WARNINGS
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS
Risk Of Metastatic Bladder Cancer With Delayed Cystectomy
Inform patients that VALSTAR has been shown to induce complete response in only about 1 in 5 patients
with BCG-refractory CIS, and that delaying cystectomy could lead to development of metastatic bladder
cancer, which is lethal. The exact risk of developing metastatic bladder cancer from such a delay may
be difficult to assess [see Clinical Studies] but increases the longer cystectomy is delayed in the
presence of persisting CIS. If there is not a complete response of CIS to treatment after 3 months or if
CIS recurs, reconsider cystectomy.
Risks In Patients With Perforated Bladder
Evaluate the bladder before the intravesical instillation of drug and do not administer VALSTAR to
patients with a perforated bladder or to those in whom the integrity of the bladder mucosa has been
compromised [see CONTRAINDICATIONS]. In case of bladder perforation, delay the administration of
VALSTAR until bladder integrity has been restored. One patient with a perforated bladder who
received 800 mg of VALSTAR intravesically developed severe leukopenia and neutropenia
approximately two weeks after drug administration [see CLINICAL PHARMACOLOGY].
Risk In Patients Undergoing Transurethral Resection Of The Bladder (TURB)
To avoid systemic exposure to VALSTAR for the patients undergoing TURB, evaluate the status of the
bladder before the intravesical instillation of drug. Delay administration at least two weeks after
transurethral resection and/or fulguration.
Risk In Patients With Irritable Bladder Symptoms
Use VALSTAR with caution in patients with severe irritable bladder symptoms. Bladder spasm and
spontaneous discharge of the intravesical instillate may occur; clamping of the urinary catheter is not
advised.
Embryo-Fetal Toxicity
Based on findings in animal studies and its mechanism of action, VALSTAR can cause fetal harm when
administered to a pregnant woman [see CLINICAL PHARMACOLOGY]. In animal reproduction
studies, intravenous administration of valrubicin to pregnant rats during the period of organogenesis at a
dose about 0.2 times the recommended human intravesical dose caused embryo-fetal malformations and
increased resorptions. Advise females who might become pregnant of the potential risk to a fetus.
Advise females of reproductive potential to use effective contraception during treatment with
VALSTAR and for 6 months following the final dose [see Use In Specific Populations].
Nonclinical Toxicology
Carcinogenesis And Mutagenesis And Impairment Of Fertility
The carcinogenic potential of valrubicin has not been evaluated.
In vitro, valrubicin was mutagenic in the bacterial reverse mutation (Ames) assayand clastogenic in the
chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells.
Studies in animals evaluating the effects of valrubicin on male or female fertility have not been
conducted. Based on effects on male reproductive organs in general toxicology studies in dogs with
intravesical instillation, valrubicin may impair fertility in male patients. When instilled into the bladder
of male dogs weekly for 6 weeks, valrubicin caused mild to moderate atrophy of the prostate with
inflammation, diffuse decrease in acinar size, epithelial changes. It also caused testicular degeneration,
marked germ cell depletion, spermatid giant cells and karyomegaly.
Use In Specific Populations
Pregnancy
Risk Summary
Based on findings in animal studies and its mechanism of action, VALSTAR can cause fetal harm when
administered to a pregnant females [see CLINICAL PHARMACOLOGY]. There are no available
data in pregnant females to inform the drug-associated risk. In animal reproduction studies, intravenous
administration of valrubicin to pregnant rats during the period of organogenesis at a dose about 0.2
times the recommended human intravesical dose caused embryo-fetal malformations and increased
resorptions [see Data]. Advise females who are or might become pregnant of the potential risk to a
fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in
clinically-recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
Daily intravenous administration of valrubicin to pregnant rats during the period of organogenesis at
doses ≥ 12 mg/kg (about 0.2 times the recommended human intravesical dose on a mg/m2 basis) was
embryo-fetal toxic and teratogenic. Administration of 12 mg/kg resulted in fetal malformations. A dose
of 24 mg/kg (about 0.3 times the recommended human intravesical dose on a mg/m2 basis) caused
numerous, severe alterations in the skull and skeleton of the developing fetuses. This dose also caused
an increase in fetal resorptions and a decrease in viable fetuses.
Lactation
Risk Summary
There are no data on the presence of valrubicin or its metabolites in human milk, the effects of
valrubicin on the breast-fed infant, or its effects on milk production. Because of the potential for
serious adverse reactions in breast-fed infants from valrubicin, advise a lactating female not to
breastfeed during treatment with VALSTAR and for 2 weeks after the final dose.
Females And Males Of Reproduction Potential
Contraception
Females
VALSTAR can cause fetal harm when administered to a pregnant female. Advise females of
reproductive potential to use effective contraception during treatment with VALSTAR and for 6 months
after the final dose [see Pregnancy].
Males
Based on genotoxicity findings, advise men with female partners of reproductive potential to use
effective contraception during treatment with VALSTAR and for 3 months following the final dose [see Nonclinical Toxicology]
Infertility
Males
Studies of the effects of VALSTAR on human male or female fertility have not been done. Based on
findings in animal studies, VALSTAR may impair fertility in males of reproductive potential [see Nonclinical Toxicology].
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Geriatric Use
Because carcinoma in situ of the bladder generally occurs in older individuals, 85% of the patients
enrolled in the clinical studies of VALSTAR were more than 60 years of age (49% of the patients
were more than 70 years of age). In the primary efficacy studies, the mean age of the population was
69.5 years. There are no specific precautions regarding use of VALSTAR in geriatric patients who are
otherwise in good health.