Prescribing Information for the Patient

Ocrevus 300mg Concentrate for Solution for Infusion

ocrelizumab

Read this entire prescribing information carefully before starting to use this medication, as it contains important information for you.

• Keep this prescribing information, as you may need to refer to it again.
• If you have any questions, consult your doctor.
• If you experience any adverse effects, consult your doctor or nurse, even if they are not listed in this prescribing information. See section4.

What is Ocrevus

Ocrevus contains the active ingredient "ocrelizumab". It is a type of protein called "monoclonal antibody". Antibodies act by binding to specific targets in the body.

What is Ocrevus used for

Ocrevus is used to treat adults with:

• Relapsing forms of multiple sclerosis (RRMS)
• Early primary progressive multiple sclerosis (PPMS)

What is Multiple Sclerosis:

Multiple sclerosis (MS) affects the central nervous system, particularly the nerves in the brain and spinal cord. In MS, the immune system (the body's defense system) functions incorrectly, attacking the protective layer (called the myelin sheath) surrounding nerve cells and causing inflammation. The breakdown of the myelin sheath prevents nerves from functioning properly.

MS symptoms depend on the part of the central nervous system affected and may include, walking and balance problems, weakness, numbness, double vision and blurred vision, poor coordination, and bladder problems.

• In relapsing forms of MSpatientsexperience repeated episodes of symptoms (relapses). Symptoms can appear suddenly over a few hours, or gradually over several days. Symptoms disappear or improve between each relapse but damage can accumulate and cause permanent disability.

• Inpatients with primary progressive MSgenerallysymptoms worsen continuously from the onset of the disease.

How Ocrevus works

Ocrevus binds to specific B lymphocytes, a type of white blood cell that is part of the immune system and plays a role in MS. Ocrevus binds to and eliminates these specific B lymphocytes. This reduces inflammation and attacks on the myelin sheath, reduces the likelihood of experiencing a relapse, and slows disease progression.

• In relapsing forms of MS (RRMS), Ocrevus helps significantly reduce the number of relapses and slow disease progression significantly. Ocrevus also significantly increases the likelihood that a patient will not show evidence of disease activity (brain lesions, relapses, and disability worsening).

• In primary progressive MS (PPMS), Ocrevus helps slow disease progression and reduce walking speed decline.

No use Ocrevus:

• if you are allergic toocrelizumabor to any of the other ingredients of this medication (listed in section6).
• if you currently have an infection.
• if you have been diagnosed with severe problems in your immune system.
• if you have cancer.

If you are unsure, talk to your doctor before using Ocrevus.

Warnings and precautions

Consult your doctor before starting to use Ocrevusif any of the following conditions apply to your case. Your doctor may decide to delay your treatment with Ocrevus or that you cannot use Ocrevus if:

• you have aninfection. Your doctor will wait until the infection has resolved before administering Ocrevus.
• you have ever hadhepatitis Bor are a carrier of the hepatitis B virus. This is because medications like Ocrevus can cause hepatitis B to reactivate. Before starting treatment with Ocrevus, your doctor will check if you are at risk of hepatitis B infection. Patients who have had hepatitis B or are carriers of the hepatitis B virus will undergo blood tests and be monitored by a doctor to detect signs of hepatitis B infection.
• you havecanceror have had cancer in the past. Your doctor may choose to delay your treatment with Ocrevus.

Effects on the immune system:

• Immune system disorders:if you have another disease that affects the immune system. You may not be eligible for treatment with Ocrevus.
• Medications that affect the immune system:if you have ever taken, are taking, or plan to takemedications thataffect the immune system– such as chemotherapy, immunosuppressants, or other medications used to treat MS. Your doctor may decide to delay your treatment with Ocrevus or ask you to stop taking these medications before starting treatment with Ocrevus. For more information, see “Other medications and Ocrevus”.

Infusion-related reactions

• Infusion-related reactions are the most common side effect of treatment with Ocrevus.
• Inform your doctor or nurse immediately if you experience any infusion-related reactions(see section4 for a list of infusion-related reactions). Infusion-related reactions can occur during infusion or up to 24 hours after infusion.
• To reduce the risk of infusion-related reactions, your doctor will administer other medications before each infusion of Ocrevus (see section3) and you will be closely monitored during infusion and at least one hour after administration.

Infections

?Inform your doctor before receiving treatment with Ocrevus if you think you may have an infection. Your doctor will wait until your infection has resolved before administering treatment with Ocrevus.

?You may be more susceptible to infections with Ocrevus. This is because the immune cells that Ocrevus acts on also help fight infections.

?Before you start treatment with Ocrevus and before subsequent infusions, your doctor may request a blood test to confirm the status of your immune system since infections may occur more frequently in cases of severe immune system problems.

?If you have been treated with Ocrevus for primary progressive multiple sclerosis and have difficulty swallowing, Ocrevus may increase the risk of severe pneumonia.

?Inform your doctor or nurse immediately if you experience any of these signs of infection during or after treatment with Ocrevus:

-fever or chills

-persistent cough

-herpes (such as cold sores, shingles, or genital ulcers).

?Inform your doctor or nurse immediately if you think MS is worsening or if you experience any new symptoms.This is because of a rare and potentially fatal brain infection called “progressive multifocal leukoencephalopathy” (PML), which can cause symptoms similar to MS. PML can occur in patients takingOcrevus.

Inform your partner or caregiverabout your treatment with Ocrevus. They may notice symptoms of PML that you do not perceive, such as memory lapses, thinking problems, difficulty walking, vision loss, or changes in speech. Your doctor may need to study them.

Vaccinations

• Inform your doctor if you have recently received any vaccine or may receive a vaccine in the near future.
• During treatment with Ocrevus, you should not receivelive or live attenuated vaccines (such as BCG for tuberculosis or yellow fever vaccine).
• Your doctor may recommend that you receive the seasonal flu vaccine.
• Your doctor will check if you need any vaccine before starting treatment with Ocrevus. Vaccines should be administered at least 6 weeks before starting treatment with Ocrevus.

Children and adolescents

Ocrevus is not intended for use in children and adolescents under 18 years of age. This is because it has not yet been studied in this age group.

Other medications and Ocrevus

Inform your doctor if you are using, have used recently, ormay have to useany other medication.

Especially, inform your doctor if:

• you have ever taken, are taking, or plan to takemedications that affect the immune system– such as chemotherapy, immunosuppressants, or other medications used to treat MS. The effect on the immune system of these medications administered with Ocrevus may be too strong. Your doctor may decide to delay your treatment with Ocrevus or ask you to stop taking these medications before starting treatment with Ocrevus.
• you are takingmedications for high blood pressure. This is because Ocrevus can lower your blood pressure. Your doctor may ask you to stop taking your blood pressure medications 12 hours before each infusion of Ocrevus.

If any of these conditions apply to your case (or you are unsure), talk to your doctor before using Ocrevus.

Pregnancy

?If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor before this medication is administered.This is because Ocrevus can cross the placental barrier and affect your baby.

?Do not use Ocrevus if you are pregnant unless you have discussed this with your doctor. Your doctor will weigh the benefits of using Ocrevus against the risk it poses to your baby.

?Consult your doctor before vaccinating your baby.

Birth control for women

If you can become pregnant (conceive), women of childbearing age should use birth control:

• during treatment with Ocrevus and
• for 4 months after the last infusion of Ocrevus.

Breastfeeding

Do not breastfeed while receiving treatment with Ocrevus. This is because Ocrevus can pass into breast milk.

Driving and operating machinery

The effect of Ocrevus on your ability to drive or operate tools or machinery is unknown.

Your doctor will inform you if MS can affect your ability to drive or operate tools or machinery safely.

Ocrevus contains sodium

This medication contains less than 1mmol ofsodium(23mg) per dose, which is essentially “sodium-free”.

Ocrevus will be administered by an experienced doctor or nurse in the use of this treatment.

They will keep you under observation during the administration of the medication in case you experience any adverse effects. Ocrevus will always be administered as an infusion (intravenous perfusion).

Medications you will receive before Ocrevus

Before receiving Ocrevus, you will be administered other medications to prevent or reduce possible adverse effects such as infusion-related reactions (see sections 2 and 4 for more information on infusion-related reactions).

You will receive a corticosteroid and an antihistamine before each infusion and may also be administered medications to reduce fever.

How much Ocrevus and how often it is administered

You will receive a total dose of 600 mg of Ocrevus every 6 months.

• The first dose of 600 mg of Ocrevus will be administered as 2 infusions (300 mg each) separated by a 2-week interval. Each infusion will last around 2 hours and 30 minutes.
• The subsequent doses of 600 mg of Ocrevus will be administered as a single infusion. Depending on the speed of the next infusion, it will last either around 3 hours and 30 minutes or 2 hours.

How to administer Ocrevus

• Ocrevus will be administered by a doctor or nurse. It will be administered as an infusion in a vein (intravenous infusion or "IV" infusion).
• You will be closely monitored while receiving Ocrevus and for at least 1 hour after the infusion. This is in case you experience any adverse effects such as infusion-related reactions. The infusion may be slowed down, temporarily interrupted, or permanently suspended if you experience an infusion-related reaction, depending on its severity (see sections 2 and 4 for more information on infusion-related reactions).

If you forget to administer a dose of Ocrevus

• If you miss a dose of Ocrevus, talk to your doctor to schedule a new infusion as soon as possible. Do not wait until your next scheduled infusion.
• It is essential to receive each infusion on time to get the full benefit of Ocrevus.

If you interrupt treatment with Ocrevus

• It is essential to continue your treatment for as long as you and your doctor consider it is helping you.
• Some adverse effects may be related to low levels of B lymphocytes. After completing treatment with Ocrevus, you may continue to experience adverse effects until your B lymphocytes return to normal levels. Your B lymphocyte levels in the blood will increase gradually until they reach normal levels. This may take between 6 months and 2.5 years, or even longer in rare cases.
• Before starting any other medication, inform your doctor about when you received your last Ocrevus infusion.

If you have any other questions about the use of this medication, ask your doctor.

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

The following side effects have been reported with Ocrevus:

Severe side effects:

Infusion-related reactions

?Infusion-related reactions are the most common side effect of treatment with Ocrevus (very common: may affect more than 1 in 10 people). In most cases, they are mild reactions, but some severe reactions can occur.

?Inform your doctor or nurse immediately if you experience any signs or symptoms of an infusion-related reaction during the infusion or within 24 hours after the infusion.The symptoms may include, among others:

-itching of the skin

-skin rash

-hives

-redness of the skin

-irritation or sore throat

-difficulty breathing

-swelling of the throat

-flushing

-low blood pressure

-fever

-fatigue

-headache

-dizziness

-nausea

-rapid heart rate.

?If you experience an infusion-related reaction, you will be given medications to treat it, and it may be necessary to slow down or stop the infusion. When the reaction has resolved, the infusion can be continued. If the infusion-related reaction is potentially life-threatening, your doctor will permanently discontinue treatment with Ocrevus.

Infections

?You may be more susceptible to infections with Ocrevus. The following infections have been observed in patients treated with Ocrevus in the context of MS:

-Very common:may affect more than 1 in 10 people

-pharyngitis and nasal discharge (upper respiratory tract infection)

-influenza.

-Common:may affect up to 1 in 10 people

-sinusitis

-bronchitis (inflammation of the bronchial tube)

-herpes infection (cold sore or shingles)

-gastroenteritis (infection of the stomach and intestine)

-respiratory tract infection

-viral infection

-skin infection (cellulitis)

Some of them may be severe.

?Inform your doctor or nurse immediately if you experience any of these signs of infection:

-fever or chills

-persistent cough

-herpes (such as cold sores, shingles, and genital ulcers).

Other side effects

Very common:may affect more than 1 in 10 people

• decrease in certain proteins in the blood (immunoglobulins) that help protect against infections.

Common:may affect up to 1 in 10 people

• eye discharge with itching, redness, and swelling (conjunctivitis)
• cough
• thick mucus accumulation in the nose, throat, or chest
• low levels of a type of white blood cell (neutropenia).

Unknown:the frequency of these side effects is unknown

• delayed reduction of white blood cells

Reporting of side effects

If you experience any type of side effect, consult your doctor or nurse, even if it is a possible side effect that does not appear in this leaflet. You can also report them directly through thenational reporting system included in theAppendix V.By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Hospital or clinic healthcare professionals will store Ocrevus under the following conditions:

• Keep this medication out of the sight and reach of children.
• Do not use this medication after the expiration date that appears on the outer packaging and on the vial label after “CAD”. The expiration date is the last day of the month indicated.
• Store this medication in a refrigerator (2oC - 8oC). Do not freeze. Store vials in the outer packaging to protect them from light.

Ocrevus must be diluted before administration. A healthcare professional will perform the dilution. It is recommended to use the medication immediately after dilution.If it is not used immediately, the storage periods during use and the conditions before use will be the responsibility of the healthcare professional and, generally, will not exceed 24 hours at 2ºC – 8ºC and 8hours after at room temperature.

Medications should not be disposed of through drains. This will help protect the environment.

Composition of Ocrevus

• The active ingredient is ocrelizumab. Each vial contains 300 mg of ocrelizumab in 10 ml at a concentration of 30 mg/ml.
• The other components are sodium acetate trihydrate (see Section 2 “Ocrevus contains sodium”), glacial acetic acid, trehalose dihydrate, polisorbate 20, and water for injection.

Appearance of the product and contents of the pack

• Ocrevus is a clear to slightly opalescent solution, and colorless to light brown.
• It is supplied as a concentrate for solution for infusion.
• This medicinal product is available in packs containing 1 or 2 vials (vials of 10 ml of concentrate). Only some pack sizes may be marketed.

Holder of the marketing authorisation and responsible for manufacturing

Roche Registration GmbH

Emil-Barell-Strasse 1

79639 Grenzach-Wyhlen

Germany

Responsible for manufacturing

Roche Pharma AG

Emil-Barell-Strasse 1

D-79639 Grenzach-Wyhlen

Germany

For further information about this medicinal product, please contact the local representative of the marketing authorisation holder:

Last update of this leaflet:

Other sources of information

The detailed information on this medicinal product is available on the website of the European Medicines Agency:http://www.ema.europa.eu.
This information is intended solely for healthcare professionals:

For further information, please read the SmPC.

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

Dosage

• Initial dose

The initial dose of 600 mg is administered as two separate intravenous infusions; first a 300 mg infusion followed by a second 300 mg infusion that is administered 2 weeks later.

• Subsequent doses

After the initial dose, subsequent doses of ocrelizumab are administered as a single intravenous infusion of 600 mg every 6 months (Table 1). The first of the subsequent doses of 600 mg should be administered 6 months after the first infusion of the initial dose. A minimum interval of 5 months should be respected between each dose of ocrelizumab.

Figure 1: Dosage and administration schedule of Ocrevus

Management of RRPs before infusion

• The treatment with ocrelizumab should be initiated and supervised by an experienced healthcare professional with access to appropriate medical support for the management of severe reactions such as infusion-related reactions (IRRs), hypersensitivity reactions, and/or anaphylactic reactions.

• Prednisolone premedication for IRRs

Administer the following two premedications before each infusion of Ocrevusto reduce the frequency and severity of IRRs:

In addition, consideration may be given to premedication with an antipyretic (e.g. paracetamol) approximately 30-60 minutes before each infusion of Ocrevus.

• It may produce hypotension, as a symptom of an IRR, during Ocrevus infusions. Therefore, consider discontinuing antihypertensive treatments for 12 hours before and during each Ocrevus infusion. No patients with a history of congestive heart failure (classes III and IV of the New York Heart Association) have been studied.

Instructions for dilution

• The product should be prepared by a healthcare professional using aseptic techniques. Do not agitate the vial.Use sterile needles and syringes to prepare the diluted infusion solution.
• The medicinal product is intended for single use.
• The concentrate may contain fine translucent and/or reflective particles associated with increased opalescence. Do not use the concentrate if it presents a change in colour or if the concentrate contains any foreign particles.
• The medicinal product should be diluted before administration. Infusion solutions are prepared by diluting the concentrate in a 0.9% sodium chloride isotonic infusion solution (300 mg/250 ml or 600 mg/500 ml) to achieve a final concentration of approximately 1.2 mg/ml.?The diluted infusion solution should be administered through a line filter with a pore size of 0.2 or 0.22 microns.
• Before starting the intravenous infusion, the contents of the infusion bag should be at room temperature to avoid a reaction to infusion due to the administration of the solution at low temperatures.

Administration

• After dilution, the treatment is administered as an intravenous infusion through a specific line.
• The infusions should not be administered as a rapid or bolus infusion.

Table 1: Dosage and administration schedule of Ocrevus

Management of IRRs during and after infusion

Patients should be monitored during the infusion and for at least 1 hour after the infusion is completed.

During infusion

• Adjustments to infusion in case of IRRs

In the event of IRRs during infusion, consult the following adjustments.

Life-threatening IRRs

If there are signs of a potentially life-threatening or incapacitating IRR during an infusion, such as acute hypersensitivity or acute respiratory distress syndrome, the infusion should be stopped immediately and the patient should receive appropriate treatment. In these patients, the infusion should be stopped permanently (see section 4.3).

Severe IRRs

If a patient experiences a severe IRR (such as dyspnea) or a combination of symptoms of flushing, fever, and sore throat, the infusion should be stopped immediately and the patient should receive symptomatic treatment. The infusion should only be restarted after the resolution of all symptoms. The initial infusion rate at the time of restarting should be half the infusion rate at the time of the reaction. No adjustment of the infusion is required for subsequent infusions, unless the patient experiences an IRR.

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 infusion rate at the time of the reaction. This reduced rate should be maintained for at least 30 minutes. If tolerated, the infusion rate may be increased according to the patient's initial infusion rate. No adjustment of the infusion is required for subsequent infusions, unless the patient experiences an IRR.

?Patients who experience severe respiratory symptoms, such as bronchospasm or exacerbation of asthma, should stop the infusion immediately and permanently. After administering symptomatic treatment, the patient should be monitored until the respiratory symptoms have resolved, as initial improvement of clinical symptoms may be followed by deterioration.

?Hypersensitivity may be clinically indistinguishable from an IRR in terms of symptoms. If hypersensitivity is suspected during infusion, the infusion should be stopped immediately and permanently.

After infusion

• Patients should be monitored for at least 1 hour after the infusion is completed to detect any possible symptoms of an IRR.
• Healthcare professionals should advise patients that an IRR may occur within 24 hours after infusion.

Shelf-life

Unopened vial

2 years

Diluted infusion solution for intravenous infusion

• Chemical and physical stability has been demonstrated for 24 hours at 2-8°C and subsequently 8 hours at room temperature.
• From a microbiological point of view, the prepared infusion solution should be used immediately. If not used immediately, the storage periods and conditions before use will be the responsibility of the user and, generally, will not exceed 24 hours at 2-8°C and subsequently 8 hours at room temperature, unless the dilution is carried out in controlled and validated aseptic conditions.
• Any unused infusion solution should be discarded.