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PROCYSBI®
(cysteamine bitartrate) Delayed-Release Capsules, for Oral Use
PROCYSBI, for oral administration, is a cystine-depleting agent that lowers the cystine content of cells in patients with nephropathic cystinosis, an inherited defect of lysosomal transport.
PROCYSBI contains the bitartrate salt of cysteamine. The chemical name for cysteamine bitartrate is ethanethiol, 2-amino, (2R,3R)-2,3-dihydroxybutanedioate (1:1) (salt). Cysteamine bitartrate is a highly water soluble white powder with a molecular weight of 227.24 and the molecular formula C2H7NS • C4H6O6. It has the following chemical structure:
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Each 25 mg delayed-release capsule contains 74 mg cysteamine bitartrate, equivalent to 25 mg cysteamine. Each 75 mg delayed-release capsule contains 221 mg cysteamine bitartrate, equivalent to 75 mg cysteamine. PROCYSBI contains the following inactive ingredients: microcrystalline cellulose, Eudragit® L 30 D-55, hypromellose, talc, triethyl citrate, sodium lauryl sulfate, and purified water. Capsule shell ingredients are gelatin, titanium dioxide, blue ink and white ink.
PROCYSBI is indicated for the treatment of nephropathic cystinosis in adults and pediatric patients 1 year of age and older.
Table 1: Starting and Maintenance Dosage of PROCYSBI by Body Weight in Cysteamine-Naïve Patients 1 Year of Age and Older (Dosage Rounded Using Available Strengths of Capsules or Packets of Oral Granules)
| Weight in kilograms | Starting PROCYSBI Dosage in mg every 12 hours, as a Fraction of the Maintenance Dosage | Maintenance PROCYSBI Dosage in mg every 12 hours* | |
| 1/6 of dosage | 1/4 of dosage | ||
| 5 or less | 25 | 50 | 200 |
| 6 to 10 | 50 | 75 | 300 |
| 11 to 15 | 75 | 100 | 400 |
| 16 to 20 | 100 | 125 | 500 |
| 21 to 25 | 100 | 150 | 600 |
| 26 to 30 | 125 | 175 | 700 |
| 31 to 40 | 125 | 200 | 800 |
| 41 to 50 | 150 | 225 | 900 |
| 51 kg and greater | 175 | 250 | 1000 |
| * Higher dosages may be required to achieve target therapeutic WBC cystine concentration [see Dosage Titration To Therapeutic Target WBC Cystine Concentration]. | |||
Administration of PROCYSBI capules or oral granules with foods and liquids not included below has not been studied clinically and is not recommended.
Administration in Applesauce or Berry Jelly
Administration in Fruit Juice (except grapefruit juice)
A bolus (straight) feeding tube is recommended.
Distributed by: Horizon Therapeutics USA, Inc., Lake Forest, IL 60045 Revised: Feb 2020
The following adverse reactions are also discussed in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The data described below reflect exposure to cysteamine in 345 patients with nephropathic cystinosis (246 patients receiving immediate-release cysteamine as cysteamine hydrochloride or phosphocysteamine, and 80 patients receiving PROCYSBI) in open-label clinical trials.
Sixty-two patients with nephropathic cystinosis (38 males and 24 females) received PROCYSBI in two clinical trials at doses ranging from 0.29 grams/m2 per day to 2.19 grams/m2 per day [see Clinical Studies]. All patients were switched from immediate-release cysteamine to PROCYSBI. Forty-three patients, ages 6 to 26 years old, received PROCYSBI in an 8-week, open-label, randomized, cross-over trial comparing PROCYSBI to immediate-release cysteamine bitartrate. Forty of 43 patients continued PROCYSBI treatment in an open-label extension trial (36 patients were treated with PROCYSBI for longer than 2 years, and 20 patients were treated for longer than 5 years). An additional 19 patients (6 renal transplanted patients and 13 patients aged 2 to 6 years) were enrolled directly into this trial (12 patients were treated with PROCYSBI for longer than 2 years, and 9 patients were treated for longer than 5 years).
In the open-label, randomized, cross-over trial, a higher incidence of adverse reactions was reported in patients during the PROCYSBI treatment period compared with the immediate-release cysteamine bitartrate treatment period (see Table 2). Other significant adverse reactions reported during clinical trials included hypersensitivity reactions, including anaphylaxis.
Table 2: Adverse Reactions in ≥5% of Patients with Nephropathic Cystinosis in a Randomized, Cross-Over Trial
| Adverse Reaction | Immediate-Release Cysteamine | PROCYSBI |
| (n = 41) % | (n = 43) % | |
| Vomiting/emesis | 12 | 19 |
| Nausea | 7 | 16 |
| Abdominal pain/discomfort | 0 | 14 |
| Headache | 0 | 9 |
| Dizziness | 0 | 5 |
| Anorexia/loss of appetite | 5 | 2 |
In the open-label extension trial (N=59), the most commonly reported adverse reactions (>15%) were vomitin g, headache, diarrhea, nausea, conjunctivitis, influenza, gastroenteritis, nasopharyngitis, abdominal pain, dehydration, ear infection, upper respiratory tract infection, fatigue, arthralgia, cough, and pain in extremity.
Seventeen cysteamine-naïve patients (fifteen patients between the ages of 1 and 5 years, one 9-year old and one 22-year old) received PROCYSBI in an open-label clinical trial [see Clinical Studies]. Serious adverse reactions occurring in at least 2 patients (>10%) were: gastroenteritis/viral gastroenteritis (n=6), vomiting (n=4), and electrolyte imbalance (n=2). Three patients with serious adverse reactions of gastroenteritis also had dehydration. Common adverse reactions reported at a frequency of >10% (occurring in at least 2 patients) are shown in Table 3.
Table 3: Adverse Reactions in >10% of Patients with Nephropathic Cystinosis Naïve to Cysteamine Treatment in an Open-Label Trial
| Adverse Reaction | PROCYSBI N = 17 n (%) |
| Vomiting | 13 (77) |
| Gastroenteritis/viral gastroenteritis | 9 (53) |
| Diarrhea | 6 (35) |
| Breath odor | 4 (24) |
| Nausea | 3 (18) |
| Electrolyte imbalance | 2 (12) |
| Headache | 2 (12) |
The most frequent adverse reactions involved the gastrointestinal and central nervous systems and were especially prominent at the initiation of cysteamine therapy. Most patients were able to resume therapy at lower doses. The most common reactions (>5%) were vomiting, anorexia, fever, diarrhea, lethargy, and rash. Other adverse reactions included nausea, bad breath, abdominal pain, headache, dizziness, and urticaria.
Withdrawals due to intolerance, vomiting, anorexia, lethargy, and fever occurred more frequently in those patients receiving 1.95 grams/m2 per day as compared with 1.3 grams/m2 per day of immediate-release cysteamine bitartrate.
The following adverse reactions have been identified during post-approval use of immediate-release cysteamine bitartrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Drugs that increase the gastric pH (e.g., medications containing bicarbonate or carbonate) may alter the pharmacokinetics of cysteamine due to the premature release of cysteamine from PROCYSBI and increase WBC cystine concentration. Concomitant administration of 20 mg omeprazole did not affect the pharmacokinetics of cysteamine when PROCYSBI was administered with 240 mL of orange juice or with 240 mL of water [see CLINICAL PHARMACOLOGY]. Monitor WBC cystine concentration when drugs that increase the gastric pH are concomitantly used [see DOSAGE AND ADMINISTRATION].
Consumption of alcohol with PROCYSBI may increase the rate of cysteamine release and/or adversely alter the pharmacokinetic properties, as well as the effectiveness and safety of PROCYSBI. Therefore, do not consume alcoholic beverages during treatment with PROCYSBI [see DOSAGE AND ADMINISTRATION].
PROCYSBI can be administered with other electrolyte and mineral replacements necessary for management of Fanconi syndrome, as well as vitamin D and thyroid hormone.
Included as part of the "PRECAUTIONS" Section
Skin and bone lesions that resemble clinical findings for Ehlers-Danlos-like syndrome have been reported in patients treated with high doses of immediate-release cysteamine bitartrate or other cysteamine salts. These include molluscoid pseudotumors (purplish hemorrhagic lesions), skin striae, bone lesions (including osteopenia, compression fractures, scoliosis and genu valgum), leg pain, and joint hyperextension. One patient on immediate-release cysteamine bitartrate with serious skin lesions subsequently died of acute cerebral ischemia with marked vasculopathy. Monitor patients for development of skin or bone lesions and interrupt PROCYSBI dosing if patients develop these lesions. PROCYSBI may be restarted at a lower dose under close supervision, then slowly increase to the appropriate therapeutic dose [see DOSAGE AND ADMINISTRATION].
Severe skin rashes such as erythema multiforme bullosa or toxic epidermal necrolysis have been reported in patients receiving immediate-release cysteamine bitartrate. If severe skin rashes develop, permanently discontinue use of PROCYSBI [see CONTRAINDICATIONS].
Gastrointestinal (GI) ulceration and bleeding have been reported in patients receiving immediate-release cysteamine bitartrate. GI tract symptoms including nausea, vomiting, anorexia and abdominal pain, sometimes severe, have been associated with cysteamine. If severe GI tract symptoms develop, consider decreasing the dose of PROCYSBI [see DOSAGE AND ADMINISTRATION].
Central Nervous System (CNS) symptoms such as seizures, lethargy, somnolence, depression, and encephalopathy have been associated with immediate-release cysteamine. Neurological complications have also been described in some patients with cystinosis who have not been treated with cysteamine. Carefully evaluate and monitor patients who develop CNS symptoms. Interrupt medication or adjust the dose as necessary for patients with severe symptoms or with symptoms that persist or progress. Inform patients that PROCYSBI may impair their ability to perform tasks such as driving or operating machinery.
Cysteamine has been associated with reversible leukopenia and elevated alkaline phosphatase levels. Monitor white blood cell counts and alkaline phosphatase levels. If tests values remain elevated, consider decreasing the dose or discontinuing the drug until values revert to normal.
Benign intracranial hypertension (pseudotumor cerebri; PTC) and/or papilledema have been reported in patients receiving immediate-release cysteamine bitartrate treatment. Monitor patients for signs and symptoms of PTC, including headache, tinnitus, dizziness, nausea, diplopia, blurry vision, loss of vision, pain behind the eye or pain with eye movement. If signs/symptoms persist, interrupt dosing or decrease the dose and refer the patient to an ophthalmologist. If the diagnosis is confirmed, permanently discontinue use of PROCYSBI.
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION and Instructions for Use)
Advise patients and caregivers that PROCYSBI may cause abnormalities of the skin, bones, and joints. Advise patients to report any skin changes or problems with their bones or joints to their physician [see WARNING AND PRECAUTIONS].
Advise patients and caregivers to contact their physician immediately if they experience a skin rash [see WARNING AND PRECAUTIONS].
Advise patients and caregivers that PROCYSBI may cause ulcers and bleeding. Advise patients to contact their physician immediately if they experience stomach pain, nausea, vomiting, loss of appetite, or are vomiting blood [see WARNING AND PRECAUTIONS].
Advise patients and caregivers that PROCYSBI may impair their ability to perform tasks such as driving or operating machinery. Advise patients to contact their physician immediately if they experience seizures, lethargy, somnolence, depression, and encephalopathy [see WARNING AND PRECAUTIONS].
Advise patients and caregivers that PROCYSBI may cause benign intracranial hypertension. Advise patients to contact their physician immediately if they experience headache, tinnitus, dizziness, nausea, double vision, blurry vision, loss of vision, or eye pain [see WARNING AND PRECAUTIONS].
Advise patients and to contact their physician immediately if they suspect they may be pregnant. Discuss with the patient the individual risks and benefits of continuing PROCYSBI during pregnancy [see Use In Specific Populations].
Advise patients that breastfeeding is not recommended while taking PROCYSBI [see Use In Specific Populations].
Discuss with the patient and caregivers the importance of required laboratory testing to determine the correct dose of PROCYSBI [see DOSAGE AND ADMINISTRATION].
Capsules
Oral Granules
Advise patients and caregivers to keep PROCYSBI in a dry place. Protect from moisture. For bottles, keep PROCYSBI delayed-release capsules in the original bottle. Do not remove the dessicant or oxygen absorber from the bottle. Do not store PROCYSBI delayed-release oral granules in opened packets [see HOW SUPPLIED].
Cysteamine has not been tested for its carcinogenic potential in long-term animal studies.
PROCYSBI was not mutagenic in the Ames test. It produced a negative response in an in-vitro sister chromatid exchange assay in human lymphocytes, but a positive response in a similar assay in hamster ovarian cells.
Repeat breeding reproduction studies were conducted in male and female rats. Cysteamine was found to have no effect on fertility and reproductive performance at an oral dose of 75 mg/kg per day (450 mg/m2 per day, 0.4 times the recommended human dose based on body surface area). At an oral dose of 375 mg/kg per day (2250 mg/m2 per day, 1.7 times the recommended human maintenance dose based on body surface area), it reduced the fertility of the adult rats and the survival of their offspring.
There are no available data on PROCYSBI use in pregnant women to inform any drug-associated risks for birth defects or miscarriage [see Data]. Cysteamine (administered as cysteamine bitartrate) was teratogenic and fetotoxic in rats at doses less than the recommended human maintenance dose.
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Advise pregnant women of the potential risk to a fetus.
Animal Data
Embryo-fetal development studies were conducted in rats using oral administration of cysteamine bitartrate, with a dose range of 37.5 to 150 mg/kg per day of cysteamine equivalent (about 0.2 to 0.7 times the recommended human maintenance dose based on body surface area). Cysteamine bitartrate was fetotoxic and produced adverse developmental effects. Observed teratogenic findings were cleft palate, kyphosis, heart ventricular septal defects, microcephaly and exencephaly.
There is no information on the presence of cysteamine in human milk, the effects on the breast-fed infant, or the effects on milk production. Cysteamine is present in the milk of lactating rats [see Data]. Because of the potential for serious adverse reactions in breastfed infants from cysteamine, breastfeeding is not recommended.
A decrease in survival occurred in neonatal rats nursed by mothers receiving cysteamine [see Nonclinical Toxicology].
The safety and effectiveness of PROCYSBI have been established in pediatric patients 1 year of age and older for the treatment of nephropathic cystinosis. Use of PROCYSBI is supported by evidence from patients switched to PROCYSBI from immediate-release cysteamine bitartrate in two trials: an open-label, randomized, cross-over trial in adults and pediatric patients aged 6 years and older (n=43) and an open-label extension trial in pediatric patients aged 2 years and older (n=59). Another open-label trial was conducted in cysteamine naïve pediatric patients 1 year to less than 6 years of age (n=15) [see Clinical Trials]. The safety profile in pediatric patients was similar to adults. In patients less than 6 years of age, vomiting occurred in 12/15 cysteamine treatment naïve patients compared to 11/13 patients switched from immediate-release cysteamine to PROCYSBI.
The safety and effectiveness of PROCYSBI have not been established in patients less than 1 year of age.
No studies with PROCYSBI have been conducted in geriatric patients.
One case of overdosing with PROCYSBI has been reported. A 16-year old male patient suffered nausea and vomiting after he mistakenly took a second dose of PROCYSBI 30 minutes after his usual dose.
Two cases of overdosing with immediate-release cysteamine bitartrate have been reported in two patients. In the first case, the patient immediately vomited after ingesting an unknown dose and did not develop any symptoms. The second case involved an accidental ingestion of a 200 to 250 mg/kg dose by a healthy 13-month-old child. Vomiting and dehydration were experienced. The child was hospitalized and fluids were administered. The patient fully recovered from the overdosing.
Should overdosing occur, the respiratory and cardiovascular systems should be supported appropriately. No specific antidote is known. Hemodialysis may be considered since cysteamine is poorly bound to plasma proteins.
The use of PROCYSBI is contraindicated in patients with a serious hypersensitivity reaction, including anaphylaxis, to penicillamine or cysteamine.
Cysteamine is an aminothiol that participates within lysosomes in a thiol-disulfide interchange reaction converting cystine into cysteine and cysteine-cysteamine mixed disulfide, both of which can exit the lysosome in patients with cystinosis.
Normal individuals and persons heterozygous for cystinosis have WBC cystine concentrations of less than 0.2 and usually below 1 nmol ½ cystine/mg protein, respectively, when measured using the mixed leukocyte assay. Untreated patients with nephropathic cystinosis have elevations of WBC cystine concentration above 2 nmol ½ cystine/mg protein.
After the administration of a single dose of PROCYSBI, peak concentrations of cysteamine were observed at 3 hours post-dose. The nadir of WBC cystine closely followed the peak concentrations at 3.5 hours post-dose, and returned to baseline WBC concentrations at 12 hours-post dose. The cystine concentration in WBC lysate was measured with LC/MS/MS and total protein content in human WBC lysate was measured using the bicinchoninic acid (BCA) assay. A correction factor was applied to the total protein content for the difference in results from the Lowry method. The cystine concentration in nmol ½ cystine/mg protein was calculated by multiplying nmol cystine/mg protein by 2 [see DOSAGE AND ADMINISTRATION].
The pharmacokinetics of cysteamine with administration of PROCYSBI were evaluated in 43 patients age ranged from 6 to 26 years (mean age 12 years) with cystinosis and with an estimated glomerular filtration rate of greater than 30 mL/minutes/1.73 m2. Table 4 shows the mean pharmacokinetic parameters for PROCYSBI and immediate-release cysteamine bitartrate at steady state. The mean (± SD) dose for PROCYSBI was 656 ± 144 mg/m2 (given every 12 hours) and for immediate-release cysteamine bitartrate was 404 ± 88 mg/m2 (given every 6 hours).
Table 4: Pharmacokinetic parameters for cysteamine at steady state* after administration of PROCYSBI or immediate-release cysteamine bitartrate
| Immediate-release cysteamine bitartrate given every 6 hours | PROCYSBI given every 12 hours | |
| Cmax (mg/L) | 2.7 ± 1.4 | 3.6 ± 1.8 |
| AUC0-6h (min*mg/L) | 351 ± 153 | NA |
| AUC0-12h (min*mg/L) | NA | 726 ± 339 |
| AUCinf (min*mg/L) | 380 ± 157 | 785 ± 358 |
| Tmax (min) | 73 ± 31 | 188 ± 88 |
| t½ (min) | 90 ± 24 | 253 ± 403 |
| CL/F (L/min) | 1.4 ± 0.8 | 1.2 ± 0.8 |
| Vd/F (L) | 198 ± 159 | 382 ± 404 |
The pharmacokinetics of cysteamine with administration of PROCYSBI are consistent with a delayed-release formulation; the mean Tmax for cysteamine was 188 minutes with PROCYSBI compared with 73 minutes for immediate-release cysteamine bitartrate.
The mean plasma cysteamine peak and AUC were similar when a single PROCYSBI dose of 600 mg was administered with 240 mL orange juice or with 240 mL water. The systemic exposure to cysteamine was similar when PROCYSBI was administered with orange juice as a whole capsule and sprinkled in applesauce in the fasted state. In a food effect study conducted in healthy subjects (n=20), administration of a meal 30 minutes following PROCYSBI administration (intact capsules) decreased Cmax by 34% and AUC0-t by 32% compared to administration of a meal 2 hours post-dose [see DOSAGE AND ADMINISTRATION].
Cysteamine was moderately bound to human plasma proteins, predominantly to albumin, with mean protein binding of about 52%. Plasma protein binding was independent of concentration over the concentration range achieved clinically with the recommended doses. The volume of distribution (Vd/F) was 382 L for PROCYSBI compared with 198 L for immediate-release cysteamine bitartrate.
After each dose of PROCYSBI the cysteamine concentration in the blood continues to decline for approximately 30 minutes and the WBC cystine concentration increases accordingly.
The apparent clearance (Cl/F) of cysteamine was similar between PROCYSBI (1.2 ± 0.8 L/min) and immediate-release cysteamine bitartrate (1.4 ± 0.8 L/min).
The half-life was 253 minutes for PROCYSBI and 90 minutes for immediate-release cysteamine bitartrate.
The pharmacokinetics of cysteamine with administration of PROCYSBI at steady state were evaluated in 11 cysteamine treatment naïve patients between the ages of 1 and 5 years of age with nephropathic cystinosis. A mean (± SD) Cmax of 1.26 ± 0.86 mg/L was reached at an average Tmax of 199 ± 138 minutes and the mean (± SD) dose was 242 ± 93 mg/m2. The mean exposure was calculated to be 206 ± 113 minutes*mg/L (AUClast) and 231 ± 123 minutes*mg/L (AUCinf). The mean CLss/F was estimated to be 0.69 ± 0.37 L/minutes with an average half-life (t1/2) of 270 ± 56 minutes. Overall, the pharmacokinetics in patients between the ages of 1 and 5 years of age is comparable with those in older children and adults.
The pharmacokinetics of cysteamine with administration of a single oral dose of 600 mg PROCYSBI were evaluated in non-cystinosis subjects with renal impairment and healthy subjects with normal renal function (eGFR >90 mL/min/1.73m2) matched for age, body mass index and sex.
The mean AUCinf and mean Cmax for cysteamine were 8%, and 3% lower, respectively, in subjects with mild renal impairment (eGFR 60 to 89 mL/min/1.73m2) compared to healthy subjects. In subjects with moderate renal impairment (eGFR 30 to 59 mL/min/1.73m2) and severe renal impairment (≤29 mL/min/1.73m2), the mean AUCinf was 49% and 35% higher and the mean Cmax was 27% and 11% higher, respectively compared to healthy subjects. The mean t½ was 7 hours, 8.3 hours, and 8.8 hours in subjects with mild, moderate, and severe renal impairment, respectively and ranged from 6.6 to 7.5 hours in healthy subjects. The mean CL/F was 1.57, 1.08, and 1.09 L/min in mild, moderate, and severe renal impairment subjects compared to 1.40 to 1.60 L/min in healthy subjects.
In subjects with end-stage renal disease receiving 4 hours of hemodialysis, the geometric mean Cmax and AUCinf of cysteamine was 60% higher when PROCYSBI was administered 3 hours before hemodialysis, and 22% higher when administered 1 hour after completion of hemodialysis compared to healthy subjects. Approximately 4.3% (25.6 mg) of the 600 mg PROCYSBI dose was removed from the body with hemodialysis. The apparent clearance of cysteamine in subjects who received PROCYBI before hemodialysis was approximately 65 mL/min.
The increased exposure to cysteamine in patients with renal impairment compared to healthy subjects is not considered to be clinically meaningful.
An in vitro study indicates cysteamine bitartrate is not an inhibitor of CYP enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). The potential for cysteamine to affect the pharmacokinetics of other drugs via these enzymes is low.
The effect of concomitant omeprazole on the pharmacokinetics of cysteamine was evaluated following co-administration of single PROCYSBI dose of 600 mg with 20 mg of omeprazole in comparison to administration of PROCYSBI alone in healthy subjects in two separate studies. In both studies omeprazole was dosed once daily for 5 days before co-administration with PROCYSBI and single dose PROCYSBI was given either with 240 mL orange juice in one study or with 240 mL water in another study. The pharmacokinetic parameters of cysteamine were not significantly different when PROCYSBI was administered with omeprazole compared to when PROCYSBI was administered alone, regardless whether PROCYSI was administered with orange juice or water [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS].
Efficacy of immediate-release cysteamine bitartrate was demonstrated in open-label clinical trials of cysteamine hydrochloride and phosphocysteamine.
An open-label clinical trial of cysteamine hydrochloride was conducted in 94 pediatric patients (mainly from the United States) with nephropathic cystinosis. Patients were treated with increasing doses of cysteamine hydrochloride (mean dose 54 mg/kg per day) to attain WBC cystine concentrations of less than 2 nmol ½ cystine/mg protein 5 to 6 hours post-dose. The clinical outcomes were compared with a historical control group of 17 pediatric patients who had been in the placebo group of a randomized placebo-controlled trial of ascorbic acid. Cysteamine-treated patients had been diagnosed at a mean age of 22 months and had a mean age of 46 months old at study entry; placebo patients had been diagnosed at about 29 months and had a mean age of about 52 months old at trial entry. The principal measures of effectiveness were serum creatinine and calculated creatinine clearance and growth (height).
The average median WBC cystine concentration during treatment was 1.7 ± 0.2 nmol 1/2 cystine/mg protein. There were 70 cysteamine-treated patients with a baseline serum creatinine of less than 2 mg/dL who were followed for at least 1 year, and 17 placebo patients. Twelve of the 94 cysteamine-treated patients required early dialysis or renal transplant. Median follow-up of cysteamine patients was over 32 months, and 20% were followed more than 5 years. Median follow-up of the placebo group was 20 months; only 1 patient was followed more than 24 months. Glomerular function among cysteaminetreated patients was maintained over time. Placebo-treated patients experienced a gradual rise in serum creatinine. Renal tubular function was not affected by treatment.
Calculated creatinine clearances were evaluated for two groups of pediatric patients, one with poor WBC cystine depletion (defined as median WBC cystine concentrations greater than 3 nmol ½ cystine/mg protein or WBC cystine concentrations not measured at least 2 times per year) and one with good WBC cystine depletion. The final mean creatinine clearance of the good depletion group was 20.8 mL/min/1.73 m2 greater than the mean for the poor-depletion group.
Height-for-age measurements of treated patients were compared with height-for-age measurements of 143 patients initially screened for inclusion in the trial. Patients on treatment maintained growth (i.e., did not show increasing growth failure compared with normal scales) although growth velocity did not increase enough to allow patients to catch up to age norms for height.
In another open-label clinical trial, 46 patients who had completed the clinical trial of cysteamine hydrochloride (averaging 6.5 years of treatment) and 93 treatment naïve patients were treated with either cysteamine hydrochloride or phosphocysteamine (patient's choice). Patients had cystinosis diagnosed by elevated WBC cystine (mean 3.63 nmol ½ cystine/mg). Newly enrolled patients and the 46 continuing patients were required to have serum creatinine less than 3 mg/dL and 4 mg/dL, respectively. Patients were randomized to doses of 1.3 or 1.95 grams/m2 per day and stratified according to whether the serum creatinine was above 1.2 mg/dL or not. Doses could be raised if WBC cystine concentrations were approximately 2 nmol ½ cystine/mg protein and lowered due to intolerance. The mean age of the newly enrolled patients was about 49 months for the cysteamine group and about 34 months for the phosphocysteamine group. The mean age of the patients in the long-term follow-up group was about 9 years.
Mean doses were 1.27 grams/m2 per day and 1.87 grams/m2 per day in the two groups and WBC cystine concentrations averaged 1.72 ± 1.65 nmol ½ cystine/mg protein and 1.86 ± 0.92 nmol ½ cystine/mg protein in the 1.3 grams/m2 per day and 1.95 grams/m2 per day in the two groups, respectively. In new patients, serum creatinine was essentially unchanged over the period of follow-up (about half of the patients were followed for 24 months) and phosphocysteamine and cysteamine hydrochloride had similar effects. The long-term follow-up group also had essentially no change in renal function (almost 80% were followed at least 2 years). In four studies of patients with untreated cystinosis, renal death (need for transplant or dialysis) occurred at median age of less than 10 years. Both new patients and patients in the long-term follow-up group maintained height (although they did not catch up from baseline). There was no apparent difference in height maintenance between the two doses.
A clinical trial comparing immediate-release cysteamine bitartrate and PROCYSBI was conducted in 43 (40 pediatric and 3 adult) patients with nephropathic cystinosis (Study RP103-03; NCT01000961). Patient age ranged from 6 to 26 years (mean age 12 years) and 56% were male. Patients with WBC cystine concentrations greater than 2 nmol ½ cystine/mg protein (measured using the mixed leukocyte assay) and estimated glomerular filtration rate (eGFR corrected for body surface area) less than 30 mL/minute/1.73 m2 at the time of screening were excluded from the trial. Prior to randomization, patients were to be on a stable dose of immediate-release cysteamine bitartrate administered every six hours. PROCYSBI dose adjustments of up to approximately 100% of the total daily dose of immediate-release cysteamine bitartrate were allowed by trial criteria. The average total daily dose of PROCYSBI for patients completing the clinical trial was approximately 91% of the average total daily dose of immediate-release cysteamine bitartrate for patients at trial entry.
This trial demonstrated that at steady-state, PROCYSBI administered every 12 hours was non-inferior to immediate-release cysteamine bitartrate administered every 6 hours with respect to the depletion of WBC cystine concentrations (Table 5). Using a linear mixed effects statistical analysis model, the least-squaremean value of WBC cystine was 0.52 ± 0.06 nmol ½ cystine/mg protein after 12 hours under PROCYSBI and 0.44 ± 0.06 nmol ½ cystine/mg protein after 6 hours under immediate-release cysteamine; a difference of 0.08 ± 0.03 nmol ½ cystine/mg protein (95.8% Confidence Interval = 0.01 to 0.15).
Table 5: Comparison of WBC cystine concentrations in open-label, randomized, cross-over clinical trial participants, who were on a stable dose of immediate-release cysteamine prior to randomization, with WBC cystine less than 2 nmol ½ cystine/mg protein throughout the trial1
| Immediate-release cysteamine bitartrate | PROCYSBI | |
| WBC cystine concentration in nmol ½ cystine/mg protein (LS Mean ± SE) | 0.44 ± 0.06 | 0.52 ± 0.06 |
| Difference in Treatment effect (LS mean ± SE) [95.8% CI; p-value] | 0.08 ± 0.03 [0.01 to 0.15; <0.0001] | |
| 1 Per–Protocol (PP) Population (N=39) | ||
Forty of the 41 patients completing the randomized trial continued treatment with PROCYSBI in an open-label extension trial, for a total treatment duration ranging from 1 month to 6.7 years in the study (Study RP103-03-04; NCT01197378). Thirty-six of the 40 patients continued treatment with PROCYSBI for at least 24 months and 20 patients continued treatment for longer than 60 months in the extension trial, and maintained their mean WBC cystine concentrations below 1 nmol ½ cystine/mg protein (measured using the mixed leukocyte assay) over this time period.
Thirteen pediatric patients, aged 2 to 6 years, were also enrolled in the extension trial and treated with PROCYSBI. All of them were on treatment with immediate-release cysteamine bitartrate at the time of enrollment. All 13 patients received at least 18 months of treatment with PROCYSBI, and their mean ± SD WBC cystine concentration (measured using the mixed leukocyte assay) decreased from 1.41 ± 1.03 nmol ½ cystine/mg protein at baseline to 1.22 ± 1.40 nmol ½ cystine/mg protein after 18 months of treatment. Seven of these pediatric patients were able to achieve a WBC cystine concentration (measured using the mixed leukocyte assay) of less than 1.0 nmol ½ cystine/mg protein after 18 months of treatment; their mean ± SD dose of PROCYSBI increased from 0.81 ± 0.25 grams/m2 per day at baseline to 0.90 ± 0.25 grams/m2 per day after 18 months of treatment.
During extended treatment with PROCYSBI, mean estimates of renal function, as measured by the eGFR, were maintained.
A clinical trial of PROCYSBI (Study RP103-08; NCT01744782) was conducted in 17 patients with a documented diagnosis of nephropathic cystinosis who were naïve to cysteamine treatment (15 patients between the ages of 1 and 5 years, one 9-year old and one 22-year old). The PROCYSBI starting dose was 1/4 the maintenance dose of 1 gram/m2/day (actual dosing was based on weight bands using the available capsule strengths, as shown in (Table 1) and the dosage was gradually increased by 10% every 2 weeks. Dosage adjustment was allowed throughout the trial and was based on subject-specific factors (e.g., weight, tolerability) and WBC cystine concentrations. WBC cystine concentrations were obtained 30 minutes after the morning dose collected bi-monthly until the patient’s WBC cystine concentration (using the mixed leukocyte assay) was < 1 nmol ½ cystine/mg protein. Treatment duration was at least 12 months.
Fourteen of the 15 patients between 1 year and less than 6 years of age completed 12 months of treatment, and 10 patients completed 18 months of treatment. Thirteen of the 14 patients achieved their highest total daily dosage of PROCYSBI following the 9-month visit (9-month visit for 8 subjects, 12-month visit for 4 subjects, and 18-month visit for 1 subject).
Some patients did not have WBC cystine samples collected at each visit or results were not reportable due to laboratory errors. Thus, the numbers of patients with available WBC cystine data varied across the time points analyzed. In patients with missing samples, dose escalation was continued if the patient’s last reported WBC cystine concentration was > 1 nmol ½ cystine/mg protein.
In patients 1 year to less than 6 years, the mean (±SD) WBC cystine concentration on Day 1, 30 minutes following the first dose, was 3.17±2.95 nmol ½ cystine/mg protein (n=15 patients). At 12 months (13 patients with samples), the mean WBC cystine concentration was 0.80 ± 0.60 nmol ½ cystine/mg protein at 30 minutes post dose. At 18 months (9 patients with samples) the mean WBC cystine concentration was 0.74 ± 0.64 nmol ½ cystine/mg protein at 30 minutes post dose.
In patients 1 year to less than 6 years, the mean (±SD) weight percentiles at Day 1 (n=14), 12 months (n=13) and 18 months (n=10) were 3.5 ± 11.1, 11.9 ± 18.3, and 30.1 ± 28.2, respectively, and patient weight z-scores were -4.0 ± 2.1, -2.2 ± 1.7, and -1.3 ± 2.0, respectively. In the same patients, similar trends were observed for height.
PROCYSBI®
(Pro-CIS-bee)
(cysteamine bitartrate) delayed-release capsules and delayed-release oral granules
What is PROCYSBI?
PROCYSBI is a prescription medicine used to treat nephropathic cystinosis in adults and children 1 year of age and older. It is not known if PROCYSBI is safe and effective in children under 1 year of age.
Do not take PROCYSBI if you are allergic to penicillamine or cysteamine.
Before taking PROCYSBI, tell your doctor about all of your medical conditions, including if you:
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
How should I take PROCYSBI?
Capsules:
Granules:
What should I avoid while taking PROCYSBI?
What are the possible side effects of PROCYSBI?
PROCYSBI can cause serious side effects, including:
The most common side effects with PROCYSBI include:
These are not all the possible side effects of PROCYSBI. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of PROCYSBI.
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use PROCYSBI for a condition for which it was not prescribed. Do not give PROCYSBI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about PROCYSBI that is written for health professionals.
What are the ingredients in PROCYSBI?
Active ingredients: cysteamine bitartrate
Inactive ingredients: Eudragit® L 30 D-55, hypromellose, microcrystalline cellulose, purified water, sodium lauryl sulfate, talc, and triethyl citrate. Capsule shell ingredients: gelatin, titanium dioxide, blue ink and white ink.
Instructions for Use
PROCYSBI®
(Pro-CIS-bee)
(cysteamine bitartrate)
delayed-release capsules and delayed-release oral granules
PROCYSBI is available as:
Your doctor will tell you the number of capsules or packets of oral granules you need to take for each dose. If you have any questions, talk to your doctor.
Taking PROCYSBI capsules
PROCYSBI capsules should be swallowed whole with fruit juice (except grapefruit juice) or water. If you cannot swallow the capsule whole, you can open each capsule and take the capsule contents with certain foods and juices, or the capsule contents can be given through a gastrostomy tube (G-tube).
Opening PROCYSBI capsules:
Taking PROCYSBI with applesauce or berry jelly:
Do not take PROCYSBI with any food other than applesauce or berry jelly.
Step 1: Place about½ cup (4 ounces) of applesauce or berry jelly into a clean container. If needed, use a smaller amount you can finish in one feeding. Do not use any other food.
Step 2: Open the PROCYSBI capsule. See “Opening PROCYSBI capsules” above. You may need to use more than 1 PROCYSBI capsule for the dose prescribed by your doctor.
Step 3: Sprinkle the granules that are inside the capsule onto the applesauce or berry jelly.
Step 4: Mix the granules with the applesauce or berry jelly. Do not crush the granules.
Step 5: Swallow the applesauce or berry jelly and granules mixture within 30 minutes after preparing. Do not chew the granules. Do not save the applesauce or berry jelly and granules for later use.
Taking PROCYSBI with fruit juice:
Do not take PROCYSBI with grapefruit juice.
Step 1: Pour about½ cup (4 ounces) of fruit juice into a clean cup.
Step 2: Open the PROCYSBI capsule. See “Opening PROCYSBI capsules” above. You may need to use more than 1 PROCYSBI capsule for the dose prescribed by your doctor.
Step 3: Sprinkle all the granules that are inside the capsule into ½ cup (4 ounces) of fruit juice.
Step 4: Stir gently until mixed. Do not crush the granules.
Step 5: Drink all of the fruit juice and granules mixture within 30 minutes of mixing. Do not chew the granules. Do not save the fruit juice or water and granules mixture for later use.
Giving PROCYSBI through a gastrostomy tube (G-tube):
It is best to use a straight (bolus) feeding tube.
For people who have a gastrostomy tube (G-tube) that is size 14 French or larger, PROCYSBI may be given as follows:
Use only strained applesauce with no chunks when giving PROCYSBI through a gastrostomy tube (G-tube).
Step 1: Flush the gastrostomy tube button with 5 mL of water to clear the button.
Step 2: Place about½ cup (4 ounces) of applesauce into a clean container. Children who weigh 55 pounds (25 kilograms) or less can take PROCYSBI with at least 1/8 cup (1 ounce) of applesauce.
Step 3: Open the PROCYSBI capsule. See “Opening PROCYSBI capsules” above. You may need to use more than 1 PROCYSBI capsule for the dose prescribed by your doctor.
Step 4: Sprinkle the granules that are inside the capsule on the applesauce. Gently mix the granules with the applesauce. Do not crush the granules.
Step 5: Place the tip of a catheter tip syringe at the bottom of the container of applesauce and granules mixture. For an adult dose, draw up about 40 mL of the mixture. When giving to a child, draw up at least 10 mL of the mixture for doses of 1 or 2 capsules.
Step 6: Place the tip of the catheter tip syringe into the feeding tube that will be connected to the gastrostomy tube. Fill the feeding tube with the applesauce and granules mixture.
Step 7: Hold the feeding tube in a horizontal (straight across) position. Give the applesauce and granules mixture through the gastrostomy tube at a quick and steady rate of 10 mL over 10 seconds.
Step 8: Repeat Step 5 through Step 7 until all of the applesauce and granules mixture is given.
Give all of the applesauce and granules mixture through the gastrostomy tube within 30 minutes of mixing. Do not save the applesauce and granules mixture for later use.
Step 9: Draw up at least 10 mL of fruit juice or water into another catheter tip syringe. Do not use grapefruit juice. Gently swirl the syringe. Flush the gastrostomy tube with the fruit juice or water. Use enough fruit juice or water to flush the gastrostomy tube so that there is no applesauce and granules mixture left in the gastrostomy tube.
Taking PROCYSBI oral granules
You must mix the PROCYSBI oral granules in packets with certain foods and juices to take your PROCYSBI dose. PROCYSBI oral granules can also be given through a gastrostomy tube (G-tube).
Opening PROCYSBI oral granules in packets:
Taking PROCYSBI with applesauce or berry jelly:
Do not take PROCYSBI with any food other than applesauce or berry jelly.
Step 1: Place about½ cup (4 ounces) of applesauce or berry jelly into a clean container. Do not use any other food.
Step 2: Open the packet of PROCYSBI oral granules. See “Opening PROCYSBI oral granules in packets” above. You may need to use more than 1 packet of PROCYSBI oral granules for the dose prescribed by your doctor.
Step 3: Sprinkle all the granules that are inside the packet onto the applesauce or berry jelly.
Step 4: Mix the granules with the applesauce or berry jelly. Do not crush the granules.
Step 5: Swallow the applesauce or berry jelly and granules mixture within 30 minutes after preparing. Do not chew the granules. Do not save the applesauce or berry jelly and granules for later use.
Taking PROCYSBI with fruit juice:
Do not take PROCYSBI with grapefruit juice.
Step 1: Pour about½ cup (4 ounces) of fruit juice into a clean cup.
Step 2: Open the PROCYSBI packet. See “Opening PROCYSBI oral granules in packets” above. You may need to use more than 1 packet of PROCYSBI oral granules for the dose prescribed by your doctor.
Step 3: Sprinkle all the granules that are inside the packet into ½ cup (4 ounces) of fruit juice.
Step 4: Stir gently until mixed. Do not crush the granules.
Step 5: Drink all of the fruit juice and granules mixture within 30 minutes of mixing. Do not chew the granules. Do not save the fruit juice and granules for later use.
Giving PROCYSBI through a gastrostomy tube (G-tube):
It is best to use a straight (bolus) feeding tube.
For people who have a gastrostomy tube (G-tube) that is size 14 French or larger, PROCYSBI may be given as follows:
Use only strained applesauce with no chunks when giving PROCYSBI through a gastrostomy tube (G-tube).
Step 1: Flush the gastrostomy tube button with 5 mL of water to clear the button.
Step 2: Place about½ cup (4 ounces) of applesauce into a clean container. Children who weigh 55 pounds (25 kilograms) or less can take PROCYSBI with at least 1/8 cup (1 ounce) of applesauce.
Step 3: Open the packet of PROCYSBI oral granules. See “Opening PROCYSBI oral granules in packets” above. You may need to use more than 1 packet of PROCYSBI oral granules for the dose prescribed by your doctor.
Step 4: Sprinkle all the granules that are inside the packet on the applesauce. Gently mix the granules with the applesauce. Do not crush the granules.
Step 5: Place the tip of a catheter tip syringe at the bottom of the container of applesauce and granules mixture. For an adult dose, draw up about 40 mL of the mixture. When giving to a child, draw up at least 10 mL of the mixture for doses of 1 or 2 packets.
Step 6: Place the tip of the catheter tip syringe into the feeding tube that will be connected to the gastrostomy tube. Fill the feeding tube with the applesauce and granules mixture.
Step 7: Hold the feeding tube in a horizontal (straight across) position. Give the applesauce and granules mixture through the gastrostomy tube at a quick and steady rate of 10 mL over 10 seconds.
Step 8: Repeat Step 5 through Step 7 until all of the applesauce and granules mixture is given. Give all of the applesauce and granules mixture through the gastrostomy tube within 30 minutes of mixing. Do not save the applesauce and granules mixture for later use.
Step 9: Draw up at least 10 mL of fruit juice into another catheter tip syringe. Do not use grapefruit juice. Gently swirl the syringe. Flush the gastrostomy tube with the fruit juice. Use enough fruit juice to flush the gastrostomy tube so that there is no applesauce and granules mixture left in the gastrostomy tube.
How should I store PROCYSBI?
Keep PROCYSBI and all medicines out of the reach of children.
This Instructions for Use has been approved by the U.S. Food and Drug Administration.
