Cysteamine Bitartrate

PROCYSBI is indicated for the treatment of nephropathic cystinosis in adults and pediatric patients 1 year of age and older. PROCYSBI is a cystine-depleting agent indicated for the treatment of nephropathic cystinosis in adults and pediatric patients 1 year of age and older. ( 1 )

PROCYSBI delayed-release capsules: 25 mg cysteamine: the capsules have a light blue opaque cap imprinted with "PRO" in white ink and a light blue opaque body imprinted with "25 mg" in white ink. 75 mg cysteamine: the capsules have a dark blue opaque cap imprinted with "PRO" in white ink and a light blue opaque body imprinted with "75 mg" in white ink. PROCYSBI delayed-release oral granules: 75 mg cysteamine: white to off-white granules in single-use packets 300 mg cysteamine: white to off-white granules in single-use packets Delayed-release capsules: 25 mg and 75 mg cysteamine ( 3 ) Delayed-release oral granules: 75 mg and 300 mg cysteamine in single-use packets ( 3 )

The use of PROCYSBI is contraindicated in patients with a serious hypersensitivity reaction, including anaphylaxis, to penicillamine or cysteamine. Hypersensitivity to penicillamine or cysteamine ( 4 )

Ehlers-Danlos-like Syndrome: Reduce dosage if skin and bone lesions occur. ( 5.1 ) Skin Rash: Discontinue if severe skin rash such as erythema multiforme bullosa or toxic epidermal necrolysis occurs. ( 5.2 ) Gastrointestinal (GI) Ulcers and Bleeding: Monitor for GI symptoms and consider decreasing the dose if severe symptoms occur. ( 5.3 ) Fibrosing Colonopathy: Evaluate patients with severe, persistent, and/or worsening abdominal symptoms for fibrosing colonopathy. If the diagnosis is confirmed, permanently discontinue PROCYSBI and switch to immediate-release cysteamine bitartrate capsules ( 5.4 ) Central Nervous System (CNS) Symptoms: Monitor for CNS symptoms; interrupt or reduce the dose for severe symptoms or those that persist or progress ( 5.5 ). Leukopenia and/or Elevated Alkaline Phosphatase Levels: Monitor white blood cell count and alkaline phosphatase levels; decrease or discontinue the dose until values revert to normal. ( 5.6 ) Benign Intracranial Hypertension: Monitor for signs and symptoms; interrupt or reduce the dose for signs/symptoms that persist, or discontinue if diagnosis is confirmed. ( 5.7 )

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 Fibrosing Colonopathy Fibrosing colonopathy, including colonic stricture formation, has been reported with postmarketing use of PROCYSBI in pediatric and young adult patients with nephropathic cystinosis. Some of these patients had been treated with PROCYSBI for prolonged periods of time. Reported symptoms include: abdominal pain, vomiting, bloody or persistent diarrhea, and fecal incontinence. Evaluate patients with severe, persistent, and/or worsening abdominal symptoms for fibrosing colonopathy. If the diagnosis is confirmed, permanently discontinue PROCYSBI and switch to immediate-release cysteamine bitartrate capsules. An association between methacrylic acid-ethyl acrylate copolymer (an inactive ingredient in PROCYSBI) and fibrosing colonopathy cannot be ruled out.

5.5 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.

5.6 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.

5.7 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) ] Fibrosing Colonopathy [see Warnings and Precautions (5.4) ] Central Nervous System Symptoms [see Warnings and Precautions (5.5) ] Leukopenia and/or Elevated Phosphatase Levels [see Warnings and Precautions (5.6) ] Benign Intracranial Hypertension [see Warnings and Precautions (5.7) ] Most common adverse reactions in: Patients 6 years of age and older previously treated with cysteamine (≥5%) are: vomiting, nausea, abdominal pain, breath odor, diarrhea, skin odor, fatigue, rash, and headache. ( 6.1 ) Patients 1 year to less than 6 years naïve to cysteamine treatment (>10%) are: vomiting, gastroenteritis/viral gastroenteritis, diarrhea, breath odor, nausea, electrolyte imbalance and headache. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Amgen Inc. at 1 800 77 AMGEN (1 800 772 6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 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 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/m 2 per day to 2.19 grams/m 2 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 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 vomiting, 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 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) 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/m 2 per day as compared with 1.3 grams/m 2 per day of immediate-release cysteamine bitartrate.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of 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) ]. Gastrointestinal: Fibrosing colonopathy reported with PROCYSBI [see Warnings and Precautions (5.4) ]. Central Nervous System : seizures, lethargy, somnolence, depression and encephalopathy [see Warnings and Precautions (5.5) ] , benign intracranial hypertension (or PTC) and/or papilledema [see Warnings and Precautions (5.7) ].

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.

Lactation: Breastfeeding is not recommended. ( 8.2 )

8.1 Pregnancy 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.

8.2 Lactation 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) ] .

8.4 Pediatric Use 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.

8.5 Geriatric Use No studies with PROCYSBI have been conducted in geriatric patients.

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.