Consumer medicine information

Polivy

Polatuzumab vedotin

BRAND INFORMATION

Brand name

Polivy

Active ingredient

Polatuzumab vedotin

Schedule

SUMMARY CMI

Polivy^®

Consumer Medicine Information (CMI) summary

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

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using Polivy?

Polivy contains the active ingredient polatuzumab vedotin. Polivy is used to treat a type of cancer called diffuse large B-cell lymphoma that has never been treated before or when the cancer has come back or has never responded to one or more previous treatments for this type of cancer and when you cannot receive a stem cell transplant.
For more information, see Section 1. Why am I using Polivy? in the full CMI.

2. What should I know before I use Polivy?

Do not use if you have ever had an allergic reaction to polatuzumab vedotin or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Polivy? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Polivy and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How is Polivy given?

Polivy is given by a slow drip into a vein (intravenous (IV) infusion) once every three weeks.

The recommended dose is based on your weight and will be determined by your doctor.

The first infusion will be given over 90 minutes. If the first infusion is well tolerated, your drip time may be shortened to 30 minutes.

More instructions can be found in Section 4. How is Polivy given? in the full CMI.

5. What should I know while using Polivy?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using polatuzumab vedotin. Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects. If you are about to have any blood tests, tell your doctor that you are taking this medicine.
Things you should not do	Do not stop your Polivy treatment without talking to your doctor first. Do not take any other medicines, whether they require a prescription or not, without first telling your doctor or consulting with a pharmacist.
Driving or using machines	Be careful driving or operating machinery until you know how Polivy affects you. Polivy may cause slight light-headedness, tiredness and dizziness in some people. If you experience infusion-related reactions or nerve damage, or if you feel tired, weak or dizzy, do not drive or use machines until symptoms stop.

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

6. Are there any side effects?

Tell your doctor or nurse immediately or seek immediate medical attention if you experience:

Signs or symptoms of a serious allergic reaction such as swelling of the face, lips, tongue, throat or other parts of the body, shortness of breath, wheezing or trouble breathing, wheezing or coughing.
Serious infections or have had long lasting or repeated infections, including any signs or symptoms of fever.

For more information, including what to do if you have any common or serious side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.

FULL CMI

Polivy^®

Active ingredient(s): polatuzumab vedotin

Consumer Medicine Information (CMI)

This leaflet provides important information about using Polivy. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Polivy.

Where to find information in this leaflet:

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

1. Why am I using Polivy?

Polivy contains the active ingredient polatuzumab vedotin. Polivy belongs to a group of medicines known as anti-neoplastic (or anti-cancer) agents. Polivy is made up of two substances:

polatuzumab - a monoclonal antibody which recognises the large B-cell cancer cells
vedotin - an anti-cancer substance

Polivy is used to treat a type of cancer called diffuse large B-cell lymphoma that has never been treated before.

Polivy is used to treat a type of cancer called diffuse large B-cell lymphoma when the cancer has come back or has never responded to one or more previous treatments for this type of cancer and when you cannot receive a stem cell transplant.

Polivy is designed to target and deliver the anti-cancer substance vedotin to the cancer cells to stop the growth and spread of the cancer cells.

2. What should I know before I use Polivy?

Warnings

Do not use Polivy if:

you currently have an active severe infection
you are allergic to polatuzumab vedotin, or any of the ingredients listed at the end of this leaflet.
always check the ingredients to make sure you can use this medicine.

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin

Check with your doctor if you:

you have ever had nerve problems such as numbness, tingling in the hands or feet or eyesight problems
you have ever had liver problems such as hepatitis
you think you may have an infection or have had long lasting or repeated infections

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy

Tell your doctor right away if you become pregnant during treatment with Polivy.

Your doctor will advise you about using effective contraception to avoid becoming pregnant while you are being treated with Polivy and for 9 months after stopping treatment. If you are male, you should also use contraception with a female partner for 6 months after treatment with Polivy.

Discuss any future child bearing plans with your doctor before starting Polivy.

Breastfeeding

Tell your doctor if you are breastfeeding or plan to breastfeed.

It is not known if Polivy passes into your breastmilk.

Do not breastfeed during treatment with Polivy for at least 3 months after the last dose'/treatment.

What other medicines Polivy is given with

Polivy is given in combination other cancer 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 come back or has not got better, after at least one previous therapy - and when you cannot receive a stem cell transplant.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Polivy and affect how it works.

oral antifungal medications, e.g. ketoconazole, itraconazole, voriconazole
some antibiotics used to treat infections e.g. rifampicin

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

4. How is Polivy given?

Follow all directions given to you by your doctor or nurse carefully.

They may differ from the information contained in this leaflet.

Polivy must be prepared by a healthcare professional and will be given in a hospital or clinic by a doctor or nurse.

Polivy is given by a drip into a vein (called an “intravenous infusion” or “IV”).

The recommended dose is based on your weight and will be determined by your doctor.

Polivy is given by a slow drip into a vein (intravenous (IV) infusion) once every three weeks.

The first infusion will be given over 90 minutes. If the first infusion is well tolerated, your drip time may be shortened to 30 minutes.

The number of infusions you will be given depends on how you respond to treatment.

If you miss a dose of Polivy

As Polivy is given under the supervision of your doctor, you are unlikely to miss a dose. However, if you forget or miss your appointment to receive Polivy, make another appointment as soon as possible. Do not wait for your next planned appointment. Your doctor will decide when your next dose of Polivy will be.

If you use too much Polivy

As Polivy is given under the supervision of your doctor it is unlikely that you will be given too much. However, if you experience any side effects after being given Polivy, tell your doctor or nurse immediately.

5. What should I know while using Polivy?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Polivy.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

Tell your doctor if you become pregnant or intend to start a family while receiving Polivy.

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

If you are about to have any blood tests, tell your doctor that you are taking this medicine.

It may interfere with the results of some tests.

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

Things you should not do

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

Driving or using machines

Be careful driving or operating machinery until you know how Polivy affects you.

Polivy may cause slight light-headedness, tiredness and dizziness in some people. If you experience infusion-related reactions or nerve damage, or if you feel tired, weak or dizzy, do not drive or use machines until symptoms stop.

Looking after your medicine

Polivy will be stored in the pharmacy or on the hospital ward in a refrigerator at a temperature between 2°C and 8°C.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Because Polivy is given with other medicines to treat cancer it may be difficult for your doctor to tell whether the side effects are due to Polivy or due to other medicines.

You may experience side effects during an infusion or after an infusion, these can be serious or less serious.

Serious side effects

Serious side effects	What to do
During an infusion: swelling of your face, lips, tongue or throat with difficulty breathing swelling of other parts of your body such as your hands or feet shortness of breath, wheezing or trouble breathing abnormal or irregular heartbeat rash, itching or hives on the skin flushing (warm, red) skin pain or swelling at site of injection feeling sick (nausea) or vomiting, diarrhoea pain or discomfort (including stomach pain, back pain, chest or neck pain) fever or chills	Tell your doctor or nurse immediately if you notice any of the following while receiving an infusion (particularly during the first infusion)
After an infusion: flu and/or cold-like symptoms, chest pain, coughing, sweating fever, sore throat, tiredness, sores in the mouth or gums bruising, bleeding gums or nose, rash on legs with red dots, blood in urine or stools numbness or tingling in the hands or feet, sharp or jabbing pain, burning or freezing sensation, pins and needles difficulty walking weakness, lack of energy, feeling unsteady muscle cramps or spasms, heart palpitations, breathing difficulties, mood changes swelling of the hands or feet, yellow skin or eyes, rapid heartbeat, appetite changes skin infection urinary tract infection upper respiratory tract infection breathlessness and difficulty in breathing changes in blood tests Confusion or memory loss, muscle spasms and cramps, facial twitching, numbness	Tell your doctor straight away if you notice any of the side effects below or if they get worse. They may happen weeks or months after your last dose. Do not try to treat yourself with other medicines.

Less serious side effects

Less serious side effects	What to do
After an infusion: nose bleeds, feeling dizzy, tired, looking pale nausea or vomiting constipation or abdominal pain diarrhoea rash, itching or hives on the skin decreased appetite, weight decrease changes in blood tests dry skin	Speak to your doctor if you have any of these less serious side effects and they worry you.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed above may also occur in some people.

Some side effects can only be found when your doctor does tests from time to time to check your progress. (for example, elevated liver enzymes, low potassium or sodium levels, low platelet count, low blood pressure).

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Polivy contains

Active ingredient
(main ingredient)

polatuzumab vedotin

Other ingredients
(inactive ingredients)

succinic acid

sodium hydroxide

sucrose

polysorbate 20

Potential allergens

This medicine does not contain lactose, gluten, tartrazine or any other azo dyes.

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

What Polivy looks like

Polivy is a white to grey powder which is dissolved in sterile water before use. It is diluted before infusion into a vein. Polivy is supplied as single-dose glass vials containing;

140 mg of active ingredient(AUST R 314866).
30 mg of active ingredient (AUST R 374135)

Who distributes Polivy

Polivy is distributed in Australia by:

Roche Products Pty Limited
ABN 70 000 132 865
Level 8, 30 – 34 Hickson Road
Sydney NSW 2000
AUSTRALIA
Customer enquiries: 1800 233 950
medinfo.roche.com/au/en.html

Please check with your pharmacist for the latest Consumer Medicine Information.

This leaflet was prepared in February 2023.

Published by MIMS April 2023

BRAND INFORMATION

Brand name

Polivy

Active ingredient

Polatuzumab vedotin

Schedule

1 Name of Medicine

Polatuzumab vedotin.

2 Qualitative and Quantitative Composition

Each vial is designed to deliver a total of 30 mg or 140 mg of polatuzumab vedotin.
Polatuzumab vedotin is a CD79b-targeted antibody-drug conjugate that preferentially binds with high affinity and selectivity to CD79b, a cell surface component of the B-cell receptor.
For the full list of excipients, see Section 6.1.

3 Pharmaceutical Form

Powder for concentrate for solution for infusion.
Polivy is a preservative-free white to grayish-white lyophilised powder supplied in single-dose vials that deliver 30 mg or 140 mg of polatuzumab vedotin. Upon reconstitution, Polivy concentrate contains 20 mg/mL of polatuzumab vedotin for intravenous infusion (see Section 4.2 Dose and Method of Administration, Method of administration).

4 Clinical Particulars

4.1 Therapeutic Indications

Polivy in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) is indicated for the treatment of adult patients with previously untreated diffuse large B-cell lymphoma (DLBCL).
Polivy in combination with bendamustine and rituximab is indicated for the treatment of previously treated adult patients with diffuse large B-cell lymphoma who are not candidates for hematopoietic stem cell transplant.

4.2 Dose and Method of Administration

General.

Substitution by any other biological medicinal product requires the consent of the prescribing physician.
In order to prevent medication errors, it is important to check the vial labels to ensure that the drug being prepared and administered is Polivy.
Polivy therapy should only be administered under the supervision of a healthcare professional experienced in the treatment of cancer patients.
Polivy must be reconstituted and diluted using aseptic techniques under the supervision of a healthcare professional. Polivy should be administered as an intravenous infusion through a dedicated infusion line equipped with a sterile, non-pyrogenic, low-protein binding in-line or add-on filter (0.2 or 0.22 micrometer pore size) and catheter (see Section 4.2 Dose and Method of Administration, Method of administration). Do not administer as an IV push or bolus.
For information on rituximab, bendamustine, cyclophosphamide, doxorubicin, or prednisone, refer to their respective full prescribing information. See Table 2 for dose modification recommendations for neutropenia and thrombocytopenia.

Dose.

Diffuse large B-cell lymphoma.

Previously untreated patients.

The recommended dose of Polivy is 1.8 mg/kg given as an intravenous infusion every 21 days for 6 cycles in combination with rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHP). Polivy, rituximab, cyclophosphamide, and doxorubicin can be administered in any order on Day 1 after the administration of prednisone. Prednisone is administered on Days 1-5 of each cycle. Cycles 7 and 8 consist of rituximab as monotherapy.

Previously treated patients.

The recommended dose of Polivy is 1.8 mg/kg given as an intravenous infusion every 21 days in combination with bendamustine and rituximab for 6 cycles. Polivy, bendamustine, and rituximab can be administered in any order on Day 1 of each cycle. The recommended dose of bendamustine is 90 mg/m²/day on Day 1 and 2 when administered with Polivy and rituximab.

Previously untreated and previously treated patients.

An antihistamine and anti-pyretic should be administered to patients prior to administration of Polivy. The initial dose of Polivy should be administered as a 90-minute intravenous infusion. Patients should be monitored for infusion-related reactions during the infusion and for at least 90 minutes following completion of the initial dose. If the prior infusion was well tolerated, the subsequent dose of Polivy may be administered as a 30-minute infusion and patients should be monitored during the infusion and for at least 30 minutes after completion of the infusion.

Duration of treatment.

The recommended duration of treatment is for 6 cycles.

Delayed or missed doses.

If a planned dose of Polivy is missed, it should be administered as soon as possible and the schedule of administration should be adjusted to maintain a 21-day interval between doses.

Dose modifications.

The infusion rate of Polivy should be slowed or interrupted if the patient develops an infusion-related reaction. Discontinue Polivy immediately and permanently if the patient experiences a life-threatening reaction.
There are different potential dose modifications for Polivy in patients with previously untreated and previously treated DLBCL. Polivy dose modifications for events of peripheral neuropathy, infusion-related reactions and myelosuppression are different by indication (see Tables 1-3).
For dose modifications to manage peripheral neuropathy, see Table 1.

For dose modifications to manage myelosuppression, see Table 2.

For dose modifications to manage infusion-related reactions, see Table 3.

Special populations.

Paediatric populations.

The safety and efficacy of Polivy in children and adolescents (< 18 years) has not been established (see Section 5.2, Pharmacokinetics in special populations).

Elderly.

No dose adjustment of Polivy is required in patients ≥ 65 years of age (see Section 5.2, Pharmacokinetics in special populations).

Renal impairment.

No dose adjustment of Polivy is required in patients with creatinine clearance (CrCL) ≥ 30 mL/min. A recommended dose has not been determined for patients with CrCL < 30 mL/min (see Section 5.2, Pharmacokinetics in special populations).

Hepatic impairment.

The administration of Polivy in patients with moderate or severe hepatic impairment (total bilirubin greater than 1.5 x upper limit of normal [ULN]) should be avoided.
No adjustment in the starting dose is required when administering Polivy to patients with mild hepatic impairment (total bilirubin greater than ULN and less than or equal to 1.5 x ULN or aspartate transaminase (AST) greater than ULN) (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2, Pharmacokinetics in special populations).
Per studied population in mild hepatic impairment (defined as AST or ALT > 1.0 to 2.5 x ULN or total bilirubin > 1.0 to 1.5 x ULN), there was a 40% increase in unconjugated monomethyl auristatin E (MMAE) exposure, which was not deemed clinically significant.

Method of administration.

Polivy must be reconstituted using sterile water for injection and diluted into an IV infusion bag containing 0.9% sodium chloride, 0.45% sodium chloride, or 5% dextrose by a healthcare professional prior to administration.
Use aseptic technique for reconstitution and dilution of Polivy. Appropriate procedures for the preparation of antineoplastic products should be used.
The reconstituted product contains no preservative and is intended for single-dose usage only. Discard any unused portion.
A dedicated infusion line equipped with a sterile, non-pyrogenic, low-protein binding in-line or add-on filter (0.2 or 0.22 micrometer pore size) and catheter must be used to administer diluted Polivy.

Reconstitution.

1. Using a sterile syringe, slowly inject 1.8 mL of sterile water for injection into the 30 mg Polivy vial or 7.2 mL of sterile water for injection into the 140 mg Polivy vial to yield a single-dose solution containing 20 mg/mL polatuzumab vedotin. Direct the stream toward the wall of the vial and not directly on the lyophilised cake.
2. Swirl the vial gently until completely dissolved. Do not shake.
3. Inspect the reconstituted solution for discoloration and particulate matter. The reconstituted solution should appear colorless to slightly brown, clear to slightly opalescent, and free of visible particulates. Do not use if the reconstituted solution is discolored, cloudy, or contains visible particulates.
To reduce microbiological hazard, the reconstituted solution should be used as soon as practicable after preparation. If storage is necessary, the reconstituted solution is stable for up to 72 hours at 2°C to 8°C and up to 20 hours at room temperature (9°C to 25°C).

Dilution.

1. Polatuzumab vedotin must be diluted to a final concentration of 0.72 - 2.7 mg/mL in an IV infusion bag with a minimum volume of 50 mL containing 0.9% sodium chloride, 0.45% sodium chloride, or 5% dextrose.
2. Determine the volume of 20 mg/mL reconstituted solution needed based on the required dose, see Equation 1.

3. Withdraw the required volume of reconstituted solution from the Polivy vial using a sterile syringe and dilute into the IV infusion bag. Discard any unused portion left in the vial.
4. Gently mix the IV bag by slowly inverting the bag. Do not shake.
5. Inspect the IV bag for particulates and discard if present.
To reduce microbiological hazard, the prepared solution for infusion should be used as soon as practicable after preparation. If storage is necessary, the solution for infusion may be held for the storage times provided in Table 4. Discard if storage time exceeds these limits. Do not freeze or expose to direct sunlight.

Avoid transportation of the prepared solution for infusion as agitation stress can result in aggregation. If the prepared solution for infusion will be transported, remove air from the infusion bag and limit transportation to 30 minutes at 9°C to 25°C or 12 hours at 2°C to 8°C. If air is removed, an infusion set with a vented spike is required to ensure accurate dosing during the infusion. The total storage plus transportation times of the diluted product should not exceed the storage duration specified in Table 4.
The product is for single use in one patient only. Discard any residue.

4.3 Contraindications

Polivy is contraindicated in patients with a known hypersensitivity to polatuzumab vedotin or any of the excipients.

4.4 Special Warnings and Precautions for Use

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

Myelosuppression.

Serious and severe neutropenia and febrile neutropenia have been reported in patients treated with Polivy as early as the first cycle of treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). Prophylactic G-CSF administration should be considered. Grade 3 or 4 thrombocytopenia or anaemia can also occur with Polivy (see Section 4.8 Adverse Effects (Undesirable Effects)). Complete blood counts should be monitored prior to each dose of Polivy. More frequent lab monitoring and/or Polivy delays or discontinuation should be considered in patients with Grade 3 or Grade 4 neutropenia and thrombocytopenia (see Section 4.2 Dose and Method of Administration).

Peripheral neuropathy.

Peripheral neuropathy has been reported in patients treated with Polivy as early as the first cycle of treatment, and the risk increases with sequential doses (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients with pre-existing peripheral neuropathy may experience worsening of this condition. Peripheral neuropathy reported with Polivy treatment is predominantly sensory peripheral neuropathy; however, motor and sensorimotor peripheral neuropathy have also been reported. Patients should be monitored for symptoms of peripheral neuropathy such as hypoesthesia, hyperesthesia, paresthesia, dysesthesia, neuropathic pain, burning sensation, weakness, or gait disturbance. Patients experiencing new or worsening peripheral neuropathy may require a delay, dose reduction, or discontinuation of Polivy (see Section 4.2 Dose and Method of Administration).

Infections.

Serious, life threatening, or fatal infections, including opportunistic infections, such as pneumonia (including Pneumocystis jirovecii and other fungal pneumonia), bacteraemia, sepsis, herpes infection, and cytomegalovirus infection have been reported in patients treated with Polivy (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be closely monitored during treatment for signs of bacterial, fungal, or viral infections. Anti-infective prophylaxis should be considered. Polivy and any concomitant chemotherapy should be discontinued in patients who develop serious infections.

Progressive multifocal leukoencephalopathy (PML).

PML has been reported with Polivy treatment (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients should be monitored closely for new or worsening neurological, cognitive, or behavioural changes suggestive of PML. Polivy and any concomitant chemotherapy should be held if PML is suspected and permanently discontinued if the diagnosis is confirmed.

Tumour lysis syndrome.

Patients with high tumour burden and rapidly proliferative tumour may be at increased risk of tumour lysis syndrome. Appropriate measures in accordance with local guidelines should be taken prior to treatment with Polivy. Patients should be monitored closely for tumour lysis syndrome during treatment with Polivy.

Embryofoetal toxicity.

Based on the mechanism of action and nonclinical studies, Polivy can be harmful to the foetus when administered to a pregnant woman (see Section 4.6 Fertility, Pregnancy and Lactation). Advise a pregnant woman of the risk to the foetus.
Females of reproductive potential should be advised to use effective contraception during treatment with Polivy and for at least 9 months after the last dose. Male patients with female partners of reproductive potential should be advised to use effective contraception during treatment with Polivy and for at least 6 months after the last dose (see Section 4.6 Fertility, Pregnancy and Lactation).

Hepatic toxicity.

Serious cases of hepatic toxicity that were consistent with hepatocellular injury, including elevations of transaminases and/or bilirubin, have occurred in patients treated with Polivy. Pre-existing liver disease, elevated baseline liver enzymes, and concomitant medications may increase the risk. Liver enzymes and bilirubin level should be monitored (see Section 4.2, Special populations; Section 5.2, Pharmacokinetics in special populations.

Use in hepatic impairment.

The safety and efficacy of Polivy in patients with AST > 2.5 x ULN, ALT > 2.5 x ULN or total bilirubin > 1.5 x ULN has not been formally studied and these patients are likely to have increased exposure to MMAE with increased risk of adverse events. The administration of Polivy in patients with moderate or severe hepatic impairment (total bilirubin greater than 1.5 x ULN) should be avoided (see Section 4.2, Special populations; Section 5.2, Pharmacokinetics in special populations).

Use in renal impairment.

The safety and efficacy of Polivy in patients with CrCL < 30 mL/min has not been formally studied (see Section 4.2, Special populations; Section 5.2, Pharmacokinetics in special populations).

Use in the elderly.

In patients with DLBCL (previously untreated and previously treated), no overall differences in safety or efficacy were observed between patients ≥ 65 years of age and younger patients (see Section 4.2, Special populations; Section 5.2, Pharmacokinetics in special populations).

Paediatric use.

The safety and efficacy of Polivy in children and adolescents below 18 years of age has not been established (see Section 4.2, Special populations; Section 5.2, Pharmacokinetics in special populations).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No dedicated clinical drug-drug interaction studies with Polivy in humans have been conducted.

Drug interactions with co-medications that are CYP3A inhibitors, inducers or substrates.

Based on physiologically-based pharmacokinetic (PBPK) model simulations of MMAE released from polatuzumab vedotin, strong CYP3A inhibitors (e.g. ketoconazole) may increase the area under the concentration-time curve (AUC) of unconjugated MMAE by 48%. Monitor patients receiving concomitant strong CYP3A inhibitors more closely for signs of toxicities. Strong CYP3A inducers (e.g. rifampicin) may decrease the AUC of unconjugated MMAE by 49%.
Unconjugated MMAE is not predicted to alter the AUC of concomitant drugs that are CYP3A substrates (e.g. midazolam).

Co-administration with other CYP substrates.

In vitro studies indicated that clinical drug-drug interactions are unlikely to occur as a result of MMAE-mediated inhibition of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or CYP2D6. MMAE does not induce CYP1A2, CYP2B6 or CYP3A4/5 in vitro.

Co-administration with drugs that are substrates of transporters.

In vitro data indicate that MMAE is a P-gp substrate but does not inhibit P-gp at clinically relevant concentrations. MMAE was not an in vitro substrate or inhibitor for the BCRP, MRP2, OATP1B1, OATP1B3, OAT1, OAT3 or OCT2 transporters. MMAE was also not an in vitro inhibitor of BSEP or OAT1.

Drug interactions of rituximab, bendamustine, cyclophosphamide, and doxorubicin in combination with polatuzumab vedotin.

The pharmacokinetics (PK) of rituximab, bendamustine, cyclophosphamide, and doxorubicin are not affected by co-administration with Polivy. Concomitant rituximab is associated with increased antibody conjugated MMAE (acMMAE) plasma AUC by 24% and decreased unconjugated MMAE plasma AUC by 37%, based on population PK analysis. The plasma AUC of acMMAE and unconjugated MMAE for Polivy plus R-CHP are in line with other studies of Polivy. No dose adjustment is required.
Bendamustine does not affect acMMAE and unconjugated MMAE plasma AUC.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of Polivy on human male and female fertility have not been studied. However, results from a repeat-dose toxicity study in rats indicate the potential for polatuzumab vedotin to impair male reproductive function and fertility. In the 4-week repeat-dose toxicity study in rats with weekly IV dosing of 2, 6, and 10 mg/kg, dose-dependent testicular seminiferous tubule degeneration with abnormal lumen contents in the epididymis was observed. Findings in the testes and epididymis did not reverse following a 6-week treatment-free period and correlated with decreased testes weight and gross findings of small and/or soft testes at recovery necropsy in males given doses ≥ 2 mg/kg. A no effect level was not established. Although there were no histological abnormalities in female reproductive organs from animal studies, dedicated fertility studies in female animals were not conducted. MMAE, the main active catabolite of polatuzumab vedotin, has been shown to have aneugenic properties in an in vivo rat bone marrow micronucleus study. These results were consistent with the pharmacological effect of MMAE on the mitotic apparatus (disruption of the microtubule network) in cells.
Therefore, men being treated with Polivy are advised to have sperm samples frozen and stored before treatment. Men being treated with Polivy are advised to use effective contraception during treatment with Polivy and not to father a child during treatment and for up to 6 months following the last dose. Effects on spermatogenesis cannot be excluded after a 6 month treatment-free period.
(Category D)
There are no adequate or well-controlled studies with Polivy in pregnant women. However, based on its mechanism of action and findings in animals, Polivy can cause foetal harm when administered to a pregnant woman.
Embryofoetal lethality and toxicity were seen in a rat embryofoetal development study in which pregnant rats received two IV doses of 0.2 mg/kg MMAE, the main active metabolite of polatuzumab vedotin, during the period of organogenesis, and included an increased incidence of post-implantation loss, and an increase in the incidence of foetal malformations including protruding tongue, malrotated hindlimbs, gastroschisis and agnathia. These adverse embryofoetal development effects occurred at exposures less than that expected in patients receiving polatuzumab vedotin.
Polivy should not be used during pregnancy unless the benefit to the mother outweighs the potential risks to the foetus. If a pregnant woman needs to be treated she should be clearly advised on the potential risk to the foetus.
Females of reproductive potential should be advised to use effective contraception during treatment with Polivy and for at least 9 months after the last dose.
See the 'Effects on fertility' section above pertaining to advice for women whose male partners are being treated with Polivy.
It is not known whether polatuzumab vedotin or its metabolites are excreted in human breast milk. A risk to breast-fed children cannot be excluded. Women should discontinue breastfeeding during Polivy treatment and for at least 3 months after the last dose.

Contraception.

Females of reproductive potential should be advised to use effective contraception during treatment with Polivy and for at least 9 months after the last dose.
Male patients with female partners of reproductive potential should be advised to use effective contraception during treatment with Polivy and for at least 6 months after the last dose.

4.7 Effects on Ability to Drive and Use Machines

Polivy may have a minor influence on the ability to drive and use machines. Infusion related reactions, peripheral neuropathy, fatigue, and dizziness may occur during treatment with Polivy (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

The safety of Polivy has been evaluated in 435 patients in Study GO39942 (POLARIX) and in 151 patients in Study GO29365. The adverse drug reactions (ADRs) described in this section were identified based on the following:
during treatment and follow-up of previously untreated DLBCL patients from the pivotal clinical trial POLARIX (GO39942), who received Polivy plus R-CHP (n=435) or R CHOP (n=438). In the Polivy plus R-CHP group, 91.7% of patients received 6 cycles of Polivy versus 88.5% of patients who received 6 cycles of vincristine in the R-CHOP group.
during treatment and follow-up of previously treated diffuse large B-cell lymphoma (DLBCL) patients (n = 151) from the pivotal clinical trial GO29365. This includes run-in phase patients (n = 6) and randomised patients (n = 39) and extension cohort patients (n = 106) who received Polivy in combination with bendamustine and rituximab (BR) compared to randomised patients (n = 39) who received BR alone. Patients in the Polivy treatment arm received a median of 5 cycles of treatment while randomised patients in the comparator arm received a median of 3 cycles of treatment.

Tabulated summary of adverse drug reactions from clinical trials.

Adverse drug reactions (ADRs) from the clinical trials are listed by MedDRA system organ class (SOC) in Table 5 (previously untreated DLBCL) and Table 6 (previously treated DLBCL).
The most frequently-reported (≥ 30%) ADRs (all grades) in patients treated with Polivy in combination with R-CHP for previously untreated DLBCL were neuropathy peripheral, nausea, neutropenia, and diarrhoea. Serious adverse reactions were reported in 24.1% of Polivy plus R-CHP treated patients which included the following that occurred in ≥ 5% of patients: febrile neutropenia (10.6%) and pneumonia (5.3%).
The ADR leading to treatment regimen discontinuation in ≥ 1% of patients treated with Polivy in combination with R-CHP for previously untreated DLBCL was pneumonia (1.1%).
The most frequently-reported (≥ 30%) ADRs (all grades) in patients treated with Polivy in combination with BR for previously treated DLBCL were anaemia, thrombocytopenia, neutropenia, diarrhoea, nausea, and peripheral neuropathy. Serious adverse events were reported in 55.6% of Polivy plus BR treated patients which included the following that occurred in ≥ 5% of patients: febrile neutropenia (9.3%), pyrexia (7.9%), pneumonia (6.6%), and sepsis (6.6%).
ADR leading to treatment regimen discontinuation in > 5% of patients were thrombocytopenia (6.0%).
The following categories of frequency have been used: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000).

Description of selected adverse drug reactions from clinical trials. Myelosuppression.

Study GO39942 (POLARIX).

0.5% of patients in the Polivy plus R-CHP arm discontinued study treatment due to neutropenia compared to no patients in the R-CHOP arm. Thrombocytopenia events led to discontinuation of treatment in 0.2% of patients in the Polivy plus R-CHP arm and none discontinued treatment in the R-CHOP arm. No patients discontinued treatment due to anaemia in either the Polivy plus R-CHP arm or R-CHOP arm.

Study GO29365.

4.0% of patients in the Polivy plus BR arms discontinued Polivy due to neutropenia compared to 2.6% of patients in the BR arm who discontinued treatment due to neutropenia. Thrombocytopenia events led to discontinuation of treatment in 7.9% of patients in the Polivy plus BR arms and 5.1% of patients in the BR arm. No patients discontinued treatment due to anaemia in either the Polivy plus BR arms or BR arm.
Peripheral neuropathy.

Study GO39942 (POLARIX).

In the Polivy plus R-CHP arm, Grade 1, 2, and 3 peripheral neuropathy were reported in 39.1%, 12.2%, and 1.6% of patients, respectively. In the R-CHOP arm, Grade 1, 2, and 3 peripheral neuropathy were reported in 37.2%, 15.5%, and 1.1% of patients, respectively. No Grade 4-5 peripheral neuropathy were reported in either the Polivy plus R-CHP arm or R-CHOP arm. 0.7% of patients discontinued study treatment in the Polivy plus R-CHP due to peripheral neuropathy compared to 2.3% in the R-CHOP arm. 4.6% of patients had study treatment dose reduction due to peripheral neuropathy compared to 8.2% in the R-CHOP arm. In the Polivy plus R-CHP arm, the median time to onset of first event of peripheral neuropathy was 2.27 months compared to 1.87 months in the R-CHOP arm. 57.8% of patients with peripheral neuropathy reported event resolution as of the clinical cut-off date compared to 66.9% in the R-CHOP arm. The median time to peripheral neuropathy resolution was 4.04 months compared to 4.6 months in the R-CHOP arm.

Study GO29365.

In the Polivy plus BR arms, Grade 1 and 2 peripheral neuropathy events were reported in 15.9% and 12.6% of patients, respectively. In the BR arm, Grade 1 and 2 peripheral neuropathy events were reported in 2.6% and 5.1% of patients, respectively. One Grade 3 peripheral neuropathy event was reported in the Polivy plus BR arms and no Grade 3 peripheral neuropathy events were reported in the BR arm. No Grade 4-5 peripheral neuropathy events were reported in either the Polivy plus BR arm or BR arm. 2.6% of patients discontinued Polivy treatment due to peripheral neuropathy and 2.0% of patients had Polivy dose reduction due to peripheral neuropathy. No patients in the BR arm discontinued treatment or had dose reductions due to peripheral neuropathy. In the Polivy plus BR arms, the median onset to first event of peripheral neuropathy was 1.6 months, and 39.1% of patients with peripheral neuropathy events reported event resolution.
Infections.

Study GO39942 (POLARIX).

Infections, including pneumonia and other types of infections, were reported in 49.7% of patients in the Polivy plus R-CHP arm and 42.7% of patients in the R-CHOP arm. Grade 3-4 infections occurred in 14.0% of patients in the Polivy plus R-CHP arm and 11.2% of patients in the R-CHOP arm. In the Polivy plus R-CHP arm, serious infections were reported in 14.0% of patients and fatal infections were reported in 1.1% of patients. In the R-CHOP arm, serious infections were reported in 10.3% of patients and fatal infections were reported in 1.4% of patients. 7 patients (1.6%) in the Polivy plus R-CHP arm discontinued treatment due to infection compared to 10 patients (2.3%) in the R-CHOP arm.

Study GO29365.

Infections, including pneumonia and other types of infections, were reported in 48.3% of patients in the Polivy plus BR arms and 51.3% of patients in the BR arm. In the Polivy plus BR arms, serious infections were reported in 27.2% of patients and fatal infections were reported in 6.6% of patients. In the BR arm, serious infections were reported in 30.8% of patients and fatal infections were reported in 10.3% of patients. Four patients (2.6%) discontinued treatment in the Polivy plus BR arms due to infection compared to two patients (5.1%) in the BR arm (see Section 4.4 Special Warnings and Precautions for Use).
Progressive multifocal leukoencephalopathy (PML).

Study GO39942 (POLARIX).

No cases of PML were reported with Polivy plus R-CHP or in the R-CHOP arm.

Study GO29365.

One case of PML, which was fatal, occurred in a patient treated with Polivy plus bendamustine and obinutuzumab. This patient had three prior lines of therapy that included anti-CD20 antibodies (see Section 4.4 Special Warnings and Precautions for Use).
Hepatic toxicity.

Study GO39942 (POLARIX).

Hepatic toxicity was reported in 10.6% of patients in the Polivy plus R-CHP arm and 7.3% of patients in the R-CHOP arm. In the Polivy plus R-CHP arm, most events were Grade 1-2 (8.7%); Grade 3 events were reported in 1.8% of patients. There were no Grade 4 or 5 events. Serious hepatic toxicity events were reported in 1 patient (0.2%) and were reversible.

Study GO29365.

In another study, two cases of serious hepatic toxicity (hepatocellular injury and hepatic steatosis) were reported and were reversible (see Section 4.4 Special Warnings and Precautions for Use).
Gastrointestinal toxicity.

Study GO39942 (POLARIX).

Gastrointestinal toxicity events were reported in 76.1% of patients in the Polivy plus R CHP arm compared to 71.9% of patients in the R-CHOP arm. Most events were Grade 1-2, and Grade ≥ 3 events were reported in 9.7% of patients in the Polivy plus R CHP arm compared to 8.2% of patients in the R-CHOP arm. The most common gastrointestinal toxicity events were nausea and diarrhoea.

Study GO29365.

Gastrointestinal toxicity events were reported in 72.8% of patients in the Polivy plus BR arms compared to 66.7% of patients in the BR arm. Most events were Grade 1-2, and Grade 3-4 events were reported in 16.5% of patients in the Polivy plus BR arms compared to 12.9% of patients in the BR arm. The most common gastrointestinal toxicity events were diarrhoea and nausea.

Laboratory abnormalities.

All identified laboratory abnormalities were reported as ADRs, see Table 5.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no information on overdose in human clinical trials. Patients who experience overdose should have immediate interruption of their infusion and be closely monitored.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Polatuzumab vedotin is a CD79b-targeted antibody-drug conjugate that preferentially delivers an anti-mitotic agent (monomethyl auristatin E, or MMAE) to B-cells, which results in the killing of malignant B-cells. The polatuzumab vedotin molecule consists of MMAE covalently attached to a humanized immunoglobulin G1 (IgG1) monoclonal antibody via a cleavable linker. The monoclonal antibody binds with nanomolar affinity and selectivity to CD79b, a cell surface component of the B-cell receptor. CD79b expression is restricted to normal cells within the B cell lineage (with the exception of plasma cells) and malignant B-cells; it is expressed in > 95% of DLBCL. Upon binding CD79b, polatuzumab vedotin is internalized and the linker is cleaved by lysosomal proteases to enable intracellular delivery of MMAE. MMAE binds to microtubules and kills dividing cells by inhibiting cell division and inducing apoptosis.

Clinical trials.

Previously untreated DLBCL.

The efficacy of Polivy was evaluated in an international, multicentre, randomised double-blind, placebo-controlled study (POLARIX, GO39942) in 879 patients with previously untreated DLBCL.
Eligible patients were age 18-80 years and had IPI score 2-5 and ECOG Performance Status 0-2. Histologies included DLBCL (NOS, ABC, GCB), high-grade B-cell lymphoma (HGBL; NOS, double-hit, triple-hit), and other large B-cell lymphoma subtypes (EBV positive, T-cell rich/histiocyte rich). Patients did not have known CNS lymphoma or peripheral neuropathy > Grade 1.
Patients were randomised 1:1 to receive Polivy plus R-CHP or R-CHOP for six 21-day cycles followed by two additional cycles of rituximab alone in both arms. Patients were stratified by IPI score (2 vs 3-5), presence or absence of bulky disease (lesion ≥ 7.5 cm), and geographical region.
Polivy was administered intravenously at 1.8 mg/kg on Day 1 of cycles 1-6. R-CHP or R CHOP were administered starting on Day 1 of Cycles 1-6 followed by rituximab alone on Day 1 of Cycles 7-8. Dosing in each treatment arm was administered according to the following:
Polivy + R-CHP arm: Polivy 1.8 mg/kg, rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², and prednisone 100 mg/day, on days 1-5 of every cycle, orally.
R-CHOP arm: rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², vincristine 1.4 mg/m², and prednisone 100 mg/day, on days 1-5 of every cycle, orally.
The two treatment groups were generally balanced with respect to baseline demographics and disease characteristics. The median age was 65 years (range 19 to 80 years), 53.6% of patients were white and 53.8% were male. 43.8% had bulky disease, 38.0% had IPI score 2, 62.0% had IPI score 3-5, and 88.7% had Stage 3 or 4 disease. The majority of patients (84.2%) had DLBCL (including NOS, ABC, and GCB). 211 patients did not have a cell of origin (COO) result reported. Of the COO evaluable population (n=668), 33.1% of patients had ABC like DLBCL and 52.7% of patients had GCB like DLBCL, by gene expression profiling.
The primary endpoint of the study was investigator-assessed progression-free survival. The median duration of follow up was 28.2 months. Efficacy results are summarised in Table 7 and in Figure 1.

In the final analysis, overall survival between the Polivy plus R-CHP and R-CHOP arms was similar, HR 0.94 (95% CI: 0.67, 1.33).

Previously treated DLBCL.

The efficacy of Polivy was evaluated in Study GO29365, an open-label, multicenter clinical trial that included a cohort of 80 patients with relapsed or refractory DLBCL after at least one prior regimen. Patients were randomized 1:1 to receive either Polivy in combination with bendamustine and a rituximab product (BR) or BR alone for six 21-day cycles. Randomisation was stratified by duration of response (DOR) to last therapy. Eligible patients were not candidates for autologous HSCT at study entry. The study excluded patients with Grade 2 or higher peripheral neuropathy, prior allogeneic HSCT, active central nervous system lymphoma, or transformed lymphoma.
Following premedication with an antihistamine and antipyretic, Polivy was given by intravenous infusion at 1.8 mg/kg on Day 2 of Cycle 1 and on Day 1 of Cycles 2-6. Bendamustine was administered at 90 mg/m² intravenously daily on Days 2 and 3 of Cycle 1 and on Days 1 and 2 of Cycles 2-6. A rituximab product was administered at a dose of 375 mg/m² intravenously on Day 1 of Cycles 1-6. The cycle length was 21 days.
Of the 80 patients randomised to receive Polivy plus BR (n = 40) or BR alone (n = 40), the median age was 69 years (range: 30-86 years), 66% were male, and 71% were white. Most patients (98%) had DLBCL not otherwise specified. The primary reasons patients were not candidates for HSCT included age (40%), insufficient response to salvage therapy (26%), and prior transplant failure (20%). The median number of prior therapies was 2 (range: 1-7), with 29% receiving one prior therapy, 25% receiving 2 prior therapies, and 46% receiving 3 or more prior therapies. Eighty percent of patients had refractory disease to last therapy.
In the Polivy plus BR arm, patients received a median of 5 cycles, with 49% receiving 6 cycles. In the BR arm, patients received a median of 3 cycles, with 23% receiving 6 cycles.
Efficacy was based on complete response (CR) rate at the end of treatment and DOR, as determined by an independent review committee (IRC). Other efficacy measures included IRC-assessed best overall response.
Response rates are summarised in Table 8.

In the Polivy plus BR arm, of the 25 patients who achieved a partial or complete response, 16 (64%) had a DOR of at least 6 months, and 12 (48%) had a DOR of at least 12 months. In the BR arm, of the 10 patients who achieved a partial or complete response, 3 (30%) had a DOR lasting at least 6 months, and 2 (20%) had a DOR lasting at least 12 months.

Immunogenicity.

As with all therapeutic proteins, there is the potential for an immune response in patients treated with polatuzumab vedotin. In Studies GO39442 (POLARIX) and GO29365, 1.4% (6/427) and 5.2% (12/233) of patients tested positive for antibodies against polatuzumab vedotin, respectively, of which none were positive for neutralising antibodies. Due to the limited number of anti-polatuzumab vedotin antibody positive patients, no conclusions can be drawn concerning a potential effect of immunogenicity on efficacy or safety.
Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of incidence of antibodies to polatuzumab vedotin with the incidence of antibodies to other products may be misleading.

5.2 Pharmacokinetic Properties

Antibody-conjugated MMAE (acMMAE) plasma exposure increased dose-proportionally over the 0.1 to 2.4 mg/kg polatuzumab vedotin dose range. After the first 1.8 mg/kg polatuzumab vedotin dose, the acMMAE mean maximum concentration (C_max) was 803 (± 233) nanogram/mL and the area under the concentration-time curve from time zero to infinity (AUC_inf) was 1860 (± 966) day*nanogram/mL. Based on the population PK analysis, Cycle 3 acMMAE AUC increased by approximately 30% over cycle 1 AUC, and achieved more than 90% of the Cycle 6 AUC. The terminal half-life at cycle 6 was approximately 12 days (95% CI of 8.1-19.5 days) for acMMAE.
Exposures of unconjugated MMAE, the cytotoxic component of polatuzumab vedotin, increased dose proportionally over the 0.1 to 2.4 mg/kg polatuzumab vedotin dose range. MMAE plasma concentrations followed formation rate limited kinetics. After the first 1.8 mg/kg polatuzumab vedotin dose, the C_max was 6.82 (± 4.73) nanogram/mL, the time to maximum plasma concentration is approximately 2.5 days, and the terminal half-life is approximately 4 days. Plasma exposures of unconjugated MMAE are < 3% of acMMAE exposures. Based on the population PK analysis, there is a decrease of plasma unconjugated MMAE exposure (AUC and C_max) after repeated every-three-week dosing.

Absorption.

Polivy is administered as an IV infusion. There have been no studies performed with other routes of administration.

Distribution.

The population estimate of central volume of distribution for acMMAE was 3.15 L, which approximated plasma volume.
In vitro, MMAE is moderately bound (71% - 77%) to human plasma proteins. MMAE does not significantly partition into human red blood cells in vitro; the blood to plasma concentration ratio is 0.79 to 0.98.
In vitro data indicate that MMAE is a P-gp substrate but does not inhibit P-gp at clinically relevant concentrations.

Metabolism.

Polatuzumab vedotin is expected undergo catabolism in patients, resulting in the production of small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE related catabolites.
In vitro studies indicate that MMAE is a substrate for CYP3A4/5.
MMAE does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, or CYP2D6.

Excretion.

Based on a population pharmacokinetic analysis, the conjugate (acMMAE) is primarily eliminated by non-specific linear clearance pathway with a value of 0.9 L/day.
In vivo studies in rats dosed with polatuzumab vedotin (radiolabel on MMAE) demonstrate that the majority (95%) of radioactivity is excreted in faeces and the minority (5%) of radioactivity is excreted in urine.