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ImmuCyst (Bacillus Calmette-Guérin (BCG), Substrain Connaught)
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Pharmacology
When administered intravesically as a cancer therapy, BCG promotes a local acute inflammatory and sub-acute granulomatous reaction with histiocytic and leukocytic infiltration in the urothelium and lamina propria of the urinary bladder. The local inflammatory effects are associated with an elimination or reduction of superficial cancerous lesions of the urinary bladder. The exact mechanism of action is unknown, but the anti-tumor effect appears to be T-lymphocyte dependent.
General Discussion of BCG Therapy for Bladder Cancer: Carcinoma In Situ of the Urinary Bladder: Carcinoma in situ (CIS) may occur either alone or in association with papillary tumors, particularly those of higher grade. CIS may be multifocal, and may also be associated with multifocal pre-malignant dysplastic lesions. While transurethral resection (TUR) is the primary treatment for CIS, it is often not curative: some lesions may be either undetectable or unresectable or both. Furthermore, even with curative TUR, CIS is associated with a high incidence of recurrence and of recurrence of higher-stage lesions, including cancer invasive of the muscle layer of the urinary bladder (stageT2 or higher). Intravesical ImmuCyst has been studied and established as both an alternative to radical surgical treatment for CIS, and as prophylaxis for recurrence of CIS.
Papillary Tumors of the Urinary Bladder: While TUR is the primary treatment of superficial papillary tumors, these tumors have a tendency to recur and to progress. This is particularly true when there are 2or more co-existing papillary tumors, when there has already been a recurrence of such tumors, or when there is co-existing CIS. In these circumstances, ImmuCyst has been shown to increase significantly the time to recurrence when administered intravesically for prophylactic purposes following TUR.
Efficacy of ImmuCyst: Clinical studies have proven the effectiveness of ImmuCyst for patients with superficial bladder cancer at the CIS, Ta and T1 stages, including 2multicentre controlled, randomized trials.
In the first, ImmuCyst was compared to doxorubicin HCl among patients with either CIS or recurrent papillary tumors or both. ImmuCyst was administered intravesically once each week for 6weeks, with an additional single instillation at 3, 6, 12, 18 and 24months following the initiation of treatment (total of 11 instillations). Doxorubicin was administeredonce each week for 5weeks, with an additional 11 singlemonthly treatments. For patients with CIS, the complete response rate (i.e., negative biopsies and urine cytology) within 6months of the initiation of treatment was 70% with ImmuCyst versus 34% with doxorubicin (p<0.001); the probability of being disease-free (i.e., having no evidence of bladder cancer) at 5years was 45% and 18%, respectively (p<0.001 by proportional hazards regression model); and among complete responders, the median time to treatment failure was 39months versus 5.1months, respectively. Among patients with papillary tumors (Ta or T1) without CIS, the probability of being disease-free at 5years was 37% with ImmuCyst versus 17% with doxorubicin (p=0.015 by proportional hazards regression model).
In the second multicentre controlled study, 2 treatment regimes of ImmuCyst were compared among similar patients to the first study. A 6-week induction course alone (total of 6 instillations) was compared to a more intensive regime consisting of the following: an induction course of 1 treatment each week for 6 weeks; after a 6-week pause, another treatment each week for 3 weeks; and then maintenance therapy consisting of 1 instillation each week for 3weeks at 6months after the initiation of the induction course, and then every 6months until 36months (total of 27 instillations). Comparing the maintenance regime to the no-maintenance regime (i.e., 6-week induction course only), the following results were found: among CIS patients, the complete response rate (defined as the absence of signs of malignancy in the urinary tract at both 3 and 6months after the first instillation) was 87% in the maintenance group versus 73% in the no-maintenance group (p=0.016). Time to recurrence was significantly increased among all patients in the maintenance group (p<0.0001); within the maintenance group, time to recurrence was significantly increased both among those with CIS (p=0.04) and among those with papillary tumors but no CIS (p<0.0001). Finally, overall survival was significantly better in the maintenance group (p=0.04).
When administered intravesically as a cancer therapy, BCG promotes a local acute inflammatory and sub-acute granulomatous reaction with histiocytic and leukocytic infiltration in the urothelium and lamina propria of the urinary bladder. The local inflammatory effects are associated with an elimination or reduction of superficial cancerous lesions of the urinary bladder. The exact mechanism of action is unknown, but the anti-tumor effect appears to be T-lymphocyte dependent.
General Discussion of BCG Therapy for Bladder Cancer: Carcinoma In Situ of the Urinary Bladder: Carcinoma in situ (CIS) may occur either alone or in association with papillary tumors, particularly those of higher grade. CIS may be multifocal, and may also be associated with multifocal pre-malignant dysplastic lesions. While transurethral resection (TUR) is the primary treatment for CIS, it is often not curative: some lesions may be either undetectable or unresectable or both. Furthermore, even with curative TUR, CIS is associated with a high incidence of recurrence and of recurrence of higher-stage lesions, including cancer invasive of the muscle layer of the urinary bladder (stageT2 or higher). Intravesical ImmuCyst has been studied and established as both an alternative to radical surgical treatment for CIS, and as prophylaxis for recurrence of CIS.
Papillary Tumors of the Urinary Bladder: While TUR is the primary treatment of superficial papillary tumors, these tumors have a tendency to recur and to progress. This is particularly true when there are 2or more co-existing papillary tumors, when there has already been a recurrence of such tumors, or when there is co-existing CIS. In these circumstances, ImmuCyst has been shown to increase significantly the time to recurrence when administered intravesically for prophylactic purposes following TUR.
Efficacy of ImmuCyst: Clinical studies have proven the effectiveness of ImmuCyst for patients with superficial bladder cancer at the CIS, Ta and T1 stages, including 2multicentre controlled, randomized trials.
In the first, ImmuCyst was compared to doxorubicin HCl among patients with either CIS or recurrent papillary tumors or both. ImmuCyst was administered intravesically once each week for 6weeks, with an additional single instillation at 3, 6, 12, 18 and 24months following the initiation of treatment (total of 11 instillations). Doxorubicin was administeredonce each week for 5weeks, with an additional 11 singlemonthly treatments. For patients with CIS, the complete response rate (i.e., negative biopsies and urine cytology) within 6months of the initiation of treatment was 70% with ImmuCyst versus 34% with doxorubicin (p<0.001); the probability of being disease-free (i.e., having no evidence of bladder cancer) at 5years was 45% and 18%, respectively (p<0.001 by proportional hazards regression model); and among complete responders, the median time to treatment failure was 39months versus 5.1months, respectively. Among patients with papillary tumors (Ta or T1) without CIS, the probability of being disease-free at 5years was 37% with ImmuCyst versus 17% with doxorubicin (p=0.015 by proportional hazards regression model).
In the second multicentre controlled study, 2 treatment regimes of ImmuCyst were compared among similar patients to the first study. A 6-week induction course alone (total of 6 instillations) was compared to a more intensive regime consisting of the following: an induction course of 1 treatment each week for 6 weeks; after a 6-week pause, another treatment each week for 3 weeks; and then maintenance therapy consisting of 1 instillation each week for 3weeks at 6months after the initiation of the induction course, and then every 6months until 36months (total of 27 instillations). Comparing the maintenance regime to the no-maintenance regime (i.e., 6-week induction course only), the following results were found: among CIS patients, the complete response rate (defined as the absence of signs of malignancy in the urinary tract at both 3 and 6months after the first instillation) was 87% in the maintenance group versus 73% in the no-maintenance group (p=0.016). Time to recurrence was significantly increased among all patients in the maintenance group (p<0.0001); within the maintenance group, time to recurrence was significantly increased both among those with CIS (p=0.04) and among those with papillary tumors but no CIS (p<0.0001). Finally, overall survival was significantly better in the maintenance group (p=0.04).
Indications
When Administered Intravesically As A Cancer Therapy, BCG Promotes A Local Acute Inflammatory And Sub-acute Granulomatous Reaction With Histiocytic And Leukocytic Infiltration In The Urothelium And Lamina Propria Of The Urinary Bladder. The Local Inflammatory Effects Are Associated With An Elimination Or Reduction Of Superficial Cancerous Lesions Of The Urinary Bladder. The Exact Mechanism Of Action Is Unknown, But The Anti-tumor Effect Appears To Be T-lymphocyte Dependent.
General Discussion Of BCG Therapy For Bladder Cancer: Carcinoma In Situ Of The Urinary Bladder: Carcinoma In Situ (CIS) May Occur Either Alone Or In Association With Papillary Tumors, Particularly Those Of Higher Grade. CIS May Be Multifocal, And May Also Be Associated With Multifocal Pre-malignant Dysplastic Lesions. While Transurethral Resection (TUR) Is The Primary Treatment For CIS, It Is Often Not Curative: Some Lesions May Be Either Undetectable Or Unresectable Or Both. Furthermore, Even With Curative TUR, CIS Is Associated With A High Incidence Of Recurrence And Of Recurrence Of Higher-stage Lesions, Including Cancer Invasive Of The Muscle Layer Of The Urinary Bladder (stageT2 Or Higher). Intravesical ImmuCyst Has Been Studied And Established As Both An Alternative To Radical Surgical Treatment For CIS, And As Prophylaxis For Recurrence Of CIS.
Papillary Tumors Of The Urinary Bladder: While TUR Is The Primary Treatment Of Superficial Papillary Tumors, These Tumors Have A Tendency To Recur And To Progress. This Is Particularly True When There Are 2or More Co-existing Papillary Tumors, When There Has Already Been A Recurrence Of Such Tumors, Or When There Is Co-existing CIS. In These Circumstances, ImmuCyst Has Been Shown To Increase Significantly The Time To Recurrence When Administered Intravesically For Prophylactic Purposes Following TUR.
Efficacy Of ImmuCyst: Clinical Studies Have Proven The Effectiveness Of ImmuCyst For Patients With Superficial Bladder Cancer At The CIS, Ta And T1 Stages, Including 2multicentre Controlled, Randomized Trials.
In The First, ImmuCyst Was Compared To Doxorubicin HCl Among Patients With Either CIS Or Recurrent Papillary Tumors Or Both. ImmuCyst Was Administered Intravesically Once Each Week For 6weeks, With An Additional Single Instillation At 3, 6, 12, 18 And 24months Following The Initiation Of Treatment (total Of 11 Instillations). Doxorubicin Was Administeredonce Each Week For 5weeks, With An Additional 11 Singlemonthly Treatments. For Patients With CIS, The Complete Response Rate (i.e., Negative Biopsies And Urine Cytology) Within 6months Of The Initiation Of Treatment Was 70% With ImmuCyst Versus 34% With Doxorubicin (p<0.001); The Probability Of Being Disease-free (i.e., Having No Evidence Of Bladder Cancer) At 5years Was 45% And 18%, Respectively (p<0.001 By Proportional Hazards Regression Model); And Among Complete Responders, The Median Time To Treatment Failure Was 39months Versus 5.1months, Respectively. Among Patients With Papillary Tumors (Ta Or T1) Without CIS, The Probability Of Being Disease-free At 5years Was 37% With ImmuCyst Versus 17% With Doxorubicin (p=0.015 By Proportional Hazards Regression Model).
In The Second Multicentre Controlled Study, 2 Treatment Regimes Of ImmuCyst Were Compared Among Similar Patients To The First Study. A 6-week Induction Course Alone (total Of 6 Instillations) Was Compared To A More Intensive Regime Consisting Of The Following: An Induction Course Of 1 Treatment Each Week For 6 Weeks; After A 6-week Pause, Another Treatment Each Week For 3 Weeks; And Then Maintenance Therapy Consisting Of 1 Instillation Each Week For 3weeks At 6months After The Initiation Of The Induction Course, And Then Every 6months Until 36months (total Of 27 Instillations). Comparing The Maintenance Regime To The No-maintenance Regime (i.e., 6-week Induction Course Only), The Following Results Were Found: Among CIS Patients, The Complete Response Rate (defined As The Absence Of Signs Of Malignancy In The Urinary Tract At Both 3 And 6months After The First Instillation) Was 87% In The Maintenance Group Versus 73% In The No-maintenance Group (p=0.016). Time To Recurrence Was Significantly Increased Among All Patients In The Maintenance Group (p<0.0001); Within The Maintenance Group, Time To Recurrence Was Significantly Increased Both Among Those With CIS (p=0.04) And Among Those With Papillary Tumors But No CIS (p<0.0001). Finally, Overall Survival Was Significantly Better In The Maintenance Group (p=0.04).
When Administered Intravesically As A Cancer Therapy, BCG Promotes A Local Acute Inflammatory And Sub-acute Granulomatous Reaction With Histiocytic And Leukocytic Infiltration In The Urothelium And Lamina Propria Of The Urinary Bladder. The Local Inflammatory Effects Are Associated With An Elimination Or Reduction Of Superficial Cancerous Lesions Of The Urinary Bladder. The Exact Mechanism Of Action Is Unknown, But The Anti-tumor Effect Appears To Be T-lymphocyte Dependent.
General Discussion Of BCG Therapy For Bladder Cancer: Carcinoma In Situ Of The Urinary Bladder: Carcinoma In Situ (CIS) May Occur Either Alone Or In Association With Papillary Tumors, Particularly Those Of Higher Grade. CIS May Be Multifocal, And May Also Be Associated With Multifocal Pre-malignant Dysplastic Lesions. While Transurethral Resection (TUR) Is The Primary Treatment For CIS, It Is Often Not Curative: Some Lesions May Be Either Undetectable Or Unresectable Or Both. Furthermore, Even With Curative TUR, CIS Is Associated With A High Incidence Of Recurrence And Of Recurrence Of Higher-stage Lesions, Including Cancer Invasive Of The Muscle Layer Of The Urinary Bladder (stageT2 Or Higher). Intravesical ImmuCyst Has Been Studied And Established As Both An Alternative To Radical Surgical Treatment For CIS, And As Prophylaxis For Recurrence Of CIS.
Papillary Tumors Of The Urinary Bladder: While TUR Is The Primary Treatment Of Superficial Papillary Tumors, These Tumors Have A Tendency To Recur And To Progress. This Is Particularly True When There Are 2or More Co-existing Papillary Tumors, When There Has Already Been A Recurrence Of Such Tumors, Or When There Is Co-existing CIS. In These Circumstances, ImmuCyst Has Been Shown To Increase Significantly The Time To Recurrence When Administered Intravesically For Prophylactic Purposes Following TUR.
Efficacy Of ImmuCyst: Clinical Studies Have Proven The Effectiveness Of ImmuCyst For Patients With Superficial Bladder Cancer At The CIS, Ta And T1 Stages, Including 2multicentre Controlled, Randomized Trials.
In The First, ImmuCyst Was Compared To Doxorubicin HCl Among Patients With Either CIS Or Recurrent Papillary Tumors Or Both. ImmuCyst Was Administered Intravesically Once Each Week For 6weeks, With An Additional Single Instillation At 3, 6, 12, 18 And 24months Following The Initiation Of Treatment (total Of 11 Instillations). Doxorubicin Was Administeredonce Each Week For 5weeks, With An Additional 11 Singlemonthly Treatments. For Patients With CIS, The Complete Response Rate (i.e., Negative Biopsies And Urine Cytology) Within 6months Of The Initiation Of Treatment Was 70% With ImmuCyst Versus 34% With Doxorubicin (p<0.001); The Probability Of Being Disease-free (i.e., Having No Evidence Of Bladder Cancer) At 5years Was 45% And 18%, Respectively (p<0.001 By Proportional Hazards Regression Model); And Among Complete Responders, The Median Time To Treatment Failure Was 39months Versus 5.1months, Respectively. Among Patients With Papillary Tumors (Ta Or T1) Without CIS, The Probability Of Being Disease-free At 5years Was 37% With ImmuCyst Versus 17% With Doxorubicin (p=0.015 By Proportional Hazards Regression Model).
In The Second Multicentre Controlled Study, 2 Treatment Regimes Of ImmuCyst Were Compared Among Similar Patients To The First Study. A 6-week Induction Course Alone (total Of 6 Instillations) Was Compared To A More Intensive Regime Consisting Of The Following: An Induction Course Of 1 Treatment Each Week For 6 Weeks; After A 6-week Pause, Another Treatment Each Week For 3 Weeks; And Then Maintenance Therapy Consisting Of 1 Instillation Each Week For 3weeks At 6months After The Initiation Of The Induction Course, And Then Every 6months Until 36months (total Of 27 Instillations). Comparing The Maintenance Regime To The No-maintenance Regime (i.e., 6-week Induction Course Only), The Following Results Were Found: Among CIS Patients, The Complete Response Rate (defined As The Absence Of Signs Of Malignancy In The Urinary Tract At Both 3 And 6months After The First Instillation) Was 87% In The Maintenance Group Versus 73% In The No-maintenance Group (p=0.016). Time To Recurrence Was Significantly Increased Among All Patients In The Maintenance Group (p<0.0001); Within The Maintenance Group, Time To Recurrence Was Significantly Increased Both Among Those With CIS (p=0.04) And Among Those With Papillary Tumors But No CIS (p<0.0001). Finally, Overall Survival Was Significantly Better In The Maintenance Group (p=0.04).
Contraindications
Because of the risk of disseminated BCG infection, ImmuCyst should not be used in immunosuppressed patients or persons with congenital or acquired immune deficiencies, whether due to concurrent disease (e.g., AIDS, leukemia, lymphoma), cancer therapy (e.g., cytotoxic drugs, radiation), or immunosuppressive therapy (e.g., corticosteroids).
ImmuCyst should not be administered to persons with active tuberculosis. Active tuberculosis should be ruled out before starting treatment with ImmuCyst. A Mantoux test [tuberculin purified protein derivative (PPD)] should be performed if PPD status is unknown.
Treatment should be postponed until resolution of a concurrent febrile illness, urinary tract infection, or gross hematuria.
Seven to 14 days should elapse before ImmuCyst is administered following biopsy, TUR or traumatic catheterization.
Because of the risk of disseminated BCG infection, ImmuCyst should not be used in immunosuppressed patients or persons with congenital or acquired immune deficiencies, whether due to concurrent disease (e.g., AIDS, leukemia, lymphoma), cancer therapy (e.g., cytotoxic drugs, radiation), or immunosuppressive therapy (e.g., corticosteroids).
ImmuCyst should not be administered to persons with active tuberculosis. Active tuberculosis should be ruled out before starting treatment with ImmuCyst. A Mantoux test [tuberculin purified protein derivative (PPD)] should be performed if PPD status is unknown.
Treatment should be postponed until resolution of a concurrent febrile illness, urinary tract infection, or gross hematuria.
Seven to 14 days should elapse before ImmuCyst is administered following biopsy, TUR or traumatic catheterization.
Safety Information / Warning
Systemic BCG Reaction: A systemic BCG reaction is a systemic granulomatous illness which may occur (although rarely) 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 ³39.5°C for ³12 hours; fever ³38.5°C for ³48hours; 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. Although rare, a systemic BCG reaction is much more likely to occur if ImmuCyst, substrain Connaught] is administered within 1 week of either biopsy, TUR or traumatic bladder catheterization (associated with hematuria). Death has been reported rarely with the use of ImmuCyst in association with systemic BCG reaction.
Additional Warnings: ImmuCyst is not recommended for prophylactic treatment following TUR of stage TaG1 papillary tumors unless they are judged to be at high risk of tumor recurrence.
In patients with small bladder capacity, increased risk of bladder contracture should be considered in decisions to treat with ImmuCyst.
BCG infection of aneurysms and prosthetic devices (including arterial grafts, cardiac devices and artificial joints) have been reported following intravesical instillation of BCG. The risk of ectopic BCG infections has not been determined but is considered to be very small. The benefits of BCG therapy must be carefully weighed against the possibility of ectopic BCG infection in patients with arterial aneurysms or prosthetic devices of any kind.
If a bacterial urinary tract infection (UTI) occurs during the course of ImmuCyst treatment, ImmuCyst instillation should be withheld until complete resolution of the bacterial UTI for 2 reasons: (1) the combination of a UTI and BCG-induced cystitis may lead to more severe adverse effects on the genitourinary tract and (2) BCG bacilli are sensitive to a wide variety of antibiotics; antimicrobial administration may therefore diminish the efficacy of ImmuCyst. Similarly, patients undergoing antimicrobial therapy for other infections should be evaluated to assess whether the therapy might diminish the efficacy of ImmuCyst.
Intravesical treatment with ImmuCyst may induce a sensitivity response to PPD which may complicate future interpretations of skin test reactions to PPD when used to diagnose suspected mycobacterial infections. Determination of a patient's reactivity to PPD should be conducted before administration of ImmuCyst.
Acute allergic reaction has been very rarely reported following intradermal injection of BCG vaccine for the prevention of tuberculosis and therefore should be taken into consideration when administering ImmuCyst intravesically.
Systemic BCG Reaction: A systemic BCG reaction is a systemic granulomatous illness which may occur (although rarely) 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 ³39.5°C for ³12 hours; fever ³38.5°C for ³48hours; 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. Although rare, a systemic BCG reaction is much more likely to occur if ImmuCyst, substrain Connaught] is administered within 1 week of either biopsy, TUR or traumatic bladder catheterization (associated with hematuria). Death has been reported rarely with the use of ImmuCyst in association with systemic BCG reaction.
Additional Warnings: ImmuCyst is not recommended for prophylactic treatment following TUR of stage TaG1 papillary tumors unless they are judged to be at high risk of tumor recurrence.
In patients with small bladder capacity, increased risk of bladder contracture should be considered in decisions to treat with ImmuCyst.
BCG infection of aneurysms and prosthetic devices (including arterial grafts, cardiac devices and artificial joints) have been reported following intravesical instillation of BCG. The risk of ectopic BCG infections has not been determined but is considered to be very small. The benefits of BCG therapy must be carefully weighed against the possibility of ectopic BCG infection in patients with arterial aneurysms or prosthetic devices of any kind.
If a bacterial urinary tract infection (UTI) occurs during the course of ImmuCyst treatment, ImmuCyst instillation should be withheld until complete resolution of the bacterial UTI for 2 reasons: (1) the combination of a UTI and BCG-induced cystitis may lead to more severe adverse effects on the genitourinary tract and (2) BCG bacilli are sensitive to a wide variety of antibiotics; antimicrobial administration may therefore diminish the efficacy of ImmuCyst. Similarly, patients undergoing antimicrobial therapy for other infections should be evaluated to assess whether the therapy might diminish the efficacy of ImmuCyst.
Intravesical treatment with ImmuCyst may induce a sensitivity response to PPD which may complicate future interpretations of skin test reactions to PPD when used to diagnose suspected mycobacterial infections. Determination of a patient's reactivity to PPD should be conducted before administration of ImmuCyst.
Acute allergic reaction has been very rarely reported following intradermal injection of BCG vaccine for the prevention of tuberculosis and therefore should be taken into consideration when administering ImmuCyst intravesically.
Precautions
General: Contains viable attenuated mycobacteria. Handle as infectious.
ImmuCyst contains live mycobacteria and should be prepared and handled using aseptic technique (see Dosage, Reconstitution of Freeze-Dried Product). BCG infections have been reported in health care workers preparing BCG for administration. When handling and reconstituting ImmuCyst, care should be taken so as to avoid needle stick injuries.
Nosocomial infections have been reported in immunosuppressed patients receiving parenteral drugs which were prepared in areas in which BCG was prepared.
Serious infections including infection causing death from disseminated BCG have been reported in patients receiving intravesical BCG. Avoid trauma and/or introduction of contaminants to the urinary tract. Seven to 14 days should elapse before ImmuCyst is administered following traumatic catheterization. The treatment schedule should subsequently be resumed as if no interruption in treatment had occurred.
ImmuCyst should be administered with caution to persons in groups at high risk for HIV infection.
Caution: The stopper of the vial for this product contains natural rubber latex which may cause allergic reactions.
Drug Interactions : Treatment combinations using immunosuppressants and/or myelosuppressants and/or radiation interfere with the immune response to ImmuCyst and increase the risk of disseminated BCG infection. Antimicrobial therapy for other infections may interfere with the effectiveness of ImmuCyst (see Warnings).
For patients with a condition that may in the future require mandatory immunosuppression (e.g., awaiting organ transplant, myasthenia gravis) the decision to treat with ImmuCyst should be considered carefully.
There are no data to suggest that the acute, local urinary tract symptoms common with intravesical BCG is due to mycobacterial infection and antituberculosis drugs (e.g., isoniazid) should not be used prophylactically to prevent the local, irritative side effects of ImmuCyst.
Pregnancy: Animal reproduction studies have not been conducted with ImmuCyst. It is also not known whether ImmuCyst can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ImmuCyst 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 ImmuCyst is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ImmuCyst in nursing infants, it is advisable to discontinue breastfeeding if the mother's condition requires treatment with ImmuCyst.
Children: Safety and effectiveness of ImmuCyst for the treatment of superfical bladder cancer in pediatric patients have not been established.
Information to be Provided to the Patient: ImmuCyst is retained in the bladder for 2 hours and then voided. To avoid transmission of BCG to others, for 6 hours after treatment patients should void while seated to avoid splashing of urine. Urine voided during this time should be disinfected with an equal volume of household bleach for 15 minutes before flushing or disposal. Unless medically contraindicated, patients should be instructed to increase fluid intake to “flush” the bladder for several hours following treatment with ImmuCyst. Patients may experience burning with the first void after treatment.
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, nausea or vomiting.
General: Contains viable attenuated mycobacteria. Handle as infectious.
ImmuCyst contains live mycobacteria and should be prepared and handled using aseptic technique (see Dosage, Reconstitution of Freeze-Dried Product). BCG infections have been reported in health care workers preparing BCG for administration. When handling and reconstituting ImmuCyst, care should be taken so as to avoid needle stick injuries.
Nosocomial infections have been reported in immunosuppressed patients receiving parenteral drugs which were prepared in areas in which BCG was prepared.
Serious infections including infection causing death from disseminated BCG have been reported in patients receiving intravesical BCG. Avoid trauma and/or introduction of contaminants to the urinary tract. Seven to 14 days should elapse before ImmuCyst is administered following traumatic catheterization. The treatment schedule should subsequently be resumed as if no interruption in treatment had occurred.
ImmuCyst should be administered with caution to persons in groups at high risk for HIV infection.
Caution: The stopper of the vial for this product contains natural rubber latex which may cause allergic reactions.
Drug Interactions : Treatment combinations using immunosuppressants and/or myelosuppressants and/or radiation interfere with the immune response to ImmuCyst and increase the risk of disseminated BCG infection. Antimicrobial therapy for other infections may interfere with the effectiveness of ImmuCyst (see Warnings).
For patients with a condition that may in the future require mandatory immunosuppression (e.g., awaiting organ transplant, myasthenia gravis) the decision to treat with ImmuCyst should be considered carefully.
There are no data to suggest that the acute, local urinary tract symptoms common with intravesical BCG is due to mycobacterial infection and antituberculosis drugs (e.g., isoniazid) should not be used prophylactically to prevent the local, irritative side effects of ImmuCyst.
Pregnancy: Animal reproduction studies have not been conducted with ImmuCyst. It is also not known whether ImmuCyst can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ImmuCyst 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 ImmuCyst is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from ImmuCyst in nursing infants, it is advisable to discontinue breastfeeding if the mother's condition requires treatment with ImmuCyst.
Children: Safety and effectiveness of ImmuCyst for the treatment of superfical bladder cancer in pediatric patients have not been established.
Information to be Provided to the Patient: ImmuCyst is retained in the bladder for 2 hours and then voided. To avoid transmission of BCG to others, for 6 hours after treatment patients should void while seated to avoid splashing of urine. Urine voided during this time should be disinfected with an equal volume of household bleach for 15 minutes before flushing or disposal. Unless medically contraindicated, patients should be instructed to increase fluid intake to “flush” the bladder for several hours following treatment with ImmuCyst. Patients may experience burning with the first void after treatment.
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, nausea or vomiting.
Side Effects / Adverse Effects
Administration of intravesical ImmuCyst causes an inflammatory response in the bladder and has been frequently associated with transient fever, hematuria, urinary frequency and dysuria. Such reactions may to some degree be taken as evidence that BCG is evoking the desired response, but careful patient monitoring is required. Symptoms of bladder irritability are reported in approximately 50% of patients receiving ImmuCyst and typically begin 4 to 6 hours after instillation and last 24 to 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 of ImmuCyst.
The following adverse reactions were reported in <5% of patients: anemia, arthralgia/myalgia, urinary incontinence, diarrhea, leukopenia, abdominal pain, liver involvement, systemic infection, pulmonary infection, headache, renal toxicity, contracted bladder, coagulopathy, abdominal pain, cardiac (unclassified) and skin rash.
Symptomatic granulomatous prostatitis, epididymo-orchitis, ureteral obstruction and renal abscess associated with administration of intravesical BCG have been reported infrequently.
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 seems to be elevated among patients who are positive for HLA-B27.
Skin rash, arthralgias and migratory arthritis are rare and may be allergic reactions.
Although uncommon, serious infectious complications of intravesical BCG have been reported. The most serious infectious complication of BCG is disseminated sepsis, associated very rarely with mortality. 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 antituberculous therapy and required orchiectomy.
Treatment of Adverse Reactions: Table V summarizes the recommended treatment of adverse reactions.
If a patient develops persistent fever or experiences an acute febrile illness consistent with BCG infection, BCG instillations should be discontinued and the patient immediately evaluated and treated for BCG infection and an infectious diseases consultation sought (see Warnings). Treatment with 2 or more antimycobacterial agents should be initiated promptly while diagnostic evaluation, including cultures, is conducted. Negative cultures do not necessarily rule out infection. Commonly, antimycobacterial therapy will comprise isoniazid, rifampin and ethambutol. In the presence of a systemic BCG reaction (see Warnings), the addition of short-term corticosteroids (e.g., prednisolone) has been shown to be beneficial both in 5 patients and in an animal model and should be considered. ImmuCyst is sensitive to the most commonly used antituberculous agents (isoniazid, rifampin and ethambutol). ImmuCyst is not sensitive to pyrazinamide.
Acute, localized irritative side effects of ImmuCyst may be accompanied by systemic manifestations consistent with a “flu-like” syndrome. Systemic adverse effects of 1 to 2 days' duration such as malaise, fever and chills often reflect hypersensitivity reactions. However, symptoms such as fever of ³38.5°C, or acute localized inflammation such as epididymitis, prostatitis, or orchitis, persisting longer than 2 to 3 days suggest active infection and evaluation for serious infectious complication should be considered.
Physicians, nurses and pharmacists should report any adverse reaction related to the administration of the product to the appropriate health authorities in accordance with local requirements and to the Medical Director, Aventis Pasteur Limited, 1755 Steeles Avenue West, Toronto, ON, Canada M2R 3T4, phone 1-888-621-1146 or fax 416-667-2939. The report should include details of the treatment history with ImmuCyst, relevant medical history, the symptoms and signs of the adverse reaction, the treatment administered for the reaction and the response to such treatment.
Overdose
Information not available
Information not available
Recommended Dosage
Treatment Schedule: Intravesical treatment of the urinary bladder should begin 7 to 14 days after biopsy or TUR and consists of induction and maintenance therapy. The induction therapy schedule consists of 1 intravesical instillation of ImmuCyst each week for 6weeks. After a 6-week pause, 1 intravesical dose should be given each week for 1 to 3 weeks.
Based on clinical studies performed with ImmuCyst, maintenance therapy following induction is highly recommended. Maintenance therapy consists of 1 dose given each week for 1 to 3 weeks at 6, 12, 18, 24, 30 and 36 months following the initiation of induction treatment.
Administration: One dose of ImmuCyst consists of the intravesical instillation of 81 mg (dry weight) BCG. This dose is prepared by either: reconstituting 1 vial containing 81 mg (dry weight) freeze-dried BCG with the contents of 1 vial containing 3 mL of diluent, or reconstituting 3 vials containing 27 mg (dry weight) freeze-dried BCG with the contents of 3 vials containing 1 mL of diluent.
The reconstituted BCG is further diluted in 50 mL of sterile, preservative-free saline, for a total of 53 mL instillation volume (see Dosage, Reconstitution of Freeze-Dried Product).
A urethral catheter is inserted into the bladder under aseptic conditions, the bladder is drained and then the 53 mL suspension of ImmuCyst is instilled slowly by gravity, following which the catheter is withdrawn.
The patient retains the suspension for as long as possible up to 2 hours. The patient should lie prone for the first 15 minutes following instillation. Thereafter, the patient is allowed to be up. At 2 hours after the instillation, all patients should void in a seated position for hygienic safety reasons (see Precautions, Information to Be Provided to the Patient). Unless medically contraindicated, patients should be instructed to increase fluid intake in order to flush the bladder in the hours following BCG treatment.
For intravesical instillation only. Do not inject s.c. or i.v.
Reconstitution of Freeze-dried Product: The preparation of the ImmuCyst 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 ImmuCyst suspension is recommended. All equipment, supplies and receptacles in contact with ImmuCyst should be handled and disposed of as biohazardous. The person responsible for mixing the agent should wear gloves, eye protection, a mask and gown to avoid inhalation of BCG organisms and inadvertent exposure of broken skin to BCG organisms.
ImmuCyst should not be handled by persons with an immunologic deficiency.
ImmuCyst should be reconstituted only with the diluent provided.
Do not remove the rubber stoppers from the vials.
Using a sterile piece of cotton moistened with a suitable antiseptic, wipe the surface of the rubber stoppers of the vials of diluent and ImmuCyst.
Using a 5 mL sterile syringe and needle, draw into the syringe a volume of air equal to the volume of diluent in the vial. Pierce the center of the rubber stopper in the vial containing diluent with the sterile needle of the syringe, invert the vial and slowly inject into it the air contained in the syringe. Keeping the point of the needle immersed in the diluent, withdraw into the syringe 3 mL of diluent for the 81 mg vial presentation or 1 mL of diluent for the 27 mg vial presentation. Then holding the syringe-plunger steady, withdraw the needle from the vial.
Using the same syringe and needle, pierce the stopper in one vial of freeze-dried material with the needle. Hold the vial of freeze-dried material upright and pull the plunger of the syringe back to create a mild vacuum in the vial. Release the plunger and allow the vacuum to pull the diluent from the syringe into the vial of freeze-dried material. After all the diluent has passed into the freeze-dried material, remove the needle and syringe.
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 of the reconstituted material from the vial into the same 5 mL syringe. Return the vial to an upright position before removing the syringe from the vial.
For the 27 mg vial presentation, repeat with 2 more vials (the same syringe and needle may be used to reconstitute and pool all 3 vials).
Further dilute the reconstituted material from the vial(s) (1 dose) in an additional 50 mL of sterile , preservative-free saline to a final volume of 53 mL for intravesical instillation.
The product should be used immediately after reconstitution. If there is an unavoidable delay between reconstitution and administration, this delay should 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 (e.g., 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 ImmuCyst instillation should be disinfected with an equal volume of 5% hypochlorite solution (undiluted household bleach) and allowed to stand for 15minutes before flushing (see Precautions, Information to Be Provided to the Patient).
Treatment Schedule: Intravesical treatment of the urinary bladder should begin 7 to 14 days after biopsy or TUR and consists of induction and maintenance therapy. The induction therapy schedule consists of 1 intravesical instillation of ImmuCyst each week for 6weeks. After a 6-week pause, 1 intravesical dose should be given each week for 1 to 3 weeks.
Based on clinical studies performed with ImmuCyst, maintenance therapy following induction is highly recommended. Maintenance therapy consists of 1 dose given each week for 1 to 3 weeks at 6, 12, 18, 24, 30 and 36 months following the initiation of induction treatment.
Administration: One dose of ImmuCyst consists of the intravesical instillation of 81 mg (dry weight) BCG. This dose is prepared by either: reconstituting 1 vial containing 81 mg (dry weight) freeze-dried BCG with the contents of 1 vial containing 3 mL of diluent, or reconstituting 3 vials containing 27 mg (dry weight) freeze-dried BCG with the contents of 3 vials containing 1 mL of diluent.
The reconstituted BCG is further diluted in 50 mL of sterile, preservative-free saline, for a total of 53 mL instillation volume (see Dosage, Reconstitution of Freeze-Dried Product).
A urethral catheter is inserted into the bladder under aseptic conditions, the bladder is drained and then the 53 mL suspension of ImmuCyst is instilled slowly by gravity, following which the catheter is withdrawn.
The patient retains the suspension for as long as possible up to 2 hours. The patient should lie prone for the first 15 minutes following instillation. Thereafter, the patient is allowed to be up. At 2 hours after the instillation, all patients should void in a seated position for hygienic safety reasons (see Precautions, Information to Be Provided to the Patient). Unless medically contraindicated, patients should be instructed to increase fluid intake in order to flush the bladder in the hours following BCG treatment.
For intravesical instillation only. Do not inject s.c. or i.v.
Reconstitution of Freeze-dried Product: The preparation of the ImmuCyst 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 ImmuCyst suspension is recommended. All equipment, supplies and receptacles in contact with ImmuCyst should be handled and disposed of as biohazardous. The person responsible for mixing the agent should wear gloves, eye protection, a mask and gown to avoid inhalation of BCG organisms and inadvertent exposure of broken skin to BCG organisms.
ImmuCyst should not be handled by persons with an immunologic deficiency.
ImmuCyst should be reconstituted only with the diluent provided.
Do not remove the rubber stoppers from the vials.
Using a sterile piece of cotton moistened with a suitable antiseptic, wipe the surface of the rubber stoppers of the vials of diluent and ImmuCyst.
Using a 5 mL sterile syringe and needle, draw into the syringe a volume of air equal to the volume of diluent in the vial. Pierce the center of the rubber stopper in the vial containing diluent with the sterile needle of the syringe, invert the vial and slowly inject into it the air contained in the syringe. Keeping the point of the needle immersed in the diluent, withdraw into the syringe 3 mL of diluent for the 81 mg vial presentation or 1 mL of diluent for the 27 mg vial presentation. Then holding the syringe-plunger steady, withdraw the needle from the vial.
Using the same syringe and needle, pierce the stopper in one vial of freeze-dried material with the needle. Hold the vial of freeze-dried material upright and pull the plunger of the syringe back to create a mild vacuum in the vial. Release the plunger and allow the vacuum to pull the diluent from the syringe into the vial of freeze-dried material. After all the diluent has passed into the freeze-dried material, remove the needle and syringe.
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 of the reconstituted material from the vial into the same 5 mL syringe. Return the vial to an upright position before removing the syringe from the vial.
For the 27 mg vial presentation, repeat with 2 more vials (the same syringe and needle may be used to reconstitute and pool all 3 vials).
Further dilute the reconstituted material from the vial(s) (1 dose) in an additional 50 mL of sterile , preservative-free saline to a final volume of 53 mL for intravesical instillation.
The product should be used immediately after reconstitution. If there is an unavoidable delay between reconstitution and administration, this delay should 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 (e.g., 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 ImmuCyst instillation should be disinfected with an equal volume of 5% hypochlorite solution (undiluted household bleach) and allowed to stand for 15minutes before flushing (see Precautions, Information to Be Provided to the Patient).
Supplied / Packaging
A freeze-dried preparation made from the Connaught strain of Bacillus Calmette-Guérin, which is an attenuated strain of M.bovis .
81 mg: Each vial contains: BCG 81mg (dry weight) and monosodium glutamate 5%w/v. Single dose packages of 1vial of the freeze-dried ImmuCyst and one 3mL vial of diluent.
27 mg: Each vial contains: BCG 27mg (dry weight) and monosodium glutamate 5%w/v. Single dose packages of 3vials of the freeze-dried ImmuCyst and three 1mL vials of diluent.
The diluent consists of approximately 0.85% w/v sodium chloride, 0.025% w/v Tween 80, 0.06% w/v sodium dihydrogen phosphate and 0.25% w/v disodium hydrogen phosphate. The product and the diluent contain no preservative. One dose consists of one 81 mg vial or the pooled contents of three 27 mg vials of reconstituted material further diluted in 50mL sterile, preservative-free saline.
The BCG organisms are viable upon reconstitution. The reconstituted product contains 10.5 ± 8.7 ´ 10 8 colony forming units (CFU) per instillation dose when resuspended in the diluent provided.
ImmuCyst and the accompanying diluent should be refrigerated at 2 to 8°C. 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 ImmuCyst be exposed to sunlight, direct or indirect. Exposure to artificial light should be kept to a minimum.
A freeze-dried preparation made from the Connaught strain of Bacillus Calmette-Guérin, which is an attenuated strain of M.bovis .
81 mg: Each vial contains: BCG 81mg (dry weight) and monosodium glutamate 5%w/v. Single dose packages of 1vial of the freeze-dried ImmuCyst and one 3mL vial of diluent.
27 mg: Each vial contains: BCG 27mg (dry weight) and monosodium glutamate 5%w/v. Single dose packages of 3vials of the freeze-dried ImmuCyst and three 1mL vials of diluent.
The diluent consists of approximately 0.85% w/v sodium chloride, 0.025% w/v Tween 80, 0.06% w/v sodium dihydrogen phosphate and 0.25% w/v disodium hydrogen phosphate. The product and the diluent contain no preservative. One dose consists of one 81 mg vial or the pooled contents of three 27 mg vials of reconstituted material further diluted in 50mL sterile, preservative-free saline.
The BCG organisms are viable upon reconstitution. The reconstituted product contains 10.5 ± 8.7 ´ 10 8 colony forming units (CFU) per instillation dose when resuspended in the diluent provided.
ImmuCyst and the accompanying diluent should be refrigerated at 2 to 8°C. 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 ImmuCyst be exposed to sunlight, direct or indirect. Exposure to artificial light should be kept to a minimum.
