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ONCOTICE™
Organon Teknika
Bacillus Calmette-Guérin (BCG), strain TICE
Antineoplastic
 
Action And Clinical Pharmacology: The precise mechanism of OncoTICE's, [Bacillus Calmette-Guérin (BCG), strain TICE], antitumor action is unknown; however, it appears to exert a variety of actions. OncoTICE induces a granulomatous reaction at the local site of administration. Activated histiocytes responding to the BCG are able to kill tumor cells. BCG acts as both a specific and a nonspecific immunopotentiating agent and is able to stimulate, either directly or indirectly, a whole range of immune responses.

In patients with flat urothelial cell carcinoma in situ of the bladder, intravesical instillation of OncoTICE causes cystoscopical and histological remission of the carcinoma in a high percentage of the patients.

In patients with a primary or relapsing superficial urothelial cell carcinoma of the bladder, the intravesical instillation of OncoTICE as an adjuvant to transurethral resection (TUR) of the carcinoma, causes a prolongation of disease-free interval, reduction of the recurrence rate and prevention of progression of the carcinoma to a higher grade and/or stage.

Indications And Clinical Uses: As a treatment of primary or relapsing flat urothelial cell carcinoma in situ (Tis) of the urinary bladder, and as an adjuvant therapy after TUR of a primary or relapsing superficial urothelial cell carcinoma of the bladder stage TA (grade 1, 2 or 3) or T1 (grade 1, 2, or 3).

OncoTICE is not indicated for the treatment of invasive bladder cancer.

Contra-Indications: OncoTICE should not be used in patients with impaired immune response irrespective whether this impairment is congenital or caused by disease, drugs, or other therapy. OncoTICE should be avoided in patients with a positive HIV serology. OncoTICE is contraindicated during pregnancy and lactation (see Precautions).

OncoTICE should not be used in patients where there is evidence of an active tuberculosis infection or other diseases which need the use of antituberculous agents.

In patients with urinary tract infections, therapy with OncoTICE should be postponed or interrupted until the bacterial culture from urine becomes negative and the therapy with antibiotics and/or urinary antiseptics is stopped.

Manufacturers' Warnings In Clinical States: OncoTICE should not be administered i.v., s.c. or i.m. OncoTICE is not for oral or intradermal use.

Before the first intravesical instillation of OncoTICE, a Mantoux test (PPD) should be performed. In the event that this test is positive, the intravesical instillation of OncoTICE is contraindicated only if there is supplementary medical evidence for an active tuberculosis infection.

Traumatic catheterization can promote systemic BCG infection. Delaying OncoTICE administration should be considered in such patients until mucosomal damage has healed.

Precautions: General: OncoTICE contains live, potentially pathogenic bacteria. Reconstitution, preparation of the OncoTICE suspension for instillation and administration should be performed under aseptic conditions. Unused OncoTICE and all equipment, supplies, and receptacles in contact with OncoTICE should be handled and disposed of as biohazardous.

In patients with known risk factors for HIV infection, it is recommended to perform adequate HIV assays prior to therapy.

Care should be taken not to traumatize the urinary tract. Seven to 14 days should elapse before OncoTICE is administered following TUR, biopsy or traumatic catheterization.

Children: Safety and effectiveness for carcinoma of the urinary bladder in children have not been established.

Pregnancy : Animal reproduction studies have not been conducted with OncoTICE. It is also not known whether OncoTICE can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. OncoTICE should be given to a pregnant woman only if clearly needed. Women should be advised not to become pregnant while on therapy.

Lactation: It is not known whether OncoTICE is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from OncoTICE in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Drug Interactions: OncoTICE is sensitive to the routinely used antituberculous agents, except for pyrazinamide. Studies on the interactions with other drugs have not been performed.

The prior or concomitant use of any immune modulator may interfere with the action of OncoTICE and may also increase risk.

Adverse Reactions: Adverse reactions are often localized to the bladder but may be accompanied by systemic manifestations. Symptoms of bladder irritability, related to the inflammatory response induced by intravesical OncoTICE are reported in about 60% of cases. They begin 3 to 4 hours after instillation and last from 24 to 72 hours. The urinary side effects are usually seen after the third treatment and tend to increase in severity after each administration. Generally there are no long-term urinary complications.

Irritative bladder adverse effects associated with OncoTICE administration have been managed symptomatically with pyridium, propantheline bromide or oxybutinin chloride, and acetaminophen or ibuprofen.

Systemic adverse effects such as malaise, fever, and chills may reflect hypersensitivity reactions and can be treated with antihistamines. The "flu-like" syndrome of 1 to 2 day's duration that frequently accompanies OncoTICE administration should be treated symptomatically.

Patients with manifest symptoms of therapy-induced BCG infections should be adequately treated with antituberculous agents following regular treatment schedules used for tuberculosis infections: when systemic infection is present, the triple drug therapy (isoniazid-rifampicin-ethambutol) with or without cycloserine is given first for several weeks and is followed by therapy with isoniazid and rifampicin; rifampicin plus isoniazid are given when there are signs of an active BCG infection without systemic involvement. In these cases, further instillations of OncoTICE are contraindicated.

Deaths have been reported as a result of systemic BCG infections and sepsis. There have been 2 cases of nephrogenic adenoma, a benign lesion of bladder epithelium, associated with intravesical BCG therapy.

In general, the adverse effects of BCG therapy in bladder carcinoma have been of short duration and moderate morbidity.

A summary of the incidence and severity of adverse effects observed in a study of 674 patients with superficial bladder cancer, treated intravesically with OncoTICE is presented in Table I. The adverse events reported in other studies have been similar.

Flu-like syndrome (which includes fever, shaking chills, malaise and myalgia) had an incidence of 33.2% of which 9% were severe. Severe was ECOG Grade 3 or 4.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdosage occurs if more than 1 vial of OncoTICE is administered per instillation. The patient should be closely monitored for signs of systemic BCG infection and treated with antituberculous medication (see Adverse Effects). tag_DosageDosage

Dosage And Administration: For each instillation, the contents of 1 vial of OncoTICE reconstituted and diluted as indicated, are instilled into the urinary bladder.

OncoTICE therapy comprises the weekly instillation of OncoTICE for 6 consecutive weeks followed by additional instillations at week 8 and 12 and monthly from months 4 to 12.

Administration: Reconstitution, Preparation and Administration of OncoTICE Suspension for Bladder Instillation: Perform the following procedures under aseptic conditions.

Reconstitution: Add 1 mL of a sterile, pyrogen-free physiological saline solution by means of a sterile syringe and allow to stand for a few minutes. Then gently swirl the vial until a homogeneous suspension is obtained. (Caution: avoid forceful agitation.)

Preparation of the Solution for Instillation: Transfer the suspension from the vial into a sterile 50 mL syringe. Rinse the vial with another 1 mL of sterile physiological saline. Add the rinse fluid to the suspension in the 50 mL syringe. Finally dilute the contents of this syringe (1 mL OncoTICE suspension + 1 mL rinse fluid) by adding sterile physiological saline solution up to a total volume of 50 mL. Mix the suspension carefully.

Note: The suspension must not be filtered.

The suspension is now ready for instillation; it contains a total of 1 to 8´10CFU of Tice BCG.

Administration: Insert a catheter via the urethra into the bladder and drain the bladder completely. Connect the 50 mL syringe containing the prepared OncoTICE suspension to the catheter, and instill 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 immobilized or, in case of a bedridden patient, should be turned over from back to prone and vice versa every 15 minutes.

After 2 hours, have the patient void the instilled suspension in a sitting position.

Note: The patient is not allowed to ingest any fluid during a period of 4 hours prior to instillation, or during the time that the OncoTICE suspension remains in the bladder after instillation (2 hours).

If a spill or contamination occurs, sodium hypochlorite (household bleach) or 70% ethanol may be used to decontaminate the area. Wastes should be treated as biohazardous and disposed of accordingly (see Precautions).



Availability And Storage: Each vial of freeze-dried preparation containing Bacillus Calmette Guérin (BCG), strain TICE which is a live, attenuated strain of Mycobacterium bovis contains: 1 to 8´10colony forming units (CFU) of Tice BCG. The culture medium from which the freeze-dried cake is prepared has the following relative composition: lactose 150 g, Sauton medium 250 mL and water 750 mL. No preservatives have been added. Vials of 2 mL, boxes of 1 and 6.

Store at 2 to 8°C and protect from light. The expiry date indicated on the label of the ampuls only applies if the vials are stored under these conditions.

The reconstituted solution for bladder instillation can be stored for up to 2 hours when refrigerated at 2 to 8°C and protected from light. Unused solution should be discarded after 2 hours.