Valrubicin (N-trifluoroacetyladriamycin-14-valerate), a semisynthetic analog of the anthracycline doxorubicin, is a cytotoxic agent with the chemical name, (2S-cis)-2-[1,2,3,4,6,11-hexahydro-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-4-[[2,3,6-trideoxy-3-[(trifluoroacetyl)amino]-α-L-lyxo-hexopyranosyl]oxyl]-2-naphthacenyl]-2-oxoethylpentanoate. Valrubicin is an orange or orange-red powder that is highly lipophilic, soluble in methylene chloride, ethanol, methanol and acetone, and relatively insoluble in water. Its chemical formula is C34H36F3NO13 and its molecular weight is 723.65. The chemical structure is shown in FIGURE 1.

FIGURE 1. Chemical Structure of Valrubicin

VALSTAR® (valrubicin) Sterile Solution for Intravesical Instillation is intended for intravesical administration in the urinary bladder. It is supplied as a nonaqueous solution that should be diluted before intravesical administration. Each vial of VALSTAR contains valrubicin at a concentration of 40 mg/mL in 50% polyoxyl castor oil/50% dehydrated alcohol, USP without preservatives or other additives. The solution is sterile and nonpyrogenic.

CLINICAL PHARMACOLOGY

VALSTAR has been administered intravesically to a total of 230 patients with transitional cell carcinoma of the bladder, including 205 patients who received multiple weekly doses ranging from 200 to 900 mg. One hundred seventy-nine of the 205 patients received the approved dose and schedule of 800 mg weekly for multiple weeks.

In the 90 study patients with BCG-refractory carcinoma in situ (CIS), 70% had received at least 2 courses of BCG and 30% had received one course of BCG and at least one additional course of treatment with another agent(s) - e.g., mitomycin, thiotepa, or interferon. VALSTAR was administered beginning at least two weeks after transurethral resection and/or fulguration. After intravesical administration of VALSTAR, 16 patients (18%) had a complete response documented by bladder biopsies and cytology at 6 months following initiation of therapy. Median duration of response from start of treatment varied according to the method of analysis (13.5 months if measured to last bladder biopsy without tumor and 21 months if measured until time of documented recurrence). A retrospective analysis in the 16 patients with complete response to VALSTAR demonstrated that time to recurrence of their disease after treatment with VALSTAR was longer than time to recurrence after previous courses of intravesical therapy.

Of the 90 patients with BCG-refractory CIS, 11% (10 patients) developed metastatic or deeply-invasive bladder cancer during follow-up; four of these patients, none who underwent cystectomy, died with metastatic bladder cancer and six were found to have developed stage progression to deeply-invasive disease (T3), with lymph node involvement in one patient, at the time of cystectomy. It is difficult to ascertain to what extent the development of advanced bladder cancer in these patients was due to the delay in cystectomy required to receive treatment with VALSTAR (3 months was the time of follow-up to determine response), as cystectomy was often delayed or was never performed despite failure of treatment with VALSTAR. In the 10 patients documented to have invasive bladder cancer or metastatic disease, the delay between the time of treatment failure (when cystectomy should have been performed) and cystectomy or documentation of advanced bladder cancer was a median of 17.5 months.

INDICATIONS AND USAGE

VALSTAR is indicated for intravesical therapy of BCG-refractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality.

CONTRAINDICATIONS

VALSTAR is contraindicated in patients with known hypersensitivity to anthracyclines or polyoxyl castor oil.

Patients with concurrent urinary tract infections should not receive VALSTAR.

VALSTAR should not be administered to patients with a small bladder capacity, i.e., unable to tolerate a 75 mL instillation.

WARNINGS

Patients should be informed that VALSTAR 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 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.

VALSTAR 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 and CLINICAL PHARMACOLOGY, Pharmacokinetics Figure 2).

In order to avoid possible dangerous systemic exposure to VALSTAR 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 VALSTAR should be delayed until bladder integrity has been restored.

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

PRECAUTIONS

Approximately 84% of patients who received intravesical VALSTAR in clinical studies experienced local adverse events, but approximately half of the patients reported irritable bladder symptoms prior to treatment. The local adverse reactions associated with VALSTAR usually occur during or shortly after instillation and resolve within 1 to 7 days after the instillate is removed from the bladder.

TABLE 1 displays the frequency of the local adverse experiences at baseline and during treatment among 170 patients who received 800 mg doses of VALSTAR® (valrubicin) Sterile Solution for Intravesical Instillation in a multiple-cycle treatment regimen. Only 7 of 143 patients who were scheduled to receive six doses failed to receive all of the planned doses because of the occurrence of local bladder symptoms.

Most systemic adverse events associated with use of VALSTAR have been mild in nature and self-limited, resolving within 24 hours after drug administration. TABLE 2 displays the adverse events other than local bladder symptoms that occurred in 1% or more of the 230 patients who received at least one dose of VALSTAR (200 to 900 mg) in a clinical trial. It cannot be determined whether these events are drug-related.

Adverse reactions other than local reactions that occurred in less than 1% of the patients who received VALSTAR intravesically in clinical trials are listed below. This list includes only adverse reactions that were suspected of being related to treatment.

Digestive System: Tenesmus.
Metabolic and Nutritional: Nonprotein nitrogen increased.
Skin and Appendages: Pruritus.
Special Senses: Taste loss.
Urogenital System: Local skin irritation, poor urine flow, and urethritis.

Inadvertent paravenous extravasation of VALSTAR was not associated with skin ulceration or necrosis.

OVERDOSAGE

There is no known antidote for overdoses of VALSTAR. The primary anticipated complications of overdosage associated with intravesical administration would be consistent with irritable bladder symptoms.

Myelosuppression is possible if VALSTAR is inadvertently administered systemically or if significant systemic exposure occurs following intravesical administration (e.g., in patients with bladder rupture/perforation). The maximum tolerated dose in humans by either intraperitoneal or intravenous administration is 600 mg/m2. Dose limiting toxicities are leukopenia and neutropenia, beginning within 1 week of dose administration, with nadirs by the second week, and recovery generally by the third week. If VALSTAR is administered when bladder rupture or perforation is suspected, weekly monitoring of complete blood counts should be performed for 3 weeks.

DOSAGE AND ADMINISTRATION

VALSTAR is recommended at a dose of 800 mg administered intravesically once a week for six weeks. Administration should be delayed at least two weeks after transurethral resection and/or fulguration. For each instillation, four 5 mL vials (200 mg valrubicin/5 mL vial) should be allowed to warm slowly to room temperature, but should not be heated. Twenty milliliters of VALSTAR should then be withdrawn from the four vials and diluted with 55 mL 0.9% Sodium Chloride Injection, USP providing 75 mL of a diluted VALSTAR solution. A urethral catheter should then be inserted into the patient's bladder under aseptic conditions, the bladder drained, and the diluted 75 mL VALSTAR solution instilled slowly via gravity flow over a period of several minutes. The catheter should then be withdrawn. The patient should retain the drug for two hours before voiding. At the end of two hours, all patients should void. (Some patients will be unable to retain the drug for the full two hours.) Patients should be instructed to maintain adequate hydration following treatment.

Patients receiving VALSTAR for refractory carcinoma in situ must be monitored closely for disease recurrence or progression. Recommended evaluations include cystoscopy, biopsy, and urine cytology every 3 months.

VALSTAR Sterile Solution for Intravesical Instillation is a clear red solution in polyoxyl castor oil/dehydrated alcohol, USP, containing 40 mg valrubicin per mL. VALSTAR Sterile Solution for Intravesical Instillation is available in single-use, clear glass vials, individually packaged in the following sizes:

Store vials under refrigeration at 2°-8°C (36°-46°F) in the carton. DO NOT FREEZE.