Cufence

HOS-217251 · has-adverse-reaction-information · PDF-Seite 6

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 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 (≥ 1/1 000 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). Table 1. Adverse reactions MedDRA- system organ class database Adverse reaction Blood and lymphatic system disorders: Uncommon: Anaemia Uncommon: Aplastic anaemia Uncommon: Sideroblastic anaemia Immune system disorders: Not known: Lupus-like syndrome Not known: Lupus nephritis Nervous system disorders: Uncommon: Dystonia Uncommon: Tremor Not known: Dysarthria Not known: Muscle rigidity Not known: Neurological deterioration Gastrointestinal disorders: Common: Nausea Not known: Colitis 6  MedDRA- system organ class database Adverse reaction 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,

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HOS-217247 · has-contraindication-information · PDF-Seite 3

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

HOS-217246 · has-indication-information · PDF-Seite 2

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.

HOS-217249 · has-interaction-information · PDF-Seite 5

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 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).

HOS-217250 · has-pregnancy-information · PDF-Seite 5

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 5 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. Breast-feeding 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.

HOS-217248 · has-warning-information · PDF-Seite 3

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). 3 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. 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.

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