PROCYSBI 25mg gastro-resistant capsules medication leaflet

PROCYSBI 25 mg gastro-resistant hard capsules

PROCYSBI 75 mg gastro-resistant hard capsules

PROCYSBI 25 mg gastro-resistant hard capsule

Each gastro-resistant hard capsule contains 25 mg of cysteamine (as mercaptamine bitartrate).

PROCYSBI 75 mg gastro-resistant hard capsule

Each gastro-resistant hard capsule contains 75 mg of cysteamine (as mercaptamine bitartrate).

For the full list of excipients, see section 6.1.

Gastro-resistant hard capsule.

PROCYSBI 25 mg gastro-resistant hard capsule

Light blue size 3 (15.9 x 5.8 mm) hard capsules imprinted “25 mg” in white ink and a light blue capimprinted with “PRO” in white ink.

PROCYSBI 75 mg gastro-resistant hard capsule

Light blue size 0 (21.7 x 7.6 mm) hard capsules imprinted “75 mg” in white ink and a dark blue capimprinted with “PRO” in white ink.

PROCYSBI 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.

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

Cysteamine therapy must be initiated promptly once the diagnosis is confirmed (i.e., increased WBCcystine) to achieve maximum benefit.

White blood cell (WBC) cystine concentration may for instance be measured by a number of differenttechniques such as specific WBC subsets (e.g., granulocyte assay) or the mixed leukocyte assay witheach assay having different target values. Healthcare professionals should refer to the assay-specifictherapeutic targets provided by individual testing laboratories when making decisions regardingdiagnosis and PROCYSBI dosing for cystinosis patients. For example the therapeutic goal is tomaintain a WBC cystine level < 1 nmol hemicystine/mg protein (when measured using the mixedleukocyte assay), 30 min after dosing For patients adherent to a stable dose of PROCYSBI, and whodo not have easy access to an adequate facility for measuring their WBC cystine, the goal of therapyshould be to maintain plasma cysteamine concentration > 0.1 mg/L, 30 min after dosing.

Measurement timing: PROCYSBI should be administered every 12 hours. The determination of WBCcystine and/or plasma cysteamine must be obtained 12.5 hours after the evening dose the day before,and therefore 30 minutes after the following morning dose is given.

Transferring patients from immediate-release cysteamine bitartrate hard capsules

Patients with cystinosis taking immediate-release cysteamine bitartrate may be transferred to a totaldaily dose of PROCYSBI equal to their previous total daily dose of immediate-release cysteaminebitartrate. Total daily dose should be divided by two and administered every 12 hours. The maximumrecommended dose of cysteamine is 1.95 g/m2/day. The use of doses higher than 1.95 g/m2/day is notrecommended (see section 4.4).

Patients being transferred from immediate-release cysteamine bitartrate to PROCYSBI should havetheir WBC cystine levels measured in 2 weeks, and thereafter every 3 months to assess optimal doseas described above.

Newly diagnosed adult patients

Newly diagnosed adult patients should be started on 1/6 to 1/4 of the targeted maintenance dose of

PROCYSBI. The targeted maintenance dose is 1.3 g/m2/day, in two divided doses, given every12 hours (see below table 1). The dose should be raised if there is adequate tolerance and the WBCcystine level remains > 1 nmol hemicystine/mg protein (when measured using the mixed leukocyteassay). The maximum recommended dose of cysteamine is 1.95 g/m2/day. The use of doses higherthan 1.95 g/m2/day is not recommended (see section 4.4).

The target values provided in the SmPC are obtained from using the mixed leucocyte assay. It shouldbe noted that therapeutic targets for cystine depletion are assay-specific and different assays havespecific treatment targets. Therefore, healthcare professionals should refer to the assay-specifictherapeutic targets provided by individual testing laboratories.

Newly diagnosed paediatric population

The targeted maintenance dose of 1.3 g/m2/day can be approximated according to the following table,which takes surface area as well as weight into consideration.

Table 1: Recommended dose

Weight in kilograms Recommended dose in mg

Every 12 hours*0-5 2005-10 30011-15 40016-20 50021-25 60026-30 70031-40 80041-50 900>50 1 000

*Higher dose may be required to achieve target WBC cystine concentration.

The use of doses higher than 1.95 g/m2/day is not recommended.

If a dose is missed, it should be taken as soon as possible. If it is within four hours of the next dose, themissed dose should be skipped going back to the regular dosing schedule. The dose should not bedoubled.

Patients with poor tolerability

Patients with poorer tolerability still receive significant benefit if white blood cell cystine levels arebelow 2 nmol hemicystine/mg protein (when measured using the mixed leukocyte assay). Thecysteamine dose can be increased to a maximum of 1.95 g/m2/day to achieve this level. The dose of1.95 g/m2/day of immediate-release cysteamine bitartrate has been associated with an increased rate ofwithdrawal from treatment due to intolerance and an increased incidence of adverse events. Ifcysteamine is initially poorly tolerated due to gastrointestinal (GI) tract symptoms or transient skinrashes, therapy should be temporarily stopped, then re-instituted at a lower dose and graduallyincreased to the appropriate dose (see section 4.4).

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 WBC cystine levelsis recommended in these patients.

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

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

Oral use.

This medicinal product can be administered by swallowing the intact capsules as well as sprinkling thecapsule contents (enteric coated beads) on food or delivery through a gastric feeding tube.

Do not crush or chew capsules or capsule contents.

Administration with food

Cysteamine bitartrate can be administered with an acidic fruit juice or water.

Cysteamine bitartrate should not be administered with food rich in fat or proteins, or with frozen foodlike ice-cream. Patients should try to consistently avoid meals and dairy products for at least 1 hourbefore and 1 hour after PROCYSBI dosing. If fasting during this period is not possible, it is acceptableto eat only a small amount (∼ 100 grams) of food (preferentially carbohydrates) during the hour beforeand after PROCYSBI administration. It is important to dose PROCYSBI in relation to food intake in aconsistent and reproducible way over time (see section 5.2).

In paediatric patients who are at risk of aspiration, aged approximately 6 years and under, the hardcapsules should be opened and the content sprinkled on food or liquid listed in section 6.6.

For instructions about the medicinal product before administration, see section 6.6.

* Hypersensitivity to the active substance, any form of cysteamine (mercaptamine), or to any ofthe excipients listed in section 6.1.

* Hypersensitivity to penicillamine.

* Breast-feeding.

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

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.

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 (see section 4.6).

Intact capsules of PROCYSBI should not be administered to children under the age of approximately6 years due to risk of aspiration (see section 4.2).

Dermatological

There have been reports of serious skin lesions in patients treated with high doses of immediate-release cysteamine bitartrate or other cysteamine salts that have responded to cysteamine dosereduction. Physicians should routinely monitor the skin and bones of patients receiving cysteamine.

If skin or bone abnormalities appear, the dose of cysteamine should be reduced or stopped. Treatmentmay be restarted at a lower dose under close supervision, and then slowly titrated to the appropriatetherapeutic dose (see sections 4.2). If a severe skin rash develops such as erythema multiforme bullosaor toxic epidermal necrolysis, cysteamine should not be re-administered (see sections 4.8).

Gastrointestinal

GI ulceration and bleeding have been reported in patients receiving immediate-release cysteaminebitartrate. Physicians should remain alert for signs of ulceration and bleeding and should informpatients and/or guardians about the signs and symptoms of serious GI toxicity and what steps to take ifthey occur.

GI tract symptoms including nausea, vomiting, anorexia and abdominal pain have been associatedwith cysteamine.

Strictures of the ileo-caecum and large bowel (fibrosing colonopathy) was first described in cysticfibrosis patients who were given high doses of pancreatic enzymes in the form of tablets with anenteric coating of methacrylic acid - ethyl acrylate copolymer (1:1), one of the excipients in

PROCYSBI. As a precaution, unusual abdominal symptoms or changes in abdominal symptomsshould be medically assessed to exclude the possibility of fibrosing colonopathy.

Central Nervous System (CNS)

CNS symptoms such as seizures, lethargy, somnolence, depression, and encephalopathy have beenassociated with cysteamine. If CNS symptoms develop, the patient should be carefully evaluated andthe dose adjusted as necessary. Patients should not engage in potentially hazardous activities until theeffects of cysteamine on mental performance are known (see section 4.7).

Leukopenia and abnormal liver function

Cysteamine has occasionally been associated with reversible leukopenia and abnormal liver function.

Therefore, blood counts and liver function should be monitored.

Benign intracranial hypertension

There have been reports of benign intracranial hypertension (or pseudotumor cerebri (PTC)) and/orpapilledema associated with cysteamine bitartrate treatment that has resolved with the addition ofdiuretic therapy (post-marketing experience with the immediate-release cysteamine bitartrate).

Physicians should instruct patients to report any of the following symptoms: headache, tinnitus,dizziness, nausea, diplopia, blurred vision, loss of vision, pain behind the eye or pain with eyemovement. A periodic eye examination is needed to identify this condition early and timely treatmentshould be provided when it occurs to prevent vision loss.

PROCYSBI contains sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially“sodium-free”.

It cannot be excluded that cysteamine is a clinically relevant inducer of CYP enzymes, inhibitor of

P-gp and BCRP at the intestinal level and inhibitor of liver uptake transporters (OATP1B1, OATP1B3and OCT1).

Co-administration with electrolyte and mineral replacement

Cysteamine can be administered with electrolyte (except bicarbonate) and mineral replacementsnecessary for management of Fanconi syndrome as well as vitamin D and thyroid hormone.

Bicarbonate should be administered at least one hour before or one hour after PROCYSBI to avoidpotential earlier release of cysteamine.

Indomethacin and cysteamine have been used simultaneously in some patients. In cases of patientswith kidney transplants, anti-rejection treatments have been used with cysteamine.

Co-administration of the proton pump inhibitor omeprazole and PROCYSBI in vivo showed no effectson cysteamine bitartrate exposure.

Women of childbearing potential should be informed about the risk of teratogenicity and advised touse an adequate method of contraception during the course of treatment. A negative pregnancy testshould be confirmed before starting treatment.

There is no adequate data from the use of cysteamine in pregnant women. Studies in animals haveshown reproductive toxicity, including teratogenesis (see section 5.3). The potential risk for humans isunknown. The effect on pregnancy of untreated cystinosis is also unknown. Therefore, cysteaminebitartrate should not be used during pregnancy, particularly during the first trimester, unless clearlynecessary (see section 4.4).

If a pregnancy is diagnosed or planned, the treatment should be carefully reconsidered.

Cysteamine excretion in human milk is unknown. However, due to the results of animal studies inbreast-feeding females and neonates (see section 5.3), breast-feeding is contra-indicated in womentaking PROCYSBI (see section 4.3).

Effects on fertility have been seen in animal studies (see section 5.3). Azoospermia has been reportedin male cystinosis patients.

Cysteamine has minor or moderate influence on the ability to drive and use machines.

Cysteamine 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.

For the immediate-release formulation of cysteamine bitartrate, approximately 35% of patients can beexpected to experience adverse reactions. These mainly involve the gastrointestinal and centralnervous systems. When these reactions appear at the initiation of cysteamine therapy, temporarysuspension and gradual reintroduction of treatment may be effective in improving tolerance.

In clinical studies with healthy volunteers, the most frequent adverse reactions were very common GIsymptoms (16%) and occurred primarily as single episodes that were mild or moderate in severity.

The adverse reactions profile for healthy subjects was similar to the adverse reactions profile inpatients relative to GI disorders (diarrhoea and abdominal pain).

The frequency of adverse reactions is defined using the following convention: 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) and not known (cannot be estimated from available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness:

Table 2: Adverse reactions

MedDRA system organ class Frequency: adverse reaction

Blood and lymphatic system disorders Uncommon: Leukopenia

Immune system disorders Uncommon: Anaphylactic reaction

Metabolism and nutrition disorders Very common: Anorexia

Psychiatric disorders Uncommon: Nervousness, hallucination

Common: Headache, encephalopathy

Uncommon: Somnolence, convulsions

Very common: Vomiting, nausea, diarrhoea

Common: Abdominal pain, breath odour, dyspepsia,

Gastrointestinal disorders gastroenteritis

Uncommon: Gastrointestinal ulcer

Common: Skin odour abnormal, rash

Skin and subcutaneous tissue disorders Uncommon: Hair colour changes, skin striae, skinfragility (molluscoid pseudotumour on elbows)

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

Renal and urinary disorders Uncommon: Nephrotic syndrome

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

Investigations Common: Liver function tests abnormal

Clinical studies experience with PROCYSBI

In clinical studies comparing PROCYSBI to the immediate-release cysteamine bitartrate, one third ofthe patients exhibited very common GI disorders (nausea, vomiting, abdominal pain). Commonnervous system disorders (headache, somnolence and lethargy) and common general disorders(asthenia) were also seen.

Post-marketing experience with immediate-release cysteamine bitartrate

Benign intracranial hypertension (or pseudotumor cerebri (PTC)) with papilledema; skin lesions,molluscoid pseudotumors, skin striae, skin fragility; joint hyperextension, leg pain, genu valgum,osteopenia, compression fracture and scoliosis have been reported with immediate-release cysteaminebitartrate (see section 4.4).

Two cases of nephrotic syndrome have been reported within 6 months of starting therapy withprogressive recovery after treatment discontinuation. Histology showed a membranousglomerulonephritis of the renal allograft in one case and hypersensitivity interstitial nephritis in theother.

A few cases of Ehlers-Danlos-like syndrome on elbows have been reported in children chronicallytreated with high doses of different cysteamine preparations (cysteamine chlorhydrate or cystamine orcysteamine bitartrate) mostly above the maximal dose 1.95 g/m2/day. In some cases, these skin lesionswere associated with skin striae and bone lesions first seen during an X-ray examination. Bonedisorders reported were genu valgum, leg pain and hyperextensive joints, osteopenia, compressionfractures, and scoliosis. In the few cases where histopathological examination of the skin wasperformed, the results suggested angioendotheliomatosis. One patient subsequently died of acutecerebral ischemia with marked vasculopathy. In some patients, the skin lesions on elbows regressedafter immediate-release cysteamine dose reduction (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 overdosing 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: Other alimentary tract and metabolism product, amino acids andderivatives, ATC code: A16AA04.

Cysteamine is the simplest stable aminothiol and a degradation product of the amino acid cysteine.

Cysteamine participates within lysosomes in a thiol-disulfide interchange reaction converting cystineinto cysteine and cysteine-cysteamine mixed disulfide, both of which can exit the lysosome in patientswith cystinosis.

Normal individuals and persons heterozygous for cystinosis have white blood cell cystine levels of< 0.2 and usually below 1 nmol hemicystine/mg protein, respectively, when measured using the mixedleukocyte assay. Individuals with cystinosis have elevations of WBC cystine above2 nmol hemicystine/mg protein.

WBC cystine is monitored in these patients to determine adequacy of dosing, levels being measured30 minutes after dosing when treated with PROCYSBI.

A pivotal phase 3 randomised, crossover PK and PD study (which was also the first ever randomisedstudy with immediate-release cysteamine bitartrate) demonstrated that at steady-state, patientsreceiving PROCYSBI every 12 hours (Q12H) maintained a comparable depletion of WBC cystinelevels compared to immediate-release cysteamine bitartrate every 6 hours (Q6H). Forty-three (43)patients were randomised; twenty-seven (27) children (ages 6 to 12 years old), fifteen (15) adolescents(ages 12 to 21 years old) and one (1) adult with cystinosis and with native kidney function based on anestimated glomerular filtration rate (GFR) (corrected for body surface area) > 30 mL/minute/1.73 m2were randomised. Of those forty-three (43) patients, two (2) siblings withdrew at the end of the firstcrossover period, due to a prior planned surgery in one (1) of them; forty-one (41) patients completedthe protocol. Two (2) patients were excluded from the per-protocol analysis because their WBCcystine level increased over 2 nmol hemicystine/mg protein during the immediate-release cysteaminetreatment period. Thirty-nine (39) patients were included in the final primary per protocol efficacyanalysis.

Table 3: Comparison of WBC cystine levels following administration of immediate-releasecysteamine bitartrate and PROCYSBI

Per -Protocol (PP) Population (N=39)

Immediate-releasecysteamine bitartrate PROCYSBI

WBC cystine level(LS Mean ± SE) in nmol hemicystine/mg 0.44 ± 0.05 0.51 ± 0.05protein*

Treatment effect(LS mean ± SE; 95.8% CI; p-value) 0.08 ± 0.03; 0.01 to 0.15; <0.0001

All Evaluable Patients (ITT) Population (N=41)

Immediate-releasecysteamine bitartrate PROCYSBI

WBC cystine level(LS Mean ± SE) in nmol hemicystine/mg 0.74 ± 0.14 0.53 ± 0.14protein*

Treatment effect(LS mean ± SE; 95.8% CI; p-value) -0.21 ± 0.14; -0.48 to 0.06; <0.001

*Measured using the mixed leukocyte assay

Forty of forty-one (40/41) patients who completed the pivotal phase 3 study were entered in aprospective study with PROCYSBI that stayed open as long as PROCYSBI could not be prescribed bytheir treating physician. In this study, the WBC cystine measured using the mixed leukocyte assay wasalways on average under optimal control at < 1 nmol hemicystine/mg protein. The estimatedglomerular filtration rate (eGFR) did not change for the study population over time.

The relative bioavailability is about 125% as compared to immediate-release cysteamine.

Food intake reduces the absorption of PROCYSBI at 30 minutes pre-dose (approximately 35%decrease in exposure) and at 30 min post-dose (approximately 16 or 45% decrease in exposure forintact and open capsules respectively). Food intake two hours after administration did not affect theabsorption of PROCYSBI.

The in vitro plasma protein binding of cysteamine, primarily to albumin, is approximately 54% andindependent of plasma drug concentration over the therapeutic range.

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.

In vitro data suggests that cysteamine bitartrate is likely to be metabolised by multiple CYP enzymes,including CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP2E1. CYP2A6 and

CYP3A4 were not involved in the metabolism of cysteamine bitartrate under the experimentalconditions.

The terminal half-life of cysteamine bitartrate is approximately 4 hours.

Cysteamine bitartrate is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9,

CYP2C19, CYP2D6, CYP2E1 and CYP3A4 in vitro.

In vitro: Cysteamine bitartrate is a substrate of P-gp and OCT2, but not a substrate of BCRP,

OATP1B1, OATP1B3, OAT1, OAT3 and OCT1. Cysteamine bitartrate is not an inhibitor of OAT1,

OAT3 and OCT2.

The pharmacokinetics of cysteamine bitartrate has not been studied in special populations.

In genotoxicity studies published for cysteamine, induction of chromosome aberrations in culturedeukaryotic cell lines has been reported. Specific studies with cysteamine did not show any mutageniceffects in the Ames test or any clastogenic effect in the mouse micronucleus test. A bacterial reversemutation assay study (“Ames test”) was performed with the cysteamine bitartrate used for PROCYSBIand cysteamine bitartrate did not show any mutagenic effects in this test.

Reproduction studies showed embryo-foetotoxic 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 slightly less than the recommended clinicalmaintenance dose of cysteamine, i.e. 1.3 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 cysteamine bitartrate gastro-resistant hard capsules.

Capsule contentmicrocrystalline cellulosemethacrylic acid - ethyl acrylate copolymer (1:1)hypromellosetalctriethyl citratesodium lauryl sulphate

Capsule shellgelatintitanium dioxide (E171)indigo carmine (E132)

Printing inkshellacpovidone K-17titanium dioxide (E171)

Not applicable.

2 years

In-use shelf life: 30 days.

Store in a refrigerator (2°C-8°C). Do not freeze.

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

After opening do not store above 25°C.

PROCYSBI 25 mg gastro-resistant hard capsule50 mL white HDPE bottle containing 60 gastro-resistant hard capsules with one 2-in-1 desiccantcylinder and one oxygen absorber cylinder, with a child resistant polypropylene closure.

Each bottle contains two plastic cylinders used for additional moisture and air protection.

Please keep the two cylinders in each bottle during the use of the bottle. The cylinders may bediscarded with the bottle after use.

PROCYSBI 75 mg gastro-resistant hard capsule400 mL white HDPE bottle containing 250 gastro-resistant hard capsules with one 2-in-1 desiccantcylinder and two oxygen absorber cylinders, with a child resistant polypropylene closure.

Each bottle contains three plastic cylinders used for additional moisture and air protection.

Please keep the three cylinders in each bottle during the use of the bottle. The cylinders may bediscarded with the bottle after use.

Handling

Sprinkling on food

Capsules for either the morning or evening dose should be opened and the contents sprinkled ontoapproximately 100 grams of apple sauce or fruit jam. Gently stir the contents into the soft food,creating a mixture of cysteamine granules and food. The entire amount of the mixture should be eaten.

This may be followed by 250 mL of an acceptable acidic liquid - fruit juice (e.g., orange juice or anyacidic fruit juice) or water. The mixture must be eaten within 2 hours after preparation and may berefrigerated from the time of preparation to the time of administration.

Administering through feeding tubes

Capsules for either the morning or evening dose should be opened and the contents sprinkled ontoapproximately 100 grams of apple sauce or fruit jam. Gently stir the contents into the soft food,creating a mixture of cysteamine granules and the soft food. The mixture should then be administeredvia gastrostomy tube, nasogastric tube or gastrostomy-jejunostomy tube using a catheter tip syringe.

Before PROCYSBI administration: Unclasp the G-tube button and attach the feeding tube. Flush with5 mL of water to clear the button. Draw the mixture up into the syringe. A maximum 60 mL mixturevolume in a catheter tip syringe is recommended for use with a straight or bolus feeding tube. Placethe opening of the syringe containing the PROCYSBI/apple sauce/fruit jam mixture into the openingof the feeding tube and fill completely with the mixture: pressing gently on the syringe and keepingthe feeding tube horizontal during administration can help to avoid clogging issues. Using a viscousfood such as apple sauce or fruit jam at a rate of about 10 mL every 10 seconds until the syringe iscompletely empty, is also suggested to avoid clogging. Repeat the above step until all of the mixture isgiven. After PROCYSBI administration, draw 10 mL of fruit juice or water up into another syringeand flush the G-tube ensuring that none of the apple sauce/fruit jam and granules mixture gets stuck onthe G-tube.

The mixture must be administered within 2 hours after preparation and may be refrigerated from thetime of preparation to the time of administration. Nothing of the mixture should be saved.

Sprinkling in orange juice or any acidic fruit juice or water

Capsules for either the morning or evening dose should be opened and the contents sprinkled into 100to 150 mL of acidic fruit juice or water. Dose administration options are provided below:

* Option 1/Syringe: Mix gently for 5 minutes, then aspirate the mixture of cysteamine granulesand acidic fruit juice or water into a dosing syringe.

* Option 2/Cup: Mix gently for 5 minutes in a cup or shake gently for 5 minutes in a covered cup(e.g., “sippy” cup). Drink the mixture of cysteamine granules and acidic fruit juice or water.

The mixture must be administered (drunk) within 30 minutes after preparation and may be refrigeratedfrom the time of preparation to the time of administration.

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

Chiesi Farmaceutici S.p.A.

Via Palermo 26/A43122 Parma

Italy

EU/1/13/861/001

EU/1/13/861/002

Date of first authorisation: 06 September 2013

Date of latest renewal: 26 July 2018

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

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