SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Onko BCG 100
Powder and solvent for suspension for intravesical use
BCG ad immunocurationem
BCG for immunotherapy
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Onko BCG 100
1 ampoule or 1 vial with the powder contains:
Live attenuated Bacillus Calmette-Guerin, Brazilian BCG Moreau substrain – 100 mg.
1 ampoule or 1 vial of Onko BCG 100 contains not less than 300 million of live BCG.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Powder and solvent for suspension for intravesical use.
White or light cream powder, dry, amorphous.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
The product is used in treatment of superficial, epithelial, non-invasive bladder tumours (carcinoma urotheliale Ta, Tis, T1).
The product should not be used in invasive bladder cancer, as chances for recovery are scarce.
Onko BCG 100 can be administered in the case of recurring adverse reactions (dysuria, increased body temperature) or increased tuberculin skin reaction.
4.2. Posology and method of administration
One dose of Onko BCG 100, corresponding to 1 dose used for 1 intravesical infusion, is the content of 1 ampoule or 1 vial (100 mg) reconstituted in 1 ml of isotonic solution of sodium chloride.
Method of administration
Add 1 ml of the solvent (sterile isotonic solution of sodium chloride) to an ampoule or vial containing the powder, using a 2 ml or 5 ml sterile syringe. Carefully aspirate three times and re-discharge the contents of the ampoule or vial in order to obtain a homogenous suspension (avoid shaking and foaming the suspension). Then, collect the suspension from the ampoule or vial into a sterile 50 ml syringe and add 49 ml of the solvent (sterile isotonic solution of sodium chloride) to the container. After reconstitution, a homogeneous, uniform suspension without visible conglomerates is obtained.
Remove urine from the bladder using a catheter inserted via the urethra. Then, slowly introduce the entire portion of BCG suspension (50 ml) via the catheter using a 50 ml sterile syringe, this operation should be done slowly.
In order to empty the catheter completely from the BCG suspension, administer 5 ml of sterile isotonic solution of sodium chloride after the suspension has been introduced.
The patient should not drink liquids for 3-4 hours prior to and 2 hours after administration of the product.
Remove catheter after product’s administration.
The instilled BCG suspension must remain in the bladder for 2 hours; during which the patient changes body position (abdomen, back and sideways) every 15 minutes, and empties the bladder after 2 hours.
The medicine should not be administered intravesically (bladder instillation) earlier than 14 days following the biopsy or transurethral resection (TUR).
The treatment should be performed once a week for six consecutive weeks, and then maintenance treatment is recommended every 3 months once a week for 3 consecutive weeks. If cancer recurrence is confirmed, the six-week treatment should be repeated.
Prior to treatment, the patient should undergo an intradermal tuberculin test (PT, PPI) to assess the degree of patient’s immune reactivity. If the skin reaction is very intense or exceeds l cm in diameter (a reaction with a diameter of more than 6 mm is considered a positive reaction), planned immunotherapy should be abandoned. After completion of the 6-week treatment, the intradermal tuberculin test should be repeated to assess the effect of the treatment on the patient’s overall immune system reactivity. In some patients, this reactivity clearly increases.
2 hours after the drug administration, urination should be recommended, and if problems arise with complete bladder emptying (urine retention after micturition), the patient should be catheterized to remove residual urine. After urination, the toilet is disinfected with standard disinfectants.
Hypersensitivity to the active substance or to any of the excipients referred to in section 6.1.
Intravesical administration of the product should not be performed in patients:
– with congenital or acquired defect of the immune system,
– treated with immunosuppressants (e.g. corticosteroids, cytostatics or radiation therapy)
– during pregnancy, lactation or in case of suspected pregnancy,
– with urinary tract infection, until obtaining sterile urine culture,
– with significant bleeding from the bladder,
– with active tuberculosis or any other disease treated with tuberculostatics,
– before 2-3 weeks after transurethral resection TUR,
– with bladder perforation.
4.4. Special warnings and precautions for use
The product contains live attenuated Mycobacterium bovis bacilli, and therefore after completed procedure, all devices and materials (syringes, catheters etc.) should be disposed of in accordance with provisions regarding hazardous waste.
Sexual abstinence is recommended within 48 hours following administration of the product into the bladder. Use condoms within at least 1 week after the instillation.
The product cannot be used intravenously, subcutaneously and intramuscularly.
After product administration, an amount of fluids taken in within 24 hours after first urination should be increased. During this time, at least 12 glasses of fluids should be taken in. Urinate on a regular basis.
Catheter insertion lubricants should not contain tuberculostatic substances.
Prepare the BCG suspension for intravesical instillation immediately before the procedure.
Precautions should be taken when treating p-tuberculostatic and p-allergic complications.
4.5. Interaction with other medicinal products and other forms of interaction
Do not use the product in patients treated concurrently with cytostatics and systemic steroids. Topical steroids are not a contraindication to drug therapy.
During BCG treatment, the administration of antibiotics that may have a bactericidal effect on mycobacteria should be limited, as well as the administration of acetylsalicylic acid derivatives (Aspirin) and some anticoagulants.
4.6. Fertility, pregnancy and lactation
The product should not be administered to pregnant women.
The product should not be administered to breastfeeding women.
4.7. Effects on ability to drive and use machines
The effect on ability to drive and use machines has not been studied.
4.8. Undesirable effects
a. Summary of the safety profile
Like all medicines, Onko BCG 100 may cause side effects.
Treatment of non-invasive bladder cancer with the product for intravesical use is well tolerated by most patients; however, both local and general side effects may occur.
Foci of tuberculosis-like granulation tissue in the lungs have been observed.
The most common adverse effect involves cystitis (cystitis acuta), developing usually after the second or third administration. Polyuria, haematuria and dysuria reported on the day of administration usually disappear within a few hours.
More serious side effects of the therapy are also known such as TB-like interstitial cystitis, prostatitis or epididymitis associated with caseous necrosis.
In patients with tuberculous prostatitis or persistent subfebrile status, a six-week treatment should be used involving QD bitherapy based on rifampicin (600 mg) and isoniazide (5 mg per kg body weight).
In patients with severe septic symptoms and arthritis, the four-month-protocol can be used, accepted for bladder tuberculosis,
involving administration of:
– three medicines daily for 2 months:
rifampicin (600 mg), isoniazide (5 mg per kg body weight)
and ethambutole (25 mg per kg body weight potentially replaced with pyrazinamide 1500 mg),
– two medicines three times a week for 2 consecutive months:
rifampicin (600 mg), isoniazide (10 mg per kg body weight).
With symptoms of arthritis, it is sometimes necessary to use corticosteroids.
In patients with the above-mentioned symptoms of generalised infection, treatment with the medicine should be absolutely discontinued.
Apart from local adverse effects, systemic side effects may also occur, such as malaise, transient increased temperature (38°C-39°C), chills, nausea, muscle and joint pain, diarrhoea and genital pain.
Systemic adverse effects usually resolve within 1-3 days.
In extremely rare cases, the above-mentioned symptoms require treatment cessation and administration of tuberculostatic agents.
Focal tuberculosis-like hepatic granulomatous lesions have also been observed.
All the more serious adverse effects associated with the intravesical administration of the medicine usually resolve after 4 months of anti-tuberculosis chemotherapy.
After administration of Onko BCG 100, the following side effects may appear:
– allergic reaction, which may include difficulty breathing, cough, rash or facial swelling,
– tuberculosis infection, which may include cough, high fever (above 39.5°C) lasting more than 12 hours, or fever (above 38.5°C) lasting more than 2 days,
– yellow eyes or skin,
– greyish or whitish faeces,
– fever (below 38.5°C) with chills, headache, myalgia or arthralgia lasting more than 2 days,
– dysuria or polyuria,
– ocular inflammation,
To alleviate side effect, it is recommended to:
– stop smoking (if the patient is a tobacco smoker),
– get some rest when feeling fatigue,
– avoid drinking alcohol,
– follow all doctor’s recommendations and take medications recommended by the doctor.
b. Tabulated list of adverse reactions
The table below was prepared in accordance with the MedDRA System Organ Classes classification (System Organ Classes and recommended terminology).
The frequency has been determined according to the following criteria: 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), not known (cannot be estimated from the available data)
MedDRA System Organ Classes
Infections and infestations
Tuberculous-like inflammation of the deeper layers of the bladder
Not known (cannot be estimated from the available data)
Tuberculous infection [cough, severe fever lasting longer than 12 hours (temperature above 39.5ºC) or fever lasting longer than two days (temperature above 38.5ºC)]
Prostatitis and/or epididymitis with formation of caseous necrosis foci
Immune system disorders
Allergic reaction (breathing difficulties, cough, rash, facial oedema)
Inflammatory conditions of the eyeball
Respiratory, thoracic and mediastinal disorders
Foci of the tuberculous-like granulation in lungs
Greyish or whiteish stools
Foci of the tuberculous-like granulation in liver
Skin and subcutaneous tissue disorders
Musculoskeletal and connective tissue disorders
Renal and urinary disorders
Vesical tenesmus on the day of administration
Marked pain when urinating
Reproductive system and breast disorders
Pain in the genital area
General disorders and administration site conditions
Fever (below 38.5ºC) with chills, headache, myalgia or arthralgia lasting longer than 2 days
Short-term increase in body temperature (38ºC – 39ºC)
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation 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 via the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products: Al. Jerozolimskie 181C, 02-222 Warsaw, phone number: + 48 22 49-21-301, fax: + 48 22 49-21-309, web page: https://smz.ezdrowie.gov.pl.
Adverse reactions can also be reported to the Marketing Authorisation Holder.
In case of administering an excessive dose or too long retention of the product in the bladder, rinse the bladder a few times with the sterile, physiological sodium chloride solution. Use a catheter to remove urine from the bladder (in patients with urinary retention) and tuberculostatics in the event of septic symptoms.
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
Pharmacotherapeutic group: Immunostimulants, ATC code: L03AX
5.2. Pharmacokinetic properties
BCG bacilli have been applied as a non-specific immunostimulating factor in the treatment of some types of carcinoma.
Intravesical administration of BCG is intended to eliminate primary tumour or to delay or prevent its consecutive recurrence. Specific mechanism of action of BCG has not been fully explained. It is believed that the drug stimulates emergence of inflammatory condition in the bladder wall which defends the organism against development of the disease, and stimulates the patient’s immune system.
5.3. Preclinical safety data
No human toxicity has been confirmed.
During tests on laboratory animals (guinea pigs and white mice), it has been concluded that the product is nontoxic.
6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
Isotonic solution of sodium chloride
6.3. Shelf life
Use the product immediately after reconstitution.
6.4. Special precautions for storage
Store in a refrigerator (2°C-8°C).
Keep the ampoules or vials in the outer carton in order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5. Nature and contents of container
100 mg of the powder in an ampoule or vial made of glass type I and 1.0 mL of the solvent in an ampoule made of glass type I in a cardboard box –packaging of 1 or 5.
Vial stopper is made of chlorobutyl or bromo butyl rubber with silicone layer.
Not all pack sizes may be marketed.
6.6. Special precautions for disposal and other handling
BCG bacilli for intravesical instillation should be prepared immediately before carrying out the procedure.
Activities related to performance of the procedure should be carried out in sterile conditions by personnel using sterile gloves, masks and caps. In case of contamination of body or any object surface with BCG suspension, disinfect the contaminated site with 70% ethyl alcohol or 2% solution of septyl.
After finishing the procedure, dispose of the devices and materials in accordance with provisions regarding hazardous waste.
7. MARKETING AUTHORISATION HOLDER
„BIOMED-LUBLIN” Wytwórnia Surowic i Szczepionek Spółka Akcyjna
Uniwersytecka Street No. 10, 20-029 Lublin, Poland
tel. +48 81 533 82 21
fax +48 81 533 80 60
8. MARKETING AUTHORISATION NUMBER
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 30 July 1999
Date of latest renewal: 09 July 2013
10. DATE OF REVISION OF THE TEXT