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.

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.

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)].

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)].

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.

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

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.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

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

8.5 Geriatric Use

In Trial 1, of the total number of CUVRIOR-treated patients, 1 (4%) was 65 years of age and older [see Clinical Studies (14)]. Clinical studies with trientine did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger adult patients. Other reported clinical experience with trientine is insufficient to determine differences in responses between geriatric and younger adult patients. In general, dose selection should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

12.1 Mechanism of Action

Trientine, a copper chelator, eliminates absorbed copper from the body by forming a stable complex that is then eliminated through urinary excretion. Trientine also chelates copper in the intestinal tract, reducing copper absorption.

12.2 Pharmacodynamics

In Trial 1, serum non-ceruloplasmin copper (NCC) and 24-hour urinary copper excretion (UCE) were measured in adult patients with Wilson's disease who were de-coppered and tolerating penicillamine and who had switched to CUVRIOR. In patients who had switched to CUVRIOR, mean UCE decreased over time (see Table 4). On the other hand, the mean serum NCC in patients who had switched to CUVRIOR was comparable to the mean serum NCC in patients who remained on penicillamine [see Clinical Studies (14)].

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

Severe pulmonary toxicity occurred in a 26-week oral toxicity study of trientine dihydrochloride in rats. However, the relevance of this finding to safety risk in patients with Wilson's disease is unknown. Deaths related to pulmonary injury occurred in male rats at 175 and 600 mg/kg/day (1/12 and 3/20 males, respectively). Pulmonary lesions were observed in male rats at 50 mg/kg/day (lower than the maximum recommended dose [1,500 mg/day trientine free base equivalent] based on body surface area). In female rats, pulmonary lesions occurred at 175 mg/kg/day (lower than the maximum recommended dose based on body surface area). Pulmonary toxicity was dose-dependent in both sexes. The lesions included alveolar fibrosis, bronchiolar hyperplasia/ epithelialization of alveolar wall, focal chronic interstitial pneumonitis, bronchiolar epithelium hypertrophy, alveolar hemorrhage (males only), necrosis/regenerative hyperplasia of terminal bronchioles (males only), and acute interstitial pneumonitis (males only). Most of the pulmonary lesions remained after a 13-week recovery period, and were considered as irreversible (e.g., alveolar fibrosis, bronchiolar hyperplasia/epithelialization of alveolar wall, focal chronic interstitial pneumonitis). Pulmonary toxicity also occurred in a 13-week oral study of trientine dihydrochloride in mice. The effects included interstitial inflammation and alveolar histiocytic infiltration, observed at a dose approximately equal to the maximum recommended dose based on body surface area. The mechanism of pulmonary toxicity was not clearly established as due to copper depletion (primary pharmacology) or due to other drug activity.

Neurological and/or musculoskeletal clinical signs (abnormal "stiff-legged" gait, limited use of limb, underactivity, body tremors) occurred in a 26-week oral toxicity study of trientine dihydrochloride in dogs at 5.5 times the estimated human exposure at the maximum recommended dose (based on AUC). The mechanism for these clinical signs was not clearly established as due to copper depletion (primary pharmacology) or due to other drug activity. Because of the severity of the clinical signs at exposures above 5.5 times the maximum exposure in humans, some dogs were sacrificed for humane reasons after 9 weeks of treatment, and treatment for the remaining animals in the same dose group was stopped after 10 weeks. Neurological and/or musculoskeletal clinical signs were generally not observed at exposures that were 3.4 times the human exposure at the maximum recommended dose.

Store at a controlled room temperature of 20°C to 25°C (68°F to 77°F); excursions between 15°C and 30°C (59°F and 86°F) are permitted [see USP Controlled Room Temperature].

Administration Instructions

Advise patients or their caretaker(s) to [see Dosage and Administration (2.2)]:

• Take CUVRIOR on an empty stomach (at least 1 hour before meals or 2 hours after meals and at least 1 hour apart from 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)]:
  • Advise patients taking an iron supplement to take CUVRIOR at least 2 hours before or 2 hours after taking an iron supplement.
  • Advise patients taking other mineral supplements to take CUVRIOR at least 1 hour before or 2 hours after taking other mineral supplements.
• Take CUVRIOR at least 1 hour apart from any other oral drug.
• Remove CUVRIOR tablets from the blister pack only at the time of dosing.
• Swallow tablets of CUVRIOR without crushing, chewing, or dissolving tablets. Advise patients that if they have difficulty swallowing the tablet whole, the scored tablet can be divided into two equal halves. Advise patients not to store the tablet for future use after the blister has been opened.

Laboratory Monitoring

Advise patients that copper level monitoring is required periodically during CUVRIOR therapy [see Dosage and Administration (2.4) and Warnings and Precautions (5.1, 5.2)].

Potential for Worsening of Clinical Symptoms at Initiation of Therapy

Advise patients or their caretaker(s) to notify their healthcare provider if they experience worsening of clinical symptoms, including neurological deterioration [see Warnings and Precautions (5.1)].

Copper or Iron Deficiency

Advise patients or their caretaker(s) to notify their healthcare provider if they experience any signs or symptoms of copper or iron deficiency [see Warnings and Precautions (5.2, 5.3)].

Hypersensitivity Reactions

Advise patients or their caretaker(s) to notify their healthcare provider if they develop a rash or other hypersensitivity reaction while taking CUVRIOR [see Warnings and Precautions (5.4)].