Vaccine Information: THERACYS
THERACYS- bacillus calmette-guerin substrain connaught live antigen injection, powder, lyophilized, for solution
Sanofi Pasteur Inc.
Rx only
WARNING
TheraCys® , BCG Live (Intravesical) contains live, attenuated mycobacteria. Because of the potential risk for transmission, it should be prepared, handled and disposed of as a biohazard material. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.)
BCG infections have been reported in health care workers, primarily from exposures resulting from accidental needle sticks or skin lacerations during the preparation of BCG for administration. Nosocomial infections have been reported in immunosuppressed patients receiving parenteral drugs that were prepared in areas in which BCG was prepared. BCG is capable of dissemination when administered by the intravesical route and serious infections, including fatal infections, have been reported in patients receiving Intravesical BCG. (See WARNINGS, PRECAUTIONS and ADVERSE REACTIONS.)
DESCRIPTION
TheraCys, BCG Live (Intravesical) is a freeze-dried preparation made from the Connaught strain of Bacillus Calmette and Guérin , which is an attenuated strain of Mycobacterium bovis.
The BCG organisms in the product are grown on media containing potatoes, glycerine, asparagine, citric acid, potassium phosphate, magnesium sulfate, ferric ammonium citrate, calcium chloride, copper sulfate and zinc sulfate. Monosodium glutamate is added to the BCG organisms prior to freeze-drying.
Each vial of TheraCys contains 81 mg of freeze-dried BCG. The freeze-dried BCG does not contain any preservative.
One dose of TheraCys consists of one 81mg vial of freeze-dried BCG reconstituted and diluted in 50 mL sterile, preservative-free saline.
The BCG organisms from the vial are viable. In vitro potency is determined by an assay of live BCG organisms based on the number of colonies observed when grown on solid medium. The reconstituted product contains 10.5 ± 8.7 × 108 colony-forming units (CFU) per vial.
CLINICAL PHARMACOLOGY
When administered intravesically as a cancer therapy, BCG promotes a local acute inflammatory and sub-acute granulomatous reaction with macrophage and lymphocyte infiltration in the urothelium and lamina propria of the urinary bladder. (1) (2) The exact mechanism of action is unknown, but the anti-tumor effect appears to be T-lymphocyte-dependent. (2) (3)
Clinical Studies
In a multicenter randomized clinical trial, TheraCys was compared to doxorubicin hydrochloride (Adriamycin®) in patients with carcinoma in situ (CIS) of the urinary bladder, recurrent Ta/T1 papillary tumors of the urinary bladder, or both. (4) Patients were stratified by the presence or absence of CIS and analyzed separately. All papillary tumors were completely resected prior to study entry. The study endpoints were disease-free survival and 2-year disease-free survival. TheraCys was administered intravesically weekly for 6 weeks, with an additional single instillation at 3, 6, 12, 18 and 24 months following the initiation of treatment (total of 11 instillations over 2 years). The initial treatment with doxorubicin was given within 3 days of TUR, followed by 4 weekly treatments and then by 11 monthly treatments (total of 16 instillations over 1 year). Cytology and cystoscopy were obtained every 3 months for 2 years. A total of 285 patients were randomized: 142 to treatment with doxorubicin (69 CIS and 73 non-CIS) and 143 to treatment with TheraCys (70 CIS and 73 non-CIS). An intent-to-treat analysis was performed.
For patients with CIS, the complete response rate (ie, negative biopsies and urine cytology) within 6 months of the initiation of treatment was 33% with doxorubicin and 71% with TheraCys (p < 0.001, Fisher’s Exact Test). The probability of being disease-free at 2 years was 23% with doxorubicin and 51% with TheraCys (p < 0.001, Z Test). The median disease-free survival was 4.9 months for doxorubicin and 30 months for TheraCys (p < 0.001, Log Rank Test).
For patients with Ta/T1 papillary tumors only, the 2-year disease-free survival was 29% with doxorubicin and 50% with TheraCys (p = 0.008, Z Test). The median disease-free survival was 10.5 months with doxorubicin and 22.5 months with TheraCys (p = 0.001, Log Rank Test).
The results are summarized in Table 1.
| Carcinoma in situ | Ta/T1 Papillary Tumors | |||
|---|---|---|---|---|
| Doxorubicin N = 69 | TheraCys N = 70 | Doxorubicin N = 73 | TheraCys N = 73 | |
| ||||
| Complete Response | 23 (33%) | 50 (71%) | - | - |
| Median Disease- free Survival * | 4.9 Months | 30 Months | 10.5 Months | 22.5 Months |
| 2-Year Disease- free Survival * | 23% | 51% | 29% | 50% |
| 95% Confidence Interval | (15%, 35%) | (41%, 65%) | (20%, 41%) | (39%, 63%) |
THERACYS Indications and Usage
TheraCys is indicated for intravesical use in the treatment and prophylaxis of carcinoma in situ (CIS) of the urinary bladder and for the prophylaxis of primary or recurrent stage Ta and/or T1 papillary tumors following transurethral resection (TUR). TheraCys is not recommended for stage TaG1 papillary tumors, unless they are judged to be at high risk of tumor recurrence.
TheraCys is not indicated as an immunizing agent for the prevention of tuberculosis.
CONTRAINDICATIONS
Because of the risk of disseminated BCG infection, TheraCys should not be used in immunosuppressed patients or persons with congenital or acquired immune deficiencies, whether due to concurrent disease (eg, AIDS, leukemia, lymphoma), cancer therapy (eg, cytotoxic drugs, radiation), or immunosuppressive therapy (eg, corticosteroids). (See PRECAUTIONS, Drug Interactions.)
TheraCys is contraindicated for patients with current symptoms or a previous history of systemic BCG reaction. (See Warnings.)
Treatment should be postponed until resolution of a concurrent febrile illness, urinary tract infection, or macroscopic hematuria.
Seven to 14 days should elapse before TheraCys is administered following biopsy, TUR, or traumatic catheterization.
TheraCys should not be administered to persons with active tuberculosis. Active tuberculosis should be ruled out before starting treatment with TheraCys. A test for detecting Mycobacterium tuberculosis infection should be performed if PPD (purified protein derivative of tuberculin) status is unknown. A positive Mantoux test, by itself, is not a contraindication to using TheraCys but an assessment must be made regarding whether the patient has signs, symptoms and/or a chest x-ray consistent with active or latent tuberculosis that requires treatment with antimycobacterial drugs. (5)
WARNINGS
Systemic BCG Reaction
A systemic BCG reaction is a systemic granulomatous illness, which may occur subsequent to exposure to BCG. Because it is usually difficult to isolate BCG organisms from affected organs, it is often unclear to what extent such a reaction is caused by an infectious process versus an inflammatory hypersensitivity reaction, hence the term “systemic BCG reaction”. Based on past clinical experience with intravesical BCG, “systemic BCG reaction” may be defined as the presence of any of the following signs, if no other etiologies for such signs are detectable: fever ≥39.5°C (≥103.1°F) for ≥12 hours; fever ≥38.5°C (≥101.3°F) for ≥48 hours; pneumonitis; hepatitis; other organ dysfunction outside of the genitourinary tract with granulomatous inflammation on biopsy; or the classical signs of sepsis, including circulatory collapse, acute respiratory distress and disseminated intravascular coagulation. (6) If TheraCys is administered within one week of either biopsy, TUR or traumatic bladder catheterization (associated with hematuria), a systemic BCG reaction is much more likely to occur. Death has been reported with the use of TheraCys in association with systemic BCG reaction in post-marketing experience.
Patients should be monitored for the presence of symptoms and signs of toxicity after each intravesical treatment. If a patient develops persistent fever or experiences an acute febrile illness consistent with BCG infection, BCG instillations should be permanently discontinued, the patient immediately evaluated and treated for BCG infection and an infectious diseases consultation sought. (See PRECAUTIONS.)
Additional Warnings
TheraCys is not a vaccine for the prevention of cancer.
TheraCys is an infectious agent. Physicians using this product should be familiar with the literature on the prevention and treatment of BCG-related complications and should be prepared in such emergencies to contact an infectious disease specialist with experience in treating the infectious complications of intravesical BCG. The treatment of the infectious complications of BCG requires long-term, multiple-drug antimycobacterial therapy. Special culture media are required for mycobacteria and physicians administering intravesical BCG should have these media readily available.
The use of TheraCys may cause tuberculin sensitivity. Since this is a valuable aid in the diagnosis of tuberculosis, it may be advisable to determine the tuberculin reactivity by testing before treatment.
Intravesical instillations of BCG should be postponed during treatment with antibiotics, since antimicrobial therapy may interfere with the effectiveness of TheraCys. (See Drug Interactions.) TheraCys should not be used in individuals with concurrent infections.
In patients with small bladder capacity, increased risk of bladder contracture should be considered in decisions to treat with TheraCys.
BCG infection of aneurysms and prosthetic devices (including arterial grafts, cardiac devices and artificial joints) have been reported following intravesical administration of BCG. (7) (8) The risk of these ectopic BCG infections has not been determined. The benefits of BCG therapy must be carefully weighed against the possibility of an ectopic BCG infection in patients with pre-existing arterial aneurysms or prosthetic devices of any kind.
If a bacterial urinary tract infection (UTI) occurs during the course of TheraCys treatment, TheraCys instillation should be withheld until complete resolution of the bacterial UTI for two reasons: • the combination of a UTI and BCG-induced cystitis may lead to more severe adverse effects on the genitourinary tract and • BCG bacilli are sensitive to a wide variety of antibiotics; (9) antimicrobial administration may therefore diminish the efficacy of TheraCys. Similarly, patients undergoing antimicrobial therapy for other infections should be evaluated to assess whether the therapy might diminish the efficacy of TheraCys.
The stopper of the vial for this product contains natural rubber latex which may cause allergic reactions.
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