o 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 ( 14 )] 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. 5.2 risk in patients with perforated bladder evaluate the bladder before the intravesical instillation of drug and do not administer valrubicin intravesical solution to patients with a perforated bladder or to those in whom the integrity of the bladder mucosa has been compromised [see contraindications ( 4 )] . in case of bladder perforation, delay the administration of valrubicin intravesical solution until bladder integrity has been restored. one patient with a perforated bladder who received 800 mg of valrubicin intravesical solution intravesically developed severe leukopenia and neutropenia approximately two weeks after drug administration [see clinical pharmacology ( 12.3 )] . 5.3 risk in patients undergoing transurethral resection of the bladder (turb) to avoid systemic exposure to valrubicin intravesical solution 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. 5.4 risk in patients with irritable bladder symptoms use valrubicin intravesical solution 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. 5.5 embryo-fetal toxicity based on findings in animal studies and its mechanism of action, valrubicin intravesical solution can cause fetal harm when administered to a pregnant woman [see clinical pharmacology ( 12.1 and 12.3 )] . 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 valrubicin intravesical solution and for 6 months following the final dose [see use in specific populations ( 8.1 and 8.3 )] .

stent with other cytotoxic drugs. 1 the use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug. valrubicin intravesical solution contains polyoxyl castor oil, which has been known to cause leaching of di(2-ethylhexyl) phthalate (dehp) a hepatotoxic plasticizer, from polyvinyl chloride (pvc) bags and intravenous tubing. valrubicin intravesical solution should be prepared and stored in glass, polypropylene, or polyolefin containers and tubing. it is recommended that non-dehp containing administration sets, such as those that are polyethylene-lined, be used. valrubicin intravesical solution is a clear red solution. visually inspect for particulate matter and discoloration prior to administration. at temperatures below 4°c (39°f), polyoxyl castor oil may begin to form a waxy precipitate. if this happens, the vial should be warmed in the hand until the solution is clear. if particulate matter is still seen, do not administer valrubicin intravesical solution. for each instillation, slowly allow four 5 ml vials (200 mg valrubicin/5 ml vial) to warm to room temperature, but do not heat. withdraw 20 ml of valrubicin intravesical solution from the four vials and dilute with 55 ml of 0.9% sodium chloride injection, usp to provide 75 ml of a diluted valrubicin intravesical solution. valrubicin intravesical solution diluted in 0.9% sodium chloride injection, usp for administration is stable for 12 hours at temperatures up to 25°c (77°f). since compatibility data are not available, do not mix valrubicin intravesical solution with other drugs. insert a urethral catheter into the patient's bladder under aseptic conditions, drain the bladder, and instill the diluted 75 ml valrubicin intravesical solution slowly via gravity flow over a period of several minutes. withdraw the catheter and retain valrubicin intravesical solution in the bladder for two hours before voiding. at the end of two hours, all patients should void. some patients may be unable to retain the drug for the full two hours. instruct patients to maintain adequate hydration following valrubicin intravesical solution treatment [see patient counseling information ( 17 )] .

nty-nine of the 205 patients received the approved dose and schedule of 800 mg weekly for multiple weeks. approximately 84% of patients who received intravesical valrubicin intravesical solution in clinical studies experienced local adverse reactions. the local adverse reactions associated with valrubicin intravesical solution usually occur during or shortly after instillation and resolve within 1 to 7 days after the instillate is removed from the bladder. seven out of 143 patients (5%) who were scheduled to receive six doses of valrubicin intravesical solution failed to receive all of the planned doses because of the occurrence of local bladder symptoms. table 1 displays the frequency of the local adverse reactions at baseline and during treatment among 179 patients who received 800 mg doses of valrubicin intravesical solution in a multiple-cycle treatment regimen. table 1 local adverse reactions before and during treatment with valrubicin intravesical solution (n=179) adverse reaction before treatment during 6-week course of treatment any local bladder symptom 45% 88% urinary frequency 30% 61% dysuria 11% 56% urinary urgency 27% 57% bladder spasm 3% 31% hematuria 11% 29% bladder pain 6% 28% urinary incontinence 7% 22% cystitis 4% 15% nocturia 2% 7% local burning symptoms – procedure related 0% 5% urethral pain 0% 3% pelvic pain 1% 1% hematuria (gross) 0% 1% table 2 displays the adverse reactions other than local bladder symptoms that occurred in 1% or more of the 230 patients who received at least one dose of valrubicin intravesical solution in a clinical trial. table 2 systemic adverse reactions (≥ 1%) following intravesical administration of valrubicin intravesical solution (n=230) body system preferred term body as a whole abdominal pain 5% asthenia 4% headache 4% malaise 4% back pain 3% chest pain 3% fever 2% cardiovascular vasodilation 2% digestive nausea 5% diarrhea 3% vomiting 2% flatulence 1% hemic and lymphatic anemia 2% metabolic and nutritional hyperglycemia 1% peripheral edema 1% musculoskeletal myalgia 1% nervous dizziness 3% respiratory pneumonia 1% skin and appendages rash 3% urogenital urinary tract infection 15% urinary retention 4% hematuria (miscroscopic) 3% adverse reactions other than local reactions that occurred in less than 1% of the patients who received valrubicin intravesical solution intravesically in clinical trials are listed below. digestive system: tenesmus metabolic and nutritional: nonprotein nitrogen increased skin and appendages: pruritus special senses: taste loss urogenital system: local skin irritation, poor urine flow, and urethritis

t rats during the period of organogenesis at doses ≥ 12 mg/kg (about 0.2 times the recommended human intravesical dose on a mg/m 2 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/m 2 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. 8.2 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 valrubicin intravesical solution and for 2 weeks after the final dose. 8.3 females and males of reproductive potential contraception females valrubicin intravesical solution can cause fetal harm when administered to a pregnant female. advise females of reproductive potential to use effective contraception during treatment with valrubicin intravesical solution and for 6 months after the final dose [see use in specific populations ( 8.1 )] . males based on genotoxicity findings, advise men with female partners of reproductive potential to use effective contraception during treatment with valrubicin intravesical solution and for 3 months following the final dose [see non clinical toxicology ( 13.1 )] infertility males studies of the effects of valrubicin intravesical solution on human male or female fertility have not been done. based on findings in animal studies, valrubicin intravesical solution may impair fertility in males of reproductive potential [see nonclinical toxicology ( 13.1 )] . 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 8.5 geriatric use because carcinoma in situ of the bladder generally occurs in older individuals, 85% of the patients enrolled in the clinical studies of valrubicin intravesical solution 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 valrubicin intravesical solution in geriatric patients who are otherwise in good health.

s the recommended human intravesical dose on a mg/m 2 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/m 2 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.

luoroacetyladriamycinol in bladder tissue was negligible. after retention, the drug was almost completely excreted by voiding the instillate. mean percent recovery of valrubicin intravesical solution, n-trifluoroacetyladriamycin, and total anthracyclines in 14 urine samples from six patients was 98.6%, 0.4%, and 99.0% of the total administered drug, respectively. during the two-hour dose-retention period, only nanogram quantities of valrubicin intravesical solution were absorbed into the plasma. n-trifluoroacetyladriamycin and n-trifluoroacetyladriamycinol were measured in blood. total systemic exposure to anthracyclines during and after intravesical administration of valrubicin intravesical solution is dependent upon the condition of the bladder wall. the mean auc 0-6 hours (total anthracyclines exposure) for an intravesical dose of 900 mg of valrubicin intravesical solution administered 2 weeks after transurethral resection of bladder tumors (n=6) was 78 nmol/l•hr. in patients receiving 800 mg of valrubicin intravesical solution 5 to 51 minutes after typical (n=8) and extensive (n=5) turb tumors, the mean auc 0-6 hours values for total anthracyclines were 409 and 788 nmol/l•hr, respectively. the auc 0-6 hours total exposure to anthracyclines was 18,382 nmol/l•hr in one patient who experienced a perforated bladder following a transurethral resection that occurred 5 minutes before administration of an intravesical dose of 800 mg of valrubicin intravesical solution. administration of a comparable intravenous dose of valrubicin intravesical solution (600 mg/m 2 ; n=2) as a 24-hour infusion resulted in an auc 0-6 hours for total anthracyclines of 11,975 nmol/l•hr. these results are shown in figure 2. figure 2. comparison of mean auc 0-6 hours in valrubicin intravesical solution clinical studies (n=number of patients) figure-2

d into the plasma. n-trifluoroacetyladriamycin and n-trifluoroacetyladriamycinol were measured in blood. total systemic exposure to anthracyclines during and after intravesical administration of valrubicin intravesical solution is dependent upon the condition of the bladder wall. the mean auc 0-6 hours (total anthracyclines exposure) for an intravesical dose of 900 mg of valrubicin intravesical solution administered 2 weeks after transurethral resection of bladder tumors (n=6) was 78 nmol/l•hr. in patients receiving 800 mg of valrubicin intravesical solution 5 to 51 minutes after typical (n=8) and extensive (n=5) turb tumors, the mean auc 0-6 hours values for total anthracyclines were 409 and 788 nmol/l•hr, respectively. the auc 0-6 hours total exposure to anthracyclines was 18,382 nmol/l•hr in one patient who experienced a perforated bladder following a transurethral resection that occurred 5 minutes before administration of an intravesical dose of 800 mg of valrubicin intravesical solution. administration of a comparable intravenous dose of valrubicin intravesical solution (600 mg/m 2 ; n=2) as a 24-hour infusion resulted in an auc 0-6 hours for total anthracyclines of 11,975 nmol/l•hr. these results are shown in figure 2. figure 2. comparison of mean auc 0-6 hours in valrubicin intravesical solution clinical studies (n=number of patients) figure-2

alrubicin intravesical solution, 16 patients (18%) had a complete response documented by bladder biopsies and cytology at 6 months following initiation of therapy. median duration of response from start of treatment varied according to the method of analysis (13.5 months if measured to last bladder biopsy without tumor and 21 months if measured until time of documented recurrence). a retrospective analysis in the 16 patients with complete response to valrubicin intravesical solution demonstrated that time to recurrence of their disease after treatment with valrubicin intravesical solution was longer than time to recurrence after previous courses of intravesical therapy. of the 90 patients with bcg-refractory cis, 11% (10 patients) developed metastatic or deeply-invasive bladder cancer during follow-up; four of these patients, none who underwent cystectomy, died with metastatic bladder cancer and six were found to have developed stage progression to deeply-invasive disease (t3), with lymph node involvement in one patient, at the time of cystectomy. it is uncertain to what extent the development of advanced bladder cancer in these patients was due to the delay in cystectomy required to receive treatment with valrubicin intravesical solution (3 months was the time of follow-up to determine response), as cystectomy was often delayed or was never performed despite failure of treatment with valrubicin intravesical solution. in the 10 patients documented to have invasive bladder cancer or metastatic disease, the delay between the time of treatment failure (when cystectomy should have been performed) and cystectomy or documentation of advanced bladder cancer was a median of 17.5 months.

� advise patients to report prolonged irritable bladder symptoms or prolonged passage of red-colored urine immediately to their physician. • instruct patients to maintain adequate hydration following valrubicin intravesical solution treatment. embryo-fetal toxicity • advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with valrubicin intravesical solution and for 6 months after the last dose. advise females to inform their healthcare provider of a known or suspected pregnancy [see warnings and precautions ( 5.5 ), use in specific populations ( 8.1 and 8.3 )] . • advise male patients with female partners of reproductive potential to use effective contraception during treatment with valrubicin intravesical solution and for 3 months after the last dose [see use in specific populations ( 8.3 )] . lactation • advise females not to breastfeed during treatment with valrubicin intravesical solution and for 2 weeks after the last dose [see use in specific populations ( 8.2 )] . healthcare professionals can email hikma at us.hikma@primevigilance.com or call 1-877-845-0689 for information on this product. manufactured by: the university of iowa pharmaceuticals iowa city, iowa 52242 manufactured for: hikma berkeley heights, nj 07922 rev. june 2022