Adverse reactions : תופעות לוואי

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         Renal and urinary disorders      Cystitis, dysuria, pollakiuria, haematuria (>1/10)
General disorders and            Influenza-like illness, pyrexia, malaise, fatigue administration site conditions
Common              Infections and infestations      Urinary tract infection (>1/100,<1/10)
Blood and lymphatic system       Anaemia disorders
Respiratory, thoracic and        Pneumonitis mediastinal disorders
Gastrointestinal disorders       Abdominal pain, nausea, vomiting, diarrhoea Musculoskeletal and connective       Arthralgia, arthritis, myalgia tissue disorders
Renal and urinary disorders          Urinary incontinence, micturition urgency, urine analysis abnormal
General disorders and                Rigors administration site conditions
Uncommon               Infections and infestations          Tuberculous infections 1 (>1/1,000, <1/100)


Blood and lymphatic system           Pancytopenia, thrombocytopenia disorders
Hepatobiliary disorders              Hepatitis

Skin and subcutaneous tissue         Rashes, eruptions and exanthems NEC1 disorders
Renal and urinary disorders          Bladder constriction, pyuria, urinary retention, ureteric obstruction
Investigations                       Hepatic enzyme increased
Rare                  Respiratory, thoracic and             Cough
(>1/10,000, <1/1,000) mediastinal disorders
Reproductive system and breast       Epididymitis disorders
Very rare              Infections and infestations          Pharyngitis, orchitis, Reiter’s syndrome, Lupus vulgaris (<1/10,000)            Blood and lymphatic system           Lymphadenopathy disorders
Metabolism and nutrition             Anorexia disorders
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            Bronchitis, dyspnoea, rhinitis mediastinal disorders
Gastrointestinal disorders           Dyspepsia3, flatulence3
Skin and subcutaneous tissue         Alopecia, hyperhidrosis disorders
Musculoskeletal and connective       Back pain tissue disorders
Renal and urinary disorders          Renal failure acute
Reproductive system and breast       Balanoposthitis, prostatitis, vulvovaginal discomfort3 disorders
General disorders and                Chest pain, oedema peripheral, granuloma2 administration site conditions
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) which may accompany the localised irritative toxicicities 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 39ºC 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 o treatment may be indicated. Fever above 39 C 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.

Although uncommon, serious infectious complications of intravesical BCG have been reported.
The most serious infectious complication of BCG is disseminated sepsis with associated mortality. In addition, M. bovis infections have been reported in lung, liver, bone, bone marrow, kidney, regional lymph nodes, and prostate in patients who have received intravesical BCG.
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. Some male genitourinary tract infections (orchitis/epididymitis) have been resistant to multiple-drug antituberculous therapy and required orchiectomy.

If a patient develops persistent fever or experiences an acute febrile illness consistent with BCG infection, BCG treatment should be discontinued and the patient immediately evaluated and treated for systemic infection (see section 4.4).

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il