VA Class:AN900

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• Valrubicin

Chemical Name:

• (2 S - cis )-2-[1,2,3,4,6,11-Hexahydro-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-4-[[2,3,6-trideoxy-3-[(trifluoroacetyl)amino)-α-l- lyxo -hexopyranosyl]oxy]-2-naphthacenyl]-2-oxoethyl pentanoate

Molecular Formula:

• C₃₄H₃₆F₃NO₁₃

Valrubicin, a semisynthetic anthracycline antibiotic, is an antineoplastic agent.1,2,3,4

Bladder Cancer

Valrubicin is used intravesically for the treatment of carcinoma in situ (CIS) of the urinary bladder that is refractory to BCG in patients who are not candidates for immediate cystectomy because of unacceptable morbidity or mortality associated with such surgery.1,2,3 Adjuvant therapy with intravesical BCG is used in patients with high risk of recurrence of disease following transurethral resection with fulguration for superficial transitional cell carcinoma of the bladder, and intravesical BCG is the treatment of choice for CIS.14,15,16,17,19,20,22 (See Immunotherapy for Bladder Cancer in Uses: BCG Vaccine 80:12 for an overview of therapy for superficial bladder cancer.) Patients with progression to T1 tumor or recurrence of either T1 tumor or CIS within 3 months following completion of a single 6-week course of intravesical BCG are at high risk of developing muscle-invasive disease, and alternative therapy, such as cystectomy, should be considered.14,15,21,23,24,34 The clinical study of valrubicin on which this indication is based involved patients with BCG-refractory CIS of the urinary bladder who were eligible for immediate cystectomy although a substantial proportion of patients did not undergo immediate cystectomy despite treatment failure with valrubicin;2,25 this phase II study did not examine the benefit of valrubicin weighed against the use of other treatment options (e.g., additional courses of intravesical BCG or intravesical therapy with another agent) or the risk of invasive or metastatic disease caused by delay of cystectomy.25 Valrubicin is designated an orphan drug by the US Food and Drug Administration (FDA) for use in the treatment of CIS of the urinary bladder.18

The current indication for valrubicin is based on data from a subset of patients enrolled in clinical trials of valrubicin who had BCG-refractory CIS of the bladder.1,2 Among the 90 patients with BCG-refractory CIS, 70% previously were treated with at least 2 courses of BCG, and 30% had received one course of BCG and at least one course of treatment with another agent(s) (e.g., mitomycin, thiotepa, interferon).1,2 Valrubicin was administered no sooner than 2 weeks following transurethral resection and/or fulguration.1 Following intravesical administration of valrubicin 800 mg once weekly for 6 weeks, a complete response rate (based on bladder biopsies and urine cytology at 3 and 6 months following initiation of therapy) of 18% was reported;1 median duration of response was 13.5 months (measured to the time of last bladder biopsy without tumor) or 21 months (measured to the time of documented recurrence).1

Retrospective data analysis showed that, in the patients who achieved a complete response to valrubicin, the time to recurrence following valrubicin therapy was longer than the time to recurrence following previous courses of intravesical treatment with other agents.1,2

Among the 90 patients with BCG-refractory CIS of the bladder receiving intravesical valrubicin, 11% (10 patients) subsequently developed metastatic or deeply invasive bladder cancer, including 4 patients (none of whom underwent cystectomy) who died of metastatic bladder cancer.1 It is unclear to what extent the delay in cystectomy associated with valrubicin therapy (including the 3-month time period needed to assess response to treatment) contributed to the development of advanced bladder cancer, because cystectomy often was delayed or never performed despite documented failure of valrubicin treatment.1 Among the patients who developed invasive bladder cancer or metastatic disease, the median delay between time to documented failure of valrubicin therapy and performance of cystectomy or diagnosis of advanced bladder carcinoma was 17.5 months.1 Careful monitoring for disease recurrence or progression is required in patients receiving valrubicin for BCG-refractory CIS;1 recommended follow-up includes cystoscopy, bladder biopsy, and urine cytology every 3 months following initiation of valrubicin therapy.1,29 If a complete response to valrubicin is not observed within 3 months of initiation of therapy, or if CIS recurs, cystectomy should be reconsidered.1,2,29

Further study is needed to establish the role of valrubicin in the treatment of superficial bladder cancer.4 A randomized trial is under way to evaluate use of valrubicin as adjunctive therapy for superficial bladder cancer administered within 2-24 hours following TUR to reduce risk of recurrence of disease resulting from tumor cell implantation.28

Reconstitution and Administration

Valrubicin is administered intravesically.1 Valrubicin is not indicated for IV administration.29 Careful aseptic technique must be used during intravesical administration of valrubicin to avoid introduction of contaminants into the urinary tract or trauma to the urinary mucosa.1

Valrubicin sterile solution contains polyoxyethylated castor oil (Cremophor^® EL), which has been known to cause leaching of diethylhexylphthalate (DEHP) from polyvinyl chloride (PVC) bags and IV tubing.1 To minimize exposure of the patient to leached DEHP, diluted valrubicin solutions preferably should be prepared and stored in glass or polypropylene containers or in plastic (polypropylene or polyolefin) bags and administered through non-DEHP containing administration sets, such as polyethylene-lined administration sets.1,29 At temperatures below 4°C, polyoxyethylated castor oil (Cremophor^® EL) may begin to form a waxy precipitate.1 If this precipitate forms, the vial of valrubicin should be warmed in the hand until the solution is clear; if particulate matter remains, the drug should be discarded.1 Vials of the solution should not be heated.1

Caution should be exercised in handling and preparing solutions of valrubicin.1 Because skin reactions may occur with accidental exposure to the drug, the manufacturer recommends the use of gloves during preparation and administration of valrubicin.1 In contrast with other anthracyclines, contact toxicity is uncommon with valrubicin and tends to be mild.1 Care must be taken to avoid contact of valrubicin solutions with the eyes since irritation of the eye has been reported with accidental exposure; if contact occurs, the eye should be flushed thoroughly with water immediately.1 Spillage of the drug should be cleaned with undiluted chlorine bleach.1

Valrubicin solution should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.1 The manufacturer states that valrubicin should not be mixed with other drugs (unless specific compatibility data are available).1

Intravesical Instillation

Valrubicin sterile solution for intravesical instillation must be diluted prior to administration. 1 For each instillation, 4 vials of the drug (each containing 200 mg valrubicin in a volume of 5 mL) should be allowed to warm slowly to room temperature.1 The contents of the vials (total volume of 20 mL) should then be withdrawn and diluted with 55 mL of 0.9% sodium chloride injection to provide 75 mL of diluted valrubicin solution.1 Following aseptic insertion of a urethral catheter and drainage of the patient's bladder, the 75 mL of diluted valrubicin solution should be instilled slowly (over several minutes) using gravity flow.1 The catheter then should be withdrawn, and the drug should be retained in the bladder for 2 hours.1 At the end of the 2-hour retention period, the patient must void.1 Some patients will be unable to retain the drug for the full 2-hour period; clamping of the urinary catheter during the retention period is not recommended, and if performed, should be executed under medical supervision and with caution.1

Dosage

Bladder Cancer

Valrubicin should be administered no sooner than 2 weeks following transurethral resection and/or fulguration.1 The condition of the patient's bladder should be evaluated prior to intravesical instillation of valrubicin.1 The drug should not be administered in patients with bladder perforation or rupture until the integrity of the bladder mucosa has been restored.1

For use in the treatment of BCG-refractory carcinoma in situ (CIS) of the urinary bladder in patients who are not candidates for immediate cystectomy, the usual dosage of valrubicin is 800 mg intravesically once a week for 6 consecutive weeks.1 Patients should be informed that red-colored urine typically is observed during the first 24 hours following administration of valrubicin.1 In addition, patients should be instructed to maintain adequate hydration following each episode of intravesical therapy with valrubicin.1

Careful monitoring for disease recurrence or progression is required in patients receiving valrubicin for BCG-refractory CIS;1 recommended follow-up includes cystoscopy, bladder biopsy, and urine cytology every 3 months following initiation of valrubicin therapy.1,29 If a complete response to treatment is not observed within 3 months of initiation of therapy, or if CIS recurs, cystectomy should be reconsidered.1,29

Intravesical therapy with valrubicin generally is well tolerated with a low incidence of adverse systemic effects.2

The risk of developing metastatic disease must be considered in patients with refractory CIS of the urinary bladder who delay cystectomy.1,2 (See Cautions: Precautions and Contraindications.) Among 90 patients with BCG-refractory CIS of the bladder receiving intravesical valrubicin in a clinical trial, 11% (10 patients) subsequently developed metastatic or deeply invasive bladder cancer during follow-up, including 4 patients (none of whom underwent cystectomy) who died of metastatic bladder cancer.1

The principal toxicity of intravesical valrubicin is local bladder irritation, which occurs during or shortly after instillation in most patients receiving the drug and usually resolves within 1-7 days.1 With the exception of urinary tract infection, which occurred in 15% of patients receiving valrubicin, adverse systemic effects generally occur in less than 5% of patients receiving intravesical therapy with the drug, are mild and self-limited, and resolve within 24 hours following administration.1 Although comparative studies in humans are lacking, evidence from animal studies indicates that valrubicin causes less toxicity (e.g., contact toxicity; cardiac, GI, skin, and renal toxicity) than doxorubicin.4,6

The incidence of adverse local effects associated with valrubicin is derived principally from data for 170 patients receiving the drug at a dose of 800 mg intravesically for multiple cycles of treatment.1 In addition, the incidence of adverse events other than local bladder manifestations is derived from a total of 230 patients who received at least one intravesical instillation of valrubicin at a dose of 200-900 mg in clinical trials.1

Genitourinary Effects

The major acute toxicity of intravesically administered valrubicin is local bladder irritation,1,4 which has occurred in 88% of patients receiving the drug in clinical trials.1 However, local bladder irritation also is present at baseline in about half of patients with carcinoma in situ of the bladder who are candidates for valrubicin treatment.1

Adverse local effects associated with valrubicin therapy typically occur during or shortly after instillation of the drug and resolve within 1-7 days after voiding of the instillate.1 In some patients, antispasmodics, urinary tract analgesics, smooth muscle relaxants, anti-inflammatory agents, or anti-infective agents have been administered before, during, or following valrubicin therapy to reduce the incidence and/or severity of bladder irritation.4,29 Other methods that have been reported for treatment of symptoms of irritable bladder following intravesical chemotherapy include rinsing of the bladder with a small amount of 0.9% sodium chloride solution to wash the remaining agent from the bladder, or instillation of lidocaine jelly via the urethra to reduce urethral burning with subsequent voiding.29,33 Among 143 patients scheduled to receive 6 doses of intravesical valrubicin in a clinical trial, 7 patients discontinued therapy with the drug because of local bladder symptoms.1

The most common local bladder symptoms reported are urinary frequency,1,4 urinary urgency,1,4 and dysuria,1,4 which occur in 61, 57, and 56% of patients, respectively.1 Bladder spasm,1 hematuria,1,4 and bladder pain1 have been reported in 31, 29, and 28% of patients, respectively.1 In addition, urinary incontinence,1 cystitis,1 nocturia,1 and procedure-related burning symptoms1,4 have been observed in 22, 15, 7, and 5% of patients, respectively.1 Urinary tract infection,1,4 urinary retention,1 and microscopic hematuria1 also were reported in 15, 4, and 3%, respectively, of patients receiving at least one dose of intravesical valrubicin in a clinical trial.1 Other adverse genitourinary effects reported in less than 5% of patients receiving valrubicin include urethral pain1 in 3%, pelvic pain1 in 1%, and gross hematuria1,4 in 1%.1 In addition, local skin irritation, poor urine flow, and urethritis each occurred in fewer than 1% of patients receiving valrubicin in clinical trials.1 Local contact irritation consisting of vaginitis and skin irritation of the labia also has been reported in patients receiving intravesical valrubicin.4

Hematologic Effects and Infectious Complications

Myelosuppression has been reported in patients exposed systemically to valrubicin (e.g., inadvertent systemic administration of the drug, intravesical administration of the drug in a patient with bladder rupture or perforation).1 Myelosuppression, manifested by severe leukopenia and neutropenia approximately 2 weeks following valrubicin administration, was observed in a single patient who received 800 mg valrubicin by intravesical instillation within 1 hour following transurethral resection of the bladder (TURB) and immediately after experiencing a perforated bladder (as a complication of TURB).1,29 The manufacturer reports that no clinical sequelae were observed in the patient as a result of the myelosuppression induced by systemic exposure to valrubicin, and hematologic values subsequently began to recover within 1 week.29 In contrast, systemic hematologic toxicity from valrubicin generally has not been observed following intravesical administration of the drug in patients who did not experience perforation of the bladder.1 In case of suspected bladder rupture or perforation in a patient who has received valrubicin by intravesical instillation, weekly monitoring of complete blood cell counts should be performed for 3 weeks.1 Other adverse hematologic effects include anemia1 , which occurred in approximately 2% of patients receiving intravesical valrubicin.1

Urinary tract infection and pneumonia have been reported in 15 and 1%, respectively, of patients receiving intravesical valrubicin in clinical trials.1

Cardiovascular Effects

Evidence from animal studies indicates that valrubicin is less cardiotoxic than doxorubicin.4,6 Limited evidence from clinical studies indicates that anthracycline-induced cardiotoxicity, such as that associated with IV doxorubicin, has not occurred in patients receiving intravesical or intravenous therapy with valrubicin.4,6

Adverse cardiovascular effects reported in patients receiving intravesical valrubicin include vasodilation and peripheral edema, which occurred in 2 and 1% of patients, respectively.1

GI Effects

GI effects occur infrequently in patients receiving valrubicin therapy by intravesical instillation.1 Abdominal pain, diarrhea, nausea, vomiting, and flatulence have been reported in 5, 3, 5, 2, and 1%, respectively, of patients receiving intravesical valrubicin.1 Tenesmus and taste loss have been reported in less than 1% of patients receiving intravesical valrubicin in clinical trials.1

Dermatologic Effects

Rash has been reported in 3% of patients receiving intravesical valrubicin.1 Pruritus occurred in less than 1% of patients receiving intravesical therapy with the drug in clinical trials.1

Local Effects

Inadvertent paravenous extravasation of valrubicin occurring in patients receiving the drug IV has not been associated with skin ulceration or necrosis;1,29 valrubicin is not indicated for IV administration.29

Other Adverse Effects

Asthenia, headache, and malaise each have been reported in 4% of patients receiving intravesical valrubicin.1 Back pain, chest pain, or dizziness occurred in 3% of patients receiving intravesical therapy with valrubicin.1 Fever has been reported in 2%, and hyperglycemia and myalgia each have been reported in 1% of patients receiving intravesical valrubicin in clinical trials.1 Other adverse effects reported in less than 1% of patients receiving intravesical valrubicin in clinical trials include increased serum concentrations of nonprotein nitrogen.1

Precautions and Contraindications

Valrubicin must be used under the supervision of a clinician experienced in the intravesical administration of cytotoxic agents.1

Patients should be informed and understand that valrubicin has been shown to induce complete response in only about 1 in 5 patients with BCG-refractory CIS and that delay of cystectomy increases the risk of developing metastatic bladder cancer, which is a lethal disease.1,2 The exact risk is not known, but the risk of developing metastatic disease generally increases with the delay of cystectomy in the presence of persisting CIS of the urinary bladder.1 When use of valrubicin therapy is being considered, the relative risk of mortality and morbidity associated with cystectomy versus the risk of metastatic bladder cancer associated with delay of cystectomy must be weighed.1 Despite its potential to cure extensive or refractory superficial bladder cancer, a small number of patients prefer to delay cystectomy in favor of continued attempts with intravesical therapy in order to preserve bladder function;2,25,32 however, the optimal intravesical therapy for refractory CIS has not been established, and all eligible patients should be considered for enrollment in clinical trials.14,32

According to the manufacturer, valrubicin should not be administered to patients with concurrent urinary tract infections or with a small bladder capacity (i.e., unable to tolerate a 75-mL intravesical instillation).1 Because of the risk of increased systemic exposure to the drug, intravesical valrubicin should not be administered to patients with a perforated bladder or any other condition causing compromise of the bladder mucosa.1 (See Pharmacokinetics: Absorption.) The condition of the bladder should be evaluated before the instillation of valrubicin; administration of the drug should be delayed as necessary until the integrity of the bladder mucosa has been restored.1

Valrubicin should be used with caution in patients with severe symptoms of irritable bladder because of the possibility of bladder spasm and spontaneous discharge of the intravesical solution;1 clamping of the urinary catheter during instillation of valrubicin is not recommended, and if performed, should be executed under medical supervision and with caution.1 Careful aseptic technique must be used during intravesical administration of valrubicin to avoid introduction of contaminants into the urinary tract or trauma to the urinary mucosa; the risk of infection associated with intravesical therapy with the drug must be considered.1

Patients receiving valrubicin therapy should be informed that irritable bladder symptoms may occur during instillation and retention of the drug and for a limited period following voiding of the instillate.1 For the first 24 hours following administration of intravesical therapy with valrubicin, passage of reddish-colored urine typically is observed.1 Patients should inform their clinician immediately if prolonged symptoms of irritable bladder or continued passage of red-colored urine occur.1

Careful monitoring for disease recurrence or progression is required in patients receiving valrubicin for BCG-refractory CIS;1 recommended follow-up includes cystoscopy, bladder biopsy, and urine cytology every 3 months following initiation of valrubicin therapy.1,29 If a complete response is not observed within 3 months following initiation of therapy with valrubicin, or if CIS recurs, cystectomy must be reconsidered.1,29

Valrubicin is contraindicated in patients who have demonstrated previous hypersensitivity to anthracyclines or polyoxyethylated castor oil (Cremophor^® EL).1

Pediatric Precautions

The manufacturer states that safety and efficacy of valrubicin solution for intravesical instillation in children have not been established.1

Geriatric Precautions

Although the safety and efficacy of intravesical valrubicin in geriatric patients have not been specifically studied to date, carcinoma in situ (CIS) of the bladder generally occurs in older individuals, and a substantial proportion of patients treated with the drug in clinical trials have been 60 years of age or older.1 Among patients enrolled in clinical studies of intravesical valrubicin for bladder cancer, 85% of patients were older than 60 years of age, and 49% of patients were older than 70 years of age.1 Among patients receiving intravesical therapy with valrubicin for BCG-refractory CIS of the urinary bladder in clinical studies, the mean age was 69.5 years.1 The manufacturer states that no specific precautions associated with the use of intravesical valrubicin appear necessary in geriatric patients who otherwise are in good health.1

Mutagenicity and Carcinogenicity

Data from in vitro tests, including assays in Salmonella typhimurium and Escherichia coli , have shown valrubicin to be mutagenic.1,26 Valrubicin shows less mutagenicity and toxicity than doxorubicin against several strains of S. typhimurium .26 In addition, valrubicin was clastogenic in the chromosomal aberration assay in Chinese hamster ovary cells.1

Studies to evaluate the carcinogenic potential of valrubicin have not been performed to date;1 however, the drug is known to cause damage to DNA in vitro.1

Pregnancy, Fertility, and Lactation

Pregnancy

Although there are no adequate and controlled studies to date in humans, valrubicin has been shown to be embryotoxic and teratogenic in animal studies.1,27 Reproduction studies in rats using daily doses of valrubicin 12 mg/kg IV (about one-sixth the recommended human intravesical dose on a mg/m² basis) administered during fetal development caused fetal malformations.1 Administration of valrubicin 24 mg/kg IV (about one-third the recommended human intravesical dose on a mg/m² basis) to rats resulted in numerous, severe abnormalities in the skull and skeleton of the developing fetuses, an increase in fetal resorptions, and a decrease in viable fetuses.1 Animal studies to evaluate the effects of intravesical valrubicin on fetal development have not been performed to date.1

Valrubicin can cause fetal harm if a pregnant woman is exposed to the drug systemically (as could occur in the case of bladder perforation during intravesical valrubicin therapy), and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.1 If the drug is used during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.1 Women of childbearing potential should be advised to avoid becoming pregnant during therapy with valrubicin.1 The manufacturer also states that men should refrain from engaging in procreative activities during therapy with valrubicin.1 All sexually active male and female patients of childbearing potential must use an effective method of contraception during valrubicin therapy.1

Fertility

Studies have not been conducted to date to determine whether valrubicin affects fertility in males or females.1

Lactation

It is not known whether valrubicin is distributed in milk.1 Because valrubicin is highly lipophilic, and because of the potential for serious adverse reactions to valrubicin in nursing infants, nursing should be discontinued before the initiation of and during valrubicin therapy.1

Because systemic exposure to valrubicin is minimal following intravesical administration of the drug in patients with an intact bladder mucosa, the potential for drug interactions is low.1 The possibility of clinically important drug interactions must be considered in patients with systemic exposure to valrubicin (e.g., inadvertent systemic administration of the drug, bladder rupture or perforation in patients receiving intravesical therapy with the drug).29 Formal studies to evaluate drug interactions with valrubicin have not been performed to date.1,29

Verapamil

In an in vitro study, the activity of valrubicin against a resistant line of human bladder tumor cells was enhanced by the calcium-channel blocking agent verapamil.5

Acute Toxicity

Pathogenesis

Limited information is available on the acute toxicity of valrubicin.1 The maximum tolerated dose of valrubicin in humans is 800 mg for intravesical administration4 and 600 mg/m² for intraperitoneal or IV administration.1,6

Manifestations

Overdosage of valrubicin administered by intravesical instillation would be expected to cause local bladder irritation.1 Dose-limiting toxicities of systemically administered valrubicin are leukopenia and neutropenia;1,6 the onset of myelosuppression occurs within 1 week of drug administration, with nadirs by the second week, and recovery typically by the third week.1,6 Myelosuppression may occur in patients receiving inadvertent systemic administration of the drug or in patients with bladder rupture or perforation receiving intravesical therapy with the drug.1

Treatment

There is no known specific antidote for valrubicin overdosage.1 If bladder rupture or perforation is suspected in a patient receiving valrubicin by intravesical instillation, weekly monitoring of complete blood cell counts should be performed for 3 weeks.1

Pharmacology

Valrubicin is an antineoplastic antibiotic similar in structure to its parent compound, doxorubicin, but differing in its mechanism of action compared with other anthracyclines.6,8 The exact mechanism(s) of action of valrubicin has not been fully elucidated.1,6,7,8 Similar to doxorubicin, valrubicin inhibits DNA and RNA synthesis.5,6,8,9 The drug readily penetrates into cells, where it inhibits the incorporation of nucleosides into nucleic acids, causes extensive chromosomal damage, and blocks cells in the G₂ phase of the cell cycle, inhibiting cell replication.1,9 Unlike doxorubicin, valrubicin binds weakly to DNA, but its metabolites interact with the enzyme DNA topoisomerase II.1,7 Topoisomerase enzymes catalyze the formation of single- or double-strand DNA breaks, facilitate passage of DNA strands through these breaks, and promote religation of the DNA strands via a covalently linked enzyme-DNA intermediate (the cleavable complex).10 This cleavable complex is involved in a reaction that alters the topology of DNA by introducing a temporary double-strand break in the sequence through which an intact helix can pass.11 Valrubicin metabolites stabilize the cleavable complex between DNA topoisomerase II and DNA resulting in increased cleavage of DNA.7

Whereas doxorubicin exhibits slow, temperature-dependent cellular uptake with localization of the drug in the nucleus, valrubicin is characterized by rapid, non-temperature-dependent cellular uptake with accumulation of the drug in the cytoplasm.5,8 Based on these observations, it is thought that valrubicin enters cells by passive diffusion, whereas the cellular uptake of doxorubicin seems to involve an energy-dependent process.5,8 Valrubicin is more active against cells in the plateau growth phase (slowly growing cells) in contrast to doxorubicin, which is more active against cells in the log growth phase (rapidly proliferating cells);5,9 this difference suggests an advantage for the use of valrubicin in the treatment of bladder cancer, which is relatively slow-growing.5

Pharmacokinetics

Absorption

Following intravesical administration of 800 mg of valrubicin and retention in the bladder for a period of 2 hours in patients with carcinoma in situ (CIS) of the bladder (and an intact bladder mucosa), minimal amounts of the drug are absorbed into the plasma; metabolites of valrubicin also have been detected in plasma.1 Following intravesical administration of 200-900 mg of valrubicin once weekly in patients with CIS of the bladder or stage Ta, T1, or T2 bladder cancer, low plasma concentrations of valrubicin (range: 0-10 ng/mL) and its metabolites, N -trifluoroacetyladriamycin (range: 0-19 ng/mL) and N -trifluoroacetyladriamycinol (range: 0-12 ng/mL), were detected within 6 hours after administration of the first, third, and sixth doses of the drug.4

When administered by continuous IV infusion, valrubicin concentrations reach steady state within 1-2 hours, and the drug rapidly disappears from the plasma after discontinuance of the infusion.6

The extent of systemic absorption of intravesically administered valrubicin depends on the condition of the bladder wall.1 Mean areas under the plasma concentration-time curves (AUCs) measured within the first 6 hours increased by approximately 5- to 10-fold, respectively, in patients receiving intravesical doses of valrubicin (800 or 900 mg) within 1 hour of typical or extensive transurethral resection (TUR) of bladder tumors compared with those receiving the drug 2 weeks after surgery.1,29 Mean AUC during the first 6 hours is about 154-fold lower following intravesical instillation of valrubicin 2 weeks after TUR of bladder tumors than that following 24-hour continuous IV infusion of a comparable dose of the drug.1,29 In a patient receiving intravesical valrubicin immediately after experiencing a perforated bladder (as a complication of TUR), AUC for total exposure to anthracyclines was 50% greater than that observed with 24-hour continuous IV infusion of a comparable dose of the drug.1,29

Distribution

Following intravesical administration of valrubicin, the drug distributes into the bladder wall.1 Only small amounts of valrubicin and its metabolites are detected in blood following intravesical administration; however, disruption of the bladder mucosa (e.g., perforated bladder) results in increased distribution of the drug in plasma.1 In patients with carcinoma in situ of the bladder receiving 800 mg of valrubicin intravesically, the mean total anthracycline concentration achieved in the bladder mucosa exceeds the concentrations that have been determined to cause cytotoxicity to 90% of human bladder cells cultured in vitro.1,30

Following IV administration in mice, valrubicin is rapidly and widely distributed in tissues, with high levels of the drug and/or its metabolites in the small intestine and liver; intermediate levels in pancreas, kidney, spleen, large intestine, lung, and heart; and low levels in muscle and fat.12 Valrubicin crosses the blood-brain barrier; small amounts of the drug and its metabolites are detected in brain tissue following IV administration in mice.12,13,29

It is not known if valrubicin or its metabolites are distributed into milk.1

Elimination

Following intravesical instillation of valrubicin, conversion of the drug to its major metabolites, N -trifluoroacetyladriamycin and N -trifluoroacetyladriamycinol, is minimal during the 2-hour retention period.1,2 Voiding of the instillate after the 2-hour retention period results in almost complete excretion of the drug.1,2 About 98.6% of an intravesical dose of the drug is excreted in the urine unchanged; N -trifluoroacetyladriamycin and total anthracyclines account for 0.4 and 99.0%, respectively, of an administered dose.1,2

Data from studies evaluating the pharmacokinetics of valrubicin following IV administration indicate that the drug is metabolized extensively in the liver and excreted principally in the bile with some of the dose excreted in the urine.6 Following a single IV dose of valrubicin 20 mg/kg in rats, plasma total anthracycline concentration declined in a biphasic manner, decreasing from 40 mcg/mL at 2.5 minutes to 1.6 mcg/mL at 6 hours, and N -trifluoroacetyladriamycin was the predominant metabolite during most of this time period; the distribution and elimination half-lives averaged 9 and 99 minutes, respectively.29,31

Following IV administration of the drug, valrubicin undergoes cleavage by nonspecific serum and tissue esterases to N -trifluoroacetyladriamycin (AD 41), which is reduced via aldo-keto reductase enzymes to produce N -trifluoroacetyladriamycinol (AD 92).4,6,7,12 N -Trifluoroacetyladriamycin has clinically important antitumor activity and greater toxicity compared with valrubicin, while N -trifluoroacetyladriamycinol is much less active.8 These 2 metabolites are further metabolized by glucuronide conjugation or cleavage to inactive aglycones.6,8,12 Minimal conversion of valrubicin to doxorubicin or doxorubicinol occurs, and valrubicin is not considered a prodrug of doxorubicin.6,8,13

Chemistry and Stability

Chemistry

Valrubicin, a semisynthetic anthracycline, is an antineoplastic agent.1,2,3,4 Valrubicin, an analog of doxorubicin, differs structurally from doxorubicin in having a 5-carbon straight-chain ester substituent instead of a hydroxyl group at the C-14 position and a trifluoroacetyl moiety on the amino group of the glycoside.5,6 Compared with doxorubicin, valrubicin is more lipophilic and binds less readily to DNA;6,7 the trifluoroacetyl substitution is thought to be responsible for the difference in the DNA binding properties of valrubicin.6 Substitution of the amino group also is thought to contribute to the reduced mutagenicity and toxicity of valrubicin compared with other anthracycline agents.26

Valrubicin occurs as an orange or orange-red powder.1 Valrubicin is highly lipophilic and insoluble in water.1,6 The drug is soluble in methylene chloride, ethanol, methanol, and acetone.1 Commercially available valrubicin solution for intravesical instillation is a sterile, clear, red, nonaqueous solution of the drug in polyoxyl 35 castor oil (Cremophor^® EL, polyoxyethylated castor oil) and dehydrated alcohol.1 When valrubicin solution for intravesical instillation is diluted with 0.9% sodium chloride injection as directed, the resultant solution has a pH of 4-7.29

Stability

Commercially available valrubicin solution for intravesical instillation should be stored in unopened vials at 2-8°C, and freezing should be avoided.1 At temperatures below 4°C, the formulation vehicle may begin to form a waxy precipitate;1 if this occurs, the vial should be warmed in the hand until the solution is clear.1 If any precipitate or particulate matter remains after warming, the solution should be discarded.1 Vials of the solution should not be heated.1 When stored under recommended conditions, commercially available valrubicin solution should remain stable up to the date of expiration marked on the package.1

Following dilution in 0.9% sodium chloride injection as directed, valrubicin solutions are stable for up to 12 hours when prepared and stored in glass, polypropylene, or polyolefin containers at temperatures up to 25°C.1

Valrubicin sterile solution contains polyoxyethylated castor oil (Cremophor^® EL), which has been known to cause leaching of diethylhexylphthalate (DEHP) from polyvinyl chloride (PVC) bags and IV tubing.1 To minimize exposure of the patient to leached DEHP, diluted valrubicin solutions preferably should be prepared and stored in glass or polypropylene bottles or in plastic (polypropylene or polyolefin) bags and administered through non-DEHP containing administration sets, such as polyethylene-lined administration sets.1,29 The manufacturer reports that, during a simulation of valrubicin administration, small amounts (approximately 0.41-0.51 mg) of DEHP were leached from an administration set containing less than 0.1% DEHP by weight.29

The physical and/or chemical compatibility of valrubicin with other drugs has not been evaluated, and the manufacturer states that valrubicin should not be admixed with other drugs.1

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs.

1. Celltech Pharmaceuticals. Valstar^® (valrubicin) sterile solution for intravesical instillation prescribing information. Rochester, NY; 2001 Dec.

2. Steinberg G, Bahnson R, Brosman S et al. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group. J Urol . 2000; 163:761-7. [PubMed 10687972]

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