Polivy

Patient Information Leaflet: Information for the Patient

Polivy 30 mg powder for concentrate for solution for infusion, 140 mg powder for concentrate for solution for infusion

polatuzumab vedotin
Please read this leaflet carefully before you are given this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• 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 Polivy is and what it is used for
2. What you need to know before you are given Polivy
3. How Polivy is administered
4. Possible side effects
5. How to store Polivy
6. Contents of the pack and other information

1. What Polivy is and what it is used for

What Polivy is
Polivy is an antitumour medicine that contains the active substance "polatuzumab vedotin".
Polivy is always used in combination with other antitumour medicines (see section "Which other medicines is Polivy administered with").

What Polivy is used for
Polivy is given to treat patients with "diffuse large B-cell lymphoma" who have never previously received any therapy.
Polivy is also given to treat patients with "diffuse large B-cell lymphoma" who have relapsed or have not improved:

• after at least one prior therapy, and
• when the patient cannot undergo stem cell transplantation.

"Diffuse large B-cell lymphoma" is a malignant tumour arising from "B-lymphocytes", also known as B-cells, which are a type of blood cell.

How Polivy works
Polivy contains a "monoclonal antibody" and a substance capable of suppressing tumour cells called "monomethyl auristatin" or "MMAE".

• The "monoclonal antibody" component of the medicine binds to a target present on B-cells.
• After binding to the B-cells, the medicine releases "MMAE" into the B-cells and destroys them.

Which other medicines is Polivy administered with
Polivy is administered in combination with other antitumour medicines:

• rituximab, cyclophosphamide, doxorubicin, and prednisone for "diffuse large B-cell lymphoma" that has never been treated before;
• rituximab and bendamustine for "diffuse large B-cell lymphoma" that has relapsed or has not improved after at least one prior therapy and when the patient cannot undergo stem cell transplantation.

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

Do not be given Polivy

• if you are allergic to polatuzumab vedotin or to any of the other ingredients of this medicine (listed in section 6);
• if you currently have a severe active infection.

If any of the above situations apply to you, Polivy must not be administered to you. If you have any doubts, consult your doctor or nurse before receiving Polivy.

Warnings and precautions

Talk to your doctor or nurse before receiving Polivy if any of the following apply to you (or if you have any doubts):

• in the past you have had brain or nerve problems such as:
  • memory problems
  • movement or sensation problems in the body such as tingling, burning, pain, and discomfort
  • vision problems
• in the past you have had liver problems
• you suspect you have an infection or have had persistent or repeated infections such as herpes (see “Infections” in section 4)
• you need to receive a vaccination or know that you might need one in the near future.

If any of the above situations apply to you (or if you have any doubts), talk to your doctor or nurse before receiving Polivy.

Pay attention to the following side effects

Polivy can cause some serious side effects that must be reported immediately to your doctor or nurse, including:

Myelosuppression

Myelosuppression is a condition in which the production of blood cells is reduced, resulting in lower numbers of red blood cells, white blood cells, and platelets. Your doctor will perform blood tests to monitor your blood cell counts.

Tell your doctor or nurse immediately if you experience:

• chills or shivering
• fever
• headache
• fatigue
• dizziness
• paleness
• unusual bleeding, bruising under the skin, prolonged bleeding after a blood draw, or bleeding from the gums.

Peripheral neuropathy

Tell your doctor or nurse immediately if you experience problems related to altered skin sensation, especially in the hands or feet, such as:

• numbness
• tingling
• burning sensation
• pain
• discomfort or weakness
• difficulty walking.

If you had any of these symptoms before starting treatment with Polivy, tell your doctor immediately if you notice any changes in them.

If you develop symptoms of peripheral neuropathy, your doctor may reduce your dose.

Infections

Signs and symptoms of infection vary from person to person. Tell your doctor or nurse immediately if you develop symptoms of infection such as:

• fever
• cough
• chest pain
• fatigue
• painful rash
• sore throat
• sharp pain while urinating
• feeling weak or generally unwell.

Progressive multifocal leukoencephalopathy (PML)

PML is a very rare and potentially fatal brain infection that has occurred in a patient treated with Polivy in combination with bendamustine and another medicine known as obinutuzumab.

Tell your doctor or nurse immediately if you experience:

• memory loss
• problems speaking
• difficulty walking
• vision problems.

If you had any of these symptoms before starting treatment with Polivy, tell your doctor immediately if you notice any changes in them. Medical treatment may be required.

Tumour lysis syndrome

Some people may have an unusual increase in certain substances in the blood (such as potassium and uric acid) due to the rapid breakdown of tumour cells during treatment. This condition is known as "tumour lysis syndrome". Your doctor, pharmacist, or nurse will perform blood tests to monitor for this condition.

Infusion-related reactions

Infusion-related reactions, including allergic or anaphylactic reactions (anaphylactic reactions are more severe allergic reactions), may occur. Your doctor or nurse will monitor you for any side effects during the infusion and for the following 30–90 minutes. If you have a severe reaction, your doctor may stop treatment with Polivy.

Liver damage

This medicine may cause inflammation or damage to liver cells, affecting normal liver function. Damaged liver cells may release certain substances (liver enzymes and bilirubin) into the blood in increased amounts, which can be detected by blood tests.

In most cases, you will not have any symptoms. However, tell your doctor or nurse immediately if you experience:

• yellowing of the skin or the whites of the eyes (jaundice).

Before treatment and regularly during treatment, your doctor will perform blood tests to check your liver function.

Skin and tissue damage due to extravasation

Extravasation means that Polivy has leaked out of the vein into the surrounding tissues at the infusion site.

Tell your doctor or nurse immediately if you feel burning, pain, or tenderness at or around the infusion site during the infusion. If Polivy leaks out of the blood vessel, redness, pain, skin discoloration, swelling, blisters, peeling, or infection of the deeper layers of the skin (cellulitis) may occur at or around the infusion site, within hours or weeks after the infusion.

Children and adolescents

This medicine must not be used in children or young people under 18 years of age, as there is no information on its use in this age group.

Other medicines and Polivy

Other medicines and vaccines

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.

Also tell your doctor or nurse if you need to receive a vaccination or know that you might need one in the near future.

Contraception (women and men)

If you are a woman of childbearing age, you must use effective contraception during treatment and for 9 months after the last dose of Polivy.

Men must use contraception during treatment and for 6 months after the last dose of Polivy.

Pregnancy

Before and during treatment, it is important that you inform your doctor if you are pregnant, suspect you are pregnant, or are planning a pregnancy. Polivy may affect the health of the unborn child.

Do not use this medicine during pregnancy unless you and your doctor decide that the benefit outweighs the possible risk to the unborn child.

Breast-feeding

Do not breast-feed during treatment with Polivy and for at least 3 months after the last dose, as a small amount of Polivy may pass into breast milk.

Fertility

Men are advised to consider sperm banking before starting treatment with this medicine.

Driving and using machines

Polivy has a minor influence on the ability to drive, ride a bicycle, or operate tools or machinery.

• If you experience infusion-related reactions, nerve damage, or symptoms such as fatigue, weakness, or dizziness (see section 4), do not drive, ride a bicycle, or use tools or machinery until your symptoms resolve.

See section 4 for more information about side effects.

Polivy contains sodium

This medicine contains less than 1 mmol of sodium (23 mg) per dose, i.e., essentially “sodium-free”.

Polivy contains polysorbate

Polivy 30 mg contains 1.8 mg of polysorbate 20 per vial. Polivy 140 mg contains 8.4 mg of polysorbate 20 per vial, equivalent to 1.2 mg/mL. Polysorbates may cause allergic reactions. Inform your doctor if you have known allergies.

3. How Polivy is administered

Polivy is administered under the supervision of a physician experienced in the administration of
this type of treatment.
Polivy is given as an intravenous infusion over 90 minutes.

How much Polivy is administered
The dose of this medicine depends on the patient's body weight.

• The usual starting dose is 1.8 mg per kilogram of body weight.
• If peripheral neuropathy occurs, the doctor may reduce the dose.

How often Polivy is administered

• Each cycle lasts 21 days.
• You will receive 6 treatment cycles of Polivy in combination with other medicines.

Which other medicines Polivy is administered with

• Rituximab, cyclophosphamide, doxorubicin, and prednisone for previously untreated "diffuse large B-cell lymphoma".
• Rituximab and bendamustine for "diffuse large B-cell lymphoma" that has relapsed or has not improved after at least one prior therapy, and in patients who are not eligible for stem cell transplantation.

If you miss a dose of Polivy

• If you miss an appointment, schedule a new one as soon as possible.
• It is essential not to miss any doses to ensure the treatment is fully effective.

If you stop treatment with Polivy
Do not stop treatment with Polivy without first talking to your doctor. Stopping treatment may worsen your condition.
If you have any questions about the use of this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them. The following side effects have been reported with this medicine.
Serious side effects
Tell your doctor or nurse immediately if you notice any of the following serious side effects, as urgent medical treatment may be required. These could be new symptoms or changes in existing symptoms:

• infusion-related reactions – your doctor will monitor you to ensure these do not occur within 30–90 minutes after the infusion
• fever and chills
• rash/hives
• serious infections
• pneumonia
• herpes infection
• viral infections
• upper respiratory tract infection
• skin infection
• urinary tract infection
• unusual bleeding or bruising under the skin
• memory loss, problems speaking, difficulty walking, or vision problems
• yellowing of the skin or whites of the eyes (jaundice)
• shortness of breath and difficulty breathing
• leakage of Polivy from the vein into surrounding tissues (also known as extravasation; see section 2. Skin and tissue damage due to extravasation) (uncommon frequency).

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

• pneumonia
• runny nose, sneezing, sore throat, and cough (upper respiratory tract infection)
• numbness, tingling, burning sensation, pain, discomfort, weakness, and/or difficulty walking (peripheral neuropathy)
• fever
• cough
• vomiting
• diarrhoea or constipation
• pain or inflammation of the mucous membranes of the mouth and/or gastrointestinal tract (mucositis)
• nausea
• abdominal (stomach) pain
• feeling tired
• loss of appetite
• weight loss
• infusion-related reactions
• common cold
• hair loss
• changes seen in blood tests:
  • low levels of all types of white blood cells (combined)
  • low levels of neutrophils (a type of white blood cell), with or without fever
  • low levels of platelets (a type of blood cell that helps blood to clot)
  • low levels of red blood cells (anaemia)
  • low levels of potassium in the blood (hypokalaemia)

Common (may affect up to 1 in 10 people)

• serious infection (sepsis)
• urinary tract infection
• viral infections
• herpes infection
• skin infections
• lung inflammation
• shortness of breath and difficulty breathing
• dizziness
• fluid retention causing swelling of the hands or lower legs (peripheral oedema)
• high levels of transaminases in the blood
• joint pain
• itching
• chills
• rash
• dry skin
• muscle pain
• changes seen in blood tests:
  • reduced number of all blood cells (pancytopenia)
  • low levels of lymphocytes (a type of white blood cell)
  • low levels of phosphate in the blood (hypophosphataemia)
  • low levels of calcium in the blood (hypocalcaemia)
  • low levels of albumin in the blood (hypoalbuminaemia)
  • high levels of the enzyme lipase in the blood

Uncommon (may affect up to 1 in 100 people)

• blurred vision

Tell your doctor or nurse immediately if you notice any of the above side effects.
Reporting of side effects
If you get any side effects, including ones not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly through 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 Polivy

Polivy will be stored by healthcare professionals at the hospital or clinic. The following information refers to storage:

• keep this medicine out of the sight and reach of children
• do not use this medicine after the expiry date stated on the carton and vial after “Exp./EXP”. The expiry date refers to the last day of that month
• store in a refrigerator (2°C - 8°C)
• do not freeze
• keep the vial in the outer packaging to protect from light.

Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What Polivy contains

• The active substance is polatuzumab vedotin.
• Polivy 30 mg: each vial contains 30 milligrams (mg) of polatuzumab vedotin.
• Polivy 140 mg: each vial contains 140 milligrams (mg) of polatuzumab vedotin.
• After reconstitution, each millilitre (mL) contains 20 mg of polatuzumab vedotin.
• The other components are: succinic acid, sodium hydroxide, sucrose, polysorbate 20. See section 2 “Polivy contains sodium and polysorbate”.

Description of the appearance of Polivy and package contents
Polivy powder for concentrate for solution for infusion is a white to off-white lyophilised powder supplied in a glass vial.
Each Polivy pack consists of 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, Kύπρος 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 European Medicines Agency website: https://www.ema.europa.eu/ .

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The following information is intended for healthcare professionals only:

Appropriate procedures for the handling and disposal of anticancer medicinal products must be followed.

Reconstitution instructions

• Polivy 30 mg: Using a sterile syringe, slowly inject 1.8 mL of Water for Injections into the 30 mg Polivy vial to obtain a single-dose solution containing 20 mg/mL of polatuzumab vedotin. Direct the stream toward the vial wall, not directly onto the lyophilized powder.
• Polivy 140 mg: Using a sterile syringe, slowly inject 7.2 mL of Water for Injections into the 140 mg Polivy vial to obtain a single-dose solution containing 20 mg/mL of polatuzumab vedotin. Direct the stream toward the vial wall, not directly onto the lyophilized powder.
• Gently rotate the vial until complete dissolution is achieved. Do not shake.
• Inspect the reconstituted solution for discoloration and presence of particles. The reconstituted solution should be colorless to brownish, clear to slightly opalescent, and free of visible particles. Do not use the reconstituted solution if discoloration, cloudiness, or visible particles are present.

Dilution instructions

1. Polivy must be diluted to a final concentration of 0.72–2.7 mg/mL in an intravenous infusion bag with a minimum volume of 50 mL containing either 9 mg/mL sodium chloride solution for injection, 4.5 mg/mL sodium chloride solution for injection, or 5% glucose solution.
2. Determine the required volume of the 20 mg/mL reconstituted solution based on the prescribed dose (see below).
3. Using a sterile syringe, withdraw the required volume of reconstituted solution from the Polivy vial and transfer it into the infusion bag. Any residual solution remaining in the vial should be discarded.
4. Gently mix the contents of the infusion bag by slowly inverting it. Do not shake.
5. Inspect the infusion bag for the presence of particles. If particles are observed, discard the bag.

Reconstituted solution
From a microbiological standpoint, the reconstituted solution should be used immediately. If not used immediately, storage duration and conditions prior to use are under the responsibility of the user and normally should not exceed 24 hours under refrigerated conditions (2–8 °C), unless reconstitution was performed under controlled and validated aseptic conditions. Chemical and physical in-use stability of the reconstituted solution has been demonstrated for up to 72 hours under refrigeration (2–8 °C) and up to 24 hours at room temperature (9–25 °C).

Diluted solution
From a microbiological standpoint, the prepared infusion solution should be used immediately. If not used immediately, storage duration and conditions prior to use are under the responsibility of the user and normally should not exceed 24 hours under refrigerated conditions (2–8 °C), unless dilution was performed under controlled and validated aseptic conditions. Chemical and physical stability of the prepared infusion solution has been demonstrated for the storage periods indicated in Table 1. If storage times exceed the limits specified in Table 1, the diluted Polivy solution must be discarded.

Table 1 Storage periods for which chemical and physical stability of the prepared infusion solution has been demonstrated

To ensure product stability, do not exceed the specified storage periods.
ANNEX IV
SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS
OF THE MARKETING AUTHORISATION
Scientific conclusions
Taking into account the assessment by the Pharmacovigilance and Risk Assessment Committee
(PRAC) of the Periodic Safety Update Report (PSUR) for polatuzumab vedotin, the scientific conclusions of the PRAC are as follows:
In light of available data on risks emerging from clinical studies, spontaneous reports and literature, including four cases with a close temporal relationship, and considering a plausible mechanism of action, the PRAC considers that a causal relationship between polatuzumab vedotin and the adverse reaction
`extravasation injury´ is at least a reasonable possibility. The PRAC concluded that the product information for medicinal products containing polatuzumab vedotin should therefore be amended accordingly.
Having reviewed the PRAC recommendation, the Committee for Human Medicinal Products (CHMP) agrees with the respective general conclusions and the rationale of the recommendation.
Grounds for the variation to the terms of the marketing authorisation
Based on the scientific conclusions on polatuzumab vedotin, the CHMP considers that the benefit-risk balance of the medicinal product containing polatuzumab vedotin remains unchanged, subject to the proposed amendments to the product information.
The CHMP recommends a variation to the terms of the marketing authorisation.