BCG Vaccine (Monograph)

Drug class: Vaccines
ATC class: L03AX03
VA class: IM100

Introduction

BCG vaccine is a lyophilized preparation of live, attenuated organisms of the Calmette-Guérin strain of Mycobacterium bovis that is used to stimulate active immunity to tuberculosis.

Uses for BCG Vaccine

Tuberculosis Prevention and Control

BCG vaccine is used to stimulate active immunity to tuberculosis. In developing countries where tuberculosis is epidemic and short-term prophylaxis with antituberculosis agents (e.g., isoniazid) or tuberculin skin test screening is not possible, BCG vaccine is used routinely to attempt tuberculosis control. While the prevalence of M. tuberculosis infection and active tuberculosis varies among different population groups in the US, the risk for M. tuberculosis infection in the overall population is low. Therefore, use of BCG vaccine is not indicated as a routine strategy for tuberculosis control in the US. Use of BCG vaccine in the US has been limited partly because its efficacy in preventing infectious forms of tuberculosis is uncertain (especially in adults) and because vaccination with BCG generally results in tuberculin sensitivity which can complicate management of individuals who are possibly infected with M. tuberculosis.

The principal strategies for preventing and controlling tuberculosis in the US are minimizing the risk for transmission by early identification and treatment of patients with active infectious tuberculosis and identification of individuals with latent M. tuberculosis infection and use of preventive antituberculosis regimens in these individuals if indicated. The US Centers for Disease Control and Prevention (CDC), Advisory Committee for the Elimination of Tuberculosis (ACET), the US Public Health Service Advisory Committee on Immunization Practices (ACIP), and the American Academy of Pediatrics (AAP) recommend that the use of BCG vaccine in the US be reserved for selected individuals when other control measures cannot be implemented or have been ineffective. The CDC, ACET, and ACIP state that BCG vaccination should be considered only for infants and children who reside in settings where the likelihood of M. tuberculosis transmission and subsequent infection is high and other measures (e.g., removing the child from the source of infection) cannot be implemented and for certain health-care personnel employed in settings where the likelihood of transmission and subsequent infection with multidrug-resistant strains of M. tuberculosis is high and comprehensive tuberculosis infection control precautions in the workplace have been unsuccessful.

Neonates and Children

The American Thoracic Society (ATS), CDC, ACET, ACIP, and AAP currently recommend that use of BCG vaccine in the US be considered for infants and children with insignificant reactions to tuberculin skin tests who are at high risk of intimate and prolonged exposure to patients with potentially infectious (e.g., sputum-positive) tuberculosis that is persistently untreated, ineffectively treated, or resistant to isoniazid and rifampin and who cannot be removed from the source of exposure and cannot be placed on long-term preventive therapy. In the US, BCG vaccine is not recommended for use in children infected with human immunodeficiency virus (HIV).

The ATS, CDC, and AAP state that use of BCG vaccine should be considered in the management of certain neonates whose mothers or other household contacts have active tuberculosis, and that such use should be individualized. If the neonate’s mother (or household contact) has clinical or radiographic evidence of possibly contagious tuberculosis, the AAP recommends that the infant be evaluated for congenital tuberculosis (using a Mantoux tuberculin skin test, chest radiograph, lumbar puncture, and cultures) and HIV infection. If congenital tuberculosis is excluded, the Mantoux test should be repeated at 3–4 months of age. The ATS and CDC state that these neonates should receive a chest radiograph and Mantoux tuberculin skin test at 4–6 weeks of age; if results of these tests are negative, the infant should be retested at 3–4 months and again at 6 months of age. The ATS, CDC, and AAP state that neonates whose mothers or other household contacts have active tuberculosis should receive isoniazid preventive therapy (even if results of the tuberculin skin test and chest radiograph do not suggest tuberculosis in the neonate) and should be examined at monthly intervals during isoniazid therapy. This recommendation is based on the fact that cell-mediated immunity of a degree sufficient to mount a significant reaction to tuberculin skin testing may not develop until as late as 6 months of age in an infant infected at birth. If the mother (or household contact) has sputum cultures or smears positive for acid-fast bacilli, has disease due to multidrug-resistant M. tuberculosis, or has poor adherence to treatment and directly observed therapy (DOT) is not possible, the ATS, CDC, and AAP state that BCG vaccine should be considered for the infant. However, because the response to the vaccine in infants may be delayed or inadequate to prevent tuberculosis, DOT for the mother or household contact and infant is preferred.

Health-care Personnel

The CDC, ACET, and ACIP currently state that use of BCG vaccine in health-care personnel is not recommended for those in settings where the risk of M. tuberculosis transmission is low; however, use of the vaccine can be considered for personnel who work in settings where a high percentage of tuberculosis patients are infected with multidrug-resistant strains of M. tuberculosis and transmission of such strains to health-care personnel and subsequent infection are likely.

While the risk for transmission of M. tuberculosis (including multidrug-resistant strains) is low in health-care facilities in most geographic areas in the US if comprehensive infection control practices are followed, the likelihood of transmission of M. tuberculosis is high in some areas of the US because of a high incidence of tuberculosis in the patient population. More than 90% of tuberculosis patients in most of these areas are infected with M. tuberculosis susceptible to isoniazid or rifampin; however, there are a few geographic areas in the US that have both an increased risk for M. tuberculosis transmission in health-care facilities and a high percentage of tuberculosis patients infected with multidrug-resistant M. tuberculosis. The preferred strategies for prevention and control of tuberculosis in all health-care facilities are comprehensive infection control measures to reduce the risk for M. tuberculosis transmission (e.g., prompt identification, isolation, and treatment of individuals with active tuberculosis disease, tuberculin skin testing to identify health-care personnel who become newly infected with M. tuberculosis, and antituberculosis therapy in health-care personnel when indicated to prevent active tuberculosis disease). Use of BCG vaccine in health-care personnel in settings with a high risk for transmission of multidrug-resistant M. tuberculosis should be considered on an individual basis and the vaccine should be used only if comprehensive infection control procedures have been unsuccessful. Health-care personnel being considered for BCG vaccination should be counseled regarding the risks and benefits associated with the vaccine and with tuberculosis preventive therapy. Vaccination with BCG should not be required for employment or assignment to specific work areas.

BCG vaccine is not recommended for use in health-care personnel who are infected with HIV or are immunocompromised for any reason. Health-care personnel who are HIV-infected or otherwise immunocompromised and work in areas where the risk for transmission of multidrug-resistant strains of M. tuberculosis is high should be fully informed of the risk of infection and the even greater risk associated with immunosuppression and development of active tuberculosis disease. At the request of the immunocompromised health-care worker, employers should offer (but not compel) a work assignment where the risk for infection would be the lowest possible.

HIV-infected Individuals

Safety and efficacy of BCG vaccine in children and adults with HIV infection have not been determined. HIV-infected individuals probably are at greater risk of BCG-related adverse effects, including disseminated BCG infection, lymphadenitis, or local ulceration, than immunocompetent individuals. Disseminated BCG disease has occurred following BCG vaccination in HIV-infected children and adults. The World Health Organization (WHO) recommends BCG vaccination for asymptomatic HIV-infected children who are at high risk for infection with M. tuberculosis (e.g., children in countries in which the prevalence of tuberculosis is high) but does not recommend use of the vaccine in children who have symptomatic HIV infection or other individuals known or suspected to be HIV-infected if they are at minimal risk for infection with M. tuberculosis. The CDC, ACET, ACIP, AAP, and the Prevention of Opportunistic Infections Working Group of the US Public Health Service and the Infectious Diseases Society of America (USPHS/IDSA) currently state that use of BCG vaccine in HIV-infected children or adults in the US is not recommended. It also has been suggested that BCG vaccine be used with caution in individuals who are known to be at high risk for HIV infection.

Travelers

Tuberculosis is much more common in many other countries than in the US, and the disease is an increasingly serious public health problem. To become infected, travelers would have to spend a long time in a closed environment where the air was contaminated by a person with untreated tuberculosis who had numerous Mycobacterium tuberculosis organisms in lung secretions and was coughing. Since tuberculosis infection generally is transmitted through the air, there is virtually no danger of travelers acquiring it from food, dishes, linens, or items that are touched; however, the disease can be transmitted through unpasteurized milk or milk products produced from infected cattle. The CDC no longer recommends BCG vaccination for international travelers since individuals who do become infected can be treated to prevent tuberculosis. The CDC currently states that travelers who anticipate possible prolonged exposure to tuberculosis should receive a tuberculin skin test prior to traveling. Individuals who have an insignificant reaction to the skin test prior to travel should have a repeat test after returning to the US. Because HIV-infected individuals may have an impaired response to the tuberculin skin test, travelers with HIV infection should inform their physician about their HIV status. Except for individuals with impaired immunity (e.g., those with HIV infection), travelers who already have a significant reaction to the skin test prior to travel are unlikely to be reinfected. Travelers should be instructed to inform their physician if they suspect that they have been exposed to tuberculosis and should then receive an appropriate medical evaluation.

Immunotherapy for Bladder Cancer

BCG is used intravesically as adjuvant therapy for the treatment of superficial bladder cancer.

Superficial bladder cancer, representing approximately 70–80% of newly diagnosed bladder tumors, is initially treated with surgical resection and/or fulguration; because of high rates of recurrence following surgery, adjuvant treatment with intravesical therapy (with immunotherapeutic or chemotherapeutic agents) is indicated in patients with intermediate to high risk of progression and/or recurrence of disease.

Over 90% of bladder tumors are transitional cell carcinomas originating from the uroepithelium. Other histologic types of bladder cancer, such as squamous cell carcinoma (6–8%) and adenocarcinoma (2%), are associated with greater resistance to treatment and a more aggressive pattern of local spread than transitional cell carcinoma. Bladder carcinoma is clinically staged according to the TNM classification. Major prognostic factors in patients with carcinoma of the bladder include the depth of tumor invasion into the bladder wall and the degree of differentiation or grade of the tumor.

Overview

Superficial bladder tumors include noninvasive papillary tumors that are limited to the bladder mucosa (stage Ta), papillary tumors that invade but do not extend beyond the lamina propria of the bladder (stage T1), and carcinoma in situ or preinvasive flat carcinoma (stage Tis). Grading, or degree of differentiation, is of greater importance for noninvasive tumors since almost all invasive tumors are high grade (i.e., poorly differentiated).

Prolonged survival, and sometimes cure, can be achieved in most patients with superficial bladder cancer; the 5-year survival rate in treated patients is 55–80%. The standard of therapy for initial treatment of superficial transitional cell bladder carcinoma is transurethral resection (TUR) of papillary tumors and/or fulguration of visible carcinoma in situ. Treatment with intravesical therapy alone has been used in selected patients who refuse or are unable to tolerate surgery. Surgery alone generally is considered adequate treatment in the small numbers of patients with superficial bladder cancer who are at low risk for progression and/or recurrence of disease (e.g., small, solitary, low-grade noninvasive papillary tumor). Some evidence suggests that a single intravesical instillation of a chemotherapeutic agent (e.g., epirubicin) immediately following TUR may prevent recurrence secondary to implantation of tumor cells during surgery; however, the benefit of intravesical therapy in patients at low risk for progression and/or recurrence of superficial bladder cancer has not been established. In a randomized study of patients with a papillary bladder tumor and low risk of recurrence, the addition of a single intravesical instillation of mitomycin immediately following TUR decreased the rate of recurrence and increased the recurrence-free interval at 24 months, but this benefit was not maintained with long-term follow-up.

Because rates of tumor recurrence or new tumor formation are high following initial treatment (50–90%), most patients with superficial bladder cancer will require additional therapy. Adjuvant therapy with intravesical instillation is recommended in patients with superficial bladder cancer who have intermediate to high risk of progression and/or recurrence of disease. Intravesical therapy with various agents, including immunotherapeutic agents (e.g., BCG), chemotherapeutic agents (e.g., mitomycin, doxorubicin, thiotepa), or cytokines (e.g., interferon alfa), has been used as adjuvant treatment in patients with superficial bladder cancer. Choice of agent for intravesical therapy generally depends on consideration of the expected benefit versus risks of therapy. Performance of a second TUR within 2–6 weeks of the initial resection may assist in the management and more accurate staging of bladder cancer. Cystectomy may eventually be required in some patients with superficial bladder cancer who have persistent symptoms (secondary to bladder contraction or other complications) and/or disease that progresses following surgery and repeated courses of intravesical therapy. In patients with BCG-refractory carcinoma in situ (CIS) of the urinary bladder who are not candidates for immediate cystectomy, intravesical therapy with valrubicin has been used.

Intravesical Immunotherapy with BCG

Intravesical instillation of BCG, an immunotherapeutic agent, is a preferred regimen for adjuvant therapy for superficial bladder cancer in patients who are at high risk of disease progression and/or recurrence and the treatment of choice for CIS; prognostic factors indicating high risk of disease progression and/or recurrence include multiple lesions, frequent recurrence of lesions (more than 3 times in a year), involvement of large portion of bladder wall, high-grade lesions (i.e., poorly differentiated tumors), carcinoma in situ or papillary tumors associated with carcinoma in situ, T1 lesions, and tumors with overexpression of nuclear p53 protein). Compared with surgery alone, treatment with surgery plus adjuvant therapy with intravesical BCG has been shown to cause regression of existing tumor, particularly in patients with residual carcinoma in situ; delay progression to muscle-invasive and/or metastatic disease; reduce the risk of tumor recurrence; increase the likelihood of bladder preservation; and decrease the risk of death from bladder cancer.

In a randomized study comparing administration of both intravesical and subcutaneous BCG with intravesical doxorubicin, the BCG regimen was associated with higher response rates and decreased recurrence rates in patients with recurrent papillary tumors and/or carcinoma in situ. In patients with carcinoma in situ, intravesical BCG therapy produces complete response rates of approximately 70% and reduces or delays the need for salvage cystectomy; however, no effect on overall survival has been observed. Intravesical BCG also has been shown to be superior to intravesical mitomycin in preventing tumor recurrence in patients with high risk of recurrence and/or progression of superficial bladder cancer; although improvement in disease-free survival was noted with use of intravesical BCG versus intravesical mitomycin at 5 years of follow-up, no difference in disease progression or overall survival has been observed. Intravesical regimens of alternating or sequential mitomycin and BCG appear to have similar efficacy and toxicity as mitomycin alone in patients with superficial bladder cancer at intermediate to high risk of recurrence.

In patients with superficial bladder cancer who have low to intermediate risk of recurrence, intravesical mitomycin has been shown to be equally effective in preventing tumor recurrence and less toxic compared with intravesical BCG. Because of the greater frequency of adverse effects, including cystitis, as well as the rare but sometimes fatal occurrence of BCG sepsis, use of intravesical BCG generally is reserved for adjuvant therapy in patients with superficial bladder cancer who have high risk of recurrence and/or progression of disease. BCG also has been used as second-line therapy in patients with disease that is refractory to intravesical treatment with chemotherapeutic agents.

Dosage

The optimal dosage regimen for adjuvant therapy with intravesical BCG has not been established. Although no comparative studies have been performed, various strains of BCG appear to be effective. The dose amount expressed in milligrams varies according to the BCG strain. The typical dose of BCG used for intravesical instillation is 1–8 × 10⁸ colony-forming units (CFUs) for the TICE strain of BCG or 10.5±8.7 × 10⁸ CFUs for the Theracys strain of BCG. Limited evidence suggests that intravesical therapy with lower doses of BCG may provide similar efficacy with reduced toxicity in patients with superficial bladder cancer; however, further study is needed to determine the comparative efficacy of low-dose BCG therapy. The addition of intradermal BCG does not affect outcome of intravesical BCG therapy and is not recommended.

Following surgery, the initial course of therapy is once weekly instillation of BCG for 6 consecutive weeks. A second 6-week course of therapy with intravesical BCG may be required for optimal response. An interval of rest between the 2 courses of therapy is necessary to avoid suppression of immune response and to optimize tumor response to intravesical BCG. According to some clinicians, the optimal schedule for induction therapy in patients receiving intravesical BCG for carcinoma in situ consists of an initial 6-week course of once-weekly treatment followed by 6 weeks of rest and then once weekly treatment for 3 additional weeks. Although retreatment with BCG in patients experiencing recurrence of tumor following an initial complete response to BCG therapy often is effective, alternative therapy should be considered in patients with noninvasive papillary tumor that does not respond to two 6-week courses of BCG therapy. Patients with progression to T1 tumor or recurrence of either T1 tumor or carcinoma in situ within 3 months following completion of a single 6-week course of intravesical BCG are at high risk of developing muscle-invasive disease, and alternative therapy, such as cystectomy, should be considered. In patients with BCG-refractory CIS of the urinary bladder who are not candidates for immediate cystectomy, intravesical therapy with valrubicin has been used.

Evidence from clinical trials indicates that long-term maintenance therapy with intravesical BCG increases rates of complete response and delays tumor recurrence in patients with superficial bladder cancer who are at high risk of progression and/or recurrence of disease. In a randomized trial of patients with papillary tumors (stage Ta or T1) at increased risk of recurrence or associated with CIS, the addition of maintenance therapy with a 3-week series of intravesical and percutaneous BCG administered once weekly at 3 and 6 months following an initial 6-week induction course and then every 6 months for 3 years delayed tumor recurrence compared with a single 6-week course of therapy; however, most patients did not receive all scheduled maintenance treatments because of adverse effects of BCG, and no effect on overall survival was demonstrated. Other investigators have reported maintenance therapy with once-monthly intravesical instillations of BCG for 1 year following completion of initial therapy. The safety and efficacy of routine use of maintenance BCG therapy have not been fully determined, and maintenance therapy with BCG generally is associated with an increased incidence of adverse local and systemic effects. Further study is needed to establish an optimal schedule for intravesical BCG and to determine whether maintenance therapy prolongs survival.

Mechanism of Action

The mechanism of action of BCG administered as intravesical therapy has not been fully determined; however, both inflammatory effects and immune response are believed to be involved. A BCG-induced granulomatous reaction within the bladder wall leads to sloughing of the epithelium and destruction of cancer cells in superficial bladder cancer. Administration of BCG intravesically with the adherence of live, attenuated BCG organisms to the bladder mucosa and tumor cells appears to be important for the development of an antitumor immune response, which includes T-lymphocyte activation and cytokine release.

Contraindications and Adverse Effects

Because of the risk of developing systemic BCG infection, the use of intravesical BCG is contraindicated in patients who are immunocompromised. Because treatment with intravesical BCG may cause disseminated BCG infection or increased severity of bladder irritation in patients with urinary tract infection, intravesical BCG therapy should not be initiated until infection is resolved.

The most frequent adverse local effect, occurring in about 90% of patients receiving intravesical BCG, is cystitis; cystitis is most likely to occur with multiple courses of intravesical BCG live and may be treated with nonsteroidal anti-inflammatory agents. Hematuria associated with cystitis occurs in 33% of patients receiving intravesical BCG. If hematuria persists for more than 48 hours, treatment with isoniazid 300 mg once daily should be initiated and continued until symptoms resolve. Another course of isoniazid should then be initiated the day preceding intravesical instillation of BCG and continued for 3 additional days for each subsequent course of therapy. The most common adverse systemic reaction associated with BCG is a flu-like syndrome consisting of low-grade fever (less than 38.5°C), malaise, and chills; high-grade fever (exceeding 39.5°C) occurs in about 3% of patients receiving intravesical BCG.

Although attenuated, BCG used for intravesical therapy is a living organism and infection may occur as a complication of therapy; systemic infection, including pneumonitis, hepatitis, and sepsis, has been reported in up to 1% of patients. Miliary tuberculosis has been reported in at least 2 patients receiving intravesical BCG. BCG therapy should be discontinued in patients who develop systemic BCG infection, and antituberculosis therapy initiated. BCG sepsis, diagnosed clinically in patients with high fever and shaking chills followed by onset of hypotension, is treated with a regimen of isoniazid (300 mg daily), rifampin (600 mg daily), and prednisolone (40 mg daily). At least 10 deaths related to BCG toxicity have been reported, and intravascular absorption of BCG (e.g., secondary to intravasation from traumatic catheterization and bleeding) appears to be an important contributing factor in most cases. Intravesical BCG therapy should be initiated no sooner than 1 week following transurethral resection, bladder biopsy, or traumatic catheterization to allow time for healing and to reduce the risk of systemic toxicity. Prophylactic administration of isoniazid 300 mg daily for 3 days in conjunction with each instillation of intravesical BCG did not reduce the incidence of adverse local or systemic effects of BCG and was associated with transient elevations in serum transaminase concentrations; routine use of isoniazid prophylaxis in patients receiving intravesical therapy with BCG live is not recommended.

Immunotherapy for Other Cancers

BCG has been used as a nonspecific immunotherapeutic agent for the local control of accessible lesions of metastatic melanoma^{† [off-label]} (e.g., by intralesional injection into superficial skin metastases and in-transit metastases). Use of BCG (by intradermal administration) with or without chemotherapy as adjuvant therapy following surgery for cutaneous melanoma does not affect disease-free survival or overall survival.

No consistent benefit has been demonstrated for the use of immunotherapy in the treatment of non-small cell lung cancer. Intrapleural administration of BCG^{† [off-label]} following resection of non-small cell lung cancer does not prolong survival or time to recurrence of disease; one randomized, placebo-controlled study demonstrated a high rate of complications (e.g., pleural empyema) and detrimental effect on disease-free survival (particularly following pneumonectomy) in patients receiving intrapleural BCG as adjuvant therapy for non-small cell lung cancer.

BCG Vaccine Dosage and Administration

Reconstitution and Administration

BCG vaccine (Organon) is administered percutaneously using a multiple-puncture device; this preparation should not be injected intradermally. Commercially available BCG vaccines should be administered only by the route specified by the manufacturer in the product labeling, and subcutaneous or IV administration should be avoided. The World Health Organization currently recommends that BCG vaccine be administered by intradermal injection, rather than by multiple-puncture methods, in order to provide a uniform and reliable dose; however, a BCG vaccine for intradermal injection no longer is commercially available in the US.

BCG vaccine for percutaneous administration is reconstituted by adding 1 mL of sterile water for injection without preservatives to each 2-mL ampul of vaccine. To ensure thorough mixing, the solution should be drawn into a syringe and expelled back into the ampul 3 times. If the percutaneous vaccine is to be used in neonates younger than 1 month of age, the vaccine should be reconstituted with 2 rather than 1 mL of sterile water for injection without preservatives. For percutaneous administration, the dose of BCG should be dropped onto the cleansed surface of the skin and a multiple-puncture disc should be applied through the vaccine. The vaccine should be allowed to flow into the wounds and dry; no dressing is required, but the site should be kept dry for 24 hours.

BCG vaccine should not be administered unless the individual has had a tuberculin skin test, preferably by the Mantoux method. The test should be performed within the 6-week period prior to administration of BCG vaccine. If results of the tuberculin skin test are insignificant, the individual may receive BCG vaccine.

Dosage

Tuberculosis

For percutaneous administration, the usual dosage of BCG vaccine in adults and children 1 month of age or older is 0.2–0.3 mL. In neonates younger than 1 month of age, the dosage of BCG vaccine for percutaneous administration should be decreased by 50% by reconstituting the vaccine with 2 mL instead of 1 mL of sterile water for injection without preservatives. If indications for BCG vaccine persist in these neonates and they have an insignificant reaction to the tuberculin skin test, a full dose of the vaccine should be given after 1 year of age.

The intensity and duration of the local reaction following administration of BCG vaccine depends on the depth of penetration and on individual variation in tissue reactions. The usual local reaction following proper intradermal injection of BCG (a BCG vaccine for intradermal injection no longer is commercially available in the US) consists of an initial skin lesion which appears within 7–10 days after administration of the vaccine. The lesion is characterized by a small red papule at the site of injection; the papule reaches its maximum diameter of approximately 8 mm within 5 weeks after administration of the vaccine. The top of the papule scales, ulcerates, and dries, and the entire lesion gradually shrinks to a smooth or scaly pink or bluish scar approximately 3 months following immunization; the lesion then becomes a smooth or pitted white scar in approximately 6 months. Following percutaneous administration, skin lesions usually appear at the site within 10–14 days and consist of small red papules that reach maximum diameter (about 3 mm) after 4–6 weeks. The lesions may scale and then slowly subside; there is usually no visible sign of the vaccination after 6 months although a faintly discernible pattern of the multiple-puncture disk points may be visible. Evidence of vaccination may be slightly more visible in individuals whose skin tends to keloid formation. If BCG is inadvertently administered to an individual with a tuberculous infection, the response to the vaccine is accelerated and generally is characterized by an induration reaction greater than 5 mm in diameter within 24–48 hours, formation of a pustule within 5–7 days, and scab formation and healing within 10–15 days.

Immunotherapy

For intravesical instillation in the local treatment of superficial bladder cancer, the manufacturers’ labeling, specialized references, and/or published protocols should be consulted for recommended dosages and scheduling. The typical dose of BCG used for intravesical instillation is 1–8 × 10⁸ colony-forming units (CFUs) for the TICE strain of BCG or 10.5±8.7 × 10⁸ CFUs for the Theracys strain of BCG. The US Food and Drug Administration (FDA) has alerted clinicians that the dose of BCG (6 × 10⁹ viable organisms) reported in several protocols for the treatment of bladder cancer (J Urol. 1982; 128:891-3. J Urol. 1982; 128:27-9. American Urology Association Update Series, Lesson 20, Vol. 2) is 10 times the actual dose given and that administration of this incorrect dose may result in severe adverse reactions and possibly death. For the investigational use of BCG vaccine as an immunotherapeutic agent in the treatment of other cancer^{† [off-label]}, clinicians should consult specialized references and published protocols for the dosage and method and sequence of administration of the vaccine following or in conjunction with surgery, radiation therapy, and/or chemotherapy.

Cautions for BCG Vaccine

Adverse effects occur in 1–10% of individuals who receive BCG. The frequency and severity of adverse reactions to BCG vaccine vary depending on the substrain of BCG used in the manufacture of the vaccine, the dosage and method of administration, and the age of the individual receiving the vaccine. BCG vaccine for intradermal use no longer is commercially available in the US, and data available on adverse reactions following administration of BCG vaccine do not necessarily pertain to the vaccines currently available in the US. Adverse reactions to BCG are usually mild and infrequent; however, adverse reactions can be severe and may occasionally occur a year or longer following administration of the vaccine.

The manufacturers’ labeling and other specialized references should be consulted for specific cautions, precautions, and contraindications associated with intravesical instillation of BCG into the bladder in the treatment of superficial bladder cancer.

Mucocutaneous Effects

Local and dermatologic reactions to BCG tend to be more severe in individuals who have received previous immunization with the vaccine.

Severe or prolonged ulceration resulting from intense skin destruction reportedly occurs at the site of injection in 1–10% of individuals following administration of BCG vaccine; scarring may occur. Ulceration may occur as a result of faulty administration technique (e.g., too deep an injection), administration of vaccine in close proximity to a previous site of BCG vaccination or tuberculin skin test, or administration of BCG vaccine to an individual with a significant (positive) reaction to a tuberculin skin test. In these cases the lesion produced by the vaccine appears at the injection site within 3 days, becomes intensely inflamed, and ulcerates within 2–3 weeks. Patients should be advised to leave the BCG skin lesion open to the air and to keep it clean and dry to facilitate healing. Application of a strong antiseptic solution or dressings to a normal scab reaction to BCG vaccine may cause dermatitis and an inflammatory reaction accompanied by ulceration. Ulceration occurs more frequently following administration of BCG vaccine into the dermis overlying plump skin (e.g., skin of the upper thigh) than into skin over the insertion of the deltoid. (See Dosage and Administration: Reconstitution and Administration.) Autoinoculation ulcers may occur; however, these ulcers are usually small and appear later than the original cutaneous reaction.

Abscesses in the skin at the site of injection may occur following administration of BCG vaccine and may be a result of secondary infection or faulty administration technique (e.g., too deep an injection). Abscesses develop rarely in the regional lymph nodes draining the site of injection; this reaction may occur in the axillae of infants who have received an excessive dose of BCG vaccine in the skin of the deltoid area.

Granulomas, which appear at the site of injection 4–6 weeks following administration of BCG vaccine, have been reported and may occur as the result of individual idiosyncrasy or the application of irritating dressings to a normal BCG local reaction. Granulomas following administration of BCG vaccine may persist for variable periods of time and may develop a keloid scar after healing is complete.

Persistent lupus reactions of the skin have occurred rarely following administration of BCG; it has been recommended that individuals with these reactions receive oral isoniazid in a daily dose of 4 mg/kg for 3 months.

One case of histiocytoma, which required excision, and one case of hidradenoma have occurred at the site of injection following administration of BCG vaccine.

Transient urticaria of the limbs and trunk has occurred within a few days following administration of BCG vaccine. Several cases of erythema nodosum and erythema multiforme have been reported; however, the frequency of erythema nodosum has varied in several clinical trials. Infrequent, generalized eruptions have occurred approximately 10 days following administration of BCG vaccine and have persisted for about 2 months; in one patient, the rash was associated with fever and slight, transient albuminuria.

Systemic Effects

Lymphadenitis reportedly occurs at the site of injection in 1–10% of individuals following administration of BCG vaccine. Lymphangitis may also occur, especially when the vaccine is administered too close to the shoulder, and is characterized by streaking from the site of injection toward the regional lymph nodes. Lymphadenopathy of the regional lymph node, which resolves spontaneously, occurs occasionally in young children. Rarely, a fistula that drains for a short while may result. If this occurs, the site of drainage usually is kept clean and the lesion allowed to heal spontaneously without medical treatment.

Osteomyelitis has been reported to occur rarely (1 case per 1 million vaccinees) following administration of BCG vaccine; osteomyelitis has been reported most frequently in neonates. Tuberculous meningitis, apparently caused by the BCG strain of M. bovis, has occurred in at least 2 immunocompetent children following BCG vaccination.

Disseminated BCG infection, which can be fatal, occurs only rarely (1–10 cases per 10 million vaccinees) following administration of BCG vaccine; most reported cases have occurred in individuals with impaired immune responses, principally children with immunodeficiencies. Disseminated and/or localized BCG infections have been reported following administration of BCG vaccine to patients with symptomatic human immunodeficiency virus (HIV) infection who are immunosuppressed in association with acquired immunodeficiency syndrome (AIDS) or other clinical manifestations of HIV infection. In at least one infant with asymptomatic HIV infection who received BCG vaccine, a possible disseminated BCG infection occurred since the BCG strain of M. bovis was isolated from the lymph node and CSF several months after vaccination. (See Cautions: Precautions and Contraindications.) Disseminated BCG infections also have been attributed to previous vaccination in several patients who subsequently manifested symptomatic HIV infection; in at least one such patient, vaccination predated BCG dissemination associated with AIDS by 30 years. If a disseminated BCG infection is suspected in an individual who has received BCG vaccine, appropriate antituberculosis agent therapy should be initiated.

Rarely, acute anaphylactic shock has occurred within minutes following administration of BCG vaccine to infants. Epinephrine should be available for immediate use in case an anaphylactic reaction occurs.

Precautions and Contraindications

BCG vaccine is contraindicated in individuals who are hypersensitive to the vaccine. Administration of BCG vaccine for the prevention of tuberculosis is contraindicated in individuals with a significant (positive) reaction to tuberculin, individuals with recent smallpox immunizations, and burn patients. A tuberculin skin test, preferably by the Mantoux method, should be performed within the 6-week period prior to administration of BCG vaccine; the vaccine should be administered only to those individuals with an insignificant reaction to the tuberculin skin test. Healthy neonates and children younger than 2 months of age who have not been exposed to tuberculosis may receive BCG vaccine without prior tuberculin skin testing.

The protection against tuberculosis afforded by BCG vaccine is only relative and is not permanent or entirely predictable. Tuberculosis should be included in the differential diagnosis of any tuberculosis-like illness in an individual who has received immunization with BCG vaccine, since full, long-lasting protection from BCG immunization cannot be assured. Revaccination with BCG should be considered if the risk of tuberculosis infection is still present for individuals who had significant (positive) reactions to a postvaccination tuberculin skin test (see Dosage and Administration: Dosage) and who have an insignificant reaction to subsequent tuberculin skin tests.

BCG vaccine is contraindicated in individuals with immunosuppression, including those with hypogammaglobulinemia, congenital immunodeficiency, sarcoidosis, leukemia, lymphoma, generalized malignancy, and human immunodeficiency virus (HIV) infection. BCG vaccine also is contraindicated in individuals in whom immunologic responses have been suppressed because of prolonged treatment with immunosuppressive therapy (e.g., corticosteroids, certain antineoplastic agents, radiation therapy). (See Drug Interactions: Immunosuppressive Agents.)One manufacturer states that BCG should not be used in children with a family history of immunodeficiency. It has been suggested that BCG vaccine should be used with caution in individuals who are known to be at high risk for HIV infection.

Individuals with chronic diseases of the skin (e.g., eczema) should receive immunization with BCG vaccine in a healthy area of skin.

Following administration of BCG vaccine, it is usually impossible to distinguish between tuberculin sensitivity caused by M. tuberculosis infection and tuberculin sensitivity resulting from the vaccine; therefore, caution should be exercised in interpreting tuberculin skin test reactions in patients who have received BCG. (See Drug Interactions: Tuberculin.)

Pregnancy

Pregnancy

Animal reproduction studies have not been performed with BCG vaccine. It is not known whether the vaccine can cause fetal harm when administered to pregnant women or can affect reproduction capacity. Use of BCG vaccine during pregnancy is not recommended. For pregnant women who plan to travel to areas where the risk of exposure to tuberculosis is expected to be high, the CDC recommends that a tuberculin skin test be performed before and after travel.

Drug Interactions

Immunosuppressive Agents

Individuals receiving immunosuppressive therapy (e.g., corticotropin, corticosteroids, alkylating agents, antimetabolites, radiation therapy) may have a diminished response to BCG vaccine and replication of the organism may be potentiated. Vaccination with BCG should be deferred until immunosuppressive therapy is discontinued. The exact interval between discontinuance of immunosuppressive therapy and regaining the ability to respond to live virus vaccines is not known, but estimates vary from 3–12 months. The ACIP currently states that short-term (less than 2 weeks), low to moderate dose systemic corticosteroid therapy; long-term, alternate-day, systemic corticosteroid therapy using low to moderate doses of short-acting drugs; topical corticosteroid therapy (e.g., nasal, cutaneous); or intra-articular, bursal, or tendon injections with corticosteroids should not be immunosuppressive and do not necessarily contraindicate vaccination with live-virus vaccines. If systemic BCG infection occurs in a patient receiving corticosteroids, antituberculosis agent therapy can be initiated.

Tuberculin

Vaccination with BCG generally results in tuberculin sensitivity; however, the degree of tuberculin sensitivity is highly variable and depends on the strain of BCG used, dosage and method of administration of the vaccine, age and nutritional status of the individual at vaccination, number of years since vaccination, and factors known to affect the reaction to the tuberculin skin test. Mean size of skin test reactions in BCG-vaccinated children has ranged from no induration up to 19 mm. If a tuberculin skin test is administered 6–12 weeks after BCG vaccination, a significant (positive) reaction to the test is obtained in most patients. However, if a tuberculin test is administered a few years after BCG vaccination, the reaction may be either significant or insignificant since tuberculin reactivity induced by BCG vaccine wanes with the passage of time. After 10 years, tuberculin reactivity is unlikely to persist in BCG-vaccinated individuals unless M. tuberculosis exposure and infection has occurred. BCG-induced tuberculin reactivity that has waned might be boosted by administering a tuberculin skin test 1 week to 1 year after the initial postvaccination skin test; ongoing periodic skin testing also might prolong reactivity to tuberculin in vaccinees.

The presence or size of postvaccination tuberculin skin test reactions does not reliably predict the degree of protection provided by BCG vaccination. The persistence of tuberculin sensitivity during the months and years after BCG vaccination is highly variable and, in addition to the previously noted factors, depends on the frequency of tuberculin sensitivity testing after vaccination, frequency of repeat vaccinations, exposure to nontuberculous mycobacteria, and infection with M. tuberculosis. An insignificant tuberculin skin test reaction in an HIV-seronegative individual who has been vaccinated with BCG generally indicates the absence of infection with M. tuberculosis.

A history of BCG vaccination does not contraindicate tuberculin skin testing, and such testing in vaccinated individuals can be used to support or exclude a diagnosis of M. tuberculosis infection. Because reactions that result from M. tuberculosis infection tend to be larger than those that result from BCG vaccination, some clinicians suggest that only large induration reactions (15 mm or more) to a standard Mantoux test (0.1 mL of a 5 TU/0.1 mL solution of PPD) be interpreted as indicating natural infection with M. tuberculosis in individuals who have been vaccinated with BCG. However, there is no reliable method of distinguishing between a reaction to tuberculin which results from vaccination with BCG and one which is caused by natural infection with M. tuberculosis. Therefore, it usually is prudent to consider reactions of 10 mm or greater to a standard Mantoux test in BCG-vaccinated individuals as indicating infection with M. tuberculosis. The CDC states that the possibility of tuberculosis infection should be considered in the differential diagnosis of any tuberculosis-like illness in a BCG-vaccinated individual, especially if the vaccinee has been exposed recently to an individual with infectious tuberculosis or was vaccinated with BCG several years before tuberculin testing. In addition to the size of the induration reaction and confirmation of BCG vaccination, other factors to consider that may guide interpretation of the reaction should include whether the patient is a recent close contact of an infectious case of tuberculosis, especially if there is evidence of transmission of infection to unvaccinated contacts of the infectious case; whether, even if there has not been recent contact with an infectious case, there is a family history of tuberculosis or the patient has recently emigrated from a country with a high prevalence of tuberculosis; and when the BCG vaccine was administered (the probability of the skin reaction indicating exposure increases as the length of time since vaccination increases).

A history of BCG vaccination, with or without a BCG scar, should not influence the decision regarding whether to treat latent tuberculosis infection.

Antituberculosis Agents

Some antituberculosis agents (e.g., isoniazid, rifampin, streptomycin) inhibit multiplication of BCG; therefore, BCG vaccine may not be effective if administered during therapy with the drugs.

Vaccines

BCG vaccine has been administered concurrently with yellow fever vaccine without interference with the immune response to either vaccine. The CDC states that BCG vaccine can be administered concurrently with other live vaccines; if concurrent administration is not possible, the vaccines should be given at 4-week intervals.

Acute Toxicity

If acute overdosage of BCG vaccine occurs and there is reason to suspect that a generalized BCG infection may develop, isoniazid or other appropriate antituberculosis agent therapy should be initiated. Complications generally do not occur if acute overdosage of BCG is treated immediately with antituberculosis agent therapy. If not treated immediately, antituberculosis agent therapy can still be successful but complications such as regional adenitis, lupus vulgaris, subcutaneous cold abscesses, and ocular lesions can occur.

Pharmacology

BCG vaccine is used to stimulate active immunity to tuberculosis. Because the Calmette-Guérin strain of M. bovis present in BCG vaccine is immunologically similar to M. tuberculosis, vaccination with BCG simulates natural infection with M. tuberculosis and promotes cell-mediated immunity against tuberculosis.

Vaccination with BCG generally results in tuberculin sensitivity, but the degree of tuberculin sensitivity is highly variable and depends partly on the strain of BCG used in the vaccine. The ability of a particular BCG vaccine to cause tuberculin sensitivity has generally been used to indicate its immunizing potential, and conversion of the tuberculin skin test following vaccination has generally been used to indicate immunity against tuberculosis. However, the relationship between tuberculin sensitivity following BCG vaccination and immunity against tuberculosis has not been adequately studied to date. Efficacy of the currently available BCG vaccines has not been demonstrated directly and can only be inferred. Although the protection against M. tuberculosis infection afforded by the vaccine is highly variable, diagnostic and clinical evidence has generally demonstrated a reduction in the incidence of tuberculosis in immunized individuals as compared with nonimmunized individuals.

The duration of protection against tuberculosis infection following administration of BCG vaccine has not been determined and depends on the potency and dosage of the vaccine used. In several studies, tuberculin sensitivity persisted 7–10 years following BCG vaccination; however, a definite relationship between tuberculin sensitivity and immunity has not been established.

BCG vaccine and the methanol-extracted residue (MER) of BCG have been shown to be potent stimulators of host defense mechanisms. In animals, BCG increases resistance of the animal to tumor growth following inoculation with tumor cells. There is also evidence of tumor (e.g., malignant melanoma) regression following intralesional injection of BCG vaccine. Inclusion of BCG in tumor antigen-containing vaccines has been reported to enhance induction by the vaccine of a tumor-specific immune response. The immunostimulant effect of specific BCG preparations is reportedly variable. The mechanism(s) of BCG’s immunostimulant effect has not been fully determined. It is not known whether antibodies or specifically sensitized cells are involved in the antitumor effect of BCG. Antimelanoma antibody titers have increased in patients with melanoma receiving BCG therapy. Although BCG has been shown to stimulate natural killer-cell (a subpopulation of lymphocytes) activity and macrophage activity, the relation of these effects to the vaccine’s antitumor activity has not been established. For BCG to have an antitumor effect, it appears that the tumor host must be immunocompetent, a sufficient dose of BCG must be given, the tumor burden must be relatively low, administered BCG must be closely associated with the tumor cells, and the tumor must be immunogenic.

Chemistry and Stability

Chemistry

BCG vaccine is a lyophilized preparation of live, attenuated organisms of the Calmette-Guérin strain of Mycobacterium bovis. Various BCG vaccines are available worldwide; all are derived from the original Calmette-Guérin strain but vary in immunogenicity and toxicity because of differences in the specific bacterial substrain used, techniques of production, and methods and routes of administration. BCG vaccine commercially available in the US contains the TICE substrain of BCG and is administered by percutaneous administration via a multiple-puncture device. A BCG vaccine for intradermal injection is no longer commercially available in the US.

BCG vaccine commercially available in the US is prepared by suspending and freeze-drying the organisms in a medium consisting of glycerin, asparagine, citric acid, potassium phosphate, magnesium sulfate, and iron ammonium citrate. The vaccine meets standards established by the Center for Biologics Evaluation and Research of the US Food and Drug Administration. The commercially available lyophilized BCG vaccine occurs as a white to creamy white, dried mass having the characteristic texture of material dried in the frozen state. Following reconstitution as directed for percutaneous administration, BCG vaccine contains 100–800 million colony-forming units of BCG bacillus per mL; the injection is free from other organisms.

BCG also is commercially available for intravesical instillation. BCG for intravesical instillation is a lyophilized preparation of live, attenuated organisms of the Calmette-Guérin strain of M. bovis and is commercially available in the US as TheraCys BCG, which contains the Connaught substrain, and as TICE BCG, which contains the TICE substrain. Following reconstitution as directed, each vial of TheraCys BCG contains 10.5±8.7 × 10⁸ CFUs of BCG bacillus and each vial of TICE BCG contains 1–8 × 10⁸ CFU of BCG bacillus. These preparations do not contain preservatives.

Stability

The lyophilized powder for injection of BCG vaccine should be protected from light and refrigerated at 2–8°C, but preferably at less than 5°C. The expiration date for lyophilized BCG vaccine is not later than 6 months after the date of issue, or not later than 1 year after the date of issue if stored at a temperature less than 5°C.

The manufacturer states that reconstituted BCG vaccine for percutaneous administration should be refrigerated, protected from light, and used within 2 hours.

BCG lyophilized powders for intravesical instillation and the diluents provided by the manufacturers should be refrigerated at 2–8°C. The lyophilized powders should be protected from direct and indirect sunlight, and exposure to artificial light should be minimized.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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