InfoCons Consumer Protection informs you – ADSTILADRIN – Package Leaflet

Before anything else

Read all of 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 further questions, ask your doctor.
• If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. See section 4.

ℹ️ 1. What ADSTILADRIN is and what it is used for

ADSTILADRIN is a gene therapy product that contains the active substance nadofaragene

firadenovec.

ADSTILADRIN is used in adults for the treatment of non-muscle invasive bladder cancer. In non- muscle invasive bladder cancer , the cancer cells are found in the tissue lining the inside of the bladder but have not spread to the bladder wall. It is used in adults whose cancer has not responded to or has come back after treatment with Bacillus Calmette -Guérin (BCG, a solution used to stimulate the immune system, the body’s natural defences, in the treatment of bladder cancer) .

The active substance in ADSTILADRIN , nadofaragene firadenovec, is based on a virus that has been changed so that it cannot spread in the body. The virus delivers a working copy of the gene that provides instructions for making the interferon- α2b (IFNα2b) protein into the cells in the surface of your bladder. Th is allows the bladder to make the IFNα2b protein which slows down or stops the cancer cells from growing and also helps to s timulate the immune system to attack them.

⚠️ 2. What you need to know before you are given ADSTILADRIN

You must not be given ADSTILADRIN

• if you are allergic to nadofaragene firadenovec or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Risk of your cancer getting worse if surgery to remove all or part of the bladder is delayed following treatment with this medicine.

Talk to your doctor before you are given ADSTILADRIN if:

• you a re immunocompromised or immune -deficient (when your immune system’s ability to fight infections is reduced) . Your doctor will evaluate if you should be given ADSTILADRIN.

27 • you have a urinary tract infection. Tell your doctor if you have signs of infection or inflammation of your bladder or kidneys before or during treatment with ADSTILADRIN, including : − cloudy or bloody urine ; − pain or burning sensation when passing urine ; − fever − pressure or cramping in the lower belly or back − a strong need to urinate often, even right after the bladder has been emptied.

If you are diagnosed with a urinary tract infection during your treatment with ADSTILADRIN, your doctor will pause the treatment until you have finished treatment with antibiotics and the urinary tract infection is cured.

If any of the above apply to you (or you are not sure), talk to your doctor before having ADSTILADRIN.

After you have been given ADSTILADRIN :

• you should f or the first 2 days after you have been given ADSTILADRIN, add two cups of household bleach (e.g. 5 % sodium hypochlorite) to the toilet bowl before passing urine. After passing of urine, wait for 15 minutes before flushing the toilet. Make sure to wash your hands after toilet use. This is due to theoretical risk that the active substance of ADSTILADRIN may be temporarily excreted through your urine,
• you should not donate blood, organs, tissues or cells.

Children and adolescents

The use of ADSTILADRIN in children or adolescents under 18 has not been studied because the disease indicated occur s in adults only.

Other medicines and ADSTILADRIN

Tell your doctor if you are using, have recently used or might use any other medicines.

Pregnancy and breast -feeding If you are pregnant, breast -feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before being given ADSTILADRIN.

Pregnancy

ADSTILADRIN is not recommended if you are pregnant or if you are a woman who can become pregnant who is not using effective contraception (birth control) . There are no data regarding the use of ADSTILADRIN in pregnant women. It is not known if ADSTILADRIN is safe to use during pregnancy or can cause harm to your unborn baby.

If you are able to become pregnant, you should use effective (double , i.e. two methods of birth control used together, typically a barrier method such as condoms alongside hormonal contraceptives ) contraception (birth control) during treatment with ADSTILADRIN, and for 6 months after you have been given the last dose. Your doctor will check if you are pregnant before you are given ADSTILADRIN.

Breast -feeding It is not known if ADSTILADRIN is passed into breastmilk. Your doctor will decide if you should continue breastfeeding during treatment with ADSTILADRIN.

Men Use effective barrier contraception during treatment with ADSTILADRIN, and for 3 months after you have been given the last dose. You should also not donate sperm during treatment with ADSTILADRIN and for 3 months after you have been given the last dose .

Partners Partners must avoid contact with semen during your treatment with ADSTILADRIN , and for 3 months after you have been given the last dose. This is to prevent your partner from com ing in contact with the virus.

If your partner is a woman who can become pregnant, they should use effective (double) contraception while you are receiving treatment with ADSTILADRIN, and for 6 months after you have been given the last dose. This is to prevent the theoretical risk of exposing foetal cells to the virus.

Discuss with your doctor which methods of contraception are suitable.

Driving and using machines

It is unlikely that ADSTILADRIN will affect your ability to drive and use machines.

ADSTILADRIN contains polysorbate 80

ADSTILADRIN contains an excipient called polysorbate 80 . Polysorbates can cause allergic reactions.

💊 3. How ADSTILADRIN is given

Treatment with ADSTILADRIN will be supervised by a doctor experienced in the management of patients with non- muscle invasive bladder cancer.

Treatment with ADSTILADRIN is given with a dose of 3 × 10 11 viral particles/mL with a volume of 75 mL passed into your bladder. The treatment will be given to you every three months until you do no longer respond to the treatment or if you can no longer tolerate the treatment.

Before you are given ADSTILADRIN Your doctor may give you another medicine (a so-called anticholinergic agent) before you are given ADSTILADRIN. This medicine is given to reduce possible irritation of the bladder and to stop you from passing urine when ADSTILADRIN is given. Take this medicine as instructed by your doctor.

How you are given ADSTILADRIN

• A urinary catheter (flexible tube) will be inserted into your bladder to empty it of urine.
• ADSTILADRIN will be passed slowly into your bladder through the urinary catheter, which will be removed after all the medicine is given .
• ADSTILADRIN will be left in your bladder for 1 hour and your doctor may ask you to change position from left to right and from your back to your stomach. This is to make sure that ADSTILADRIN reaches the whole surface of your bladder.
• If you get bladder cramping or pass urine during the procedure, your doctor may ask you to change position.
• After 1 hour , your doctor will empty your bladder with a urinary catheter, or you may be asked to pass urine.

If you are given more ADSTILADRIN than you should

As this medicine is given to you by a doctor, it is unlikely that you will be given too much. If it does occur, your doctor will treat the symptoms as necessary.

If you miss an appointment to get ADSTILADRIN

• Call your doctor right away to reschedule your appointment.
• It is very important that you do not miss a dose of this medicine.

If you stop receiving ADSTILADRIN Stopping your treatment may stop the effect of the medicine. Do not stop treatment with ADSTILADRIN unless you have discussed this with your doctor.

If you have any further questions on the use of this medicine, ask your doctor.

❗ 4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following side effects may happen with ADSTILADRIN:

In a clinical study, fainting (common, may affect up to 1 in 10 people) has been reported as a serious side effect. Immediately seek medical attention if you experience fainting.

Very common (may affect more than 1 in 10 people)

• Fluid leaking from where the medicine was given (instillation site discharge)
• Feeling tired ( fatigue)
• Fever ( pyrexia)
• Chills
• Involuntary contraction of the bladder muscle ( bladder spasm )
• Sudden urge to pass urine ( micturition urgency)
• Blood in the urine ( haematuria)
• Painful urination ( dysuria)
• Pain in parts of the body that collect and pass out urine ( lower urinary tract pain)
• Abnormally frequent urination ( pollakiuria)
• Diarrh oea
• Belly ( abdominal) pain
• Headache
• Infection of parts of the body that collect and pass out urine ( urinary tract infection)

Common (may affect up to 1 in 10 people)

• Pain
• Flu-like illnes s
• Feeling generally unwell ( malaise)
• Drug intolerance
• Lack of control over passing urine ( urinary incontinence)
• Need to pass urine at night ( nocturia)
• Inability to complet ely empty the bladder ( urinary retention)
• Bleeding in parts of the body that collect and pass out urine ( haemorrhage urinary tract)
• Urine odour abnormal
• Inflammation in the bladder which can cause pain and discomfort when passing urine ( cystitis noninfective)
• Feeling sick ( nausea)
• Vomiting
• Urgent need to empty the bowels ( defaecation urgency)
• Stomach and gut ( gastrointestinal ) pain
• Dizziness
• Fainting ( syncope)
• Sensations like numbness, tingling, pins and needles ( paraesthesia)
• Muscle pain ( myalgia)
• Joint pain ( arthralgia)
• Pain in the fingers, toes, feet, hands (pain in extremity)
• Muscular weakness
• Muscle, bone and join ( musculoskeletal ) stiffness
• Night sweats
• Excessive sweating ( hyperhidrosis)
• Allergic inflammation of the skin ( dermatitis allergic) 30 • High blood pressure ( hypertension)
• Hot flush
• Excessive urine ( urine output increased)
• Decreased appetite
• Low levels of blood platelets , components that help the blood to clot (thrombocytopenia)
• Low levels of neutrophils, a type of white blood cell that fights infection ( neutropenia)
• Feeling restless
• Vulvovaginal discomfort Talk to your doctor if you develop any other side effects.

Reporting of side effects

If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V . By reporting side effects you can help provide more information on the safety of this medicine.

🌡️ 5. How to store ADSTILADRIN

The following information is for healthcare professionals who will prepare and give the medicine.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the vial label and on the carton after EXP. The expiry date refers to the last day of that month.

Protect the vials from light. Keep vials in outer carton.

Before vial thawing procedure is initiated − Store below – 60°C. − Can be stored at – 20 ± 5℃ for a maximum of three months. When stored at -20 ± 5°C the date of placement at -20 ± 5°C should be noted. In addition, the date for when the medicinal product should be discarded if not used, must be written on the carton. These dates should be three months apart but sho uld not pass the original expiry date. This discard date supersedes the original expiry date.

From vial thawing procedure is initiated − Keep refrigerated at 2- 8°C for a total of 7 days (including thawing time), and/or − Keep at room temperature for a maximum of 24 hours (including thawing time).

In-use stability after withdrawal from the vial If unable to administer the suspension shortly after withdrawal, the solution may be stored in syringes for up to 6 hours at room temperature (20- 25°C), protected from light.

From a microbiological point of view, unless the method of opening precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in- use storage times and conditions prior to use are the responsibility of the user.

For thawing details see the information intended for healthcare professionals at the end of this leaflet.

Do not throw away any medicines via wastewater or household waste. Disposable materials that have come into contact with ADSTILADRIN should be placed in biohazard containers for destruction.

31 Non-disposable equipment may be decontaminated according to the facility’s standard operating procedures. These measures will help protect the environment.

📦 6. Contents of the pack and other information

What ADSTILADRIN contains

− The active substance is nadofaragene firadenovec. Each vial contains 20 mL suspension with a concentration of 3 × 10 11 viral particles/mL. − The other excipients are Syn3NODA, citric acid monohydrate (for pH adjustment) (E 330) , sodium citrate (for pH adjustment) ( E 331) , polysorbate 80 (E 433) (see section 2

“ADSTILADRIN contains polysorbate 80”) , hydroxypropylbetadex (E 459) , sodium

dihydrogen phosphate dihydrate (for pH adjustment) (E 339) , trometamol (for pH adjustment) , sucrose, magnesium chloride hexahydrate (E 511) , glycerol (E 422), and water for injections.

What ADSTILADRIN looks like and contents of the pack

ADSTILADRIN is an intravesical suspension. When thawed, ADSTILADRIN is an opalescent colourless suspension.

The vials are single- use transparent Type 1 glass vials with a bromobutyl rubber stopper sealed with a tamper -evident crimp.

ADSTILADRIN is supplied in a carton containing four (4) 20 mL single -use vials.

Marketing Authorisation Holder

Ferring Pharmaceuticals A/S Amager Strandvej 405 2770 Kastrup Denmark

Manufacturer

FinVector Oy Microkatu 1s 70210 Kuopio Finland For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

België/Belgique/Belgien Ferring N.V.

Tel/Tél: +32 53 72 92 00 [email protected] Lietuva CentralPharma Communications UAB Tel: +370 5 243 0444 [email protected] България Фармонт ЕООД Тел: +359 2 807 5022 [email protected] Luxembourg/Luxemburg Ferring N.V.

Belgique/Belgien Tel/Tél: +32 53 72 92 00 [email protected] Česká republika Ferring Pharmaceuticals CZ s.r.o.

Tel: +420 234 701 333 [email protected] Magyarország Ferring Magyarország Gyógyszerkereskedelmi Kft.

Tel: +36 1 686 2128 [email protected] 32 Danmark Ferring Lægemidler A/S Tlf: +45 88 16 88 17 Malta E.J. Busuttil Ltd.

Tel: +356 21447184 [email protected] Deutschland Ferring Arzneimittel GmbH Tel: +49 431 5852 0 info- [email protected] Nederland Ferring B.V.

Tel: +31 235680300 [email protected] Eesti CentralPharma Communications OÜ Tel: +372 601 5540 [email protected] Norge Ferring Legemidler AS Tlf: +47 22 02 08 80 [email protected] Ελλάδα Ferring Ελλάς ΜΕΠΕ Τηλ: +30 210 68 43 449 Österreich Ferring Arzneimittel Ges.m.b.H Tel: +43 1 60 8080 [email protected] España Ferring S.A.U.

Tel: +34 91 387 70 00 [email protected] Polska Ferring Pharmaceuticals Poland Sp. z o.o.

Tel: +48 22 246 06 80 [email protected] France Ferring S.A.S.

Tél: +33 1 49 08 67 60 [email protected] Portugal Ferring Portuguesa – Produtos Farmacêuticos, Sociedade Unipessoal, Lda.

Tel: +351 21 940 51 90 Hrvatska Clinres farmacija d.o.o.

Tel: +385 1 2396 900 info@clinres -farmacija.hr Ireland Ferring Ireland Ltd.

Tel: + 44 (0) 800 111 4126 [email protected] România Ferring Pharmaceuticals Romania SRL Tel: +40 356 113 270 Slovenija SALUS, Veletrgovina, d.o.o.

Tel: +386 1 5899 100 regulatory@salus. eu Ísland Vistor e hf.

Sími: +354 535 70 00 Slovenská republika Ferring Slovakia s.r.o.

Tel: +421 2 54 416 010 [email protected] Italia Ferring S.p.A.

Tel: +39 02 640 00 11 Suomi/Finland Ferring Lääkkeet Oy Puh/Tel: +358 207 401 440 [email protected] Κύπρος A.Potamitis Medicare Ltd Τηλ: +357 22583333 [email protected] Sverige Ferring Läkemedel AB Tel: +46 40 691 69 00 [email protected] 33 Latvija CentralPharma Communications SIA Tālr: +371 674 50497 [email protected] This leaflet was last revised in .

This medicine has been given ‘conditional approval’. This means that there is more evidence to come about this medicine. The European Medicines Agency will review new information on this medicine at least every year and this leaflet will be updated as nece ssary.

Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site: https://www.ema.europa.eu ————————————————————————————————————————

🩺 Information intended for healthcare professionals only

Important: Please refer to the Summary of Product Characteristics (SmPC) before using.

Immunocompromised, immune -deficient and pregnant healthcare professionals Healthcare professionals who are immunocompromised, immune -deficient, or pregnant should not prepare, administer, or come in contact with ADSTILADRIN due to the theoretical risk of adenoviral infection.

Precautions to be taken before handling or administering the medicinal product This medicinal product contains genetically modified organisms (GMOs).

• Any ADSTILADRIN spills should be treated with a virucidal agent (such as 5 % sodium hypochlorite or hydrogen peroxide disinfectant) for 30 minutes. Disinfectant should be present in the preparation area and patient room in case of spill.
• Personal protective equipment (including gloves, safety glasses, apron or protective clothing) should be worn while handling or administering ADSTILADRIN.

Thawing and thawing time When thawing at room temperature:

Frozen ADSTILADRIN vials will thaw in approximately 3- 5 hours outside the cardboard nest when placed at room temperature (20- 25°C) (8- 10 hours inside the nest). Protect the vials from light, even if thawed outside the cardboard nest.

When thawing in refrigerator:

Frozen ADSTILADRIN vials will thaw in approximately 4- 5 hours outside the cardboard nest when placed in the refrigerator (2 -8°C) (11- 13 hours inside the nest). Subsequent time for bringing thawed ADSTILADRIN to room temperature is approximately 2 hours 30 minutes outside of the cardboard nest (6 hours inside the nest).

Do not expose the vials to higher temperatures.

34 All four vials should be inspected for visible particles and discoloration. The suspension is clear to slightly opalescent and may contain opalescent flecks. Do not use if visible particles or discoloration are observed. Mix gently. Do not shake.

Once the thawing procedure is initiated (at 2 -8°C and/or at room temperature), the date and time for placing and removing the product from the specified storage condition, should be noted on the carton. When removing the product, the time remaining at the specific storage condition should be noted on the carton.

Items required for instillation

• Four (4) thawed vials of ADSTILADRIN
• Four (4) vented vial adaptors (20 mm) suitable for a 30R vial
• Two (2) standard 50 or 60 mL polypropylene Luer lock syringes or one (1) Luer lock syringe equal to or greater than 75 mL (max 100 mL)
• Two (2) Luer lock adaptors:
• One (1) straight, or intermittent, urethral catheter with a proximal funnel opening that will accommodate the Luer lock adaptor.
• Use only catheters made of vinyl/PVC (uncoated or coated with hydrogel), red rubber latex or silicone to instil ADSTILADRIN. Do not use catheters coated or embedde d with silver or antibiotics.

Preparation 1. Using aseptic technique, remove the cap from an ADSTILADRIN vial and attach a vented vial adaptor according to manufacturer’s instructions.

2. Connect the syringe to the vial adaptor and withdraw the contents of the vial into the syringe. Repeat steps 1 -2 for the remaining three (3) vials until 75 mL has been withdrawn into one (1) or two (2) syringes. The volumes in the syringes do not have to be equal.

3. Discard any remaining volume according to universal precautions.

4. Use ADSTILADRIN within 6 hours of drawing into syringe.

Bladder instillation of ADSTILADRIN

• Premedication with an anticholinergic before each instillation of ADSTILADRIN is recommended.
• ADSTILADRIN must be brought to room temperature before administration.
• Before administering ADSTILADRIN to the patient, insert one straight, or intermittent, urinary catheter with a proximal funnel opening that will accommodate the Luer lock adapt or.
• Use only catheters made of vinyl/PVC (uncoated or coated with hydrogel), red rubber latex or silicone to instil ADSTILADRIN. Do not use catheters coated or embedded with silver or antibiotics.
• Use the catheter to completely empty the patient’s bladder before instillation of ADSTILADRIN. Do not remove the catheter.
• Attach the Luer lock end of the catheter adaptor to the syringe containing ADSTILADRIN and insert the tapered end of the catheter adaptor into the funnel opening of the catheter.
• Slowly instil 75 mL of ADSTILADRIN into the bladder through the catheter, ensuring that the complete volume is administered.
• After instillation the catheter should be removed.
• ADSTILADRIN should be retained in the bladder for 1 hour. During the 1- hour dwell time, the patient should reposition approximately every 15 minutes from left to right, back and abdomen to maximize bladder surface exposure. If the patient exhibits bladder cramping or premature voiding during the dwell time, repositioning of the patient may be adjusted or discontinued.
• Evacuate ADSTILADRIN from the bladder as part of routine emptying of the bladder, or the patient may void and completely empty the bladder after 1 hour has elapsed.

35 – Voided urine should be disinfected for 15 minutes with two cups of virucidal agent before flushing of the toilet; this should be done for the first 2 days after each treatment.

Measures to take in case of accidental exposure Accidental exposure to nadofaragene firadenovec, including contact with skin, eyes and mucous membranes, is to be avoided.

• In case of accidental exposure to skin, the affected area must be thoroughly cleaned with soap and water for at least 15 minutes.
• In case of accidental exposure to eyes, the affected area must be thoroughly flushed with water for at least 15 minutes.
• In case of accidental ingestion, immediately rise the mouth and drink plenty of water.

Precautions to be taken for the disposal of the medicinal product Unused medicinal product and disposable materials that have come into contact with ADSTILADRIN should be placed in biohazard containers for destruction. Non- disposable equipment must be decontaminated according to the facility’s biohazard standard operating procedures .

📄 Package Leaflet – official source

This article reproduces the information in the official package leaflet, as authorised in the European Union. You can consult the original document here: Product information ADSTILADRIN (PDF, ec.europa.eu).

You can check this medicine at any time in the Union Register of medicinal products (EU number EU/1/26/2035).

⚠️ Important: This article is for information purposes only and does not replace medical advice or the package leaflet inside the medicine box. Read the leaflet carefully before use. For any questions about your treatment, talk to your doctor or pharmacist. If you experience side effects, tell your doctor or pharmacist and report them through your national reporting system.