美国FDA对其Mitosol的最终批准决定；MITOSOL（丝裂霉素），MOBIUS THERAPEUTICS产品，新批准剂型为外用溶液，用于青光眼手术。MITOSOL能准确提供丝裂霉素C剂量，帮助青光眼手术顺利进行。丝裂霉素以前剂型均为注射剂。这将为青光眼手术治疗增加便利性、安全性和恒定性。　 青光眼在美国为导致失明的第二大原因。Mitosol采用一种新的给药系统即：外用溶液，递送精确剂量的活性成分丝裂霉素C（mitomycin-c），眼科医师在使用过程中无需改变他们目前的手术技术。 【商品名】Mitosol 【英文通用名】Mitomycin-c 【中文通用名】丝裂霉素C （别名：自力霉素、丝裂霉素、丝裂霉素协和MMC） 【化学性质】蓝紫色有光泽的结晶。360℃以上分解。溶于水、甲醇、丙醇、乙酸丁酯和环已酮，微溶于苯、四氯化碳和醚，几乎不溶于石油醚。其水溶液对酸、碱均不稳定。　　　 【适应证】用于青光眼手术中，特别是难治性青光眼患者。 MITOSOL (mitomycin) kit [Mobius Therapeutics LLC] HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Mitosol® (mitomycin for solution) safely and effectively. See full prescribing information for Mitosol® (mitomycin for solution). Mitosol® (mitomycin for solution) Initial U.S. Approval: 1974   INDICATIONS AND USAGE Mitosol® is an antimetabolite indicated as an adjunct to ab externo glaucoma surgery. (1)   DOSAGE AND ADMINISTRATION Mitosol® is intended for topical application to the surgical site of glaucoma filtration surgery. It is not intended for intraocular administration. (2) 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 has dissolved into solution. (2.1) Fully saturate sponges provided within the Mitosol® Kit utilizing the entire reconstituted contents of the vial in the manner prescribed in the Instructions for Use. (2.2) 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. (2.2)   DOSAGE FORMS AND STRENGTHS Each vial contains a sterile lyophilized mixture of 0.2 mg mitomycin and 0.4 mg mannitol; when reconstituted with Sterile Water for Injection, the solution contains 0.2 mg/mL mitomycin. (3)   CONTRAINDICATIONS Hypersensitivity to mitomycin. (4.1) Women who are or may become pregnant during therapy. (4.2)   WARNINGS AND 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. (5.1) Hypotony. The use of mitomycin has been associated with an increased instance of post-operative hypotony. (5.2) Cataract Development. Use in phakic patients has been correlated to a higher instance of lenticular change and cataract formation. (5.3)   ADVERSE REACTIONS The most frequent adverse reactions to Mitosol® occur locally and include hypotony, hypotony maculopathy, blebitis, endophthalmitis, vascular reactions, corneal reactions, and cataract. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mobius Therapeutics LLC at 1-877-393-6486 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling  Revised: 02/2012 FULL PRESCRIBING INFORMATION 1. INDICATIONS AND USAGE Mitosol® is an antimetabolite indicated for use as an adjunct to ab externo glaucoma surgery. 2. 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. 2.1 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. 2.2 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. 2.3 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. 3. 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. CONTRAINDICATIONS 4.1 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. 5. WARNINGS AND PRECAUTIONS 5.1 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. 5.2 Hypotony The use of mitomycin has been associated with an increased instance of post-operative hypotony. 5.3 Cataract Formation Use in phakic patients has been correlated to a higher instance of lenticular change and cataract formation. 6 ADVERSE REACTIONS 6.1 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. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category X (see Contraindications, 4.2). 8.3 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. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use No overall differences in safety and effectiveness have been observed between elderly and younger patients. 11. 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 C15H18N405 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. 12. CLINICAL PHARMACOLOGY 12.1 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. 12.3 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. 13. NONCLINICAL TOXICOLOGY 13.1 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. 14. 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 12. 16. HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 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 mLTB 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 (NDC49771-002-03). 16.2 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. 17. PATIENT COUNSELING INFORMATION Instruct patients to discuss with their physician if they are pregnant or if they might become pregnant (see Contraindications, 4.2). Instruct patients to discuss with their physician if they have demonstrated a hypersensitivity to mitomycin in the past (see Contraindications, 4.1). 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, 8.3). Patients should be advised of the toxicity of Mitosol® and potential complications. Manufactured for: Mobius Therapeutics, LLC 4041 Forest Park Avenue St. Louis, MO 63108 Mitosol® (mitomycin for solution) 0.2 mg/vial