PROCYSBI Capsule / Granules Ref.[10908] Active ingredients: Mercaptamine

5.1 Ehlers-Danlos-like Syndrome

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 (2.1, 2.4)].

5.2 Skin Rash

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 (4)].

5.3 Gastrointestinal Ulcers and Bleeding

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 (2.1, 2.4)].

5.4 Central Nervous System Symptoms

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.

5.5 Leukopenia and/or Elevated Alkaline Phosphatase Levels

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.

5.6 Benign Intracranial Hypertension

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.

The following adverse reactions are also discussed in other sections of the labeling:

• Ehlers-Danlos-like Syndrome [see Warnings and Precautions (5.1)]
• Skin Rash [see Warnings and Precautions (5.2)]
• Gastrointestinal (GI) Ulcers and Bleeding [see Warnings and Precautions (5.3)]
• Central Nervous System Symptoms [see Warnings and Precautions (5.4)]
• Leukopenia and/or Elevated Phosphatase Levels [see Warnings and Precautions (5.5)]
• Benign Intracranial Hypertension [see Warnings and Precautions (5.6)]

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.

Clinical Trials Experience with PROCYSBI in Patients Switched from Immediate-Release Cysteamine Bitartrate

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 (14.2)]. 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:

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.

Clinical Trials Experience with PROCYSBI in Cysteamine-Naïve Patients

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 (14.2)]. 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:

Clinical Trials Experience with Immediate-Release Cysteamine

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.

Musculoskeletal: Joint hyperextension, leg pain, osteopenia, compression fracture, scoliosis, genu valgum [see Warnings and Precautions (5.1)].

Skin: Erythema multiforme bullosa, toxic epidermal necrolysis, Ehlers-Danlos-like syndrome, molluscoid pseudotumors, skin striae, skin fragility [see Warnings and Precautions (5.1, 5.2)].

Central Nervous System: seizures, lethargy, somnolence, depression and encephalopathy [see Warnings and Precautions (5.4)], benign intracranial hypertension (or PTC) and/or papilledema [see Warnings and Precautions (5.6)].

7.1 Drugs that Increase Gastric pH

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 (12.3)]. Monitor WBC cystine concentration when drugs that increase the gastric pH are concomitantly used [see Dosage and Administration (2.5)].

7.2 Use with Alcohol

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 (2.6)].

7.3 Other Medications Used for the Management of Fanconi Syndrome

PROCYSBI can be administered with other electrolyte and mineral replacements necessary for management of Fanconi syndrome, as well as vitamin D and thyroid hormone.

Risk Summary

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.

Data

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.

Risk Summary

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.

Data

A decrease in survival occurred in neonatal rats nursed by mothers receiving cysteamine [see Nonclinical Toxicology (13)].

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 (14.2)]. 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.