Cuvrior Drug Information

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.

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 . 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

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

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, 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. 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.

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. 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 . 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.

Pediatric Use The safety and effectiveness of CUVRIOR in pediatric patients have not been established.

is contraindicated in patients with hypersensitivity to trientine or to any of the excipients in CUVRIOR . Hypersensitivity to trientine or to any of the excipients in CUVRIOR.

Occasional cases of trientine overdose have been reported. A large overdose of 60 g of trientine hydrochloride (equivalent to 80 g CUVRIOR) resulted in nausea, vomiting, dizziness, mild acute kidney injury, mild hypophosphatemia, low serum zinc, and low serum copper. The patient recovered following intravenous hydration and supportive measures.

There is no antidote for trientine acute overdose. Chronic use of trientine hydrochloride at dosages above the maximum recommended dosage has resulted in sideroblastic anemia.