Consumer medicine information

Trientine Waymade

Trientine dihydrochloride

BRAND INFORMATION

Brand name

Trientine Waymade

Active ingredient

Trientine dihydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Trientine Waymade.

SUMMARY CMI

Trientine Waymade

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new. Please report side effects. See the full CMI for further details.

1. Why am I using Trientine Waymade?

Trientine Waymade contains the active ingredient trientine dihydrochloride. Trientine Waymade is used to treat Wilson's disease in people who can not take another medicine called penicillamine because of side effects. For more information, see Section 1. Why am I using Trientine Waymade? in the full CMI.

2. What should I know before I use Trientine Waymade?

Do not use if you have ever had an allergic reaction to trientine dihydrochloride or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use Trientine Waymade? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Trientine Waymade and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Trientine Waymade?

  • Always take this medicine exactly as your doctor or pharmacist has told you.
  • Adults: The usual dose is between 3 and 5 capsules per day in divided doses.
  • Children: The dose will depend on age and weight.
  • The capsules should be swallowed whole with water and should not be opened or chewed.
  • The capsules should be taken on an empty stomach, at least one hour before meals or two hours after meals. The capsules should be taken at least one hour apart from any other medicine, food, or milk.

More instructions can be found in Section 4. How do I use Trientine Waymade? in the full CMI.

5. What should I know while using Trientine Waymade?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Trientine Waymade.
  • Tell your doctor immediately if symptoms of your disease get worse.
  • Keep all of your doctor's appointments so that your doctor can check for symptoms of your disease and copper levels in your blood and urine.
Things you should not do
  • Do not stop using this medicine suddenly or change treatment without speaking with your doctor even if you feel better.
Looking after your medicine
  • Keep container tightly closed. Store at 2° to 8°C (Refrigerate. Do not freeze).
  • Store in the original container and retain the silica gel sachet in the bottle in order to protect from moisture.
  • If removed from the refrigerator, Trientine Waymade capsules should be stored below 30°C in the original container and must be used within 60 days.

For more information, see Section 5. What should I know while using Trientine Waymade? in the full CMI.

6. Are there any side effects?

The most common side effects are nausea and abdominal or stomach pain or discomfort. Serious side effects include severe diarrhoea or abdominal pain, shaking, lack of coordination, slurred speech, muscle stiffness, worsening of muscle spasms (especially when starting treatment).

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

Trientine Waymade

Active ingredient: Trientine dihydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using Trientine Waymade. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Trientine Waymade.

Where to find information in this leaflet:

1. Why am I using Trientine Waymade?
2. What should I know before I use Trientine Waymade?
3. What if I am taking other medicines?
4. How do I use Trientine Waymade?
5. What should I know while using Trientine Waymade?
6. Are there any side effects?
7. Product details

1. Why am I using Trientine Waymade?

Trientine Waymade contains the active ingredient trientine dihydrochloride. Trientine Waymade binds to copper and is known as a chelating agent.

Trientine Waymade is used to treat Wilson's disease in people who can not take another medicine called penicillamine because of side effects.

Wilson's Disease is a condition which results in too much copper in the body. This medicine binds to copper and allows it to pass out of the body.

2. What should I know before I use Trientine Waymade?

Warnings

Do not use Trientine Waymade if:

  • you are allergic to trientine dihydrochloride, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • have any other medical conditions
  • take any medicines for any other condition.

If you were already taking another trientine medicine, your doctor may change your daily dose when switching to Trientine Waymade treatment.

Your doctor will need to regularly check for symptoms of your disease and copper levels in your blood and urine. Regular monitoring is especially important at the start of your treatment or when your dose is changed, in growing children and pregnant women to ensure that copper levels are maintained at a suitable level. The doctor may need to increase or decrease your dose of Trientine Waymade.

Regular monitoring is also important if you have liver or kidney problems.

This medicine may reduce the level of iron in your blood and your doctor may prescribe you iron supplementation (see additional information under 3. What if I am taking other medicines?).

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant. Trientine Waymade can be harmful to the unborn baby when taken by a woman during pregnancy so your doctor will discuss with you the benefits and risks of using it. If you are pregnant and taking Trientine Waymade you will be monitored throughout your pregnancy for any effect on the baby or changes in your copper levels.

Talk to your doctor if you are breastfeeding or intend to breastfeed. It is not known if Trientine Waymade passes into your breast milk.

Children

Do not give this medicine to a child under the age of 6 years. Safety and effectiveness in children younger than 6 years have not been established.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Trientine Waymade and affect how it works.

Some medicines should not be given at the same time as they may stop Trientine Waymade from being absorbed into the body.

If you take other medicines, including non-prescription medicines, vitamins or supplements, they should be taken at least one hour before or after your dose of Trientine Waymade.

Medicines that may reduce the effect of Trientine Waymade include:

  • Mineral supplements containing iron or zinc

If your doctor advises you to take an iron supplement or an antacid, separate the dose by at least 1 hour before or after your Trientine Waymade dose.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Trientine Waymade.

4. How do I use Trientine Waymade?

How much to take

  • Your doctor will decide the correct dose for you.
  • Adults: the usual dose is 3 to 5 capsules a day. The total daily dose should be divided into 2 to 4 smaller doses as directed by your doctor.
  • Children: the dose will depend on age and body weight. The total daily dose should be divided into 2 or 3 smaller doses as directed by your doctor.
  • Follow the instructions provided and use Trientine Waymade until your doctor tells you to stop. This medicine is for long-term use because Wilson's disease is a life-long condition.

When to take Trientine Waymade

  • Trientine Waymade should be taken on an empty stomach, at least 1 hour before or 2 hours after food.
  • The capsules should be swallowed whole with water and should not be opened or chewed. Tell your doctor if you have difficulties swallowing this medicine.

If you forget to take Trientine Waymade

Discuss with your Doctor or Pharmacist about what to do if you miss your dose. Trientine Waymade should be taken regularly at the same time each day. If you miss your dose at the usual time, take your next dose at scheduled time.

Do not take a double dose to make up for the dose you missed.

Do not exceed the daily dose prescribed by your Doctor.

If you use too much Trientine Waymade

If you think that you have used too much Trientine Waymade, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using Trientine Waymade?

Things you should do

Keep all of your doctor's appointments so that your progress can be checked.

  • Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Call your doctor straight away if you:

  • notice your symptoms get worse during treatment with Trientine Waymade, especially when first starting treatment.

Remind any doctor, dentist or pharmacist you visit that you are using Trientine Waymade.

Things you should not do

  • Do not stop using this medicine suddenly.
  • Do not change your treatment without speaking with your doctor.
  • Do not open or break the capsules. If the capsule contents comes into contact with your body, wash the area immediately with water.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Trientine Waymade affects you.

Looking after your medicine

  • Keep container tightly closed.
  • Store at 2° to 8°C (Refrigerate. Do not freeze).
  • Store in the original container and retain the silica gel sachet in the bottle in order to protect from moisture.
  • If removed from the refrigerator, Trientine Waymade capsules should be stored below 30°C in the original container and must be used within 60 days.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal related:
  • Nausea
  • Abdominal or stomach pain or discomfort
Skin related:
  • Skin rashes
Other side effects:
  • Tiredness, being short of breath when exercising, dizziness and looking pale. These could be symptoms of anaemia which is a deficiency in the number or quality of red blood cells
  • Muscle stiffness and/or pain
  • Pain in your joints
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Gastrointestinal related:
  • Severe stomach pains
  • Diarrhoea with blood or mucus, stomach pain, fever
Nervous system related:
  • Shaking, lack of coordination, slurred speech, difficulty speaking, muscle stiffness, worsening of muscle spasms.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Some of these side effects (for example, changes in liver function, changes in blood tests) can only be found when your doctor does tests from time to time to check your progress.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Trientine Waymade contains

Active ingredient
(main ingredient)		Each capsule contains 250 mg of trientine dihydrochloride
Other ingredients
(inactive ingredients)		Stearic acid
Gelatin
Titanium dioxide
Sunset yellow FCF
Purified water
TekPrint SW-9008 Black Ink

Do not take this medicine if you are allergic to any of these ingredients.

What Trientine Waymade looks like

Trientine Waymade are cylindrical hard gelatin capsules filled with a white to off white color powder. The capsule has an opaque orange colour cap printed with ‘NAV’ in black ink and an opaque white coloured body printed with “101” in black ink.

Trientine Waymade is supplied in a white bottle with a screw cap, containing 100 capsules and a sachet of dried silica gel as desiccant.

Do not eat the desiccant.

(Aust R 327984).

Who distributes Trientine Waymade

Clinect Pty Ltd
120-132 Atlantic Drive, Keysborough
VIC 3173, Australia
Free Call Australia: 1800 899 005

This leaflet was prepared in September 2023

Published by MIMS November 2023

BRAND INFORMATION

Brand name

Trientine Waymade

Active ingredient

Trientine dihydrochloride

Schedule

S4

 

1 Name of Medicine

Trientine dihydrochloride.

2 Qualitative and Quantitative Composition

Each capsule contains 250 mg trientine dihydrochloride (equivalent to 166.7 mg trientine base).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Cylindrical size "1" hard gelatin capsule with opaque orange colour cap printed with "NAV" in black ink and opaque white colour body printed with "101" in black ink. Capsule filled with white to off white colour powder.

4 Clinical Particulars

4.1 Therapeutic Indications

Trientine Waymade is indicated in the treatment of patients with Wilson's disease who are intolerant of penicillamine.

4.2 Dose and Method of Administration

Dosage.

The starting dose would usually correspond to the lowest recommended dose and the dose should subsequently be adapted according to the patient's clinical response (see Section 4.4 Special Warnings and Precautions for Use).
The daily dose of Trientine Waymade should be increased only when the clinical response is not adequate, or the concentration of free serum copper is persistently above 3.1 micromol/L. Optimal long-term maintenance dosage should be determined at 6-12 month intervals.

Adults.

The recommended initial dose of Trientine Waymade is 750-1250 mg/day (equivalent to 500-833 mg/day trientine base) for adults given in divided doses two, three or four times daily. This may be increased to a maximum of 2000 mg/day (1333 mg/day trientine base) for adults.

Paediatric patients.

The recommended initial dose of Trientine Waymade is 20 mg/kg/day (equivalent to 13 mg/kg/day trientine base) rounded off to the nearest 250 mg, given in two or three divided doses. This may be increased to a maximum of 1500 mg/day (equivalent to 1000 mg/day trientine base) for paediatric patients age 12 or under.

Patients primarily presenting hepatic symptoms.

The recommended dose in patients primarily presenting hepatic symptoms is the same as the recommended adult dose. It is advised, however, to monitor patients presenting with hepatic symptoms every two to three weeks after initiation of treatment with Trientine Waymade.

Patients primarily presenting neurological symptoms.

Dose recommendations are the same as for adults. However, up titration should be done with moderation and consideration, and adapted according to the patient's clinical response such as worsening of tremor as patients could be at risk of neurological deterioration at initiation of treatment (see Section 4.4 Special Warnings and Precautions for Use). It is further advised to monitor patients presenting with neurological symptoms every one to two weeks after initiation of treatment with Trientine Waymade until target dose is reached.

Method of administration.

The capsules should be swallowed whole with water and should not be opened or chewed.
It is important that Trientine Waymade 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 medicine, food, or milk. This permits maximum absorption and reduces the likelihood of inactivation of the drug by metal binding in the gastrointestinal tract.
Because of the potential for contact dermatitis, any site of exposure to the capsule contents should be washed with water promptly.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed, see Section 6.1 List of Excipients.

4.4 Special Warnings and Precautions for Use

When switching a patient from another trientine formulation, caution is advised because different trientine salts are available which may have a different trientine content (base) and a different bioavailability. Dose adjustment may be required (see Section 4.2 Dose and Method of Administration).
Trientine dihydrochloride is not indicated as an alternative to penicillamine in the treatment of rheumatoid arthritis or cystinuria. Penicillamine-induced systemic lupus erythematosus may not resolve on transfer to Trientine Waymade.
Trientine dihydrochloride is a chelating agent which has been found to reduce serum iron levels possibly reducing its absorption. Iron supplementation may be necessary in some cases and should be administered at a different time of the day to Trientine Waymade.
There is no evidence that calcium or magnesium antacids alter the efficacy of trientine but it is good practice to separate their administration. (i.e. antacids should be taken after meals). See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
There is no advantage in using trientine and penicillamine in combination.

Monitoring.

Patients receiving trientine should remain under regular medical supervision and be monitored using all available clinical data for appropriate control of clinical symptoms and copper levels in order to optimise treatment. Frequency of monitoring is recommended to be at least twice a year. More frequent monitoring is advised during the initial phase of treatment and during phases of disease progression or when dose adjustments are made as to be decided by the treating physician (see Section 4.2 Dose and Method of Administration).
The aim of maintenance treatment is to maintain free copper levels in plasma (also known as nonceruloplasmin plasma copper) and the urinary copper excretion within the acceptable limits.
The determination of serum free copper, calculated using the difference between the total copper and the ceruloplasmin-bound copper (normal level of free copper in the serum is usually 1.6 to 2.4 micromol/L) can be a useful index for monitoring therapy.
The measurement of copper excretion in the urine may be performed during therapy. Since chelation therapy leads to an increase in urinary copper levels, this may/ will not give an accurate reflection of the excess copper load in the body but may be a useful measure of treatment compliance.
The use of appropriate copper parameter target ranges is described in clinical practice guidelines related to Wilson's disease.
Like with all anti-copper agents, overtreatment carries the risk of copper deficiency, which is especially harmful for children and pregnant women (see Section 4.6 Fertility, Pregnancy and Lactation) since copper is required for proper growth and mental development. Therefore, monitoring for manifestations of overtreatment should be undertaken.
Patients with renal and/or hepatic impairment receiving trientine should remain under regular medical supervision for appropriate control of symptoms and copper levels. Close monitoring of renal and/or liver function is also recommended in these patients (see Section 4.2 Dose and Method of Administration).
Worsening of neurological symptoms may occur at the beginning of chelation therapy due to excess of free serum copper during the initial response to treatment. It is possible that this effect may be more evident in patients with pre-existing neurological symptoms. It is recommended to monitor patients closely for such signs and symptoms and to consider careful titration to reach the recommended therapeutic dose and to reduce dose when necessary.
Dose adjustments in the trientine dose should be considered in case of signs of reduced efficacy such as (persistent) increase in liver enzymes, and worsening of tremor. When trientine doses are adjusted this should be done in small steps. The trientine dose may also be reduced in case of side effects of trientine, such as gastrointestinal complaints and haematological changes. Trientine doses should be reduced to a more tolerable dose and may be increased again, once side effects have been resolved.

Use in the elderly.

Clinical studies of trientine dihydrochloride 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.

Paediatric use.

Controlled studies of the safety and effectiveness of trientine dihydrochloride in paediatric patients have not been conducted. It has been used clinically in paediatric patients as young as 6 years.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Zinc.

There are insufficient data to support the concomitant use of zinc and trientine. The combination of trientine with zinc is not recommended as interaction of zinc with trientine is likely, thereby reducing the effect of both active substances.

Other anti-copper agents.

No interaction studies have been performed on the concomitant administration of trientine with penicillamine.

Food.

Trientine is poorly absorbed following oral intake and food further inhibits trientine absorption. Specific food interaction studies have been performed with trientine in healthy subjects, showing a reduction of the extent of absorption of trientine up to 45%. Systemic exposure is critical for its principal mechanism of action, copper chelation (see Section 5.1 Pharmacodynamic Properties). Therefore, it is recommended that trientine is taken at least 1 hour before meals or 2 hours after meals and at least one hour apart from any other medicinal product, food, or milk to allow for maximum absorption and reduce the likelihood of the formation of complexes by metal binding in the gastrointestinal tract (see Section 4.2 Dose and Method of Administration).

Other products.

Trientine has been found to reduce serum iron levels. Therefore, iron supplementation may be necessary in some cases. Concomitant oral iron or other heavy metals should be administered at a different time than trientine to prevent the formation of complexes (see Section 4.4 Special Warnings and Precautions for Use).
There is no evidence that calcium and magnesium antacids alter the efficacy of trientine but it is recommended to separate their administration.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category D)
Trientine dihydrochloride was teratogenic in animals at clinically relevant doses, possibly due to the induction of copper deficiency or zinc toxicity. Fetal brain abnormalities like haemorrhages and haematomas, delayed ossification in the cranium, exencephaly, microcephaly, and hydrocephaly have been observed in mice and rats treated with trientine. There are no adequate and well-controlled studies in pregnant women. Trientine Waymade should be used during pregnancy only if the potential benefit justified the potential risk to the fetus.
If used in pregnancy, careful monitoring of maternal serum copper levels is required, and the dose of trientine adjusted as required to maintain serum copper levels within the normal range.
 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 Waymade is administered to a nursing mother.

4.7 Effects on Ability to Drive and Use Machines

No studies have been identified which evaluated the impact of trientine on the ability to drive or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial experience.

Weiss 20131 reported 7.1% (10/141) patients receiving trientine discontinued due to adverse events which was statistically lower than 28.8% (94/326) for penicillamine (p = 0.039). The most frequent adverse events associated with discontinuation of trientine treatment were: arthralgia (n = 4), gastric complaints such as nausea and gastric pain (n = 2), pruritus, myalgia, nephropathy, leukopenia, increase in antinuclear antibodies, erythema, lupus erythematosus, hirsutism (n = 1 for each) and other non-specified adverse events (n = 4).
A significantly higher rate of neurologic deterioration was reported for symptomatic patients with neurological presentations who received first line treatment with trientine (4/20, 20%) than penicillamine (6/114, 5.3%) (p = 0.042), although the differences were not significant (p = 0.672) for second-line treatments with trientine and penicillamine (8/51, 15.7% and 1/13, 7.3%, respectively). The rate of hepatic deterioration for symptomatic patients with hepatic presentations was not significantly different between trientine and penicillamine treatments.

Tabulated list of adverse reactions.

Table 1 presents the list of adverse reactions according to the MedDRA system organ classification. Frequencies are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).
There have been reports of neurological deterioration at the start of treatment in Wilson's disease patients treated with copper chelators including trientine, with symptoms of, for example, dystonia, rigidity, tremor and dysarthria (see Section 4.2 Dose and Method of Administration).

Paediatric population.

Clinical trials including a limited number of children in the age range of 5-17 years at the start of treatment indicate that frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is a report of an adult woman who ingested 30 grams of trientine dihydrochloride without apparent ill effects. In a second case, a large overdose of trientine (40 g; 200 tablets) resulted in self-limiting dizziness and vomiting with no further clinical sequelae or significant biochemical abnormalities.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Trientine has a structure similar to polyamines and chelates copper by forming a stable complex with the four constituent nitrogens in a planar ring. The pharmacodynamic action of trientine is dependent on its property of chelating copper and elimination of the trientine-copper complex in the urine. Trientine may also chelate copper in the intestinal tract and in the process inhibit copper absorption.

Clinical trials.

Weiss 20131 conducted a multicentre, retrospective observational study to compare the efficacy and safety of trientine versus penicillamine (DPA) in patients with WD (n = 380) treated at tertiary care centres in Germany and Austria, and additional patients from the EUROWILSON registry (n = 25). The cohort consisted of outcomes for patients with WD treated with DPA (n = 326) and trientine (n = 141) for at least six months. The primary efficacy outcome was the change in hepatic and neurologic outcomes (i.e. clinical symptoms and tests) at 6, 12, 24, 36, and 48 months after initiation of the treatment regimen. Hepatic outcome measures were based on clinical symptoms, course of liver enzymes, and liver function tests. Patients with either of these clinical or biochemical signs of liver disease were considered symptomatic. The course of neurologic disease was evaluated by the physician.
Stable hepatic disease under second-line therapy was reported for 4 of 16 (25%) penicillamine treatments and for 10 of 45 (22.2%) trientine treatments. No hepatic worsening was seen in chelation monotherapy for patients who presented without hepatic symptoms. A higher rate of hepatic improvement was observed for second-line therapy when symptomatic patients were considered of all patients with hepatic presentation (31/45, 68.9% versus 31/103, 30.1%).
Stable neurologic disease for second-line therapy was reported for 9 of 13 (69.2%) d- penicillamine treatments and for 17 of 51 (33.3%) trientine treatments. With second-line therapy, neurologic worsening was comparable between groups, with a trend favoring penicillamine (penicillamine: 1 of 13, 7.3%; trientine: 8 of 51, 15.7%). No statistically significant differences were found for the rate of improvement for second-line (penicillamine 3 of 13, 23.1% versus trientine 26 of 51, 51%) chelation therapy.
There were no differences between the treatments based on the number of overall discontinuations (p = 0.36) with 142/326 (43.6%) discontinuing from penicillamine and 36/141 (25.5%) from trientine therapy. Discontinuation as a result of adverse events was more frequent for penicillamine treatment than for trientine treatment with 94/326 (28.8%) of DPA treatments stopped because of adverse events versus 10/141 (7.1%) of trientine treatments (p = 0.039).

Chelating properties.

Preclinical studies.

Studies in animals have shown that trientine dihydrochloride has cupriuretic activities in both normal and copper-loaded animals.

5.2 Pharmacokinetic Properties

Absorption.

Following oral administration, trientine absorption is low and variable in patients with Wilson's disease. Trientine is absorbed with Tmax occurring between 0.5 and 4 hours post-dose in healthy volunteers and patients. Exposure seems to be highly variable between subjects. The terminal half-life in plasma is approximately 13.5 h.

Distribution.

Trientine is widely distributed in tissues with relatively high concentrations measured in the liver, heart, and kidney in the rat.

Metabolism.

Trientine is acetylated in two major metabolites, N1-acetyltriethylenetetramine (MAT) and N1,N10-diacetyltriethylenetetramine (DAT). MAT and DAT are capable of chelating copper, albeit with a lower affinity than trientine. However, the extent of MAT and DAT's contribution to the overall effect of trientine on copper levels in Wilson's Disease patients remains to be determined.

Excretion.

Trientine and its metabolites are rapidly excreted in the urine. Unabsorbed trientine is eliminated through faecal excretion.

5.3 Preclinical Safety Data

Genotoxicity.

Trientine has shown positive effects in in vitro genotoxicity studies, including the Ames test and genotoxicity tests in mammalian cells. In vivo, trientine was however negative in the mouse micronucleus test.

Carcinogenicity.

No data available.

6 Pharmaceutical Particulars

6.1 List of Excipients

Stearic acid; gelatin; titanium dioxide; sunset yellow FCF; purified water; TekPrint SW-9008 Black Ink.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Keep container tightly closed.
Store at 2° to 8°C (Refrigerate. Do not freeze).
Store in the original container and retain the silica gel sachet in the bottle in order to protect from moisture.
If removed from the refrigerator, Trientine Waymade capsules should be stored below 30°C in the original container and must be used within 60 days.

6.5 Nature and Contents of Container

100 capsules in a white HDPE bottle with a cap with screw cap, also containing a sachet of dried silica gel as desiccant.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.


CAS number.

38260-01-4.

References

1 Weiss K H, Thirik F, Gotthardt DN, et al. Efficacy and safety of oral chelators in treatment of patients with Wilson Disease. Clin Gastroenterol Hepatol. 2013; 11:1028-1035.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Summary Table of Changes