CUFENCE 200mg capsules medication leaflet

Cufence 100 mg hard capsules

Cufence 200 mg hard capsules

Cufence 100 mg hard capsules

Each hard capsule contains 150 mg trientine dihydrochloride equivalent to 100 mg trientine.

Cufence 200 mg hard capsules

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

For the full list of excipients see section 6.1.

Hard capsule.

Cufence 100 mg hard capsules

White, oval-shaped size 3 capsule printed with ‘Cufence 100’ in grey ink.

Cufence 200 mg hard capsules

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

Cufence is indicated for the treatment of Wilson’s disease in patients intolerant to D-Penicillaminetherapy, in adults, adolescents and children aged 5 years or older.

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 recommended dose and the dose shouldsubsequently be adapted according to the patient’s clinical response (see section 4.4).

The recommended dose is 800 - 1 600 mg 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 thetrientine dihydrochloride salt) (see section 4.4).

There is insufficient clinical information available for Cufence to determine whether there existdifferences in responses between the elderly and younger patients. In general, dose selection should becautious, usually starting at the low end of the dosing range as recommended for adults, reflecting thegreater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or othertreatments.

There is limited information in patients with renal impairment. Therefore, the recommended dose inpatients with renal impairment is the same as for adults. For specific precautions see section 4.4.

There is limited information in patients with hepatic impairment. Therefore, the recommended dose inpatients 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 therecommended adult dose. It is advised, however, to monitor patients presenting with hepaticsymptoms 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 withmoderation and consideration, and adapted according to the patient’s clinical response such asworsening 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 everyone to two weeks after initiation of treatment with Cufence until target dose is reached.

The dose is lower than for adults and depends on age and body weight. The dose should be adjustedaccording to clinical response; 400 - 1 000 mg have been used at initiation of therapy (seesection 4.4).

Children < 5 years

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

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 hoursafter meals, and at least one hour apart from any other medicinal product, food or milk (seesection 4.5).

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

When switching a patient from another trientine formulation, caution is advised because differenttrientine salts are available which may have a different trientine content (base) and a differentbioavailability. Dose adjustment may be required (see section 4.2).

Trientine is a chelating agent which has been found to reduce serum iron levels. Iron supplementationmay be necessary in some cases. Concomitant oral iron should be administred at a different time thantrientine (see section 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.

There is no evidence that calcium and magnesium antacids alter the efficacy of trientine but it isrecommended to separate their administration (see section 4.5).

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 Cufence should remain under regular medical supervision and be monitored usingall available clinical data for appropriate control of clinical symptoms and copper levels in order tooptimise treatment. Frequency of monitoring is recommended to be at least twice a year. Morefrequent monitoring is advised during the initial phase of treatment and during phases of diseaseprogression or when dose adjustments are made as to be decided by the treating physician (seesection 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 andthe ceruloplasmin-bound copper (normal level of free copper in the serum is usually 100 to150 microgram/L), can be a useful index for monitoring therapy.

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.

The use of appropriate copper parameter target ranges is described in clinical practice guidelinesrelated to Wilson’s disease.

Like with all anti-copper agents, overtreatment carries the risk of copper deficiency, which isespecially harmful for children and pregnant women (see section 4.6) since copper is required forproper growth and mental development. Therefore, monitoring for manifestations of overtreatmentshould be undertaken.

Patients with renal and/or hepatic impairment receiving trientine should remain under regular medicalsupervision for appropriate control of symptoms and copper levels. Close monitoring of renal and/orliver 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 offree serum copper during the initial response to treatment. It is possible that this effect may be moreevident in patients with pre-existing neurological symptoms. It is recommended to monitor patientsclosely for such signs and symptoms and to consider careful titration to reach the recommendedtherapeutic dose and to reduce dose when necessary.

Dose adjustments in the trientine dose should be considered in case of signs of reduced efficacy suchas (persistent) increase in liver enzymes, and worsening of tremor. When trientine doses are adjustedthis should be done in small steps. The trientine dose may also be reduced in case of side effects oftrientine, such as gastrointestinal complaints and haematological changes. Trientine doses should bereduced to a more tolerable dose and may be increased again, once side effects have been resolved.

No interaction studies have been performed.

Zinc

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

Other anti-copper agents

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

D-Penicillamine.

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 areduction of the extent of absorption of trientine up to 45%. Systemic exposure is critical for itsprincipal mechanism of action, copper chelation (see section 5.1). Therefore, it is recommended thattrientine is taken at least 1 hour before meals or 2 hours after meals and at least one hour apart fromany other medicinal product, food, or milk to allow for maximum absorption and reduce the likelihoodof 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 benecessary in some cases. Concomitant oral iron or other heavy metals should be administred at adifferent 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 isgood practice to separate their administration (see section 4.4).

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).

Trientine should be used in pregnancy only after careful consideration of the benefits compared withthe risks of discontinuing treatment in the individual patient. Factors to consider include the knownrisks associated with untreated or undertreated Wilson’s disease, risks associated with the stage ofdisease, 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 begiven to reducing the dose of trientine to the lowest effective dose and monitoring compliance with thetreatment regimen.

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. Since copper is required for propergrowth and mental development, dose adjustments may be required to ensure that the foetus will notbecome 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 andceruloplasmin levels where appropriate.

There is limited clinical data suggesting that trientine is not excreted in breast milk. However, a risk tothe newborns/infants cannot be excluded.

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

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

Nausea can commonly occur on initial treatment and occasionally skin rash can occur. Duodenitis andsevere colitis have been reported. Neurological deterioration can occur at the start of the treatment.

Table 1. 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 (≥ 1/1000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot beestimated from the available data).

Table 1. Adverse reactions

MedDRA- system organ class database Adverse reaction

Blood and lymphatic system disorders: Uncommon: Anaemia

Uncommon: Aplastic anaemia

Uncommon: Sideroblasticanaemia

Immune system disorders: Not known: Lupus-likesyndrome

Not known: Lupus nephritis

Nervous system disorders: Uncommon: Dystonia

Uncommon: Tremor

Not known: Dysarthria

Not known: Muscle rigidity

Not known: Neurologicaldeterioration

Gastrointestinal disorders: Common: Nausea

Not known: Colitis

Not known: Duodenitis

MedDRA- system organ class database Adverse reaction

Skin and subcutaneous tissue disorders: Uncommon: Rash

There have been reports of neurological deterioration at the start of treatment in Wilson’s diseasepatients treated with copper chelators including trientine, with symptoms of, for example, dystonia,rigidity, tremor and dysarthria (see section 4.2).

Clinical studies with Cufence including a limited number of children in the age range of 5 to 17 yearsat the start of treatment indicate that frequency, type and severity of adverse reactions in children areexpected to be the same as in adults.

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.

In the event of overdose the patient should be observed, appropriate biochemical analysis performedand 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 excretionand of non-ceruloplasmin bound copper. Close monitoring is required to optimise the dose or adapttreatment if necessary (see section 4.4).

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

Trientine is a copper-selective chelator that enhances systemic elimination of divalent copper byforming a stable complex that is readily excreted by the kidneys. Trientine is a chelator with apolyamine-like structure and copper is chelated by forming a stable complex with the four constituentnitrogens in a planar ring. Thus, the pharmacodynamic action of trientine is dependent on its chemicalproperty of chelating copper and not on its interaction with receptors, enzyme systems or any otherbiological system that might differ between species. Trientine may also chelate copper in the intestinaltract and so inhibit copper absorption.

The bioavailability of trientine capsules in human beings has not been established. Based onpreclinical data, the mechanism of absorption and the high first pass effect, it is expected that trientinebioavailability is low and highly variable following oral administration. Clinical studies showed thattrientine is absorbed with tmax occurring between 0.5 and 6 hours post-dose in healthy volunteers andpatients. 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 peakconcentrations by 2 hours and reduces the extent of absorption of trientine by approximately 45%.

Trientine has low human plasma protein binding and is widely distributed in tissues with relativelyhigh concentrations measured in liver, heart, and kidney in the rat.

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 theplasma exposure to the MAT metabolite is approximately 3 times that of unchanged trientine, whileexposure to the DAT metabolite is slightly lower compared to trientine. The metabolites of trientinehave Cu-chelating properties, however the stability of these Cu-complexes is low due to theintroduction of the acetyl groups. Clinical data in healthy volunteers suggest limited contribution ofchelating activity by the MAT and DAT metabolites.The extent of MAT and DAT’s contribution tothe 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.

After absorption trientine and its metabolites are rapidly excreted in the urine, either bound to copperor unbound. The unabsorbed fraction of orally administered trientine is bound to intestinal copper andeliminated through faecal excretion.

The elimination half-life of trientine is approximately 4 hours (mean t1/2 of 3.8 ± 1.3 hours measured atsteady 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 hoursfor DAT after a single dose administration of trientine in healthy subjects.

Age /gender/body weight

Data from clinical studies conducted in adult healthy subjects indicate that age, gender and bodyweight do not seem to influence the pharmacokinetics of trientine.

No pharmacokinetic analysis has been performed on interethnic differences.

Non-clinical data reveal no special hazard for humans based on a series of studies investigatingcardiovascular safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to embryofoetaldevelopment.

Effects in non-clinical studies were largely consistent with induced copper deficiency in the plasmaand liver of previously copper normative animals and as such could be attributed to thepharmacological action of trientine. The main toxicological findings associated with trientine, whichwere generally seen across all species examined, included body weight loss or lower body weightgain, altered urinary electrolytes, low plasma copper levels and various histopathological changes inthe lungs (mainly interstitial pneumonitis). All effects were reversible with the exception of the lungfindings; however the dose levels where these effects were observed are far in excess of those usedclinically. Moreover, there was some doubt about the relationship to trientine, as the lung findingswere 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 oftrientine. Some functional neurological abnormalities were also identified, particularly in severlyaffected animals, however no associated nerve damage was observed. Electrocardiography was alsounaffected.

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 noevidence of embryo-foetal toxicity at lower dose levels despite dose-related reductions in serumcopper. These effects were observed only at exposures sufficiently in excess of maximum humanexposure to indicate little relevance to clinical use.

No fertility data are available but estrous cyclicity was unaffected and reproductive organs were notidentified as target organs in general repeat dose toxicity studies.

The OECD SIDS triethylenetetramine 2002 classifies the genotoxic profile of trientine as lowpriority/concern. Some positive in vitro mutagenicity data were obtained but in vivo test systemsshowed no mutagenic activity. No long term animal carcinogenicity trials have to date been performedwith trientine via the oral route, but via the dermal route, there was no increases in cancers abovebaseline. Moreover, there is evidence to suggest that trientine actually reduces endogenous DNAdamage 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 oftrientine therapy.

Trientine dihydrochloride is a known irritant, especially to mucus membranes, upper respiratory tractand skin, and induces skin sensitisation in guinea pigs, mice and man (OECD SIDStriethylenetetramine 2002).

Magnesium stearate

Colloidal anhydrous silica

Gelatin

Titanium dioxide (E171)

Shellac

Propylene glycol (E1520)

Titanium dioxide (E171)

Iron oxide black (E172)

Iron oxide yellow (E172)

Not applicable.

3 years.

After first opening the bottle: 3 months.

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

Cufence 100 mg hard capsules

White opaque HDPE bottle with an HDPE child-resistant screw cap and induction heat seal liner witha sachet of dried silica gel as desiccant.

Pack size: 1 bottle of 200 hard capsules.

Cufence 200 mg hard capsules

Amber glass bottle with a polypropylene cap and induction heat seal liner with a sachet of dried silicagel as desiccant.

Pack size: 1 bottle of 100 hard capsules.

Not all pack-sizes may be marketed.

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

Univar Solutions BV

Schouwburgplein 303012 CL Rotterdam

The Netherlands

EU/1/19/1365/002

EU/1/19/1365/001

Date of first authorisation: 25 July 2019

Date of latest renewal:

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

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