
  • infection of the stomach and bowel - gastroenteritis (nausea or vomiting, fever)
  • eye inflammation or infection - conjunctivitis (itchy, red or sore eyes)
  • skin infection - cellulitis (rash, itching or hives on the skin)
Tell your doctor or nurse straight away if you have any of these side effects, even if it has been sometime since your last infusion or injection. These side effects can sometimes be serious.
If you experience signs and symptoms of infection, your doctor may need to do a blood test to check your white blood cell levels even if it has been some time (e.g. several weeks or months) since your last infusion or injection.

Serious side effects

Serious side effectsWhat to do
Infusion related reactions, injection reactions or allergic reactions:
Infusion related reactions orinjection reactions can happen during and within 24 hours after the infusion or injection.
Symptoms may include, but are not limited to:
  • itchy skin
  • rash
  • hives
  • redness of the skin
  • throat irritation or pain
  • shortness of breath
  • swelling of the throat, face, lips, tongue, or other parts of the body
  • reactions in the area where the injection is given (Ocrevus SC only)
  • redness on your face (flushing)
  • low blood pressure
  • fever
  • fatigue
  • nausea
  • headache
  • fast heart beat
Infections and signs or symptoms such as:
  • fever or chills
  • cough that does not go away
  • herpes (such as cold sore, shingles and genital sores)
Stomach and bowel problems such as:
  • diarrhoea that doesn't go away
  • stomach pain
  • blood in your stools
During your infusion or injection, tell your doctor or nurse straight away if you experience signs and symptoms of infusion related reactions or injection reactions.
After your infusion or injection, call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these side effects. These may be serious side effects.
Tell your doctor straight away if you have any of these side effects, even if it has been sometime since your last infusion or injection.

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 Ocrevus IV contains

Active ingredient
(main ingredient)		Each vial of Ocrevus IV contains 300 mg of ocrelizumab
Other ingredients
(inactive ingredients)		sodium acetate trihydrate
trehalose dihydrate
acetic acid
polysorbate 20
water for injections

What Ocrevus SC contains

Active ingredient
(main ingredient)		Each vial of Ocrevus SC contains 920 mg of ocrelizumab
Other ingredients
(inactive ingredients)		vorhyaluronidase alfa
sodium acetate trihydrate
trehalose dihydrate
acetic acid
polysorbate 20
methionine
water for injections

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

What Ocrevus IV looks like

Ocrevus IV is registered on the ARTG as AUST R 275778.

Ocrevus IV is supplied as a single-dose glass vial containing 10 mL of solution for intravenous infusion (30 mg/mL). Ocrevus is diluted before infusion into a vein.

Ocrevus IV is a clear or slightly opalescent, and colourless to pale brown liquid.

What Ocrevus SC looks like

Ocrevus SC is registered on the ARTG as AUST R 446150.

Ocrevus SC is supplied as a single-dose glass vial containing 23 mL of solution for subcutaneous injection (40 mg/mL).

Ocrevus SC is a clear or slightly opalescent, and colourless to pale brown liquid.

Who distributes Ocrevus

Ocrevus is supplied in Australia by:

Roche Products Pty Limited
ABN 70 000 132 865
Level 8, 30-34 Hickson Road
Sydney NSW 2000
Australia

Website: www.roche-australia.com or www.medinfo.roche.com accessible by scanning the below QR code:

This leaflet is for people in Australia only. If you are not in Australia, you can contact Roche/Genentech in your country at www.medinfo.roche.com.

This leaflet was prepared in March 2025

Published by MIMS May 2025

BRAND INFORMATION

Brand name

Ocrevus

Active ingredient

Ocrelizumab

Schedule

S4

 

1 Name of Medicine

Ocrevus (ocrelizumab).

2 Qualitative and Quantitative Composition

Ocrevus (ocrelizumab) is a recombinant humanised anti-CD20 monoclonal antibody (IgG1 subtype).

Ocrevus intravenous (IV) formulation: concentrate for solution for infusion.

Ocrevus concentrate solution for intravenous (IV) infusion is a clear or slightly opalescent, and colourless to pale brown solution at pH 5.3, supplied as a single-use vial containing 30 mg/mL ocrelizumab. Each vial contains 300 mg of ocrelizumab in a 10 mL vial.

Ocrevus subcutaneous (SC) formulation: solution for subcutaneous injection.

Ocrevus solution for subcutaneous (SC) injection is a clear to slightly opalescent, and colourless to pale brown, preservative-free solution supplied as a single-use vial containing 40 mg/mL ocrelizumab. Each vial contains 920 mg ocrelizumab in 23 mL in a 50 mL vial.

Excipients with known effect.

Ocrevus SC contains the excipient vorhyaluronidase alfa, an enzyme used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ocrevus IV.

Ocrevus is supplied in a single-dose vial containing 10 mL of preservative-free concentrate solution for infusion.

Ocrevus SC.

Ocrevus is supplied in a single-dose vial containing 23 mL of preservative-free solution for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Ocrevus is indicated for the treatment of patients with relapsing forms of multiple sclerosis (RMS) to delay the progression of physical disability and to reduce the frequency of relapse.
Ocrevus is indicated for the treatment of patients with primary progressive multiple sclerosis (PPMS) to delay the progression of physical disability.

4.2 Dose and Method of Administration

Patients may start Ocrevus treatment using Ocrevus IV or SC. Patients currently receiving Ocrevus IV may switch to Ocrevus SC.

Ocrevus IV.

Ocrevus IV is not intended for subcutaneous administration.
Dosage. Ocrevus IV is administered as an IV infusion through a dedicated line under the close supervision of an experienced healthcare professional (HCP) with access to appropriate medical support to manage severe reactions such as serious infusion-related reactions (IRRs). Ocrevus IV infusions should not be administered as an intravenous push or bolus. Use isotonic 0.9% sodium chloride solution as the infusion vehicle. In the event an IV infusion cannot be completed the same day, the remaining liquid in the infusion bag must be discarded (see Section 6.3 Shelf Life).
Observe the patient for at least one hour after the completion of the infusion (see Section 4.4 Special Warnings and Precautions for Use). After the initial dose IRRs are not increased in severity or frequency when Ocrevus IV is given as a single 600 mg dose compared with 2 x 300 mg doses separated by 2 weeks (see Section 4.8 Adverse Effects (Undesirable Effects)).

Premedication for infusion related reactions (IRR).

Premedicate with 100 mg IV methylprednisolone (or an equivalent) approximately 30 minutes prior to each Ocrevus infusion (see Section 4.4 Special Warnings and Precautions for Use) and with an antihistaminic drug approximately 30-60 minutes before each infusion of Ocrevus IV to further reduce the frequency and severity of IRRs.
The addition of an antipyretic (e.g. paracetamol) may also be considered approximately 30-60 minutes before each infusion of Ocrevus IV.

Dosing.

Ocrevus IV is administered by IV infusion as a 600 mg dose every 6 months.

Initial dose.

The initial 600 mg dose is administered as two separate IV infusions; one 300 mg infusion, followed by a second 300 mg infusion two weeks later (see Table 1).

Subsequent doses.

Subsequent doses of Ocrevus IV thereafter are administered as a single 600 mg IV infusion every 6 months (see Table 1). A minimum interval of 5 months should be maintained between each dose of Ocrevus IV.
If patients did not experience a serious infusion-related reaction (IRR) with any previous Ocrevus IV infusion, a shorter (2-hour) infusion can be administered for subsequent doses (see Table 1, Option 2) (see Section 4.8 Adverse Effects (Undesirable Effects), Clinical trials; Section 5.1 Pharmacodynamic Properties, Clinical trials).

Infusion adjustments during treatment.

No dose reductions of Ocrevus IV are recommended.
In case of IRRs during any infusion, see the following adjustments below. Additional information on IRRs can be found, see Section 4.4 Special Warnings and Precautions for Use.

Life-threatening IRRs.

Immediately stop Ocrevus IV if there are signs of a life-threatening or disabling IRR during an infusion, such as acute hypersensitivity or acute respiratory distress syndrome. The patient should receive appropriate supportive treatment. Permanently discontinue Ocrevus IV in these patients.

Severe IRRs.

If a patient experiences a severe IRR or a complex of flushing, fever, and throat pain symptoms, the infusion should be interrupted immediately and the patient should receive symptomatic treatment. The infusion should be restarted only after all symptoms have resolved. The initial infusion rate at restart should be half the infusion rate at the time of onset of the reaction.

Mild to moderate IRRs.

If a patient experiences a mild to moderate IRR (e.g. headache), the infusion rate should be reduced to half the rate at the onset of the event. This reduced rate should be maintained for at least 30 minutes. If tolerated, the infusion rate may then be increased according to the patient's initial infusion schedule.
See Section 4.4 Special Warnings and Precautions for Use for a full description of the symptoms associated with IRRs.

Ocrevus SC.

Ocrevus SC is not intended for intravenous administration.
Dosage. Ocrevus SC must be administered as a subcutaneous injection only, under the supervision of an HCP. Prior to administration, remove Ocrevus SC from refrigeration and allow the solution to come to room temperature.
For the initial dose, post-injection monitoring with access to appropriate medical support to manage any severe injection reactions, for at least one hour after injection is recommended. For subsequent doses, the suitable administration setting (e.g. clinic or home) and post-injection monitoring is at the treating physician's discretion.
Administer 23 mL (920 mg) of Ocrevus SC solution subcutaneously in the abdomen over approximately 10 minutes. Use of a SC infusion set (e.g. winged/butterfly) is recommended. Do not administer any residual hold-up volume remaining in the SC infusion set to the patient.
The injection site should be the abdomen, except for the area 5 cm around the navel. Ocrevus SC injections should not be administered into areas where the skin is red, bruised, tender or hard, or areas where there are moles or scars.

Premedication for injection reactions.

Premedicate orally with 20 mg dexamethasone (or equivalent) and an antihistaminic drug (e.g. desloratadine) shortly before each Ocrevus SC administration (see Section 4.4 Special Warnings and Precautions for Use) to reduce the risk of local and systemic injection reactions.
The administration of an antipyretic (e.g. paracetamol) may also be considered shortly before each Ocrevus SC administration.

Dosing.

Ocrevus SC is administered as a 920 mg subcutaneous injection every 6 months.
No division of the initial dose or subsequent doses into separate administrations is required.
A minimum interval of 5 months should be maintained between each dose of Ocrevus SC.

Ocrevus IV and Ocrevus SC.

Delayed or missed doses. If a planned dose of Ocrevus is missed, it should be administered as soon as possible; do not wait until the next planned dose. The treatment interval of 6 months (with a minimum of 5 months) for Ocrevus should be maintained between doses.
Special populations.

Children.

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

Elderly.

The safety and efficacy of Ocrevus in patients > 65 years of age have not been established.

Renal impairment.

The safety and efficacy of Ocrevus in patients with renal impairment have not been formally studied. A change in dose is not expected to be required for patients with renal impairment (see Section 5.2 Pharmacokinetic Properties).

Hepatic impairment.

The safety and efficacy of Ocrevus in patients with hepatic impairment have not been formally studied. A change in dose is not expected to be required for patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

Method of administration.

Ocrevus IV. Ocrevus IV should be prepared by a healthcare professional using aseptic technique. A sterile needle and syringe should be used to prepare the diluted infusion solution.
Ocrevus IV may contain fine translucent and/or reflective particles associated with enhanced opalescence. Do not use the solution if discoloured or if the solution contains discrete foreign particulate matter.

Instructions for dilution.

Ocrevus IV must be diluted before administration. Solutions of Ocrevus for IV administration are prepared by dilution into an infusion bag containing 0.9% sodium chloride (300 mg/250 mL or 600 mg/500 mL), to a final drug concentration of approximately 1.2 mg/mL.
The diluted infusion solution must be administered using an infusion set with a 0.2 or 0.22 micron in-line filter.
Prior to the start of the IV infusion, the content of the infusion bag must be at room temperature to avoid an infusion reaction to the administration of the solution at low temperatures.
Ocrevus SC. Ocrevus SC should be prepared by an HCP using aseptic technique.
Ocrevus SC is a single-dose, ready-to-use solution for subcutaneous injection only and should not be diluted or mixed with other drugs.
Ocrevus SC solution should be visually inspected to ensure that no particulate matter or discolouration is present. Do not use the solution if discoloured or if the solution contains discrete foreign particulate matter.

Preparation of the syringe.

Prior to use, remove the vial from the refrigerated storage and allow the solution to come to room temperature.
Aseptically withdraw the entire contents of Ocrevus SC solution from the vial with a syringe and transfer needle (21G recommended).
Remove the transfer needle and attach a SC infusion set (e.g. winged/butterfly) containing a 24-26G needle for injection. Use a SC infusion set with residual hold-up volume not exceeding 0.8 mL for administration.
Prime the SC infusion line with the drug product solution to eliminate the air in the infusion line and stop before the fluid reaches the needle.
Ensure the syringe contains exactly 23 mL of drug product solution after priming and expelling any excess volume from the syringe.
Administer immediately to avoid needle clogging.
Immediate use is recommended as Ocrevus SC does not contain any antimicrobial preservative. If the dose is not administered immediately, see Storage of the syringe below. Do not store the prepared syringe that has been attached to the already-primed SC infusion set.

Storage of the syringe.

If the dose is not to be administered immediately, aseptically withdraw the entire contents of Ocrevus SC from the vial into the syringe to account for the dose volume (23 mL) plus the priming volume for the SC infusion set. Replace the transfer needle with a syringe closing cap. Do not attach a SC infusion set for storage. If storage is necessary, the syringe must be closed with a syringe cap. The closed syringe can be held at 2°C-8°C for up to 72 hours followed by 8 hours at ambient temperatures ≤ 25°C in diffuse daylight (see Section 6.4 Special Precautions for Storage).
If the syringe was stored in a refrigerator, allow the syringe to reach room temperature prior to administration.

4.3 Contraindications

Ocrevus is contraindicated in patients with a known hypersensitivity to ocrelizumab or any of the excipients.

4.4 Special Warnings and Precautions for Use

In order to improve traceability of biological medicinal products, the trade name and the batch number of the administered product should be clearly recorded or stated in the patient medical record.

Infusion related reactions (IRRs) and injection reactions (IRs).

IRRs are associated with the administration of Ocrevus IV and IRs are associated with the administration of Ocrevus SC. IRRs and IRs may be related to cytokine release and/or other chemical mediators.
A hypersensitivity reaction could also occur (acute allergic reaction to drug).
IRRs and IRs may be clinically indistinguishable from type 1 (IgE-mediated) acute hypersensitivity reactions (see Hypersensitivity reactions).
For premedication to reduce the frequency and severity of IRRs and risk of IRs, see Section 4.2 Dose and Method of Administration.

Infusion related reactions (IRRs) with Ocrevus IV.

Symptoms of IRRs may occur during any infusion, but have been more frequently reported during the first infusion (see Section 4.8 Adverse Effects (Undesirable Effects)). These reactions may present as pruritus, rash, urticaria, erythema, throat irritation, oropharyngeal pain, dyspnoea, pharyngeal or laryngeal oedema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea, tachycardia and anaphylaxis. Patients treated with Ocrevus should be observed for at least one hour after the completion of the infusion for any symptom of IRR.
For premedication to reduce the frequency and severity of IRRs, see Section 4.2 Dose and Method of Administration.

Managing IRRs with Ocrevus IV.

For patients experiencing life-threatening, severe or mild to moderate IRR symptoms, see Section 4.2 Dose and Method of Administration.
Patients who experience severe pulmonary symptoms, such as bronchospasm or asthma exacerbation, must have their infusion interrupted immediately and permanently. After administering symptomatic treatment, monitor the patient until the pulmonary symptoms have resolved because initial improvement of clinical symptoms could be followed by deterioration.
Hypotension as a symptom of IRR may occur during Ocrevus infusions. Therefore withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each Ocrevus infusion. Patients with a history of congestive heart failure (New York Heart Association III and IV) were not studied in the controlled clinical trials.

Injection reactions (IRs) with Ocrevus SC.

Symptoms of IRs may occur during or within 24 hours of an injection. Symptoms of IRs have been more frequently reported with the first injection. IRs can be local IRs or systemic IRs.
Common symptoms of local IRs at the injection site include erythema, pain, swelling and pruritus. Common symptoms of systemic IRs include headache and nausea (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients treated with the initial dose of Ocrevus SC should be observed for at least one hour after the completion of injection for any symptom of severe IR. For subsequent doses, the suitable administration setting (e.g. clinic or home) and post-injection monitoring is at the treating physician's discretion. If IRs occur, symptomatic treatment is recommended.
Immediately stop Ocrevus SC if there are signs of a life-threatening IR. The patient should receive supportive treatment. Permanently discontinue Ocrevus in these patients.
If a patient experiences a severe IR, the injection should be interrupted immediately, and the patient should receive symptomatic treatment. The injection should be completed only after all the symptoms have resolved.

Hypersensitivity reactions.

Symptoms of a hypersensitivity reaction may be difficult to distinguish from IRRs or IRs. A hypersensitivity reaction may present during any administration, although typically would not present during the first administration. For subsequent administration, more severe symptoms than previously experienced, or new severe symptoms, should prompt consideration of a potential hypersensitivity reaction. If a hypersensitivity reaction is suspected, the administration and treatment must be stopped immediately and permanently. Patients with known IgE-mediated hypersensitivity to Ocrevus or any excipients must not be treated (see Section 4.3 Contraindications).

Infections.

Serious, including life-threatening or fatal, bacterial, fungal, and new or reactivated viral infections have been observed during and following completion of treatment with anti-CD20 B-cell depleting therapies.
Delay Ocrevus administration in patients with an active infection until the infection is resolved.

Progressive multifocal leukoencephalopathy (PML).

JC virus infection resulting in PML has been observed very rarely in patients treated with anti-CD20 antibodies, including Ocrevus, and is mostly associated with risk factors (patient population e.g. lymphopenia, advanced age polytherapy with immunosuppressants).
Since a risk of PML cannot be ruled out, physicians should be vigilant for any new or worsening neurological symptoms or signs suggestive of PML as these can be similar to an MS relapse. Physicians treating patients should consider PML in the differential diagnosis of patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.
Physicians should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g. cognitive, neurological or psychiatric symptoms). If such symptoms occur, further administration of Ocrevus should be immediately suspended until a diagnosis of PML has been excluded. To establish or exclude a diagnosis of PML evaluation including MRI scan, CSF testing for JC viral DNA and repeat neurological assessments, should be considered. Once PML has been excluded, the administration of Ocrevus may resume.
If a diagnosis of PML is confirmed, Ocrevus must be permanently discontinued. Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.

Hepatitis B reactivation.

Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, has been reported in patients treated with anti-CD20 antibodies.
HBV screening should be performed in all patients before initiation of treatment with Ocrevus as per institutional guidelines. Patients with active HBV (i.e. an active infection confirmed by positive results for Hepatitis B surface antigen (HBsAg) and anti-HB testing) should not be treated with Ocrevus. Patients with positive serology (i.e. negative for HBsAg and positive for HB core antibody (HBcAb+)) and carriers of HBV (positive for surface antigen (HBsAg+)) should consult liver disease experts before start of treatment and should be monitored and managed according to current clinical practice.

Late neutropenia.

Cases of late onset of neutropenia have been reported. Although some cases were Grade 3 or 4, the majority of the cases were Grade 1 or 2. Cases of late onset of neutropenia have been reported at least 4 weeks after the latest Ocrevus infusion. In patients with signs and symptoms of infection, measurement of blood neutrophils is recommended (see Section 4.8 Adverse Effects (Undesirable Effects)).

Immune-mediated colitis.

Immune-mediated colitis, which can present as a severe and acute-onset form of colitis, has been reported in patients receiving Ocrevus in the post-marketing setting. Some cases of colitis were serious, requiring hospitalisation, with a few patients requiring surgical intervention. The time from treatment initiation to onset of symptoms in these cases ranged from a few weeks to years. Monitor patients for immune-mediated colitis during Ocrevus treatment and evaluate promptly if signs and symptoms that may indicate immune-mediated colitis, such as persistent diarrhoea or other gastrointestinal signs and symptoms, occur.

Treatment with immunosuppressants before, during or after Ocrevus.

In other auto-immune conditions, use of Ocrevus concomitantly with immunosuppressive medications (e.g. chronic corticosteroids, non-biologic and biologic disease-modifying antirheumatic drugs [DMARDS], mycophenolate mofetil, cyclophosphamide, azathioprine) resulted in an increase of serious infections, including opportunistic infections. Infections included and were not limited to atypical pneumonia and Pneumocystis jirovecii pneumonia, varicella pneumonia, tuberculosis, histoplasmosis. In rare cases, some of these infections were fatal. Risk factors for serious infections included higher doses of Ocrevus than recommended in MS, other comorbidities, chronic use of immunosuppressants/corticosteroids, and patients from Asia.
Ocrevus should not be co-administered with other disease-modifying MS therapies. It is not recommended to use other immunosuppressives concomitantly with Ocrevus except corticosteroids for symptomatic treatment of relapses.
When initiating Ocrevus after an immunosuppressive therapy or initiating an immunosuppressive therapy after Ocrevus, the potential for overlapping pharmacodynamic effects should be taken into consideration (see Section 5.1 Pharmacodynamic Properties). Exercise caution when prescribing Ocrevus taking into consideration the pharmacodynamics of other disease-modifying MS therapies.

Vaccinations.

The safety of immunisation with live or live-attenuated vaccines following Ocrevus therapy has not been studied and vaccination with live or live-attenuated vaccines is not recommended during treatment and until B-cell repletion (see Section 5.1 Pharmacodynamic Properties).
After treatment with Ocrevus IV over 2 years, the proportion of patients with positive antibody titres against S. pneumoniae, mumps, rubella and varicella were generally similar to the proportions at baseline.
In a randomised open-label study, RMS patients treated with Ocrevus IV were able to mount humoral responses, albeit decreased, to tetanus toxoid, 23-valent pneumococcal polysaccharide, keyhole limpet hemocyanin neoantigen, and seasonal influenza vaccines.
Physicians should review the immunisation status of patients before starting treatment with Ocrevus. Patients should complete vaccinations at least 6 weeks prior to initiation of Ocrevus, although for seasonal influenza vaccines, it is still recommended to vaccinate patients on Ocrevus.

Exposure in utero to ocrelizumab and vaccination of neonates and infants with live or live-attenuated vaccines.

Due to the potential depletion of B-cells in neonates and infants of mothers who have been exposed to Ocrevus during pregnancy, it is recommended that vaccination with live or live-attenuated vaccines be delayed until B-cell levels have recovered. It is therefore recommended to measure the CD19-positive B-cell level in neonates and infants prior to vaccination and to discuss the safety and timing of vaccination with the infant's physician.
It is recommended that all vaccinations other than live or live-attenuated should follow the local immunisation schedule and measurement of vaccine-induced response titres should be considered to check whether individuals can mount a protective immune response because the efficacy of the vaccination may be decreased.

Malignancy.

Immunomodulatory drugs may increase the risk of malignancy. In controlled trials, malignancies, including breast cancer, occurred more frequently in Ocrevus-treated patients although the incidence was within the background rate expected for an MS population. However, a possible increased risk of malignancy cannot be excluded. Patients should follow standard cancer screening guidelines.

Use in renal impairment.

The safety and efficacy of Ocrevus in patients with renal impairment have not been formally studied. Patients with mild renal impairment were included in clinical trials. Ocrevus is a monoclonal antibody and cleared via catabolism rather than renal excretion, and a change in dose is not expected to be required for patients with renal impairment (see Section 5.2 Pharmacokinetic Properties).

Use in hepatic impairment.

The safety and efficacy of Ocrevus in patients with hepatic impairment have not been formally studied. Patients with mild hepatic impairment were included in clinical trials. Ocrevus is a monoclonal antibody and cleared via catabolism rather than hepatic metabolism, and a change in dose is not expected to be required for patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

Paediatric use.

The safety and efficacy of Ocrevus in children and adolescents (< 18 years of age) have not been studied.

Use in the elderly.

The safety and efficacy of Ocrevus in patients > 55 years of age have not been established.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug interaction studies have been performed as no drug interactions are expected via CYP and other metabolising enzymes or transporters.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Preclinical data reveal no special hazards for humans based on studies of male and female fertility in cynomolgus monkeys. No impact on male or female fertility as assessed by fertility indices was detected in male and female cynomolgus monkeys in which Ocrevus was administered intravenously at weekly doses of up to 100 mg/kg. Exposure (based on serum area under curve (AUC)) in these studies was up to at least 150 times that expected in patients at the recommended clinical dose.
(Category C)
Ocrevus should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus. Ocrevus is a humanised monoclonal antibody and immunoglobulins are known to cross the placental barrier. Women of child bearing potential should use effective contraception while receiving Ocrevus and for 6 months after the last dose of Ocrevus (see Section 5.2 Pharmacokinetic Properties).
There are no adequate and well-controlled data from studies in pregnant women, however transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy.
Postponing vaccination with live or live-attenuated vaccines is recommended for neonates and infants who have been exposed to Ocrevus in utero until B-cell levels have recovered. B-cell levels in neonates and infants following maternal exposure to Ocrevus have not been studied in clinical trials and the potential duration of B-cell depletion in neonates and infants is unknown (see Section 4.4 Special Warnings and Precautions for Use, Vaccinations).

Labour and delivery.

The safe use of Ocrevus during labour and delivery has not been established.
 As human IgG is excreted in human milk and the potential for Ocrevus absorption leading to B-cell depletion is unknown, women should be advised to discontinue breast-feeding during Ocrevus therapy. Animal studies have shown excretion of Ocrevus in breast milk.
Measurable levels of ocrelizumab were detected in the milk of monkeys (approximately 0.2% of steady state trough serum levels) during the lactation period.
It is unknown whether Ocrevus is excreted in human breast milk or has any effect on the breast-fed child and on milk production.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Ocrevus on the ability to drive and to use machines have been performed. The pharmacological activity and adverse events reported to date do not indicate such an effect is likely.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

The safety profile of Ocrevus is based on data in patients with RMS and PPMS who were administered Ocrevus intravenously or subcutaneously.
The safety of Ocrevus has been established in 1311 patients from pivotal MS clinical studies with Ocrevus IV, which includes 825 patients in active-controlled RMS clinical trials and 486 patients in a placebo-controlled PPMS trial. Table 2 summarises the adverse drug reactions (ADRs) that have been reported in association with the use of Ocrevus IV in clinical trials. The most frequently reported ADRs were IRRs and respiratory tract infections.
RMS. The ADRs described in this section were identified based on data from two identical active-controlled studies (WA21092 and WA21093) evaluating the efficacy and safety of Ocrevus in adults with RMS. In the two studies, patients (n = 825) were given Ocrevus IV 600 mg, every 6 months (with the first dose administered as two 300 mg IV infusions separated by two weeks and all subsequent doses as a single, 600 mg infusion), or interferon beta-1a (IFN) 44 microgram (n = 826) s.c. three times per week. The controlled period of the study was 96 weeks (four doses of Ocrevus).
PPMS. The ADRs described in this section were identified based on data from a placebo-controlled study (WA25046) evaluating the efficacy and safety of Ocrevus in adults with PPMS. Patients were given Ocrevus IV 600 mg (n = 486) or placebo (n = 239) every 6 months (administered as two 300 mg infusions separated by two weeks during the entire study).
Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000) and very rare (< 1/10,000). Adverse reactions are presented in order of decreasing frequency.
Infusion related reactions (IRRs) with Ocrevus IV. Across the RMS and PPMS trials, symptoms associated with IRRs included, but are not limited to, pruritus, rash, urticaria, erythema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, throat irritation, oropharyngeal pain, dyspnoea, pharyngeal or laryngeal oedema, nausea and tachycardia. In the controlled clinical trials there were no fatal IRRs.
In the active-controlled RMS clinical trials, IRRs were the most common adverse event in patients treated with Ocrevus IV 600 mg with an overall incidence of 34.3% compared with an incidence of 9.9% in the interferon beta-1a treatment group (placebo infusion). The incidence of IRRs was highest during dose 1, infusion 1 (27.5%) and decreased over time to < 10% at dose 4. The majority of IRRs in both treatment groups were mild to moderate (see Section 4.4 Special Warnings and Precautions for Use).
In the placebo-controlled PPMS clinical trial, the incidence of IRRs was highest during dose 1, infusion 1 (27.4%) and decreased with subsequent doses to < 10% at dose 4. A greater proportion of patients in each group experienced IRRs with the first infusion of each dose compared with the second infusion of that dose. The majority of IRRs were mild to moderate (see Section 4.4 Special Warnings and Precautions for Use).
Due to overall more infusions with the two x 300 mg regimen in the PPMS clinical trial, the total number of IRRs were higher. Therefore, after dose 1 it is recommended to administer Ocrevus in a single 600 mg infusion in patients with RMS or PPMS (see Table 2) to reduce the total number of infusions (and concurrent exposure to prophylactic methylprednisolone) and IRRs (see Section 4.4 Special Warnings and Precautions for Use).

Alternative shorter infusion of subsequent doses.

In a study (MA30143 Shorter Infusion Substudy) designed to characterize the safety profile of shorter (2-hour) Ocrevus infusions in patients with Relapsing-Remitting Multiple Sclerosis, the incidence, intensity, and types of symptoms of IRRs were consistent with those of infusions administered over 3.5 hours (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Ocrevus SC. The safety of Ocrevus SC has been evaluated in 312 patients from MS clinical studies which, includes patients from the pivotal study OCARINA II and patients from OCARINA I. Of those 312 patients, 181 patients from OCARINA II and 118 patients from OCARINA I were given at least one dose of Ocrevus SC 920 mg.
The safety observed for Ocrevus SC was consistent with the known safety profile of Ocrevus IV presented in Table 2, except for the very common ADR of IRs, which are observed with the SC route of administration.
Injection reactions (IRs) with Ocrevus SC. Based on the observed symptoms, IRs are categorised into systemic IRs and local IRs.
In OCARINA II (ocrelizumab naïve patients), the most common symptoms reported with systemic IRs and local IRs included: headache, nausea, injection site erythema, injection site pain, injection site swelling, and injection site pruritus. 118 patients received at least one injection of Ocrevus SC 920 mg. IRs occurred in 48.3% of these patients after the first injection. Of the 118 patients, 11.0% and 45.8% patients experienced at least one event of systemic IR and local IR, respectively. Among the patients with IR, the majority of patients (82.5%) had IRs occur within 24 hours of the end of injection as opposed to during the injection. All IRs were non-serious and of mild (71.9%) or moderate (28.1%) severity. The median duration was 3 days for systemic IRs and 4 days for local IRs. All patients recovered from IRs, of which 26.3% required symptomatic treatment.
In OCARINA I, 125 patients received one or more injections of Ocrevus SC 1200 mg which is a higher dose tested than the recommended dose. Of the 125 patients who received the first injection, 16.0% of patients experienced at least one event of systemic IR and 64.0% of patients experienced at least one event of local IR. Of the 104 patients who received the second injection, the incidence of systemic IR and local IR decreased to 7.7% and 37.5%, respectively. All IRs were non serious, of which all except one IR were of mild or moderate severity for the first injection. All IRs were non serious and of mild or moderate severity for the second injection. 21.2% and 17.9% of patients experiencing IR required symptomatic treatment after the first and second injection, respectively.
Infection. There was no increase in serious infections associated with Ocrevus treatment. In RMS patients the rate of serious infections was lower than for interferon beta-1a, and in PPMS patients the rate was similar to placebo.
In the active-controlled RMS and placebo-controlled PPMS clinical trials with Ocrevus IV, respiratory tract infections and herpes infections (both predominantly mild to moderate) were more frequently reported in the Ocrevus treatment arm.

Respiratory tract infections.

The proportion of respiratory tract infections was higher in the Ocrevus treated patients compared to interferon and placebo. The infections were predominantly mild to moderate and consisted mostly of upper respiratory tract infections (including nasopharyngitis) and bronchitis (see Table 2).

Herpes.

In the active-controlled RMS clinical trials with Ocrevus IV, herpes infections were reported more frequently in Ocrevus treated patients than interferon beta-1a treated patients including herpes zoster (2.1% vs 1.0%), herpes simplex (0.7% vs 0.1%) and oral herpes (3.0% vs 2.2%), genital herpes (0.1% vs 0%), herpes virus infection (0.1% vs 0%). Infections were predominantly mild to moderate in severity and patients recovered with treatment by standard therapies. There were no reports of disseminated herpes.
In the placebo-controlled PPMS clinical trial with Ocrevus IV, a higher proportion of patients with oral herpes (2.7% vs 0.8%) were observed in the Ocrevus treatment arm.
Serious infections from clinical trials in autoimmune conditions other than MS. Ocrevus in combination with concomitant immunosuppressive medications (e.g. chronic steroids, non-biologic and biologic disease-modifying antirheumatic drugs (DMARDs), mycophenolate mofetil, cyclophosphamide and azathioprine) has been studied in other autoimmune conditions.
The majority of available data is from studies in patients with rheumatoid arthritis (RA), where an imbalance in serious infections was observed including, but not limited to, atypical pneumonia and Pneumocystis jirovecii pneumonia, varicella pneumonia, tuberculosis, histoplasmosis in the Ocrevus-immunosuppressant group. In rare cases some of these infections were fatal. Serious infections were reported more frequently in the 1000 mg dose group compared to the 400 mg dose group or immunosuppressant-placebo group.
Risk factors for serious infections in these trials included other comorbidities, chronic use of immunosuppressants/steroids, and patients from Asia.
Laboratory abnormalities.

Immunoglobulins.

Treatment with Ocrevus resulted in a decrease in total immunoglobulins over the controlled period of the Ocrevus IV studies, mainly driven by reduction in IgM.
In the active-controlled RMS clinical trials, the proportion of patients at baseline reporting IgG, IgA and IgM < lower limit of normal (LLN) in the Ocrevus IV treatment arm was 0.5%, 1.5% and 0.1%, respectively. Following treatment, the proportion of Ocrevus-treated patients reporting IgG, IgA and IgM < LLN at 96 weeks was 1.5%, 2.4% and 16.5%, respectively.
In the placebo-controlled PPMS clinical trial, the proportion of patients at baseline reporting IgG, IgA and IgM < LLN in the Ocrevus IV treatment arm was 0.0%, 0.2% and 0.2%, respectively. Following treatment, the proportion of Ocrevus IV-treated patients reporting IgG, IgA and IgM < LLN at 120 weeks was 1.1%, 0.5% and 15.5%, respectively.
The pooled data of the Ocrevus IV pivotal clinical studies (RMS and PPMS) and their open-label extensions (up to approximately 7 years of exposure) have shown an apparent association between decreased levels of immunoglobulins and serious infections (SI), and was most apparent for IgG (0.5% of patients had a SI during a period with IgG < LLN). The type, severity, latency, duration, and outcome of SIs observed during episodes of immunoglobulins below LLN were consistent with the overall SIs observed in patients treated with OCR.

Neutrophils.

In the active-controlled treatment period of the RMS clinical trials, decreased neutrophils were observed in 14.7% of Ocrevus IV patients as compared to 40.9% of patients treated with interferon beta-1a. In the placebo-controlled PPMS clinical trial, the proportion of Ocrevus patients presenting decreased neutrophils was slightly higher (12.9%) than placebo patients (10.0%).
In the majority of cases decreased neutrophils were transient (only observed once for a given patient treated with Ocrevus IV) and were Grade 1 and 2 in severity.
Overall, approximately 1% of the patients in the Ocrevus group had Grade 3 or 4 neutropenia. These were not temporally associated with an infection.
Neutropenia can also occur several months after the administration of Ocrevus, as observed in the post-market setting (see Section 4.4 Special Warnings and Precautions for Use, Late neutropenia).

Post-marketing experience.

The following adverse events have been identified during the post-marketing use of Ocrevus. Because these events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency and/or establish a causal relationship to Ocrevus exposure.
Immune-mediated colitis has been reported in patients treated with Ocrevus in the post-marketing setting (see Section 4.4 Special Warnings and Precautions for Use).

Reporting of suspected adverse reactions.

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 is limited clinical trial experience with doses higher than the approved dose of Ocrevus. The highest dose tested to date in MS patients is 2000 mg, administered as two 1000 mg IV infusions separated by two weeks (phase II dose finding study in RRMS) and 1200 mg, administered as a SC injection (phase Ib dose finding study). The ADRs were consistent with the safety profile for Ocrevus in the pivotal clinical studies. There was an overall greater incidence of AEs on 1200 mg SC.
There is no specific antidote in the event of an overdose. Interrupt the infusion or injection immediately and observe the patient for IRRs or IRs (see Section 4.4 Special Warnings and Precautions for Use).
Treatment of overdose should consist of general supportive measures.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Ocrelizumab is a recombinant humanised monoclonal antibody that selectively targets CD20-expressing B-cells.

Pharmacodynamic effect.

The precise mechanisms through which ocrelizumab exerts its therapeutic clinical effects in multiple sclerosis (MS) are not fully elucidated but is presumed to involve immunomodulation through the reduction in the number and function of CD20-expressing B-cells. Following cell surface binding, it is hypothesised that ocrelizumab selectively depletes CD20-expressing B-cells through antibody-dependent cellular phagocytosis, antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and apoptosis. It is presumed that the capacity of B-cell reconstitution and pre-existing humoral immunity are preserved since the cell surface antigen CD20 is expressed on pre-B cells and mature and memory B cells, but not on lymphoid stem cells and plasma cells. In addition, total numbers of cells of the innate immune system and total T-cell numbers are not affected.
Treatment with Ocrevus leads to rapid depletion of CD19+ B-cells in blood by 14 days post-treatment (first time-point of assessment) as an expected pharmacologic effect. This was sustained throughout the treatment period with Ocrevus IV. For the B-cell counts, CD19 is used as the presence of Ocrevus interferes with the detection of CD20 by the assay.
In the phase III studies, between each dose of Ocrevus IV, up to 5% of patients showed B-cell repletion (> lower limit of normal (LLN) or baseline) at least at one time point. The extent and duration of B-cell depletion was consistent in the primary progressive MS (PPMS) and relapsing forms of MS (RMS) trials.
The longest follow up time after the last Ocrevus infusion (phase II WA21493, n = 51) indicates that the median time to B-cell repletion (return to baseline/LLN, whichever occurred first) was 72 weeks (range 27-175 weeks). Ninety percent of all patients had their B-cells repleted to LLN or baseline by approximately two and a half years after the last infusion.

Clinical trials.

Ocrevus IV.

Relapsing forms of MS (RMS).

The efficacy and safety of Ocrevus were evaluated in two randomised, double-blind, double-dummy, active comparator-controlled clinical trials with identical design in patients with RMS. Study design and baseline characteristics of the study population are summarised in Table 3.
Demographic and baseline characteristics were well balanced across the two treatment groups. Patients receiving Ocrevus (group A) were given 600 mg every 6 months (dose 1 - two x 300 mg IV infusions, administered two weeks apart), and subsequent doses were administered as a single 600 mg IV infusion. Patients in group B were administered interferon beta-1a (Rebif) 44 microgram subcutaneous (s.c.) injection three times per week.
Key clinical and magnetic resonance imaging (MRI) efficacy results are presented in Table 4 and Figure 1.
Results of the pre-specified pooled analyses of time to CDP sustained for at least 12 weeks (40% risk reduction for Ocrevus compared to interferon beta-1a, p = 0.0006) were highly consistent with the results sustained for at least 24 weeks (40% risk reduction for Ocrevus compared to interferon beta-1a, p = 0.0025).

Shorter infusion substudy.

The safety of the shorter (2-hour) Ocrevus IV infusion was evaluated in a prospective, multicenter, randomized, double-blind, controlled, parallel arm substudy to study MA30143 (Ensemble) in patients with Relapsing-Remitting Multiple Sclerosis that were naïve to other disease modifying treatments. The first dose of Ocrevus IV was administered as two 300 mg infusions (600 mg total) separated by 14 days. Patients were randomized from their second dose or onwards (dose 2 to 6) in a 1:1 ratio to either the conventional infusion group with Ocrevus IV infused over approximately 3.5 hours every 24 weeks, or the shorter infusion group with Ocrevus IV infused over approximately 2 hours every 24 weeks. The randomization was stratified by region and the dose at which patients were first randomized.
The primary endpoint was the proportion of patients with IRRs occurring during or within 24 hours following the first randomized infusion of Ocrevus IV. The primary analysis was performed when 580 patients were randomized. The proportion of patients with IRRs occurring during or within 24 hours following the first randomized infusion was 24.6% in the shorter infusion group compared to 23.1% in the conventional infusion group. The stratified group difference was similar. Overall, in all randomized doses, the majority of the IRRs were mild or moderate and only two IRRs were severe in intensity, with one severe IRR in each group. There were no life-threatening, fatal, or serious IRRs.

Primary progressive MS (PPMS).

The efficacy and safety of Ocrevus were evaluated in a randomised, double-blind, placebo-controlled clinical trial in patients with PPMS (study WA25046). Study design and baseline characteristics of the study population are presented in Table 5. Demographic and baseline characteristics were well balanced across the two treatment groups.
Throughout the treatment period patients receiving Ocrevus (group A) were given 600 mg every 6 months (as two x 300 mg IV infusions, administered two weeks apart) (see Section 4.2 Dose and Method of Administration). Patients in group B were administered placebo. The two x 300 mg infusions in PPMS demonstrated consistent PK/PD profiles to the 600 mg infusions in RMS.
Key clinical and MRI efficacy results are presented in Table 6 and Figure 2.
A post-hoc analysis suggested that patients who are 50 years of age or below, or patients who have inflammation determined by MRI (Gd enhancing or T2 lesion) may receive a greater treatment benefit than patients who are over 50 years of age or patients who do not have inflammation by MRI.
Ocrevus SC.

OCARINA II.

Study CN42097 (OCARINA II) was a multicentre, randomised, open-label, parallel arm trial conducted to evaluate the pharmacokinetics, pharmacodynamics, safety, immunogenicity, radiological and clinical effects of Ocrevus SC compared with Ocrevus IV in patients with RMS or PPMS. OCARINA II was designed to demonstrate non-inferiority of treatment with Ocrevus SC versus Ocrevus IV based on the primary PK endpoint of area under the concentration time curve (AUC) up to week 12 post-injection/infusion (AUCw1-12).
A total of 236 patients with RMS or PPMS (213 patients with RMS, 23 patients with PPMS), were randomised in a 1:1 ratio to the SC arm or IV arm. During the controlled period (day 0 to week 24), patients received either a single 920 mg SC injection at study day 1 or two 300 mg IV infusions at study day 1 and 14. After the controlled period, all patients had the opportunity to receive further injections of 920 mg SC at weeks 24 and 48 (dose 2 and 3). Patients were excluded if they had previous treatment with anti-CD20 antibodies within the last 24 months, including ocrelizumab.
Patients were aged 18-65 years with an EDSS between 0 to 6.5 at screening. The demographics were similar and baseline characteristics were well balanced across the two treatment groups. The mean age was 39.9 years in the SC arm and 40.0 years in the IV arm. 34.7% of patients were male in the SC arm and 40.7% patients were male in the IV arm. The mean/median duration since MS diagnosis was 5.70/3.10 years in the SC arm and 4.78/2.35 years in the IV arm.
Non-inferiority of the ocrelizumab exposure after administration of 920 mg Ocrevus SC compared to 600 mg Ocrevus IV was demonstrated based on the PK primary endpoint, AUC up to week 12 (AUCW1-12) post-injection (see 3.2 Pharmacokinetic Properties).

OCARINA I.

Study CN41144 (OCARINA I) was a multi-center, randomised, open-label, parallel arm trial conducted to evaluate the pharmacokinetics, safety, tolerability, and immunogenicity of Ocrevus SC compared with Ocrevus IV in patients with RMS or PPMS. The study was used to determine the bioavailability of Ocrevus SC to select the SC dose for the subsequent Phase 3 Study, CN42097 (OCARINA II). This was done by modelling, comparing the pharmacokinetic profile between Ocrevus SC and Ocrevus IV based on the area under the concentration time curve (AUC) (see Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamics Properties, Immunogenicity).
Immunogenicity. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to Ocrevus with the incidence of antibodies to other products may be misleading.

Ocrevus IV.

Patients in the MS trials (WA21092, WA21093 and WA25046) were tested at multiple time points (baseline and every 6 months post treatment for the duration of the trial) for anti-drug antibodies (ADAs). Out of 1311 patients treated with ocrelizumab, 12 (~1%) tested positive for treatment-emergent ADAs, of which two patients tested positive for neutralising antibodies. The impact of treatment-emergent ADAs on safety and efficacy cannot be assessed given the low incidence of ADA associated with Ocrevus.

Ocrevus SC.

Across OCARINA II and OCARINA I, no patients had treatment emergent ADAs to Ocrevus.
The incidence of treatment-emergent anti-vorhyaluronidase alfa antibodies in patients treated with Ocrevus SC in OCARINA I was 2.3% (3/132). No patients from OCARINA II had treatment-emergent anti-vorhyaluronidase alfa antibodies.

5.2 Pharmacokinetic Properties

Pharmacokinetics of ocrelizumab in the MS studies were described by a two compartment model with time-dependent clearance, and with pharmacokinetic (PK) parameters typical for an IgG1 monoclonal antibody. Clearance and central volume were estimated at 0.17 L/day and 2.78 L, peripheral volume and inter-compartment clearance at 2.68 L and 0.294 L/day, and initial time-dependent clearance at 0.0489 L/day which declined with a half-life of 33 weeks.

Ocrevus IV.

The overall exposure (AUC over the 24 week dosing intervals) was identical in the 2 x 300 mg PPMS study and the 1 x 600 mg RMS studies, as expected given an identical dose of 600 mg IV was administered. AUCτ after the fourth dose of 600 mg Ocrevus IV was 3510 microgram/mL.day, and mean maximum concentration (Cmax) was 212 microgram/mL in RMS (600 mg infusion) and 141 microgram/mL in PPMS (300 mg infusions). Terminal half-life was 26 days.

Ocrevus SC.

After administration of 920 mg Ocrevus SC, the estimated mean exposure (AUC over the 24 week dosing interval) was 3730 microgram/mL.day.
The primary PK endpoint in OCARINA II, AUCW1-12, after 920 mg Ocrevus SC was shown to be non-inferior to 600 mg Ocrevus IV. The geometric mean ratio (GMR) for AUCw1-12 was 1.29 (90% CI: 1.23-1.35).

Absorption.

Ocrelizumab IV is administered intravenously.
The estimated bioavailability after SC administration of 920 mg Ocrevus SC was 81%. The mean Cmax was 132 microgram/mL and tmax was reached after approximately 4 days (range 2-13 days).

Distribution.

The population PK estimate of the central volume of distribution was 2.78 L. Peripheral volume and inter-compartment clearance were estimated at 2.68 L and 0.294 L/day.

Metabolism.

The metabolism of ocrelizumab has not been directly studied, as antibodies are cleared principally by catabolism.

Excretion.

Constant clearance was estimated at 0.17 L/day, and initial time-dependent clearance at 0.0489 L/day which declined with a half-life of 33 weeks. The terminal elimination half-life was 26 days.

Pharmacokinetics in special populations.

Elderly patients.

No studies have been conducted to investigate the PK of ocrelizumab in patients ≥ 65 years.

Paediatric patients.

No studies have been conducted to investigate the PK of ocrelizumab in children and adolescents (< 18 years of age).

Renal impairment.

No formal PK study has been conducted. Patients with mild renal impairment were included in clinical trials and no change in the PK of ocrelizumab was observed in those patients.

Hepatic impairment.

No formal PK study has been conducted. Patients with mild hepatic impairment were included in clinical trials and no change in the PK of ocrelizumab was observed in those patients.

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity studies have not been conducted with Ocrevus. As ocrelizumab is a monoclonal antibody it would not be expected to have genotoxic potential.

Carcinogenicity.

Carcinogenicity studies with Ocrevus have not been conducted.

Reproductive toxicity.

It is not known whether Ocrevus can cause harm to the foetus when administered to pregnant women or whether it affects reproductive capacity. In an embryo-foetal developmental study in cynomolgus monkeys, there was no evidence of maternal toxicity, teratogenicity or embryotoxicity following weekly intravenous ocrelizumab administration at doses up to 100 mg/kg (at least 200 times the anticipated exposure, based on serum AUC, than in patients at the recommended clinical dose). IgG molecules are known to cross the placental barrier and ocrelizumab causes depletion of B-cells in the foetuses of treated cynomolgus monkeys.
In a pre- and post-natal development study in cynomolgus monkeys, weekly intravenous administration of ocrelizumab at 20 and 100 mg/kg (associated with respective exposures at least 40 and 175 times the clinical exposure, based on serum AUC) was associated with glomerulopathy (7/24 neonates), and lymphoplasmacytic inflammation in the kidney (2/24 neonates). Testicular weights of the neonates were significantly reduced in the 100 mg/kg group compared with controls, although relationship to treatment is uncertain. There were two cases of moribundity (2/24) at 100 mg/kg, one attributed to weakness due to premature birth accompanied by opportunistic infection and the other to an infective meningoencephalitis involving the cerebellum of the offspring from a maternal dam with an active infection (mastitis). The course of both neonatal infections could have potentially been impacted by B-cell depletion. Newborn offspring of maternal animals exposed to Ocrevus were noted to have depleted B-cell populations during the post-natal phase.

Other.

Preclinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, acute and repeated dose toxicity.
SC administration of ocrelizumab with vorhyaluronidase alfa was well tolerated in rats and minipigs in local tolerance studies.
No carcinogenicity, genotoxicity, or fertility studies were conducted for vorhyaluronidase alfa. Reproductive toxicology studies with vorhyaluronidase alfa revealed embryofetal losses in mice, with no effect level 4675 times higher than the clinical dose. There was no evidence of teratogenicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

Ocrevus IV.

Sodium acetate trihydrate, trehalose dihydrate, acetic acid, polysorbate 20, water for injections.

Ocrevus SC.

Vorhyaluronidase alfa (an enzyme used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously), sodium acetate trihydrate, trehalose dihydrate, acetic acid, polysorbate 20, methionine, water for injections.

6.2 Incompatibilities

Ocrevus IV.

No incompatibilities between Ocrevus IV and polyvinyl chloride or polyolefin bags, and IV administration sets have been observed. Do not use diluents other than 0.9% sodium chloride to dilute Ocrevus IV since use has not been tested.

Ocrevus SC.

No incompatibilities between Ocrevus SC and polypropylene, polycarbonate, polyethylene, polyvinyl chloride, polyurethane and stainless steel have been observed.

6.3 Shelf Life

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.

6.4 Special Precautions for Storage

Ocrevus IV.

Store vial in a refrigerator at 2°C to 8°C. Keep vial in the outer carton in order to protect from light. Do not freeze. Do not shake. Do not use after the expiry date (EXP) shown on the pack.

Storage of the reconstituted solution.

Ocrevus does not contain any anti-microbial preservative; therefore, care must be taken to ensure the sterility of the prepared solution. Product is for single dose in one patient only. Discard any residue.
To reduce microbiological hazard, the prepared infusion solution should be used immediately. If storage is necessary, the prepared infusion can be held at 2°C-8°C for up to 24 hours and subsequently 8 hours at room temperature.
In the event an IV infusion cannot be completed the same day, the remaining solution should be discarded.

Ocrevus SC.

Ocrevus does not contain any anti-microbial preservative; therefore, care must be taken to ensure the sterility of the solution. Product is for single dose in one patient only. Discard any residue.
Store vial in a refrigerator at 2°C to 8°C. Keep vial in the outer carton in order to protect from light. Do not freeze. Do not shake. Do not use after the expiry date (EXP) shown on the pack.
If necessary, the unopened vial can be left at temperatures ≤ 25°C for up to 12 hours.
The vials can be removed and placed back into the refrigerator so that the total combined time out of the refrigerator of the unopened vial may not exceed 12 hours at ≤ 25°C.

Storage of the syringe.

To reduce microbiological hazard, the prepared syringe should be used immediately. If storage is necessary, the syringe must be closed with a syringe cap. The closed syringe can be held at 2°C-8°C for up to 72 hours followed by 8 hours at ambient temperatures ≤ 25°C in diffuse daylight.

6.5 Nature and Contents of Container

Ocrevus IV is a concentrate for solution for infusion supplied at a volume of 10 mL in a 15 mL glass vial.
Ocrevus SC is a solution for injection supplied at a volume of 23 mL in a 50 mL glass vial.

6.6 Special Precautions for Disposal

Disposal of unused/expired medicines-Ocrevus IV and SC.

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal.
The following should be strictly adhered to regarding the use and disposal of syringes and other medicinal sharps:
Needles and syringes should never be reused.
Place all used needles and syringes into a sharps container (puncture-proof disposable container).

6.7 Physicochemical Properties

Chemical structure.


CAS number.

637334-45-3.

7 Medicine Schedule (Poisons Standard)

Schedule 4. Prescription Only Medicine.

Summary Table of Changes