Immunobladder

BCG (Tokyo 172 strain, dried).

Each vial contains live Bacillus Calmette and Guérin (BCG) (as wet weight with 70% of water content) 80 mg.
One ampoule of isotonic sodium chloride solution, JP is accompanied as diluent.
Bile from a bovine gall bladder is used in manufacturing process of Immunobladder.
Immunobladder is a freeze-dried preparation sealed in an amber glass-vial. When reconstituted with accompanying diluent, white or pale-yellow homogeneous suspension is obtained.
pH: 5.5 - 7.0.
Osmotic pressure ratio: 1.05 - 1.16.
Note: Osmotic pressure ratio: ratio relative to isotonic sodium chloride solution, JP.
Dilution for the determination was prepared according to Dosage & Administration.
Excipients/Inactive Ingredients: Stabilizer: Monosodium L-Glutamate Monohydrate, JPC 140 mg.
Accompanying diluent: Isotonic sodium chloride solution, JP 2 mL.

Pharmacology: Antitumor properties of BCG: When MBT-2 cell (mouse transitional cell carcinoma cell line) was mixed with various amount of BCG and transplanted to syngeneic mice subcutaneously, BCG suppressed the proliferation of MBT-2 cells dose-dependently. Histopathological examination of the transplanted site of MBT-2 cell-BCG mixture showed the marked infiltration of macrophages and lymphocytes.
Mechanism of action: The exact mechanism of antitumor-action of BCG is still unknown, but following hypothesis has been suggested: BCG is internalized within tumor cells through binding with fibronectin on the surface of tumor cells. These tumor cells; which internalize BCG, present antigens of BCG and/or tumor specific antigens to T-lymphocytes directly as antigen presenting cells (APC) or indirectly through macrophages after phagocytosed by macrophages, and thus T-lymphocytes are sensitized to BCG antigens as well as antigens of tumor cell. Cytotoxic T-lymphocytes directly kill target tumor cells. Various cytokines produced by helper T-lymphocytes also have an effect to damage tumor cells. Cytokines of Th1-type activates macrophages to enhance efficient phagocytosis and degradation of tumor cells.
Clinical studies: Efficacy in clinical studies: The summaries as follows show the results of clinical trials conducted at a total of 27 institutions including the University of Tokyo, Japan. (See Table 1.)

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Adverse reactions in the clinical trials: The incidence rate of subjective and/or objective symptoms out of evaluated 198 patients (superficial bladder cancer: 154 cases, carcinoma in situ: 44 cases) was 78.3% (155 cases), that of without any symptom was 21.7% (43 cases) in the clinical trials conducted before approval.
The most commonly observed adverse reactions were symptoms of bladder irritation, such as urodynia (57.6%), frequency of urination (56.6%), gross hematuria (29.3%), cloudy urine (21.2%), and dysuria (15.2%). Diminished bladder capacity (18.7%), fever (33.8%), proteinuria (29.8%), occult blood in urine (28.7%), urinary sediment (red blood cell) (38.1%), and urinary sediment (white blood cell) (59.1%) were also commonly observed.
Postmarketing Clinical Study: Clinical study of adjuvant therapy in patients with superficial bladder cancer after transurethral resection of bladder tumor (TURBT).
A randomized comparison study was performed to evaluate the efficacy of Immunobladder as adjuvant therapy after TURBT in patients with superficial bladder cancer (excluding a single primary lesion, or G3). In the study, Immunobladder was administered intravesically to 39 patients at a dose of 80 mg once a week (6 times in total), while doxorubicin hydrochloride was administered intravesically to 40 patients at a dose of 20 mg/40 mL once a week (2 times in total), then once every 2 weeks (7 times in total), and then once a month (8 times in total). In an unscheduled interim analysis, the recurrence-free survival rate was 71.8% (95% CI: 55.1%, 85.0%) for the Immunobladder group and 42.5% (95% CI: 27.0%, 59.1%) for the doxorubicin hydrochloride group (data cutoff date: 31 March 2003). However, since the basis for setting the significance level in the interim analysis is unknown, the analysis results cannot state the statistically significant efficacy of Immunobladder. (See figure.)

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Pharmacokinetics: BCG seldom attaches to and penetrates through a normal urothelium of bladder wall after intravesical instillation. However, BCG will attach to damaged urotherium of a bladder due to bladder cancer, TUR or traumatic catheterization, be internalized into tumor cells and there grow to some extent, and then be carried to regional lymph-nodes. During these processes, antigenic information of BCG and tumor cell is transferred from phagocytic cells to T-lymphocytes. Thus T-lymphocytes, both CD4+ and CD8+ T-lymphocytes, are sensitized to antigens of tumor cells and those of BCG. Sensitized CD4+ T-lymphocytes secrete various kinds of lymphokines to activate macrophages and thus activated macrophages can kill BCG and also destroy tumor cells. Sensitized CD8+ T-lymphocytes have potentiated cytotoxic activity to kill tumor cells. NK cells are also activated by BCG stimulation and get enhanced activity to kill tumor cells.

Superficial urinary cancer, carcinoma in situ of the urinary bladder.
Precaution: Immunobladder is not a vaccine for the prevention of cancer.
Intravesical treatment with Immunobladder should be initiated after confirming by biopsy that the disease is not invasive, since invasive bladder cancer (histological invasive depth: T2 and above) is not indicated for Immunobladder.
The efficacy and safety of Immunobladder in maintenance therapy for patients recovered by administration of Immunobladder have not been established in Immunobladder.

Formulation: Each vial (80 mg) of Immunobladder is usually reconstituted with 2 mL of accompanying diluent (isotonic sodium chloride solution, JP) to make a 40 mg/mL suspension. The reconstituted suspension is further diluted by adding 39 mL of isotonic sodium chloride solution, JP, to make a diluted homogeneous BCG suspension for instillation.
Method of administration: A urethral catheter is inserted into bladder under aseptic conditions, the bladder is drained, and then a suspension containing 80 mg of BCG is instilled very slowly. The patient is asked to retain the suspension for a total of up to two hours if possible. This procedure is repeated usually once a week for eight weeks.
The dosage and number of the administration can be appropriately increased or decreased according to the status of the disease and patient's conditions. The interval of administration can also be extended if needed.
Precaution: For patients treated with antibiotics for other infectious disease, intravesical instillations of Immunobladder should be postponed until completion of the treatment.
Route of administration: Immunobladder should be used only for intravesical instillation. Do not inject percutaneously or by other routes (e.g. intracutaneously, subcutaneously, intramuscularly or intravenously).
Administration: Care should be taken not to traumatize the urinary tract when inserting a urethral catheter for the instillation of Immunobladder. If damage of urinary tract has occurred, the instillation of Immunobladder should be postponed for 7 to 14 days.
Velocity of instillation: Immunobladder should be instilled as slowly as possible.
Void: As for the first void after instillation of Immunobladder, patients should be advised to void while seated to void completely. In order to avoid an accident due to dizziness, it is advisable to stand up slowly after void.
Disposal of urine: Take the first urine after instillation of Immunobladder in an appropriate container (e.g. urinal) and disinfected in order to prevent BCG infection before flushing.
One of the methods for disinfections is adding a half volume of 10% sodium hypochlorite solution and standing for 15 minutes.

Immunobladder should not be given to the following patients.
Immunosuppressed patients due to complicated diseases, such as AIDS, leukemia, malignant lymphoma, or patients under anticancer therapy (e.g., cytotoxic drugs, radiation), or persons with congenital or acquired immune deficiencies.
[Immunosuppressed and/or immunodeficiency patients might not respond to this immuno-modulating agent properly and also are at increased risk to develop disseminated BCG infection.]
Persons who live with HIV infection and patients receiving immunosuppressive dose of steroid or other immunosuppressive agents.
[Immunosuppressed and/or immunodeficiency patients might not respond to this immuno-modulating agent properly and also are at increased risk to develop disseminated BCG Infection.]
Patients with active tuberculosis.
[Patients with active tuberculosis are at higher risk to develop severe adverse reactions with Immunobladder.]
Patients with febrile illness, urinary tract infection, or gross hematuria.
[Patients with febrile illness, urinary tract infection, or gross hematuria are at increased risk to develop severe adverse reactions with Immunobladder.]
Pregnant women or women suspected of being pregnant.
[In animal reproduction studies, Immunobladder was confirmed not to influence on the reproductive abilities of the animal and fetus when administered prior to or at the early stage of pregnancy, but the effects of Immunobladder given at the later stages of the pregnancy on fetus and in maintaining the pregnancy have not been determined.]
Patients with previous history of systemic hypersensitivity to BCG.
[Serious adverse reactions may occur.]

Immunobladder should be used only by the urologists who are well experienced in the treatment of bladder cancer at an institution that is well equipped and staffed to handle an emergency.
Immunobladder contains live Mycobacterium bovis bacillus Calmette-Guérin (BCG). Intravesical instillation of Immunobladder following traumatic catheterization or soon after transurethral resection of bladder tumor (TURBT) or biopsy of bladder tumor has the potential risk to cause severe, sometimes fatal, disseminated infection with BCG. Therefore, the instillation should be postponed for 7 to 14 days following TUR, biopsy or traumatic catheterization while monitoring the recovery of the trauma.
Intravesical instillation of Immunobladder has the potential risk to induce hypersensitive reactions against mycobacterial antigens. When any suggestive symptoms, such as high fever, cough, skin rash, are noticed, further instillation should be stopped and treatment with steroid should be started immediately. Also, administration of anti-tuberculosis drugs should be considered.
Cases of nosocomial iatrogenic infections with BCG have been reported in USA due to the contamination of US-equivalent product into other therapeutics. Immunobladder should be handled carefully as an infectious agent.

Administration with special caution (Immunobladder should be administered with special caution to the following patients.
Patients with previous history of tuberculosis or persons who showed strong positive reaction in tuberculin skin-testing [These patients may drastically respond to Immunobladder].
Patients with history of drug allergy.
Important precautions: Immunobladder should be used after giving the patient or his/her appropriate representative enough information about his/her disease status, necessity to use Immunobladder, method of administration of Immunobladder, period of administration, expected adverse reactions, and necessity of reporting to his/her doctor on adverse reactions, if they occur.
Care should be taken not to traumatize the urinary tract or not to introduce contaminants into the urinary system when administered.
Patients should be monitored for the presence and degree of subjective and/or objective symptoms due to adverse reaction after each intravesical instillation.
Patients should be advised to be attentive to systemic adverse reactions, such as fever, chills, malaise, flu-like symptoms, or increased fatigue, and to report promptly to their physician if he/she experiences any of these symptoms, as well as severe urinary adverse reactions, such as burning, pain by voiding, urgency, frequency of urination, or other symptoms such as joint pain, cough, or skin rash.
It is advisable to perform tuberculin skin-testing prior the start of treatment with Immunobladder.
Use in the elderly: The incidence of superficial bladder cancer and carcinoma in situ (CIS) of the bladder is higher in elderly persons.
No trends toward increased adverse reactions or abnormalities in laboratory examinations have been observed in elderly patients.
Use in children: The safety in children has not been established (no clinical experience).

No abnormality was observed in the animal (rats) reproduction studies, where BCG was administered to rats prior or early stages of pregnancy. The influence of Immunobladder on the later stages of pregnancy and on fetus has not been confirmed. Further, intravesical instillation of Immunobladder may cause problems in maintaining pregnancy. Immunobladder should not be administered to a pregnant woman or woman suspected of being pregnant.
Women who might become pregnant should be advised not to become pregnant while on therapy with Immunobladder.
It is not known whether Immunobladder is excreted in human milk when instilled into urinary bladder. If it is excreted as many drugs, there is potential risk for serious adverse reactions from Immunobladder in nursing infants, so, a decision should be made whether to discontinue nursing or to discontinue intravesical instillation of Immunobladder, taking into account the importance of the instillation-therapy to the mother.

The incidence rate of subjective and/or objective symptoms was 78.3% (155 cases) out of evaluated 198 patients in the clinical trials conducted for approval.
The incidence rate of subjective and/or objective symptoms was 64.4% (2,210 cases) out of evaluated 3,431 patients in the post-marketing surveillance.
The summary of adverse reactions seen in the clinical trials and post-marketing surveillance are as follows (incidence unknown for some adverse reactions).
Serious adverse reactions: BCG Infections: Because Immunobladder contains live mycobacteria, intravesical instillation of Immunobladder may cause disseminated, local, and/or ectopic BCG infections. Cases of sepsis, hepatitis, cerebrospinal meningitis, cystitis, pyelonephritis, nephritis, prostatitis, epididymitis, and aneurysms due to BCG infections have been reported. If a patient develops such symptoms, intravesical instillation of Immunobladder should be discontinued. The patients who developed any of these symptoms should be treated by anti-tuberculosis chemotherapy with the combination of isoniazid, rifampicin with or without ethambutol. In addition to the appropriate symptomatic treatment, pyrazinamide should not be used, because BCG is resistant to pyrazinamide.
Disseminated BCG infections: Fatal cases due to disseminated BCG infection have been reported. Such dissemination might be induced by traumatic catheterization. Flu-like febrile symptoms lasting more than 48 hours, fever ≥39°C, systemic manifestations increasing in intensity with repeated instillations, or persistent abnormalities in liver function tests suggest disseminated BCG infection.
Local BCG infections: BCG infections of uro-genital organs, such as kidney, renal pelvis, ureter, bladder, urethra, prostate and epididymis have been reported.
Ectopic BCG infection: BCG infection of aneurysms has also been reported.
Interstitial pneumonia: Treatment with Immunobladder may develop severe interstitial pneumonia. The patient who developed interstitial pneumonia complains subjective symptoms such as high fever, cough, and dyspnea and shows characteristic abnormalities in chest X-ray examination and hypoxemia in arterial blood examination. If not treated properly, death may occur. If interstitial pneumonia is suspected, further instillation of Immunobladder should be discontinued and potent steroid-therapy should be promptly started in addition to appropriate supportive therapy.
If the differential diagnosis between disseminated BCG infection is difficult it is advisable to use steroids in combination with antituberculosis drugs.
Systemic delayed-type hypersensitivity (DTH): Deaths presumably due to DTH with anaphylaxis-like symptoms, such as cough, skin-rash, have been reported in the clinical trials of Immunobladder. (The patients who showed any symptom suggestive systemic DTH should be discontinued from further instillation of Immunobladder and immediately treated with steroids in combination with antituberculosis chemotherapy.)
Contracted bladder: Contracted bladders have been reported during treatment with Immunobladder.
Renal failure: The patient should be closely monitored for signs of serious renal disorder such as renal failure. Appropriate measure such as discontinuation of the treatment should be taken when any abnormalities are noticed.
Reiter's syndrome (conjunctivitis, polyarthritis, etc): Reiter's syndromes have been reported during treatment with Immunobladder.
Other adverse reactions: See Table 2.

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Contraindication for coadministration (Immunobladder should not be administered together with the following drugs). (See Table 3.)

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Precautions for coadministration (Immunobladder should be administered with care when coadministrated with the following drugs). (See Table 4.)

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Immunobladder is a freeze-dried preparation of BCG, an attenuated strain of Mycobacterium bovis. It is hardly considered that medical staff using Immunobladder will be infected with BCG under normal handling circumstances. However, Immunobladder should be handled using aseptic technique wearing rubber gloves and mask.
When damaged skin, such as injured fingers, accidentally made contact with Immunobladder, the surrounding region of skin should be immediately disinfected with rubbing alcohol.
All containers and equipment in contact with Immunobladder should be disinfected by boiling or soaking in antiseptic solution.
Precautions for handling: Reconstitute Immunobladder just before use.
Before adding the accompanying diluent, check the dryness of the product in the vial. Then remove the plastic cover from the top of vial and wipe the surface of gum-stopper and surrounding with a sterile cotton-piece soaked with alcohol. Wipe the neck of attached ampoule containing the accompanying diluent (isotonic sodium chloride solution, JP) with cotton-piece soaked with alcohol, and put the cut mark side up and snap it towards the opposite side to open.
Inject the diluent into the vial of Immunobladder and allow the solution to stand for about 1 minute, and then shake the vial gently to make a homogeneous suspension. Avoid foaming since this will make the withdrawal of the suspension difficult. Withdraw the entire suspension into the syringe and further dilute in additional isotonic sodium chloride solution, JP to prepare homogeneous BCG suspension for intravesical instillation.

Immunobladder and the accompanying diluent should be refrigerated between +2 and +8 degrees C. Do not freeze. The product contains live bacteria and should be protected from the sunlight, direct or indirect. Exposure to artificial light should be kept to a minimum.

Cancer Immunotherapy

L03AX03 - BCG vaccine ; Belongs to the class of other immunostimulants.

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