Theracys (BCG Live (Intravesical))
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Theracys (BCG Live (Intravesical))

TheraCys®
[BCG Live (Intravesical)]

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.)

DRUG 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 (bcg live intravesical) contains 81 mg of freeze-dried BCG. Prior to use, each vial is reconstituted with the accompanying diluent (3 mL), which contains 0.85% w/v sodium chloride, 0.025% w/v polysorbate 80, 0.06% w/v sodium dihydrogen phosphate and 0.25% w/v disodium hydrogen phosphate. Neither the freeze-dried BCG nor the diluent contain preservative.

One dose of TheraCys (bcg live intravesical) consists of one 81mg vial of reconstituted material further diluted in 50 mL sterile, preservative-free saline.

The BCG organisms are viable upon reconstitution. In vitro potency is determined by an assay of the number of colonies grown on solid medium. The reconstituted product contains 10.5 ± 8.7 x 108 colony-forming units (CFU) per vial when resuspended in the diluent provided.

What are the possible side effects of BCG (TheraCys, Tice BCG Vaccine)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

  • fever, chills, cough, body aches, joint pain, weakness, vomiting, or other flu symptoms;
  • nausea, vomiting, stomach pain, jaundice (yellowing of your skin or eyes);
  • pain or burning when you urinate;
  • difficult urination;
  • more frequent or urgent urinating;
  • blood in your urine, lower back pain;
  • pain or swelling in your testicles;
  • easy bruising or...

Read All Potential Side Effects and See Pictures of Theracys »

What are the precautions when taking bcg live (intravesical) (Theracys)?

Before receiving this medication, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients (such as latex), which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: immune system problems (e.g., HIV, certain cancers such as leukemia/lymphoma), radiation treatment, current infection/fever (e.g., bladder infection, active tuberculosis), injury/procedure in the bladder within the last 7 days (e.g., catheterization, biopsy, signs of bloody urine).

Before using this medication, tell your doctor or pharmacist...

Read All Potential Precautions of Theracys »

Last reviewed on RxList: 10/28/2008
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

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 (bcg live (intravesical)) is not recommended for stage TaG1 papillary tumors, unless they are judged to be at high risk oftumor recurrence.

TheraCys (bcg live (intravesical)) is not indicated as an immunizing agent for the prevention oftuberculosis.

DOSAGE AND ADMINISTRATION

One dose of TheraCys, BCG Live (Intravesical) consists of the intravesical instillation of 81 mg (dry weight) BCG. This dose is prepared by reconstituting 1 vial containing 81 mg freeze-dried BCG with the contents of 1 vial containing 3 mL diluent. The reconstituted BCG is further diluted in 50 mL of sterile, preservative-free saline, for a total of 53 mL instillation volume. (See Preparation ofAgent.)

For intravesical instillation only. Do not inject subcutaneously or intravenously.

A urethral catheter is inserted into the bladder under aseptic conditions, the bladder is drained and then 53 mL suspension of TheraCys (bcg live (intravesical)) is instilled slowly by gravity, following which the catheter is withdrawn.

The patient retains the suspension for as long as possible for a total of up to two hours. During the first 15 minutes following instillation, the patient should lie prone. Thereafter, the patient is allowed to be up. At the end of 2 hours, all patients should void in a seated position for safety reasons. Patients should be instructed to increase fluid intake in order to flush the bladder in the hours following BCG treatment.

Preparation ofAgent

The preparation of the TheraCys (bcg live (intravesical)) suspension should be done using aseptic technique. To avoid cross-contamination, parenteral drugs should not be prepared in areas where BCG has been prepared. A separate area for the preparation of the TheraCys (bcg live (intravesical)) suspension is strongly recommended. All equipment, supplies and receptacles in contact with TheraCys (bcg live (intravesical)) should be handled and disposed of as biohazardous. The pharmacist or individual responsible for mixing the agent should wear gloves and eye protection and take precautions to avoid contact of BCG with broken skin. If the preparation cannot be performed in a biocontainment hood, then a mask and gown may be worn to avoid inhalation of BCG organisms and inadvertent exposure to broken skin.

TheraCys (bcg live (intravesical)) should not be handled by persons with an immunologic deficiency.

Do not remove the rubber stopper from the vial.

Apply a sterile piece of cotton moistened with a suitable antiseptic to the surface of the rubber stoppers of the vial of diluent and vial of TheraCys (bcg live (intravesical)) . Reconstitute the freeze-dried material with the total 3 mL volume of diluent. Shake the vial gently until a fine, even suspension results. Avoid foaming since this will prevent withdrawal of the proper dose. Withdraw the entire contents (approximately 3 mL) of the reconstituted material into the syringe.

The reconstituted material from the vial (1 dose) is further diluted in an additional 50 mL of sterile, preservative-free saline to a final volume of 53 mL for intravesical instillation.

TheraCys (bcg live (intravesical)) should be used immediately after reconstitution. However, if there is an unavoidable delay between reconstitution and administration, this delay must not exceed 2 hours. Any reconstituted product which exhibits flocculation or clumping that cannot be dispersed with gentle shaking should not be used.

Reconstituted product should not be exposed to sunlight, direct or indirect. Exposure to artificial light should be kept to a minimum.

Instructions for Disposal

After use, unused product, packaging and all equipment and materials used for instillation of the product (eg, syringes, catheters) should be placed immediately in a container for biohazardous materials and disposed of according to local requirements applicable to biohazardous materials.

Urine voided during the 6 hour period following TheraCys (bcg live (intravesical)) instillation should be disinfected with an equal volume of 5% hypochlorite solution (undiluted household bleach) and allowed to stand for 15 minutes before flushing. (See PRECAUTIONS: PATIENT INFORMATION.)

Treatment Schedule

Intravesical treatment of the urinary bladder should begin 7 to 14 days after biopsy or transurethral resection and consists of induction and maintenance therapy. For the induction therapy, one dose of TheraCys (bcg live (intravesical)) is administered each week for 6 consecutive weeks. Induction therapy should be followed by maintenance therapy, consisting of one dose given 3, 6, 12, 18 and 24 months following the initial dose.

HOW SUPPLIED

TheraCys (bcg live (intravesical)) is supplied in packages containing one vial of the freeze-dried product, containing 81 mg (dry weight) (10.5 ± 8.7 x 108 CFU) and one vial containing 3 mL of diluent - Product No. 49281-880-01.

CPT Code: 90586

CPT is a registered trademark ofthe American Medical Association.

Storage

TheraCys, BCG Live (Intravesical) and the accompanying diluent should be refrigerated at 2°to 8°C (35°to 46°F). It should not be used after the expiration date marked on the vial, otherwise it may be inactive.

At no time should the freeze-dried TheraCys (bcg live (intravesical)) be exposed to sunlight, direct or indirect. Exposure to artificial light should be kept to a minimum.

Manufactured by: Sanofi Pasteur Limited, Toronto, Ontario, Canada. Distributed by: Sanofi Pasteur Inc. Swiftwater, PA 18370 USA. FDA Rev date: n/a

Last reviewed on RxList: 10/28/2008
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

Data from Clinical Studies

Administration of TheraCys (bcg live (intravesical)) causes an inflammatory response in the bladder and has been frequently associated with transient fever, hematuria, urinary frequency and dysuria; careful patient monitoring is required. Symptoms of bladder irritability are reported in approximately 50% of patients receiving TheraCys (bcg live (intravesical)) and typically begin 4-6 hours after instillation and last 24-72 hours. The irritative side effects are usually seen following the third instillation and tend to increase in severity after each administration. The mechanism of action of the irritative side effects has not been studied, but is most consistent with an immunological mechanism. There is no evidence that dose reduction or antituberculous drug therapy can prevent or lessen the irritative symptoms ofTheraCys (bcg live (intravesical)) .

The adverse reactions which occurred among 127 recipients of TheraCys (bcg live (intravesical)) during a US clinical trial are listed in Table 2. (4) The adverse reactions are combined totals caused by both the original bladder cancer and the TheraCys (bcg live (intravesical)) treatment.

Table 2: Adverse Reactions: Toxicity Data Derived From a US Clinical Trial (4)

Adverse Event Percent of Patients
(N = 127)
Overall (Grade ≥ 3)
Adverse Event Percent of Patients
(N = 127)
Overall (Grade ≥ 3)
Dysuria 52% (4%) Nausea/Vomiting 16% (0%)
Urinary Frequency 40% (2%) Anorexia 11% (0%)
Malaise 40% (2%) Renal Toxicity (NOS) 10% (2%)
Hematuria 39% (7%) Genital Pain 10% (0%)
Fever (>38°C) 38% (3%) Arthralgia/Myalgia 7% (1%)
Chills 34% (3%) Urinary Incontinence 6% (0%)
Cystitis 29% (0%) Cramps/Pain 6% (0%)
Anemia 21% (0%) Diarrhea 6% (0%)
Urinary Tract Infection 18% (1%) Contracted Bladder 5% (0%)
Urgency 18% (0%) Leukopenia 5% (0%)

The following adverse reactions were reported in < 5% of patients: coagulopathy, abdominal pain, liver involvement, systemic infection, pulmonary infection, cardiac (unclassified), headache, skin rash, tissue in urine, local infection, constipation, dizziness, fatigue, thrombocytopenia, ureteral obstruction and flank pain.

In a US Clinical Trial, 112 patients received TheraCys (bcg live (intravesical)) . The incidence of adverse reactions associated with intravesical TheraCys (bcg live (intravesical)) is given below.

The following adverse events were reported in =1% of patients: tissue in urine, local infection, constipation, dizziness, fatigue, thrombocytopenia and flank pain.

In this study, local irritative symptoms were more common with TheraCys (bcg live (intravesical)) than with doxorubicin; however, grade ≥ 3 irritative toxicity was similar, occurring in approximately 2-7% of patients. Systemic symptoms (fever, chills, malaise, etc.) were also more common with TheraCys (bcg live (intravesical)) . Overall, grade ≥ 3 toxicities were seen in 26 patients (23%) treated with TheraCys (bcg live (intravesical)) and 25 patients (21%) treated with doxorubicin. "Systemic infection" was reported to occur in three patients treated with TheraCys (bcg live (intravesical)) (one grade 2 and two grade 3) and one patient treated with doxorubicin (grade 2). In four patients, treatment was discontinued because of toxicity (two with irritative symptoms, one with severe hematuria and one with possible BCG infection). In addition, six patients refused further treatment because of severe local toxicity and/or chills. Six of these ten patients received TheraCys (bcg live (intravesical)) . Table 3 compares the common adverse events reported in this study.

Table 3: Comparative Toxicity from a US Clinical Trial (4)

  Study Arm
TheraCys (N=112) Doxorubicin (N=119)
All Grades Grade =3 All Grades Grade =3
Dysuria 58 (52%) 4 (4%) 48 (40%) 7 (6%)
Frequency 45 (40%) 2 (2%) 34 (29%) 5 (4%)
Malaise 45 (40%) 2 (2%) 17 (14%) 0
Hematuria 44 (39%) 8 (7%) 33 (28%) 8 (7%)
Fever (>38°C) 43 (38%) 3 (3%) 11 (9%) 0
Chills 38 (34%) 3 (3%) 7 (6%) 0
Cystitis 33 (29%) 0 23 (19%) 1 (<1%)
Urgency 20 (18%) 1 (<1%) 14 (12%) 3 (2%)
Nausea/Vomiting 18 (16%) 0 10 (8%) 1 (<1%)
Bladder Cramps/Pain 7 (6%) 0 6 (5%) 2 (1%)

Acute, localized irritative side effects of TheraCys (bcg live (intravesical)) may be accompanied by systemic manifestations consistent with a "flu-like" syndrome. Systemic adverse effects of 1-2 days' duration such as malaise, fever and chills often reflect hypersensitivity reactions.

However, symptoms such as fever of ≥ 38.5°C, or acute localized inflammation such as epididymitis, prostatitis, or orchitis, persisting longer than 48 hours suggest active infection and evaluation for serious infectious complication should be considered.

Data from Postmarketing Experience

These events were reported voluntarily from a population of uncertain size, it is not possible to reliably calculate their frequencies.

Symptomatic granulomatous prostatitis, epididymo-orchitis, and renal abscess associated with administration of intravesical BCG have been reported.

Ocular symptoms (including uveitis, conjunctivitis, iritis, keratitis, granulomatous choreoretinitis) alone, or in combination with joint symptoms (arthritis or arthralgia), urinary symptoms and/or skin rash, have been reported following administration of intravesical BCG. The risk appears to be elevated among patients who are positive for HLA-B27. (13)

Skin rash, arthralgia and migratory arthritis may be allergic reactions.

Serious infectious complications of intravesical BCG have been reported. The most serious infectious complication of BCG is disseminated sepsis associated with death. In addition, BCG infections have been reported in eye, lung, liver, bone, bone marrow, kidney, regional lymph nodes, peritoneum and prostate in patients who have received intravesical BCG. Some male genitourinary tract infections (orchitis/epididymitis) have been refractory to multiple drug antimycobacterial therapy and required orchiectomy.

Treatment ofAdverse Reactions

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 disease consultation sought. (See WARNINGS and PRECAUTIONS.) Treatment with two or more antimycobacterial agents should be initiated promptly while diagnostic evaluation, including cultures, is conducted. Negative cultures do not necessarily rule out infection. TheraCys (bcg live (intravesical)) is sensitive to the most commonly used antimycobacterial agents (isoniazid, rifampin and ethambutol). TheraCys (bcg live (intravesical)) is not sensitive to pyrazinamide. (14)

Reporting ofAdverse Reactions

Patients should be encouraged to report all adverse events after treatment with TheraCys (bcg live (intravesical)) . Adverse events should be reported by health care providers to MEDWATCH (call 1-800-FDA-1088 or report on line to www.fda.gov/medwatch). Physicians, physician assistants, nurses and pharmacists should report adverse occurrences temporally related to the administration of the product to the Pharmacovigilance Department, Sanofi Pasteur Inc., Discovery Drive, Swiftwater PA 18370 or call 1-800-822-2463.

Read the Theracys (bcg live (intravesical)) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Treatment combinations using immunosuppressants and/myelosuppressants and/or radiation interfere with the development of the immune response to TheraCys (bcg live (intravesical)) and increase the risk of disseminated BCG infection. Antimicrobial therapy for other infections may interfere with the effectiveness ofTheraCys (bcg live (intravesical)) . (12)

As there are no data to suggest that the acute, local urinary tract symptoms common with intravesical BCG are due to mycobacterial infection, antimycobacterial drugs (eg, isoniazid) should not be used prophylactically to prevent the local, irritative side effects ofTheraCys (bcg live (intravesical)) .

For patients with a condition that may in the future require mandatory immunosuppression (eg, awaiting an organ transplant, myasthenia gravis) the decision to treat with TheraCys (bcg live (intravesical)) should be considered carefully.

REFERENCES

13. Wittes RC, et al. Characterization of BCG-associated sterile arthritis and Reiter's syndrome. New Delhi, India: 10th International Congress of Immunology. 1998:1245-9.

14. van der Meijden APM, et al. The possible influence of antibiotics on results of Bacillus Calmette-Guérin intravesical therapy for superficial bladder cancer. J Urol 1991;146:444-6. Product Information as ofJuly 2006.

Last reviewed on RxList: 10/28/2008
This monograph has been modified to include the generic and brand name in many instances.

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 for ≥ 12 hours; fever ≥ 38.5°C 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 (bcg live (intravesical)) 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 (bcg live (intravesical)) 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 (bcg live (intravesical)) is not a vaccine for the prevention ofcancer.

TheraCys (bcg live (intravesical)) 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 (bcg live (intravesical)) 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 (bcg live (intravesical)) 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 live (intravesical)) .

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 ofany kind.

If a bacterial urinary tract infection (UTI) occurs during the course of TheraCys (bcg live (intravesical)) treatment, TheraCys (bcg live (intravesical)) 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 (bcg live (intravesical)) . Similarly, patients undergoing antimicrobial therapy for other infections should be evaluated to assess whether the therapy might diminish the efficacy of TheraCys (bcg live (intravesical)) .

Caution: the stopper ofthe vial for this product contains natural rubber latex which may cause allergic reactions.

Management of Serious BCG Complications

Acute, localized irritative toxicities of TheraCys (bcg live (intravesical)) may be accompanied by systemic manifestations, consistent with a "flu-like" syndrome. Systemic adverse effects of 1-2 days' duration such as malaise, fever and chills often reflect hypersensitivity reactions. However, symptoms such as fever of ≥ 101.3°F (38.5°C), or acute localized inflammation such as epididymitis, prostatitis, or orchitis persisting longer than 2-3 days suggest active infection and evaluation for serious infectious complications should be considered.

In patients who develop persistent fever or experience an acute febrile illness consistent with BCG infection, two or more antimycobacterial agents should be administered while diagnostic evaluation, including cultures, is conducted. BCG treatment should be discontinued. Negative cultures do not necessarily rule out infection. Physicians using this product should be familiar with the literature on prevention, diagnosis and treatment of BCG-related complications and, when appropriate, should consult an infectious disease specialist or other physician with experience in the diagnosis and treatment of mycobacterial infections.

TheraCys (bcg live (intravesical)) is sensitive to the most commonly used antimycobacterial agents (isoniazid, rifampin and ethambutol). TheraCys (bcg live (intravesical)) is not sensitive to pyrazinamide.

PRECAUTIONS

General

TheraCys (bcg live (intravesical)) contains live mycobacteria and should be prepared and handled using aseptic technique. (See DOSAGE AND ADMINISTRATION, Preparation of Agent.) BCG infections have been reported in health care workers preparing BCG for administration. Needle stick injuries should be avoided during the handling and mixing of TheraCys (bcg live (intravesical)) .

Nosocomial infections have been reported in immunosuppressed patients receiving parenteral drugs that were prepared in areas in which BCG was prepared. (10) (11)

BCG is capable of dissemination when administered by intravesical route and serious infections, including fatal infections, have been reported in patients receiving intravesical BCG. (6) Care should be taken not to traumatize the urinary tract or to introduce contaminants into the urinary system. Seven to 14 days should elapse before TheraCys (bcg live (intravesical)) is administered following TUR, biopsy, or traumatic catheterization.

TheraCys (bcg live (intravesical)) may be administered to persons in groups at high risk for HIV infection only after careful evaluation of risk/benefit and with extra caution.

The use of TheraCys (bcg live (intravesical)) may cause a falsely positive tuberculin reaction sensitivity. It may therefore be advisable to test to determine the true tuberculin reactivity before treatment. (5)

Pregnancy Category C

Animal reproduction studies have not been conducted with TheraCys (bcg live (intravesical)) . It is also not known whether TheraCys (bcg live (intravesical)) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. TheraCys (bcg live (intravesical)) should not be given to a pregnant woman unless clearly needed. Women should be advised not to become pregnant while on therapy.

Nursing Mothers

It is not known whether TheraCys (bcg live (intravesical)) can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from TheraCys (bcg live (intravesical)) in nursing infants, it is advisable to discontinue nursing or to discontinue the drug, taking into account the importance ofthe drug to the mother.

Pediatric Use

Safety and effectiveness of TheraCys (bcg live (intravesical)) for the treatment of superficial bladder cancer in pediatric patients have not been established. Therefore, TheraCys (bcg live (intravesical)) should not be used in pediatric patients.

REFERENCES

5. CDC. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings. MMWR 2005;54(RR-17):1-89.

6. Lamm DL, et al. Incidence and treatment of complications of Bacillus Calmette-Guérin intravesical therapy in superficial bladder cancer. J Urol 1992;147:596-600.

7. Stone D. Mycobacterium bovis infection of an implantable defibrillator following intravesical therapy with bacille Calmette-Guérin. Clin InfDis 1993;16:825-6.

8. Wolf YG, et al. Infection of a ruptured aortic aneurysm and an aortic graft with bacille Calmette-Guérin after intravesical administration for bladder cancer. J Vasc Surg 1995;22:80-4.

9. Durek C, et al. Interference of modern antibacterials with bacillus Calmette-Guérin viability. J Urol 1999;162:1959-62.

10. Stone MM, et al. Brief report: Meningitis due to iatrogenic BCG infection in two immunocompromised children. N Engl J Med 1995,333:561-3.

11. Waecker NJ, et al. Nosocomial transmission of Mycobacterium bovis bacille Calmette-Guérin to children receiving cancer therapy and to their health-care providers. Clin Infect Dis 2000;30:356-62.

12. Böhle A, Jocham D. Intravesical immunotherapy with Bacillus Calmette-Guérin, facts, figures and results. München, Germany: Urban & Fischer; 2000. p. 111-2.

Last reviewed on RxList: 10/28/2008
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

Overdosage occurs if more than one vial of TheraCys (bcg live (intravesical)) is administered per instillation. If overdosage occurs, the patient should be closely monitored for signs of active local or systemic infection. For acute local or systemic reactions suggesting active infection, an infectious disease specialist experienced in BCG complications should be consulted.

CONTRAINDICATIONS

Because of the risk of disseminated BCG infection, TheraCys (bcg live (intravesical)) 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 (bcg live (intravesical)) is contraindicated for patients with current symptoms or a previous history of systemic BCG reaction. (See WARNINGS.) Treatment should be postponed until resolution ofa concurrent febrile illness, urinary tract infection, or gross hematuria. Seven to 14 days should elapse before TheraCys (bcg live (intravesical)) is administered following biopsy, TUR, or traumatic catheterization.

TheraCys (bcg live (intravesical)) should not be administered to persons with active tuberculosis. Active tuberculosis should be ruled out before starting treatment with TheraCys (bcg live (intravesical)) . 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 (bcg live (intravesical)) 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)

REFERENCES

5. CDC. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings. MMWR 2005;54(RR-17):1-89.

Last reviewed on RxList: 10/28/2008
This monograph has been modified to include the generic and brand name in many instances.

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 (bcg live (intravesical)) 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 (bcg live (intravesical)) (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 (bcg live (intravesical)) (p < 0.001, Fisher's Exact Test). The probability of being disease-free at 2 years was 23% with doxorubicin and 51% with TheraCys (bcg live (intravesical)) (p < 0.001, Z Test). The median disease-free survival was 4.9 months for doxorubicin and 30 months for TheraCys (bcg live (intravesical)) (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 (bcg live (intravesical)) (p=0.008, Z Test). The median disease-free survival was 10.5 months with doxorubicin and 22.5 months with TheraCys (bcg live (intravesical)) (p=0.001, Log Rank Test).

The results are summarized in Table 1.

Table 1: US Clinical Trial – Efficacy (4)

  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%)
* Based upon Kaplan-Meier estimates

REFERENCES

1. Mikkelsen DJ, Ratliff TL. Mechanisms of action of intravesical Bacillus Calmette-Guérin for bladder cancer. In: Urologic Oncology. 1989:195-211.

2. O'Donnell MA, DeWolf WC. BCG immunotherapy for superficial bladder cancer. New prospects for an old warhorse. Surg Oncol Clin North Amer 1995;4:189-202.

3. Prescott S, et al. Intravesical Evans strain BCG therapy: quantitative immunohistochemical analysis of the immune response within the bladder wall. J Urol 1992:147:1636-42.

4. Lamm DL, et al. A randomized trial of intravesical doxorubicin and immunotherapy with Bacille Calmette-Guérin for transitional-cell carcinoma of the bladder. N Eng J Med 1991;325:1205-9.

Last reviewed on RxList: 10/28/2008
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

TheraCys (bcg live (intravesical)) is retained in the bladder for as long as possible up to 2 hours and then voided. To avoid transmission of BCG to others, for 6 hours after treatment, patients should void while seated in order to avoid splashing of urine. Urine voided during this time should be disinfected for 15 minutes with an equal volume of household bleach before flushing or disposal. Unless medically contraindicated, patients should be instructed to increase fluid intake in order to "flush" the bladder for several hours following treatment with TheraCys (bcg live (intravesical)) . Patients may experience burning with the first void after treatment.

Because TheraCys (bcg live (intravesical)) contains live mycobacteria, excreted urine may also contain live bacteria. Patients should be advised on appropriate infection control procedures to protect family and close contacts from infection.

Fever, chills, malaise, flu-like symptoms, increased fatigue or an increase in urinary symptoms, (such as burning or pain on urination) are not uncommon. However, patients should notify their physicians if any of these symptoms last more than 48 hours or increase in severity. Patients should also notify their physicians if they experience any of the following: an increase in urinary symptoms (such as urgency, frequency of urination, blood in urine), joint pain, eye complaints (such as pain, irritation or redness), cough, skin rash, jaundice or vomiting.

Last reviewed on RxList: 10/28/2008
This monograph has been modified to include the generic and brand name in many instances.

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PATIENT INFORMATION

TheraCys (bcg live (intravesical)) is retained in the bladder for as long as possible up to 2 hours and then voided. To avoid transmission of BCG to others, for 6 hours after treatment, patients should void while seated in order to avoid splashing of urine. Urine voided during this time should be disinfected for 15 minutes with an equal volume of household bleach before flushing or disposal. Unless medically contraindicated, patients should be instructed to increase fluid intake in order to "flush" the bladder for several hours following treatment with TheraCys (bcg live (intravesical)) . Patients may experience burning with the first void after treatment.

Because TheraCys (bcg live (intravesical)) contains live mycobacteria, excreted urine may also contain live bacteria. Patients should be advised on appropriate infection control procedures to protect family and close contacts from infection.

Fever, chills, malaise, flu-like symptoms, increased fatigue or an increase in urinary symptoms, (such as burning or pain on urination) are not uncommon. However, patients should notify their physicians if any of these symptoms last more than 48 hours or increase in severity. Patients should also notify their physicians if they experience any of the following: an increase in urinary symptoms (such as urgency, frequency of urination, blood in urine), joint pain, eye complaints (such as pain, irritation or redness), cough, skin rash, jaundice or vomiting.

Last reviewed on RxList: 10/28/2008
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Theracys Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

BCG VACCINE - INTRAVESICAL

COMMON BRAND NAME(S): Theracys

WARNING: This medication contains live bacteria that have been weakened to decrease the chances of causing an illness. However, this medication has rarely caused very serious, possibly fatal infections. Tell your doctor immediately if you develop any signs of infection (e.g., high/persistent fever).

USES: This medication is used to treat a certain type of bladder cancer (carcinoma in situ-CIS) and prevent it from returning. It is also used to prevent another type of bladder cancer (papillary tumor) from returning after surgery to remove it. This medication works by causing the body's defense system (immune system) to become more active.

This form of the medication is not used to prevent tuberculosis.

HOW TO USE: This medication is given into the bladder through a tube (catheter) by a health care professional as directed by your doctor. This medication is usually given weekly for the first 6 weeks and then less often thereafter as directed by your doctor.

Do not drink any fluids for 4 hours before treatment. The medication is left in the bladder for up to 2 hours and then released by urinating. Follow your doctor's instructions carefully. There may be some burning pain when you first urinate. Since the urine contains live bacteria that may infect you or others, you must sit down to urinate for 6 hours after treatment to avoid splashing of the urine. After each time you urinate during this 6-hour period, pour household bleach (about the same amount of bleach as the amount of urine) into the toilet, then wait 15 minutes before flushing. Always wash your hands afterward. Talk to your doctor about other important things you must do to prevent infection.

Drink plenty of fluids after your first urination unless otherwise directed by your doctor. Doing so helps clear the medication from your body.

Disclaimer

Theracys Consumer (continued)

SIDE EFFECTS: Bladder irritation (e.g., difficult/painful/frequent/bloody urination), fever, or chills may occur. High/persistent fever may be a sign of an infection. Tell your doctor or pharmacist promptly if any of these effects occur, persist, or worsen. Your doctor may prescribe additional medications to help control these symptoms. Nausea, vomiting, loss of appetite, or diarrhea may also occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: muscle/joint pain, pain/swelling of the testes, unusual tiredness, fast/pounding heartbeat, shortness of breath, cough, vision changes, redness/swelling/pain in the eye, eye sensitivity to light, severe stomach/abdominal pain, yellowing skin/eyes.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US, you may report side effects to the Vaccine Adverse Event Reporting System (VAERS) at 1-800-822-7967. In Canada, you may report side effects to Health Canada at 1-866-234-2345.

Read the Theracys (bcg live (intravesical)) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: Before receiving this medication, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients (such as latex), which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: immune system problems (e.g., HIV, certain cancers such as leukemia/lymphoma), radiation treatment, current infection/fever (e.g., bladder infection, active tuberculosis), injury/procedure in the bladder within the last 7 days (e.g., catheterization, biopsy, signs of bloody urine).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: certain blood vessel disease (aneurysm), man-made medical devices/parts in the body (e.g., pacemakers, artificial joints, arterial grafts).

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor. It is recommended that women receiving this medication avoid pregnancy. Consult your doctor for more details and to discuss using at least 2 reliable forms of birth control (e.g., condoms, birth control pills) while receiving this medication. If you become pregnant or think you may be pregnant, tell your doctor immediately.

It is not known whether this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

Disclaimer

Theracys Consumer (continued)

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious interactions may occur: antibiotics (e.g., isoniazid, rifampin, penicillins such as amoxicillin, macrolides such as erythromycin), drugs that weaken the immune system (e.g., abatacept, efalizumab, corticosteroids such as prednisone, cancer chemotherapy), mefloquine.

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting BCG vaccine.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use.

This medication may interfere with the tuberculosis (TB) skin test, possibly causing false test results. If a skin test is needed, it is recommended that patients finish it before treatment.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Keep all regular medical and laboratory appointments.

MISSED DOSE: For the best possible benefit, it is important to receive each scheduled dose of this medication as directed. If you miss a dose, contact your doctor to establish a new dosing schedule.

STORAGE: Not applicable. This medication is given in a hospital or clinic and will not be stored at home.

Information last revised August 2010. Copyright(c) 2010 First Databank, Inc.

Theracys Patient Information Including Side Effects

Brand Names: TheraCys, Tice BCG Vaccine

Generic Name: BCG (Pronunciation: bee cee jee)

What is BCG (Theracys)?

BCG (Bacillus Calmette and Guérin) is made using the organisms of a bacteria.

This medication is injected directly into the bladder, where it causes inflammation and increases certain white blood cells known as natural killer cells. These killer cells act to destroy invading cells such as tumor cells in the bladder.

BCG is used to treat bladder cancer that is localized (has not spread to other parts of the body).

BCG may also be used for other purposes not listed in this medication guide.

What are the possible side effects of BCG (Theracys)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

  • fever, chills, cough, body aches, joint pain, weakness, vomiting, or other flu symptoms;
  • nausea, vomiting, stomach pain, jaundice (yellowing of your skin or eyes);
  • pain or burning when you urinate;
  • difficult urination;
  • more frequent or urgent urinating;
  • blood in your urine, lower back pain;
  • pain or swelling in your testicles;
  • easy bruising or bleeding;
  • eye pain, redness, watering, severe burning or itching; or
  • vision changes, increased sensitivity to light.

Less serious side effects may include:

  • mild nausea, stomach pain, or loss of appetite;
  • mild bladder or groin pain;
  • urine leakage or incontinence;
  • diarrhea, constipation;
  • headache;
  • mild skin rash;
  • dizziness, tired feeling; or
  • tissue particles in your urine (not blood).

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect. You may report side effects to FDA at 1-800-FDA-1088.

Read the Theracys (bcg live (intravesical)) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about BCG (Theracys)?

You should not be treated with this medication if you are allergic to BCG, or if you have tuberculosis, a fever, a bladder infection, blood in your urine, or a weak immune system (caused by certain drugs or disease such as AIDS, leukemia, or lymphoma).

You should also not receive BCG if you have had a bladder biopsy, surgery, or catheter within the past 14 days.

Before you receive BCG, tell your doctor if you are allergic to latex rubber, or if you have myasthenia gravis, a pacemaker or other artificial heart device, an artificial joint or other prosthetic, or any type of infection (including HIV).

Also tell your doctor if you have ever had tuberculosis, bypass surgery, or an aneurysm (dilated blood vessel), or if you currently need to have an organ transplant (kidney, liver, heart, etc).

Your doctor may ask you to drink extra fluids for several hours after your BCG treatment to help flush out your bladder. Follow your doctor's instructions about the type and amount of liquids you should drink.

Call your doctor right away if you have a fever after receiving BCG, especially if the fever lasts for several hours or longer.

Antibiotics can make BCG less effective and should be avoided during your treatment with BCG. If you have an infection that must be treated with an antibiotic, you may need to stop receiving BCG for a short time. Follow your doctor's instructions and be sure to tell any other doctor who treats you that you are receiving BCG.

Side Effects Centers

Theracys Patient Information including How Should I Take

What should I discuss with my health care provider before I receive BCG (Theracys)?

You should not receive this medication if you are allergic to BCG, or if you have:

  • tuberculosis;
  • a weak immune system from diseases such as AIDS, leukemia, or lymphoma;
  • fever, a bladder infection, or blood in your urine;
  • if you are using steroids or receiving chemotherapy or radiation treatments; or
  • if you have had a bladder biopsy, surgery, or catheter within the past 14 days.

Before you receive BCG, tell your doctor if you are allergic to latex rubber, or if you have:

  • any type of bacterial, fungal, or viral infection (including HIV);
  • myasthenia gravis;
  • a pacemaker or other artificial heart device;
  • an artificial joint or other prosthetic;
  • a history of aneurysm (dilated blood vessel);
  • if you have ever had bypass surgery;
  • if you have ever had tuberculosis; or
  • if you need to have an organ transplant (kidney, liver, heart, etc).

If you have any of these conditions, you may need a dose adjustment or special tests to safely receive BCG.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Before you receive BCG, tell your doctor if you are pregnant. Use effective birth control, and tell your doctor if you become pregnant during treatment.

It is not known whether BCG passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

How is BCG given (Theracys)?

BCG is a freeze-dried product that is mixed with saline and other diluents (liquids) in an amount equal to approximately 8 ounces. This liquid mixture is injected directly into the bladder using a catheter inserted into the urethra (the tube for passing urine out of your bladder). You will receive this medication in a clinic or hospital setting.

This medication is usually given once every week for 6 weeks, and then given every 3 to 6 months for up to 2 years. Follow your doctor's instructions about your specific dosing schedule.

After BCG is placed into the bladder, you will need hold the medication in your bladder as long as possible up to 2 hours. During that time you may be encouraged to lie down or stay relaxed.

For at least 6 hours after you are treated with BCG, your urine will still contain some of the medication and the bacteria it is made from. To prevent the spread of this bacteria, use a toilet rather than a urinal, and sit on the toilet while urinating.

Before you flush the toilet, disinfect the urine with household bleach in an amount that is approximately equal to how much you have urinated. Pour the bleach into the toilet in which you urinated, let it stand for 15 minutes and then flush.

Your doctor may ask you to drink extra fluids for several hours after your BCG treatment to help flush out your bladder. Follow your doctor's instructions about the type and amount of liquids you should drink.

Call your doctor right away if you have a fever after receiving BCG, especially if the fever lasts for several hours or longer.

Being treated with BCG can cause you to have unusual results with certain medical tests. Tell any doctor who treats you that you are using BCG.

Side Effects Centers

Theracys Patient Information including If I Miss a Dose

What happens if I miss a dose (Theracys)?

Call your doctor for instructions if you miss an appointment for your BCG treatment.

What happens if I overdose (Theracys)?

Seek emergency medical attention if you think you have received too much of this medicine.

Overdose symptoms may include signs of an infection, such as fever, chills, body aches, weakness, or other flu symptoms.

What should I avoid while receiving BCG (Theracys)?

Antibiotics can make BCG less effective and should be avoided during your treatment with BCG. If you have an infection that must be treated with an antibiotic, you may need to stop receiving BCG for a short time. Follow your doctor's instructions and be sure to tell any other doctor who treats you that you are receiving BCG.

What other drugs will affect BCG (Theracys)?

Before you receive BCG, tell your doctor if you are taking an antibiotic, or if you are using any drugs that weaken your immune system, such as:

  • cancer medicine or radiation;
  • cyclosporine (Neoral, Sandimmune, Gengraf);
  • sirolimus (Rapamune), tacrolimus (Prograf);
  • basiliximab (Simulect), efalizumab (Raptiva), muromonab-CD3 (Orthoclone);
  • mycophenolate mofetil (CellCept);
  • azathioprine (Imuran), leflunomide (Arava), etanercept (Enbrel); or
  • steroids such as prednisone, fluticasone (Advair), mometasone (Asmanex, Nasonex), dexamethasone (Decadron, Hexadrol) and others.

This list is not complete and there may be other drugs that can interact with BCG. Tell your doctor about all your prescription and over-the-counter medications, vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start a new medication without telling your doctor.

Where can I get more information?

Your doctor or pharmacist can provide more information about BCG.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 1.03. Revision date: 12/15/2010.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

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Side Effects Centers

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