DESCRIPTION

Trientine hydrochloride is N,N’-bis (2-aminoethyl)-1,2-ethanediamine dihydrochloride.It is a white to pale yellow crystalline hygroscopic powder. It isfreely soluble in water, soluble in methanol, slightly soluble inethanol, and insoluble in chloroform and ether.

The empirical formula is C6H18N4•2HCl with a molecular weight of 219.2. The structural formulais:

NH2(CH2)2NH(CH2)2NH(CH2)2NH2•2HCl

Trientine hydrochlorideis a chelating compound for removal of excess copper from the body.SYPRINE1 (TrientineHydrochloride) is available as 250mg capsules for oral administration.Capsules SYPRINE contain gelatin, iron oxides, stearic acid, and titaniumdioxide as inactive ingredients.

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Registeredtrademark of MERCK & CO., Inc. COPYRIGHT © MERCK & CO.,Inc., 1985, 1989 All rights reserved

CLINICAL PHARMACOLOGY

Introduction

Wilson's disease (hepatolenticular degeneration)is an autosomal inherited metabolic defect resulting in an inabilityto maintain a near-zero balance of copper. Excess copper accumulatespossibly because the liver lacks the mechanism to excrete free copperinto the bile. Hepatocytes store excess copper but when their capacityis exceeded copper is released into the blood and is taken up intoextrahepatic sites. This condition is treated with a low copper dietand the use of chelating agents that bind copper to facilitate itsexcretion from the body.

Clinical Summary

Forty-one patients (18 male and 23 female) betweenthe ages of 6 and 54 with a diagnosis of Wilson's disease and whowere intolerant of d-penicillamine were treated in two separate studieswith trientine hydrochloride. The dosage varied from 450 to 2400mgper day. The average dosage required to achieve an optimal clinicalresponse varied between 1000mg and 2000mg per day. Themean duration of trientine hydrochloride therapy was 48.7 months (range2-164 months). Thirty-four of the 41 patients improved, 4 had no changein clinical global response, 2 were lost to follow-up and one showeddeterioration in clinical condition. One of the patients who improvedwhile on therapy with trientine hydrochloride experienced a recurrenceof the symptoms of systemic lupus erythematosus which had appearedoriginally during therapy with penicillamine. Therapy with trientinehydrochloride was discontinued. No other adverse reactions, exceptiron deficiency, were noted among any of these 41 patients.

One investigator treated 13 patients with trientine hydrochloridefollowing their development of intolerance to d-penicillamine. Retrospectively,he compared these patients to an additional group of 12 patients withWilson's disease who were both tolerant of and controlled with d-penicillaminetherapy, but who failed to continue any copper chelation therapy.The mean age at onset of disease of the latter group was 12 yearsas compared to 21 years for the former group. The trientine hydrochloridegroup received d-penicillamine for an average of 4 years as comparedto an average of 10 years for the non-treated group.

Various laboratory parameters showed changes in favor of the patientstreated with trientine hydrochloride. Free and total serum copper,SGOT, and serum bilirubin all showed mean increases over baselinein the untreated group which were significantly larger than with thepatients treated with trientine hydrochloride. In the 13 patientstreated with trientine hydrochloride, previous symptoms and signsrelating to d-penicillamine intolerance disappeared in 8 patients,improved in 4 patients, and remained unchanged in one patient. Theneurological status in the trientine hydrochloride group was unchangedor improved over baseline, whereas in the untreated group, 6 patientsremained unchanged and 6 worsened. Kayser-Fleischer rings improvedsignificantly during trientine hydrochloride treatment.

The clinical outcome of the two groups also differed markedly.Of the 13 patients on therapy with trientine hydrochloride (mean durationof therapy 4.1 years; range 1 to 13 years), all were alive at thedata cutoff date, and in the non-treated group (mean years with notherapy 2.7 years; range 3 months to 9 years), 9 of the 12 died ofhepatic disease.

Chelating Properties

Preclinical Studies

Studies in animals have shown that trientine hydrochloridehas cupriuretic activities in both normal and copper-loaded rats.In general, the effects of trientine hydrochloride on urinary copperexcretion 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 penicillamineand trientine hydrochloride on separate occasions in selected patientstreated with penicillamine for at least one year. Six-hour excretionrates of copper were determined off treatment and after a single doseof 500mg of penicillamine or 1.2g of trientine hydrochloride.The mean urinary excretion rates of copper were as follows:

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

These results demonstrate that SYPRINE is effectiveas a cupriuretic agent in patients with Wilson's disease althoughon a molar basis it appears to be less potent or less effective thanpenicillamine. Evidence from a radio-labelled copper study indicatesthat the different cupriuretic effect between these two drugs couldbe due to a difference in selectivity of the drugs for different copperpools within the body.

Pharmacokinetics

Data on the pharmacokinetics of trientine hydrochlorideare not available. Dosage adjustment recommendations are based uponclinical use of the drug (see DOSAGE AND ADMINISTRATION).

INDICATIONS AND USAGE

SYPRINE is indicated in the treatment of patientswith Wilson's disease who are intolerant of penicillamine. Clinicalexperience with SYPRINE is limited and alternate dosing regimens havenot been well-characterized; all endpoints in determining an individualpatient's dose have not been well defined. SYPRINE and penicillaminecannot be considered interchangeable. SYPRINE should be used whencontinued treatment with penicillamine is no longer possible becauseof intolerable or life endangering side effects.

Unlike penicillamine, SYPRINE is not recommended in cystinuria orrheumatoid arthritis. The absence of a sulfhydryl moiety renders itincapable of binding cystine and, therefore, it is of no use in cystinuria.In 15 patients with rheumatoid arthritis, SYPRINE was reported notto be effective in improving any clinical or biochemical parameterafter 12 weeks of treatment.

SYPRINE is notindicated for treatment of biliary cirrhosis.

CONTRAINDICATIONS

Hypersensitivity to this product.

WARNINGS

Patient experience with trientine hydrochloride islimited (see CLINICAL PHARMACOLOGY). Patientsreceiving SYPRINE should remain under regular medical supervisionthroughout the period of drug administration. Patients (especiallywomen) should be closely monitored for evidence of iron deficiencyanemia.

PRECAUTIONS

General

There are no reports of hypersensitivity in patientswho have been administered trientine hydrochloride for Wilson's disease.However, there have been reports of asthma, bronchitis and dermatitisoccurring after prolonged environmental exposure in workers who usetrientine hydrochloride as a hardener of epoxy resins. Patients shouldbe observed closely for signs of possible hypersensitivity.

Information for Patients

Patients should be directed to take SYPRINE on anempty stomach, at least one hour before meals or two hours after mealsand at least one hour apart from any other drug, food, or milk. Thecapsules should be swallowed whole with water and should not be openedor chewed. Because of the potential for contact dermatitis, any siteof exposure to the capsule contents should be washed with water promptly.For the first month of treatment, the patient should have his temperaturetaken nightly, and he should be asked to report any symptom such asfever or skin eruption.

Laboratory Tests

The most reliable index for monitoring treatmentis the determination of free copper in the serum, which equals thedifference between quantitatively determined total copper and ceruloplasmin-copper.Adequately treated patients will usually have less than 10mcgfree copper/dL of serum.

Therapy may be monitoredwith a 24-hour urinary copper analysis periodically (i.e., every 6-12months). Urine must be collected in copper-free glassware. Since alow copper diet should keep copper absorption down to less than onemilligram a day, the patient probably will be in the desired stateof negative copper balance if 0.5 to 1.0 milligram of copper is presentin a 24-hour collection of urine.

Drug Interactions

In general, mineral supplements should not be givensince they may block the absorption of SYPRINE. However, iron deficiencymay 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 andSYPRINE each inhibit absorption of the other, two hours should elapsebetween administration of SYPRINE and iron.

It is important that SYPRINE be taken on an empty stomach, at leastone hour before meals or two hours after meals and at least one hourapart from any other drug, food, or milk. This permits maximum absorptionand reduces the likelihood of inactivation of the drug by metal bindingin the gastrointestinal tract.

Carcinogenesis,Mutagenesis, ImpairmentofFertility

Data on carcinogenesis, mutagenesis, and impairmentof fertility are not available.

Pregnancy

Pregnancy CategoryC. Trientine hydrochloride was teratogenic in rats at doses similarto the human dose. The frequencies of both resorptions and fetal abnormalities,including hemorrhage and edema, increased while fetal copper levelsdecreased when trientine hydrochloride was given in the maternal dietsof rats. There are no adequate and well-controlled studies in pregnantwomen. SYPRINE should be used during pregnancy only if the potentialbenefit justifies the potential risk to the fetus.

Nursing Mothers

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

Pediatric Use

Controlled studies of the safety and effectivenessof SYPRINE in pediatric patients have not been conducted. It has beenused clinically in pediatric patients as young as 6 years with noreported adverse experiences.

Geriatric Use

Clinical studies of SYPRINE did not include sufficientnumbers of subjects aged 65 and over to determine whether they responddifferently from younger subjects. Other reported clinical experienceis insufficient to determine differences in responses between theelderly and younger patients. In general, dose selection should becautious, usually starting at the low end of the dosing range, reflectingthe greater frequency of decreased hepatic, renal, or cardiac function,and of concomitant disease or other drug therapy.

ADVERSE REACTIONS

Clinical experience with SYPRINE has been limited.The following adverse reactions have been reported in a clinical studyin patients with Wilson's disease who were on therapy with trientinehydrochloride: iron deficiency, systemic lupus erythematosus (see CLINICAL PHARMACOLOGY). Inaddition, the following adverse reactions have been reported in marketeduse: dystonia, muscular spasm, myasthenia gravis.

SYPRINE is not indicated for treatment of biliary cirrhosis, butin one study of 4 patients treated with trientine hydrochloride forprimary biliary cirrhosis, the following adverse reactions were reported:heartburn; epigastric pain and tenderness; thickening, fissuring andflaking of the skin; hypochromic microcytic anemia; acute gastritis;aphthoid ulcers; abdominal pain; melena; anorexia; malaise; cramps;muscle pain; weakness; rhabdomyolysis. A causal relationship of thesereactions to drug therapy could not be rejected or established.

OVERDOSAGE

There is a report of an adult woman who ingested30 grams of trientine hydrochloride without apparent ill effects.No other data on overdosage are available.

DOSAGE AND ADMINISTRATION

Systemic eva luation of dose and/or interval betweendose has not been done. However, on limited clinical experience, therecommended initial dose of SYPRINE is 500-750mg/day for pediatricpatients and 750-1250mg/day for adults given in divided dosestwo, three or four times daily. This may be increased to a maximumof 2000mg/day for adults or 1500mg/day for pediatric patientsage 12 or under. The daily dose of SYPRINE should be increased onlywhen the clinical response is not adequate or the concentration offree serum copper is persistently above 20mcg/dL. Optimal long-termmaintenance dosage should be determined at 6-12 month intervals (see PRECAUTIONS,Laboratory Tests).

It is importantthat SYPRINE be given on an empty stomach, at least one hour beforemeals or two hours after meals and at least one hour apart from anyother drug, food, or milk. The capsules should be swallowed wholewith water and should not be opened or chewed.

HOW SUPPLIED

No. 3408— Capsules SYPRINE, 250mg,are light brown opaque capsules coded SYPRINE on one side and MSD661on the other. They are supplied as follows:

NDC 0006-0661-68 in bottles of 100.

Storage

Keep container tightly closed.

Store at 2-8°C (36-46°F).

MERCK &CO., INC., Whitehouse Station, NJ 08889, USA

Issued January 2001

Printed in USA

7664604

Revised: 02/2007