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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.
Valrubicin 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 Twenty milliliters of valrubicin should then be withdrawn from the four vials and diluted with 55 mL 0.9% Sodium Chloride Injection, USP providing 75 mL of a diluted valrubicin solution. * A urethral catheter should then be inserted into the patients bladder under aseptic conditions, the bladder drained, and the diluted 75 mL valrubicin 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 * The catheter should then be withdrawn.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 valrubicin 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.
Administration Precautions: As recommended with other cytotoxic agents, caution should be exercised in handling and preparing the solution of valrubicin. Contact toxicity, common and severe with other anthracyclines, is not typical with valrubicin and, when observed, has been mild. Skin reactions may occur with accidental exposure. The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug. Irritation of the eye has also been reported with accidental exposure. If this happens, the eye should be flushed with water immediately and thoroughly. Procedures for proper handling and disposal of anticancer drugs should be used.¹-⁴ Spills should be cleaned up withundiluted chlorine bleach.
Valrubicin sterile solution 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. valrubicin solutions 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.
Preparation for Administration: valrubicin Sterile Solution for Intravesical Instillation is a clear red solution. It should be visually inspected for particulate matter and discoloration prior to administration. At temperatures below 4°C, 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, valrubicin should not be administered.
Stability: Unopened vials of valrubicin are stable until the date indicated on the package when stored under refrigerated conditions at 2°-8°C (36°-46°F). Vials should not be heated. valrubicin 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, valrubicin should not be mixed with other drugs.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Valrubicin in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Valrubicin in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding FDA-Labeled Use of Valrubicin in pediatric patients.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Valrubicin in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Valrubicin in pediatric patients.
Contraindications
VALSTAR is contraindicated in patients with known hypersensitivity to anthracyclines or polyoxyl castor oil.
Patients with concurrent urinary tract infections should not receive valrubicin.
valrubicin should not be administered to patients with a small bladder capacity, i.e., unable to tolerate a 75 mL instillation.
Warnings
Valrubicin is contraindicated in patients with known hypersensitivity to anthracyclines or polyoxyl castor oil.
Patients with concurrent urinary tract infections should not receive valrubicin.
VALSTAR should not be administered to patients with a small bladder capacity, i.e., unable to tolerate a 75 mL instillation.
Adverse Reactions
Clinical Trials Experience
Approximately 84% of patients who received intravesical valrubicin 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 valrubicin 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.
Valrubicin can cause fetal harm if a pregnant woman is exposed to the drug systemically. Such exposure could occur after perforation of the urinary bladder during valrubicin therapy. Daily intravenous doses of 12 mg/kg (about one sixth of the recommended human intravesical dose on a mg/m2 basis) given to rats during fetal development caused fetal malformations. A dose of 24 mg/kg (about one third the recommended human intravesical dose on a mg/m2 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. Thus, valrubicin is embryo-toxic and teratogenic. There are no preclinical studies of the effects of intra-vesical valrubicin on fetal development and no adequate and well controlled studies of valrubicin in pregnant women. If valrubicin is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women who might become pregnant should be advised to avoid doing so during therapy with VALSTAR.
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Valrubicin in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Valrubicin during labor and delivery.
Nursing Mothers
It is not known whether VALSTAR is excreted in human milk. Nevertheless, the drug is highly lipophilic and any exposure of infants to VALSTAR could pose serious health risks. Women should discontinue nursing before the initiation of VALSTAR therapy.
Pediatric Use
There is no FDA guidance on the use of Valrubicin with respect to pediatric patients.
Geriatic 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.
Gender
There is no FDA guidance on the use of Valrubicin with respect to specific gender populations.
Race
There is no FDA guidance on the use of Valrubicin with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Valrubicin in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Valrubicin in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Valrubicin in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Valrubicin in patients who are immunocompromised.
If VALSTAR is administered when bladder rupture or perforation is suspected, weekly monitoring of complete blood counts should be performed for 3 weeks.
Patients receiving VALSTAR for refractory carcinoma in situ must be monitored closely for disease recurrence or progression.
IV Compatibility
There is limited information regarding IV Compatibility of Valrubicin in the drug label.
Overdosage
There is limited information regarding Valrubicin overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Valrubicin Pharmacology in the drug label.
Mechanism of Action
Valrubicin is an anthracycline that affects a variety of interrelated 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.
Structure
There is limited information regarding Valrubicin Structure in the drug label.
Pharmacodynamics
There is limited information regarding Pharmacodynamics of Valrubicin in the drug label.
Pharmacokinetics
Pharmacokinetics after Intravesical Administration of VALSTAR: 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 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. VALSTAR metabolites 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 AUC0-6 hours (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) 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. Administration of a comparable intravenous dose of VALSTAR (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.
The patient with a perforated bladder who received 800 mg of VALSTAR intravesically developed severe leukopenia and neutropenia approximately two weeks after drug administration. Systemic hematologic toxicity from VALSTAR was not seen after an intravesical dose of 800 mg of VALSTAR unless perforation of the urinary bladder occurred.
Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Valrubicin in the drug label.
Clinical Studies
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.
How Supplied
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:
