Label: TRIENTINE HYDROCHLORIDE capsule

Trientine hydrochloride is 1,2-Ethanediamine, N,N'-bis (2-aminoethyl)-,dihydrochloride. It is a white to pale yellow crystalline powder. It is freely soluble in water, soluble in methanol, slightly soluble in alcohol (96%), and insoluble in chloroform and   in ether.
The empirical formula is C6H18N4•2HCl with a molecular weight of 219.16. The structural formula is: NH2(CH2)2NH(CH2)2NH(CH2)2NH2•2HCI
Trientine hydrochloride is a chelating compound for removal of excess copper from the body. Trientine hydrochloride capsules USP 250 mg are available as 250 mg capsules for oral administration.Trientine hydrochloride capsules USP 250 mg contains gelatin, iron oxide black, iron oxide red, iron oxide yellow, potassium hydroxide, propylene glycol, shellac, stearic acid and  titanium dioxide as inactive ingredients.

Introduction
Wilson's disease (hepatolenticular degeneration)is an autosomal inherited metabolic defect resulting in an inability to maintain a near-zero balance of copper. Excess copper accumulates possibly because the liver lacks the mechanism to excrete free copper into the bile. Hepatocytes store excess copper but when their capacity is exceeded copper is released into the blood and is taken up into extrahepatic sites. This condition is treated with a low copper diet and the use of chelating agents that bind copper to facilitate its excretion from the body.
Clinical Summary
Forty-one patients (18 male and 23 female)between the ages of 6 and 54 with a diagnosis of Wilson's disease and who were intolerant of d-penicillamine were treated in two separate studies with trientine hydrochloride. The dosage varied from 450 to 2,400 mg per day. The average dosage required to achieve an optimal clinical response varied between 1,000 mg and 2,000 mg per day. The mean duration of trientine hydrochloride therapy was 48.7 months (range 2 to 164 months). Thirty-four of the 41 patients improved, 4 had no change in clinical global response, 2 were lost to follow-up and one showed deterioration in clinical condition. One of the patients who improved while on therapy with trientine hydrochloride experienced a recurrence of the symptoms of systemic lupus erythematosus which had appeared originally during therapy with penicillamine. Therapy with trientine hydrochloride was discontinued. No other adverse reactions, except iron deficiency, were noted among any of these 41 patients.
One investigator treated 13 patients with trientine hydrochloride following their development of intolerance to d-penicillamine. Retrospectively, he compared these patients to an additional group of 12 patients with Wilson's disease who were both tolerant of and controlled with d-penicillamine therapy, but who failed to continue any copper chelation therapy. The mean age at onset of disease of the latter group was 12 years as compared to 21 years for the former group. The trientine hydrochloride group received d-penicillamine for an average of 4 years as compared to an average of 10 years for the non-treated group.
Various laboratory parameters showed changes in favor of the patients treated with trientine hydrochloride. Free and total serum copper, SGOT and serum bilirubin all showed mean increases over baseline in the untreated group which were significantly larger than with the patients treated with trientine hydrochloride. In the 13 patients treated with trientine hydrochloride, previous symptoms and signs relating to d-penicillamine intolerance disappeared in 8 patients, improved in 4 patients, and   remained unchanged in one patient. The neurological status in the trientine hydrochloride group was unchanged or improved over baseline, whereas in the untreated group, 6 patients remained unchanged and 6 worsened. Kayser-Fleischer rings improved significantly during trientine hydrochloride treatment.
The clinical outcome of the two groups also differed markedly. Of the 13 patients on therapy with trientine hydrochloride (mean duration of therapy 4.1 years; range 1 to 13 years), all were alive at the data cutoff date, and in the non-treated group (mean years with no therapy 2.7 years; range 3 months to 9 years), 9 of the 12 died of hepatic disease.
Chelating Properties
Preclinical Studies
Studies in animals have shown that trientine hydrochloride has cupriuretic activities in both normal and copper-loaded rats. In general, the effects of trientine hydrochloride on urinary copper excretion are similar to those of equimolar doses of penicillamine, although in one study they were significantly smaller.
Human Studies
Renal clearance studies were carried out with penicillamine and trientine hydrochloride on separate occasions in selected patients treated with penicillamine for at least one year. Six-hour excretion rates of copper were determined off treatment and after a single dose of 500 mg of penicillamine or 1.2 g of trientine hydrochloride. The mean urinary excretion rates of copper were as follows:

In patients not previously treated with chelating agents, a similar comparison was made:

These results demonstrate that trientine hydrochloride is effective as a cupriuretic agent in patients with Wilson's disease although on a molar basis it appears to be less potent or less effective than penicillamine. Evidence from a radio-labelled copper study indicates that the different cupriuretic effect between these two drugs could be due to a difference in selectivity of the drugs for different copper pools within the body.
Pharmacokinetics
Data on the pharmacokinetics of trientine hydrochloride are not available. Dosage adjustment recommendations are based upon clinical use of the drug (see DOSAGE AND ADMINISTRATION).

Trientine hydrochloride capsules USP 250 mg is indicated in the treatment of patients with Wilson's disease who are intolerant of penicillamine. Clinical experience with trientine hydrochloride capsules USP 250 mg is limited and alternate dosing regimens have not been well-characterized; all endpoints in determining an individual patient's dose have not been well defined. Trientine hydrochloride capsules USP 250 mg and penicillamine cannot be considered interchangeable. Trientine hydrochloride capsules USP 250 mg should be used when continued treatment with penicillamine is no longer possible because of intolerable or life endangering side effects.
Unlike penicillamine, trientine hydrochloride capsules USP 250 mg is not recommended in cystinuria or rheumatoid arthritis. The absence of a sulfhydryl moiety renders it incapable of binding cystine and, therefore, it is of no use in cystinuria. In 15 patients with rheumatoid arthritis, trientine hydrochloride capsules USP 250 mg was reported not to be effective in improving any clinical or biochemical parameter after 12 weeks of   treatment.
Trientine hydrochloride capsules USP 250 mg is not indicated for treatment of biliary cirrhosis.

Hypersensitivity to this product.

Patient experience with trientine hydrochloride is limited (see CLINICAL PHARMACOLOGY). Patients receiving trientine hydrochloride should remain under regular medical supervision throughout the period of drug administration. Patients (especially women) should be closely monitored for evidence of iron deficiency anemia.

Clinical experience with trientine hydrochloride has been limited. The following adverse reactions have been reported in a clinical study in patients with Wilson's disease who were on therapy with trientine hydrochloride: iron deficiency, systemic lupus erythematosus (see CLINICAL PHARMACOLOGY). In addition, the following adverse reactions have been reported in marketed use: dystonia, muscular spasm, myasthenia gravis.
Trientine hydrochloride is not indicated for treatment of biliary cirrhosis, but in one study of 4 patients treated with trientine hydrochloride for primary biliary cirrhosis, the following adverse reactions were reported: heartburn; epigastric pain and tenderness; thickening, fissuring and flaking of the skin; hypochromic microcytic anemia; acute gastritis; aphthoid ulcers; abdominal pain; melena; anorexia; malaise; cramps; muscle pain; weakness; rhabdomyolysis. A causal relationship of these reactions to drug therapy could not be rejected or established.
To report SUSPECTED ADVERSE REACTIONS, contact Novadoz Pharmaceuticals LLC at 1-855-668-2369 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

There is a report of an adult woman who ingested 30 grams of trientine hydrochloride without apparent ill effects. No other data on overdosage are available.

Systemic evaluation of dose and/or interval between dose has not been done. However, on limited clinical experience, the recommended initial dose of trientine hydrochloride capsules USP 250 mg is 500 to 750 mg/day for pediatric patients and 750 to 1250 mg/day for adults given in divided doses two, three or four times daily. This may be increased to a maximum of 2000 mg/day for adults or 1500 mg/day for pediatric patients age 12 or under.
The daily dose of trientine hydrochloride capsules USP 250 mg should be increased only when the clinical response is not adequate or the concentration of free serum copper is persistently above 20 mcg/dL. Optimal long-term maintenance dosage should be determined at 6-12 month intervals (see PRECAUTIONS, Laboratory Tests).
It is important that trientine hydrochloride capsules USP 250 mg be given on an empty stomach, at least one hour before meals or two hours after meals and at least one hour apart from any other drug, food, or milk. The capsules should be swallowed whole with water and should not be opened or chewed.

Trientine hydrochloride capsules, USP 250 mg, are capsules with light brown opaque body imprinted with "250" and light brown opaque cap imprinted with "TRN" in black ink. They are supplied as follows:
NDC 72205-008-91 in bottles of 100.
STORAGE
Dispense in a tight container and store in a refrigerator; 2 to 8°C (36 to 46°F). Keep container tightly closed.

Manufactured by:
MSN Laboratories Private Limited
Telangana – 509 228,
INDIA

Distributed by:
Novadoz Pharmaceuticals LLC
Piscataway, NJ 08854-3714
Issued on: 
June 2022

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