Prescription Drugs

CLINICAL PHARMACOLOGY Action MUTAMYCIN (mitomycin) selectively inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content correlates with the degree of MUTAMYCIN (mitomycin) -induced cross-linking. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed. In humans, MUTAMYCIN (mitomycin) is rapidly cleared from the serum after intravenous administration. Time required to reduce the serum concentration by 50% after a 30 mg bolus injection is 17 minutes. After injection of 30 mg, 20 mg, or 10 mg I.V., the maximal serum concentrations were 2.4 µg/mL, 1.7 µg/mL, and 0.52 µg/mL, respectively. Clearance is effected primarily by metabolism in the liver, but metabolism occurs in other tissues as well. The rate of clearance is inversely proportional to the maximal serum concentration because, it is thought, of saturation of the degradative pathways. Approximately 10% of a dose of MUTAMYCIN (mitomycin) is excreted unchanged in the urine. Since metabolic pathways are saturated at relatively low doses, the percent of a dose excreted in urine increases with increasing dose. In children, excretion of intravenously administered MUTAMYCIN (mitomycin) is similar. Animal Toxicology MUTAMYCIN (mitomycin) has been found to be carcinogenic in rats and mice. At doses approximating the recommended clinical dose in man, it produces a greater than 100% increase in tumor incidence in male Sprague-Dawley rats, and a greater than 50% increase in tumor incidence in female Swiss mice.

CLINICAL PHARMACOLOGY Mechanism of Action Mitosol® inhibits the synthesis of deoxyribonucleic acid (DNA). The guanine and cytosine content correlates with the degree of mitomycin-induced cross-linking. Cellular RNA and protein synthesis may also be suppressed. Pharmacokinetics Absorption The systemic exposure of mitomycin following ocular administration of Mitosol® in humans is unknown. Based on a comparison of the proposed dose of up to 0.2 mg to intravenous (IV) doses of mitomycin used clinically for treatment of oncologic indications (up to 20 mg/m2), systemic concentrations in humans upon ocular administration are expected to be multiple orders of magnitude lower than those achieved by IV administration. Metabolism In humans, mitomycin is cleared from ophthalmic tissue after intraoperative topical application and irrigation, as metabolism occurs in other affected tissues. Systemic clearance is affected primarily by metabolism in the liver. The rate of clearance is inversely proportional to the maximal serum concentration because of saturation of the degradative pathways. Excretion Approximately 10% of an injectable dose of mitomycin is excreted unchanged in the urine. Since metabolic pathways are saturated at relatively low doses, the percent of a dose excreted in urine increases. Clinical Studies In placebo-controlled studies reported in the medical literature, mitomycin reduced intraocular pressure (IOP) by 3 mmHg in patients with open-angle glaucoma when used as an adjunct to ab externo glaucoma surgery by Month 12. In studies with a historical control reported in the medical literature, mitomycin reduced intraocular pressure (IOP) by 5 mmHg in patients with open-angle glaucoma when used as an adjunct to ab externo glaucoma surgery by Month

Find Lowest Prices on Mutamycin® (mitomycin) for Injection, USP WARNING MUTAMYCIN® (mitomycin for injection, USP) should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available. Bone marrow suppression, notably thrombocytopenia and leukopenia, which may contribute to overwhelming infections in an already compromised patient, is the most common and severe of the toxic effects of MUTAMYCIN (see WARNINGS and ADVERSE REACTIONS sections). Hemolytic Uremic Syndrome (HUS) a serious complication of chemotherapy, consisting primarily of microangiopathic hemolytic anemia, thrombocytopenia, and irreversible renal failure has been reported in patients receiving systemic MUTAMYCIN (mitomycin) . The syndrome may occur at any time during systemic therapy with MUTAMYCIN (mitomycin) as a single agent or in combination with other cytotoxic drugs, however, most cases occur at doses ≥ 60 mg of MUTAMYCIN (mitomycin) . Blood product transfusion may exacerbate the symptoms associated with this syndrome. The incidence of the syndrome has not been defined. DESCRIPTION MUTAMYCIN® (mitomycin for injection, USP) (also known as mitomycin and/or mitomycin-C) is an antibiotic isolated from the broth of Streptomyces caespitosus which has been shown to have antitumor activity. The compound is heat stable, has a high melting point, and is freely soluble in organic solvents.

Find Lowest Prices on Mitosol® (mitomycin) for Solution DESCRIPTION Mitomycin is an antibiotic isolated from the broth of Streptomyces verticillus Yingtanensis which has been shown to have antimetabolic activity. Mitomycin is a blue-violet crystalline powder with the molecular formula of C15H18N4O5 and a molecular weight of 334.33. Its chemical name is 7-amino-9α-methoxymitosane and it has the following structural formula: Mitosol® is a sterile lyophiliized mixture of mitomycin and mannitol, which, when reconstituted with Sterile Water for Injection, provides a solution for application in glaucoma filtration surgery. Mitosol® is supplied in vials containing 0.2 mg of mitomycin. Each vial also contains mannitol 0.4 mg, at a 1:2 ratio of mitomycin to mannitol. Each mL of reconstituted solution contains 0.2 mg mitomycin and has a pH between 5.0 and 8.0.

INDICATIONS MUTAMYCIN (mitomycin) is not recommended as single-agent, primary therapy. It has been shown to be useful in the therapy of disseminated adenocarcinoma of the stomach or pancreas in proven combinations with other approved chemotherapeutic agents and as palliative treatment when other modalities have failed. MUTAMYCIN (mitomycin) is not recommended to replace appropriate surgery and/or radiotherapy. DOSAGE AND ADMINISTRATION MUTAMYCIN (mitomycin) should be given intravenously only, using care to avoid extrava-sation of the compound. If extravasation occurs, cellulitis, ulceration, and slough may result. Each vial contains either mitomycin 5 mg and mannitol 10 mg, mitomycin 20 mg and mannitol 40 mg, or mitomycin 40 mg and mannitol 80 mg. To administer, add Sterile Water for Injection, 10 mL, 40 mL, or 80 mL respectively. Shake to dissolve. If product does not dissolve immediately, allow to stand at room temperature until solution is obtained. After full hematological recovery (see guide to dosage adjustment) from any previous chemotherapy, the following dosage schedule may be used at 6 to 8 week intervals: 20 mg/m2 intravenously as a single dose via a functioning intravenous catheter. Because of cumulative myelosuppression, patients should be fully reevaluated after each course of MUTAMYCIN (mitomycin) , and the dose reduced if the patient has experienced any toxicities. Doses greater than 20 mg/m2 have not been shown to be more effective, and are more toxic than lower doses. The following schedule is suggested as a guide to dosage adjustment: Nadir After Prior Dose Percentage of Prior Dose to be Given Leukocytes/mm3 Platelets/mm3 > 4000 > 100,000 100% 3000–3999 75,000–99,999 100% 2000–2999 25,000–74,999 70% < 2000 < 25,000 50% No repeat dosage should be given until leukocyte count has returned to 4000/mm3 and platelet count to 100,000/mm3. When MUTAMYCIN (mitomycin) is used in combination with other myelosuppressive agents, the doses should be adjusted accordingly. If the disease continues to progress after two courses of MUTAMYCIN (mitomycin) , the drug should be stopped since chances of response are minimal. Stability Unreconstituted MUTAMYCIN (mitomycin) stored at room temperature is stable for the lot life indicated on the package. Avoid excessive heat (over 40°C, 104°F). Reconstituted with Sterile Water for Injection to a concentration of 0.5 mg per mL, MUTAMYCIN (mitomycin) is stable for 14 days refrigerated or 7 days at room temperature. Diluted in various I.V. fluids at room temperature, to a concentration of 20 to 40 micrograms per mL: The combination of MUTAMYCIN (mitomycin) (5 mg to 15 mg) and heparin (1,000 units to 10,000 units) in 30 mL of 0.9% Sodium Chloride Injection is stable for 48 hours at room temperature. I.V. Fluid Stability 5% Dextrose Injection 3 hours 0.9% Sodium Chloride Injection 12 hours Sodium Lactate Injection 24 hours Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. HOW SUPPLIED MUTAMYCIN® (mitomycin for injection, USP) NDC 0015-3001-20 – Each vial contains 5 mg mitomycin. NDC 0015-3002-20 – Each vial contains 20 mg mitomycin. NDC 0015-3059-20 – Each vial contains 40 mg mitomycin. For information on package sizes available, refer to the current price schedule. REFERENCES 1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. NIH Publication No. 83-2621. For sale by the Superintendent of Documents, US Government Printing Office, Washington, DC 20402. 2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA 1985; 253 (11):1590-1592. 3. National Study Commission on Cytotoxic Exposure–Recommendations for Handling Cytotoxic Agents. Available from Louis P. Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure, Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, Massachusetts 02115. 4. Clinical Oncological Society of Australia. Guidelines and Recommen- dations for Safe Handling of Antineoplastic Agents. Med J Australia 1983; 1:426-428. 5. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA–A Cancer Journal for Clinicians 1983; (Sept/Oct) 258-263. 6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm 1990; 47:1033–1049. 7. Controlling Occupational Exposure to Hazardous Drugs (OSHA WORK PRACTICE GUIDELINES). Am J Health-Syst Pharm 1996;53:1669-1685. Bristol-Myers Sqibb Company, Princeton, NJ 08543 U.S.A. Revised January 2000. FDA Rev date: 11/2/2000

INDICATIONS Mitosol® is an antimetabolite indicated for use as an adjunct to ab externo glaucoma surgery. DOSAGE AND ADMINISTRATION Mitosol® is intended for topical application to the surgical site of glaucoma filtration surgery. It is not intended for intraocular administration. If intraocular administration occurs, cell death leading to corneal infarction, retinal infarction, and ciliary body atrophy may result. Method of Reconstitution: Each vial of Mitosol® contains 0.2 mg of mitomycin and mannitol in a 1:2 concentration ratio. To reconstitute, add 1 mL of Sterile Water for Injection, then shake to dissolve. If product does not dissolve immediately, allow to stand at room temperature until the product dissolves into solution. Method of Use: Sponges provided within the Mitosol® Kit should be fully saturated with the entire reconstituted contents in the manner prescribed in the Instructions for Use. A treatment area approximating 10mm x 6mm +/- 2mm should be treated with the Mitosol®. Apply fully saturated sponges equally to the treatment area, in a single layer, with the use of a surgical forceps. Keep the sponges on the treatment area for two (2) minutes, then remove and return to the Mitosol® Tray for defined disposal in the Chemotherapy Waste Bag provided. Stability Lyophilized Mitosol® stored at controlled room temperature (i.e., 20 - 25°C or 68° - 77° F) is stable for the shelf life indicated on the package. Avoid excessive heat. Protect from light. Reconstituted with Sterile Water for Injection at a concentration of 0.2 mg/ml, mitomycin is stable for one (1) hour at room temperature. HOW SUPPLIED Dosage Forms and Strengths Mitosol® is a sterile lyophilized mixture of mitomycin and mannitol, which, when reconstituted with Sterile Water for Injection, provides a solution for application in glaucoma filtration surgery. Mitosol® is supplied in vials containing 0.2 mg of mitomycin. Each vial also contains mannitol 0.4 mg, at a 1:2 ratio of mitomycin to mannitol. Each mL of reconstituted solution contains 0.2 mg mitomycin and has a pH between 5.0 and 8.0. 4. Mitosol® (mitomycin for solution) is available in a kit containing: One Vial containing 0.2 mg mitomycin One 1 mL syringe (Sterile Water For Injection) with Connector One Plunger Rod One Vial Adapter with Spike One 1 mL TB Syringe, Luer Lock One Sponge Container Six 3 mm Absorbent Sponges Six 6 mm Absorbent Sponges Six Half Moon Sponges One Instrument Wedge Sponge One Alcohol Prep Pad, Sterile One Chemotherapy Waste Bag Three kits are supplied in each carton (NDC 49771-002-03). Storage and Handling Storage Store kits at 20° - 25° C (68° - 77° F). Protect from light. Handling Procedures Procedures for Proper Handling and Disposal of anti-cancer drugs should be followed. Appropriate containment and disposal devices are included within the Mitosol® (mitomycin for solution) Kit for Ophthalmic Use. Manufactured for: Mobius Therapeutics, LLC 4041 Forest Park Avenue St. Louis, MO 63108. Revised 01/2012

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

PATIENT INFORMATION Mitosol® mitocycin for solution 0.2 mg/vial Read INSTRUCTIONS FOR USE Before Proceeding Instructions for Use A. Black Outer Pack (Figure A) One Chemotherapy Waste Bag One Instructions for Use One Package Insert One Inner Tray The Black Outer Pack is to be handled opened, and its STERILE contents dispensed by the non-sterile circulating nurse. B. STERILE Inner Tray (Figure B) One Vial containing 0.2 mg mitomycin One 1 mL syringe (Sterile Water For Injection) with Connector One Plunger Rod One Vial Adapter with Spike One 1 mL TB Syringe, Luer Lock One Sponge Container Six 3 mm Absorbent Sponges Six 6 mm Absorbent Sponges Six Half Moon Sponges One Instrument Wedge Sponge One Alcohol Prep Pad, Sterile One Chemotherapy Waste Bag The Sterile Inner Tray is to be handled, opened, and its Contents assembled and dispensed by the sterile scrub technician. This tray and its contents are STERILE. 1. Getting Started Non-Sterile Circulating Nurse: Open black outer pack. Affect sterile transfer of contents to the sterile field. Sterile Surgical Technician: Open sterile inner tray. 2. Reconstituting Mitosol® Screw white plunger rod to rubber plunger of pre-filled syringe. (Fig. 1) Press firmly and screw the blue end of the vial adapter into the blue end of the syringe connector. (Fig. 2) Open and remove alcohol prep pad. Remove vial cap; disinfect vial stopper with alcohol prep pad. Holding vial face up, push spiked end of vial adapter down on the vial lid until seated and secure. (Fig. 3) Inject entire contents of sterile water (1 ml) into vial. (Fig. 4) Gently swirl vial and contents until complete reconstitution of Mitosol®. If product does not dissolve immediately, allow to stand at room temperature until the product has dissolved into solution. 3. Preparing sponges Invert vial and syringe and draw full volume of medication into syringe. Unscrew the syringe and connector from vial and vial adapter (Fig. 6) Place vial and vial adaptor in chemotherapy waste disposal bag (yellow bag). Take sponge container from sterile inner tray. Screw both syringes into sponge container; the TB syringe to one end, the pre-filled syringe to the other. Mitosol® must be used within 1 hour of reconstitution: Inject medication into sponge container, saturating sponges. Reconstituted Mitosol® should remain undisturbed in sponge container for 60 seconds. (Fig. 7) If any excess fluid remains, withdraw plunger of TB syringe, drawing excess fluid/air into syringe. 4. Using Mitosol® With both syringes connected, the TB syringe to one end, the pre-filled syringe to the other, open sponge container, offering contents to surgeon for placement on surgical site. (Fig. 8) Apply saturated sponges to surgical site for two minutes. Remove sponges from eye and copiously irrigate surgical site. As used sponges are removed from surgical site, accept back into container for disposal. Close container lid. With syringes still connected to sponge container, remove entire assembly from surgical field in chemotherapy waste disposal bag. DISPOSE OF CHEMOTHERAPY WASTE BAG AND ITS CONTENTS AS CHEMOTHERAPY WASTE

OVERDOSE No information provided. CONTRAINDICATIONS MUTAMYCIN (mitomycin) is contraindicated in patients who have demonstrated a hypersensitive or idiosyncratic reaction to it in the past. MUTAMYCIN (mitomycin) is contraindicated in patients with thrombocytopenia, coagulation disorder, or an increase in bleeding tendency due to other causes.

OVERDOSE No information provided. CONTRAINDICATIONS Hypersensitivity Mitosol® is contraindicated in patients that have demonstrated a hypersensitivity to mitomycin in the past. 4.2 Pregnant women Mitosol® may cause fetal harm when administered to a pregnant woman. Mitomycin administered parenterally has been shown to be teratogenic in mice and rats when given at doses equivalent to the usual human intravenous dose. Mitosol® is contraindicated in women who are or may become pregnant during therapy. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

SIDE EFFECTS Bone Marrow Toxicity: This was the most common and most serious toxicity, occurring in 605 of 937 patients (64.4%). Thrombocytopenia and/or leukopenia may occur anytime within 8 weeks after onset of therapy with an average time of 4 weeks. Recovery after cessation of therapy was within 10 weeks. About 25% of the leukopenic or thrombocytopenic episodes did not recover. MUTAMYCIN (mitomycin) produces cumulative myelosuppression. Integument and Mucous Membrane Toxicity: This has occurred in approximately 4% of patients treated with MUTAMYCIN (mitomycin for injection, USP). Cellulitis at the injection site has been reported and is occasionally severe. Stomatitis and alopecia also occur frequently. Rashes are rarely reported. The most important dermatological problem with this drug, however, is the necrosis and consequent sloughing of tissue which results if the drug is extravasated during injection. Extravasation may occur with or without an accompanying stinging or burning sensation and even if there is adequate blood return when the injection needle is aspirated. There have been reports of delayed erythema and/or ulceration occurring either at or distant from the injection site, weeks to months after MUTAMYCIN (mitomycin) , even when no obvious evidence of extravasation was observed during administration. Skin grafting has been required in some of the cases. Renal Toxicity: 2% of 1,281 patients demonstrated a statistically significant rise in creatinine. There appeared to be no correlation between total dose administered or duration of therapy and the degree of renal impairment. Pulmonary Toxicity: This has occurred infrequently but can be severe and may be life threatening. Dyspnea with a nonproductive cough and radiographic evidence of pulmonary infiltrates may be indicative of MUTAMYCIN (mitomycin) -induced pulmonary toxicity. If other etiologies are eliminated, MUTAMYCIN (mitomycin) therapy should be discontinued. Steroids have been employed as treatment of this toxicity, but the therapeutic value has not been determined. A few cases of adult respiratory distress syndrome have been reported in patients receiving MUTAMYCIN (mitomycin) in combination with other chemotherapy and maintained at FIO2 concentrations greater than 50% perioperatively. Hemolytic Uremic Syndrome (HUS): This serious complication of chemotherapy, consisting primarily of microangiopathic hemolytic anemia (hematocrit ≤ 25%), thrombocytopenia ( ≤ 100,000/mm3), and irreversible renal failure (serum creatinine ≥ 1.6 mg/dL) has been reported in patients receiving systemic MUTAMYCIN (mitomycin) . Microangiopathic hemolysis with fragmented red blood cells on peripheral blood smears has occurred in 98% of patients with the syndrome. Other less frequent complications of the syndrome may include pulmonary edema (65%), neurologic abnormalities (16%), and hypertension. Exacerbation of the symptoms associated with HUS has been reported in some patients receiving blood product transfusions. A high mortality rate (52%) has been associated with this syndrome. The syndrome may occur at any time during systemic therapy with MUTAMYCIN (mitomycin) as a single agent or in combination with other cytotoxic drugs. Less frequently, HUS has also been reported in patients receiving combinations of cytotoxic drugs not including MUTAMYCIN (mitomycin) . Of 83 patients studied, 72 developed the syndrome at total doses exceeding 60 mg of MUTAMYCIN (mitomycin) . Consequently, patients receiving ≥ 60 mg of MUTAMYCIN (mitomycin) should be monitored closely for unexplained anemia with fragmented cells on peripheral blood smear, thrombocytopenia, and decreased renal function. The incidence of the syndrome has not been defined. Therapy for the syndrome is investigational. Cardiac Toxicity: Congestive heart failure, often treated effectively with diuretics and cardiac glycosides, has rarely been reported. Almost all patients who experienced this side effect had received prior doxorubicin therapy. Acute Side Effects Due to MUTAMYCIN (mitomycin) were fever, anorexia, nausea, and vomiting. They occurred in about 14% of 1,281 patients. Other: Headache, blurring of vision, confusion, drowsiness, syncope, fatigue, edema, thrombophlebitis, hematemesis, diarrhea, and pain. These did not appear to be dose related and were not unequivocally drug related. They may have been due to the primary or metastatic disease processes. Malaise and asthenia have been reported as part of postmarketing surveillance. Bladder fibrosis/contraction has been reported with intravesical administration (see PRECAUTIONS). DRUG INTERACTIONS No information provided.

SIDE EFFECTS Ophthalmic Adverse Reactions The most frequent adverse reactions to Mitosol® occur locally, as an extension of the pharmacological activity of the drug. These reactions include: Blebitis: bleb ulceration, chronic bleb leak, encapsulated/cystic bleb, bleb-related infection, wound dehiscence, conjunctivial necrosis, thin-walled bleb Cornea: corneal endothelial damage, epithelial defect, anterior synechiae, superficial punctuate keratitis, Descemet's detachment, induced astigmatism Endophthalmitis Hypotony: choroidal reactions (choroidal detachment, choroidal effusion, serous choroidal detachment, suprachoroidal hemorrhage, hypotony maculopathy, presence of supraciliochoroidal fluid, hypoechogenic suprachoroidal effusion) Inflammation: iritis, fibrin reaction Lens: cataract development, cataract progression, capsule opacification, capsular constriction and/or capsulotomy rupture, posterior synechiae Retina: retinal pigment epithelial tear, retinal detachment (serous and rhegatogenous) Scleritis: wound dehiscence Vascular: hyphema, central retinal vein occlusion, hemiretinal vein occlusion, retinal hemorrhage, vitreal hemorrhage and blood clot, subconjunctival hemorrhage, disk hemorrhage Additional Reactions: macular edema, sclera thinning or ulceration, intraocular lens capture, disk swelling, malignant glaucoma, lacrimal drainage system obstruction, ciliary block, corneal vascularization, visual acuity decrease, cystic conjunctival degeneration, upper eyelid retraction, dislocated implants, severe loss of vision. DRUG INTERACTIONS No information provided.

WARNINGS Patients being treated with MUTAMYCIN (mitomycin) must be observed carefully and frequently during and after therapy. The use of MUTAMYCIN (mitomycin) results in a high incidence of bone marrow suppression, particularly thrombocytopenia and leukopenia. Therefore, the following studies should be obtained repeatedly during therapy and for at least eight weeks following therapy: platelet count, white blood cell count, differential, and hemoglobin. The occurrence of a platelet count below 100,000/mm3 or a WBC below 4,000/mm3 or a progressive decline in either is an indication to withhold further therapy until blood counts have recovered above these levels. Patients should be advised of the potential toxicity of this drug, particularly bone marrow suppression. Deaths have been reported due to septicemia as a result of leukopenia due to the drug. Patients receiving MUTAMYCIN (mitomycin) should be observed for evidence of renal toxicity. MUTAMYCIN (mitomycin) should not be given to patients with a serum creatinine greater than 1.7 mg percent. Usage in Pregnancy Safe use of MUTAMYCIN (mitomycin) in pregnant women has not been established. Teratological changes have been noted in animal studies. The effect of MUTAMYCIN (mitomycin) on fertility is unknown. PRECAUTIONS Acute shortness of breath and severe bronchospasm have been reported following the administration of vinca alkaloids in patients who had previously or simultaneously received MUTAMYCIN (mitomycin) . The onset of this acute respiratory distress occurred within minutes to hours after the vinca alkaloid injection. The total number of doses for each drug has varied considerably. Bronchodilators, steroids and/or oxygen have produced symptomatic relief. A few cases of adult respiratory distress syndrome have been reported in patients receiving MUTAMYCIN (mitomycin) in combination with other chemotherapy and maintained at FIO2 concentrations greater than 50% perioperatively. Therefore, caution should be exercised using only enough oxygen to provide adequate arterial saturation since oxygen itself is toxic to the lungs. Careful attention should be paid to fluid balance and overhydration should be avoided. Bladder fibrosis/contraction has been reported with intravesical administration (not an approved route of administration), which in rare cases has required cystectomy. Nursing Mothers It is not known if mitomycin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from mitomycin, it is recommended that nursing be discontinued when receiving mitomycin therapy. Pediatric Use Safety and effectiveness in pediatric patients have not been established.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Cell Death Mitomycin is cytotoxic. Use of mitomycin in concentrations higher than 0.2 mg/mL or use for longer than 2 minutes may lead to unintended corneal and/or scleral damage including thinning or perforation. Direct contact with the corneal endothelium will result in cell death. Hypotony The use of mitomycin has been associated with an increased instance of post-operative hypotony. Cataract Formation Use in phakic patients has been correlated to a higher instance of lenticular change and cataract formation. Patient Counseling Information Instruct patients to discuss with their physician if they are pregnant or if they might become pregnant (see CONTRAINDICATIONS). Instruct patients to discuss with their physician if they have demonstrated a hypersensitivity to mitomycin in the past (see CONTRAINDICATIONS). Nursing mothers should be advised that it is not known if Mitosol® is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue use of the drug, taking into account the importance of the drug to the mother. It is recommended that women receiving Mitosol® not breast feed because of the potential for serious adverse reactions in nursing infants (see Use in Specific Populations). Patients should be advised of the toxicity of Mitosol® and potential complications. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of Fertility Adequate long-term studies in animals to evaluate carcinogenic potential have not been conducted with Mitosol®. Intravenous administration of mitomycin has been found to be carcinogenic in rats and mice. At doses approximating the recommended clinical injectable dose in humans, mitomycin produces a greater than 100 percent increase in tumor incidence in male Sprague-Dawley rats, and a greater than 50 percent increase in tumor incidence in female Swiss mice. The effect of Mitosol® on fertility is unknown. Use In Specific Populations Pregnancy Teratogenic Effects: Pregnancy Category X (see CONTRAINDICATIONS). Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from Mitosol®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. It is recommended that women receiving Mitosol® not breast feed because of the potential for serious adverse reactions in nursing infants. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use No overall differences in safety and effectiveness have been observed between elderly and younger patients.