Valrubicin

Patients should be informed that VALSTAR (valrubicin) 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 (valrubicin) 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 (valrubicin) 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 (valrubicin) should be delayed until bladder integrity has been restored.

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

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)

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.

Patients should be informed that VALSTAR (valrubicin) 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 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 VALSTAR (valrubicin) are related to irritable bladder symptoms that may occur during instillation and retention of VALSTAR (valrubicin) 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 childbearing 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 VALSTAR (valrubicin) . All patients of reproductive age should be advised to use an effective contraception method during the treatment period.

• Valrubicin has been shown to induce complete responses in only about 1 in 5 patients. Delaying cystectomy (removal of the bladder) could lead to development of metastatic bladder cancer, which is lethal. Discuss with your doctor the relative risk of cystectomy versus the risk of metastatic bladder cancer.
• Major toxicities from valrubicin are related to irritable bladder symptoms that may occur during use of valrubicin. For the first 24 hours following use, red-tinged urine is typical. Report prolonged irritable bladder symptoms or prolonged passage of red-colored urine immediately to your doctor.
• You or your partner should not become pregnant while you are using valrubicin. You should use birth control to prevent pregnancy in yourself or your partner during your treatment with valrubicin. Talk to your doctor about birth control methods that will work for you. If you or your partner become pregnant while using valrubicin, call your doctor.
• Do not use this medication if you
  • have an allergy to valrubicin or to any of its inactive ingredients
  • have an allergy to anthracyclines medications or to polyoxyl castor oil
  • currently have urinary tract infection
  • have a small bladder capacity (unable to tolerate a 75 mL within the bladder)

Call your doctor for instructions if you miss an appointment for your valrubicin injection.

• If you need to store this medicine at home, talk with your doctor, nurse, or pharmacist about how to store it.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about valrubicin, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about valrubicin. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using valrubicin.

Review Date: October 4, 2017

For intravesical use only; not for IV or IM use.

Intravesicular bladder instillation: Insert urinary catheter, empty bladder prior to instillation, slowly by gravity flow, instill 800 mg/75 mL (in 0.9% sodium chloride injection), remove catheter. Retain in the bladder for 2 hours, then void. Administer through non-PVC tubing due to the polyoxyl castor oil component. Maintain adequate hydration following treatment.

Store intact vials at 2°C to 8°C (36°F to 48°F). Do not freeze. Solutions diluted in 0.9% sodium chloride are stable for 12 hours at room temperature.

Data not available

This drug should be used during pregnancy only if the benefit outweighs the risk. US FDA pregnancy category: C Comments: -All patients (male and female) of reproductive age should be advised to use an effective contraception method during the treatment period. -If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.

Animal studies have revealed evidence of embryotoxicity and teratogenicity. There are no controlled data in human pregnancy. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Breastfeeding is not recommended during use of this drug. Excreted into human milk: Unknown Excreted into animal milk: Data not available Comments: The drug is highly lipophilic and any exposure of infants could pose serious health risks.