warnings and cautions
5 WARNINGS AND PRECAUTIONS • Hypersensitivity Reactions: More common with rapid intravenous infusion. Administer intramuscularly or by slow subcutaneous or intravenous infusion. ( 5.1 ) • Auditory and Ocular Toxicity: Have been reported when administered over prolonged periods of time, at high doses, or in patients with low ferritin levels. ( 5.2 ) • Renal Toxicity: Cases of acute renal failure, renal tubular disorders and increase in serum creatinine have occurred. Monitor patients for changes in renal function. ( 5.3 ) • Respiratory Toxicity: Acute respiratory distress syndrome has occurred. Risk increased with high intravenous doses. Recommended daily dose should not be exceeded. ( 5.4 ) • Growth Suppression: Has occurred in pediatric patients treated with high doses and concomitant low ferritin levels. Dose reduction may partially resume growth velocity to pre-treatment rates. ( 5.5 ) • Serious Infections: Cases of mucormycosis and Yersinia infections, some fatal, have occurred. Discontinue deferoxamine mesylate and initiate appropriate treatment immediately. ( 5.6 ) • Cardiac Dysfunction with Concomitant Use of Vitamin C: Avoid coadministration in patients with cardiac failure. Delay Vitamin C for one month after start of deferoxamine mesylate. Avoid exceeding 200 mg daily in adults. Monitor cardiac function with combined treatment. ( 5.7 ) • Risks of Deferoxamine Mesylate Treatment in Patients with Aluminum Overload: Risks include neurological dysfunction (including seizures), dialysis dementia, and aggravation of hyperparathyroidism. ( 5.8 ) • Effects on Ability to Drive and Use Machines: May cause dizziness. ( 5.9 ) • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use effective contraception. ( 5.10 , 8.1 , 8.3 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, have occurred in deferoxamine mesylate-treated patients. Reactions have included flushing of the skin, urticaria, hypotension, and shock. These reactions typically occur when deferoxamine mesylate was administered by rapid intravenous injection. Therefore, administer deferoxamine mesylate intramuscularly or by slow subcutaneous or intravenous infusion. 5.2 Auditory and Ocular Toxicity Ocular and auditory toxicities have been reported in deferoxamine mesylate-treated patients. The ocular toxicities observed have included blurring of vision; cataracts after prolonged administration in chronic iron overload; decreased visual acuity, including visual loss, visual defects, scotoma; impaired peripheral, color, and night vision; optic neuritis, cataracts, corneal opacities, and retinal pigmentary abnormalities. The auditory toxicities reported have been tinnitus and hearing loss, including high frequency sensorineural hearing loss. Risk factors for both ocular and auditory disturbances include prolonged treatment duration, higher doses, or low ferritin levels. In most cases, both ocular and auditory disturbances were reversible upon immediate cessation of treatment [see Adverse Reactions ( 6 )] . Visual acuity tests, slit-lamp examinations, funduscopy and audiometry are recommended periodically in patients treated for prolonged periods of time. Toxicity is more likely to be reversed if symptoms or test abnormalities are detected early. 5.3 Renal Toxicity Renal toxicity, including increases in serum creatinine (possibly dose-related), acute renal failure and renal tubular disorders has occurred in deferoxamine mesylate-treated patients. Deferoxamine mesylate is contraindicated in patients with severe renal disease [see Contraindications ( 4 )] . Monitor serum creatinine to assess for changes in renal function. 5.4 Respiratory Toxicity Acute respiratory distress syndrome has occurred in deferoxamine mesylate-treated patients following treatment with excessively high intravenous doses of deferoxamine mesylate in patients with acute iron intoxication or thalassemia. The recommended daily doses should therefore not be exceeded. 5.5 Growth Suppression High doses of deferoxamine mesylate and concomitant low ferritin levels have also been associated with growth suppression in pediatric patients. After reduction of deferoxamine mesylate dose, growth velocity may partially resume to pre-treatment rates. Monitor growth (weight and height) in pediatric patients treated with deferoxamine mesylate every 3 months. 5.6 Serious Infections Yersinia Infections Deferoxamine mesylate may increase the risk of Yersinia enterocolitica and Yersinia pseudotuberculosis infections. Avoid starting deferoxamine mesylate treatment in patients with active Yersinia infections. Should Yersinia infection develop, interrupt deferoxamine mesylate treatment until the infection is resolved. Mucormycosis Cases of mucormycosis, some with a fatal outcome, have occurred in deferoxamine mesylate-treated patients. Signs or symptoms are specific to the site of infection. If mucormycosis is suspected, discontinue deferoxamine mesylate, conduct mycological testing, and treat immediately. 5.7 Cardiac Dysfunction with Concomitant Use of Vitamin C Cardiac dysfunction has occurred in deferoxamine mesylate-treated patients with severe chronic iron overload following concomitant treatment with high doses of vitamin C (more than 500 mg daily in adults). The cardiac dysfunction was reversible when vitamin C was discontinued. The following precautions should be taken when vitamin C and deferoxamine mesylate are to be used concomitantly: • Vitamin C supplements should not be given to patients with cardiac failure. • Start supplemental vitamin C only after an initial month of regular treatment with deferoxamine mesylate. • Give vitamin C only if the patient is receiving deferoxamine mesylate regularly, ideally soon after setting up the infusion pump. • Do not exceed a daily vitamin C dose of 200 mg in adults, given in divided doses. In general, 50 mg daily suffices for pediatric patients under 10 years old and 100 mg for older pediatric patients. • Clinical monitoring of cardiac function is advisable during such combined therapy. 5.8 Risks of Deferoxamine Mesylate Treatment in Patients with Aluminum Overload Deferoxamine mesylate may cause neurological dysfunction (including seizures) in patients with aluminum-related encephalopathy and receiving dialysis, possibly due to an acute increase in circulating aluminum [see Adverse Reactions ( 6 )] . Deferoxamine mesylate may precipitate the onset of dialysis dementia. Treatment with deferoxamine mesylate in the presence of aluminum overload may result in decreased serum calcium and aggravation of hyperparathyroidism. 5.9 Effects on Ability to Drive and Use Machines Deferoxamine mesylate may cause dizziness, which may impair the ability to drive a car or operate machinery. Patients should not drive or operate machinery until they know how deferoxamine mesylate will affect their ability to engage in these activities. 5.10 Embryo-Fetal Toxicity Based on findings in animals, deferoxamine mesylate can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of deferoxamine to pregnant mice and rabbits during the period of organogenesis caused adverse developmental outcomes including decreased fetal body weights and malformations at maternal doses less than those in patients at maximum recommended human dose (MRHD). Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with deferoxamine mesylate and for one month after the last dose [see Use in Specific Populations ( 8.1 , 8.3 ), Nonclinical Toxicology ( 13.1 )] .