Ocular symptoms (including uveitis, conjunctivitis, iritis, keratitis, granulomatous choreoretinitis) alone, or in combination with joint symptoms (arthritis or arthralgia), urinary symptoms and/or skin rash, have been reported following administration of intravesical BCG. The risk appears to be elevated among patients who are positive for HLA-B27.⁵ Although uncommon, serious infectious complications ofintravesical BCG have been reported. The most serious infectious complication

of BCG is disseminated sepsis with associated mortality. In addition, M. bovis infections have been reported in lung, liver, bone, bone marrow, kidney, regional lymph nodes, 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.

In SWOG Study 8216, 112 patients received TheraCysÒ .² The incidence of adverse reactions associated with intravesical TheraCysÒ is given below.

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

In this study, local irritative symptoms were more common with TheraCysÒ than with doxorubicin; however, grade ≥³ irritative toxicity was similar, occurring in 2-7% of patients. Systemic symptoms (fever, chills, malaise, etc.) were also more common with TheraCysÒ ^. Overall, grade ≥3 toxicities were seen in 26 patients (23%) treated with TheraCysÒ and 25 patients (21%) treated with doxorubicin. "Systemic infection"was reported to occur in three patients treated with TheraCysÒ (one grade 2 and two grade 3) and one patient treated with doxorubicin (grade 2). In four patients, treatment was discontinued because of toxicity (two with irritative symptoms, one with severe hematuria, and one with possible BCG infection). In addition, six patients refused further treatment because of severe local toxicity and/or chills. Six of these ten patients received TheraCysÒ . Table 3 compares the common adverse events reported in SWOG Study 8216.

Patients should be encouraged to report all adverse events after treatment with TheraCysÒ . Adverse events should be reported by health care providers to MEDWATCH (call 1-800-FDA-1088). Physicians, physician assistants, nurses and pharmacists should report adverse occurrences temporally related to the administration of the product to the Director of Medical Affairs, Aventis Pasteur Inc., Discovery Drive, Swiftwater PA 18370 or call 1-800-822-2463.

Symptoms of bladder irritability, related to the inflammatory response induced, are reported in approximately 50% of patients receiving TheraCysÒ (refer to Table No. 2). The symptoms typically begin 4-6 hours after instillation and last 24-72 hours. The irritative side effects are usually seen following the third instillation, and tend to increase in severity after each administration. The irritative bladder adverse effects can usually be managed symptomatically with products such as pyridium, propantheline bromide, oxybutynin chloride and acetaminophen. 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 toxicity of TheraCysÒ .

The "flu-like"symptoms (malaise, fever, and chills) which may accompany the localized, irritative toxicities often reflect hypersensitivity reactions which can be treated symptomatically. Antihistamines have also been used.

Drug combinations containing immunosuppressants and/or bone marrow depressants and/or radiation interfere with the development of the immune response and should not be used in combination with TheraCysÒ . Antimicrobial therapy for other infections may interfere with the effectiveness of TheraCysÒ . There are no data to suggest that the acute, local urinary tract toxicity common with BCG is due to mycobacterial infection, and antituberculosis drugs (e.g., isoniazid) should not be used to prevent or treat the local, irritative toxicities of TheraCysÒ .

For patients with a condition that may in the future require mandatory immunosuppression (e.g., awaiting an organ transplant, myasthenia gravis) the decision to treat with TheraCysÒ should be considered carefully.

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