Bcg — medac

Package leaflet: Information for the user

BCG-medac, powder and solvent for suspension for intravesical use
Bacillus Calmette-Guérin
Please read all of this leaflet carefully before using this medicine because it contains
important information for you.

• Keep this leaflet as you may need to read it again.
• If you have any further questions, please ask your doctor or pharmacist.
• If you experience any side effects, including any not listed in this leaflet, please inform your doctor or pharmacist. See section 4.

Table of contents

1. What BCG-medac is and what it is used for
2. What you need to know before using BCG-medac
3. How to use BCG-medac
4. Possible side effects
5. How to store BCG-medac
6. Contents of the pack and other information

1. What BCG-medac is and what it is used for

The full name of the medicine is BCG-medac, powder and solvent for preparation of suspension for intravesical use. In the remainder of this leaflet, this medicine will be referred to as BCG-medac.
BCG-medac contains attenuated (weakened) Mycobacterium bovis bacteria with low infectious potential.
BCG-medac stimulates the immune system and is used in the treatment of several types of bladder cancer. This medicine is effective when cancer is limited to the cells lining the inner surface of the bladder (transitional epithelium) and has not invaded the deeper layers of the bladder wall.
BCG-medac is administered directly into the bladder as an instillation.
In the case of flat bladder tumours (carcinoma in situ), BCG-medac is used to treat lesions confined to the epithelial lining of the bladder. There are different grades of malignancy of cancer that may occur in the bladder epithelium and the adjacent cellular layer (called the lamina propria).
BCG-medac is also used to prevent recurrence of bladder cancer (prophylaxis).

2. Important information before using BCG-medac

When not to use BCG-medac

• if the patient is allergic to live BCG bacteria (Bacillus Calmette-Guérin) or to any of the other ingredients of this medicine (listed in section 6),
• if the patient has a weakened immune system due to a concurrent disease (e.g. HIV infection, leukaemia, lymphoma), anticancer therapy (e.g. cytostatic drugs, radiotherapy) or immunosuppressive therapy (e.g. corticosteroids),
• if the patient has active tuberculosis,
• if the patient has previously undergone radiotherapy to the bladder or adjacent body areas,
• if the patient is breastfeeding,
• if within the last 2–3 weeks the patient has undergone a surgical procedure via the urethra (TUR; transurethral resection), had a tissue sample taken from the bladder (bladder biopsy), or experienced trauma during catheterization,
• if bladder perforation has occurred,
• if blood is visible in the urine,
• if the patient has an acute urinary tract infection.

BCG-medac must never be administered subcutaneously, intradermally, intramuscularly, intravenously, or as a vaccine. This medicine must be administered directly into the bladder as a bladder instillation.

Warnings and precautions

The doctor will provide the patient with a patient alert card, which must always be carried (see also section 4).

Before starting treatment with BCG-medac, discuss this with your doctor or pharmacist if:

• the patient has fever or blood in the urine. In such cases, treatment with BCG-medac should be temporarily discontinued,
• the patient has a small bladder capacity, as this may decrease further after treatment,
• the patient is a carrier of HLA-B27 antigen (human leukocyte antigen B27), as they may be more prone to joint inflammation (reactive arthritis),
• the patient has joint inflammation associated with inflammation of the skin, eyes, and urinary tract (Reiter's syndrome),
• the patient has a localized blood vessel dilation (aneurysm) or has a prosthesis. Infections of implants and prostheses may occur.
• the patient has liver problems or is taking medications that may affect the liver. This is particularly important when triple antibiotic therapy is used together with antituberculosis drugs.

General recommendations for personal hygiene

After the instillation, the patient should sit down when urinating to prevent splashing of urine and avoid contaminating the surrounding area with BCG bacteria.

After urination, hands and genital area should be washed. This is particularly important after the first urination following BCG instillation. If skin lesions become contaminated, an appropriate disinfectant should be used (consult your doctor or pharmacist).

Tests for detection of Bacillus Calmette-Guérin

Detection of BCG bacteria is generally difficult. A negative test result does not exclude BCG infection outside the urinary bladder.

Urinary tract infection

Before each intravesical administration of BCG, the doctor should ensure that the patient does not have an acute urinary tract infection. If an acute urinary tract infection is diagnosed during BCG therapy, treatment should be suspended until urine test results return to normal and antibiotic treatment has been completed.

Patients in contact with immunocompromised individuals

Patients treated with BCG-medac should follow appropriate hygiene practices as described above. This is particularly important when in contact with immunocompromised individuals, as BCG bacteria may be harmful to patients with weakened immune systems. To date, however, no cases of transmission of BCG bacteria between humans have been reported.

Transmission of infection via sexual contact

The use of condoms during sexual intercourse is recommended for one week following BCG administration.

BCG-medac and other medicines

Inform your doctor or pharmacist about all medicines currently or recently taken, as well as any medicines you plan to take.

This is particularly important when using the following medicines, which may interact with BCG bacteria:

• Antituberculosis drugs (e.g. ethambutol, streptomycin, p-aminosalicylic acid (PAS), isoniazid (INH), and rifampicin)
• Antibiotics (fluoroquinolones, doxycycline, gentamicin)
• Antiseptic agents
• Lubricants (personal moisturizers)

BCG bacteria are resistant to pyrazinamide and cycloserine.

Pregnancy, breastfeeding, and effects on fertility

Pregnancy

If the patient is pregnant or suspects she may be pregnant, she should not use BCG-medac.

Breastfeeding

BCG-medac should not be used during breastfeeding.

Fertility

BCG bacteria have been shown to affect sperm production, and their administration may cause reduced sperm count or absence of sperm in semen. This effect was reversible in animal studies. However, men should consult their doctor about the possibility of sperm storage before starting treatment.

Driving and operating machinery

This medicine may affect the ability to drive and operate machinery. The patient should not drive or operate machinery until they know how BCG-medac affects them.

If you have any doubts regarding the use of this medicine, consult your doctor, nurse, or pharmacist.

3. How to use BCG-medac

Dosage
BCG-medac is prepared and administered exclusively by experienced medical personnel. The contents of one vial are intended for single, intravesical administration.
Administration of the medicinal product
BCG-medac is instilled into the urinary bladder under low pressure using a catheter.
The medicinal product should remain inside the bladder for 2 hours. To achieve this, patients should not drink any fluids for 4 hours before and 2 hours after administration of the medicinal product.
To ensure distribution of the medicinal product throughout the entire bladder mucosa, movement during instillation is recommended to enhance treatment efficacy. After 2 hours, the bladder should be emptied while sitting to avoid splashing of urine.
Patients who are not on a fluid-restricted diet should drink plenty of fluids for 48 hours after each administration of the medicinal product.
Use in children
The safety and efficacy of BCG-medac in children have not been established.
Use in elderly patients
There are no special recommendations for the use of BCG-medac in elderly patients. However, liver function should be taken into consideration prior to administration of BCG.
Duration of treatment
In the standard treatment regimen (induction therapy), BCG-medac is administered intravesically once weekly for 6 consecutive weeks. Four weeks after completion of induction therapy, intravesical administration of the medicinal product may be resumed (so-called maintenance therapy) for at least 1 year, as described below. The treating physician will discuss this with the patient.
Induction therapy

• BCG instillation may begin approximately 2–3 weeks after transurethral surgical procedure (TUR; transurethral resection) or bladder tissue biopsy, provided no trauma occurred during catheterization. The medicinal product is administered once weekly for 6 weeks.
• After this induction therapy, many patients receive maintenance therapy, during which additional doses of the medicinal product may be administered.

Maintenance therapy

• Maintenance therapy consists of 3 weekly instillations administered at least once a year for up to 3 years, in months 3, 6, 12, 18, 24, 30, and 36. In this treatment schedule, the patient will receive a total of 15 to 27 instillations over a period of 1 to 3 years. If necessary, the physician will discuss with the patient the need for maintenance therapy every 6 months after the first year of treatment.

Although maintenance therapy reduces the likelihood of disease recurrence and may reduce tumor progression, in some patients adverse effects and discomfort associated with treatment may outweigh the benefits. Therefore, it is important that the physician discusses treatment-related discomforts with the patient and considers the patient's treatment preferences before initiating or continuing maintenance therapy.
Administration of a higher than recommended dose of BCG-medac
Overdose is unlikely because one vial of BCG-medac contains a single dose administered as an intravesical instillation. There are no data indicating that overdose may cause any symptoms other than those adverse reactions listed below (see section 4).

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everyone will experience them.
Adverse reactions to BCG treatment are common, but are usually mild and transient. The number of
adverse reactions generally increases with the number of BCG doses administered.
The most serious adverse reaction is severe systemic infection. You should contact your doctor immediately if any of the following symptoms occur, which may appear at any time and sometimes occur with a delay, emerging weeks, months or even years after the last dose.
The patient warning card should be shown to all treating physicians.

• Fever above 39.5°C for at least 12 hours or fever above 38°C lasting for weeks
• Unexplained weight loss
• Worsening general condition
• Inflammatory symptoms may vary and may present as:
  o difficulty breathing or cough not resembling a common cold (bronchopneumonia)
  o liver problems: feeling of pressure in the right upper abdomen or abnormalities in liver function tests (especially an enzyme called alkaline phosphatase), or
  o eye pain and redness, vision problems or blurred vision; conjunctivitis (so-called "pink eye")
• Granulomatous inflammation confirmed by biopsy.

Systemic infection/reaction to BCG
If the bladder is accidentally damaged during treatment with the medicinal product BCG-medac
or if BCG-medac is inadvertently administered into a muscle or vein, this may lead to severe systemic
BCG infection. Severe systemic BCG infection may lead to BCG sepsis. BCG sepsis is a life-threatening condition. If worrying symptoms or signs occur, seek immediate medical attention from your treating physician or contact an infectious disease specialist! This infection is not caused by virulent bacteria. The doctor will prescribe medications to manage adverse reactions, and BCG treatment may be discontinued.
In contrast to BCG infection, BCG reaction often presents as mild fever, flu-like symptoms and general malaise 24–48 hours after instillation as an initial immunological response. The doctor may prescribe certain medications to treat these symptoms. If symptoms worsen, contact your doctor.
Delayed BCG infection
In isolated cases, BCG bacteria may persist in the body for years. Infection may occur at any time, and sometimes symptoms and signs of infection appear late, even years after the last dose of BCG-medac. Inflammatory symptoms may resemble severe infection/reaction to BCG, as mentioned above. Problems related to implants or transplants may also represent adverse reactions to BCG treatment and require immediate treatment.
Therefore, it is extremely important to always carry the patient warning card and show it to every treating physician to ensure appropriate management in case of delayed BCG infection. The physician will also be able to assess whether symptoms are related to BCG treatment or not.

Below is the complete list of possible adverse reactions:

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

• Nausea
• Cystitis and other inflammatory conditions of the bladder (granulomas). These adverse reactions may be an important component of the antitumor effect.
• Frequent urination accompanied by discomfort and pain. These symptoms may occur in up to 90% of patients.
• Inflammatory conditions of the prostate gland (asymptomatic granulomatous prostatitis)
• Transient systemic reactions to BCG bacteria, such as fever below 38.5°C, flu-like symptoms (malaise, fever, chills), and general discomfort.
• Fatigue

Common (may affect up to 1 in 10 people)

• Fever above 38.5°C
• Muscle pain
• Diarrhea
• Abdominal pain
• Urinary incontinence

Uncommon (may affect up to 1 in 100 people)

• Severe systemic infections/reactions to BCG bacteria, BCG sepsis (more detailed information provided below)
• Blood cell deficiency (cytopenia)
• Anemia (decrease in hemoglobin levels in blood)
• Reiter's syndrome (joint inflammation associated with inflammatory skin, eye and urinary tract conditions)
• Lung inflammation (bronchopneumonia)
• Inflammatory reactions in the lungs (lung granuloma)
• Hepatitis
• Skin abscess
• Rash, joint inflammation (arthritis), joint pain (arthralgia). In most cases, these symptoms result from an allergic (hypersensitivity) reaction to BCG. In some cases, treatment discontinuation may be necessary.
• Urinary tract infection, presence of blood in urine (macroscopic hematuria)
• Abnormal bladder size (contraction), abnormal urine flow (urinary tract obstruction), bladder shrinkage
• Orchitis (inflammation of the testicles)
• Epididymitis (inflammation of the epididymis)
• Inflammatory condition of the prostate gland (symptomatic granulomatous prostatitis)
• Low blood pressure (hypotension)
• Abnormal liver function test results

Rare (may affect up to 1 in 1000 people)

• Vascular infection (e.g., infection at the site of a blood vessel dilation)
• Kidney abscess

Very rare (may affect up to 1 in 10,000 people)

• BCG infection of an implant and adjacent tissue (e.g., infection of an aortic graft, cardiac defibrillator, hip or knee joint prosthesis)
• Inflammation of neck lymph nodes, regional lymph node infection
• Allergic reactions (hypersensitivity), e.g., eyelid swelling, cough
• Ocular inflammatory conditions (chorioretinitis)
• Conjunctivitis, uveitis
• Vascular fistula
• Vomiting, intestinal fistula, peritonitis
• Bacterial infection of bone tissue and bone marrow
• Bone marrow infection
• Psoas muscle abscess
• Drug-resistant orchitis or epididymitis
• Infection of the glans penis
• Swelling of arms or legs

Frequency not known (frequency cannot be estimated from available data)

• Vasculitis (possibly in the brain)
• Genital organ disorders (e.g., vaginal pain)
• Pain during sexual intercourse (dyspareunia)
• Severe immunological reactions with fever, hepatosplenomegaly, lymphadenopathy, jaundice and rash (hemophagocytic syndrome)
• Kidney failure, kidney tissue inflammation, renal pelvis (pyelonephritis, nephritis [including tubulointerstitial nephritis, interstitial nephritis and glomerulonephritis])
• Absence or low number of sperm in semen (azoospermia, oligospermia)
• Increased level of prostate-specific antigen (PSA, a laboratory test for the prostate gland)

Reporting of adverse reactions
If any adverse reactions occur, including any not listed in this leaflet, inform your doctor, pharmacist or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions at the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products:
Al. Jerozolimskie 181C, PL-02-222 Warsaw, Tel.: +48 22 49-21-301, Fax: +48 22 49-21-309, Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorization holder.
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store BCG-medac

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and carton following the word EXP.
Store in a refrigerator (2°C – 8°C).
Do not freeze.
Store in the original packaging to protect from light.
The prepared product has been shown to be physically and chemically stable for 24 hours when stored protected from light at room temperature (20°C – 25°C) or in a refrigerator (2°C – 8°C).
From a microbiological standpoint, the medicinal product should be used immediately.
If the product is not used immediately, the user is responsible for the storage conditions and duration prior to use, which should generally not exceed 24 hours at a temperature of 2°C to 8°C, unless reconstitution was carried out under controlled and validated aseptic conditions.

6. Contents of the pack and other information

What BCG-medac contains
The active substance in this medicine is live BCG bacteria (Bacillus Calmette-Guérin, RIVM strain derived from strain 1173-P2).
After reconstitution, one vial contains:
BCG (Bacillus Calmette-Guérin), RIVM strain derived from strain 1173-P2
2 x 10 to 3 x 10 viable particles.
The other ingredients of the powder are: polygeline, anhydrous glucose, polysorbate 80.
The other ingredients of the solvent are: sodium chloride and water for injections.

What BCG-medac looks like and contents of the pack
BCG-medac is a white or almost white powder or porous tablet with yellow and grey tints, and a colourless, clear solution used as solvent. Each pack contains 1, 3 or 5 vial(s), bag(s) of solvent with a vial connector and catheter connector, catheter(s) and Luer-Lock connector(s) for conical fittings. Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
medac
Gesellschaft für
klinische Spezialpräparate mbH
Theaterstr. 6
22880 Wedel
Germany
e-mail: [email protected]

Information intended exclusively for healthcare professionals:
Treatment of symptoms, signs and symptom complexes

*Note: BCG bacteria are sensitive to currently used anti-tuberculosis medicinal products
except for pyrazinamide. If treatment with three anti-tuberculosis drugs is necessary, the
drugs usually recommended are: isoniazid (INH), rifampicin, and ethambutol.
** Definition – see: Infection/Systemic reaction to BCG bacteria
Important information regarding the use of BCG-medac
BCG-medac may be administered only by experienced personnel belonging to medical professionals.
Appropriate storage conditions (see section 5) and package integrity must be ensured.
BCG-medac should be administered under conditions required for intravesical endoscopy.
BCG-medac must not be administered subcutaneously, intradermally, intramuscularly, intravenously, or for vaccination against tuberculosis.
The Luer-Lock connector, which is part of the solvent bag, may only be used for intravesical instillation!
General principles and protective measures for handling BCG-medac
Direct contact with BCG-medac should generally be avoided. BCG-medac is a medicinal product that may cause infection in humans and poses a risk to medical personnel. Exposure may occur if the medicinal product enters the body through broken skin, by inhalation of aerosols, droplets entering the eyes or contacting mucous membranes, or by accidental ingestion. Eating, drinking, or smoking should not be permitted in work areas, and food, beverages, or tobacco products should not be stored there. BCG-medac must not be prepared in rooms where cytotoxic medicinal products for intravenous use are prepared, nor by personnel who prepare cytotoxic medicinal products for intravenous use.
The medicinal product must not be prepared by persons with diagnosed immunodeficiency.
It is recommended to wear a disposable, back-fastening, splash-resistant protective gown, disposable gloves, an FFP2 respiratory mask, and protective goggles with side shields as personal protective equipment during drug preparation. BCG-medac may be transported only in closed containers (storage conditions after reconstitution, see section 6.3).
After completion of work, wipe down work surfaces with an appropriate disinfectant solution. After work and in case of skin contact, perform hand disinfection using a disinfectant, allow it to dry, wash hands, and use skin care products.
Tuberculin skin tests
Intravesical treatment with BCG-medac may cause increased sensitivity to tuberculin and may complicate subsequent interpretation of tuberculin skin tests in the diagnosis of mycobacterial infections. Therefore, tuberculin reactivity should be determined before administration of BCG-medac.
Preparation of the reconstituted intravesical suspension
Prior to use, the medicinal product should be mixed under aseptic conditions with sterile 0.9% (9 mg/ml) sodium chloride solution (see instructions for use, step 7). The catheter should be inserted with special care to avoid trauma to the urethral and bladder mucosa, which could lead to systemic BCG infection. The use of a lubricant is recommended to minimize the risk of traumatic catheterization and to increase patient comfort during the procedure. In women, the amount of lubricant needed may be smaller than in men. No antiseptic effect of the lubricant that could influence the efficacy of the product has been observed. The bladder should be emptied after catheterization to reduce the amount of potentially introduced lubricant before administration of BCG-medac. The suspension should be mixed gently by swirling before use. Macroscopically visible particles do not affect the efficacy and safety of the medicinal product.
The vial contents are intended for single use/one dose only. Any remaining suspension must be discarded.
Any unused medicinal products or waste materials must be disposed of in accordance with local regulations.
Emergency procedures and spill management for BCG-medac
Wear protective clothing and avoid generating dust.
Cover spilled BCG-medac suspension with absorbent cellulose material and moisten it with a disinfectant proven effective against mycobacteria. After wiping up the spilled suspension, clean the surface again with a disinfectant solution and allow it to dry. In case of skin contamination, apply an appropriate disinfectant.
First aid
In case of contamination, always consult a physician.
In case of skin contact: remove contaminated clothing. Disinfect and clean the skin and check whether wounds are contaminated.
In case of eye contact: rinse the affected eye with an adequate amount of eye irrigation solution or, alternatively, with water. Remove contact lenses if necessary.
In case of ingestion: rinse mouth thoroughly with large amounts of water.
In case of inhalation: ensure adequate supply of fresh air.
For further information regarding the catheter, refer to the appropriate instructions for use.
Instructions for users of BCG-medac
Components and use of the instillation kit with catheter and Luer-Lock connector for conical fitting
Main components of the instillation kit

Connecting the vial to the solvent bag

1. Prepare a waste bag (E) for disposal of the set after infusion to prevent contamination.

2. Remove the cap from the vial (A) and disinfect the stopper according to local regulations.

3. Tear off the protective cover (B) from the solvent bag (C) and completely remove the protective cover.

4. Remove the protective cap from the vial connector (C1).

5. Push the connector firmly into the vial’s rubber stopper until it stops.

Mixing the powder with the solvent

6. Break the flow blockage in the vial connector tubing (C1) by bending it several times up and down.

7. Hold the solvent bag so that the vial is positioned below it.

Squeeze the solvent bag several times to transfer sufficient solvent into the vial.
Ensure that the vial is not completely filled to allow for subsequent transfer of the suspension back into the solvent bag. A small amount of solvent may remain in the bag.
While mixing the medicinal product with the solvent, gently move the vial to minimize excessive foaming. If significant foaming occurs, leave the vial undisturbed for a short period (a few minutes).
The contents of the vial must form a uniform suspension. This may take several minutes.

8. Invert the solvent bag and hold it so that the vial is positioned above the bag with its bottom facing upwards.

Hold the vial securely.
Squeeze the solvent bag several times until the vial is emptied.
If any powder remains in the vial, repeat steps 7 and 8.
From a microbiological standpoint, the medicinal product should be used immediately.
If the medicinal product is not used immediately, refer to section 5, “How to store BCG-medac”.
Do not administer the suspension at refrigerated storage temperature to avoid causing the patient an urge to urinate, which would shorten the exposure time.

Catheterization

9. Catheterize the patient according to local regulations and instructions for use, using the provided Luer-Lock catheter (D) and lubricant (D1), or another suitable catheter and/or lubricant.

Empty the bladder using the catheter.
Note when using a separately selected catheter with a conical connector:
To connect the bag to the individually selected catheter, the provided Luer-Lock to conical connector (F) must be used (not shown).
For this purpose, perform the following additional steps:

• Remove the protective cap from the catheter connector (C2, see step 10).
• Before connecting, invert and mix the contents of the bag.
• Connect the Luer-Lock to conical connector (F) to the catheter connector (C2), which is part of the bag.
• Carefully attach the bag with the connector (F) to the patient’s catheter.
• Then proceed to step 11.

Connecting the catheter to the solvent bag

10. Before connecting the bag containing the BCG suspension to the catheter, thoroughly mix the bag’s contents.

Do not administer the suspension at refrigerated storage temperature.
Remove the protective cap from the catheter connector (C2).
Connect the patient’s Luer-Lock catheter (D) to the catheter connector (C2), which is part of the solvent bag.

Infusion

11. Break the flow blockage in the catheter connector tubing (C2) by bending it several times up and down.

While performing this step, hold the patient’s catheter securely.

12. Hold the solvent bag so that the vial is positioned above the bag with its bottom facing upwards.

Gently squeeze the solvent bag with the other hand to perform a slow infusion of the medicinal product into the patient’s bladder.
Squeeze until both the solvent bag and the vial are completely emptied.

13. Squeeze out any remaining air from the solvent bag to empty the catheter as completely as possible.

After infusion

14. Closing the clamp (C3) prevents backflow of fluid into the catheter and minimizes the risk of contamination. Alternatively, the solvent bag may be squeezed while performing steps 15 and 16.

15. Carefully remove the catheter from the bladder without disconnecting the emptied solvent bag from the catheter. Avoid contamination from splashing drops of suspension.

16. Place the set with the catheter into the waste bag and dispose of it according to national regulations.

The vial contents are intended for single use/one dose only. Any remaining suspension must be discarded.