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Valstar

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Valstar

CLINICAL PHARMACOLOGY

Mechanism of Action: Valrubicin is an anthracycline that affects a variety of inter-related biological functions, most of which involve nucleic acid metabolism. It readily penetrates into cells, where it inhibits the incorporation of nucleosides into nucleic acids, causes extensive chromosomal damage, and arrests cell cycle in G2. Although valrubicin does not bind strongly to DNA, a principal mechanism of its action, mediated by valrubicin metabolites, is interference with the normal DNA breaking-resealing action of DNA topoisomerase II.

Pharmacokinetics after Intravesical Administration of VALSTAR (valrubicin) : When 800 mg VALSTAR (valrubicin) was administered intravesically to patients with carcinoma in situ, VALSTAR (valrubicin) penetrated into the bladder wall. The mean total anthracycline concentration measured in bladder tissue exceeded the levels causing 90% cytotoxicity to human bladder cells cultured in vitro. During the two-hour dose-retention period, the metabolism of VALSTAR (valrubicin) to its major metabolites N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol was negligible. After retention, the drug was almost completely excreted by voiding the instillate. Mean percent recovery of VALSTAR (valrubicin) , N-trifluoroacetyladriamycin, and total anthracyclines in 14 urine samples from six patients was 98.6%, 0.4%, and 99.0% of the total administered drug, respectively. During the two-hour dose-retention period, only nanogram quantities of VALSTAR (valrubicin) were absorbed into the plasma. VALSTAR (valrubicin) metabolites N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol were measured in blood.

Total systemic exposure to anthracyclines during and after intravesical administration of VALSTAR (valrubicin) is dependent upon the condition of the bladder wall. The mean AUC0-6 hours (total anthracyclines exposure) for an intravesical dose of 900 mg of VALSTAR (valrubicin) administered 2 weeks after transurethral resection of bladder tumors (n=6) was 78 nmol/L•hr. In patients receiving 800 mg of VALSTAR (valrubicin) 5 to 51 minutes after typical (n=8) and extensive (n=5) transurethral resection of bladder tumors (TURBs), the mean AUC0-6 hours values for total anthracyclines were 409 and 788 nmol/L•hr, respectively. The AUC0-6 hours total exposure to anthracyclines was 18,382 nmol/L•hr in one patient who experienced a perforated bladder following a transurethral resection that occurred 5 minutes before administration of an intravesical dose of 800 mg of VALSTAR (valrubicin) . Administration of a comparable intravenous dose of VALSTAR (valrubicin) (600 mg/m²; n=2) as a 24-hour infusion resulted in an AUC0-6 hours for total anthracyclines of 11,975 nmol/L•hr. These results are shown in FIGURE 2.

FIGURE 2. Comparison of Mean AUC0-6 hours in VALSTAR (valrubicin) Clinical Studies (N=number of patients)

Comparison of Mean AUC0-6 hours in VALSTAR Clinical Studies - Illustration

The patient with a perforated bladder who received 800 mg of VALSTAR (valrubicin) intravesically developed severe leukopenia and neutropenia approximately two weeks after drug administration. Systemic hematologic toxicity from VALSTAR (valrubicin) was not seen after an intravesical dose of 800 mg of VALSTAR (valrubicin) unless perforation of the urinary bladder occurred.

Clinical Trials

VALSTAR (valrubicin) 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 (valrubicin) was administered beginning at least two weeks after transurethral resection and/or fulguration. After intravesical administration of VALSTAR (valrubicin) , 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 (valrubicin) demonstrated that time to recurrence of their disease after treatment with VALSTAR (valrubicin) 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 (valrubicin) (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 (valrubicin) . 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.

Last reviewed on RxList: 11/24/2008
This monograph has been modified to include the generic and brand name in many instances.

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