CUVRIOR

1 INDICATIONS AND USAGE CUVRIOR is indicated for the treatment of adult patients with stable Wilson's disease who are de-coppered and tolerant to penicillamine. CUVRIOR is a copper chelator indicated for the treatment of adult patients with stable Wilson's disease who are de-coppered and tolerant to penicillamine. ( 1 )

2 DOSAGE AND ADMINISTRATION Recommended Dosage and Administration Starting total daily dosage of CUVRIOR in adults is 300 mg up to 3,000 mg orally in divided doses (2 times daily). See full prescribing information for recommended conversion table when switching from penicillamine to CUVRIOR. ( 2.1 ) Total daily dosage of CUVRIOR should not exceed 3,000 mg. ( 2.1 ) If the number of CUVRIOR tablets prescribed per day cannot be equally divided among doses, then divide total daily dosage such that the higher number of tablets is taken with the first daily dose. ( 2.1 ) Take CUVRIOR on an empty stomach. ( 2.2 ) Swallow tablets without crushing, chewing, or dissolving tablets. ( 2.2 ) Switching from Other Trientine Products CUVRIOR is not substitutable on a milligram-per-milligram basis with other trientine products. ( 2.3 ) See full prescribing information for additional information on switching from other trientine products. ( 2.3 ) Clinical Monitoring and Laboratory Monitoring of Copper Adjust CUVRIOR dosage according to clinical assessment and laboratory monitoring of copper. ( 2.4 ) See full prescribing information for monitoring recommendations. ( 2.4 ) 2.1 Recommended Dosage and Administration The recommended starting total daily dosage of CUVRIOR in adult patients is 300 mg up to 3,000 mg taken orally in divided doses (two times daily). Table 1 provides the recommended starting total daily dosage of CUVRIOR in adult patients switching from penicillamine to CUVRIOR [see Clinical Studies (14) ] . Discontinue penicillamine before starting CUVRIOR. Table 1: Recommended Starting Total Daily Dosage of CUVRIOR when Switching from Penicillamine to CUVRIOR Penicillamine Total Daily Dosage CUVRIOR Starting Total Daily Dosage 125 mg 300 mg 250 mg 600 mg 375 mg 900 mg 500 mg 900 mg 625 mg 1,200 mg 750 mg 1,500 mg 875 mg 1,800 mg 1,000 mg 2,100 mg 1,125 mg 2,400 mg 1,250 mg 2,400 mg 1,375 mg 2,700 mg 1,500 mg or greater 3,000 mg Adjust the total daily dosage of CUVRIOR according to clinical assessment and laboratory monitoring of copper [see Dosage and Administration (2.4) ] . The total daily dosage of CUVRIOR should not exceed 3,000 mg. If the number of CUVRIOR tablets prescribed per day cannot be equally divided among doses, then divide the total daily dosage such that the higher number of tablets is administered with the first daily dose. Table 2 provides the recommended approach to administration of CUVRIOR tablets to achieve the total daily dosage. Table 2: Recommended Administration Schedule of CUVRIOR Tablets to Achieve Total Daily Dosage CUVRIOR Number of CUVRIOR Tablets to Administer Total Daily Dosage Morning Evening 300 mg 1 0 600 mg 1 1 900 mg 2 1 1,200 mg 2 2 1,500 mg 3 2 1,800 mg 3 3 2,100 mg 4 3 2,400 mg 4 4 2,700 mg 5 4 3,000 mg 5 5 2.2 Important Administration Instructions Discontinue penicillamine before starting CUVRIOR [see Dosage and Administration (2.1) ] . Administer CUVRIOR on an empty stomach, at least 1 hour before meals or 2 hours after meals and at least 1 hour apart from any other food or milk. Avoid concomitant use of mineral supplements (e.g. iron, zinc, calcium, magnesium). If concomitant use of mineral supplements is unavoidable [see Drug Interactions (7.1) ] : Iron supplements: Administer CUVRIOR at least 2 hours before or 2 hours after administration of an iron supplement . Other mineral supplements: Administer CUVRIOR at least 1 hour before or 2 hours after administration of other mineral supplements. Administer CUVRIOR at least 1 hour apart from any other oral drug. Do not remove tablets from the blister pack until just before dosing. Swallow tablets of CUVRIOR without crushing, chewing, or dissolving tablets. For patients who have difficulty swallowing the tablet whole, the scored tablet can be divided into two equal halves. Do not store the tablet for future use after the blister has been opened. Avoid the use of CUVRIOR in patients who are unable to swallow tablets . 2.3 Switching to CUVRIOR from Other Trientine Products CUVRIOR is not substitutable on a milligram-per-milligram basis with other trientine products. If switching a patient from a trientine hydrochloride formulation to CUVRIOR, note that the content of the active moiety (trientine base) is not the same as CUVRIOR. A 250 mg capsule of trientine hydrochloride contains 167 mg of trientine base; in contrast, each 300 mg tablet of CUVRIOR contains 150 mg of trientine base [see Clinical Pharmacology (12.3) ] . 2.4 Clinical Monitoring and Laboratory Monitoring of Copper Adjust the total daily dosage of CUVRIOR according to clinical assessment and serum non-ceruloplasmin copper (NCC) levels. Evaluate serum NCC levels when initiating CUVRIOR treatment, after 3 months of treatment and approximately every 6 months thereafter. Therapy may also be monitored periodically (every 6 to 12 months) with measurement of 24-hour urinary copper excretion (UCE) [see Warnings and Precautions (5.1 , 5.2) ].

4 CONTRAINDICATIONS CUVRIOR is contraindicated in patients with hypersensitivity to trientine or to any of the excipients in CUVRIOR [see Warnings and Precautions (5.4) ] . Hypersensitivity to trientine or to any of the excipients in CUVRIOR. ( 4 )

5 WARNINGS AND PRECAUTIONS Potential for Worsening of Clinical Symptoms at Initiation of Therapy : May include neurological deterioration. Adjust dosage or discontinue CUVRIOR if clinical condition worsens. ( 5.1 ) Copper Deficiency : Periodic monitoring is required. ( 5.2 ) Iron Deficiency : If iron deficiency develops, a short course of iron supplementation may be given. ( 5.3 , 7.1 ) Hypersensitivity Reactions : If rash or other hypersensitivity reaction occurs, consider discontinuing CUVRIOR. ( 5.4 ) 5.1 Potential for Worsening of Clinical Symptoms at Initiation of Therapy Worsening of clinical symptoms, including neurological deterioration, may occur at the beginning of CUVRIOR therapy due to mobilization of excess stores of copper. Adjust the dosage or discontinue CUVRIOR if the patient's clinical condition worsens. Evaluate serum non-ceruloplasmin copper (NCC) levels when initiating CUVRIOR treatment, after 3 months of treatment and approximately every 6 months thereafter . Therapy may also be monitored periodically (every 6 to 12 months) with measurement of 24-hour urinary copper excretion (UCE) [see Dosage and Administration (2.4) ]. 5.2 Copper Deficiency Copper deficiency may develop following treatment with CUVRIOR. Close monitoring for manifestations of copper deficiency is required particularly when copper requirements may change, such as in pregnancy, where appropriate control of copper levels are required to ensure proper growth and mental development [see Dosage and Administration (2.4) and Use in Specific Populations (8.1) ] . 5.3 Iron Deficiency Iron deficiency may develop following treatment with CUVRIOR, especially in menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. If necessary, iron may be given in short courses, but at least two hours should elapse between administration of CUVRIOR and iron [see Drug Interactions (7.1) and Use in Specific Populations (8.1) ]. 5.4 Hypersensitivity Reactions Hypersensitivity reactions, characterized by rash, have been reported with the use of trientine. In Trial 1, rash was reported in 12% (3/26) of CUVRIOR-treated patients, and one of these patients discontinued CUVRIOR because of the rash [see Adverse Reactions (6.1) ]. If a patient develops a rash or other hypersensitivity reaction during treatment with CUVRIOR, assess clinically and consider discontinuing CUVRIOR [see Contraindications (4) ] .

7 DRUG INTERACTIONS Mineral Supplements (e.g. iron, zinc, calcium, magnesium): Avoid concomitant use. If concomitant use is unavoidable ( 2.2 , 7.1 ): Iron : Take CUVRIOR at least 2 hours before or 2 hours after iron. Other Mineral Supplements : Take CUVRIOR at least 1 hour before or 2 hours after other mineral supplements. Other Drugs for Oral Administration : Take CUVRIOR at least 1 hour apart from any other oral drug. ( 2.2 , 7.1 ) 7.1 Mineral Supplements and Other Oral Drugs CUVRIOR has the potential to chelate non-copper cations in mineral supplements and other oral drugs, and could be rendered ineffective prior to systemic absorption. Mineral Supplements Avoid concomitant use of mineral supplements such as iron, zinc, calcium, or magnesium with CUVRIOR because they may reduce the absorption of CUVRIOR. However, if iron deficiency develops [see Warnings and Precautions (5.3) ], iron supplementation may be given in short courses, but because iron and CUVRIOR each inhibit absorption of the other, administer CUVRIOR at least 2 hours before or 2 hours after administration of an iron supplement [see Dosage and Administration (2.2) ]. If concomitant use of other mineral supplements is unavoidable, administer CUVRIOR at least 1 hour before or 2 hours after administration of other mineral supplements. Other Drugs for Oral Administration Administer CUVRIOR at least 1 hour apart from any other oral drug.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Potential for Worsening of Clinical Symptoms at Initiation of Therapy [see Warnings and Precautions (5.1) ] Copper Deficiency [see Warnings and Precautions (5.2) ] Iron Deficiency [see Warnings and Precautions (5.3) ] Hypersensitivity Reactions [see Warnings and Precautions (5.4) ] Most common adverse reactions (>5%) are abdominal pain, change of bowel habits, rash, alopecia, and mood swings. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Orphalan at 1-800-961-8320 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials 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. Common Adverse Reactions Table 3 presents common adverse reactions over a 24-week period from Trial 1, a prospective, randomized, multi-center study that was conducted in adult patients with Wilson's disease who were de-coppered and tolerant to penicillamine [see Clinical Studies (14) ] . Patients were either switched to receive CUVRIOR (N=26) or continued to receive penicillamine (N=27). Table 3: Common Adverse Reactions Adverse reactions that occurred in >5% of CUVRIOR-treated patients and greater than in patients who continued to receive penicillamine. from a Clinical Study of CUVRIOR in Adult Patients with Wilson's Disease (Trial 1) Adverse Reaction CUVRIOR (N=26) n (%) Penicillamine (N=27) n (%) Abdominal pain Abdominal pain is composed of several similar terms 5 (19%) 1 (4%) Change of bowel habits Includes constipation, abnormal feces, soft feces 4 (15%) 0 Rash Rash is composed of several similar terms 3 (12%) 0 Alopecia 2 (8%) 1 (4%) Mood swings 2 (8%) 0 Other Adverse Reactions In Trial 1, anemia developed in 4% (1/26) of CUVRIOR-treated patients and in no patients who continued to receive penicillamine. In addition, the following adverse reactions have been reported in clinical studies of patients with Wilson's disease who were on therapy with trientine hydrochloride: Metabolism and Nutrition Disorders : Iron deficiency Musculoskeletal and Connective Tissue Disorders : Systemic lupus erythematosus 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of trientine hydrochloride. Because these reactions are 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: Gastrointestinal Disorders : Colitis Musculoskeletal and Connective Tissue Disorders : Muscle spasms, Rhabdomyolysis Nervous System Disorders: Dystonia, Myasthenia gravis

8.1 Pregnancy Risk Summary Available data from published literature and postmarketing experience over several decades with use of trientine for the treatment of Wilson's disease have not identified any drug-associated risks for major birth defects, miscarriages, or other adverse maternal or fetal outcomes. Untreated Wilson's disease may result in worsening disease symptoms during pregnancy and increase the risk of miscarriages in some symptomatic patients (see Clinical Considerations ) . In animal reproduction studies, oral administration of trientine in rats during organogenesis resulted in increased embryo-fetal loss at a dose lower than the maximum recommended dose and produced fetal abnormalities at 2.7 times the maximum recommended dose. Copper supplementation in pregnant rats produced a marked reduction in trientine-induced fetal abnormalities. Oral administration of trientine dihydrochloride to pregnant mice during organogenesis increased the percentage of mice with total embryo-fetal loss at approximately 4.3 times the maximum recommended dose and produced fetal abnormalities at approximately 1.1 times the maximum recommended dose. The mechanism of embryo-fetal harm (e.g., copper depletion) was not determined in the mouse study [see Warnings and Precautions (5.2) and Data ]. Monitor copper levels throughout pregnancy and use the minimum effective dosage of CUVRIOR throughout pregnancy. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Untreated Wilson's disease or discontinuation of treatment during pregnancy may result in worsening neurological and hepatic symptoms, including rare reports of hepatic decompensation and liver failure. Untreated Wilson's disease may also increase the risk of miscarriage in some symptomatic patients. Increased copper deposition in the placenta and fetal liver may adversely impact the fetus. Maternal Adverse Reactions Trientine may chelate non-copper cations (e.g., iron, calcium). Maintain appropriate levels during pregnancy [see Dosage and Administration (2.2) , Warnings and Precautions (5.2 , 5.3) , and Drug Interactions (7.1) ] . Fetal/Neonatal Adverse Reactions Chelator-induced copper deficiency may have adverse effects on the fetus. Data Animal Data In embryo-fetal development studies in rats, trientine was administered orally at doses up to approximately 835 mg/kg/day during organogenesis. An increased incidence of resorptions was observed at a dose lower than the maximum recommended dose (1,500 mg/day trientine free base equivalent), based on body surface area. An increased incidence of fetal abnormalities, including hemorrhage and edema, was observed at 2.7 times the maximum recommended dose, based on body surface area. When pregnant rats were treated with trientine and supplemented with copper (concentration of 50 mcg/g in the diet), fetal abnormalities were markedly reduced, indicating that the mechanism of embryo-fetal harm in rats with no copper supplementation was based on copper depletion (primary pharmacology of trientine). In embryo-fetal development studies in mice, trientine dihydrochloride was administered orally at doses up to approximately 2,000 mg/kg/day during organogenesis. A dose-dependent increase in the incidence of abnormal fetuses occurred at all doses. Fetal abnormalities included hemorrhages and delayed ossification which were observed starting at 500 mg/kg/day, microcephaly and hydrocephaly starting at 1,000 mg/kg/day, and exencephaly at 2,000 mg/kg/day (the doses were 1.1, 2.1, and 4.3 times the maximum recommended dose, respectively, based on body surface area). The percentage of dams with total resorption was increased at 2,000 mg/kg/day (5.3 times the maximum recommended dose based on body surface area). The mechanism of embryo-fetal harm (e.g. copper depletion) was not determined in this study.