Trientine

Pregnancy Category: C

Lactation: Excretioin in breast milk unknown; use caution

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

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.

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 2400 mg per day. The average dosage required to achieve an optimal clinical response varied between 1000 mg and 2000 mg per day. The mean duration of trientine hydrochloride therapy was 48.7 months (range 2-164 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, SG0T, 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

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.

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 SYPRINE 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).

Patients should be directed to take SYPRINE 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. Because of the potential for contact dermatitis, any site of exposure to the capsule contents should be washed with water promptly. 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.

• It is used to treat Wilson's disease.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Have your urine checked as you have been told by your doctor.
• During the first month you take trientine, take your temperature every night. Call your doctor if you have a fever or skin irritation.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

Use trientine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Take on an empty stomach. Take at least 1 hour before or 2 hours after meals. Take at least 1 hour before or after any other drug, food, or milk.
• Do not take iron products within 2 hours of this medicine.
• If you take other products with minerals in them (like aluminum, calcium, magnesium, or zinc), talk with your doctor. You may need to avoid these products while taking trientine.
• Swallow whole. Do not chew, open, or crush.
• Take with a full glass of water.
• If the capsule is opened or broken, do not touch the contents. If the contents are touched or they get in the eyes, wash hands or eyes right away.

What do I do if I miss a dose?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of lupus like a rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, chest pain or shortness of breath, or swelling in the arms or legs.
• Fever.
• Trouble controlling body movements.
• Muscle spasm.
• Muscle weakness.
• Feeling very tired or weak.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

• Chelating Agent

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

13 and older:
750 to 1250 mg, orally, in divided doses given 2, 3, or 4 times daily
Maximum dose: 2000 mg daily

12 and under:
500 to 750 mg, orally, in divided doses given 2, 3, or 4 times daily
Maximum dose: 1500 mg daily

Comments:
-Increase dose for inadequate clinical response or free serum copper persistently above 20 mcg/dL.
-Re-evaluate dose every 6 to 12 months.
-Clinical experience with this drug is limited and alternate dosing regimens have not been well characterized.
-All dosing endpoints are not well defined.
-This drug is not interchangeable with penicillamine.
-Use this drug when penicillamine treatment is not possible because of intolerable or life threatening side effects.
-This drug is not recommended for cystinuria or rheumatoid arthritis.
-It is incapable of binding cystine, so it is of no use in cystinuria.
-In a small study, it was ineffective for rheumatoid arthritis.
-This drug is not indicated for treatment of biliary cirrhosis.

Use: Treatment of Wilson's disease in patients who are intolerant of penicillamine.

Data not available