2.1 Recommended Dosing

For Intravesical Use Only. Do NOT administer by intravenous or intramuscular routes.

VALSTAR is recommended at a dose of 800 mg administered intravesically once a week for six weeks. Delay administration at least two weeks after transurethral resection and/or fulguration [ see Warnings and Precautions ( 5.2, 5.3)].

2.2 Preparation, Handling, and Administration

Handle and dispose of VALSTAR in a manner consistent with other cytotoxic drugs. 1 The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug.

VALSTAR contains polyoxyl castor oil, which has been known to cause leaching of di(2-ethylhexyl) phthalate (DEHP) a hepatotoxic plasticizer, from polyvinyl chloride (PVC) bags and intravenous tubing. VALSTAR should be prepared and stored in glass, polypropylene, or polyolefin containers and tubing. It is recommended that non-DEHP containing administration sets, such as those that are polyethylene-lined, be used.

VALSTAR is a sterile, clear red solution. Visually inspect for particulate matter and discoloration prior to administration. At temperatures below 4°C (39°F), polyoxyl castor oil may begin to form a waxy precipitate. If this happens, the vial should be warmed in the hand until the solution is clear. If particulate matter is still seen, do not administer VALSTAR.

For each instillation, slowly allow four 5 mL vials (200 mg valrubicin/5 mL vial) to warm to room temperature, but do not heat. Withdraw 20 mL of VALSTAR from the four vials and dilute with 55 mL of 0.9% Sodium Chloride Injection, USP to provide 75 mL of a diluted VALSTAR solution. VALSTAR diluted in 0.9% Sodium Chloride Injection, USP for administration is stable for 12 hours at temperatures up to 25°C (77°F). Since compatibility data are not available, do not mix VALSTAR with other drugs.

Insert a urethral catheter into the patient's bladder under aseptic conditions, drain the bladder, and instill the diluted 75 mL VALSTAR solution slowly via gravity flow over a period of several minutes. Withdraw the catheter and retain VALSTAR in the bladder for two hours before voiding. At the end of two hours, all patients should void. Some patients may be unable to retain the drug for the full two hours. Instruct patients to maintain adequate hydration following VALSTAR treatment [see Patient Counseling Information ( 17)] .

5.1 Risk of Metastatic Bladder Cancer with Delayed Cystectomy

Inform patients 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 Studies ( 14)] 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, reconsider cystectomy.

5.2 Risks in Patients with Perforated Bladder

Evaluate the bladder before the intravesical instillation of drug and do not administer VALSTAR to patients with a perforated bladder or to those in whom the integrity of the bladder mucosa has been compromised [see Contraindications ( 4)] . In case of bladder perforation, delay the administration of VALSTAR until bladder integrity has been restored. One patient with a perforated bladder who received 800 mg of VALSTAR intravesically developed severe leukopenia and neutropenia approximately two weeks after drug administration [see Clinical Pharmacology ( 12.3)] .

5.3 Risk in Patients Undergoing Transurethral Resection of the Bladder (TURB)

To avoid systemic exposure to VALSTAR for the patients undergoing TURB, evaluate the status of the bladder before the intravesical instillation of drug. Delay administration at least two weeks after transurethral resection and/or fulguration.

5.4 Risk in Patients with Irritable Bladder Symptoms

Use VALSTAR 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.

5.5 Embryo-Fetal Toxicity

Based on findings in animal studies and its mechanism of action, VALSTAR can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 and 12.3)] . In animal reproduction studies, intravenous administration of valrubicin to pregnant rats during the period of organogenesis at a dose about 0.2 times the recommended human intravesical dose caused embryo-fetal malformations and increased resorptions. Advise females who might become pregnant of the potential risk to a fetus.

Advise females of reproductive potential to use effective contraception during treatment with VALSTAR and for 6 months following the final dose [see Use in Specific Populations ( 8.1 and 8.3)] .

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of VALSTAR was assessed in 230 patients with transitional cell carcinoma of the bladder, including 205 patients who received multiple weekly doses. One hundred seventy-nine of the 205 patients received the approved dose and schedule of 800 mg weekly for multiple weeks.

Approximately 84% of patients who received intravesical VALSTAR in clinical studies experienced local adverse reactions. 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. Seven out of 143 patients (5%) who were scheduled to receive six doses of VALSTAR failed to receive all of the planned doses because of the occurrence of local bladder symptoms.

TABLE 1 displays the frequency of the local adverse reactions at baseline and during treatment among 179 patients who received 800 mg doses of VALSTAR in a multiple-cycle treatment regimen.

TABLE 2 displays the adverse reactions other than local bladder symptoms that occurred in 1% or more of the 230 patients who received at least one dose of VALSTAR in a clinical trial.

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.

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

8.1 Pregnancy

Risk Summary

Based on findings in animal studies and its mechanism of action, VALSTAR can cause fetal harm when administered to a pregnant females [see Clinical Pharmacology ( 12.1 and 12.3)] . There are no available data in pregnant females to inform the drug-associated risk. In animal reproduction studies, intravenous administration of valrubicin to pregnant rats during the period of organogenesis at a dose about 0.2 times the recommended human intravesical dose caused embryo-fetal malformations and increased resorptions [see Data]. Advise females who are or might become pregnant of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Daily intravenous administration of valrubicin to pregnant rats during the period of organogenesis at doses ≥ 12 mg/kg (about 0.2 times the recommended human intravesical dose on a mg/m 2 basis) was embryo-fetal toxic and teratogenic. Administration of 12 mg/kg resulted in fetal malformations. A dose of 24 mg/kg (about 0.3 times the recommended human intravesical dose on a mg/m 2 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.

8.2 Lactation

Risk Summary

There are no data on the presence of valrubicin or its metabolites in human milk, the effects of valrubicin on the breast-fed infant, or its effects on milk production. Because of the potential for serious adverse reactions in breast-fed infants from valrubicin, advise a lactating female not to breastfeed during treatment with VALSTAR and for 2 weeks after the final dose.

8.3 Females and Males of Reproduction Potential

Contraception

Females

VALSTAR can cause fetal harm when administered to a pregnant female. Advise females of reproductive potential to use effective contraception during treatment with VALSTAR and for 6 months after the final dose [see Use in Specific Populations ( 8.1)] .

Males

Based on genotoxicity findings, advise men with female partners of reproductive potential to use effective contraception during treatment with VALSTAR and for 3 months following the final dose [see Non Clinical Toxicology ( 13.1)]

Infertility

Males

Studies of the effects of VALSTAR on human male or female fertility have not been done. Based on findings in animal studies, VALSTAR may impair fertility in males of reproductive potential [see Nonclinical Toxicology ( 13.1)] .

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Because carcinoma in situ of the bladder generally occurs in older individuals, 85% of the patients enrolled in the clinical studies of VALSTAR 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 VALSTAR in geriatric patients who are otherwise in good health.

12.1 Mechanism of Action

Valrubicin is an anthracycline that affects a variety of interrelated biological functions, most of which involve nucleic acid metabolism. In cells, it inhibits the incorporation of nucleosides into nucleic acids, causes chromosomal damage, and arrests the cell cycle in G 2. Although valrubicin does not bind strongly to DNA, valrubicin metabolites interfere with the normal DNA breaking-resealing action of DNA topoisomerase II.

12.3 Pharmacokinetics

When 800 mg VALSTAR was administered intravesically to patients with carcinoma in situ, VALSTAR 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 to its major metabolites N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol in bladder tissue was negligible. After retention, the drug was almost completely excreted by voiding the instillate. Mean percent recovery of VALSTAR, 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 were absorbed into the plasma. N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol were measured in blood.

Total systemic exposure to anthracyclines during and after intravesical administration of VALSTAR is dependent upon the condition of the bladder wall. The mean AUC 0-6hours (total anthracyclines exposure) for an intravesical dose of 900 mg of VALSTAR administered 2 weeks after transurethral resection of bladder tumors (n=6) was 78 nmol/L•hr. In patients receiving 800 mg of VALSTAR 5 to 51 minutes after typical (n=8) and extensive (n=5) TURB tumors, the mean AUC 0-6hours values for total anthracyclines were 409 and 788 nmol/L•hr, respectively. The AUC 0-6hours 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. Administration of a comparable intravenous dose of VALSTAR (600 mg/m 2; n=2) as a 24-hour infusion resulted in an AUC 0-6hours for total anthracyclines of 11,975 nmol/L•hr. These results are shown in FIGURE 2.

13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility

The carcinogenic potential of valrubicin has not been evaluated.

In vitro, valrubicin was mutagenic in the bacterial reverse mutation (Ames) assayand clastogenic in the chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells.

Studies in animals evaluating the effects of valrubicin on male or female fertility have not been conducted. Based on effects on male reproductive organs in general toxicology studies in dogs with intravesical instillation, valrubicin may impair fertility in male patients. When instilled into the bladder of male dogs weekly for 6 weeks, valrubicin caused mild to moderate atrophy of the prostate with inflammation, diffuse decrease in acinar size, epithelial changes. It also caused testicular degeneration, marked germ cell depletion, spermatid giant cells and karyomegaly.