Patients should be informed that ValstarÔ has been shown to induce complete response in only about 1 in 5 patients with BCG-refractory CIS, and that delaying cystectomy could lead to development of metastatic bladder cancer, which is lethal. The exact risk of developing metastatic bladder cancer from such a delay may be difficult to assess (see CLINICAL PHARMACOLOGY, CLINICAL TRIALS) but increases the longer cystectomy is delayed in the presence of persisting CIS. If there is not a complete response of CIS to treatment after 3 months or if CIS recurs, cystectomy must be reconsidered.

ValstarÔ should not be administered to patients with a perforated bladder or to those in whom the integrity of the bladder mucosa has been compromised (see

PRECAUTIONS

In order to avoid possible dangerous systemic exposure to ValstarÔ for the patients undergoing transurethral resection of the bladder, the status of the bladder should be evaluated before the intravesical instillation of drug. In case of bladder perforation, the administration of ValstarÔ should be delayed until bladder integrity has been restored.

ValstarÔ should be administered under the supervision of a physician experienced in the use of intravesical cancer chemotherapeutic agents.

General

Aseptic techniques must be used during administration of intravesical ValstarÔ to avoid introducing contaminants into the urinary tract or traumatizing unduly the urinary mucosa.

Information for Patients

Patients should be informed that ValstarÔ has been shown to induce complete responses in only about 1 in 5 patients, and that delaying cystectomy could lead to development of metastatic bladder cancer, which is lethal. They should discuss with their physician the relative risk of cystectomy versus the risk of metastatic bladder cancer (see CLINICAL PHARMACOLOGY, CLINICAL TRIALS) and be aware that the risk increases the longer cystectomy is delayed in the presence of persisting CIS.

Patients should be informed that the major acute toxicities from ValstarÔ are related to irritable bladder symptoms that may occur during instillation and retention of ValstarÔ and for a limited period following voiding. For the first 24 hours following administration, red tinged urine is typical. Patients should report prolonged irritable bladder symptoms or prolonged passage of red-colored urine immediately to their physician.

Women of child-bearing potential should be advised not to become pregnant during treatment. Men should be advised to refrain from engaging in procreative activities while receiving therapy with ValstarÔ. All patients of reproductive age should be advised to use an effective contraception method during the treatment period.

Irritable Bladder Symptoms

ValstarÔ should be used with caution in patients with severe irritable bladder symptoms. Bladder spasm and spontaneous discharge of the intravesical instillate may occur; clamping of the urinary catheter is not advised and if performed, should be executed under medical supervision and with caution.

Drug Interactions

Because systemic exposure to ValstarÔ is negligible following intravesical administration, the potential for drug interactions is low. No drug interaction studies were conducted.

Carcinogenesis Mutagenesis Impairment of Fertility

The carcinogenic potential of ValstarÔ has not been evaluated but the drug does cause damage to DNA in vitro. ValstarÔ was mutagenic in in vitro assays in Salmonella typhiurium and Escherichia coli. ValstarÔ was clastogenic in the chromosomal aberration assay in CHO cells. Studies of the effects of ValstarÔ on male or female fertility have not been done.

Pregnancy

Pregnancy Category C. Valrubicin can cause fetal harm if a pregnant woman is exposed to the drug systemically. Such exposure could occur after perforation of the urinary bladder during valrubicin therapy. Daily intravenous doses of 12 mg/kg (about one sixth of the recommended human intravesical dose on a mg/m² basis) given to rats during fetal development caused fetal malformations. A dose of 24 mg/kg (about one third the recommended human intravesical dose on a mg/m² basis) caused numerous, severe alterations in the skull and skeleton of the developing fetuses. This dose also caused an increase in fetal resorptions and a decrease in viable fetuses. Thus, valrubicin is embryotoxic and teratogenic. There are no preclinical studies of the effects of intravesical valrubicin on fetal development and no adequate and well controlled studies of valrubicin in pregnant women. If valrubicin is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprized of the potential hazard to the fetus. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women who might become pregnant should be advised to avoid doing so during therapy with ValstarÔ.

Nursing Mothers

It is not known whether ValstarÔ is excreted in human milk. Nevertheless, the drug is highly lipophilic and any exposure of infants to ValstarÔ could pose serious health risks. Women should discontinue nursing before the initiation of ValstarÔ therapy.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Because carcinoma in situ of the bladder generally occurs in older individuals, 85% of the patients enrolled in the clinical studies of ValstarÔ were more than 60 years of age (49% of the patients were more than 70 years of age). In the primary efficacy studies, the mean age of the population was 69.5 years. There are no specific precautions regarding use of ValstarÔ product in geriatric patients who are otherwise in good health.

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