Columvi

Patient Information Leaflet

Columvi 2.5 mg concentrate for solution for infusion, 10 mg concentrate for solution for infusion

glofitamab
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.
  • Your doctor will give you a patient card. Read it carefully and follow the instructions provided. Always carry this patient card with you.
  • Always show your patient card to your doctor or nurse when you see them, or if you go to hospital.
• If you have any questions, ask your doctor or nurse.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor or nurse. See section 4.

Contents of this leaflet

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

1. What Columvi is and what it is used for

What Columvi is
Columvi is an anticancer medicine that contains the active substance glofitamab.
What Columvi is used for
Columvi is used to treat adults with a cancer called “diffuse large B-cell lymphoma”.
Columvi may be given alone (as monotherapy) or together with other medicines (“chemotherapy”).

• Columvi is given alone when the cancer has come back (relapsed) or has not responded to previous treatments (refractory), and you have received two or more prior therapies.
• Columvi is given together with the medicines gemcitabine and oxaliplatin when the cancer has come back (relapsed) or has not responded to previous treatments (refractory), and when you cannot undergo a stem cell transplant.

Diffuse large B-cell lymphoma is a cancer that affects part of the immune system (the body’s
defences):

• it affects a type of white blood cells called “B cells”
• B cells multiply uncontrollably and accumulate in tissues.

How Columvi works

• The active substance in Columvi, glofitamab, is a bispecific monoclonal antibody, a type of protein that binds to two specific targets in the body. It binds to a specific protein on the surface of B cells, including cancerous B cells, and also to another protein on the surface of “T cells” (another type of white blood cells). In this way, T cells are activated, multiply, and cause the destruction of B cells, including cancerous ones.

2. What you should know before you are given Columvi

Do not be given Columvi if:

• you are allergic to glofitamab or to any of the other ingredients of this medicine (listed in section 6);
• you are allergic to obinutuzumab, another medicine given before starting treatment with Columvi (see also section 3 “How Columvi is administered”), or to any of the other ingredients of this medicine.

If you are unsure whether any of the above situations apply to you, speak to your doctor or nurse before being given Columvi.

Warnings and precautions

Talk to your doctor before being given Columvi if:

• you have an infection;
• you have had a long-term (chronic) infection or an infection that keeps coming back (recurrent);
• you have or have had kidney, liver, or heart problems;
• you are planning to receive a vaccination in the near future.

If any of the above situations apply to you (or if you are unsure), speak to your doctor before being given Columvi.

Be aware of serious side effects.

Some side effects of Columvi are serious and can be life-threatening. These side effects may occur at any time during treatment with Columvi.

Contact your doctor immediately if you experience any of the following side effects during treatment with Columvi. The symptoms of each side effect are listed in section 4.

• Cytokine release syndrome: an exaggerated inflammatory condition associated with medicines that stimulate T cells, characterized by fever and impairment of various organs. Cytokine release syndrome is more likely to occur during Cycle 1 after administration of Columvi (see section 3 “How Columvi is administered”). Close monitoring is required. Before each infusion, you may be given medicines to help reduce the possible side effects of cytokine release syndrome.
• Immune effector cell-associated neurotoxicity syndrome (ICANS): effects on the nervous system. Symptoms include confusion, disorientation, reduced attention, seizures, or difficulty writing and/or speaking. Close monitoring is required.
• Tumour lysis syndrome: during treatment, some people may develop abnormal levels of certain salts in the blood (such as potassium and uric acid), caused by the rapid destruction of cancer cells. Your doctor or nurse will perform blood tests to check for this condition. You must be well hydrated before each infusion, and you may be given medicines to help lower high levels of uric acid. This may help reduce the possible side effects of tumour lysis syndrome.
• Tumour flare reaction: a reaction to certain medicines that act on the immune system that is/was similar to worsening of cancer.
• Infections: signs of infection may occur, which can vary depending on where in the body the infection develops.

If you have or suspect you have any of the above symptoms, inform your doctor immediately.

Your doctor may:

• give you other medicines to reduce symptoms and prevent complications;
• temporarily interrupt your treatment, or
• stop your treatment completely.

Children and adolescents

This medicine must not be given to children and adolescents under 18 years of age, as Columvi has not been studied in this age group.

Other medicines and Columvi

Tell your doctor or nurse if you are taking, have recently taken, or might take any other medicines, including those not requiring a prescription and herbal medicines.

Pregnancy and contraception

• If you are pregnant, think you may be pregnant, or are planning to become pregnant, consult your doctor before taking this medicine.
• If you are pregnant, you must not be given Columvi, as Columvi may harm the unborn baby.
• If you are of childbearing potential, you must use effective contraception during treatment with Columvi and for 2 months after the last dose.
• If you become pregnant during treatment with Columvi, inform your doctor immediately.

Breast-feeding

Do not breast-feed during treatment with Columvi and for at least 2 months after the last dose, as it is not known whether this medicine passes into breast milk and could harm your baby.

Driving and using machines

Columvi may affect your ability to drive, ride a bicycle, or use tools or machinery. Do not drive or use tools or machinery for at least 48 hours after each of the first two doses of Columvi, or if you develop symptoms of immune effector cell-associated neurotoxicity syndrome (ICANS) (such as confusion, disorientation, reduced attention, seizures, or difficulty writing and/or speaking) and/or symptoms of cytokine release syndrome (such as fever, rapid heartbeat, dizziness or mental fogginess, chills, or shortness of breath). If you currently have any of these symptoms, avoid performing these activities and speak to your doctor, nurse, or pharmacist. See section 4 for more information about side effects.

Columvi contains polysorbates

This medicine contains 1.25 mg of polysorbate 20 per 2.5 mL vial and 5 mg of polysorbate 20 per 10 mL vial, equivalent to 0.5 mg/mL. Polysorbates may cause allergic reactions. Inform your doctor if you have known allergies.

3. How Columvi is administered

Columvi will be administered under the supervision of a doctor experienced in anticancer treatments,
at a hospital or clinic.

Medicines administered before treatment with Columvi

• Seven days before starting treatment with Columvi, you will be given another medicine, obinutuzumab, to reduce the number of B cells in your blood.
• 30–60 minutes before administration of Columvi, you may be given other medicines (premedication) to help reduce reactions associated with cytokine release syndrome. These medicines may include:
  • a corticosteroid such as dexamethasone;
  • a medicine to reduce fever such as paracetamol;
  • an antihistamine such as diphenhydramine.

Dose and frequency of administration of Columvi
With Columvi, you may receive up to 12 treatment cycles. Each cycle lasts 21 days. During the first two cycles, your doctor will start treatment with Columvi at a low dose and gradually increase it to the full dose.
A typical schedule is described below.

1st Cycle: includes pre-treatment and 2 low doses of Columvi over 21 days:

• Day 1 – pre-treatment with obinutuzumab
• Day 8 – initial dose of Columvi 2.5 mg
• Day 15 – intermediate dose of Columvi 10 mg

2nd–12th Cycles: one single dose will be administered every 21 days:

• Day 1 – full dose of Columvi 30 mg

How Columvi is administered and monitoring
Columvi is administered intravenously by infusion (intravenous infusion). Your doctor will monitor you throughout all Columvi infusions and adjust the infusion time depending on your response to treatment.

• The first infusion will be given over 4 hours. When Columvi is administered alone, your doctor will monitor you closely during the first infusion and for 10 hours after completion. When Columvi is administered together with the medicines gemcitabine and oxaliplatin, your doctor will monitor you closely during the first infusion and for 4 hours after completion of the infusion, to detect any signs or symptoms of cytokine release syndrome.
• For subsequent infusions, your doctor may need to monitor you after completion of the infusion. This will be necessary if you experienced moderate or severe cytokine release syndrome with the previous dose.
• If you do not experience cytokine release syndrome after 3 doses, your doctor may administer subsequent infusions over 2 hours.

If you miss a dose of Columvi
If you miss an appointment, schedule another one immediately. It is very important not to miss any dose so that the treatment remains fully effective.

Before stopping treatment with Columvi
Talk to your doctor before stopping treatment. Stopping treatment may worsen your condition.

If you have any questions about the use of this medicine, speak with your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Serious side effects
Tell your doctor immediately if you experience any of the following serious side effects listed below,
as urgent medical treatment may be required.

• Cytokine release syndrome (very common): symptoms may include, but are not limited to, fever, rapid heartbeat, dizziness or mental confusion, nausea, headache, rash, confusion, chills, shortness of breath.
• Immune effector cell-associated neurotoxicity syndrome (common): symptoms may include, but are not limited to, confusion, disorientation, reduced attention, seizures, or difficulty writing and/or speaking.
• Infections (very common): symptoms may include, but are not limited to, fever, chills, difficulty breathing, sharp pain during urination.
• Tumour flare symptoms (very common): symptoms may include, but are not limited to, tenderness in enlarged lymph nodes, chest pain, inability to breathe easily, pain at the tumour site.
• Tumour lysis syndrome (common): symptoms may include, but are not limited to, weakness, shortness of breath, confusion, irregular heartbeat, muscle cramps.

Other side effects
Tell your doctor or nurse immediately if you notice the onset or worsening of any of the following side effects:
Columvi used alone
Very common (may affect more than 1 in 10 people)

• in blood tests, decreased levels of:
  • neutrophils (a type of white blood cells; neutropenia), which may cause fever or symptoms of infection
  • red blood cells (anaemia), which may cause tiredness, feeling unwell, and pale skin
  • platelets (a type of blood cell; thrombocytopenia), which may cause bruising or bleeding
• fever
• in blood tests, low levels of phosphate, magnesium, calcium, or potassium
• rash
• constipation
• diarrhoea
• feeling unwell (nausea)
• viral infections, such as lung infection, shingles (herpes zoster)
• headache

Common (may affect up to 1 in 10 people)

• in blood tests, low sodium levels, which may cause tiredness, muscle twitching, or cramps
• in blood tests, increased levels of liver enzymes and bilirubin (a yellow substance in the blood), which may cause yellowing of the skin or eyes and dark-coloured urine
• bacterial infections, such as urinary tract infection, stomach infection
• fungal infection
• infections of nose and throat (upper respiratory tract infections)
• lung infections such as bronchitis or lung infection (lower respiratory tract infections), which may cause fever, cough, and breathing difficulties
• blood infection (sepsis), which may cause fever, chills, and confusion
• in blood tests, low levels of lymphocytes (a type of white blood cells; lymphopenia), which may affect the body’s ability to fight infections
• fever with low neutrophil levels (febrile neutropenia)
• vomiting
• bleeding in the stomach or intestines (gastrointestinal haemorrhage), which may cause black stools or blood in vomit
• confusion
• tremor
• drowsiness

Uncommon (may affect less than 1 in 100 people)

• swelling of the spinal cord (myelitis), which may cause muscle weakness or numbness

Columvi used in combination with anti-cancer medicines
Very common (may affect more than 1 in 10 people)

• in blood tests, decreased levels of:
  • platelets (a type of blood cell; thrombocytopenia), which may cause bruising or bleeding
  • neutrophils (a type of white blood cells; neutropenia), which may cause fever or any symptoms of infection
  • red blood cells (anaemia), which may cause tiredness, feeling unwell, and pale skin
  • lymphocytes (a type of white blood cells; lymphopenia), which may affect the body’s ability to fight infections
• feeling unwell (nausea)
• numbness, tingling, burning sensation, pain, discomfort, weakness, and/or difficulty walking (peripheral neuropathy)
• diarrhoea
• in blood tests, increased levels of liver enzymes
• rash
• fever
• vomiting
• muscle and bone pain
• abdominal pain (stomach pain)
• constipation
• in blood tests, low levels of potassium (hypokalaemia) or sodium (hyponatraemia)
• infection with COVID-19 caused by a virus called coronavirus (SARS-CoV-2)
• lung infection (pulmonary infection) which may cause fever, cough, and difficulty breathing
• respiratory tract infections, such as runny nose, sore throat, sinus infections, and bronchitis

Common (may affect up to 1 in 10 people)

• headache
• in blood tests, low levels of magnesium, calcium, or phosphate
• new or recurring viral infections, such as shingles (herpes zoster) and cytomegalovirus infection
• bacterial infections, such as urinary tract infections
• blood infection (sepsis), which may cause fever, chills, and confusion
• fungal infection
• increased bilirubin levels in the blood, which may cause yellowing of the skin or eyes
• fever with low neutrophil levels (a type of white blood cells)
• inflammation of the large intestine (colitis), which may cause abdominal pain, blood in stools, and urgency to pass stools
• inflammation of the pancreas
• inflammation of the lungs (pneumonia), which may cause cough and difficulty breathing

Uncommon (may affect less than 1 in 100 people)

• tremors
• elevated liver enzymes (shown in blood tests), which may be a sign of liver inflammation
• lung infection (Pneumocystis jirovecii pneumonia)

If you notice the onset or worsening of any of the side effects listed above, inform your doctor immediately.
Reporting of side effects
If you get any side effects, including those not listed in this leaflet, talk to 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 Columvi

It is the responsibility of the doctor, pharmacist, or nurse to store this medicinal product properly and to ensure the safe disposal of unused product. The following information is intended for healthcare professionals:

• Keep this medicinal product out of the sight and reach of children.
• Do not use this medicinal product after the expiry date stated on the outer packaging and on the vial label following Scad./EXP. The expiry date refers to the last day of that month.
• Store in a refrigerator (2-8 °C).
• Do not freeze.
• Keep the vial in the outer packaging to protect the medicinal product from light.
• Do not use this medicinal product if it appears cloudy, shows changes in colour, or contains particles.

Any unused medicinal product and waste materials derived from this medicinal product must be disposed of in accordance with local regulations.

6. Package contents and other information

What Columvi contains

• The active substance is glofitamab.
• Columvi 2.5 mg: each vial contains 2.5 milligrams of glofitamab (in 2.5 mL of concentrate), at a concentration of 1 mg/mL.
• Columvi 10 mg: each vial contains 10 milligrams of glofitamab (in 10 mL of concentrate), at a concentration of 1 mg/mL.
• The other components are: L-histidine, L-histidine monohydrochloride monohydrate, L-methionine, sucrose, polysorbate 20 (E432), and water for injections (see section 2, “Columvi contains polysorbates”).

Description of the appearance of Columvi and contents of the pack
Columvi concentrate for solution for infusion (sterile concentrate) is a clear, colourless solution contained in a glass vial.
Each pack of Columvi contains one vial.

Marketing Authorisation Holder
Roche Registration GmbH
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

Manufacturer
Roche Pharma AG
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

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

België/Belgique/Belgien Latvija
Luxembourg/Luxemburg Roche Latvija SIA
N.V. Roche S.A. Tel: +371 - 6 7039831
België/Belgique/Belgien
Tél/Tel: +32 (0) 2 525 82 11

България Lietuva
Рош България ЕООД UAB “Roche Lietuva”
Тел: +359 2 474 5444 Tel: +370 5 2546799

Česká republika Magyarország
Roche s. r. o. Roche (Magyarország) Kft.
Tel: +420 - 2 20382111 Tel: +36 - 1 279 4500

Danmark Nederland
Roche Pharmaceuticals A/S Roche Nederland B.V.
Tlf: +45 - 36 39 99 99 Tel: +31 (0) 348 438050

Deutschland Norge
Roche Pharma AG Roche Norge AS
Tel: +49 (0) 7624 140 Tlf: +47 - 22 78 90 00

Eesti Österreich
Roche Eesti OÜ Roche Austria GmbH
Tel: + 372 - 6 177 380 Tel: +43 (0) 1 27739

Ελλάδα, Κύπρος Polska
Roche (Hellas) A.E. Roche Polska Sp.z o.o.
Ελλάδα Tel: +48 - 22 345 18 88
Τηλ: +30 210 61 66 100

España Portugal
Roche Farma S.A. Roche Farmacêutica Química, Lda
Tel: +34 - 91 324 81 00 Tel: +351 - 21 425 70 00

France România
Roche Roche România S.R.L.
Tél: +33 (0) 1 47 61 40 00 Tel: +40 21 206 47 01

Hrvatska Slovenija
Roche d.o.o. Roche farmacevtska družba d.o.o.
Tel: +385 1 4722 333 Tel: +386 - 1 360 26 00

Ireland, Malta Slovenská republika
Roche Products (Ireland) Ltd. Roche Slovensko, s.r.o.
Ireland, L-Irlanda Tel: +421 - 2 52638201
Tel: +353 (0) 1 469 0700

Ísland Suomi/Finland
Roche Pharmaceuticals A/S Roche Oy
c/o Icepharma hf Puh/Tel: +358 (0) 10 554 500
Sími: +354 540 8000

Italia Sverige
Roche S.p.A. Roche AB
Tel: +39 - 039 2471 Tel: +46 (0) 8 726 1200

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:

The diluted solution of Columvi may be administered using an intravenous infusion bag or
an intravenous infusion syringe.
Columvi must be administered via intravenous infusion through a dedicated infusion line.
It must not be administered as an intravenous bolus or push.
For instructions on dilution of Columvi prior to administration, see below.
Dilution instructions

• Columvi is preservative-free and for single use only.
• Columvi must be diluted by a healthcare professional under aseptic conditions prior to intravenous administration.
• Do not shake the vial. Before administration, visually inspect the Columvi vial to ensure there are no particles or discoloration. Columvi is a clear, colourless solution. Discard the vial if the solution is cloudy, discoloured, or contains visible particles.
• Using a sterile needle and syringe, withdraw from the infusion bag the appropriate volume of 9 mg/mL (0.9%) sodium chloride injection or 4.5 mg/mL (0.45%) sodium chloride injection as described in Table 1, and discard it.
• Using a sterile needle and syringe, withdraw from the vial the volume of concentrated Columvi required for the intended dose and dilute it in the infusion bag (see Table 1). Discard any unused portion remaining in the vial.
• After dilution, the final concentration of glofitamab must be between 0.1 mg/mL and 0.6 mg/mL.
• To mix the solution, gently invert the infusion bag to avoid excessive foaming. Do not shake.
• Inspect the infusion bag to ensure there are no particles. If particles are present, discard the bag.
• Prior to starting the intravenous infusion, the contents of the infusion bag must be at room temperature (25 °C).
• When administering Columvi using an infusion syringe, withdraw the entire contents of the infusion bag into a syringe. Alternatively, for preparing the dose for a syringe pump, a two-syringe method may be used with a connector.

Table 1. Dilution of Columvi for infusion

Administration
Administer only by intravenous infusion.
Do not administer by intravenous push or bolus.
Administer by intravenous infusion through a dedicated infusion line using an intravenous infusion bag or intravenous infusion syringe, both with the use of a pump, for up to 8 hours.
The infusion bag or syringe of Columvi may empty before the recommended infusion duration is reached. To ensure the entire dose of Columvi is administered, flush the infusion line by replacing the empty Columvi infusion bag or syringe with an infusion bag or syringe containing 9 mg/mL (0.9%) sodium chloride injection solution or 4.5 mg/mL (0.45%) sodium chloride injection solution connected to the same infusion line.
Continue the infusion at the same rate until the recommended infusion duration is completed.

Incompatibilities
Only 9 mg/mL (0.9%) or 4.5 mg/mL (0.45%) sodium chloride injection solution should be used to dilute Columvi, as other solvents have not been tested.
When diluted with 9 mg/mL (0.9%) sodium chloride injection solution, Columvi is compatible with intravenous infusion bags made of polyvinyl chloride (PVC), polyethylene (PE), polypropylene (PP), or non-PVC polyolefin. When diluted with 4.5 mg/mL (0.45%) sodium chloride injection solution, Columvi is compatible with PVC intravenous infusion bags.
Columvi is compatible with polypropylene (PP) syringes when diluted with 9 mg/mL (0.9%) or 4.5 mg/mL (0.45%) sodium chloride injection solution.
No incompatibilities have been observed with administration sets having product-contact surfaces made of polyurethane (PUR), PVC, PE, polybutadiene (PBD), polyether-urethane (PEU), polycarbonate (PC), silicone, polytetrafluoroethylene (PTFE), or acrylonitrile-butadiene-styrene (ABS), and with in-line filters having a membrane made of polyethersulfone (PES) or polysulfone. The use of in-line filters with a membrane is optional.

Diluted solution for intravenous infusion
Chemical and physical stability after dilution has been demonstrated for up to 72 hours at 2–8 °C and 24 hours at 30 °C, followed by a maximum infusion time of 8 hours.
From a microbiological standpoint, the diluted solution should be used immediately. If not used immediately, the storage times and conditions after dilution prior to use are the responsibility of the user and normally should not exceed 24 hours at 2–8 °C, unless dilution occurs under controlled and validated aseptic conditions.

Disposal
The Columvi vial is for single use only.
Unused medicine or waste material derived from this medicine must be disposed of in accordance with local regulations.