Valstar

  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)].

  Preparation, Handling, and Administration

Handle and dispose of VALSTAR in a manner consistent with other cytotoxic drugs. 1The 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)] .

  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 ( 12.1and 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 2basis) 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 2basis) 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.

  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.

  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)] .

  Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

  Geriatric Use

Because carcinoma in situof 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.

  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.

  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)] .

  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.

  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.

  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 ( 12.1and 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 ( 8.1and 8.3)] .