April 30, 2016
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Mechanism Of Action

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. 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 WBC cystine 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 Laboratory Monitoring].


The pharmacokinetics of PROCYSBI were evaluated in 43 patients with cystinosis and with an estimated glomerular filtration rate of > 30 mL/minutes/1.73 m2. Table 4 shows the mean PK parameters for PROCYSBI and immediate-release cysteamine bitartrate after one dose at steady state. The mean Cmax and AUCinf were 3.6 mg/L and 726 min*mg/L for PROCYSBI and 2.7 mg/L and 380 min*mg/L for immediate-release cysteamine bitartrate.

Table 4: PK parameters for cysteamine after a single dose of PROCYSBI or immediate-release cysteamine bitartrate at steady state

  Immediate-release cysteamine bitartrate PROCYSBI
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
t1/2 (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 PROCYSBI are consistent with a delayed-release formulation; the mean Tmax for PROCYSBI was 188 minutes compared with 73 minutes for immediate-release cysteamine bitartrate.

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 plasma clearance (Cl/F) was similar between PROCYSBI (1.2 L/min) and immediate-release cysteamine bitartrate (1.4 L/min).

The half-life was 253 minutes for PROCYSBI and 90 minutes for immediate-release cysteamine bitartrate.

Drug Interaction Studies

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.


A single PROCYSBI dose of 600 mg was administered with 240 mL of orange juice in healthy subjects after administration of 20 mg of omeprazole once daily for 5 days. The pharmacokinetic parameters of cysteamine were not significantly different when PROCYSBI was administered with omeprazole compared to when PROCYSBI was administered alone [see DRUG INTERACTIONS]. The effect of omeprazole on the pharmacokinetics of cysteamine was not studied after administration of PROCYSBI with water [see DOSAGE AND ADMINISTRATION].

Clinical Studies

Clinical Trials With Immediate-Release Cysteamine

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 ½ 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 na´ve 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 g/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.

Clinical Trials With PROCYSBI

Multi-Center, Open-Label, Randomized Clinical Trial

This clinical trial comparing immediate-release cysteamine bitartrate and PROCYSBI was conducted in 43 (40 pediatric and 3 adult) patients with nephropathic cystinosis. 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 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, crossover 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 V2 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]
1Per–Protocol (PP) Population (N=39)

Multi-Center, Single-Arm, Open-Label, Long-Term Extension Clinical Trial

Forty of the 41 patients completing the randomized trial continued treatment with PROCYSBI in an ongoing, open-label extension trial, for a total treatment duration ranging from 3 to 35 months. Thirty-four of the 36 patients continued treatment with PROCYSBI for at least 22 months in the extension trial and maintained their mean WBC cystine concentrations below 1 nmol ½ cystine/mg protein over this time period.

Thirteen pediatric patients, aged 2 to 6 years, were also enrolled in the extension trial. All of them were on treatment with immediate-release cysteamine bitartrate at the time of enrollment. Twelve of the 13 patients received at least 12 months of treatment with PROCYSBI, and their mean ± SD WBC cystine concentration decreased from 1.40 ± 1.08 nmol ½ cystine/mg protein at screening to 1.13 ± 0.56 nmol ½ cystine/mg protein after 12 months of treatment. Seven of these pediatric patients were able to achieve a WBC cystine concentration of less than 1.0 nmol ½ cystine/mg protein after 12 months of treatment; their mean ± SD dose of PROCYSBI increased from 0.84 ± 0.22 grams/m² per day at screening to 1.06 ± 0.33 grams/m² per day after 12 months of treatment.

During extended treatment with PROCYSBI, mean estimates of renal function, as measured by the estimated glomerular filtration rate (eGFR), were maintained.

Last reviewed on RxList: 8/28/2015
This monograph has been modified to include the generic and brand name in many instances.

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