WILZIN 25mg capsules medication leaflet

Wilzin 25 mg hard capsules

Each hard capsule contains 25 mg of zinc (corresponding to 83.92 mg of zinc acetate dihydrate).

For the full list of excipients, see section 6.1.

Hard capsule.

Capsule with aqua blue opaque cap and body, imprinted '93-376”.

Treatment of Wilson’s disease.

Wilzin treatment should be initiated under the supervision of a physician experienced in the treatmentof Wilson’s disease (see section 4.4). Wilzin is a life-long therapy.

There is no difference in dose between symptomatic and presymptomatic patients.

Wilzin is available in hard capsules of 25 mg or 50 mg.

* Adults:

The usual dose is 50 mg 3 times daily with a maximum dose of 50 mg 5 times daily.

* Children and adolescents:

Data are very limited in children under 6 years but since the disease is fully penetrant,prophylactic treatment should be considered as early as possible. The recommended dose is asfollows:

- from 1 to 6 years: 25 mg twice daily

- from 6 to 16 years if bodyweight under 57 kg: 25 mg three times daily

- from 16 years or if bodyweight above 57 kg: 50 mg three times daily.

* Pregnant women:

A dose of 25 mg 3 times daily is usually effective but the dose should be adjusted to copperlevels (see section 4.4 and section 4.6).

In all cases, dose should be adjusted according to therapeutic monitoring (see section 4.4.).

Wilzin must be taken on an empty stomach, at least 1 hour before or 2-3 hours after meals. In case ofgastric intolerance, often occurring with the morning dose, this dose may be delayed to mid-morning,between breakfast and lunch. It is also possible to take Wilzin with a little protein, such as meat (seesection 4.5).

In children who are unable to swallow capsules, these should be opened and their content suspended ina little water (possibly sugar or syrup flavoured water).

When switching a patient on chelating treatment to Wilzin for maintenance therapy, the chelatingtreatment should be maintained and co-administered for 2 to 3 weeks since this is the time it takes forthe zinc treatment to induce maximum metallothionein induction and full blockade of copperabsorption. The administration of the chelating treatment and Wilzin should be separated by at least1 hour.

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

Zinc acetate dihydrate is not recommended for the initial therapy of symptomatic patients because ofits slow onset of action. Symptomatic patients must be initially treated with a chelating agent; oncecopper levels are below toxic thresholds and patients are clinically stable, maintenance treatment with

Wilzin can be considered.

Nevertheless, while awaiting zinc induced duodenal metallothionein production and consequentialeffective inhibition of copper absorption, zinc acetate dehydrate could be administered initially insymptomatic patients in combination with a chelating agent.

Although rare, clinical deterioration may occur at the beginning of the treatment, as has also beenreported with chelating agents. Whether this is related to mobilisation of copper stores or to naturalhistory of the disease remains unclear. A change of therapy is recommended in this situation.

Caution should be exercised when switching patients with portal hypertension from a chelating agentto Wilzin, when such patients are doing well and the treatment is tolerated. Two patients of a series of16 died from hepatic decompensation and advanced portal hypertension after being changed frompenicillamine to zinc therapy.

Therapeutic monitoring

The aim of the treatment is to maintain the plasma free copper (also known as non-ceruloplasminplasma copper) below 250 microgram/l (normal: 100-150 microgram/l) and the urinary copperexcretion below 125 microgram/24 h (normal: < 50 microgram/24 h). The non-ceruloplasmin plasmacopper is calculated by subtracting the ceruloplasmin-bound copper from the total plasma copper,given that each milligram of ceruloplasmin contains 3 micrograms of copper.

The urinary excretion of copper is an accurate reflection of body loading with excess copper onlywhen patients are not on chelation therapy. Urinary copper levels are usually increased with chelationtherapy such as penicillamine or trientine.

The level of hepatic copper cannot be used to manage therapy since it does not differentiate betweenpotentially toxic free copper and metallothionein bound copper.

In treated patients, assays of urinary and/or plasma zinc may be a useful measure of treatmentcompliance. Values of urinary zinc above 2 mg/24 h and of plasma zinc above 1250 microgram/lgenerally indicate adequate compliance.

Like with all anti-copper agents overtreatment carries the risk of copper deficiency, which isespecially harmful for children and pregnant women since copper is required for proper growth andmental development. In these patient groups, urinary copper levels should be kept a little above theupper limit of normal or in the high normal range (i.e. 40 - 50 microgram/24 h).

Laboratory follow-up including haematological surveillance and lipoproteins determination shouldalso be performed in order to detect early manifestations of copper deficiency, such as anaemia and/orleukopenia resulting from bone marrow depression, and decrease in HDL cholesterol and HDL/totalcholesterol ratio.

As copper deficiency may also cause myeloneuropathy, physicians should be alert to sensory andmotor symptoms and signs which may potentially indicate incipient neuropathy or myelopathy inpatients treated with Wilzin.

Other anti-copper agents

Pharmacodynamic studies were conducted in Wilson’s disease patients on the combination of Wilzin(50 mg three times daily) with ascorbic acid (1 g once daily), penicillamine (250 mg four times daily),and trientine (250 mg four times daily). They showed no significant overall effect on copper balancealthough mild interaction of zinc with chelators (penicillamine and trientine) could be detected withdecreased faecal but increased urinary copper excretion as compared with zinc alone. This is probablydue to some extent of complexion of zinc by the chelator, thus reducing the effect of both activesubstances.

When switching a patient on chelating treatment to Wilzin for maintenance therapy, the chelatingtreatment should be maintained and co-administered for 2 to 3 weeks since this is the time it takes forthe zinc treatment to induce maximum metallothionein induction and full blockade of copperabsorption. The administration of the chelating treatment and Wilzin should be separated by at least1 hour.

Other medicinal products

The absorption of zinc may be reduced by iron and calcium supplements, tetracyclines andphosphorus-containing compounds, while zinc may reduce the absorption of iron, tetracyclines,fluoroquinolones.

Studies of the co-administration of zinc with food performed in healthy volunteers showed that theabsorption of zinc was significantly delayed by many foods (including bread, hard boiled eggs, coffeeand milk). Substances in food, especially phytates and fibres, bind zinc and prevent it from enteringthe intestinal cells. However, protein appears to interfere the least.

Data on a limited number of exposed pregnancies in patients with Wilson’s disease give no indicationof harmful effects of zinc on embryo/foetus and mother. Five miscarriages and 2 birth defects(microcephaly and correctable heart defect) were reported in 42 pregnancies.

Animal studies conducted with different zinc salts do not indicate direct or indirect harmful effectswith respect to pregnancy, embryonal/foetal development, parturition or postnatal development(see section 5.3).

It is extremely important that pregnant Wilson’s disease patients continue their therapy duringpregnancy. Which treatment should be used, zinc or chelating agent should be decided by thephysician. Dose adjustments to guarantee that the foetus will not become copper deficient must bedone and close monitoring of the patient is mandatory (see section 4.4).

Zinc is excreted in human breast milk and zinc-induced copper deficiency in the breast-fed baby mayoccur. Therefore, breast-feeding should be avoided during Wilzin therapy.

No studies on the effects on the ability to drive and use machines have been performed.

Reported adverse reactions are listed below, by system organ class and by frequency.

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).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System organ class Adverse drug reactions

Blood and lymphatic system disorders uncommon: sideroblastic anaemia, leukopenia

Gastrointestinal disorders common: gastric irritation

Investigations common: blood amylase, lipase and alkalinephosphatase increased

Anaemia may be micro-, normo- or macrocytic and is often associated with leukopenia. Bone marrowexamination usually reveals characteristic 'ringed sideroblasts' (i.e. developing red blood cellscontaining iron-engorged paranuclear mitochondria). They may be early manifestations of copperdeficiency and may recover rapidly following reduction of zinc dosage. However, they must bedistinguished from haemolytic anaemia which commonly occurs where there is elevated serum freecopper in uncontrolled Wilson’s disease.

The most common undesirable effect is gastric irritation. This is usually worst with the first morningdose and disappears after the first days of treatment. Delaying the first dose to mid-morning or takingthe dose with a little protein may usually relieve the symptoms.

Elevations of serum alkaline phosphatase, amylase and lipase may occur after a few weeks oftreatment, with levels usually returning to high normal within the first one or two years of treatment.

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.

Three cases of acute oral overdose with zinc salts (sulphate or gluconate) have been reported in theliterature. Death occurred in a 35 year-old woman on the fifth day after ingestion of 6 g of zinc(40 times the proposed therapeutic dose) and was attributed to renal failure and haemorrhagicpancreatitis with hyperglycaemic coma. The same dose did not produce any symptoms except forvomiting in an adolescent who was treated by whole-bowel irrigation. Another adolescent whoingested 4 g of zinc had serum zinc level of about 50 mg/l 5 hours later and only experienced severenausea, vomiting and dizziness.

Treatment of overdose should be with gastric lavage or induced emesis as quickly as possible toremove unabsorbed zinc. Heavy metal chelation therapy should be considered if plasma zinc levels aremarkedly elevated (> 10 mg/l).

Pharmacotherapeutic group: various alimentary tract and metabolism products, ATC code: A16AX05.

Wilson's disease (hepatolenticular degeneration) is an autosomal recessive metabolic defect in hepaticexcretion of copper in the bile. Copper accumulation in the liver leads to hepatocellular injury andeventual cirrhosis. When the liver capacity of storing copper is exceeded copper is released into theblood and is taken up in extra hepatic sites, such as the brain, resulting in motor disorders andpsychiatric manifestations. Patients may present clinically with predominantly hepatic, neurologic, orpsychiatric symptoms.

The active moiety in zinc acetate dihydrate is zinc cation, which blocks the intestinal absorption ofcopper from the diet and the reabsorption of endogenously secreted copper. Zinc induces theproduction of metallothionein in the enterocyte, a protein that binds copper thereby preventing itstransfer into the blood. The bound copper is then eliminated in the stool following desquamation of theintestinal cells.

Pharmacodynamic investigations of copper metabolism in patients with Wilson’s disease includeddeterminations of net copper balance and radiolabelled copper uptake. A daily regimen of 150 mg of

Wilzin in three administrations was shown to be effective in significantly reducing copper absorptionand inducing a negative copper balance.

Since the mechanism of action of zinc is an effect on copper uptake at the level of the intestinal cell,pharmacokinetic evaluations based on blood levels of zinc do not provide useful information on zincbioavailability at the site of action.

Zinc is absorbed in the small intestine and its absorption kinetics suggest a tendency to saturation atincreasing doses. Fractional zinc absorption is negatively correlated with zinc intake. It ranges from 30to 60% with usual dietary intake (7-15 mg/d) and decreases to 7% with pharmacological doses of100 mg/d.

In the blood, about 80% of absorbed zinc is distributed to erythrocytes, with most of the remainderbeing bound to albumin and other plasma proteins. The liver is the main storage for zinc and hepaticzinc levels are increased during maintenance therapy with zinc.

The plasma elimination half-life of zinc in healthy subjects is around 1 hour after a dose of 45 mg. Theelimination of zinc results primarily from faecal excretion with relatively little from urine and sweat.

The faecal excretion is in the greatest part due to the passage of unabsorbed zinc but it is also due toendogenous intestinal secretion.

Preclinical studies have been conducted with zinc acetate and with other zinc salts. Pharmacologicaland toxicological data available showed large similarities between zinc salts and among animalspecies.

The oral LD50 is approximately 300 mg zinc/kg body weight (about 100 to 150 times the humantherapeutic dose). Repeat-dose toxicity studies have established that the NOEL (No Observed Effect

Level) is about 95 mg zinc/kg body weight (about 48 times the human therapeutic dose).

The weight of evidence, from in vitro and in vivo tests, suggests that zinc has no clinically relevantgenotoxic activity.

Reproduction toxicology studies performed with different zinc salts showed no clinically relevantevidence of embryotoxicity, foetotoxicity or teratogenicity.

No conventional carcinogenicity study has been conducted with zinc acetate dihydrate.

Capsule contentmaize starchmagnesium stearate

Capsule shellgelatintitanium dioxide (E171)brilliant blue FCF (E133)

Printing inkblack iron oxide (E172)shellac

Not applicable.

3 years.

Do not store above 25°C.

White HDPE bottle with a polypropylene and HDPE closure and contains a filler (cotton coil). Eachbottle contains 250 capsules.

No special requirements

Recordati Rare Diseases

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EU/1/04/286/001

Date of first authorisation: 13 October 2004

Date of latest renewal: 13 October 2009

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

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