Onko bcg 50 / onko bcg® 50 immunotherapeutic agent for patients with bladder cancer

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT

Onko BCG 50 / Onko BCG® 50
Immunotherapeutic agent for patients with bladder cancer
Onko BCG 100 / Onko BCG® 100
Immunotherapeutic agent for patients with bladder cancer

Composition:

Active substance:
1 ampoule or 1 vial of powder contains 50 mg (not less than 150 million CFU) of live attenuated mycobacteria of the Bacillus Calmette-Guérin strain, Brazilian substrain Moreau;

1 ampoule or 1 vial of powder contains 100 mg (not less than 300 million CFU) of live attenuated mycobacteria of the Bacillus Calmette-Guérin strain, Brazilian substrain Moreau;

the product does not contain preservatives;

Excipient: sodium glutamate;

Solvent: 0.9% isotonic sodium chloride solution.

Pharmaceutical form.

Powder for preparation of a suspension for intravesical administration.

Main physicochemical properties:
before reconstitution – dry, free-flowing powder of white or cream color; after reconstitution – homogeneous suspension without visible aggregates.

Pharmacotherapeutic group.

Antineoplastic and immunomodulating agents. Immunostimulants. Other immunostimulants. ATC code: L03AX03.

Immunological and biological properties.

Pharmacodynamics.

BCG vaccine, as a non-specific stimulator of cellular immunity, has been used in the treatment of non-invasive forms of bladder cancer (Ta – non-invasive papillary carcinoma, Tis – carcinoma in situ, flat type, T1 – tumor invading the subepithelial lamina propria), as well as for the prevention of recurrence of non-invasive bladder cancer after surgical tumor removal. BCG instillation stimulates an increase in granulocytes, monocytes/macrophages, and T-lymphocytes. Enhanced production of cytokines such as TNF-α, IFN-γ, and interleukins (IL-1, IL-2, IL-5, IL-6, IL-8, IL-10, IL-12) is also observed. Due to these effects, intravesical instillation of BCG enables elimination of the primary superficial tumor or delays or prevents its recurrence.

The specific mechanism of BCG action has not been fully elucidated. It is believed that the preparation induces a local inflammatory response in the bladder wall, which protects the organism against disease progression, and also stimulates the patient's immune system.

Clinical characteristics.

Indications.

The medicinal product is indicated:

• for the treatment of epithelial, non-invasive forms of bladder cancer and for the prevention of recurrences after surgical intervention:
• epithelial cancer limited exclusively to the mucosa (non-invasive papillary carcinoma) (Ta);
• epithelial cancer localized in the lamina propria of the bladder mucosa (non-muscle-invasive) (T1);
• carcinoma in situ (flat carcinoma in situ) (Tis).

Contraindications.

Intravesical instillation of the medicinal product is contraindicated in the following individuals:

• with hypersensitivity to the active substance or to any of the excipients;
• with congenital or acquired immunodeficiency;
• undergoing treatment with immunosuppressants (e.g., cytostatics, radiation therapy, or corticosteroids);
• diagnosed with active tuberculosis or other diseases requiring treatment with antituberculosis agents;
• with manifest urinary tract infection until sterile urine culture is obtained;
• within 2–3 weeks after transurethral resection of the tumor (TUR);
• with significant hematuria from the bladder;
• with bladder perforation;
• pregnant women, women suspected of pregnancy, or during breastfeeding;
• children.

Special safety precautions.

The medicinal product must be prepared and administered by qualified healthcare personnel. Healthcare workers with impaired immunity must not handle or administer the solution. All procedures related to administration must be performed under sterile conditions using sterile gloves, masks, and forceps. In case the suspension comes into contact with skin or surfaces, these should be disinfected with 70 % ethyl alcohol solution or 2 % Septil solution.

The medicinal product contains live attenuated Mycobacterium bovis bacilli; therefore, after the procedure, instruments and materials (vials, syringes, catheters, etc.) must be immersed in a disinfectant solution for 6 hours and then destroyed in accordance with regulations for the disposal of health-hazardous waste.

Interaction with other medicinal products and other forms of interaction.

Patients should inform their physician about all medicinal products taken recently, including those available without prescription.

The medicinal product should not be administered to patients concurrently receiving cytostatics and steroids. However, local application of steroids is not a contraindication to treatment with this medicinal product.

During the course of BCG therapy, the use of antibiotics active against Mycobacterium tuberculosis, acetylsalicylic acid, and certain anticoagulants should be limited.

Special precautions for use.

The suspension for instillation into the urinary bladder must be prepared immediately before use and administered promptly after reconstitution. After dissolution, a homogeneous suspension without visible aggregates should be formed. The use of the medicinal product after the expiry date stated on the packaging is strictly prohibited.

The patient should avoid taking fluids for 3–4 hours before and 2 hours after administration of the medicinal product.

Unless otherwise directed by the physician, the patient should increase fluid intake during the 24 hours following the first urination after instillation. During this period, at least 12 glasses of fluid should be consumed, and urination should be maintained regularly.

Sexual intercourse is not recommended within 48 hours after instillation of the medicinal product into the urinary bladder. Condoms should be used for at least one week following instillation.

Patients with immunodeficiency should avoid contact with individuals undergoing BCG therapy.

In case of a missed instillation of Onco BCG 50 or Onco BCG 100, the patient should immediately contact their physician.

This medicinal product is not recommended for the treatment of invasive forms of bladder cancer.

In the presence of dysuria, elevated temperature, or a slight increase in tuberculin skin test reaction, the medicinal product may be administered at a dose of 50 mg.

Use during pregnancy or breastfeeding.

Do not use during pregnancy or breastfeeding.

Ability to affect reaction rate when driving or operating machinery.

The effect on the ability to drive or operate machinery has not been studied.

Method of Administration and Dosage.

The contents of 1 ampoule or 1 vial of Onco BCG 50, dissolved in 1 ml of 0.9% sodium chloride solution, constitute 1 dose used for 1 instillation into the urinary bladder.

The contents of 1 ampoule or 1 vial of Onco BCG 100, dissolved in 1 ml of 0.9% sodium chloride solution, constitute 1 dose used for 1 instillation into the urinary bladder.

Treatment regimen for non-invasive forms of bladder cancer

The standard treatment regimen consists of weekly instillations of 1 dose of the drug into the urinary bladder for 6 weeks. This course is called induction therapy. In case of tumor recurrence, the 6-week course should be repeated.

After a 4-week break, a maintenance treatment course with Onco BCG 50, 100 is recommended. For maintenance therapy, 1 dose of the drug should be instilled once weekly for 3 consecutive weeks at 3, 6, 12, 18, 24, 30, and 36 months, starting from the first day of treatment. The complete 3-year treatment cycle (induction + maintenance) comprises a total of 27 bladder instillations.

Prevention of Recurrences

Intravesical instillation should not be performed earlier than 14 days after tumor or bladder mucosa biopsy, transurethral resection of the tumor (TUR), or traumatic catheterization, since in the presence of trauma, when BCG bacilli enter the bloodstream, complications may develop, including miliary tuberculosis or even sepsis.

Method of Administration

The drug is administered into the urinary bladder via a urethral catheter. Lubricants used to facilitate catheter insertion through the urethra into the bladder must not contain antituberculosis agents.

The drug is not intended for intravenous, subcutaneous, or intramuscular administration.

Prior to initiating a course of intravesical BCG instillations, a Mantoux test (PPD, RT) should be performed to assess the patient's immunological response. If the skin reaction is too strong or exceeds 1 cm in diameter (a reaction exceeding 6 mm in diameter is considered positive), planned immunotherapy should be discontinued. After completion of the 6-week course, the Mantoux test should be repeated to evaluate the impact of treatment on the patient’s overall immunological reactivity. In some patients, this reactivity increases significantly.

Preparation and administration of the drug by qualified medical personnel should be performed as follows: Using a sterile 5 ml syringe, add 1 ml of solvent (sterile 0.9% sodium chloride solution) to the ampoule/vial containing the powder. Carefully draw the contents into the syringe and expel back into the ampoule three times to obtain a homogeneous suspension, avoiding vigorous shaking. Then transfer the suspension (1 ml) from the ampoule/vial into a sterile 50 ml syringe and add 49 ml of sterile 0.9% sodium chloride solution. As a result, a homogeneous, uniform suspension without visible aggregates is obtained.

Through a 12–14 F catheter inserted via the urethra, empty the bladder and irrigate it with sterile 0.9% sodium chloride solution to ensure the absence of blood in the irrigation fluid. Then slowly instill the entire dose (50 ml) of BCG suspension through the catheter, followed by an additional 5 ml of sterile 0.9% sodium chloride solution to completely flush the BCG suspension from the catheter.

After administration, remove the catheter and immerse it in a disinfectant solution. The instilled BCG suspension must remain in the bladder for 2 hours. During this time, the patient should change body position every 15 minutes (lying on the abdomen, back, and sides). Six hours after instillation, the patient should void the bladder into a container with disinfectant solution. In case of difficulty with complete bladder emptying (urinary retention after voiding), medical personnel should insert a catheter into the patient’s bladder to ensure complete drainage of residual urine into the same container. Six hours after instillation, the disinfectant solution should be poured into the toilet, which must also be disinfected using standard disinfectants.

Children

Do not use.

Overdose

The likelihood of overdose is low, as the contents of 1 ampoule/vial constitute a single dose. However, in case of accidental administration of an excessive dose or prolonged retention of the drug in the bladder, qualified medical personnel should use a catheter to drain retained urine (in patients with post-void urinary retention) and repeatedly irrigate the bladder with sterile 0.9% sodium chloride solution. If mycobacterial infection develops subsequently, antituberculosis drugs should be initiated urgently. The above measures must be performed by qualified medical personnel.

Adverse Reactions

Adverse reactions are listed by system organ classes according to the Medical Dictionary for Regulatory Activities (MedDRA), using MedDRA frequency definitions: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), and frequency not known (cannot be estimated based on available data).

Gastrointestinal disorders:

very common – nausea;

common – abdominal pain, diarrhea;

very rare – vomiting, intestinal fistula, peritonitis, dyspepsia, flatulence, appendicitis, mumps gland tuberculosis, hepatic tuberculosis, cecal tuberculosis, cecal abscess;

frequency not known – grayish or whitish stools.

Renal and urinary disorders:

very common – cystitis, granulomatous inflammation of the urinary bladder, hematuria, frequent micturition with discomfort and pain, dysuria;

common – bladder irritation, imperative urgency, urinary incontinence, abnormal urine test results;

uncommon – urinary tract infections, bladder contracture, urinary retention, urinary tract obstruction, pyuria (leukocyturia);

rare – renal abscesses;

very rare – acute renal failure, kidney inflammation, renal tuberculosis, bladder tuberculosis, vesicoureteral reflux, nocturia;

frequency not known – frequent micturition with discomfort and pain on the day of drug administration, polyuria, excessive urination, severe pain during micturition.

Reproductive system and breast disorders:

very common – asymptomatic granulomatous prostatitis;

uncommon – epididymitis (inflammation of the epididymis), orchitis (testicular inflammation);

rare – symptomatic granulomatous prostatitis;

very rare – inflammation and abscess of testes and epididymis unresponsive to anti-tuberculosis treatment, inflammation of the glans penis and inner foreskin layer, prostatitis, erectile dysfunction, discomfort in the external genital area;

frequency not known – genital pain.

General disorders and administration site conditions:

very common – temperature above 38.5 °C, weakness, influenza-like symptoms (malaise, fever, chills), general discomfort;

common – tremor, persistent temperature above 38.5 °C;

uncommon – hypotension;

very rare – chest pain, peripheral edema, granulomatosis (observed in various organs: aorta, epididymis, gastrointestinal tract, kidneys, liver, lymph nodes, peritoneal cavity, prostate gland, spleen, bones), multiorgan failure, septic shock;

frequency not known – fever (above 38.5 °C) with chills, headache, muscle or joint pain lasting more than 2 days, transient increase in body temperature (38–39 °C).

Musculoskeletal and connective tissue disorders:

common – myalgia;

uncommon – arthritis, joint pain;

very rare – osteomyelitis, bone marrow infection, abscess of the psoas major muscle, arthropathy, bone and joint infections, myelosuppression, spinal inflammation, spinal tuberculosis, back pain.

Infections and infestations:

uncommon – BCG bacillus infection;

rare – BCG sepsis;

very rare – BCG bacillus infection of implants and surrounding tissues (e.g., aortic prosthesis infection, pacemaker infection, hip or knee joint prosthesis infection, postoperative wound infection), lupus;

frequency not known – tuberculosis-like inflammation of deep bladder wall layers, tuberculous infection (cough, high fever lasting more than 12 hours (above 39.5 °C) or fever lasting more than 2 days (temperature above 38.5 °C)), prostatitis and/or epididymitis with foci of serous necrosis.

Blood and lymphatic system disorders:

uncommon – anemia, cytopenia, thrombocytopenia;

very rare – generalized lymphadenopathy, cervical lymphadenitis, regional lymphadenitis, cryoglobulinemia.

Immune system disorders:

uncommon – Reiter's disease (conjunctivitis, asymmetric arthritis of small joints);

very rare – hypersensitivity reaction, Mikulicz's disease;

frequency not known – allergic reaction (dyspnea, cough, rash, facial swelling).

Respiratory, thoracic and mediastinal disorders:

uncommon – BCG-induced pneumonia, pulmonary granulomatosis;

rare – cough;

very rare – bronchitis, dyspnea, rhinitis, pharyngitis, extensive alveolar damage, purulent pleuritis.

Hepatobiliary disorders:

uncommon – hepatitis;

frequency not known – foci of tuberculosis-like granulation tissue in the liver.

Skin and subcutaneous tissue disorders:

uncommon – rash, abscesses, dermatoses;

very rare – alopecia, hyperhidrosis;

frequency not known – jaundice.

Cardiac disorders:

rare – vascular infection;

very rare – vascular fistulas, mycotic aneurysm, hemorrhagic vasculitis (Henoch-Schönlein purpura), cardiotoxicity.

Respiratory, thoracic and mediastinal disorders:

frequency not known – foci of tuberculosis-like granulation tissue in the lungs.

Eye disorders:

very rare – uveitis, keratitis, conjunctivitis, scleritis;

frequency not known – endophthalmitis, jaundice of the eyes.

Nervous system disorders:

very rare – dizziness, hypoesthesia, paresthesia, somnolence, headache, hypertension, neuralgia, asthenia.

Metabolism and nutrition disorders:

very rare – anorexia.

Investigations:

uncommon – elevated liver enzymes;

very rare – increased prostate-specific antigen (PSA) levels, weight loss.

Treatment of non-invasive forms of bladder cancer with Onco BCG 50 or Onco BCG 100 via intravesical instillations is generally well tolerated by most patients, although some may experience both local and systemic adverse effects. These are usually non-threatening and resolve quickly.

The most commonly observed complications (in approximately 90% of patients) are mild, transient local bladder disorders: cystitis (typically appearing after the second or third instillation), polyuria, hematuria, and painful micturition, which occur on the day of instillation and usually resolve after administration of non-steroidal anti-inflammatory drugs.

More serious adverse outcomes have also been reported, such as tuberculosis-like inflammation of deeper bladder wall layers, prostatitis and/or epididymitis with foci of caseous necrosis, joint inflammation, and foci of tuberculous granulomatosis in the lungs and liver.

Systemic reactions may also develop, including fatigue, malaise, transient fever (38–39 °C), chills, nausea, muscle and joint pain, genital pain, and diarrhea. These symptoms typically last no more than 1–3 days.

In 5% of patients, symptoms of intoxication and life-threatening septic conditions may develop, requiring intensive therapy. Additional treatment with anti-tuberculosis drugs is required in approximately 5–10% of patients undergoing BCG immunotherapy, particularly during intensive maintenance courses.

Instillation of the drug into a bladder with damaged mucosa (e.g., immediately after transurethral resection) may allow attenuated bacilli to enter the bloodstream, potentially leading to miliary tuberculosis or even sepsis. Since the implementation of strict safety criteria for BCG therapy, the number of reports on serious complications has significantly decreased. Therefore, the interval between surgery and BCG instillation (at least 14 days), atraumatic catheter insertion, absence of active urinary tract infection, careful patient monitoring during therapy, and prompt initiation of anti-tuberculosis treatment are of particular importance.

Patients with a small bladder capacity are considered to be at higher risk of developing bladder fibrosis. In patients positive for HLA-B27, symptoms of rheumatic disease or Reiter’s disease (reactive arthritis) may be exacerbated.

Patients should immediately contact their physician or go to the nearest hospital if any of the following symptoms occur:

• allergic reaction, which may manifest as breathing difficulties, cough, rash, or facial swelling;
• tuberculous infection, which may present with cough, fever lasting more than 12 hours (temperature above 39.5 °C) or more than 2 days (temperature above 38.5 °C).

Patients should promptly inform their physician if any of the following symptoms are observed:

• yellowing of the eyes or skin;
• grayish or whitish stools;
• fever (temperature above 38.5 °C) with chills, headache, muscle or joint pain lasting more than 2 days;
• significant pain during urination or excessive urination;
• ocular inflammation;
• hematuria.

Management of complications during or after BCG therapy

Severity of adverse reactions	Recommended measures
I°— mild or moderate symptoms / lasting up to 48 hours. Frequency, hematuria, dysuria, temperature < 38.5 °C, malaise, fatigue, and weakness.	Nonsteroidal analgesics and anti-inflammatory drugs, spasmolytics. Continue BCG instillation course.
II° — severe symptoms / lasting more than 48 hours. Severe frequency, dysuria, prolonged fever, temperature > 38.5 °C. Recommended investigations: urine culture, chest X-ray, liver transaminase levels.	Nonsteroidal analgesics and anti-inflammatory drugs, spasmolytics, ciprofloxacin, ofloxacin or isoniazid (INH) (300 mg/day) until symptoms resolve. Treat nonspecific infection according to antibiogram results. Resumption of BCG instillation is allowed only after complete resolution of symptoms. Dose reduction should be considered.
III° — local regional symptoms or allergic reactions. Allergic: skin rash, joint pain, rheumatoid arthritis, conjunctivitis. Epididymitis, symptomatic granulomatous prostatitis, tuberculous renal granulomatosis, specific hepatitis, pneumonia, osteitis. Recommended investigations: general urine analysis, urine culture, chest X-ray, abdominal ultrasound.		Antihistamines, nonsteroidal anti-inflammatory drugs. Consider initiating isoniazid (INH) and rifampicin (RFP) if symptoms persist longer than 15 days: INH (300 mg/day) and RFP (600 mg/day) for 3 months INH and RFP for 6 months Temporary discontinuation of BCG therapy.
IV° — systemic, severe, septic adverse effects. Symptoms of multiorgan involvement, sepsis, respiratory failure, circulatory failure, hepatomegaly, leukopenia. Additional investigations: complete blood count and biochemical profile, microbiological analysis of blood and urine, liver biopsy, bronchial brush biopsy if necessary.		Hospitalization, immediate initiation of antituberculosis therapy (INH, RFP, ethambutol), prednisolone 40 mg/day, ciprofloxacin. Symptomatic treatment.

To prevent the occurrence of adverse effects, it is recommended to:

• stop smoking (if the patient is a smoker);
• drink plenty of fluids (water);
• rest in case of feeling exhausted;
• avoid alcohol consumption;
• follow all physician's recommendations and take only prescribed medications.

Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua/.

Shelf life.

2 years.

Shelf life of the solvent – 4 years.

After reconstitution, the suspension should be used immediately.

Storage conditions.

Store at a temperature of 2 ºC to 8 ºC (in the refrigerator).

Store in a light-protected place in the original packaging.

Keep out of reach of children.

Incompatibility.

Use only solvents specified in the section "Administration and dosage".

Packaging.

Onco BCG 50:

1 ampoule or 1 vial of powder with 1 ampoule of solvent (1 ml) in a cardboard box.

5 ampoules or 5 vials of powder with 5 ampoules of solvent (1 ml each) in a cardboard box.

Onco BCG 100:

1 ampoule or 1 vial of powder with 1 ampoule of solvent (1 ml) in a cardboard box.

5 ampoules or 5 vials of powder with 5 ampoules of solvent (1 ml each) in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Synthaverus S.A.

Manufacturer's address and location of business operations.

10 University Street, 20-029 Lublin, Poland.