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  • CLASSES

    Chelating Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Oral copper chelating agent
    Indicated for the treatment of Wilson's disease; capsules indicated for use in patients who have intolerance to penicillamine and tablets indicated for use in patients with stable disease who are de-coppered and tolerant to penicillamine
    Trientine tetrahydrochloride tablets are not substitutable on a milligram-per-milligram basis with other trientine products

    COMMON BRAND NAMES

    CLOVIQUE, Syprine

    HOW SUPPLIED

    CLOVIQUE/Syprine/Trientine/Trientine Hydrochloride Oral Cap: 250mg

    DOSAGE & INDICATIONS

    For the treatment of Wilson's disease (hepatolenticular degeneration).
    In patients intolerant to penicillamine.
    Oral dosage (trientine hydrochloride capsules)
    Adults

    Initially, 750 to 1,250 mg/day PO given in 2 to 4 divided doses. May increase dosage (Max: 2,000 mg/day) if clinical response is inadequate or if free serum copper concentration is persistently above 20 mcg/dL. Determine the optimal long-term maintenance dosage at 6 to 12-month intervals.

    Adolescents

    Initially, 20 mg/kg/day (Max initial range: 750 to 1,250 mg/day) PO in 2 to 4 divided doses, rounded to the nearest 250-mg increment. May increase dosage (Max: 2,000 mg/day) if clinical response is inadequate or if free serum copper concentration is persistently above 20 mcg/dL. Determine the optimal long-term maintenance dosage at 6 to 12-month intervals.

    Children 6 to 12 years

    Initially, 20 mg/kg/day (Max initial range: 500 to 750 mg/day) PO in 2 to 3 divided doses, rounded to the nearest 250-mg increment. May increase dosage (Max: 1,500 mg/day) if clinical response is inadequate or if free serum copper concentration is persistently above 20 mcg/dL. Determine the optimal long-term maintenance dosage at 6 to 12-month intervals. Controlled studies of safety and effectiveness in pediatric patients have not been conducted; however, trientine hydrochloride has been used in clinically in children as young as 6 years of age without reports of adverse experiences.

    In patients who are de-coppered and tolerant to penicillamine.
    NOTE: Discontinue penicillamine before starting trientine tetrahydrochloride.
    Oral dosage (trientine tetrahydrochloride tablets)
    Adults

    Initial dosage ranges from 300 to 3,000 mg PO per day and is dependent on previous penicillamine total daily dosage: IF PENICILLAMINE TOTAL DAILY DOSAGE WAS 125 MG: initiate trientine at 300 mg/day PO divided twice daily; IF PENICILLAMINE TOTAL DAILY DOSAGE WAS 250 MG: initiate trientine at 600 mg/day PO divided twice daily; IF PENICILLAMINE TOTAL DAILY DOSAGE WAS 375 TO 500 MG: initiate trientine at 900 mg/day PO divided twice daily; IF PENICILLAMINE TOTAL DAILY DOSAGE WAS 625 MG: initiate trientine at 1,200 mg/day PO divided twice daily; IF PENICILLAMINE TOTAL DAILY DOSAGE WAS 750 MG: initiate trientine at 1,500 mg/day PO divided twice daily; IF PENICILLAMINE TOTAL DAILY DOSAGE WAS 875 MG: initiate trientine at 1,800 mg/day PO divided twice daily; IF PENICILLAMINE TOTAL DAILY DOSAGE WAS 1,000 MG: initiate trientine at 2,100 mg/day PO divided twice daily; IF PENICILLAMINE TOTAL DAILY DOSAGE WAS 1,125 TO 1,250 MG: initiate trientine at 2,400 mg/day PO divided twice daily; IF PENICILLAMINE TOTAL DAILY DOSAGE WAS 1,375 MG: initiate trientine at 2,700 mg/day PO divided twice daily; IF PENICILLAMINE TOTAL DAILY DOSAGE WAS 1,500 MG OR MORE: initiate trientine at 3,000 mg/day PO divided twice daily. If the number of trientine 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. Adjust the total daily dose of trientine according to clinical assessment and laboratory monitoring of copper. Maximum dose is 3,000 mg/day.

    MAXIMUM DOSAGE

    Adults

    2,000 mg/day PO for trientine hydrochloride capsules; 3,000 mg/day PO for trientine tetrahydrochloride tablets.

    Geriatric

    2,000 mg/day PO for trientine hydrochloride capsules; 3,000 mg/day PO for trientine tetrahydrochloride tablets.

    Adolescents

    2,000 mg/day PO for trientine hydrochloride capsules; safety and efficacy of oral trientine tetrahydrochloride tablets have not been established.

    Children

    6 to 12 years: 1,500 mg/day PO for oral trientine hydrochloride capsules; safety and efficacy of oral trientine tetrahydrochloride tablets have not been established.
    Less than 6 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    NOTE: Trientine tetrahydrochloride tablets are not substitutable on a milligram-per-milligram basis with other trientine products. If switching a patient from a trientine hydrochloride formulation to trientine tetrahydrochloride tablets, note that the content of the active moiety (trientine base) is not the same as trientine tablets. A 250 mg capsule of trientine hydrochloride contains 167 mg of trientine base; in contrast, each 300 mg tablet of trientine tetrahydrochloride contains 150 mg of trientine base.
    General Administration Information:
    Avoid the use of trientine in patients who are unable to swallow capsules or tablets.
    Administer 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.
    Administer at least 1 hour apart from any other oral drug.
    Avoid concomitant use of mineral supplements (e.g. iron, zinc, calcium, magnesium). If concomitant use of mineral supplements is unavoidable:
    Iron supplements: Administer trientine at least 2 hours before or 2 hours after administration of an iron supplement.
    Other mineral supplements: Administer trientine at least 1 hour before or 2 hours after administration of other mineral supplements.
     
    Capsules (trientine hydrochloride)
    Have the patient swallow the capsules whole with water. Do not cut, crush, chew, or break the capsules.
    Because of the potential for contact dermatitis, any site of exposure to the capsule contents should be promptly washed with water.
    The manufacturer recommends taking the patient's temperature every night for the first month of treatment. Fever or skin eruption may warrant trientine discontinuation.
     
    Tablets (trientine tetrahydrochloride)
    Have the patient swallow the tablets whole without crushing, chewing, or dissolving the tablets. For patients who have difficulty swallowing the tablet whole, the scored tablet can be divided into two equal halves.
    Do not remove tablets from the blister pack until just before dosing; do not store the tablet for future use after the blister has been opened.

    STORAGE

    CLOVIQUE:
    - Store at or below 77 degrees F
    - Store in original container
    Syprine:
    - Store at or below 77 degrees F
    - Store in original container

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    There are no reports of hypersensitivity in patients who have been administered trientine hydrochloride for Wilson's disease. However, there have been reports of asthma, bronchitis and dermatitis occurring after prolonged environmental exposure in workers who use trientine hydrochloride as a hardener of epoxy resins. Hypersensitivity reactions, characterized by rash, have been reported with the use of trientine tetrahydrochloride. Monitor treated patients for signs of possible hypersensitivity. If rash or other hypersensitivity reaction occurs, assess clinically and consider discontinuing trientine treatment.

    Neurologic events

    Worsening of clinical symptoms, including neurological deterioration, may occur at the beginning of trientine therapy in patients with Wilson'd disease due to mobilization of excess stores of copper. Adjust the dosage or discontinue trientine if the patient's clinical condition worsens or neurologic events or neurologic deterioration occur (e.g., new or worsening tremor, involuntary movements, difficulty swallowing, difficulty speaking and poor articulation, lack of coordination, spasticity, dystonic postures, and muscle rigidity). Evaluate serum non-ceruloplasmin copper (NCC) levels when initiating trientine 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).

    Hypocupremia

    Copper deficiency (hypocupremia) may develop following treatment. Close monitoring for manifestations of copper deficiency is required particularly when copper requirements may change. Follow recommendations for monitoring of copper status during therapy. 

    Iron-deficiency anemia

    Use trientine cautiously in patients with iron-deficiency anemia. Trientine may impair iron metabolism and transport. Iron deficiency may develop following treatment with trientine, especially in menstruating or pregnant women, or as a result of the low copper diet recommended for Wilson's disease. Monitor these patients closely. If necessary, iron may be given in short courses, but at least 2 hours should elapse between administration of trientine and iron.

    Biliary cirrhosis

    Trientine hydrochloride is not indicated for the treatment of biliary cirrhosis. Of 4 patients with primary biliary cirrhosis who took trientine hydrochloride 1,200 mg/day for 6 months, 2 developed gastrointestinal (GI) side effects, 1 developed GI side effects and a skin rash, and 1 developed acute rhabdomyolysis within 48 hours of receiving the first trientine dose. Due to the side effects, trientine was discontinued in all 4 patients. Although the data are only from 4 patients, all 4 had adverse reactions. The rate of adverse events appears to be higher than the rate observed in patients who received trientine for Wilson's disease.

    Pregnancy

    Use trientine during pregnancy only if the potential benefit justifies the potential risk to the fetus. Guidelines recommend trientine treatment continuation during pregnancy; use the minimum effective dosage. Monitor copper concentrations closely during pregnancy as appropriate control of copper concentrations is important for the proper growth and mental development of the fetus. Trientine may also chelate non-copper cations (e.g., iron, calcium); maintain appropriate concentrations during pregnancy.  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, and in some cases has resulted in fulminant hepatic failure.  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 (MRD) and produced fetal abnormalities at 2.7 times the MRD. 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 embryofetal loss at approximately 4.3 times the MRD and produced fetal abnormalities at approximately 1.1 times the MRD. The mechanism of embryo-fetal harm (e.g., copper depletion) was not determined in the mouse study.

    Breast-feeding

    Excretion of trientine into breast milk is not known. Available published literature have not reported drug-associated adverse effects in infants exposed to trientine through breastmilk. There are no data on the effects of trientine on milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for trientine and any potential adverse effects on the breastfed infant from trientine or from the underlying condition. 

    ADVERSE REACTIONS

    Severe

    sideroblastic anemia / Delayed / Incidence not known
    lupus-like symptoms / Delayed / Incidence not known
    myasthenia gravis / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known

    Moderate

    constipation / Delayed / 0-15.0
    anemia / Delayed / 4.0-4.0
    iron deficiency / Delayed / Incidence not known
    contact dermatitis / Delayed / Incidence not known
    colitis / Delayed / Incidence not known
    zinc deficiency / Delayed / Incidence not known
    dystonic reaction / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known

    Mild

    abdominal pain / Early / 19.0-19.0
    rash / Early / 1.0-11.5
    emotional lability / Early / 8.0-8.0
    arthralgia / Delayed / 6.7-6.7
    fever / Early / Incidence not known
    pyrosis (heartburn) / Early / Incidence not known
    alopecia / Delayed / Incidence not known
    muscle cramps / Delayed / Incidence not known

    DRUG INTERACTIONS

    Food: (Major) Take trientine either 1 hour before food or 2 hours after food and at least 1 hour apart from milk in order to minimize the likelihood of trientine inactivation by metal binding in the gastrointestinal tract.
    Minerals: (Major) In general, oral mineral supplements should not be given since they may block the oral absorption of trientine. However, iron deficiency may develop, especially in children and 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 since iron and trientine each inhibit oral absorption of the other, 2 hours should elapse between administration of trientine and iron doses.

    PREGNANCY AND LACTATION

    Pregnancy

    Use trientine during pregnancy only if the potential benefit justifies the potential risk to the fetus. Guidelines recommend trientine treatment continuation during pregnancy; use the minimum effective dosage. Monitor copper concentrations closely during pregnancy as appropriate control of copper concentrations is important for the proper growth and mental development of the fetus. Trientine may also chelate non-copper cations (e.g., iron, calcium); maintain appropriate concentrations during pregnancy.  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, and in some cases has resulted in fulminant hepatic failure.  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 (MRD) and produced fetal abnormalities at 2.7 times the MRD. 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 embryofetal loss at approximately 4.3 times the MRD and produced fetal abnormalities at approximately 1.1 times the MRD. The mechanism of embryo-fetal harm (e.g., copper depletion) was not determined in the mouse study.

    Excretion of trientine into breast milk is not known. Available published literature have not reported drug-associated adverse effects in infants exposed to trientine through breastmilk. There are no data on the effects of trientine on milk production. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for trientine and any potential adverse effects on the breastfed infant from trientine or from the underlying condition. 

    MECHANISM OF ACTION

    Trientine is an oral chelator that is structurally unique from other known chelating agents. Trientine chelates heavy metals including copper, iron, and zinc and forms stable complexes that can be excreted by the kidneys. Urinary copper, iron, and zinc concentrations all increased in parallel with trientine excretion. Copper is chelated by forming a stable complex with the 4 constituent nitrogens in a planar ring. Cupriuresis is dose-dependent. Both trientine and a metabolite, acetyltrien, chelate copper, although the chelating ability of acetyltrien is lower. In addition to increased urinary copper excretion, trientine decreases intestinal copper absorption.

    PHARMACOKINETICS

    Trientine is administered orally. Trientine is acetylated into two major active metabolites, 1-N-acetyltriethylenetetramine (or acetyltrien) and 1-N-10-N-diacetyltriethylenetetramine. Both trientine and its metabolites are excreted in the urine. The amount of trientine excreted in the urine is about 1% of the administered dose, and the amount of the acetyltrien metabolite excreted in the urine is about 8% of the dose. Most of the parent drug occurs in the urine over the first 6 hours after drug receipt whereas acetyltrien excretion occurs over at least 26 hours. The mean terminal half-life of trientine ranges from 13.8 to 16.5 hours.
    Among patients who got penicillamine for at least 1 year and had a basal copper excretion rate of 17 to 19 mcg over 6 hours, the mean 6-hour excretion rate of copper was 234 mcg after a single 1,200 mg trientine hydrochloride capsule dose. In contrast, the mean 6-hour excretion rate of copper was 320 mcg after a single 500 mg penicillamine dose. Among patients who had not previously received a chelating agent, the mean basal excretion rate of copper over 6 hours was 68 to 71 mcg, and the rate after a single trientine dose was 1,326 mcg and after a single penicillamine dose was 1,074 mcg. After a single trientine 1,200 mg dose to 8 patients who were basically untreated, the plasma copper concentration rose slightly for the first few hours after a dose before falling by 6 hours after drug administration. After trientine 1,200 to 2,400 mg/day for 43 months, the baseline plasma copper concentration was much lower, and the concentration after a single 1,200 mg dose fell slightly over 6 hours. Trientine still increased copper clearance after 43 months of use.
    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 trientine tetrahydrochloride tablets. In patients who had switched to trientine tetrahydrochloride, mean UCE decreased over time. On the other hand, the mean serum NCC in patients who had switched to trientine tetrahydrochloride was comparable to the mean serum NCC in patients who remained on penicillamine. Serum NCC concentrations at week 24 were 59.3, 63.9, and 58 mcg/L after trientine tetrahydrochloride doses of less than 900 mg, 900 to 1,800 mg, and 1,800 to 3,600 mg, respectively. Corresponding 24-hour UCE values were 312.5, 223.8, and 340.9 mcg, respectively. Serum NCC concentrations at week 36 were 100.3, 49.1, and 53.9 mcg/L, respectively. Corresponding 24-hour UCE values were 425.6, 267.8, and 274 mcg, respectively.
     
    Affected cytochrome P450 isoenzymes and drug transporters: None

    Oral Route

    Trientine should be taken on an empty stomach in order to minimize the likelihood of inactivation by metal binding in the gastrointestinal tract. Food, milk, drugs, and mineral supplements could form a complex with trientine in the GI tract, which may prevent trientine absorption.
    Trientine hydrochloride capsules: Data on the pharmacokinetics of trientine hydrochloride are not available.
    Trientine tetrahydrochloride tablets: Trientine tetrahydrochloride is not substitutable on a milligram-per-milligram basis with other trientine products, as they supply different ratios of the trientine base (active moiety). The pharmacokinetic profile of the tablets has been evaluated in healthy subjects following single oral administration of up to 1,500 mg trientine tetrahydrochloride under fasting conditions. The median time to the peak concentration (Tmax) of trientine ranged from 1.25 to 2 hours. Mean Cmax after 900 mg and 1,500 mg trientine tetrahydrochloride were 2,030 +/- 981, and 3,430 +/- 1,480 ng/mL, respectively. The AUC of trientine increased in a dose proportional manner over the range of 900 mg to 1,500 mg (mean AUCinf of 9,750 +/- 4,910 and 17,200 +/- 9, 470 ng x hour/mL, respectively). After administration of 900 mg (3 tablets) of trientine tetrahydrochloride, the mean AUC was 11% lower compared to 750 mg (3 capsules) of trientine hydrochloride. After administration of 1,500 mg (5 tablets) of trientine tetrahydrochloride, the mean AUC was comparable to 1,250 mg (5 capsules) of trientine hydrochloride.