Cufence

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 

 

Cufence 200 mg hard capsules 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

Each hard capsule contains 300 mg trientine dihydrochloride equivalent to 200 mg trientine. 

 

For the full list of excipients see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Hard capsule. 

 

White, oval-shaped size 0 capsule printed with ‘Cufence’ in grey ink. 

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Cufence is indicated for the treatment of Wilson’s disease in patients intolerant to D-Penicillamine 

therapy, in adults, adolescents and children aged 5 years or older. 

 

4.2 Posology and method of administration 

 

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

Wilson’s disease. 

 

Posology 

 

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). 

 

The recommended dose is 800 – 1,600 mg (4-8 capsules) daily in 2 to 4 divided doses. 

 

The recommended doses of Cufence are expressed as mg of trientine base (i.e. not in mg of the 

trientine dihydrochloride salt) (see section 4.4). 

 

Special populations 

Elderly 

There is insufficient clinical information available for Cufence to determine whether there exist 

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 as recommended for adults, reflecting the 

greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other 

drug therapy.  

 

Renal impairment 

There is limited information in patients with renal impairment. Therefore, the recommended dose in 

patients with renal impairment is the same as for adults. For specific precautions see section 4.4. 

 

Hepatic impairment 



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There is limited information in patients with hepatic impairment. Therefore, the recommended dose in 

patients with hepatic impairment is the same as for adults. For specific precautions see section 4.4. 

 

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 Cufence. 

 

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). It is further advised to monitor patients presenting with neurological symptoms every 

one to two weeks after initiation of treatment with Cufence until target dose is reached. 

 

Paediatric population 

The dose is lower than for adults and depends on age and body weight. The dose should be adjusted 

according to clinical response; 400 – 1,000 mg (2-5 capsules) have been used at initiation of therapy 

(see section 4.4). 

 

Children < 5 years  

The safety and efficacy of Cufence in children aged 0 to 5 years have not yet been established. No data 

are available. 

 

Method of administration 

For oral use.  

 

Capsules should be swallowed whole with water.  

 

It is important that Cufence is 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 medicinal product, food or milk (see 

section 4.5). 

 

4.3 Contraindications 

 

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

 

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).   

 

Trientine is a chelating agent which has been found to reduce serum iron levels. Iron supplementation 

may be necessary in some cases. Concomitant oral iron should be administred at a different time than 

trientine (see section 4.5). 

 

The combination of trientine with zinc is not recommended. There are only limited data on 

concomitant use available and no specific dose recommendations can be made. 

 

There is no evidence that calcium and magnesium antacids alter the efficacy of trientine but it is 

recommended to separate their administration (see section 4.5). 

 

In patients who were previously treated with D-Penicillamine, lupus-like reactions have been reported 

during subsequent treatment with trientine, however it is not possible to determine if there is a causal 

relationship with trientine. 

 



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Monitoring 

Patients receiving Cufence 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).  

 

The aim of maintenance treatment is to maintain free copper levels in plasma (also known as non-

ceruloplasmin 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 100 to 

150 microgram/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) 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). 

 

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. 

 

4.5 Interaction with other medicinal products and other forms of interaction 

 

No interaction studies have been performed.  

 

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 D-

Penicillamine. 

 

Food 



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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). 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). 

 

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 administred at a 

different time than trientine to prevent the formation of complexes (see section 4.4). 

 

Although there is no evidence that calcium and magnesium antacids alter the efficacy of trientine, it is 

good practice to separate their administration (see section 4.4). 

 

4.6 Fertility, pregnancy and lactation 

 

Pregnancy 

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-induced 

copper deficiency (see section 5.3). 

 

Trientine should be used in pregnancy only after careful consideration of the benefits compared with 

the risks of discontinuing treatment in the individual patient. Factors to consider include the known 

risks associated with untreated or undertreated Wilson’s disease, risks associated with the stage of 

disease, the risk of those alternative treatments which are available and the possible effects of trientine 

(see section 5.3).  

 

If treatment with trientine is to be continued following a risk-benefit analysis, consideration should be 

given to reducing the dose of trientine to the lowest effective dose and monitoring compliance with the 

treatment regimen. 

 

The pregnancy should be closely monitored in order to detect possible foetal abnormality and to assess 

maternal serum copper levels throughout the pregnancy. The dose of trientine used should be adjusted 

in order to maintain serum copper levels within the normal range. Since copper is required for proper 

growth and mental development, dose adjustments may be required to ensure that the foetus will not 

become copper deficient and close monitoring of the patient is essential (see section 4.4) 

 

Babies born to mothers being treated with trientine should be monitored for serum copper and 

ceruloplasmin levels where appropriate. 

 

Breastfeeding 

There is limited clinical data suggesting that trientine is not excreted in breast milk. However, a risk to 

the newborns/infants cannot be excluded.  

 

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from 

trientine therapy taking into account the benefit of breast-feeding for the child and the benefit of 

therapy for the woman. 

 

Fertility 

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

 

4.7 Effects on ability to drive and use machines 

 

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



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4.8 Undesirable effects 

 

Summary of the safety profile 

Nausea can commonly occur on initial treatment and occasionally skin rash can occur. Duodenitis and 

severe colitis have been reported. Neurological deterioration can occur at the start of the treatment.  

 

Tabulated list of adverse reactions 

The table presented below is according to the MedDRA system organ classification (SOC and 

Preferred Term Level). 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). 

 

MedDRA- system organ class database Adverse reaction 

Blood and lymphatic system disorders: Uncommon: Anaemia 

Uncommon: Aplastic anaemia 

Uncommon: Sideroblastic 

anaemia 

Nervous system disorders: Uncommon: Dystonia 

Uncommon: Tremor  

Not known: Dysarthria  

Not known: Muscle rigidity 

Not known: Neurological  

deterioration 

Immune system disorders: Not known: Lupus-like 

syndrome  

Not known: Lupus nephritis 

Gastrointestinal disorders: Common: Nausea  

Not known: Colitis 

Not known: Duodenitis 

Skin and subcutaneous tissue disorders: Uncommon: Rash 

 

Description of selected adverse reactions 

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). 

 

Paediatric population 

Clinical trials with Cufence including a limited number of children in the age range of 5 to 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 of suspected adverse reactions 

Reporting suspected adverse reactions after authorisation 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 via the national reporting system 

listed in Appendix V. 

 

4.9 Overdose 

 

Occasional cases of trientine overdose have been reported. In cases up to 20 g of trientine base there 

were 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 biochemical 

abnormalities reported.  

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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In the event of overdose the patient should be observed, appropriate biochemical analysis performed 

and symptomatic treatment given. There is no antidote. 

 

Chronic overtreatment can lead to copper deficiency and reversible sideroblastic anaemia. 

Overtreatment and excess copper removal can be monitored using values of urine copper excretion 

and of non-ceruloplasmin bound copper. Close monitoring is required to optimise the dose or adapt 

treatment if necessary (see section 4.4). 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1  Pharmacodynamic properties 

 

Pharmacotherapeutic group: Other alimentary tract and metabolism, various alimentary tract and 

metabolism products, ATC code: A16AX12 

 

Mechanism of action 

Trientine is a copper-selective chelator that enhances systemic elimination of divalent copper by 

forming a stable complex that is readily excreted by the kidneys. Trientine is a chelator with a 

polyamine-like structure and copper is chelated by forming a stable complex with the four constituent 

nitrogens in a planar ring. Thus, the pharmacodynamic action of trientine is dependent on its chemical 

property of chelating copper and not on its interaction with receptors, enzyme systems or any other 

biological system that might differ between species. Trientine may also chelate copper in the intestinal 

tract and so inhibit copper absorption. 

 

5.2 Pharmacokinetic properties 

 

Absorption 

The bioavailability of trientine capsules in human beings has not been established. Based on 

preclinical data, the mechanism of absorption and the high first pass effect, it is expected that trientine 

bioavailability is low and highly variable following oral administration. Clinical studies showed that 

trientine is absorbed with tmax occurring between 0.5 and 6 hours post-dose in healthy volunteers and 

patients. Exposure to trientine is highly variable between subjects, with a variation of up to 60%. 

 

The intake of food within 30 minutes prior to trientine administration delays the time to peak 

concentrations by 2 hours and reduces the extent of absorption of trientine by approximately 45%. 

 

Distribution 

Trientine has low human plasma protein binding and is widely distributed in tissues with relatively 

high concentrations measured in liver, heart, and kidney in the rat.  

 

Biotransformation 

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

N(1),N(10)-diacetyltriethylenetetramine (DAT). Clinical data in healthy subjects indicate that the 

plasma exposure to the MAT metabolite is approximately 3 times that of unchanged trientine, while 

exposure to the DAT metabolite is slightly lower compared to trientine. The metabolites of trientine 

have Cu-chelating properties, however the stability of these Cu-complexes is low due to the 

introduction of the acetyl groups. Clinical data in healthy volunteers suggest limited contribution of 

chelating activity by the MAT and DAT metabolites.The extent of MAT and DAT’s contribution to 

the overall effect of Cufence on copper levels in Wilson’s Disease patients remains to be determined. 

 

Trientine is metabolised by acetylation via spermidine/spermine N-acetyltransferase and not via 

N-acetyltransferase 2. 

 

Elimination 



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After absorption trientine and its metabolites are rapidly excreted in the urine, either bound to copper 

or unbound. The unabsorbed fraction of orally administered trientine is bound to intestinal copper and 

eliminated through faecal excretion. 

The elimination half-life of trientine is approximately 4 hours (mean t1/2 of 3.8 ± 1.3 hours measured at 

steady state in WD patients and 4.4 ± 4.7 hours measured after a single dose in healthy volunteers). 

The elimination half-lives of the two metabolites were 14.1 ±  3.7 hours for MAT and 8.5 ± 3.0 hours 

for DAT after a single dose administration of trientine in healthy subjects. 

 

Special populations 

 

Age /Gender/ Body weight 

Data from clinical studies conducted in adult healthy subjects indicate that age, gender and body 

weight do not seem to influence the pharmacokinetics of trientine.  

 

Ethnicity 

No pharmacokinetic analysis has been performed on interethnic differences.     

 

 

5.3 Preclinical safety data 

 

Non-clinical data reveal no special hazard for humans based on a series of studies investigating 

cardiovascular safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to embryofoetal 

development. 

 

Effects in non-clinical studies were largely consistent with induced copper deficiency in the plasma 

and liver of previously copper normative animals and as such could be attributed to the 

pharmacological action of trientine. The main toxicological findings associated with trientine, which 

were generally seen across all species examined, included body weight loss or lower body weight 

gain, altered urinary electrolytes, low plasma copper levels and various histopathological changes in 

the lungs (mainly interstitial pneumonitis). All effects were reversible with the exception of the lung 

findings; however the dose levels where these effects were observed are far in excess of those used 

clinically. Moreover, there was some doubt about the relationship to trientine, as the lung findings 

were also observed in most of the control dogs in the 26 week study. In dogs, ataxia, tremors, 

abnormal gait and underactivity were observed following administration of very high levels of 

trientine. Some functional neurological abnormalities were also identified, particularly in severly 

affected animals, however no associated nerve damage was observed. Electrocardiography was also 

unaffected. 

 

In pregnant animals, high dose trientine associated with significant reductions in serum copper, 

revealed an early effect on embryo survival and a marginally lower foetal weight.  There was no 

evidence of embryo-foetal toxicity at lower dose levels despite dose-related reductions in serum 

copper. These effects were observed only at exposures sufficiently in excess of maximum human 

exposure to indicate little relevance to clinical use. 

 

No fertility data are available but estrous cyclicity was unaffected and reproductive organs were not 

identified as target organs in general repeat dose toxicity studies.  

 

The OECD SIDS triethylenetetramine 2002 classifies the genotoxic profile of trientine as low 

priority/concern. Some positive in vitro mutagenicity data were obtained but in vivo test systems 

showed no mutagenic activity. No long term animal carcinogenicity trials have to date been performed 

with trientine via the oral route, but via the dermal route, there was no increases in cancers above 

baseline. Moreover, there is evidence to suggest that trientine actually reduces endogenous DNA 

damage in a strain of rat (Long-Evans Cinnamon) considered to represent an appropriate model of 

Wilson’s disease. This suggests a reduced carcinogenic risk for Wilson’s disease patients as a result of 

trientine therapy. 

 



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Trientine dihydrochloride is a known irritant, especially to mucus membranes, upper respiratory tract 

and skin, and induces skin sensitisation in guinea pigs, mice and man (OECD SIDS 

triethylenetetramine 2002).  

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Capsule content: 

Magnesium stearate 

Colloidal anhydrous silica 

 

Capsule shell: 

Gelatin 

Titanium dioxide (E171) 

 

Printing ink: 

Shellac  

Propylene glycol  

Titanium dioxide (E171) 

Iron oxide black (E172) 

Iron oxide yellow (E172) 

 

6.2 Incompatibilities 

 

Not applicable. 

 

6.3 Shelf life 

 

3 years. 

 

After first opening the bottle: 3 months. 

 

6.4 Special precautions for storage 

 

This medicinal product does not require any special storage conditions unopened.  After opening the 

bottle, store in a refrigerator (2ºC-8ºC). 

 

Do not freeze. 

 

Keep the bottle tightly closed in order to protect from moisture. 

 

6.5 Nature and contents of container 

 

Amber glass bottle with a polypropylene cap and induction heat seal liner with a sachet of dried silica 

gel as desiccant. 

 

Pack size: 1 bottle of 100 hard capsules. 

 

6.6 Special precautions for disposal 

 

Any unused medicinal product or waste material should be disposed of in accordance with local 

requirements. 

 

 



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7. MARKETING AUTHORISATION HOLDER 

 

Univar Solutions BV 

Schouwburgplein 30 

3012 CL Rotterdam 

The Netherlands 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/19/1365/001 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 25 July 2019 

 

 

10. DATE OF REVISION OF THE TEXT 

 

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

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

 

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


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ANNEX II 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 

 



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A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer responsible for batch release 

 

Aesica Pharmaceuticals GmbH 

Alfred Nobel Strasse 10 

Monheim 40789 

Germany 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  

 

• Periodic safety update reports (PSURs) 
 

The requirements for submission of PSURs for this medicinal product are set out in the list of 

Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and 

any subsequent updates published on the European medicines web-portal. 

 

The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 

months following authorisation.  

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

• Risk management plan (RMP) 
 

The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 

and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 

authorisation and any agreed subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

 

• At the request of the European Medicines Agency; 
 

• Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile or 

as the result of an important (pharmacovigilance or risk minimisation) milestone being 

reached.  

 

• Obligation to conduct post-authorisation measures  
 

The MAH shall complete, within the stated timeframe, the below measures: 

 

Description Due date 

PAES: In order to further characterise the efficacy of trientine dihydrochloride in 

the treatment of Wilson’s disease in patients with predominantly hepatic, 

Final report: 

Q4 2025 (main study)  



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Description Due date 

neurologic or psychiatric symptoms as well as in paediatric patients, the MAH 

should conduct and submit the results of an open label, prospective study to 

investigate the clinical course of hepatic, neurological and psychiatric disease from 

the time of initiation of treatment with trientine dihydrochloride up to 24 months of 

therapy. The study will also contain a PK/PD sub-study to evaluate the dose-

response relationship especially during the up-titration phase. The study should be 

conducted according to an agreed protocol. 

 

Q4 2022 PK/PD sub-

study  

 

 



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ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



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A. LABELLING 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 

PACKAGING 

 

CARTON/BOTTLE 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Cufence 200 mg hard capsules  

trientine  

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each capsule contains 300 mg trientine dihydrochloride, equivalent to 200 mg trientine. 

 

 

3. LIST OF EXCIPIENTS 

 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Hard capsule. 

100 capsules 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

 

8. EXPIRY DATE 

 

EXP 

After first opening, the bottle can be kept for 3 months. 

 

Open date ___________________ 

 

 

9. SPECIAL STORAGE CONDITIONS 

 



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Store in a refrigerator after opening. 

Do not freeze. 

Keep the bottle tightly closed in order to protect from moisture. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Univar Solutions BV 

Schouwburgplein 30 

3012 CL Rotterdam 

The Netherlands 

 

 

12. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/19/1365/001  

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

 

15. INSTRUCTIONS ON USE 

 

 

 

16. INFORMATION IN BRAILLE 

 

Cufence 200mg 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC {number} 

SN {number} 

NN {number} 

 



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B. PACKAGE LEAFLET 



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Package leaflet: Information for the patient 

 

Cufence 200 mg hard capsules 

trientine 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 
side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 

 

1. What Cufence is and what it is used for 

2. What you need to know before you take Cufence 

3. How to take Cufence 

4. Possible side effects 

5. How to store Cufence 

6. Contents of the pack and other information 

 

 

1. What Cufence is and what it is used for 

 

Cufence is a medicine used for the treatment of Wilson’s disease in adults, adolescents and children 

aged 5 years or older. It is for use by patients who cannot take another medicine, D-Penicillamine, 

because of side effects. 

 

Cufence contains the active substance trientine, a copper-chelating agent that is used to remove excess 

of copper from the body. Cufence attaches to the copper, which is then passed from the body.  

 

 

2. What you need to know before you take Cufence  

 

Do not take Cufence 

 

If you are allergic to trientine or any of the other ingredients of this medicine (listed in section 6).  

 

Signs of an allergic reaction include rash, itching, swelling of the face, fainting and breathing 

problems. 

 

Warnings and precautions  

 

Your doctor will need to regularly check for symptoms of the 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 Cufence.  

 

Nervous system problems can occur (for example, shaking, lack of coordination, slurred speech, 

muscle stiffness and worsening of muscle spasms), especially in patients just starting treatment with 

Cufence. If you notice these whilst taking Cufence, you must tell your doctor immediately. 

 

Lupus-like reactions (symptoms may include persistent rash, fever, joint pain, and tiredness) have 

been reported in some patients switched to trientine medicine after penicillamine medicine. However, 



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it was not possible to determine if the reaction was due to trientine or to previous penicillamine 

treatment. 

 

Other medicines and Cufence 

 

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 

medicines. 

 

If you are taking iron tablets or medicines that neutralise the acid in your stomach, leave at least 

2 hours before or after you have taken Cufence because they may reduce Cufence’s effect. 

It is recommended that trientine is taken at least one hour apart from any other medicinal product. 

 

Cufence with food and drink 

 

Take this medicine with water only. Do not take it with other drinks, milk or food because they may 

reduce the medicine’s effect. Avoid eating or drinking (except water) for 1 hour before, or 2 hours 

after taking Cufence. 

 

Pregnancy and breast-feeding 

 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 

your doctor or pharmacist for advice before taking this medicine. It is very important to continue 

treatment to maintain normal copper levels during pregnancy. You and your doctor should fully 

discuss the potential benefits of treatment whilst considering any possible risks that there may be. 

Your doctor will advise you which treatment and which dose is best in your situation. If you become 

pregnant whilst taking Cufence, talk to your doctor. 

 

If you are pregnant and taking Cufence, you will be monitored throughout your pregnancy for any 

effects on the baby or changes in your copper levels.  

 

The limited information available suggests that Cufence does not pass into breast milk, but it is not 

certain that there is no risk to the baby.  It is important to tell your doctor if you are breast-feeding or 

plan to do so. Your doctor will then help you decide whether to stop breast-feeding or to stop taking 

Cufence, considering the benefit of breast-feeding to the baby and the benefit of Cufence to the 

mother. Your doctor will decide which treatment and which dose is best in your situation. 

 

Driving and using machines 

 

Trientine is not likely to have an effect on your ability to drive or use machines. 

 

 

3. How to take Cufence 

 

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 

or pharmacist if you are not sure. 

 

Adults (including the elderly) 

 

The usual dose is between 4 and 8 capsules per day, to be taken by mouth. 

 

Use in children and adolescents (5 to 17 years) 

 

In children and adolescents, the dose depends on age and body weight and will be adjusted by your 

doctor. At the start of treatment the dose varies between 2 and 5 capsules per day. 

 

Method of administration 

 



21 

Your doctor will decide the correct dose for you. 

The total daily dose can be divided into 2 to 4 smaller doses, as indicated by your doctor. Swallow the 

capsules whole with a drink of water on an empty stomach, at least 1 hour before or 2 hours after food.  

 

Patients who have difficulties swallowing should contact their doctor. 

 

If you take more Cufence than you should 

 

If you take more medicine than you should, you may get nausea, vomiting and dizziness. You must 

contact your doctor or another health care provider immediately. 

 

If you forget to take Cufence 

 

If you forget to take a dose take your next dose at its usual scheduled time. 

Do not take a double dose to make up for a forgotten dose. 

 

If you stop taking Cufence 

 

This medicine is for long-term use because Wilson’s disease is a life-long condition. Do not stop or 

change your treatment without speaking with your doctor even if you feel better. 

 

If you have any further questions on the use of this medicine, ask your doctor or pharmacist 

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them. 

Occasionally (frequency unknown; cannot be estimated from available data), treatment with this 

medicine can cause inflammation of the small intestine or colon.  If you have any of the following side 

effects contact your doctor immediately: 

- Severe stomach pains 
- Persistent diarrhoea 
- Nervous system problems (for example shaking, lack of coordination, slurred speech, muscle 

stiffness, worsening of muscle spasms).  

 

Other side effects may include: 

Common (may affect up to 1 in 10 people) 

- Nausea (especially when starting treatment) 
 

Uncommon (may affect up to 1 in 100 people) 

- Skin rashes 
- Anaemia (you may feel unusually tired) 
 

Reporting of side effects 

 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects, you can help provide more information on the 

safety of this medicine. 

 

 

5. How to store Cufence 

 

Keep this medicine out of the sight and reach of children. 

 

Do not use after the expiry date which is stated on the bottle label and outer carton.  The expiry date 

refers to the last day of the month.   

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


22 

 

Use within 3 months after first opening the bottle. Keep the bottle tightly closed in order to protect 

from moisture. Do not use if the capsules become sticky or wet. After opening the bottle, store in a 

refrigerator (2ºC-8ºC). Do not freeze. 

 

Medicines should not be disposed of via wastewater or household waste.  Ask your pharmacist how to 

dispose of medicines no longer required.  These measures will help to protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Cufence contains 

 

- The active substance is trientine. Each capsule contains 300 mg trientine dihydrochloride, 
equivalent to 200 mg trientine. 

- The other ingredients are  
Capsule content: 

Magnesium stearate 

Colloidal anhydrous silica 

 

Capsule shell: 

Gelatin 

Titanium dioxide (E171) 

 

Printing ink: 

Shellac  

Propylene glycol  

Titanium dioxide (E171) 

Iron oxide black (E172) 

Iron oxide yellow (E172) 

 

What Cufence looks like and contents of the pack 

 

Amber glass bottle with a polypropylene cap and induction heat seal liner with a sachet of dried silica 

gel as desiccant. Each hard capsule is white, oval-shaped size 0 with Cufence printed in grey ink. 

 

Pack size: one bottle of 100 hard capsules.  

 

Marketing Authorisation Holder 

Univar Solutions BV 

Schouwburgplein 30 

3012 CL Rotterdam 

The Netherlands 

 

Manufacturer 

Aesica Pharmaceuticals GmbH 

Alfred-Nobel Strasse 10 

40789 Monheim 

Germany  

 

  

This leaflet was last revised in . 

 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu.There are also links to other websites about rare diseases and treatments. 

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

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET