Trientine (Monograph)

Brand names: Cuvrior, Syprine
Drug class: Heavy Metal Antagonists

Medically reviewed by Drugs.com on Nov 20, 2023. Written by ASHP.

Introduction

Heavy metal antagonist; selective copper-chelating agent.

Uses for Trientine

Wilson Disease

Trientine hydrochloride (Syprine) is used to promote excretion of copper in patients with Wilson disease who are intolerant of penicillamine. Manufacturer states that trientine hydrochloride should be used when continued treatment with penicillamine is no longer possible (e.g., because of intolerable or life-threatening adverse effects). Designated an orphan drug by FDA for use in Wilson disease.

Trientine hydrochloride is not indicated for the treatment of biliary cirrhosis. The manufacturer states that trientine hydrochloride is ineffective in the treatment of cystinuria or rheumatoid arthritis and is therefore not recommended for these conditions.

Trientine tetrahydrochloride (Cuvrior) is used for treatment of adults with Wilson disease who are de-coppered and tolerant to penicillamine. Designated an orphan drug by FDA for use in Wilson disease excluding patients intolerant to penicillamine.

American Association for the Study of Liver Diseases (AASLD) recommends a chelating agent (penicillamine or trientine) for initial therapy of symptomatic patients. Penicillamine traditionally used as the chelating agent of choice, but is associated with many adverse effects. Trientine may be better tolerated and should be considered in patients who cannot take penicillamine.

Trientine Dosage and Administration

General

Patient Monitoring

• Patients receiving trientine hydrochloride therapy should measure their body temperature nightly for the first month of therapy and report any symptoms of fever or skin eruption.

• Closely monitor patients (particularly female patients) taking trientine for evidence of iron deficiency anemia.

• Evaluate serum non-ceruplasmin copper (NCC) levels when initiating trientine tetrahydrochloride treatment, after 3 months of therapy, and approximately every 6 months thereafter.

• Consider periodic monitoring (i.e., every 6–12 months) of therapy with a 24-hour urinary copper analysis.

Dispensing and Administration Precautions

• If exposure to the trientine hydrochloride capsule contents occurs, promptly wash the site of exposure with water to prevent contact dermatitis.

Other General Considerations

• Because clinical experience with trientine hydrochloride is limited, administer the drug under regular medical supervision.

• Manifestations of Wilson disease, particularly neurologic symptoms, may worsen in some patients during initial therapy.

Administration

Oral Administration

Trientine hydrochloride (Syprine): Administer orally on an empty stomach, at least 1 hour before or 2 hours after meals, and at least 1 hour apart from any other drug, food, or milk.

Swallow capsules whole with water; do not open or chew.

Potential for contact dermatitis with contents of capsule; promptly wash any site of exposure with water.

Administer total daily dosage in divided doses 2–4 times daily.

Trientine tetrahydrochloride (Cuvrior): Administer on an empty stomach, at least 1 hour before or 2 hours after meals, and at least 1 hour apart from any other oral drug, food, or milk.

Swallow whole without crushing, chewing, or dissolving the tablet.

If a patient has difficulty swallowing a tablet whole, the scored tablet can be divided into 2 equal halves.

Do not remove tablets from blister packs until just before dosing and do not store tablets for future use after the blister has been opened.

Administer total daily dosage in divided doses 2 times daily.

Dosage

Recommended dosage regimens of trientine hydrochloride are based on limited clinical experience; studies have not been conducted evaluating specific doses and/or dosing intervals.

Trientine tetrahydrochloride is not substitutable on a mg-per-mg basis with other trientine products.

If switching from a trientine hydrochloride formulation to trientine tetrahydrochloride, the content of the active moiety (trientine base) is not the same as trientine tetrahydrochloride. 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.

Pediatric Patients

Wilson Disease

Oral

Trientine hydrochloride (Syprine): Initial dosage of 500–750 mg daily, administered in 2–4 divided doses. A weight-based dosage of 20 mg/kg daily, rounded to the nearest 250 mg and administered in 2–3 divided doses, also has been used.

May increase up to maximum recommended dosage of 1500 mg daily for pediatric patients ≤12 years of age.

Once disease symptoms and laboratory abnormalities stabilize, may continue on a lower dosage for maintenance therapy.

Individualize dosage based on urinary copper excretion and serum free copper concentrations in order to maintain negative copper balance. Serum free copper concentrations <10 mcg/dL usually are indicative of adequate treatment. Increase dosage only if inadequate clinical response or if serum free copper concentrations persistently exceed 20 mcg/dL.

Monitor 24-hour urinary copper analysis periodically (i.e., every 6–12 months). Under a low copper diet, 24-hour urinary copper excretion of 0.5–1 mg usually indicates negative copper balance; patients on adequate maintenance treatment should have a 24-hour urinary copper excretion of about 0.2–0.5 mg.

Adults

Wilson Disease

Oral

Trientine hydrochloride (Syprine): Initial dosage of 750-1250 mg daily, administered in 2–4 divided doses.

May increase up to maximum recommended dosage of 2000 mg daily in adults.

Once disease symptoms and laboratory abnormalities stabilize, may continue on a lower dosage for maintenance therapy. Typical maintenance dosages generally are in the range of 750-1000 mg daily administered in 2–3 divided doses.

Individualize dosage based on urinary copper excretion and serum free copper concentrations in order to maintain negative copper balance. Serum free copper concentrations <10 mcg/dL usually are indicative of adequate treatment. Increase dosage only if inadequate clinical response or if serum free copper concentrations persistently exceed 20 mcg/dL.

Monitor 24-hour urinary copper analysis periodically (i.e., every 6–12 months). Under a low copper diet, 24-hour urinary copper excretion of 0.5–1 mg usually indicates negative copper balance; patients on adequate maintenance treatment should have a 24-hour urinary copper excretion of about 0.2–0.5 mg.

Trientine tetrahydrochloride (Cuvrior): Initial total daily dosage of 300 mg up to 3000 mg in divided doses twice daily. Adjust dosage based on clinical assessment and laboratory copper monitoring; maximum total daily dosage is 3000 mg.

If the number of tablets given 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 initial daily dose.

For patients switching from penicillamine to trientine tetrahydrochloride, the recommended starting total daily dosage of trientine tetrahydrochloride is presented in Table 1.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

No specific dosage recommendations at this time.

Geriatric Use

No specific dosage recommendations at this time. Use caution and initiate at lower end of the dosing range.

Pregnant Patients

Some experts recommend dosage reduction.

Cautions for Trientine

Contraindications

• Hypersensitivity to trientine or any ingredient in the formulation.

Warnings/Precautions

Iron Deficiency

Iron deficiency may occur, particularly in children and menstruating or pregnant women; low copper diet also may contribute.

Closely monitor patients, particularly women, for iron deficiency anemia. May treat iron deficiency with short courses of iron supplementation; however, separate administration of iron and trientine by ≥2 hours.

Sensitivity Reactions

Hypersensitivity reactions not reported in trientine hydrochloride-treated patients with Wilson disease; however, asthma, bronchitis, and dermatitis reported after prolonged environmental exposure to trientine hydrochloride when used as an epoxy resin hardener.

Monitor closely for possible hypersensitivity reactions.

Hypersensitivity reactions (e.g., rash) have occurred with use of trientine tetrahydrochloride. If a hypersensitivity reaction occurs during therapy, assess patient clinically and consider discontinuation of trientine tetrahydrochloride.

Copper Deficiency

Copper deficiency may occur following treatment. Monitor for manifestations of copper deficiency, particularly when copper requirements may change, such as in pregnancy.

Potential Worsening of Clinical Symptoms at Therapy Initiation

Due to the mobilization of excess copper stores, worsening of clinical symptoms (e.g., neurological deterioration) may occur at therapy initiation. Evaluate serum non-ceruplasmin copper (NCC) levels when initiating trientine tetrahydrochloride treatment, after 3 months of therapy, and approximately every 6 months thereafter. Consider periodic monitoring (i.e., every 6–12 months) of trientine therapy with a 24-hour urinary copper analysis.

Specific Populations

Pregnancy

AASLD states that treatment for Wilson disease should be continued during pregnancy because interruption of therapy can result in acute liver failure. Limited clinical experience indicates successful pregnancy outcomes when trientine was used during pregnancy. AASLD recommends that dosage be reduced to the minimum necessary (e.g., 25–50% of the prepregnancy dosage), particularly during the third trimester, to promote better wound healing if cesarean section is performed. Monitor patient frequently.

Lactation

AASLD suggests all medications used to treat Wilson disease are excreted into breast milk and generally recommends against their use in nursing women due to the risk of causing copper deficiency in the infant.

Pediatric Use

Controlled studies in pediatric patients not conducted. Trientine hydrochloride has been used clinically in patients as young as 6 years of age with no reported adverse experiences.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Use caution and initiate at lower end of the dosing range in geriatric patients.

Common Adverse Effects

Trientine hydrochloride: iron deficiency, systemic lupus erythematosus.

Most common adverse effects (>5%) with trientine tetrahydrochloride: abdominal pain, change of bowel habits, rash, alopecia, mood swings.

Drug Interactions

Specific Drugs

Formal drug interaction studies not conducted to date. Administer trientene at least 1 hour apart from any oral drug.

Trientine Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations occur between 0.8–4 hours.

Onset

Increased cupruresis most evident during the first 12 hours following oral administration with highest rate of cupruresis occurring within the first 4 hours.

Food

Food inhibits absorption.

Elimination

Metabolism

Metabolized to 2 major acetyl metabolites, DAT and MAT; MAT also has chelating properties, but is a substantially weaker chelator of copper, iron, and zinc than parent drug.

Elimination Route

Excreted in urine as unchanged drug (1%) and metabolites (8%).

Half-life

1.3–4 hours following single dosing and about 10 hours following steady-state dosing at 1.2 g daily. Mean terminal half-life of trientene ranges from 13.8-16.5 hours.

Stability

Storage

Oral

Capsules

2–8°C in tightly closed container.

Tablets

20-25°C; excursions permitted between 15-30°C.

Actions

• Selective copper chelating agent that is structurally distinct from penicillamine; chelates copper to form stable complex that is excreted by the kidneys.

• Removes excess copper in patients with Wilson disease.

• On a molar basis, appears to be less potent than penicillamine as a cupriuretic agent.

• Also chelates other metals including iron and zinc.

Advice to Patients

• Swallow trientine capsules whole with water, and do not chew or open.

• Swallow trientine tablets without crushing, chewing, or dissolving. If a patient has difficulty swallowing the tablet whole, divide the scored tablet into 2 equal halves.

• Because contents of the capsule may cause contact dermatitis, immediately wash any site of skin exposure with water.

• Inform patients who are administered the capsule to measure their body temperature nightly for the first month of treatment and report any symptoms such as fever or skin eruption.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements (e.g., iron, mineral supplements), as well as any concomitant illnesses.

• Importance of informing patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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