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  • CLASSES

    Anthracyclines

    DEA CLASS

    Rx

    DESCRIPTION

    Anthracycline/topoisomerase II inhibitor
    Indicated for intravesical use in 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
    A delay in cystectomy increases the risk of developing metastatic bladder cancer in the presence of persisting CIS; if a complete response does not occur after 3 months of valrubicin therapy, reconsider cystectomy

    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. 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, non-comparative 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.
    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

    General Information

    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.

    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; valrubicin should not be administered for at least 2 weeks after transurethral resection of the bladder (TURB) and/or fulguration. 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. The mean AUC of valrubicin was 78 nmol/L*hour in 6 patients who received valrubicin 900 mg intravesically 2 weeks after TURB (n = 6); in patients who received valrubicin 800 mg 5 to 51 minutes after typical (n = 8) and extensive (n = 5) TURB, the mean AUC values were 409 and 788 nmol/L*hour, respectively. The AUC was 18,382 nmol/L*hour in one patient with a perforated bladder that occurred 5 minutes prior to intravesical administration of valrubicin 800 mg. 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.

    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
    peripheral edema / Delayed / 1.0-1.0
    hyperglycemia / Delayed / 1.0-1.0
    leukopenia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known

    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 (unspecified) / Early / 3.0-3.0
    vomiting / Early / 2.0-2.0
    fever / Early / 2.0-2.0
    skin irritation / Early / 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 has similar effects as doxorubicin as far as damaging DNA, inducing chromosomal breaks and translocations, arresting the cell cycle, and inhibiting DNA and RNA synthesis. However, valrubicin and N-acylanthracycline analogues do not bind strongly with DNA as do other anthracyclines. Valrubicin inhibits the incorporation of thymidine and uridine into DNA and RNA more rapidly and to a greater degree than doxorubicin, inhibiting DNA and RNA synthesis to a greater extent. It enters the cell more quickly than doxorubicin because its lipophilic nature allows for passive diffusion across cell membranes as opposed to the time and temperature dependent uptake of doxorubicin. The active metabolites of valrubicin inhibits topoisomerase II, an enzyme responsible for the resealing of DNA strands during transcription; valrubicin itself does not affect topoisomerase II. Valrubicin inhibits the incorporation of nucleosides into nucleic acids, causes chromosomal damage, and arrests the cell cycle in the G2 phase.

    PHARMACOKINETICS

    Valrubicin is administered intravesically into the bladder.  Systemic exposure of valrubicin is limited and is dependent upon the integrity of the bladder wall. During the 2-hour retention period, valrubicin is minimally metabolized to N-trifluoroacetyladriamycin (AD-41) and N-trifluoroacetyladriamycinol (AD-92). Both metabolites have some antitumor activity in vitro with AD-41 more active than AD-92; however, AD-41 is not as active as valubicin and is much more toxic. The drug and metabolites are almost completely (99%) excreted by voiding the instillate.

    Other Route(s)

    Intravesical route
    The mean total valrubicin concentration within the bladder exceeded levels causing 90% cytotoxicity to human bladder cells in vitro; however these levels are required to reach cytotoxic concentrations intracellularly. Due to the lipophilic nature of valrubicin, it rapidly crosses bladder cell membranes. The anthracycline concentration decreases with increasing depth from the urothelial surface. Concentrations were > 3 times the IC90 for bladder cell cancer lines at a depth of > 1250 µm, which exceeds the depth of T1 bladder tumors. At depths of 1400—1800 µm, which exceeds the depth of invasion of T2 tumors, the concentration of anthracyclines is approximately equal to the IC90.