FDA label 2bb6e8f9-de72-43bf-ad13-7dfdcb4eff60

5 WARNINGS AND PRECAUTIONS Secondary Malignancy or Leukemia: Increased risk of secondary malignancies following treatment. ( 5.1 ) Veno-occlusive Disease: Can cause severe or fatal VOD. Monitor for elevations in AST, ALT, total bilirubin, hepatomegaly, weight gain, or ascites. Consider delaying next dose. ( 5.2 ) Extravasation: Immediately interrupt the injection or infusion and apply ice. ( 2.7 , 5.3 ) Myelosuppression: Monitor blood cell counts before each cycle. Delay next dose if severe myelosuppression has not improved. ( 5.4 ) Immunizations: Vaccination with live viral vaccines is not recommended before or during treatment. ( 5.5 ) Severe Mucocutaneous Reactions: Discontinue treatment ( 5.6 ) Renal Toxicity: Monitor creatinine and electrolytes frequently. ( 5.7 ) Hepatotoxicity: Monitor transaminases, alkaline phosphatase and bilirubin prior to and during treatment. ( 5.8 ) Potentiation of Radiation Toxicity and Radiation Recall: Reduce dose by 50% during concomitant radiation. Use caution when administering within two months of radiation. ( 5.9 ) Embryo-fetal Toxicity: Can cause fetal harm. Advise patients of the potential risk to a fetus and to use effective contraception. ( 5.10 , 8.1 , 8.3 ) 5.1 Secondary Malignancy or Leukemia The risk of developing secondary malignancies, including leukemia, is increased following treatment with COSMEGEN. 5.2 Veno-occlusive Disease Severe and fatal hepatic veno-occlusive disease (VOD) can occur with COSMEGEN. Risk factors for the development of VOD include age younger than 4 years or concomitant radiotherapy. After treatment with COSMEGEN, monitor frequently for signs and symptoms of VOD; these include elevations in AST, ALT, total bilirubin, hepatomegaly, weight gain, or ascites. If patients develop VOD, considering delaying next dose of COSMEGEN. Resume, reduce dose or permanently discontinue based on severity of reaction and disease being treated. 5.3 Extravasation Extravasation of COSMEGEN can result in severe local tissue injury manifesting as blistering, ulcerations and persistent pain requiring wide excision surgery followed by split-thickness skin grafting. If any signs or symptoms of extravasation occur, immediately interrupt the injection or infusion. Apply ice to the site intermittently for 15 minutes, 4 times a day for 3 days [see Dosage and Administration ( 2.7 )] . Observe closely and consult plastic surgery if necessary based on severity of reaction. 5.4 Myelosuppression Severe and fatal myelosuppression, which may include neutropenia, thrombocytopenia and anemia, can occur with COSMEGEN. The nadir in neutrophil counts generally occurs 14 to 21 days after administration. Obtain complete blood counts prior to each treatment cycle. Delay next dose of COSMEGEN if severe myelosuppression has not improved. Consider dose reduction for patients with prolonged myelosuppression based on severity of reaction and disease being treated. 5.5 Immunizations The safety with live viral vaccines following COSMEGEN has not been studied and vaccination with live virus vaccines is not recommended before or during treatment. 5.6 Severe Mucocutaneous Reactions Severe mucocutaneous reactions, such as Steven-Johnson syndrome and Toxic Epidermal Necrolysis (TEN), can occur with COSMEGEN. Permanently discontinue COSMEGEN in patients who experience a severe mucocutaneous reaction. 5.7 Renal Toxicity Abnormalities of renal function can occur with COSMEGEN. Monitor creatinine and electrolytes frequently during COSMEGEN therapy. 5.8 Hepatotoxicity Hepatotoxicity can occur with COSMEGEN. Monitor AST, ALT, alkaline phosphatase, and bilirubin prior to and during COSMEGEN therapy. 5.9 Potentiation of Radiation Toxicity and Radiation Recall COSMEGEN can increase radiation-induced gastrointestinal toxicity, myelosuppression, or erythema and vesiculation of the skin or buccal and pharyngeal mucosa. Reduce the dose of COSMEGEN by 50% during concomitant radiation. Radiation recall, affecting previously treated radiation fields, can occur in patients who receive COSMEGEN after prior radiation therapy. Although the risk can occur with distant radiation exposure, the risk appears highest when COSMEGEN is administered within two months of prior radiation. 5.10 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, COSMEGEN can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of dactinomycin to pregnant animals during the period of organogenesis was teratogenic, resulting in malformations at doses lower than the recommended human dose. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with COSMEGEN and for at least 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with COSMEGEN and for 3 months after the final dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: Secondary Malignancy and Leukemia [see Warnings and Precautions ( 5.1 )] Veno-occlusive Disease [see Warnings and Precautions ( 5.2 )] Extravasation [see Warnings and Precautions ( 5.3 )] Myelosuppression [see Warnings and Precautions ( 5.4 )] Immunizations [see Warning and Precautions ( 5.5 )] Severe Mucocutaneous Reactions [see Warnings and Precautions ( 5.6 )] Renal Toxicity [see Warnings and Precautions ( 5.7 )] Hepatotoxicity [see Warnings and Precautions ( 5.8 )] Potentiation of Radiation Toxicity and Radiation Recall [see Warnings and Precautions ( 5.9 )] Common adverse reactions are: infection, alopecia, rash, dysphagia, fatigue, fever, nausea, vomiting, anemia, neutropenia, thrombocytopenia, mucositis, and hepatotoxicity. The following adverse reactions have been identified in clinical studies or postmarketing reports. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Infections: infections including sepsis with fatal outcome Hematologic : anemia, leukopenia, thrombocytopenia, pancytopenia, reticulocytopenia, neutropenia, febrile neutropenia, disseminated intravascular coagulation Immune system: hypersensitivity Metabolism and nutrition: anorexia, hypocalcemia, tumor lysis syndrome Nervous system: peripheral neuropathy Ocular: optic neuropathy Vascular: thrombophlebitis, hemorrhage Respiratory, thoracic and mediastinal: pneumonitis, pneumothorax Gastrointestinal: nausea, vomiting, abdominal pain, diarrhea, constipation, gastrointestinal ulceration, cheilitis, dysphagia, esophagitis, ulcerative stomatitis, ascites, proctitis, mucositis Hepatobiliary: liver function test abnormalities, hepatomegaly, hepatitis, hepatic failure with reports of death, hepatic veno-occlusive disease Dermatologic: alopecia, rash, dermatitis, acne, erythema multiforme, Stevens Johnson Syndrome, radiation recall, toxic epidermal necrolysis Musculoskeletal and connective tissue: myalgia, growth retardation Renal and urinary: renal impairment, renal failure General: fatigue, fever, malaise Common adverse reactions are: infection, alopecia, rash, dysphagia, fatigue, fever, nausea, vomiting, anemia, neutropenia, thrombocytopenia, mucositis, and hepatotoxicity ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases at 1-800-575-8374 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.