CYSTAGON 150mg capsules medication leaflet

CYSTAGON 150 mg hard capsules

Each hard capsule contains 150 mg of cysteamine (as mercaptamine bitartrate)

For a full list of excipients, see section 6.1.

Hard Capsule

White, opaque hard capsules with CYSTAGON 150 on the body and RECORDATI RARE

DISEASES on the cap.

CYSTAGON is indicated for the treatment of proven nephropathic cystinosis. Cysteamine reducescystine accumulation in some cells (e.g. leukocytes, muscle and liver cells) of nephropathic cystinosispatients and, when treatment is started early, it delays the development of renal failure.

CYSTAGON treatment should be initiated under the supervision of a physician experienced in thetreatment of cystinosis.

The goal of therapy is to keep leucocyte cystine levels below 1 nmol hemicystine/mg protein. Whiteblood cell (WBC) cystine levels should therefore be monitored to adjust the dose. The WBC levelsshould be measured 5 to 6 hours after dosing and should be checked frequently when initiating therapy(e.g. monthly) and every 3-4 months when on a stable dose.

* For children up to age 12 years, CYSTAGON dosing should be on the basis of body surfacearea (g/m2/day). The recommended dose is 1.30 g/m2/day of the free base divided four timesdaily.

* For patients over age 12 and over 50 kg weight, the recommended CYSTAGON dose is2 g/day, divided four times daily.

Starting doses should be 1/4 to 1/6 of the expected maintenance dose, increased gradually over 4-6 weeks to avoid intolerance. The dose should be raised if there is adequate tolerance and theleucocyte cystine level remains >1 nmol hemicystine/mg protein. The maximum dose of CYSTAGONused in clinical trials was 1.95 g/m2/day.

The use of doses higher than 1.95 g/m2/day is not recommended (see section 4.4).

Digestive tolerance of cysteamine is improved when the medicinal product is taken just after or withfood.

In children who are at risk of aspiration, aged approximately 6 years and under, the hard capsulesshould be opened and the content sprinkled on food. Experience suggests that foods such as milk,potatoes and other starch based products seem to be appropriate for mixing with the powder. However,acidic drinks, e.g. orange juice, should generally be avoided as the powder tends not to mix well andmay precipitate out.

Patients on dialysis or post-transplantation:

Experience has occasionally shown that some forms of cysteamine are less well tolerated (i.e. leadingto more adverse events) when patients are on dialysis. A closer monitoring of the leucocyte cystinelevels is recommended in these patients.

Patients with hepatic insufficiency:

Dose adjustment is not normally required; however, leucocyte cystine levels should be monitored.

Hypersensitivity to the active substance or to any of the excipients

The use of CYSTAGON is contra-indicated during breast-feeding. CYSTAGON should not be usedduring pregnancy, particularly during the first trimester, unless clearly necessary (see section 4.6 andsection 5.3), as it is teratogenic in animals.

CYSTAGON is contraindicated in patients who have developed hypersensitivity to penicillamine.

CYSTAGON therapy must be initiated promptly after confirmation of the diagnosis of nephropathiccystinosis to achieve maximum benefit.

Nephropathic cystinosis must have been diagnosed by both clinical signs and biochemicalinvestigations (leucocyte cystine measurements).

Cases of Ehlers-Danlos like syndrome and vascular disorders on elbows have been reported inchildren treated with high doses of different cysteamine preparations (cysteamine chlorhydrate orcystamine or cysteamine bitartrate) mostly above the maximal dose 1.95 g/m2/day. These skin lesionswere associated with vascular proliferation, skin striae and bone lesions.

It is therefore recommended to monitor regularly skin and to consider X-ray examinations of the boneas necessary. Self-examination of the skin by the patient or the parents should also be advised. If anysimilar skin or bone abnormalities appear, it is recommended to decrease the dose of CYSTAGON.

The use of doses higher than 1.95g/m2/day is not recommended (see sections 4.2 and 4.8).

Monitoring of blood cell count is recommended on a regular basis.

Oral cysteamine has not been shown to prevent eye deposition of cystine crystals. Therefore, wherecysteamine ophthalmic solution is used for that purpose, its usage should continue.

In contrast to phosphocysteamine, CYSTAGON does not contain phosphate. Most patients willalready be receiving phosphate supplements and the dose of these may need to be altered when

CYSTAGON is substituted for phosphocysteamine.

Intact CYSTAGON hard capsules should not be administered to children under the age ofapproximately 6 years due to risk of aspiration (see section 4.2).

No interaction studies have been performed

Interactions with other medicines have not been studied. CYSTAGON can be administered withelectrolyte and mineral replacements necessary for management of the Fanconi syndrome as well asvitamin D and thyroid hormones. Indomethacin and CYSTAGON have been used simultaneously insome patients. In cases of patients with kidney transplants, anti-rejection treatments have been usedwith cysteamine.

There are no adequate data from the use of cysteamine bitartrate in pregnant women. Studies inanimals have shown reproductive toxicity, including teratogenesis (see section 5.3). The potential riskfor humans is unknown. The effect on pregnancy of untreated cystinosis is also unknown.

Therefore, CYSTAGON should not be used during pregnancy, particularly during the first trimester,unless clearly necessary.

If a pregnancy is diagnosed or planned, the treatment should be carefully reconsidered and the patientmust be advised of the possible teratogenic risk of cysteamine.

CYSTAGON excretion in human's milk is unknown. However, due to the results of animal studies inbreast-feeding mothers and neonates (see section 5.3), breast-feeding is contra-indicated in womentaking CYSTAGON.

CYSTAGON has minor or moderate influence on the ability to drive ans use machines

CYSTAGON may cause drowsiness. When starting therapy, patients should not engage in potentiallyhazardous activities until the effects of the medicinal product on each individual are known.

Approximately 35% of patients can be expected to experience adverse reactions. These mainly involvethe gastrointestinal and central nervous systems. When these effects appear at the initiation ofcysteamine therapy, temporary suspension and gradual reintroduction of treatment may be effective inimproving tolerance.

Reported adverse reactions are listed below, by system organ class and by frequency. Frequencies aredefined as: very common (≥ 1/10), common (≥1/100 to 1/10) and uncommon (≥1/1,000 to 1/100).

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

Investigations Common: Liver function tests abnormal

Blood and lymphatic system disorders Uncommon: Leukopenia

Nervous system disorders Common: Headache, encephalopathy

Uncommon: Somnolence, convulsions

Gastrointestinal disorders Very common: Vomiting, nausea, diarrhoea

Common: Abdominal pain, breath odour, dyspepsia,gastroenteritis

Uncommon: Gastrointestinal ulcer

Renal and urinary disorders Uncommon: Nephrotic syndrome

Skin and subcutaneous tissue disorders Common: Skin odour abnormal, rash

Uncommon: Hair colour changes, skin striae, skinfragility (molluscoid pseudotumor on elbows)

Musculoskeletal and connective tissue Uncommon: Joint hyperextension, leg pain, genudisorders valgum, osteopenia, compression fracture, scoliosis.

Metabolism and nutrition disorders Very common: Anorexia

General disorders and administration site Very common: Lethargy, pyrexiaconditions Common: Asthenia

Immune system disorders Uncommon: Anaphylactic reaction

Psychiatric disorders Uncommon: Nervousness, hallucination

Cases of nephrotic syndrome have been reported within 6 months of starting therapy with progressiverecovery after treatment discontinuation. In some cases, histology showed a membranousglomerulonephritis of the renal allograft and hypersensitivity interstitial nephritis.

Cases of Ehlers-Danlos like syndrome and vascular disorders on elbows have been reported inchildren chronically treated with high doses of different cysteamine preparations (cysteaminechlorhydrate or cystamine or cysteamine bitartrate) mostly above the maximal dose 1.95 g/m2/day.

In some cases, these skin lesions were associated with vascular proliferation, skin striae and bonelesions first seen during an X-ray examination. Bone disorders reported were genu valgum, leg painand hyperextensive joints, osteopenia, compression fractures, and scoliosis.

In cases where histopathological examination of the skin was performed, the results suggestedangioendotheliomatosis.

One patient subsequently died of acute cerebral ischemia with marked vasculopathy.

In some the patients, the skin lesions on elbows regressed after CYSTAGON dose reduction.

Cysteamine mechanism of action by interfering with the cross-linking of collagen fibers has beenpostulated (see section 4.4).

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.

An overdose of cysteamine may cause progressive lethargy.

Should overdosage occur, the respiratory and cardiovascular systems should be supportedappropriately. No specific antidote is known. It is not known if cysteamine is removed byhaemodialysis.

Pharmacotherapeutic group: Alimentary tract and metabolism product, ATC code: A16AA04.

Normal individuals and heterozygous subjects for cystinosis have white cell cystine levels of < 0.2,and usually below 1 nmol hemicystine/mg protein, respectively. Individuals with nephropathiccystinosis have elevations of white cell cystine above 2 nmol hemicystine/mg protein

Cysteamine reacts with cystine to form the mixed disulfide of cysteamine and cysteine.

The mixed disulfide is then exported from the lysosomes by an intact lysine transport system. Thedecrease in leucocyte cystine levels is correlated to the cysteamine plasma concentration over the sixhours following the administration of CYSTAGON.

The leucocyte cystine level reaches its minimum (mean ( sd) value: 1.8  0.8 hours) slightly laterthan the peak plasma cysteamine concentration (mean ( sd) value: 1.4  0.4 hours) and returns to itsbaseline level as the plasma cysteamine concentration decreases at 6 hours post-dose.

In one clinical study, baseline white cell cystine levels were 3.73 (range 0.13 to 19.8) nmolhemicystine/mg protein and were maintained close to 1 nmol hemicystine/mg protein with acysteamine dose range of 1.3 to 1.95 g/m2/day.

An earlier study treated 94 children with nephropathic cystinosis with increasing doses of cysteamineto attain white cell cystine levels of less than 2 nmol hemicystine/mg protein 5 to 6 hours post-dose,and compared their outcome with an historical control group of 17 children treated with placebo. Theprincipal efficacy measurements were serum creatinine and calculated creatinine clearance and growth(height). The mean white cell cystine level attained during treatment was 1.7 + 0.2 nmolhemicystine/mg protein. Among cysteamine patients, glomerular function was maintained over time.

Placebo treated patients, in contrast, experienced a gradual rise in serum creatinine. Patients ontreatment maintained growth as compared to untreated patients. However, growth velocity did notincrease enough to allow patients to catch up the normal for their age. Renal tubular function was notaffected by treatment. Two other studies have shown similar results.

In all studies, patient response was better when treatment was started at an early age with good renalfunction.

Following a single oral dose of cysteamine bitartrate equivalent to 1.05 g of cysteamine free base inhealthy volunteers, the mean ( sd) values for the time to peak and peak plasma concentration are 1.4( 0.5) hours and 4.0 ( 1.0) µg/ml, respectively. In patients at steady state, these values are 1.4 ( 0.4)hours and 2.6 ( 0.9) µg/ml, respectively, after a dose ranging from 225 to 550 mg.

Cysteamine bitartrate (CYSTAGON) is bioequivalent to cysteamine hydrochloride andphosphocysteamine.

The in vitro plasma protein binding of cysteamine, which is mostly to albumin, is independent ofplasma drug concentration over the therapeutic range, with a mean ( sd) value of 54.1 % ( 1.5). Theplasma protein binding in patients at steady state is similar: 53.1 % ( 3.6) and 51.1 % ( 4.5) at 1.5and 6 hours post-dose, respectively.

In a pharmacokinetic study performed in 24 healthy volunteers for 24 hours, the mean estimate ( sd)for the terminal half-life of elimination was 4.8 ( 1.8) hours.

The elimination of unchanged cysteamine in the urine has been shown to range between 0.3 % and1.7% of the total daily dose in four patients; the bulk of cysteamine is excreted as sulphate.

Very limited data suggest that cysteamine pharmacokinetic parameters may not be significantlymodified in patients with mild to moderate renal insufficiency. No information is available for patientswith severe renal insufficiency.

Genotoxicity studies have been performed: although in published studies using cysteamine, inductionof chromosome aberrations in cultured eukaryotic cell lines has been reported, specific studies withcysteamine bitartrate did not show any mutagenic effects in the Ames test or any clastogenic effect inthe mouse micronucleus test.

Reproduction studies showed embryofoetotoxic effects (resorptions and post-implantation losses) inrats at the 100 mg/kg/day dose level and in rabbits receiving cysteamine 50 mg/kg/day. Teratogeniceffects have been described in rats when cysteamine is administered over the period of organogenesisat a dose of 100 mg/kg/day.

This is equivalent to 0.6 g/m2/day in the rat, which is less than half the recommended clinicalmaintenance dose of cysteamine, i.e. 1.30 g/ m2/day. A reduction of fertility was observed in rats at375 mg/kg/day, a dose at which body weight gain was retarded. At this dose, weight gain and survivalof the offspring during lactation was also reduced. High doses of cysteamine impair the ability oflactating mothers to feed their pups. Single doses of the drug inhibit prolactin secretion in animals.

Administration of cysteamine in neonate rats induced cataracts.

High doses of cysteamine, either by oral or parenteral routes, produce duodenal ulcers in rats and micebut not in monkeys. Experimental administration of the drug causes depletion of somatostatin inseveral animal species. The consequence of this for the clinical use of the drug is unknown.

No carcinogenic studies have been conducted with CYSTAGON.

microcrystalline cellulose,pregelatinized starch,magnesium stearate/sodium lauryl sulfate,colloidal silicon dioxide,croscarmellose sodium

gelatin,titanium dioxide,black ink on hard capsules containing E172

Not applicable.

2 years.

Do not store above 25°C.

Keep the container tightly closed in order to protect from light and moisture.

HDPE bottles of 100 and 500 hard capsules. A desiccant unit containing black activated carbon andsilica gel granules is included in the bottle.

Not all pack sizes may be marketed.

Not applicable.

Recordati Rare Diseases

Immeuble “Le Wilson”70 avenue du Général de Gaulle

F-92800 Puteaux

France

EU/1/97/039/003 (100 hard capsules per bottle), EU/1/97/039/004 (500 hard capsules per bottle).

Date of first authorisation: 23 June 1997.

Date of latest renewal: 23 June 2007

Detailed information on this product is available on the website of the European Medicines Agency(EMA) http://www.ema.europa.eu