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.

Posology

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.

Paediatric population

No data are available

Method of administration

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. If a closed-system transfer device is not available, the 50 ml OncoTICE suspension is instilled into the bladder by gravity flow. 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 contra-indicated 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 anti-tumour 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 relevant

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

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

(<1/10,000)

Infections and infestations

Pharyngitis, orchitis, Reiter's syndrome, Lupus vulgaris

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

Not known

Immune system disorders

Hemophagocytic lymphohistiocytosis3

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) which may accompany the localised, irritative toxicities that often reflect hypersensitivity reactions and be treated symptomatically. 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 by pneumonitis, hepatitis, cytopenia, vasculitis, infective aneurysm and/or sepsis 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.