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Trientine: Drug information

Trientine: Drug information
(For additional information see "Trientine: Patient drug information" and see "Trientine: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Clovique [DSC];
  • Cuvrior;
  • Syprine
Brand Names: Canada
  • MAR-Trientine;
  • Waymade-Trientine
Pharmacologic Category
  • Chelating Agent
Dosing: Adult
Wilson disease

Wilson disease (alternative agent): Note: Trientine hydrochloride capsules (Clovique and generics, Syprine) are not substitutable on a mg-per-mg basis with trientine tetrahydrochloride tablets (Cuvrior) due to differences in bioavailability and amount of trientine base in each formulation (AASLD [Schilsky 2022]; Mohr 2023; manufacturer’s labeling).

Trientine hydrochloride capsules (Clovique and generics, Syprine): Oral: Initial: 750 to 1,250 mg/day or 15 to 20 mg/kg/day in 2 to 4 divided doses (AASLD [Schilsky 2022]; manufacturer's labeling). Increase dose over a 2- to 3-week period based on clinical response up to a maximum of 2 g/day; usual maintenance dose: 10 to 15 mg/kg/day in 2 to 3 divided doses (AASLD [Schilsky 2022]).

Trientine tetrahydrochloride tablets (Cuvrior):

Initial dosage (patients switching from penicillamine): Oral: Discontinue penicillamine and initiate trientine tetrahydrochloride at 300 to 3,000 mg/day in 2 equally divided doses based on penicillamine total daily dose according to the table below.

Dose Conversion from Penicillamine to Trientine Tetrahydrochloride Tablets (Cuvrior)

Current penicillamine total daily dosage

Initial trientine tetrahydrochloride (Cuvrior) total daily dosagea

a Total daily dose should be divided equally into 2 doses; if the number of tablets cannot be equally divided between doses, then administer the higher dose in the morning and the lower dose in the evening.

125 mg/day

300 mg/day

250 mg/day

600 mg/day

375 mg/day

900 mg/day

500 mg/day

900 mg/day

625 mg/day

1,200 mg/day

750 mg/day

1,500 mg/day

875 mg/day

1,800 mg/day

1,000 mg/day

2,100 mg/day

1,125 mg/day

2,400 mg/day

1,375 mg/day

2,700 mg/day

≥1,500 mg/day

3,000 mg/day

Dosage titration: Adjust total daily dose based on clinical response up to a maximum of 3 g/day.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Older Adult

Refer to adult dosing. Use with caution; initiate at lower end of the dosing range.

Dosing: Pediatric

(For additional information see "Trientine: Pediatric drug information")

Note: Trientine is available in 2 formulations; the trientine hydrochloride capsule (Clovique and generics, Syprine) and trientine tetrahydrochloride tablet (Cuvrior) are not bioequivalent due to differences in amount of trientine base delivered per dose and bioavailability (AASLD [Schilsky 2022]; Mohr 2023; manufacturer's labeling). Dosing is product specific; use caution; the tetrahydrochloride tablets (Cuvrior) are only approved in adults.

Wilson disease

Wilson disease: Children and Adolescents: Trientine hydrochloride capsules (Clovique and generics, Syprine): Oral: Initial: 20 mg/kg/day (round dose to the nearest 250 mg) in 2 to 3 divided doses; maximum initial daily dose: 1,000 mg/day; titrate dose based on clinical response and free serum copper (non-ceruloplasmin bound copper) concentrations and/or 24-hour urinary copper excretion; usual maintenance dose: 10 to 15 mg/kg/day or 900 to 1,500 mg/day in 2 to 3 divided doses (AASLD [Schilsky 2022]; EASL 2012; ESPGHAN [Socha 2018]).

Maximum daily dose:

Children: 1,500 mg/day.

Adolescents: 2,000 mg/day.

Dosing: Kidney Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling.

Adverse Reactions

The following adverse drug reactions are derived from product labeling unless otherwise specified.

>10%:

Dermatologic: Skin rash

Gastrointestinal: Abdominal pain, change in bowel habits (including abnormal stools, constipation, and soft stools)

1% to 10%:

Dermatologic: Alopecia

Hematologic: Anemia

Nervous system: Emotional lability

Frequency not defined:

Endocrine & metabolic: Iron deficiency

Neuromuscular & skeletal: Systemic lupus erythematosus

Postmarketing:

Dermatologic: Fixed drug eruption (Roberts 2008)

Gastrointestinal: Colitis (Boga 2015), gastritis (Roberts 2008)

Hematologic & oncologic: Aplastic anemia (Roberts 2008), pancytopenia (Roberts 2008), sideroblastic anemia (reversible) (Roberts 2008)

Nervous system: Myasthenia gravis, neurological deterioration (worsening) (European Association for the Study of the Liver 2012)

Neuromuscular & skeletal: Dystonia, muscle spasm, rhabdomyolysis (Aslan 2019)

Contraindications

Hypersensitivity to trientine or any component of the formulation.

Warnings/Precautions

Concerns related to adverse effects:

• Copper deficiency: Induced by treatment; may lead to hepatic iron overload and/or sideroblastic anemia; reassess dose (AASLD [Schilsky 2022]).

• Hypersensitivity: Hypersensitivity reactions, characterized by rash, have been reported with trientine tetrahydrochloride (Cuvrior). Hypersensitivity has not been reported with trientine hydrochloride (Clovique and generics, Syprine); however, industrial workers exposed to trientine for prolonged periods have reported asthma, bronchitis, and dermatitis.

• Iron deficiency: May cause iron-deficiency potentially resulting in anemia, especially in menstruating or pregnant females.

• Neurologic worsening: May occur with treatment initiation; less common than with penicillamine (AASLD [Schilsky 2022]).

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral, as hydrochloride:

Clovique: 250 mg [DSC]

Syprine: 250 mg

Generic: 250 mg, 500 mg

Tablet, Oral, as tetrahydrochloride:

Cuvrior: 300 mg [scored]

Generic Equivalent Available: US

May be product dependent

Pricing: US

Capsules (Syprine Oral)

250 mg (per each): $255.20

Capsules (Trientine HCl Oral)

250 mg (per each): $229.43 - $242.44

500 mg (per each): $460.00

Tablets (Cuvrior Oral)

300 mg (per each): $229.20

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as hydrochloride:

Generic: 250 mg

Administration: Adult

Oral: Administer at least 1 hour before or 2 hours after meals and at least 1 hour apart from any drug, food, or milk. May be taken closer to meals if needed to improve adherence (AASLD [Schilsky 2022]; EASL 2012).

Trientine hydrochloride capsules (Clovique and generics, Syprine): Do not open or chew capsule; swallow whole with water; any skin exposed to the contents of a capsule should be promptly washed with water.

Trientine tetrahydrochloride tablets (Cuvrior): Swallow whole; do not crush, chew, or dissolve tablets. Scored tablet may be divided into 2 equal halves.

Administration: Pediatric

Oral: Trientine hydrochloride capsules (Clovique and generics, Syprine): Administer on an empty stomach at least 1 hour before or at least 2 hours after meals and at least 1 hour apart from any other drug, food, or milk; however, administration closer to meals may be considered if it improves adherence (AASLD [Schilsky 2022]; EASL 2012; manufacturer's labeling). Swallow capsule whole with water; do not chew or open capsule. Any skin exposed to the contents of a capsule should be promptly washed with water.

Use: Labeled Indications

Wilson disease:

Trientine hydrochloride capsules (Clovique and generics, Syprine): Treatment of patients with Wilson disease who are intolerant to penicillamine.

Limitations of use: Not recommended in cystinuria or rheumatoid arthritis; not indicated for biliary cirrhosis.

Trientine tetrahydrochloride tablets (Cuvrior): Treatment of adult patients with stable Wilson disease who are decoppered and tolerant to penicillamine.

Medication Safety Issues
Sound-alike/look-alike issues:

Trientine may be confused with TRENtal®, tretinoin

Metabolism/Transport Effects

None known.

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

Polyvalent Cation Containing Products: May decrease the serum concentration of Trientine. Management: Avoid concomitant use of trientine and polyvalent cations. If oral iron supplements are required, separate the administration by 2 hours. For other oral polyvalent cations, give trientine 1 hour before, or 1 to 2 hours after the polyvalent cation. Risk D: Consider therapy modification

Food Interactions

Food, dairy products, or other sources of polyvalent cations will be chelated by trientine. Management: Should be taken 1 hour before or 2 hours after meals and at least 1 hour apart from any drug, food, or milk. May be taken closer to meals if needed to improve adherence (AASLD [Schilsky 2022]; EASL 2012).

Pregnancy Considerations

Treatment of Wilson disease should be maintained during pregnancy; dose reduction (25% to 50% of prepregnancy dose) should be considered (AASLD [Schilsky 2022]).

Breastfeeding Considerations

It is not known if trientine is present in breast milk. The manufacturer recommends that caution be exercised when administering trientine to breastfeeding patients.

Dietary Considerations

Should be taken 1 hour before or 2 hours after meals and at least 1 hour apart from any drug, food, or milk.

Monitoring Parameters

Periodic 24-hour urinary copper assessment (every 6 to 12 months); serum non-ceruloplasmin bound copper (NCC) at baseline, 3 months after treatment initiation, and approximately every 6 months thereafter; liver biochemistries; CBC; tests of liver synthetic function (eg, INR); urinalysis (AASLD [Schilsky 2022]); fever and skin changes during the first month of therapy.

Treatment efficacy : Adequacy of the initial dose is monitored by the rate of urinary copper excretion; 24-hour urinary copper excretion may exceed 1,000 mcg per 24 hours at treatment initiation and decrease as copper stores are depleted (eg, ~150 to 500 mcg per 24 hours during maintenance therapy) (AASLD [Schilsky 2022]).

Lack of efficacy: Nonadherence versus poor trientine absorption may need to be investigated if urinary copper excretion rises over time (eg >500 mcg per 24 hours) in conjunction with a rise in serum copper and NCC (eg >15 mcg/dL) despite appropriately titrated trientine dosage (AASLD [Schilsky 2022]).

Overtreatment: Overtreatment may need to be investigated if urinary copper excretion is <100 mcg per 24 hours and/or serum copper levels and NCC (eg <5 mcg/dL) are lower than expected (AASLD [Schilsky 2022]).

Mechanism of Action

Trientine is an oral chelating agent structurally dissimilar from penicillamine and other available chelating agents. Induces cupriuresis by chelating with copper to form stable, soluble complexes that are excreted in the urine; also chelates copper in the intestinal tract to decrease copper absorption.

Pharmacokinetics (Adult Data Unless Noted)

Absorption: Poor (AASLD [Schilsky 2022]); trientine tetrahydrochloride is absorbed faster and to a greater extent than trientine hydrochloride (Weiss 2021).

Metabolism: To acetyltrien (chelating activity significantly less than parent) (AASLD [Schilsky 2022]).

Half-life elimination: Trientine hydrochloride (as Univar [international product]): Mean 23.2 hours (Weiss 2021); Trientine tetrahydrochloride: 13.8 to 16.5 hours.

Time to peak, serum: Trientine hydrochloride (as Univar [international product]): Median: 3 hours (range: 1.25 to 6.02 hours) (Weiss 2021); Trientine tetrahydrochloride: 1.25 to 2 hours.

Excretion: Urine (1% as parent; 8% as metabolite) (AASLD [Schilsky 2022]).

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AT) Austria: Cufence;
  • (AU) Australia: Trientine Waymade;
  • (BR) Brazil: Willentine;
  • (CH) Switzerland: Triogen;
  • (CO) Colombia: Cubrital | Cuchel | Syprine;
  • (DE) Germany: Cufence;
  • (ES) Spain: Cufence;
  • (FI) Finland: Cufence | Trientine tillomed;
  • (FR) France: Cufence | Trientine dichlorhydrate | Triethylenetetramine;
  • (GB) United Kingdom: Cufence | Trientine | Trientine dihydrochloride tillomed;
  • (GR) Greece: Cufence | Trientine/univar;
  • (HU) Hungary: Cufence;
  • (IE) Ireland: Cufence;
  • (IN) India: Cuchel;
  • (JP) Japan: Metalite;
  • (KR) Korea, Republic of: Metalite | Syprine | Trientab;
  • (LT) Lithuania: Cufence | Trientine;
  • (LU) Luxembourg: Cufence;
  • (MY) Malaysia: Syprine | Trientine;
  • (NL) Netherlands: Cufence;
  • (NO) Norway: Cufence | Syprine;
  • (NZ) New Zealand: Trientine Waymade;
  • (PR) Puerto Rico: Clovique | Syprine | Trientine HCL | Trientine hydrochloride;
  • (PT) Portugal: Cufence | Syprine | Trientina | Trientine;
  • (SE) Sweden: Cufence | Trientine tillomed;
  • (SG) Singapore: Syprine;
  • (SI) Slovenia: Cufence | Syprine;
  • (TR) Turkey: Novils | Sipryne | Wilentin;
  • (TW) Taiwan: Metacu | Metalite | Syprine | Trientine
  1. Aslan N, Yavuz S, Yildizdas D, et al. Trientine-induced rhabdomyolysis in an adolescent with Wilson's disease. Indian J Crit Care Med. 2019;23(10):489-490. doi:10.5005/jp-journals-10071-23271 [PubMed 31749561]
  2. 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. doi:10.1186/s40360-015-0031-z [PubMed 26589720]
  3. Clovique (trientine hydrochloride) [prescribing information]. Warrendale, PA: Kadmon Pharmaceuticals; December 2018.
  4. Condamine L, Hermine O, Alvin P, Levine M, Rey C, Courtecuisse V. Acquired sideroblastic anaemia during treatment of Wilson's disease with triethylene tetramine dihydrochloride. Br J Haematol. 1993;83(1):166-168. [PubMed 8435326]
  5. Cuvrior (trientine tetrahydrochloride) [prescribing information]. Chicago, IL: Orphalan; April 2022.
  6. 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):609-616. [PubMed 7583074]
  7. European Association for Study of Liver. EASL clinical practice guidelines: Wilson's disease. J Hepatol. 2012;56(3):671-685. doi:10.1016/j.jhep.2011.11.007 [PubMed 22340672] 10.1016/j.jhep.2011.11.007
  8. Kodama H, Murata Y, Iitsuka T, et al, “Metabolism of Administrated Triethylene Tetramine Dihydrochloride In Humans,” Life Sci, 1997, 61(9):899-907. [PubMed 9284083]
  9. Mohr I, Bourhis H, Woimant F, et al. Experience on switching trientine formulations in Wilson disease: Efficacy and safety after initiation of TETA 4HCl as substitute for TETA 2HCl. J Gastroenterol Hepatol. 2023;38(2):219-224. doi:10.1111/jgh.16050 [PubMed 36331262]
  10. Perry AR, Pagliuca A, Fitzsimons EJ, Mufti GJ, Williams R. Acquired sideroblastic anaemia induced by a copper-chelating agent. Int J Hematol. 1996;64(1):69-72. [PubMed 8757970]
  11. Refer to manufacturer’s labeling.
  12. Roberts EA, Schilsky ML; American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47(6):2089-2111. doi:10.1002/hep.22261 [PubMed 18506894]
  13. Schilsky ML, Roberts EA, Bronstein JM, et al. 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. Published online December 7, 2022. doi:10.1002/hep.32805 [PubMed 36152019]
  14. Shiono Y, Hayashi H, Wakusawa S, Yano M. Ultrastructural identification of iron and copper accumulation in the liver of a male patient with Wilson disease. Med Electron Microsc. 2001;34(1):54-60. [PubMed 11479773]
  15. Socha P, Janczyk W, Dhawan A, et al. Wilson's Disease in Children: A Position Paper by the Hepatology Committee of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2018;66(2):334-344. doi: 10.1097/MPG.0000000000001787. [PubMed 29341979]
  16. Syprine (trientine hydrochloride) [prescribing information]. Bridgewater, NJ: Bausch Health US, LLC; September 2020.
  17. Trientine hydrochloride capsules [prescribing information]. Parsippany, NJ: Teva Pharmaceuticals; January 2022.
  18. Walshe JM, “Treatment of Wilson's Disease With Trientine (Triethylene Tetramine) Dihydrochloride,” Lancet, 1982, 1(8273):643-7. [PubMed 6121964]
  19. Weiss KH, Thompson C, Dogterom P, et al. Comparison of the pharmacokinetic profiles of trientine tetrahydrochloride and trientine dihydrochloride in healthy subjects. Eur J Drug Metab Pharmacokinet. 2021;46(5):665-675. doi:10.1007/s13318-021-00704-1 [PubMed 34357516]
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