Leaflet CUPRIOR 150mg film-coated tablets

Cuprior 150 mg film-coated tablets

Each film-coated tablet contains trientine tetrahydrochloride equivalent to 150 mg trientine.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet)

Yellow, 16 mm x 8 mm oblong film-coated tablet with a score line on each side.

The tablet can be divided into equal doses.

Cuprior is indicated for the treatment of Wilson’s disease in adults, adolescents and children ≥ 5 yearsintolerant to D-penicillamine therapy.

Treatment should only be initiated by specialist physicians with experience in the management of

Wilson’s disease.

The starting dose would usually correspond to the lowest dose in the range and the dose shouldsubsequently be adapted according to the patient’s clinical response (see section 4.4).

Adult

The recommended dose is between 450 mg and 975 mg (3 to 6 and a half film-coated tablets) per dayin 2 to 4 divided doses.

The starting dose in paediatrics is lower than for adults and depends on age and may be calculatedusing body weight. The dose should subsequently be adapted according to the child’s clinical response(see section 4.4).

Children and adolescents (≥ 5 years to 18 years)

The dose is usually between 225 mg and 600 mg per day (1 and a half to 4 film-coated tablets) in 2 to4 divided doses.

Children aged < 5 years

The safety and efficacy of trientine in children aged < 5 years have not been established.

The pharmaceutical form is not suitable for administration to children < 5 years.

The recommended doses of Cuprior are expressed as mg of trientine base (i.e. not in mg of thetrientine tetrahydrochloride salt).

No dose adjustment is required in elderly patients.

There is limited information in patients with renal impairment. No specific dose adjustment is requiredin these patients (see section 4.4).

Cuprior is for oral use. The film-coated tablets should be swallowed with water. The scored film-coated tablet can be divided in two equal halves, if required, to provide a more precise dose orfacilitate administration.

It is important that Cuprior is given on an empty stomach, at least one hour before meals or two hoursafter meals and at least one hour apart from any other medicinal product, food, or milk (see section4.5).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

When switching a patient from another formulation trientine, caution is advised because dosesexpressed in trientine base may not be equivalent (see section 4.2).

Trientine is a chelating agent which has been found to reduce serum iron levels. Iron supplements maybe necessary in case of iron deficiency anaemia and should be administered at a different time (seesection 4.5).

The combination of trientine with zinc is not recommended. There are only limited data onconcomitant use available and no specific dose recommendations can be made.

In patients who were previously treated with D-penicillamine, lupus-like reactions have been reportedduring subsequent treatment with trientine, however it is not possible to determine if there is a causalrelationship with trientine.

Patients receiving Cuprior should remain under regular medical supervision and be monitored forappropriate control of symptoms and copper levels in order to optimise the dose (see section 4.2).

The aim of maintenance treatment is to maintain free copper levels in the serum within acceptablelimits. The most reliable index for monitoring therapy is the determination of serum free copper whichis calculated using the difference between the total copper and the ceruloplasmin-bound copper(normal level of free copper in the serum is usually 100 to 150 microgram/L).

The measurement of copper excretion in the urine may be performed during therapy. Since chelationtherapy leads to an increase in urinary copper levels, this may/will not give an accurate reflection ofthe excess copper load in the body but may be a useful measure of treatment compliance.

Worsening of clinical symptoms, including neurological deterioration, may occur at the beginning ofchelation therapy due to excess of free serum copper during the initial response to treatment. Closemonitoring is required to optimise the dose or to adapt treatment if necessary.

Overtreatment carries the risk of copper deficiency. Monitoring for manifestations of overtreatmentshould be undertaken, particularly when copper requirements may change, such as in pregnancy (seesection 4.6) and in children where appropriate control of copper levels are required to ensure propergrowth and mental development.

Patients with renal impairment receiving trientine should remain under regular medical supervision forappropriate control of symptoms and copper levels. Close monitoring of renal function is alsorecommended in these patients (see section 4.2).

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free.’

No interaction studies have been performed.

Trientine has been found to reduce serum iron levels, possibly by reducing its absorption, and ironsupplements may be required. Since iron and trientine may inhibit absorption of each other, ironsupplements should be taken after at least two hours have elapsed from the administration of trientine.

As trientine is poorly absorbed following oral intake and the principal mechanism of action requires itssystemic exposure (see section 5.1), it is important that the film-coated tablets are taken on emptystomach at least one hour before meals or 2 hours after meals and at least one hour apart from anyother medicinal product, food, or milk (see section 4.2). This maximises the absorption of trientine andreduces the likelihood of the medicinal product binding to metals in the gastrointestinal tract.

However, no food interaction studies have been performed and so the extent of the food effect onsystemic trientine exposure is unknown.

Although there is no evidence that calcium or magnesium antacids alter the efficacy of trientine, it isgood practice to separate their administration.

There is a limited amount of data from the use of trientine in pregnant women.

Studies in animals have shown reproductive toxicity, which was probably a result of trientine-inducedcopper deficiency (see section 5.3).

Cuprior should only be used in pregnancy after careful consideration of the benefits compared with therisks of treatment in the individual patient. Factors which need to be born in mind include the risksassociated with the disease itself, the risk of those alternative treatments which are available and thepossible teratogenic effects of trientine (see section 5.3).

Since copper is required for proper growth and mental development, dose adjustments may berequired to ensure that the foetus will not become copper deficient and close monitoring of the patientis essential (see section 4.4).

The pregnancy should be closely monitored in order to detect possible foetal abnormality and to assessmaternal serum copper levels throughout the pregnancy. The dose of trientine used should be adjustedin order to maintain serum copper levels within the normal range.

Babies born to mothers being treated with trientine should be monitored for serum copper levels whereappropriate.

It is unknown whether trientine is excreted in human milk. A risk to the newborns/infants cannot beexcluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstainfrom Cuprior therapy taking into account the benefit of breast-feeding for the child and the benefit oftherapy for the woman.

It is unknown whether trientine has an effect on human fertility.

Cuprior has no or negligible influence on the ability to drive and use machines.

The most commonly reported adverse reaction with trientine is nausea. Serious iron deficiencyanaemia and severe colitis may occur during treatment.

The following adverse reactions have been reported with the use of trientine for Wilson’s disease.

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 beestimated from the available data).

System organ class Adverse reactions

Blood and lymphatic system disorders Uncommon: sideroblastic anaemia.

Not known: iron deficiency anaemia.

Gastrointestinal disorders Common: nausea.

Not known: duodenitis, colitis (including severe colitis).

Skin and subcutaneous tissue disorder Uncommon: skin rash, pruritus, erythema.

Not known: urticaria.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Occasional cases of trientine overdose have been reported. In cases up to 20 g of trientine base therewere no apparent adverse effects reported. A large overdose of 40 g of trientine base resulted in self-limiting dizziness and vomiting with no other clinical sequelae or significant biochemicalabnormalities reported.

There is no antidote for trientine acute overdose.

Chronic over treatment can lead to copper deficiency and reversible sideroblastic anaemia.

Overtreatment and excess copper removal can be monitored using values of urine copper excretionand of non-ceruloplasmin bound copper. Close monitoring is required to optimise the dose or to adapttreatment if necessary (see section 4.4).

Pharmacotherapeutic group: Other alimentary tract and metabolism products, various alimentary tractand metabolism products, ATC code: A16AX12.

Trientine is a copper-chelating agent whose principal mechanism of action is to eliminate absorbedcopper from the body by forming a stable complex that is then eliminated through urinary excretion.

Trientine may also chelate copper in the intestinal tract and so inhibit copper absorption.

The absorption of trientine following oral administration is low and variable in patients with Wilsondisease. The pharmacokinetic profile of Cuprior has been evaluated after a single oral dose of 450 mg,600 mg and 750 mg trientine in healthy male and female subjects. Plasma levels of trientine roserapidly following administration with the median peak level reached after 1.25 to 2 hours. Thetrientine plasma concentration then declined in a multiphasic manner, initially rapidly, followed by aslower elimination phase. The overall pharmacokinetic profiles were similar between males andfemales, although males had higher levels of trientine.

Little is known on the distribution of trientine in organs and tissues.

Trientine is acetylated in two majors metabolites, N(1)-acetyltriethylenetetramine (MAT) and

N(1),N(10)-diacetyltriethylenetetramine (DAT). MAT may also participate to the overall clinicalactivity of Cuprior, however the extent of MAT to the overall effect of Cuprior on copper levelsremains to be determined.

Trientine and its metabolites are rapidly excreted in the urine, although low levels of trientine couldstill be detected in the plasma after 20 hours. Unabsorbed trientine is eliminated through faecalexcretion.

Plasma exposures in humans have shown a linear relationship with oral doses of trientine.

Preclinical data obtained with trientine have shown adverse reactions not observed in clinical studies,but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance toclinical use as follows:

In mice administered in drinking water, trientine displayed increased frequencies of inflammation ofthe lung interstitium and liver periportal fatty infiltration. Hematopoietic cell proliferation was seen inthe spleen of males. Kidney and body weights were reduced in males as was the incidence of renalcytoplasmic vacuolisation. The NOAEL was established at approximately 92 mg/kg/day for males and99 mg/kg/day for females. In rats administered oral trientines doses, up to 600 mg/kg/day for 26weeks, histopathology revealed a dose-related incidence and severity of focal chronic interstitialpneumonitis accompanied by fibrosis of the alveolar wall. The microscopic changes in lung wereconsidered indicative of a persistent inflammatory reaction or persistent toxic effect on alveolar cells.

Taking into account that trientine has irritating properties, it was estimated that the observed chronicinterstitial pneumonitis was explained by a cytotoxic effect of trientine upon accumulation intobronchiolar epithelial cells and alveolar pneumocytes. These findings were not reversible. The rat

NOAEL was considered 50 mg/kg/day for females, a NOAEL was not established for males.

Dogs receiving oral doses of trientine up to 300 mg/kg/day, showed neurological and/ormusculo-skeletal clinical symptoms (abnormal gait, ataxia, weak limbs, body tremors) in repeat-dosetoxicity studies, attributed to the copper-depleting activity of trientine. The NOAEL was established at50 mg/kg/day resulting in safety margins of about 4 in males and 17 in females, towards humantherapeutic exposures.

Overall, trientine has shown positive effects in in vitro genotoxicity studies, including the Ames testand genotoxicity tests in mammalian cells. In vivo, trientine was however negative in the mousemicronucleus test.

When rodents were fed throughout pregnancy a diet containing trientine, the frequency of resorptionsand the frequency of abnormal fetuses at term showed a dose-related increase. These effects arepossibly due to trientine induced-copper and zinc deficiency.

In silico data predict that trientine displays irritating and sensitising properties. Positive results forsensitization potential in Guinea pig maximization tests were reported.

Mannitol

Colloidal anhydrous silica

Glycerol dibehenate

Polyvinyl alcohol

Talc

Titanium dioxide (E 171)

Glycerol monocaprylocaprate (Type I)

Iron oxide yellow (E 172)

Sodium laurilsulfate

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

oPA/Alu/PVC//Alu blisters, each blister contains 8 film-coated tablets.

Pack size: 72 or 96 film-coated tablets.

Not all pack sizes may be marketed.

No special requirements.

Orphalan226 Boulevard Voltaire75011 Paris

France

EU/1/17/1199/001 72 film-coated tablets

EU/1/17/1199/002 96 film-coated tablets

Date of first authorisation: 5 September 2017

Date of latest renewal: 17 August 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.