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warnings and cautions
5 WARNINGS AND PRECAUTIONS • Delaying cystectomy can lead to development of metastatic bladder cancer, which is lethal. ( 5.1 ) • 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. ( 5.2 , 12.3 ) • Evaluate the status of the bladder before the intravesical instillation of valrubicin intravesical solution. ( 5.3 ) • Use with caution in patients with severe irritable bladder symptoms. ( 5.4 ) • Embryo-Fetal Toxicity: Valrubicin intravesical solution can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.5 , 8.1 , 8.3 ) 5.1 Risk of Metastatic Bladder Cancer with Delayed Cystectomy Inform patients that valrubicin intravesical solution 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 ( 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 )] .
6 ADVERSE REACTIONS The most frequently reported adverse reactions ( > 5%) after administration of valrubicin intravesical solution are urinary frequency, dysuria, urinary urgency, bladder spasm, hematuria, bladder pain, urinary incontinence, cystitis, urinary tract infection, nocturia, local burning symptoms, abdominal pain, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma at us.hikma@primevigilance.com or call 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of valrubicin intravesical solution was assessed in 230 patients with transitional cell carcinoma of the bladder, including 205 patients who received multiple weekly doses. One hundred seventy-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