Briumvi

Patient Information Leaflet

Briumvi 150 mg concentrate for solution for infusion

ublituximab

This medicinal product is subject to additional monitoring. This will allow for rapid identification of new safety information. You can help by reporting any side effects you experience while taking this medicine. See the end of section 4 for information on how to report side effects.
Please read this leaflet carefully before you are given this medicine, as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor or nurse. See section 4.

Contents of this leaflet

1. What Briumvi is and what it is used for
2. What you need to know before you are given Briumvi
3. How Briumvi is administered
4. Possible side effects
5. How to store Briumvi
6. Contents of the pack and other information

1. What Briumvi is and what it is used for

What Briumvi is
Briumvi contains the active substance ublituximab, a type of protein called a monoclonal antibody.
Antibodies work by binding to specific targets in the body.

What Briumvi is used for
Briumvi is used to treat adult patients with relapsing forms of multiple sclerosis (RMS), in which the patient experiences relapses (flare-ups) followed by periods with milder symptoms or no symptoms.

What is multiple sclerosis
Multiple sclerosis (MS) affects the central nervous system, particularly the nerves in the brain and spinal cord. In MS, certain white blood cells in the blood called B-cells, which are part of the immune system (the body's defense system), do not function properly and attack the protective layer (the so-called myelin sheath) surrounding nerve cells, causing damage and inflammation. The destruction of the myelin sheath prevents nerves from functioning properly and causes the symptoms of MS. MS symptoms depend on the part of the central nervous system affected and may include problems with balance and walking, muscle weakness, numbness, double vision, blurred vision, poor coordination, and bladder problems.

In relapsing forms of MS, patients experience repeated attacks of symptoms (relapses), which may occur suddenly within a few hours or gradually over several days. Between relapses, symptoms disappear or improve, but damage can accumulate and lead to permanent disability.

How Briumvi works
Briumvi works by binding to a target on the surface of B-cells called CD20. B-cells are a type of white blood cell that are part of the immune system. In multiple sclerosis, the immune system attacks the protective layer surrounding nerve cells. B-cells are involved in this process. Briumvi targets and eliminates B-cells, thereby reducing the likelihood of relapse, relieving symptoms, and slowing the progression of the disease.

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

You must not be given Briumvi:

• if you are allergic to ublituximab or to any of the other ingredients of this medicine (listed in section 6),
• if you have a serious infection,
• if you have been told you have severe problems with your immune system, or
• if you have a tumour.

If you are unsure, consult your doctor before being given Briumvi.
Warnings and precautions
Consult your doctor before you are given Briumvi if any of the following conditions apply to you. Your doctor may decide to delay treatment with Briumvi, or determine that you should not receive Briumvi if:

• you have an infection. Your doctor will wait until the infection has resolved before administering Briumvi;
• you have previously had hepatitis B or are a carrier of the hepatitis B virus. This is because medicines like Briumvi can cause reactivation of the hepatitis B virus. Before treatment with Briumvi, your doctor will check that you are not at risk of developing hepatitis B infection. Patients who have had hepatitis B or are carriers of the hepatitis B virus will have blood tests and will be monitored by the doctor for any signs of hepatitis B infection;
• you have recently received any vaccine or may receive a vaccine in the near future;
• you have a tumour or have had one in the past. Your doctor may decide to delay treatment.

Infusion-related reactions

• Infusion-related reactions are the most common side effect of treatment with Briumvi. These are allergic reactions that develop while the medicine is being administered or shortly afterwards. These reactions can be serious.
• Symptoms of an infusion-related reaction may include:
  • skin itching
  • hives
  • redness of the face or skin
  • throat irritation
  • difficulty breathing
  • swelling of the tongue or throat
  • wheezing
• chills
• fever
• headache
• dizziness
• feeling faint
• nausea
• abdominal pain (stomach ache)
• rapid heartbeat.
  • Inform your doctor or nurse immediately if you have or suspect you are having an infusion-related reaction. Infusion-related reactions can occur during or up to 24 hours after the infusion.
  • To reduce the risk of infusion-related reactions, your doctor will administer other medicines before each Briumvi infusion (see section 3) and will closely monitor you during the infusion.
  • In case of an infusion-related reaction, it may be necessary to interrupt or slow down the infusion rate.

Infections

• Consult your doctor before you are given Briumvi if you have or suspect you have an infection. Your doctor will wait until the infection has resolved before administering Briumvi.
• If you are given Briumvi, you may be more likely to develop infections, because the immune cells targeted by Briumvi also help fight infections.
• Inform your doctor or nurse immediately if you develop an infection or notice any of the following signs of infection during or after treatment with Briumvi:
  • fever or chills
  • persistent cough
  • herpes (e.g. cold sores, shingles or genital herpes)
• Inform your doctor or nurse immediately if you think your MS is worsening or if you notice new symptoms, as there is a very rare but potentially fatal brain infection called “progressive multifocal leukoencephalopathy” (PML) that can cause symptoms similar to those of MS. PML can occur in patients taking medicines like Briumvi and other medicines used to treat MS.
• Inform your partner or caregiver about your treatment with Briumvi, as they may notice symptoms of PML that you might not be aware of, such as memory lapses, difficulty thinking, difficulty walking, loss of vision, or changes in speech, which your doctor may need to investigate.

Vaccinations

• Inform your doctor if you have recently received any vaccine or if you may receive a vaccine in the near future.
• Your doctor will check whether you need any vaccinations before starting treatment with Briumvi. Any vaccinations with live or live-attenuated vaccines must be administered at least 4 weeks before starting treatment with Briumvi. During treatment with Briumvi, live or live-attenuated vaccines must not be given until your doctor confirms that your immune system is no longer weakened.
• Any vaccinations with inactivated vaccines should be administered at least 2 weeks before starting treatment with Briumvi, when possible. If you wish to be vaccinated with inactivated vaccines during treatment with Briumvi, consult your doctor.

Children and adolescents
Briumvi is not intended for use in children and adolescents under 18 years of age, as it has not yet been studied in this age group.
Other medicines and Briumvi
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. In particular, inform your doctor:

• if you are taking, have recently taken, or might take medicines that affect the immune system, such as chemotherapy, immunosuppressants (except corticosteroids), or other medicines used to treat MS, as they may have an additive effect on the immune system;
• if you plan to receive vaccinations (see above section “Warnings and precautions”).

If any of these conditions apply to you (or if you are unsure), consult your doctor before you are given Briumvi.
Pregnancy and breastfeeding

• If you are pregnant, suspect you may be pregnant, or are planning a pregnancy, inform your doctor before you are given Briumvi. This is because Briumvi can cross the placenta and affect the baby.
• If you are pregnant, do not use Briumvi unless you have discussed it with your doctor. Your doctor will assess the benefit of treatment with Briumvi for you against the risk to the baby.
• If you have had a child after receiving Briumvi during pregnancy, it is important to inform the paediatrician so they can advise you on when your child can be vaccinated.
• It is not known whether Briumvi passes into breast milk. Consult your doctor to determine the best way to feed your baby if you are using Briumvi.

Contraception in women
If you are able to become pregnant (i.e. fertile), you must use contraceptive measures:

• during treatment with Briumvi and
• for at least 4 months after the last infusion of Briumvi.

Driving and using machines
It is unlikely that Briumvi will affect your ability to drive or use machines.
Briumvi contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per dose, i.e. it is essentially ‘sodium-free’.

3. How Briumvi is administered

Briumvi will be administered to you by a doctor or a nurse experienced in the use of this treatment, who will closely monitor you during the administration of the medicine in case you experience any adverse reactions. Briumvi will always be given as an intravenous infusion (through a drip into a vein).

Medicines administered before treatment with Briumvi
Before receiving Briumvi, you will be given other medicines to prevent or reduce possible side effects, such as infusion-related reactions (for information on infusion-related reactions, see sections 2 and 4).
Before each infusion, you will receive a corticosteroid and an antihistamine, and you may also receive medicines to reduce fever.

What doses and how often Briumvi will be administered

• The first dose of Briumvi will be 150 mg. This infusion will last 4 hours.
• The second dose of Briumvi will be 450 mg and will be given 2 weeks after the first dose. This infusion will last 1 hour.
• Subsequent doses of Briumvi will be 450 mg, administered 24 weeks after the first dose and then every 24 weeks thereafter. These infusions will last 1 hour.

How Briumvi is administered

• Briumvi will be administered to you by a doctor or nurse. Before administration, Briumvi must be diluted. This dilution will be performed by a healthcare professional. The medicine will be given to you by intravenous infusion (through a drip into a vein).
• You will be closely monitored during the Briumvi infusion and for at least 1 hour after the first two infusions, in case you experience any adverse reactions, such as infusion-related reactions. If an infusion-related reaction occurs, the infusion may be slowed down, temporarily paused, or permanently stopped depending on the severity (for information on infusion-related reactions, see sections 2 and 4).

If you miss an infusion of Briumvi

• If you miss an infusion of Briumvi, contact your doctor to reschedule it as soon as possible. Do not wait until your next scheduled infusion.
• To get the full benefit from Briumvi, it is important that you receive each infusion at the scheduled time.

If you stop treatment with Briumvi

• It is important that you continue treatment for as long as you and your doctor consider it beneficial for you.
• Some side effects may be related to low levels of B cells. These side effects may continue to occur even after stopping treatment with Briumvi, until B cell levels return to normal.
• Before starting any other medicine, inform your doctor about the date of your last Briumvi infusion.

If you have any questions about the use of this medicine, consult your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following side effects have been reported for Briumvi:

Serious side effects

Infusion-related reactions

• Infusion-related reactions are the most common side effect of treatment with Briumvi (very common: may affect more than 1 in 10 people). In most cases, these are mild reactions, but serious reactions can also occur.

• Immediately inform your doctor or nurse if you experience any signs or symptoms of an infusion-related reaction during or up to 24 hours after the infusion. Symptoms may include, but are not limited to:

  • skin itching
  • hives
  • facial or skin redness
  • throat irritation
  • difficulty breathing
  • swelling of the tongue or throat
  • wheezing
  • chills
  • fever
  • headache
  • dizziness
  • feeling faint
  • nausea
  • abdominal pain (stomach ache)
  • rapid heartbeat

• If you experience an infusion-related reaction, you will be given medicines to treat it, and it may be necessary to slow down or stop the infusion. Once the reaction has resolved, the infusion may continue. If the infusion-related reaction is life-threatening, your doctor will permanently discontinue treatment with Briumvi.

Infections

• If you are given Briumvi, you may be more likely to develop infections, some of which may be serious. The following infections have been observed in patients treated with Briumvi for MS:

  • Very common (may affect more than 1 in 10 people)
  • upper respiratory tract infections (infections of the nose and throat)
  • respiratory tract infections
  • Common (may affect up to 1 in 10 people)
  • lower respiratory tract infections (lung infections such as bronchitis or pneumonia)
  • herpes infections (e.g., cold sores or genital herpes)
  • Uncommon (may affect up to 1 in 100 people)
  • infection of the membranes lining the brain and spinal cord (meningitis), infection of the brain (encephalitis), or both (meningoencephalitis)

• Immediately inform your doctor or nurse if you notice any of the following signs of infection:

  • fever or chills
  • persistent cough
  • herpes (e.g., cold sores, shingles, or genital herpes)
  • headache with fever, stiff neck, sensitivity to light, nausea, confusion, seizures, personality changes, lack of coordination (ataxia), altered consciousness and/or coma. These may be symptoms of an infection of the membranes surrounding the brain and spinal cord (meningitis), infection of the brain (encephalitis), or both (meningoencephalitis), which can be fatal.

Your doctor will wait until the infection has resolved before administering Briumvi.

Other side effects

Common (may affect up to 1 in 10 people)

• neutropenia (low levels of neutrophils, a type of white blood cell)
• limb pain (arms or legs)

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, tell your doctor or nurse. You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Briumvi

Store in a refrigerator (2 °C – 8 °C).
Briumvi will be stored by healthcare professionals at the hospital or clinic under the following conditions:

• This medicinal product must not be used after the expiry date stated on the outer carton and on the label of the vial after 'Exp'. The expiry date refers to the last day of that month.
• This medicinal product must be stored in a refrigerator (2 °C – 8 °C). It must not be frozen. The vial should be kept in its outer packaging to protect the medicinal product from light.

It is recommended to use the medicinal product immediately after dilution. If not used immediately, the storage times and conditions prior to use are the responsibility of the healthcare professional and should normally not exceed 24 hours at a temperature of 2 °C to 8 °C, followed by a maximum of 8 hours at room temperature.
Do not dispose of any medicinal product via wastewater. This will help protect the environment.

6. Package contents and other information

What Briumvi contains

• The active substance is ublituximab. Each vial contains 150 mg of ublituximab in 6 mL at a concentration of 25 mg/mL.
• The other components are sodium chloride, sodium citrate, polysorbate 80, hydrochloric acid and water for injections.

Description of the appearance of Briumvi and contents of the pack

• Briumvi is a solution ranging from clear to opalescent, from colourless to slightly yellow.
• It is supplied as a concentrate for solution for infusion.
• This medicinal product is available in packs of 1 or 3 vials (glass vials containing 6 mL of concentrate). Not all pack sizes may be marketed.

Marketing Authorisation Holder
Neuraxpharm Pharmaceuticals, S.L.
Avda. Barcelona 69
08970 Sant Joan Despí - Barcelona
Spain

Manufacturer
Neuraxpharm Pharmaceuticals, S.L.
Avda. Barcelona 69
08970 Sant Joan Despí
Barcelona - Spain

For further information on this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Lietuva
Neuraxpharm Belgium Neuraxpharm Pharmaceuticals, S.L.
Tél/Tel: +32 (0)2 732 56 95 Tel:+34 93 475 96 00

България Luxembourg/Luxemburg
Neuraxpharm Pharmaceuticals, S.L. Neuraxpharm France
Teл.: +34 93 475 96 00 Tél/Tel: +32 474 62 24 24

Česká republika Magyarország
Neuraxpharm Bohemia s.r.o. Neuraxpharm Hungary Kft.
Tel: +420 739 232 258 Tel.: +3630 464 6834

Danmark Malta
Neuraxpharm Sweden AB Neuraxpharm Pharmaceuticals, S.L.
Tlf.: +46 (0)8 30 91 41 Tel.:+34 93 475 96 00
(Sverige)

Deutschland Nederland
neuraxpharm Arzneimittel GmbH Neuraxpharm Netherlands B.V.
Tel: +49 2173 1060 0 Tel.: +31 70 208 5211

Eesti Norge
Neuraxpharm Pharmaceuticals, S.L. Neuraxpharm Sweden AB
Tel: +34 93 475 96 00 Tlf:+46 (0)8 30 91 41
(Sverige)

Ελλάδα Österreich
Brain Therapeutics IKE Neuraxpharm Austria GmbH
Τηλ: +302109931458 Tel.:+ 43 (0) 1 208 07 40

España Polska
Neuraxpharm Spain, S.L.U. Neuraxpharm Polska Sp. z.o.o.
Tel: +34 93 475 96 00 Tel.: +48 783 423 453

France Portugal
Neuraxpharm France Neuraxpharm Portugal, Unipessoal Lda
Tél: +33 1.53.62.42.90 Tel: +351 910 259 536

Hrvatska România
Neuraxpharm Pharmaceuticals, S.L. Neuraxpharm Pharmaceuticals, S.L.
Tel: +34 93 475 96 00 Tel: +34 93 475 96 00

Ireland Slovenija
Neuraxpharm Ireland Ltd Neuraxpharm Pharmaceuticals, S.L.
Tel: +353 (0)1 428 7777 Tel: +34 93 475 96 00

Ísland Slovenská republika
Neuraxpharm Sweden AB Neuraxpharm Slovakia a.s.
Sími: +46 (0)8 30 91 41 Tel: +421 255 425 562
(Svíþjóð)

Italia Suomi/Finland
Neuraxpharm Italy S.p.A. Neuraxpharm Sweden AB
Tel: +39 0736 980619 Puh/Tel: +46 (0)8 30 91 41
(Ruotsi/Sverige)

Κύπρος Sverige
Brain Therapeutics IKE Neuraxpharm Sweden AB
Τηλ: +302109931458 Tel: +46 (0)8 30 91 41

Latvija
Neuraxpharm Pharmaceuticals, S.L.
Tel: +34 93 475 96 00

Other sources of information
More detailed information on this medicinal product is available on the website of the European Medicines Agency, https://www.ema.europa.eu .

The following information is intended exclusively for healthcare professionals:

Refer to the SmPC for further information.
Dosage

• First and second dose

The first dose is administered as an intravenous infusion of 150 mg (first infusion), followed
by an intravenous infusion of 450 mg 2 weeks later (second infusion).

• Subsequent doses

Subsequent doses of Briumvi are administered as a single intravenous infusion of 450 mg
every 24 weeks (Table 1). The first subsequent 450 mg dose should be administered
24 weeks after the first infusion. A minimum interval of 5 months must be maintained
between one dose of Briumvi and the next.
Figure 1: Dose and dosing regimen of Briumvi

First infusion	Second infusion	Subsequent infusions
Day 1	Day 15	Every 6 months

Management of IRR prior to infusion

• Treatment with Briumvi must be initiated and supervised by a healthcare professional experienced in the management of severe reactions, with immediate access to appropriate medical support for severe reactions, such as severe infusion-related reactions (IRRs).
• Premedication for IRRs

The following two premedications must be administered approximately 30–60 minutes before each Briumvi infusion to reduce the frequency and severity of IRRs:

• 100 mg of methylprednisolone or 10–20 mg of dexamethasone (or equivalent);
• diphenhydramine. Additionally, premedication with an antipyretic (e.g., paracetamol) may be considered.

Instructions for dilution

• Briumvi must be prepared by a healthcare professional using aseptic technique. Do not shake the vial.

• The product is for single use only.

• Do not use the solution if it appears discolored or contains foreign particles.

• Briumvi must be diluted prior to administration. Intravenous infusion solutions of Briumvi are prepared by diluting the medicinal product in an infusion bag containing 0.9% isotonic sodium chloride solution. For the first infusion, dilute one vial of the medicinal product in the infusion bag (150 mg/250 mL) to achieve a final concentration of approximately 0.6 mg/mL. For subsequent infusions, dilute three vials of the medicinal product in the infusion bag (450 mg/250 mL) to achieve a final concentration of approximately 1.8 mg/mL.

• Prior to initiating intravenous infusion, the contents of the infusion bag should be at room temperature.

Method of administration

• After dilution, Briumvi is administered by intravenous infusion through a dedicated line.
• Briumvi infusions must not be administered by rapid intravenous injection or bolus.

Table 1: Dose and dosing regimen of Briumvi

The duration of the infusion may be longer if the infusion is interrupted or slowed.
The next infusion must be administered 24 weeks after the first infusion.
Management of IRRs during and after infusion
Patients must be monitored during the infusion and for at least one hour after completion of the first two infusions.
During infusion

• Infusion modifications in case of IRR

In case of IRR during infusion, apply the following modifications.
Potentially life-threatening IRR
If signs of a potentially life-threatening or disabling IRR occur during an infusion, the infusion must be stopped immediately and the patient must receive appropriate treatment. In these patients, Briumvi must be permanently discontinued (see section 4.3).
Severe IRR
If the patient experiences a severe IRR, the infusion must be stopped immediately and the patient must receive symptomatic treatment. The infusion may be resumed only after resolution of all symptoms. Upon resumption, start at an infusion rate equal to half of the rate used when the IRR occurred. If tolerated, the infusion rate may then be increased as indicated in Table 1.
Mild to moderate IRR
If the patient experiences a mild to moderate IRR, the infusion rate must be reduced by half compared to the rate used when the event occurred. This reduced rate must be maintained for at least 30 minutes. If tolerated, the infusion rate may then be increased as indicated in Table 1.
After infusion

• Patients treated with Briumvi must be monitored for at least one hour after completion of the first two infusions to identify any symptoms of IRR.
• Physicians must inform patients that an IRR may occur within 24 hours following the infusion.

Shelf life
Unopened vial
3 years
Diluted solution for intravenous infusion

• Chemical and physical in-use stability has been demonstrated for 24 hours at a temperature of 2 to 8 °C and, subsequently, for 8 hours at room temperature.
• From a microbiological standpoint, the prepared infusion should be used immediately. If not used immediately, the times and conditions of storage prior to use are the responsibility of the user and normally should not exceed 24 hours at a temperature of 2 to 8 °C and, subsequently, 8 hours at room temperature, unless dilution has been carried out under controlled and validated aseptic conditions.
• In cases where the intravenous infusion cannot be completed on the same day, any remaining solution must be discarded.

Annex IV
Scientific conclusions and grounds for the variation of the terms of the marketing authorisation(s)
Scientific conclusions
Taking into account the assessment by the Pharmacovigilance and Risk Assessment Committee (PRAC) of the Periodic Safety Update Report(s) (PSUR) for ublituximab, the scientific conclusions of the PRAC are as follows:
Based on available data on encephalitis/meningitis/meningoencephalitis from clinical trials and spontaneous reports, including a close temporal relationship in seven cases, and on the basis of a plausible mechanism of action, the PRAC considers that a causal relationship between ublituximab and encephalitis/meningitis/meningoencephalitis is at least a reasonable possibility and therefore concludes that the product information for medicinal products containing ublituximab should be updated accordingly.
Having reviewed the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the general conclusions and reasoning of the recommendation.
Grounds for the variation of the terms of the marketing authorisation(s)
Based on the scientific conclusions regarding ublituximab, the CHMP considers that the benefit-risk balance of the medicinal product(s) containing ublituximab remains unchanged, subject to the proposed amendments to the product information.
The CHMP recommends the variation of the terms of the marketing authorisation(s).