Valstar

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Valstar

Classes

Anthracyclines

Administration

Hazardous Drugs Classification
NIOSH 2016 List: Group 1
NIOSH (Draft) 2020 List: Table 1
Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
Use double chemotherapy gloves and a protective gown. Prepare in a biological safety cabinet or compounding aseptic containment isolator with a closed system drug transfer device. Eye/face and respiratory protection may be needed during preparation and administration.

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.

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

Common Brand Names

Valstar

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

Dosage And 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.

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.

Drug Interactions

There are no drug interactions associated with Valrubicin products.

How Supplied

Valrubicin/Valstar Intravesical Sol: 1mL, 40mg

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.

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.

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.