Valrubicin (Mucosal-Local)


VA CLASSIFICATION
Primary: AN200

Commonly used brand name(s): Valstar.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antineoplastic—

Indications

Accepted

Carcinoma, bladder (treatment)—Intravesical valrubicin is indicated for treatment of carcinoma in situ of the urinary bladder that is refractory to Bacillus Calmette-Guerin (BCG), in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality {01}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    723.65 {01}

Solubility
    Soluble in acetone, ethanol, methanol, and methylene chloride; insoluble in water {01}.

Mechanism of action/Effect:

Valrubicin is an anthracycline glycoside that affects a number of biological functions involving nucleic acid metabolism {01}. After penetration into cells, it inhibits incorporation of nucleosides into nucleic acids, causes extensive chromosomal damage, and arrests cells in the G 2 phase of cell division {01}. Although it does not bind strongly to DNA, its metabolites interfere with the normal DNA breaking-resealing action of DNA topoisomerase II {01}.

Absorption:

Valrubicin penetrates easily into the bladder cell wall after intravesical administration {01}. The degree of any systemic absorption depends on the condition of the bladder wall {01}. Serum concentrations usually are very low (nanogram quantities), even after extensive transurethral resection, although a case has been reported in which concentrations after administration to a patient with a perforated bladder were similar to those achieved after intravenous administration {01}.

Biotransformation:

Negligible during typical bladder retention periods {01}. Major metabolites are N-trifluoroacetyladriamycin and N-trifluoroacetyladriamycinol, which have been measured in blood {01}.

Elimination:
    Almost entirely by voiding the instillate {01}.


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to other anthracyclines may be sensitive to valrubicin {01}.

Patients sensitive to polyoxyethylene glycol triricinolate may be sensitive to valrubicin also, since the solution contains a polyoxyethylene glycol triricinolate vehicle {01}.

Carcinogenicity

Studies have not been done; however, valrubicin causes damage to DNA in vitro {01}.

Mutagenicity

Valrubicin was found to be mutagenic in in vitro assays in Salmonella typhimurium and Escherichia coli and was clastogenic in the chromosomal aberration assay in CHO cells {01}.

Pregnancy/Reproduction
Fertility—
Studies in men and women have not been done {01}.

Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}. However, there is a potential for valrubicin to cause fetal harm if systemic absorption occurs (e.g., in a patient with a perforated bladder) {01}.

Studies in rats at intravenous doses of 24 mg per kg of body weight (mg/kg) (about one third of the recommended human intravesical dose on a mg per square meter of body surface area basis) found numerous severe alterations in the skulls and skeletons of the developing fetuses, as well as an increase in fetal resorptions and a decrease in the number of viable fetuses {01}.

It is recommended that women being treated with valrubicin avoid becoming pregnant during treatment {01}. Use of a contraceptive during therapy is recommended for men and women of reproductive age being treated with intravesical valrubicin. Risk-benefit should be considered before initiating valrubicin therapy during pregnancy {01}.

FDA Pregnancy Category C {01}.

Breast-feeding

It is not known whether valrubicin is distributed into breast milk {01}. However, because the medication is highly lipophilic, there is the potential for exposure of and harm to breast-fed infants {01}. Breast-feeding is not recommended during valrubicin therapy {01}.

Pediatrics

Safety and efficacy have not been established {01}.


Geriatrics


Although appropriate studies on the relationship of age to the effects of valrubicin have not been performed in the geriatric population, 85% of patients in clinical studies were older than 60 years of age and no specific problems were detected {01}.

Drug interactions and/or related problems
Because systemic absorption of valrubicin is negligible, the potential for interactions with other medications is considered to be low {01}.

Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Irritative bladder symptoms, severe{01}    (bladder spasm and spontaneous discharge of the intravesical instillate may occur; clamping of the urinary catheter is not advised but, if necessary, should be done under medical supervision and with caution {01})


» Perforated bladder{01}    (risk of systemic absorption and adverse effects such as bone marrow depression; it is recommended that administration be delayed until bladder integrity is restored {01})


» Sensitivity to valrubicin or other anthracyclines{01}
» Small bladder capacity    (use is not recommended in patients with a small bladder capacity, i.e., the inability to tolerate a 75-mL instillation {01})


» Urinary tract infection{01}    (use is not recommended {01})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Cystoscopy{01} and
Biopsy{01} and
Urine cytology{01}    (recommended every 3 months to monitor for disease recurrence or progression {01})




Side/Adverse Effects

Note: The primary acute adverse effects associated with valrubicin are local, irritable bladder symptoms that usually occur during or shortly after instillation and resolve within 1 to 7 days after valrubicin is voided from the bladder {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent (> 20%)
    
Local, irritable bladder symptoms, including dysuria{01} (painful or difficult urination), hematuria{01} (blood in urine), urinary frequency{01} (frequent urination), urinary incontinence{01} (loss of bladder control), urinary urgency{01} (strong urge to urinate)
    
red color in urine{01}

Note: Red color in urine is typical, and usually persists for about 24 hours after instillation {01}.
Prolonged irritable bladder symptoms (lasting more than 7 days) or red color in urine lasting more than 24 hours should be reported immediately {01}.


Incidence less frequent (< 10%)
    
Local, irritable bladder symptoms, including nocturia{01} (unusual nighttime urination), urethral pain{01}
burning sensation{01} —related to procedure

Incidence rare (< 1%)
    
Loss of sense of taste{01}
    
pruritus{01} (itching)
    
tenesmus{01} (frequent urge to defecate)





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute
    
Irritable bladder symptoms{01} (painful or difficult urination; trouble in holding urine; unusually frequent urination)
    
myelosuppression, specifically leukopenia or neutropenia{01} (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination)—with inadvertent systemic administration or significant systemic exposure due to bladder rupture or perforation{01}

Note: Dose-limiting leukopenia or neutropenia usually begins within 1 week after administration; the nadir in blood counts usually occurs by the second week with recovery by the third week {01}.



Treatment of overdose
There are no known antidotes to valrubicin overdose {01}.


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Valrubicin (Mucosal-Local) .

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to valrubicin or other anthracyclines

Pregnancy—Not recommended during pregnancy because of potential for adverse effects





Breast-feeding—Not recommended because of potential for adverse effects
Other medical problems, especially severe irritable bladder symptoms, perforated bladder, small bladder capacity, or urinary tract infection

Proper use of this medication
Emptying bladder before instillation of each dose

» Following physician's instructions for holding solution in bladder for 2 hours; telling physician if unable to retain solution for prescribed time

» Importance of ample fluid intake after instillation

» Proper dosing

Precautions while using this medication
Red-tinged urine is typical during the first 24 hours after administration; telling physician if redness persists


General Dosing Information
Patients receiving intravesical valrubicin should be under the supervision of a physician experienced in such therapy {01}.

Prior to valrubicin administration, the bladder is emptied either by voiding or by drainage through a urethral catheter inserted into the bladder under aseptic conditions {01}. The diluted valrubicin solution is then instilled into the bladder over a period of several minutes by gravity flow through the catheter {01}. After instillation, the patient attempts to hold the solution for 2 hours before voiding {01}.

It is recommended that patients maintain adequate hydration following valrubicin administration {01}.

If valrubicin is administered to a patient in whom bladder perforation or rupture is suspected, weekly monitoring of complete blood counts for 3 weeks is recommended to detect possible myelosuppression {01}.

Safety considerations for handling this medication
Although contact toxicity from handling valrubicin solution is typically mild, use of gloves is recommended during preparation and administration to prevent skin reactions with accidental exposure {01}. Accidental exposure of the eye should be followed immediately by thorough flushing of the eye with water {01}.

Other general precautions recommended during preparation of cytotoxic agents are also recommended for valrubicin {01}.


Topical Dosage Forms

VALRUBICIN STERILE SOLUTION

Usual adult dose
Bladder carcinoma
Intracavitary, 800 mg once a week for six weeks {01}.

Note: It is recommended that administration of valrubicin be delayed for at least two weeks after transurethral resection and/or fulguration {01}.



Usual pediatric dose
Safety and efficacy have not been established {01}.

Strength(s) usually available
U.S.—


40 mg per mL (Rx) [Valstar (polyoxyethylene glycol triricinolate) (dehydrated alcohol)]

Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F) {01}. Protect from freezing {01}.

Note: A waxy precipitate may start to form at temperatures below 4 °C. If this occurs, the vial may be warmed in the hands until the solution clears. {01}


Preparation of dosage form:
Valrubicin sterile solution is prepared for intravesical administration by allowing 800 mg (4 vials) to warm slowly to room temperature (they should not be heated) {01}. Then the 800 mg is diluted with 55 mL of 0.9% sodium chloride injection, producing 75 mL of solution {01}.

Polyoxyethylene glycol triricinolate, present in the formulation, is known to cause leaching of di(2-ethylhexyl)phthalate (DEHP), a hepatotoxic plasticizer, from polyvinyl chloride (PVC) bags and intravenous tubing. Therefore, use of glass, polypropylene, or polyolefin containers and tubing is preferred for preparation, storage, and administration of valrubicin {01}.

Stability:
Diluted valrubicin is stable for 12 hours when stored at temperatures up to 25 °C (77 °F) {01}.

Incompatibilities:
Valrubicin should not be mixed with other medications {01}.

Additional information:
Procedures for proper handling and disposal of anticancer agents should be used {01}.

Accidental spills should be cleaned up with undiluted chlorine bleach {01}.



Developed: 04/12/1999



References
  1. Valstar package insert (Medeva—US), Rev 10/98, Rec 1/99.
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