Oncotice Powder For Instillation Fluid For Intravesical Use Containing 2-8 X 10^8 Cfu Tice Bcg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
OncoTICE® powder for instillation fluid for intravesical use containing 2-8 x 108 CFU Tice BCG
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
OncoTICE BCG 12.5mg per vial containing 2-8 x 108 CFU Tice BCG.
7
After reconstitution in 50ml saline the suspension contains 0.4-1.6 x 10 CFU/ml.
OncoTICE is a freeze-dried preparation containing attenuated bacilli of Mycobacterium bovis, prepared from a culture of Bacillus Calmette-Guerin (BCG). For excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Powder for instillation fluid for intravesical use
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
OncoTICE is indicated for treatment of primary or concurrent carcinoma-in-situ of the urinary bladder and for the prevention of recurrence of high grade and/or relapsing superficial papillary transitional cell carcinoma of the urinary bladder (Stage Ta (grade 2 or 3) or T1 (grade 1,2 or 3)) after transurethral resection.
OncoTICE is only recommended for stage Ta grade 1 papillary tumours, when there is judged to be a high risk of tumour recurrence.
4.2 Posology and method of administration
For preparation of the OncoTICE suspension see section 6.6.
Dosage
Adults and the elderly
The contents of one vial of OncoTICE, reconstituted and diluted as indicated, are instilled into the urinary bladder.
Induction treatment
Weekly instillation with OncoTICE during the first 6 weeks.
When used as an adjuvant therapy after TUR of a superficial urothelial cell carcinoma of the bladder (see “Therapeutic indications”), treatment with OncoTICE should be started between 10 and 15 days after performing the
TUR. Treatment should not be started until mucosal lesions after TUR have healed. Treatment should also be delayed in cases of gross haematuria or major bladder irritability.
Maintenance treatment
Maintenance treatment consists of weekly instillation with OncoTICE during 3 consecutive weeks at months 3, 6, and 12 after initiation of the treatment. The need for maintenance treatment every 6 months beyond the first year of treatment should be evaluated on the basis of tumour classification and clinical response.
Children
Not recommended
Intravesical instillation
Insert a catheter via the urethra into the bladder and drain the bladder completely. Connect the 50ml syringe containing the prepared OncoTICE suspension to the catheter, and instil the suspension into the bladder. After instillation, remove the catheter. The instilled OncoTICE suspension must remain in the bladder for a period of 2 hours. During this period care should be taken that the instilled OncoTICE suspension has sufficient contact with the whole mucosal surface of the bladder. Therefore the patient should not be immobilised or, in case of a bed-ridden patient, should be turned over from back to abdomen and vice versa every 15 minutes. After two hours, have the patient void the instilled suspension in a sitting position.
Urine should be voided in a sitting position for 6 hours after treatment and two cups of household bleach should be added to the toilet before flushing. The bleach and urine should be left to stand in the toilet for 15 minutes before flushing.
NOTE: The patient must not ingest any fluid for a period starting 4 hours prior to instillation, until bladder evacuation is permitted (i.e. 2 hours after instillation).
4.3 Contraindications
Urinary tract infections. Therapy with OncoTICE should be interrupted until the bacterial culture from urine becomes negative and therapy with antibiotics and/or urinary antiseptics is stopped.
Gross haematuria. In these cases OncoTICE therapy should be stopped or postponed until the haematuria has been successfully treated or has resolved.
In patients with a positive Tuberculin test, OncoTICE instillations are contraindicated only if there is supplementary medical evidence for an active tuberculous infection.
Treatment with anti-tuberculosis drugs like streptomycin, para-amino-salicylic acid (PAS), isoniazid (INH), rifampicin and ethambutol.
Impaired immune response irrespective of whether this impairment is congenital or caused by disease, drugs or other therapy.
Positive HIV serology.
Pregnancy and lactation.
4.4 Special warnings and precautions for use
Before the first intravesical instillation of OncoTICE, a Tuberculin test (PPD) should be performed. If the test is positive, OncoTICE instillations are contraindicated only if there is supplementary medical evidence for an active tuberculous infection.
Traumatic catheterisation or other injuries to the urethra or bladder mucosa can promote systemic BCG infection. Administration of OncoTICE should be delayed in such patients until mucosal damage has healed.
It is recommended that patients known to be at risk of HIV infection be adequately screened prior to commencing therapy.
Patients should be monitored for the presence of symptoms of systemic BCG infection and signs of toxicity after each intravesical treatment.
OncoTICE should not be administered intravenously, subcutaneously or intramuscularly.
In order to protect the partner, the patient should be recommended to either refrain from intercourse within one week after OncoTICE instillation, or to use a condom.
The use of OncoTICE may sensitise patients to tuberculin resulting in a positive reaction to PPD.
Reconstitution and preparation of the OncoTICE suspension for instillation and administration should be performed under aseptic conditions.
Spillage of OncoTICE suspension may cause Tice BCG contamination. Any spilled OncoTICE suspension should be cleaned by covering with paper towels soaked with tuberculocidal disinfectant, such as household bleach, for at least 10 minutes. All waste materials should be disposed of as biohazard material
Accidental exposure to Tice BCG could occur through self-inoculation, by dermal exposure through an open wound, or by inhalation or ingestion of OncoTICE suspension. Tice BCG exposure should not produce significant adverse health outcomes in healthy individuals. However, in case of suspected, accidental self-inoculation, PPD skin testing is advised at the time of the accident and six weeks later to detect skin test conversion.
4.5 Interaction with other medicinal products and other forms of interaction
Tice BCG is sensitive to most antibiotics and in particular to the routinely used anti-tuberculosis drugs like streptomycin, para-amino salicylic acid (PAS), isoniazid (INH), rifampicin and ethambutol. Therefore the anti-tumour activity of OncoTICE may be influenced by concomitant therapy with antibiotics. If a patient is being treated with an antibiotic it is recommended to postpone the intravesical instillation until the end of the antibiotic-treatment (see also "Contra-indications").
Immunosuppressants and/or bone marrow depressants and/or radiation may interfere with the development of the immune response and thus with the antitumour efficacy and should therefore not be used in combination with OncoTICE.
4.6 Pregnancy and lactation
OncoTICE instillation for carcinoma of the bladder is contraindicated during pregnancy and lactation (see section 4.3).
4.7 Effects on ability to drive and use machines
Not applicable
4.8 Undesirable effects
The side effects of intravesical OncoTICE therapy are generally mild and transient. Toxicity and side-effects appear to be directly related to the cumulative CFU count of BCG administered with the various instillations. Approximately 90% of patients develop local irritative symptoms in the bladder. Pollakiuria and dysuria are reported very frequently. The cystitis and typical inflammatory reactions (granulomas) which occur in the mucosa of the bladder after instillation of BCG, and which cause these symptoms, may be an essential part of the anti-tumour activity of the BCG. In most cases, the symptoms disappear within two days after instillation and the cystitis does not require treatment. During maintenance treatment with BCG, the symptoms of cystitis may be more pronounced and prolonged. In these cases, when severe symptoms are present, isoniazid (300 mg daily) and analgesics can be given until disappearance of symptoms.
Table 1 Side effects reported during post-marketing surveillance
|
Occurrence |
MedDRA SOClass |
Preferred terms |
|
Very common (>1/10) |
Renal and urinary disorders |
Cystitis, dysuria, pollakiuria, haematuria |
|
General disorders and administration site conditions |
Influenza-like illness, pyrexia, malaise, fatigue | |
|
Common (>1/100, <1/10) |
Infections and infestations |
Urinary tract infection |
|
Blood and lymphatic system disorders |
Anaemia | |
|
Respiratory, thoracic and mediastinal disorders |
Pneumonitis | |
|
Gastrointestinal disorders |
Abdominal pain, nausea, vomiting, diarrhoea | |
|
Musculoskeletal and connective tissue disorders |
Arthralgia, arthritis, myalgia | |
|
Renal and urinary disorders |
Urinary incontinence, micturition urgency, urine analysis abnormal |
|
General disorders and administration site conditions |
Rigors | |
|
Uncommon (>1/1,000, <1/100) |
Infections and infestations |
Tuberculous infections1 |
|
Blood and lymphatic system disorders |
Pancytopenia, thrombocytopenia | |
|
Hepatobiliary disorders |
Hepatitis | |
|
Skin and subcutaneous tissue disorders |
Rashes, eruptions and exanthems NEC1 | |
|
Renal and urinary disorders |
Bladder constriction, pyuria, urinary retention, ureteric obstruction |
|
Occurrence |
MedDRA SOClass |
Preferred terms |
|
Uncommon (>1/1,000, <1/100) |
Investigations |
Hepatic enzyme increased |
|
Rare (>1/10,000, <1/1,000) |
Respiratory, thoracic and mediastinal disorders |
Cough |
|
Reproductive system and breast disorders |
Epididymitis | |
|
Very rare |
Infections and infestations |
Pharyngitis, orchitis, Reiter’s syndrome, Lupus vulgaris |
|
(<1/10,000) |
Blood and lymphatic system disorders |
Lymphadenopathy |
|
Metabolism and nutrition disorders |
Anorexia | |
|
Psychiatric disorders |
Confusional state | |
|
Nervous system disorders |
Dizziness, dysaesthesia3, hyperaesthesia3, paraesthesia, somnolence, headache, hypertonia, neuralgia3 | |
|
Eye disorders |
Conjunctivitis | |
|
Ear and labyrinth disorders |
Vertigo3 | |
|
Vascular disorders |
Hypotension | |
|
Respiratory, thoracic and mediastinal disorders |
Bronchitis, dyspnoea, rhinitis | |
|
Gastrointestinal disorders |
Dyspepsia3, flatulence3 | |
|
Skin and subcutaneous tissue disorders |
Alopecia, hyperhidrosis | |
|
Musculoskeletal and connective tissue disorders |
Back pain | |
|
Renal and urinary disorders |
Renal failure acute | |
|
Reproductive system and breast disorders |
Balanoposthitis, prostatitis, vulvovaginal discomfort3 | |
|
General disorders and administration site conditions |
Chest pain, oedema peripheral, granuloma2 | |
|
Investigations |
Prostatic specific antigen increased, weight decreased |
NEC = not elsewhere classified
1 High Level Term instead of Preferred Term
2 Granuloma NOS has been observed in various organs including the aorta, bladder, epididymis, gastrointestinal tract, kidney, liver, lungs, lymphnodes, peritoneum, prostate
3 Only isolated cases reported during post-marketing surveillance
Also commonly observed are malaise, a low to medium grade fever and/or influenza-like symptoms (fever, rigors, malaise and myalgia). These symptoms usually appear within 4 hours after instillation and last for 24 to 48 hours. Fever higher than 39°C typically resolves within 24 to 48 hours when treated with antipyretics (preferably paracetamol) and fluids. However, it is frequently not possible to distinguish these uncomplicated febrile reactions from early systemic BCG infection and antituberculosis treatment may be indicated. Fever above 39oC that does not resolve within 12 hours despite antipyretic therapy must be considered as systemic BCG-infection, necessitating clinical confirmatory diagnostics and treatment.
Systemic BCG infections could be due to traumatic catheterisation, bladder perforation or premature BCG instillation after extensive TUR of a superficial carcinoma of the bladder. These systemic infections may be manifested initially by pneumonitis, hepatitis and/or cytopenia after a period of fever and malaise during which symptoms progressively increase. Patients with
symptoms of therapy-induced systemic BCG infection should be adequately treated with anti-tuberculosis drugs according to treatment schedules used for tuberculosis infections. In these cases, further treatment with Tice BCG is contraindicated.
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 Yellow Card Scheme, website www.mhra.gov.uk/yellowcard.
4.9 Overdose
Overdosage occurs when more than one vial of OncoTICE is administered per instillation. In case of overdosage, the patient should be closely monitored for signs of systemic BCG infection and if necessary treated with anti-tuberculosis drugs.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
OncoTICE is an immunostimulating agent (ATC code L 03-AX03).
It has anti-tumor activity, but the exact mechanism of action is not known. Published data suggest that an active non-specific immune response takes place. BCG invokes a local inflammatory response involving a variety of immune cells, such as macrophages, natural killer cells and T cells.
5.2 Pharmacokinetic properties
For the treatment and recurrence prophylaxis of bladder cancer, the attachment of BCG to the bladder wall after voiding has been shown to be important. This allows a targeted pharmacological effect at the site of application.
5.3 Preclinical safety data
As a result of the wide clinical application of BCG vaccination in the preceding decades the risks of BCG in human subjects are well-characterised. Intra-vesical administration to dogs has been found to be safe and without significant toxicity. No evidence of birth defects, genetic damage or carcinogenecity in humans are available from the extensive adverse reaction literature of BCG used as a vaccine.
6.1 List of excipients
Lactose Asparagine Citric Acid (E330)
Dibasic Potassium Phosphate Magnesium Sulfate Iron Ammonium Citrate Glycerol (E422)
Zinc formate
Ammonium Hydroxide (E527)
6.2 Incompatibilities
OncoTICE is incompatible with hypo and hypertonic solutions. OncoTICE should only be mixed with physiological saline as described in section 6.6. Other incompatibility studies have not been performed.
6.3 Shelf life
12 months
In-use stability of the reconstituted product has been demonstrated for 2 hours at 2 - 8°C protected from light. From a microbiological point of view, unless the method of opening/reconstitution/dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.
6.4 Special precautions for storage
Store at 2 - 8°C, protect from light
6.5 Nature and contents of container
2ml Type 1 glass vials in packs of 1 and 3
6.6 Special precautions for disposal
OncoTICE contains live, attenuated mycobacteria. Because of the potential risk for transmission, it should be prepared, handled and disposed of as a biohazard material (see section 4.4).
Perform the following procedures under aseptic conditions using sterile physiological saline solution as the diluent and suitable techniques to ensure protection of the health care worker:
Reconstitution
Transfer 50ml of the diluent into a sterile container and add 1ml from the sterile container to the vial. Allow to stand for a few minutes then gently swirl until a homogenous suspension is obtained. Forceful agitation should be avoided.
Preparation of the solution for instillation
Transfer the reconstituted contents of the vial back into the container. Rinse the vial by transferring 1ml from the container back into the vial, then add back to the container. Mix the suspension carefully.
The suspension, with a total volume of 50ml is now ready for instillation; it contains a total of 2-8 x 108 CFU of Tice BCG.
7 MARKETING AUTHORISATION HOLDER
N V Organon Kloostertraat 6 P0 Box 20 5340 BH, Oss The Netherlands
8 MARKETING AUTHORISATION NUMBER(S)
PL 05003/0046
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
04/08/2000 / 19/03/2004
10 DATE OF REVISION OF THE TEXT
24/04/2014