Trientine Hydrochloride Capsules USP – Wilson’s disease

Trientine hydrochloride is a chelating compound for removal of excess copper from the body. Trientine capsules contain gelatin, iron oxides, stearic acid, and titanium dioxide as inactive ingredients.

Trientine hydrochloride is N,N’-bis (2-aminoethyl)-1,2-ethanediamine dihydrochloride. It is a white to pale yellow crystalline hygroscopic powder. It is freely soluble in water, soluble in methanol, slightly soluble in ethanol, and insoluble in chloroform and ether. The empirical formula is C₆H₁₈N₄•2HCl with a molecular weight of 219.2. The structural formula is:

NH₂(CH₂)₂NH(CH₂)₂NH(CH₂)₂NH₂•2HCl

Trientine is indicated in the treatment of patients with Wilson’s disease who are intolerant of penicillamine. Clinical experience with trientine 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 and penicillamine cannot be considered interchangeable. Trientine should be used when continued treatment with penicillamine is no longer possible because of intolerable or life endangering side effects.

Unlike penicillamine, trientine 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 was reported not to be effective in improving any clinical or biochemical parameter after 12 weeks of treatment.

Trientine is not indicated for treatment of biliary cirrhosis.

Systemic evaluation of dose and/or interval between dose has not been done. However, on limited clinical experience, the recommended initial dose of trientine is 500-750 mg/day for pediatric patients and 750-1250 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 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.

It is important that trientine 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.

Hypersensitivity to this product.

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.

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.

6.1 Usage in Pregnancy

Pregnancy Category C

Trientine hydrochloride was teratogenic in rats at doses similar to the human dose. The frequencies of both resorptions and fetal abnormalities, including hemorrhage and edema, increased while fetal copper levels decreased when trientine hydrochloride was given in the maternal diets of rats. There are no adequate and well-controlled studies in pregnant women. Trientine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

6.2 Nursing Mothers

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when trientine is administered to a nursing mother.

6.3 Pediatric Use

Controlled studies of the safety and effectiveness of trientine in pediatric patients have not been conducted. It has been used clinically in pediatric patients as young as 6 years with no reported adverse experiences.

6.4 Geriatric Use

Clinical studies of trientine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience is insufficient to determine differences in responses between the elderly and younger patients. In general, dose selection should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

WARNINGS

Patient experience with trientine hydrochloride is limited. Patients receiving trientine 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.

PRECAUTIONS

General

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. Patients should be observed closely for signs of possible hypersensitivity.

Clinical experience with trientine 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. In addition, the following adverse reactions have been reported in marketed use: dystonia, muscular spasm, myasthenia gravis.

Trientine 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.

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.

In general, mineral supplements should not be given since they may block the 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 absorption of the other, two hours should elapse between administration of trientine and iron.

It is important that trientine be taken 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. This permits maximum absorption and reduces the likelihood of inactivation of the drug by metal binding in the gastrointestinal tract.

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).

1) How Available:

1. a) Generic name: Trientine 250mg Capsules, by TAJ.

2) How Supplied:

Capsules Trientine, 250 mg, are light brown opaque capsules. They are supplied as follows in bottles of 100.

3) Storage:

Keep container tightly closed.

Store at 2-8°C (36-46°F).

Rx only

Wilson’s disease (WD), the most common inherited disorder of copper metabolism, results from a failure of the copper excretory pathway. This leads to toxic accumulation of copper in the liver and eventually other organs. The worldwide prevalence of WD is estimated to be one in 30,000 individuals.

The condition can be treated with a low copper diet and chelating agents that bind copper to facilitate its excretion from the body. Trientine hydrochloride is a chelating agent indicated for treatment of patients with WD who are intolerant of the first-line treatment, penicillamine.³

INDICATIONS AND USAGE

Trientine hydrochloride is indicated in the treatment of patients with Wilson’s disease who are intolerant of penicillamine. Clinical experience with Trientine 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 and penicillamine cannot be considered interchangeable. Trientine should be used when continued treatment with penicillamine is no longer possible because of intolerable or life endangering side effects.

Unlike penicillamine, Trientine 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 was reported not to be effective in improving any clinical or biochemical parameter after 12 weeks of treatment.

Trientine is not indicated for treatment of biliary cirrhosis.

IMPORTANT SAFETY INFORMATION

• Trientine is contraindicated in patients hypersensitive to Trientine or any components of the formulation. Patients should be observed closely for signs of possible hypersensitivity.
• Patients receiving Trientine 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.
• The treatment can be monitored by the determination of free copper in the serum. Therapy may be monitored with a 24-hour urinary copper analysis periodically (i.e., every 6-12 months).
• Patients should be directed to take Trientine 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. For the first month of treatment, the patient should have his temperature taken nightly, and he should be asked to report any symptom such as fever or skin eruption.
• In general, mineral supplements should not be given since they may block the absorption of Trientine.
• Trientine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• The following adverse reactions have been reported in a clinical study: iron deficiency, systemic lupus erythematosus. In addition, dystonia, muscular spasm, myasthenia gravis have been reported in marketed use.