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  • CLASSES

    Anthracyclines

    DEA CLASS

    Rx

    DESCRIPTION

    Anthracycline/topoisomerase II inhibitor
    Used for the treatment of BCG-resistant carcinoma in situ (CIS) of the bladder in patients for whom immediate cystectomy is associated with an unacceptable risk of morbidity or mortality; for intravesical administration only
    Contraindicated in patients with perforated bladder, active urinary tract infection, and small bladder capacity

    COMMON BRAND NAMES

    Valstar

    HOW SUPPLIED

    Valstar Intravesical Sol: 1mL, 40mg

    DOSAGE & INDICATIONS

    For the treatment of BCG-refractory bladder cancer in situ (CIS) in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality.
    Intravesical dosage
    Adults

    800 mg intravesically once a week for six weeks; delay administration at least two weeks after transurethral resection and/or fulguration. If there is not a complete response to treatment after 3 months or if CIS recurs, reconsider cystectomy. When administered to 90 patients with transitional bladder cell cancer at the FDA-approved dose in a clinical trial (n = 230), 18% of valrubicin-treated patients had a complete remission at 6 months following initiation of therapy; the median duration of response was 13.5 months (by last bladder biopsy) and 21 months (by time of documented recurrence). Eleven percent of patients developed metastatic or deeply-invasive bladder cancer, with a median of 17.5 months between the time of treatment failure and either cystectomy or documentation of advanced bladder cancer; the extent of the effect of a delayed cystectomy (due to valrubicin treatment) on the development of advanced disease is uncertain. A separate open-label, noncomparative study evaluated 90 patients with recurrent CIS after failure of multiple therapies, including at least 1 course of BCG. After a median follow-up of 30 months, intravesical treatment with valrubicin resulted in a complete response in 21% of patients; median time to failure and/or last follow-up for patients with a complete response was greater than 18 months. Of patients with non-response or recurrent disease who underwent cystectomy (n = 44), 15% (6 patients) had stage pT3 or greater disease at the time of surgery; one patient underwent cystectomy 1 month after valrubicin failure, while the delay in cystectomy for the other 5 patients ranged from 6 to 36 months.

    MAXIMUM DOSAGE

    Adults

    800 mg intravesically.

    Elderly

    800 mg intravesically.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    As systemic absorption of valrubicin is very low, it appears that no dosage adjustments are needed. Specific guidelines for dosage adjustments in hepatic impairment are not available.

    Renal Impairment

    As systemic absorption of valrubicin is very low, it appears that no dosage adjustments are needed. Specific guidelines for dosage adjustments in renal impairment are not available.

    ADMINISTRATION

     
    CAUTION: Observe and exercise appropriate precautions for handling, preparing, and administering cytotoxic drugs.

    Injectable Administration

    For intravesical administration only; do not administer as IV or IM.
    Valrubicin should only be administered under the supervision of a physician experienced in the use of intravesical cancer chemotherapy.
    Valrubicin solution contains CremophorEL (polyoxyl castor oil), which causes leaching of the plasticizer from PVC bags and tubing. Prepare and store valrubicin solutions in glass, polypropylene, or polyolefin bags and tubing. Use non-DEHP containing (e.g., polyethylene-lined) administration sets.
    Visually inspect for particulate matter and discoloration prior to administration whenever solution and container permit.

    Other Injectable Administration

    Reconstitution:
    Four 200 mg vials should be allowed to warm to room temperature but should not be heated.
    At temperatures below 4 degrees C (39 degrees F), polyoxyl castor oil may begin to form a waxy precipitate. If this occurs, warm the vial in the hand until the solution is clear. Do not administer valrubicin if particulate matter is still seen.
    Withdraw 800 mg (20 mL) of valrubicin from the vials and dilute with 55 mL of 0.9% Sodium Chloride Injection, for a total volume of 75 mL.
    Do not mix valrubicin with other drugs, as compatibility data are not available.
    Diluted valrubicin solutions are stable for 12 hours at temperatures up to 25 degrees C (77 degrees F).
     
    Intravesical Administration:
    Insert a urethral catheter into the patient's bladder under aseptic conditions.
    Drain the bladder, and then instill the diluted valrubicin solution slowly (over several minutes) via gravity.
    Withdraw the catheter.
    The patient should retain the valrubicin solution in the bladder for 2 hours before voiding; some patients may not be able to retain the drug for the full 2 hours. At the end of 2 hours, all patients should void.
    Patients should maintain adequate hydration after valrubicin treatment.

    STORAGE

    Valstar:
    - Do not freeze
    - Refrigerate (between 36 and 46 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    Bladder perforation

    Valrubicin administration is contraindicated in patients with bladder perforation or in those in whom the integrity of the bladder mucosa has been compromised. Evaluate the bladder prior to drug instillation in all patients; if the bladder is perforated, delay administration until bladder integrity is restored. Systemic exposure to valrubicin after intravesical administration is dependent on the condition of the bladder wall, and is increased by approximately 5-fold to 10-fold in patients treated within 5 to 51 minutes after typical (n = 8) and extensive (n = 5) TURB. Valrubicin should not be administered for at least 2 weeks after transurethral resection of the bladder (TURB) and/or fulguration. One patient with a perforated bladder who received valrubicin 800 mg intravesically developed severe leukopenia and neutropenia approximately 2 weeks after drug administration. After inadvertent exposure to the peritoneal cavity, leukopenia and neutropenia may be expected beginning within 1 week of administration, nadirs by the second week, and general recovery by the third week. If valrubicin is given and bladder rupture or perforation is suspected, weekly blood counts should be monitored for 3 weeks.

    Irritable bladder, urinary tract infection (UTI)

    Valrubicin is contraindicated in patients with active urinary tract infection (UTI). Patients should receive appropriate treatment for the infection prior to valrubicin therapy. Additionally, other patients with irritable bladder symptoms, including neurogenic bladder, should use valrubicin with caution as bladder spasm and spontaneous discharge of the instillate may occur; clamping of the urinary catheter is not advised.

    Anthracycline hypersensitivity, polyoxyethylated castor oil hypersensitivity

    Valrubicin is contraindicated in patients with known anthracycline hypersensitivity or polyoxyethylated castor oil hypersensitivity. Additionally, valrubicin is contraindicated in patients with small bladder capacity who are unable to tolerate a 75 mL instillation.

    Bladder cancer

    Patients should be informed that valrubicin induces complete responses in only 20% of patients with BCG-refractory bladder carcinoma and delaying cystectomy could lead to the development of metastatic bladder cancer, which is fatal. The exact risk of developing metastatic disease is not known, but the incidence increases the longer cystectomy is delayed in the presence of persistent disease. Patients should be closely monitored every 3 months for progression or recurrence of their disease. If complete response is not documented within 3 months, cystectomy should be reconsidered.

    Pregnancy

    Although there are no available data in pregnant women, valrubicin is a potential teratogen due to teratogenesis and fetal death in animal studies. Systemic exposure to valrubicin due to bladder perforation during therapy can increase the risk of fetal harm. Pregnancy should be avoided by females during treatment with valrubicin and for 6 months after the last dose; male partners taking valrubicin should avoid pregnancy with female partners for 3 months after the last dose. Daily IV administration of valrubicin to pregnant rats during organogenesis at doses approximately 0.2 times the recommended human intravesical dose on a mg/m2 basis was embryo-fetal toxic and teratogenic, resulting in fetal malformations. At doses approximately 0.3 times the recommended human intravesical dose on a mg/m2 basis, numerous, severe alterations in the skull and skeleton occurred in developing fetuses; additionally, this dose resulted in an increase in fetal resorptions and a decrease in viable fetuses.

    Contraception requirements, infertility, male-mediated teratogenicity, reproductive risk

    Counsel patients about the reproductive risk and contraception requirements during valrubicin treatment. Valrubicin can be teratogenic if taken by the mother during pregnancy. Females should avoid pregnancy and use effective contraception during and for at least 6 months after treatment with valrubicin. Males with female partners of reproductive potential should also use effective contraception during treatment and for at least 3 months after the final dose due to the risk of male-mediated teratogenicity. Females of reproductive potential should undergo pregnancy testing prior to initiation of valrubicin. Women who become pregnant while receiving valrubicin should be apprised of the potential hazard to the fetus. In addition, based on animal studies, valrubicin may cause impaired fertility or infertility in males of reproductive potential; studies on human male and female fertility have not been completed.

    Breast-feeding

    It is not known if valrubicin is excreted in breast milk. Because of the highly lipophilic nature of the drug and the potential to the infant of serious adverse effects, breast-feeding should be discontinued during valrubicin therapy and for 2 weeks after the last dose.

    ADVERSE REACTIONS

    Moderate

    dysuria / Early / 56.0-56.0
    bladder spasm / Early / 31.0-31.0
    hematuria / Delayed / 1.0-29.0
    urinary incontinence / Early / 22.0-22.0
    cystitis / Delayed / 15.0-15.0
    urinary retention / Early / 4.0-4.0
    urethral pain / Early / 3.0-3.0
    chest pain (unspecified) / Early / 3.0-3.0
    anemia / Delayed / 2.0-2.0
    peripheral vasodilation / Rapid / 2.0-2.0
    neutropenia / Delayed / 0-1.0
    leukopenia / Delayed / 0-1.0
    peripheral edema / Delayed / 1.0-1.0
    hyperglycemia / Delayed / 1.0-1.0

    Mild

    increased urinary frequency / Early / 61.0-61.0
    urinary urgency / Early / 57.0-57.0
    infection / Delayed / 1.0-15.0
    nocturia / Early / 7.0-7.0
    abdominal pain / Early / 5.0-5.0
    nausea / Early / 5.0-5.0
    asthenia / Delayed / 4.0-4.0
    malaise / Early / 4.0-4.0
    headache / Early / 4.0-4.0
    diarrhea / Early / 3.0-3.0
    back pain / Delayed / 3.0-3.0
    dizziness / Early / 3.0-3.0
    rash / Early / 3.0-3.0
    vomiting / Early / 2.0-2.0
    fever / Early / 2.0-2.0
    skin irritation / Early / 0-1.0
    pelvic pain / Delayed / 1.0-1.0
    flatulence / Early / 1.0-1.0
    tenesmus / Delayed / 0-1.0
    myalgia / Early / 1.0-1.0
    pruritus / Rapid / 0-1.0
    urine discoloration / Early / 10.0

    DRUG INTERACTIONS

    There are no drug interactions associated with Valrubicin products.

    PREGNANCY AND LACTATION

    Pregnancy

    Although there are no available data in pregnant women, valrubicin is a potential teratogen due to teratogenesis and fetal death in animal studies. Systemic exposure to valrubicin due to bladder perforation during therapy can increase the risk of fetal harm. Pregnancy should be avoided by females during treatment with valrubicin and for 6 months after the last dose; male partners taking valrubicin should avoid pregnancy with female partners for 3 months after the last dose. Daily IV administration of valrubicin to pregnant rats during organogenesis at doses approximately 0.2 times the recommended human intravesical dose on a mg/m2 basis was embryo-fetal toxic and teratogenic, resulting in fetal malformations. At doses approximately 0.3 times the recommended human intravesical dose on a mg/m2 basis, numerous, severe alterations in the skull and skeleton occurred in developing fetuses; additionally, this dose resulted in an increase in fetal resorptions and a decrease in viable fetuses.

    It is not known if valrubicin is excreted in breast milk. Because of the highly lipophilic nature of the drug and the potential to the infant of serious adverse effects, breast-feeding should be discontinued during valrubicin therapy and for 2 weeks after the last dose.

    MECHANISM OF ACTION

    Valrubicin is an anthracycline topoisomerase inhibitor that affects a variety of interrelated biological functions, most of which involve nucleic acid metabolism. In cells, it inhibits the incorporation of nucleotides into nucleic acids, causes chromosomal damage, and arrests the cell cycle in G2. Although valrubicin does not bind strongly to DNA, its metabolites interfere with the normal DNA breaking-resealing action of DNA topoisomerase II.

    PHARMACOKINETICS

    Valrubicin is administered intravesically into the bladder. During the 2-hour retention period, valrubicin is minimally metabolized to N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol. After retention, valrubicin is almost completely excreted by voiding the instillate. Mean percent recovery of valrubicin, N-trifluoroacetyladriamycin, and total anthracyclines in 14 urine samples from 6 patients was 98.6%, 0.4%, and 99% of the total administered drug, respectively.

    Other Route(s)

    Intravesical route
    The mean total valrubicin concentration in bladder tissue exceeded levels causing 90% cytotoxicity to human bladder cells in vitro. During the 2-hour dose retention period, only nanogram quantities of valrubicin were absorbed into the plasma. Metabolites N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol were measured in blood. Total systemic exposure to valrubicin during and after intravesical administration is dependent upon the condition of the bladder wall. The mean AUC for an intravesical dose of valrubicin (900 mg) administered 2 weeks after transurethral resection of bladder tumors (n = 6) was 78 nmol/L x hour. The mean AUC for total valrubicin was 409 and 788 nmol/L x hour, respectively, in patients receiving valrubicin 800 mg administered 5 to 51 minutes after typical (n = 8) and extensive (n = 5) TURB tumors. The valrubicin AUC was 18,382 nmol/L x hour in one patient who experienced a perforated bladder following a transurethral resection that occurred 5 minutes before administration of an intravesical dose of valrubicin 800 mg. Administration of a comparable intravenous dose of VALSTAR (600 mg/m2; n = 2) as a 24-hour infusion resulted in AUC of 11,975 nmol/L x hour.