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The following adverse reactions are also discussed in other sections of the labeling: gastrointestinal ulceration and bleeding, somnolence, encephalopathy, seizures, interstitial nephritis, elevated alkaline phosphatase, and leukopenia [see WARNINGS AND PRECAUTIONS].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Causality of side effects is sometimes difficult to determine because adverse effects may result from the underlying disease.

Clinical Trials Experience with Immediate-release Cysteamine

Cysteamine or phosphocysteamine have been administered to 246 children with cystinosis in three clinical trials (the National Collaborative Cysteamine Trial [NCCS], the Long Term Trial, and a trial in the United Kingdom).

The most frequent adverse reactions involved the gastrointestinal and central nervous systems. These were especially prominent at the initiation of cysteamine therapy. Most patients were able to resume therapy at lower doses without incident of adverse reactions.

Adverse reactions were not collected systematically in the NCCS trial that treated 93 children but were often listed by investigators. The following rates may therefore be underestimated. The most common reactions ( > 5%) were vomiting 35%, anorexia 31%, fever 22%, diarrhea 16%, lethargy 11%, and rash 7%. Other adverse reactions included nausea, bad breath, abdominal pain, headache, dizziness, and urticaria.

Withdrawals due to intolerance, vomiting associated with medication, anorexia, lethargy, and fever occurred more frequently in those patients receiving 1.95 grams/m²/day as compared to 1.30 grams/m²/day of immediate-release cysteamine bitartrate.

Clinical Trials Experience with PROCYSBI

The data described below reflect exposure to PROCYSBI in 40 healthy volunteers in 3 clinical trials (Trials 2, 5, and 6) and 72 patients with nephropathic cystinosis in 3 clinical trials (Trials 1, 3 and 4). Healthy volunteers ranged in age from 19 to 64 years old and patients with nephropathic cystinosis ranged in age from 2 to 32 years old. Patients received PROCYSBI at doses ranging 0.5 grams/m²/day to 2.23 grams/m²/day and included 45 males and 27 females. [see Clinical Studies]. The frequency of adverse reactions was similar across trials noting abdominal pain, nausea, and headache as the most commonly reported events in ≥ 5% of individuals in all trials.

The most commonly reported adverse reactions ( ≥ 5%) in healthy volunteers were diarrhea and nausea, abdominal pain /discomfort, headache, vomiting and abnormal urine odor. The most commonly reported adverse reactions ( ≥ 5%) in patients with nephropathic cystinosis, were vomiting, abdominal pain/discomfort, headaches, nausea, diarrhea, anorexia/decreased appetite, breath odor, fatigue, dizziness, skin odor and rash.

There have not been any unexpected serious adverse events (SAEs) reported by patients in clinical trials attributable to PROCYSBI (cysteamine bitartrate) delayed-release capsules. In Trial 3, the pivotal clinical trial comparing PROCYSBI to the immediate-release cysteamine bitartrate, a higher incidence of adverse reactions were reported in patients during the PROCYSBI treatment period compared to the immediate-release cysteamine treatment period (see Table 2). Other significant adverse reactions reported during clinical trials included anaphylaxis and allergic reaction.

TABLE 2: Comparison of adverse reactions that occurred in 5% or more patients while receiving immediate release cysteamine or PROCYSBI during Trial 3

Adverse Reaction Immediate-release cysteamine
(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

Trial 4 includes patients continuing treatment from Trial 3. In Trial 4, 40 patients have been treated for longer than one year and 3 patients have been treated for at least 19 months. The most commonly reported adverse reactions ( ≥ 5%) were vomiting, abdominal pain, nausea, breath odor, diarrhea, skin odor, and decreased appetite.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of immediate-release cysteamine bitartrate: benign intracranial hypertension (or PTC) with papilledema; skin lesions, molluscoid pseudotumors, skin striae, skin fragility; joint hyperextension, leg pain, genu valgum, osteopenia, compression fracture and scoliosis [see WARNINGS AND PRECAUTIONS].

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.

Following the pivotal Phase 3 trial, 40 subjects have been treated for at least one year with PROCYSBI in an Extension Trial. There were no unexpected or serious safety concerns experienced by subjects attributable to PROCYSBI. Based on the average number of gastro-intestinal AEs per subject per month that went slightly downward from 0.11 gastrointestinal disorder AEs/subject/month to ~ 0.09 gastrointestinal disorder AEs/subject/month, there was a gradual decrease in gastrointestinal disorder AEs with long term PROCYSBI therapy (p < 0.05). This decrease was also seen in the average number of total AEs/subject/month; from ~ 0.15 total AEs/subject/month at the beginning of the trial to ~ 0.08 total AEs/subject/month (p < 0.05, post-hoc analysis).

In two randomized clinical trials with healthy volunteers, there were no unexpected serious adverse events reported that were attributable to PROCYSBI. The most frequent adverse events (AEs) reported by the subjects related to PROCYSBI were GI symptoms (16%).. The AE profile for healthy subjects was similar to the AE profile in patients relative to gastro-intestinal disorders (diarrhea and abdominal pain).