Trientine: A Copper-Removing Drug for Wilson Disease

Trientine (chemical name triethylenetetramine) is a prescription drug that binds copper so the body can get rid of it. Its one approved use is Wilson disease, an inherited condition in which copper piles up in the liver and the brain. Trientine has been on the United States market since 1985, first as trientine hydrochloride capsules that need a refrigerator, and since 2022 also as trientine tetrahydrochloride tablets that keep at room temperature. The two salts carry different label wording about who they are for. This page sets out what the drug labels say, what the trials and long-term patient studies found, how trientine compares with the older drug penicillamine and with zinc, what the European and American liver guidelines say, and where the evidence is still thin.

Table of Contents

  1. What Trientine Is
  2. Wilson Disease in Brief
  3. How Trientine Removes Copper
  4. Two Salts and Their Approvals
  5. Doses and Timing on the Labels
  6. Warnings and Side Effects
  7. Trientine Compared With Penicillamine
  8. The CHELATE Trial
  9. Trientine Compared With Zinc
  10. Neurological Worsening at the Start of Treatment
  11. Pregnancy and Breastfeeding
  12. Monitoring as the Guidelines Describe It
  13. What Is Not Known
  14. Key Research Papers
  15. Connections
  16. Featured Videos

What Trientine Is

Trientine is a small molecule made of four nitrogen-containing groups joined in a chain. Those nitrogen groups grip copper tightly. A drug that grips a metal and carries it out of the body is called a chelator (from the Greek word for a crab's claw). Trientine is one of two chelators used for Wilson disease; the other is penicillamine, which came first.

Trientine began as a second-line drug. In 1982 the British physician John Walshe reported on 20 patients with Wilson disease who had developed severe reactions to penicillamine and were switched to trientine dihydrochloride. He described trientine as safe and highly effective, both for reversing symptoms and for keeping patients stable, and noted that most of the reactions that had forced the switch went away on trientine. Two patients with lupus caused by penicillamine were not helped by the change (Walshe 1982).

The same chemical is also used in industry as a hardener for epoxy resins, which is why the older drug label mentions asthma, bronchitis and skin rashes in factory workers exposed to it over long periods.

Wilson Disease in Brief

Wilson disease is inherited from both parents. It is caused by changes in a gene called ATP7B, which makes a copper pump in liver cells. That pump normally loads copper onto the blood protein ceruloplasmin and pushes extra copper out into the bile, so it leaves the body in the stool. When the pump fails, copper builds up in the liver first. Once the liver's storage is full, copper spills into the blood and settles in the brain, the eyes and other organs. The result can be liver disease, movement and speech problems, psychiatric symptoms, or a combination.

The 2025 European guideline describes treatment with two kinds of drugs: chelators (penicillamine and trientine) and zinc salts. It recommends only chelators for significant liver disease (European Association for the Study of the Liver 2025). The full story of the disease, its diagnosis and its history is on the Wilson's Disease page.

How Trientine Removes Copper

The trientine tetrahydrochloride label describes two actions. Trientine forms a stable complex with copper that has already been absorbed, and that complex leaves the body in the urine. It also binds copper inside the gut, which reduces how much copper is absorbed from food.

The second action was measured directly in a 2024 study of 16 healthy volunteers. They swallowed a small dose of radioactive copper (copper-64), and scans showed how much reached the liver. After 7 days of trientine tetrahydrochloride (8 people), the copper signal in the liver 1 hour after the dose fell from an average of 6.17 to 1.47 units, and at 15 hours from 14.24 to 6.19, which the authors read as strong blocking of copper absorption from the gut. After 7 days of penicillamine (8 people), the 15-hour signal fell only slightly, from 16.30 to 12.17. The authors suggest this may explain why the two drugs work about equally well even though trientine pushes less copper into the urine, and they question whether the same urine-copper targets fit both drugs (Kirk 2024).

Unlike penicillamine, trientine has no sulfur (thiol) group. The older label states that for this reason it cannot bind cystine and is of no use in cystinuria, a kidney-stone disease penicillamine is also used for. The same label reports that in 15 patients with rheumatoid arthritis, trientine did not improve any clinical or laboratory measure after 12 weeks.

Once absorbed, trientine is converted into two active acetylated forms. The tetrahydrochloride label gives a half-life of 13.8 to 16.5 hours for trientine itself, and states that trientine and its breakdown products leave in the urine.

Two Salts and Their Approvals

The drug is sold as two different salts, which carry different amounts of the active trientine.

The approval of the tetrahydrochloride salt rested on the CHELATE trial, described below. A 2024 review written by employees of the manufacturer states that regulators in the European Union, the United Kingdom, Australia, China and several other countries approved the same salt for adults and children aged 5 or older who are intolerant of penicillamine, a different wording from the United States label (Kamlin 2024).

The need for cold storage has a real cost. A French registry study of 43 patients who took one or both salts for at least a year found both effective, but people on the refrigerated dihydrochloride salt stopped it more often, and the authors linked those interruptions mainly to the cold-storage requirement (Woimant 2022).

Doses and Timing on the Labels

The two labels give different dose ranges because the salts carry different amounts of trientine base.

Food and other minerals change how much trientine is absorbed. Both labels state that the drug is taken on an empty stomach, at least 1 hour before meals or 2 hours after meals, and at least 1 hour apart from other drugs, food or milk. The capsules and tablets are swallowed whole, not opened, crushed or chewed; the tetrahydrochloride tablet is scored and may be split in half. The older label notes that any skin touched by the capsule contents is washed promptly, because of the risk of contact dermatitis.

The labels list mineral supplements as an interaction. The hydrochloride label states that mineral supplements may block the absorption of trientine. The tetrahydrochloride label names iron, zinc, calcium and magnesium supplements as products that may reduce its absorption and directs that they not be combined with it; when one cannot be left out, it sets a gap of at least 2 hours before or after iron, and at least 1 hour before or 2 hours after other minerals. A 2023 summary of the American guidance adds that trientine can cause irritation of the esophagus and lists taking it with plenty of fluid (Alkhouri 2023).

Overdose information is limited. The older label mentions an adult woman who swallowed 30 grams of trientine hydrochloride without apparent ill effects. The newer label describes a 60-gram overdose that caused nausea, vomiting, dizziness, mild kidney injury and low blood zinc and copper, with recovery after intravenous fluids. It also states there is no antidote, and that long-term use above the maximum dose has caused sideroblastic anemia (a form of anemia in which the body cannot use iron properly).

Warnings and Side Effects

Contraindication. Both labels list one contraindication: hypersensitivity (allergy) to trientine or, for the tablets, to any of their inactive ingredients.

Iron deficiency. The hydrochloride label warns that patients, "especially women," are monitored for iron-deficiency anemia, and states that iron deficiency may develop especially in children and in menstruating or pregnant women, or as a result of the low-copper diet. Both labels state that iron may be given in short courses, at least 2 hours apart from trientine, because each blocks the absorption of the other. In one long-term study, one of 77 patients stopped trientine because of anemia (Weiss 2022).

Copper deficiency. The tetrahydrochloride label warns that removing too much copper can cause copper deficiency, and that close monitoring is needed when copper needs change, such as in pregnancy.

Worsening at the start of treatment. The tetrahydrochloride label warns that symptoms, including neurological symptoms, may get worse when the drug is started, because stored copper is being moved, and that the dose is reduced or the drug stopped if this happens. The section on neurological worsening below sets out what the studies found.

Hypersensitivity and rash. The older label states that there were no reports of hypersensitivity in patients treated for Wilson disease, and that patients are watched closely for it, with temperature taken nightly during the first month and any fever or skin eruption reported. The tetrahydrochloride label reports rash in 3 of 26 people (12%) taking the tablets in its trial, one of whom stopped the drug because of it. The 2023 summary of the American guidance still states that no hypersensitivity reactions have been reported, which no longer matches the newer label.

Lupus-like reactions. Both labels list systemic lupus erythematosus among reactions seen in studies of trientine hydrochloride. In the older label's clinical summary, one patient whose lupus had first appeared on penicillamine had it come back on trientine, and trientine was stopped. The French registry recorded one recurrence of a lupus-like syndrome on the dihydrochloride salt (Woimant 2022).

Bowel inflammation. The tetrahydrochloride label lists colitis among reactions reported after approval of trientine hydrochloride. Neither United States label uses the phrase "inflammatory bowel disease." Case reports describe the problem. A Swedish series of 19 long-term patients recorded two cases of serious colitis, one also with duodenitis, that improved after the drug was withdrawn (Dahlman 1995). A 40-year-old woman developed bloody diarrhea within a month of starting trientine; a colonoscopy showed ileitis and pancolitis consistent with drug injury, which improved on stopping, came back on restarting and resolved after a switch to zinc (Boga 2015). A 51-year-old woman with cirrhosis developed severe hemorrhagic colitis on trientine that was followed by worsening of her liver disease and a liver transplant (Schult 2022). Hospitals treat bloody diarrhea as an urgent sign.

Other reactions. The older label lists dystonia, muscle spasms and myasthenia gravis as reports from marketed use. The tetrahydrochloride label lists the same three plus rhabdomyolysis (muscle breakdown) as reports after approval of trientine hydrochloride, and notes that for voluntary reports it is not always possible to estimate how often they occur or to prove the drug caused them. In the CHELATE trial the tetrahydrochloride label lists, for tablets versus penicillamine, abdominal pain in 19% versus 4%, change in bowel habits in 15% versus 0%, rash in 12% versus 0%, hair loss in 8% versus 4%, and mood swings in 8% versus 0%.

Animal findings. The tetrahydrochloride label reports lung damage in rats given trientine dihydrochloride for 26 weeks, including at doses below the maximum human dose, and states that its relevance to people with Wilson disease is unknown. It also reports that trientine was positive in several laboratory tests for genetic damage (including the Ames test in bacteria) and negative in others, and that cancer studies in animals have not been done.

Trientine Compared With Penicillamine

No randomized trial has compared trientine with penicillamine as the first treatment for newly diagnosed Wilson disease. The 2023 summary of the American guidance states this directly (Alkhouri 2023). The comparisons come from long-term patient records and from one switch trial in already-stable adults.

The largest record review covered 405 patients from Germany, Austria and a European registry, followed for an average of 13.3 years. It analyzed 326 courses of penicillamine and 141 of trientine. Side effects that forced the drug to be stopped were more frequent with penicillamine (P = .039). Liver improvement was seen in more than 90% of untreated patients who started either drug, and nerve-symptom improvement in more than 55%, with no significant difference between the drugs. Liver transplantation was needed in 9 of 326 on penicillamine and 3 of 141 on trientine. Neurological deterioration was less frequent in patients given penicillamine first (6 of 295) than in those given trientine first (4 of 38; P = .018). The authors concluded the two drugs produce comparable outcomes, with more side effects on penicillamine (Weiss 2013).

A second review followed 77 patients switched from penicillamine to trientine dihydrochloride for an average of 8 years. Liver symptoms were absent in 35% and improved in 49.4%, stayed the same in 10.4% and worsened in 5.2%; none progressed to acute liver failure or needed a transplant. Nerve symptoms were absent in 46.7%, improved in 14.3%, stayed stable in 36.4% and worsened in 2.6%. Side effects arising during treatment were reported by 24.7%, most often bowel problems (9.1%) and nervous-system problems (5.2%) (Weiss 2022).

The 2023 summary of the American guidance states that trientine may be better tolerated than penicillamine, that it seems to have fewer side effects, including paradoxical neurological worsening, that side effects of penicillamine tend to resolve when trientine is substituted, and that neurological worsening caused by penicillamine may not resolve after the switch. It lists colitis and lupus-like reactions on trientine as rare (Alkhouri 2023). The same summary lists extra vitamin B6 (pyridoxine) for people on penicillamine; neither trientine label contains such an instruction.

A 2019 systematic review of 23 studies (2,055 patients) found that most studies compared penicillamine with no treatment, zinc, trientine or succimer (another chelator); 11 of the 23 were of low quality, and the authors called for cautious reading of the findings (Appenzeller-Herzog 2019).

The CHELATE Trial

CHELATE was a randomized, open-label (patients and doctors knew which drug was given), non-inferiority trial. Non-inferiority means it was designed to show that the new drug is not worse than the old one by more than a set margin, not that it is better. It ran at 15 centers in nine countries. It enrolled adults aged 18 to 75 with stable Wilson disease who had taken penicillamine for at least one year. After a 12-week check of stability, 53 patients were randomly assigned either to stay on penicillamine (27) or to switch milligram for milligram to trientine tetrahydrochloride (26) (Schilsky 2022).

The main measure was copper not bound to ceruloplasmin (the loosely bound, potentially toxic copper in the blood), measured by a special laboratory method that the label notes is not commercially available. The results, both ways:

The trial was funded by the manufacturer of trientine tetrahydrochloride, and one author was an employee of the manufacturer. It tested only people who were already stable and tolerating penicillamine, so it says nothing directly about starting treatment, about people with active liver or brain disease, or about children. The label's adverse-reaction table, which groups several related terms together, gives abdominal pain as 19% versus 4%, a slightly different figure from the published paper's 15% versus 4%.

Trientine Compared With Zinc

Zinc works differently. It does not pull copper out through the urine. It makes gut-lining cells produce a protein (metallothionein) that traps copper, so the copper is shed in the stool. The 2025 European guideline lists zinc salts alongside the chelators but recommends only chelators for significant liver disease (European Association for the Study of the Liver 2025). The 2023 summary of the American guidance states that zinc is now recommended as a first-line treatment for people without symptoms, that it can be considered for people whose disease mainly affects the nervous system, and that maintenance may be a lower dose of a chelator or full-dose zinc (Alkhouri 2023).

A German and Austrian record review of 288 treated patients, with a median follow-up of 17.1 years, found that the liver failed to respond more often on zinc (14 of 88 treatments) than on chelators (4 of 313 treatments; P < .001), and that survival without a transplant favored chelators. Patients whose liver did not respond to zinc improved after a chelator was restarted (Weiss 2011). The 2019 systematic review found that zinc and penicillamine had no clear difference in deaths or symptom control, with some signs that zinc was safer, but most studies were of low quality, and most of that review's comparisons involved penicillamine rather than trientine (Appenzeller-Herzog 2019).

Because trientine binds zinc in the gut, the two are not taken at the same moment; the labels' mineral-spacing rules above apply to zinc too.

Neurological Worsening at the Start of Treatment

A well-known problem in Wilson disease is that some people with brain involvement get worse soon after starting any copper-lowering drug, before they get better. The explanation offered on the tetrahydrochloride label is the movement of stored copper.

A 2023 meta-analysis of 32 studies (1,512 patients) found early neurological worsening in 14.3% overall: 21.8% of people with the neurological form, 1.3% of people with the liver form, and none of the people without symptoms. Of the 217 cases, 70.5% occurred on penicillamine, 14.2% on trientine and 6.9% on zinc, but the authors state their data could not show whether this reflected how often each drug was used first or a true difference in risk. Symptoms resolved fully in 24.2%, partly in 27.3%, and did not improve in 39.8% (Antos 2023).

A Heidelberg study of 128 patients with nerve features found early worsening (within the first 3 months) in 30 of 115 (26.1%) with neurological or mixed presentation and never in those with liver-only or no symptoms. Later worsening (after more than 12 months) was linked by the authors to stopping or skipping doses. Worsening was seen on penicillamine, trientine and zinc, and early worsening was reversible in half of the cases (Mohr 2023).

Whether trientine carries a lower risk than penicillamine is not settled. The 2023 summary of the American guidance states that early worsening "seems less common" with trientine (Alkhouri 2023). The large 2013 record review found the opposite in its numbers: deterioration in 4 of 38 patients given trientine first versus 6 of 295 given penicillamine first (Weiss 2013). Only a small number of patients started on trientine in that review, and the meta-analysis could not compare risks, so the question is open.

Pregnancy and Breastfeeding

The two labels word pregnancy differently. The older trientine hydrochloride label states that the drug was teratogenic (caused birth defects) in rats at doses similar to the human dose, that there are no adequate and well-controlled studies in pregnant women, and that it is used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

The newer tetrahydrochloride label states that published reports and several decades of use have not identified a drug-associated risk of major birth defects, miscarriage or other harm to mother or baby. It adds that untreated Wilson disease, or stopping treatment in pregnancy, may worsen liver and nerve symptoms, with rare reports of liver failure, and may raise the risk of miscarriage. It states that copper levels are monitored throughout pregnancy and the lowest effective dose is used, because removing too much copper may harm the fetus. In its animal data, fetal abnormalities in rats were markedly reduced when the mothers were given extra copper, pointing to copper loss as the cause.

In people, Walshe reported in 1982 that six patients became pregnant while taking trientine and all six infants developed normally (Walshe 1982). A multicenter review of 282 pregnancies in 136 women with Wilson disease found a miscarriage rate of 26% overall, significantly lower in women already diagnosed and treated than in those not yet diagnosed; birth defects occurred in 7 of 209 live births (3%). The authors concluded that treatment is continued in pregnancy (Pfeiffenberger 2018).

On breastfeeding, the older label states that it is not known whether trientine passes into human milk. The newer label states that published data on trientine in breast milk are inconsistent, that no harm to breastfed infants has been reported, and that there are no data on milk production.

Monitoring as the Guidelines Describe It

The 2025 European guideline bases monitoring on symptoms, liver tests and copper measures (24-hour urine copper and exchangeable copper), used to detect missed doses and over- or under-treatment (European Association for the Study of the Liver 2025).

The 2023 summary of the American guidance lists 24-hour urine copper plus, twice a year, liver tests, a clotting test (international normalized ratio), a complete blood count, a urine test (especially for people on penicillamine or trientine), and blood copper and ceruloplasmin for trends. For trientine it gives a urine-copper target of more than 1,000 µg a day just after starting and 150 to 500 µg a day once stable. It names low blood counts, a rising ferritin, or a urine copper below 100 µg a day on a chelator as possible signs of over-treatment (Alkhouri 2023).

The labels add their own schedules. The tetrahydrochloride label checks non-ceruloplasmin copper at the start, after 3 months and about every 6 months, with 24-hour urine copper every 6 to 12 months. The older hydrochloride label calls free copper in the blood the most reliable measure, states that adequately treated patients usually have less than 10 mcg/dL, and gives 0.5 to 1.0 mg of copper in a 24-hour urine collection as a sign of negative copper balance.

The copper-64 study above raises a question about these targets: because trientine also blocks copper absorption in the gut, urine copper on trientine may run lower than on penicillamine without meaning the treatment is weaker (Kirk 2024). The lab tests themselves are explained on the Ceruloplasmin Test and Copper Test pages.

What Is Not Known

Key Research Papers

  1. Schilsky ML, Czlonkowska A, Zuin M, Cassiman D, Twardowschy C, Poujois A, Gondim FAA, Denk G, Cury RG, Ott P, Moore J, Ala A, D'Inca R, Couchonnal-Bedoya E, D'Hollander K, Dubois N, Kamlin COF, Weiss KH. Trientine tetrahydrochloride versus penicillamine for maintenance therapy in Wilson disease (CHELATE): a randomised, open-label, non-inferiority, phase 3 trial. Lancet Gastroenterol Hepatol. 2022;7(12):1092-1102. PubMed PMID: 36183738
  2. European Association for the Study of the Liver. EASL-ERN Clinical Practice Guidelines on Wilson's disease. J Hepatol. 2025;82(4):690-728. PubMed PMID: 40089450
  3. Schilsky ML, Roberts EA, Bronstein JM, Dhawan A, Hamilton JP, Rivard AM, Washington MK, Weiss KH, Zimbrean PC. A multidisciplinary approach to the diagnosis and management of Wilson disease: Executive summary of the 2022 Practice Guidance on Wilson disease from the American Association for the Study of Liver Diseases. Hepatology. 2023;77(4):1428-1455. PubMed PMID: 36152019
  4. Alkhouri N, Gonzalez-Peralta RP, Medici V. Wilson disease: a summary of the updated AASLD Practice Guidance. Hepatol Commun. 2023;7(6):e0150. PubMed PMID: 37184530
  5. Weiss KH, Thurik F, Gotthardt DN, Schäfer M, Teufel U, Wiegand F, Merle U, Ferenci-Foerster D, Maieron A, Stauber R, Zoller H, Schmidt HH, Reuner U, Hefter H, Trocello JM, Houwen RH, Ferenci P, Stremmel W. Efficacy and safety of oral chelators in treatment of patients with Wilson disease. Clin Gastroenterol Hepatol. 2013;11(8):1028-35.e1-2. PubMed PMID: 23542331
  6. Weiss KH, Kruse C, Manolaki N, Zuin M, Ferenci P, van Scheppingen D, Wijnberg L, de Koning CE, Dhawan A. Multicentre, retrospective study to assess long-term outcomes of chelator based treatment with trientine in Wilson disease patients withdrawn from therapy with d-penicillamine. Eur J Gastroenterol Hepatol. 2022;34(9):940-947. PubMed PMID: 35482910
  7. Kirk FT, Munk DE, Swenson ES, Quicquaro AM, Vendelbo MH, Schilsky ML, Ott P, Sandahl TD. Effects of trientine and penicillamine on intestinal copper uptake: A mechanistic 64 Cu PET/CT study in healthy humans. Hepatology. 2024;79(5):1065-1074. PubMed PMID: 38088886
  8. Appenzeller-Herzog C, Mathes T, Heeres MLS, Weiss KH, Houwen RHJ, Ewald H. Comparative effectiveness of common therapies for Wilson disease: A systematic review and meta-analysis of controlled studies. Liver Int. 2019;39(11):2136-2152. PubMed PMID: 31206982
  9. Weiss KH, Gotthardt DN, Klemm D, Merle U, Ferenci-Foerster D, Schaefer M, Ferenci P, Stremmel W. Zinc monotherapy is not as effective as chelating agents in treatment of Wilson disease. Gastroenterology. 2011;140(4):1189-1198.e1. PubMed PMID: 21185835
  10. Antos A, Członkowska A, Smolinski L, Bembenek J, Przybyłkowski A, Skowrońska M, Kurkowska-Jastrzębska I, Litwin T. Early neurological deterioration in Wilson's disease: a systematic literature review and meta-analysis. Neurol Sci. 2023;44(10):3443-3455. PubMed PMID: 37311952
  11. Mohr I, Pfeiffenberger J, Eker E, Merle U, Poujois A, Ala A, Weiss KH. Neurological worsening in Wilson disease - clinical classification and outcome. J Hepatol. 2023;79(2):321-328. PubMed PMID: 37116715
  12. Pfeiffenberger J, Beinhardt S, Gotthardt DN, Haag N, Freissmuth C, Reuner U, Gauss A, Stremmel W, Schilsky ML, Ferenci P, Weiss KH. Pregnancy in Wilson's disease: Management and outcome. Hepatology. 2018;67(4):1261-1269. PubMed PMID: 28859232
  13. Walshe JM. Treatment of Wilson's disease with trientine (triethylene tetramine) dihydrochloride. Lancet. 1982;1(8273):643-7. PubMed PMID: 6121964
  14. Dahlman T, Hartvig P, Löfholm M, Nordlinder H, Lööf L, Westermark K. Long-term treatment of Wilson's disease with triethylene tetramine dihydrochloride (trientine). QJM. 1995;88(9):609-16. PubMed PMID: 7583074
  15. Boga S, Jain D, Schilsky ML. Trientine induced colitis during therapy for Wilson disease: a case report and review of the literature. BMC Pharmacol Toxicol. 2015;16:30. PubMed PMID: 26589720
  16. Schult A, Andersson M, Asin-Cayuela J, Olsson KS. Hemorrhagic colitis induced by trientine in a 51-year-old patient with Wilson's disease waiting for liver transplantation: A case report. World J Hepatol. 2022;14(8):1687-1691. PubMed PMID: 36157863
  17. Woimant F, Debray D, Morvan E, Obadia MA, Poujois A. Efficacy and Safety of Two Salts of Trientine in the Treatment of Wilson's Disease. J Clin Med. 2022;11(14):3975. PubMed PMID: 35887738
  18. Kamlin COF, M Jenkins T, L Heise J, S Amin N. Trientine Tetrahydrochloride, From Bench to Bedside: A Narrative Review. Drugs. 2024;84(12):1509-1518. PubMed PMID: 39420162

Drug labels read for this page: the current United States prescribing information for trientine hydrochloride capsules (reference label revised 2020, and a generic label published 2026) and for trientine tetrahydrochloride tablets (revised 2025), via DailyMed: trientine; approval dates from Drugs@FDA: trientine.

PubMed Topic Searches

  1. PubMed: trientine and Wilson disease
  2. PubMed: trientine tetrahydrochloride
  3. PubMed: neurological worsening on chelation in Wilson disease
  4. PubMed: trientine and colitis

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