CYSTEAMINE: 1,663 Adverse Event Reports & Safety Profile

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, (2 R ,3 R )-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 C 2 H 7 NS ∙ C 4 H 6 O 6 . It has the following chemical structure: Each PROCYSBI delayed-release capsule contains either 25 mg cysteamine (equivalent to 74 mg cysteamine bitartrate) or 75 mg cysteamine (equivalent to 221 mg cysteamine bitartrate). Each packet of PROCYSBI delayed-release oral granules contains either 75 mg cysteamine (equivalent to 221 mg cysteamine bitartrate) or 300 mg cysteamine (equivalent to 884 mg cysteamine bitartrate). PROCYSBI delayed release granules contain the following inactive ingredients: Eudragit ® L 30 D-55 (methacrylic acid-ethyl acrylate copolymer), hypromellose, microcrystalline cellulose, purified water, sodium lauryl sulfate, talc, and triethyl citrate. Additionally the capsule shell contains the following inactive ingredients: gelatin, ink (blue and white), and titanium dioxide.

Chemical

Structure

AND USAGE CYSTADROPS is a cystine-depleting agent indicated for the treatment of corneal cystine crystal deposits in adults and children with cystinosis. CYSTADROPS is a cystine-depleting agent indicated for the treatment of corneal cystine crystal deposits in adults and children with cystinosis. ( 1 )

AND ADMINISTRATION Recommended Dosage in Cysteamine-Naïve Patients See full prescribing information for weight-based dosing tables for the starting and maintenance dosage. ( 2.2 ) For initial intolerance, temporarily discontinue and then re-start PROCYSBI at a lower dosage and gradually increase to the maintenance dosage. ( 2.2 ) Switching from Immediate-release Cysteamine to PROCYSBI Start with a total daily dose of PROCYSBI equal to the previous total daily dose of immediate-release cysteamine bitartrate. ( 2.3 )

Dose Titration

Adjust dose to achieve a therapeutic target white blood cell (WBC) cystine concentration. ( 2.4 , 2.5 ) If a dose adjustment is required, increase the dosage by 10%. The maximum dosage is 1.95 grams/m 2 per day. ( 2.4 ) If adverse reactions occur, decrease the dosage. Some patients may be unable to achieve their therapeutic target. ( 2.4 ) Preparation and Administration ( 2.6 ) Capsules : Swallow whole; do not crush or chew capsules or capsule contents. Take the capsules with fruit juice (except grapefruit juice) or water.

Oral

Granules: Do not crush or chew the granules. Sprinkle and mix the granules in applesauce, berry jelly or fruit juice (except grapefruit juice). For patients who cannot swallow the capsules or with gastrostomy tubes, see the full prescribing information on how to prepare and administer the capsules and oral granules. Administer PROCYSBI at least 1 hour before or 1 hour after medications containing bicarbonate or carbonate. Do not eat for at least 2 hours before and for at least 30 minutes after taking PROCYSBI. If unable to take PROCYSBI without eating, take with food but limit the amount of food to approximately 4 ounces (½ cup) 1 hour before through 1 hour after administration. Avoid high fat food close to dosing. Avoid drinking alcohol while taking PROCYSBI.

2.1 Important Dosing Instructions Initiate cysteamine treatment immediately after diagnosis of nephropathic cystinosis. Cysteamine-naïve Patients: Start PROCYSBI at a fraction of the maintenance dosage.

Patients

1 year to less than 6 years : Gradually increase the dosage, allowing a minimum of 2 weeks between adjustments [see Dosage and Administration (2.2) ] .

Patients

6 years of age and older : Gradually increase the dosage over 4 to 6 weeks until the maintenance dosage is achieved. Patients switching from immediate-release cysteamine: Start the total daily dosage of PROCYSBI at a dosage equal to the previous total daily dosage of immediate-release cysteamine [see Dosage and Administration (2.3) ] . If adverse reactions occur, decrease the PROCYSBI dosage. After the maintenance dosage of PROCYSBI is achieved: The dosage may need to be further increased to achieve a therapeutic target WBC cystine concentration. The maximum dosage of PROCYSBI is 1.95 grams/m 2 of body surface area per day [see Dosage and Administration (2.4 , 2.5) ] . Round dose calculations to the nearest incremental dosage that can be administered using the available strengths of PROCYSBI delayed-release capsules or packets of oral granules. Only use whole capsules or entire contents of the packets.

2.2 Starting and Maintenance Dosing in Cysteamine-Naïve Patients Start treatment with a dosage equal to ⅙ to ¼ of the maintenance dosage. The maintenance dosage after initial dose escalation is 1.3 g/m 2 of body surface area per day divided into two doses given every 12 hours.

Table

1 shows the recommended starting and maintenance dosages of PROCYSBI, converted from body-surface area to body weight.

Patients

1 year to less than 6 years : Increase the dosage in 10% increments to the maintenance dosage, while monitoring WBC cystine concentrations. Allow a minimum of 2 weeks between dosage adjustments [see Dosage and Administration (2.4 , 2.5) ] . If a patient achieves the therapeutic target WBC cystine concentration at a dosage below the recommended weight-based maintenance dosage, then stop dosage escalation and use the dosage as the patient's maintenance dosage.

Patients

6 years of age and older : Gradually increase the dosage over 4 to 6 weeks until the maintenance dosage is achieved. If a patient experiences initial intolerance, temporarily discontinue PROCYSBI and then re-start at a lower dosage and gradually increase dosage.

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 Higher dosages may be required to achieve target therapeutic WBC cystine concentration [see Dosage and Administration (2.4) ] . ⅙ of dosage ¼ 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

2.3 Switching Patients from Immediate-Release Cysteamine Bitartrate When switching patients from immediate-release cysteamine bitartrate to PROCYSBI, the starting total daily dose of PROCYSBI is equal to the previous total daily dose of immediate-release cysteamine bitartrate. Divide the total daily dose by two and administer every 12 hours. For patients who may experience temporary intolerance upon starting PROCYSBI, decrease the dosage and then gradually increase to the maintenance dosage. Measure the WBC cystine concentration two weeks after initiation of PROCYSBI <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span> . Adjust the PROCYSBI dosage as needed to achieve the therapeutic target WBC cystine concentration <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) ]</span> . The maximum dosage of PROCYSBI is 1.95 grams/m 2 per day.

2.4 Dosage Titration to Therapeutic Target WBC Cystine Concentration Measure WBC cystine concentration and titrate the PROCYSBI dosage as needed to achieve the therapeutic target WBC cysteine concentration <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span> . If the measured WBC cystine concentration is above the target level for cystine depletion, consider the following before dose adjustment: adherence to medication and dosing interval, the timing between the last dose and the blood draw for the laboratory measurement, and the timing of PROCYSBI administration in relation to food or other administration instructions. If a dose adjustment is required, increase the dosage by 10%, rounded to nearest dosage that can be administered using the available strengths of capsules or packets of oral granules. For patients 1 year to less than 6 years of age, allow a minimum of two weeks between dose increments. The maximum dosage of PROCYSBI is 1.95 grams/m 2 per day. If adverse reactions occur, decrease the PROCYSBI dosage. Some patients may be unable to achieve their therapeutic target due to poor tolerability of PROCYSBI <span class="opacity-50 text-xs">[see Warnings and Precautions (5) , Adverse Reactions (6.1) ]</span>.

2.5 Laboratory Monitoring WBC cystine concentration may be measured using the mixed leukocyte assay or by using assays for specific WBC subsets (e.g., granulocyte method). The methods used for measuring cystine and total protein content may also vary among individual laboratories <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> . Normal WBC cystine ranges and therapeutic target levels for cystine depletion depend upon the assay method used by the individual laboratory. WBC cystine values obtained from using different assay methods may not be comparable. Refer to the assay-specific therapeutic target for cystine depletion. When using the mixed leukocyte assay, the recommended target WBC cystine concentration is less than 1 nmol ½ cystine/mg protein . The recommended frequency of monitoring WBC cystine concentration is as follows: Cysteamine-naïve patients 1 year to less than 6 years : Obtain measurement two weeks after initiation of PROCYSBI treatment and continue monitoring during dosage titration period until the therapeutic target WBC cystine concentration is achieved. Once the therapeutic target is achieved, continue monitoring monthly for 3 months, then quarterly for 1 year, and then twice-yearly, at a minimum. Cysteamine-naïve patients greater than 6 years : Obtain measurement after reaching the maintenance PROCYSBI dosage, then monthly for 3 months, quarterly for 1 year, and then twice-yearly, at a minimum. Patients switching from immediate-release cysteamine to PROCYSBI : Obtain measurement two weeks after initiation of PROCYSBI treatment and continue monitoring if further dosage titration is required to achieve therapeutic target WBC cystine concentration. Once the therapeutic target is achieved, continue monitoring quarterly for 6 months, then twice yearly, at a minimum. Obtain blood samples for WBC cystine concentration measurement 12 hours after the patient&apos;s last PROCYSBI dose, prior to administration of the next dose (i.e., trough concentration). In addition, it is important to accurately record the time of the last dose, the actual dose, and the time the blood sample was taken.

2.6 Preparation and Administration PROCYSBI delayed-release capsules: Swallow capsules whole. Do not crush or chew capsules or capsule contents. Take capsules with fruit juice (except grapefruit juice) or water. For patients who cannot swallow the capsules, the capsules can be opened and the capsule contents sprinkled on and mixed in applesauce, berry jelly or fruit juice (except grapefruit juice) and administered orally, as described below. For patients with a gastrostomy tube, the capsules can be opened and the capsule contents mixed in applesauce and administered via the gastrostomy tube, as described below. PROCYSBI delayed-release oral granules: Do not crush or chew oral granules. Sprinkle and mix the intact granules in applesauce, berry jelly or fruit juice (except grapefruit juice) and administered orally, as described below. For patients with a gastrostomy tube, the oral granules can be mixed in applesauce and administered via a gastrostomy tube, as described below. Administer PROCYSBI at least 1 hour before or 1 hour after medications containing bicarbonate or carbonate <span class="opacity-50 text-xs">[see Drug Interactions (7.1) ]</span>. Do not eat for at least 2 hours before taking PROCYSBI and for at least 30 minutes after to maximize absorption. If patients are unable to take PROCYSBI without eating, take with food and limit the amount of food to approximately 4 ounces (½ cup) within 1 hour before taking PROCYSBI through 1 hour after taking PROCYSBI. Take PROCYSBI in a consistent manner in regard to food. Avoid high fat food close to dosing of PROCYSBI. Avoid drinking alcohol while taking PROCYSBI <span class="opacity-50 text-xs">[see Drug Interactions (7.2) ]</span>.

Oral

Administration in Food or Liquid Administration of PROCYSBI capsules 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: Place approximately 4 ounces (½ cup) or a smaller amount that can be consumed in one feeding of either applesauce or berry jelly into a clean container. Open the capsule(s) or packet(s). Sprinkle all the intact granules that are inside the capsule(s) or packet(s) on applesauce or berry jelly. Mix the granules with the applesauce or berry jelly. Do not crush the granules. Consume the entire contents within 30 minutes of mixing. Do not chew the granules. Do not save the applesauce or berry jelly and granules for later use. Administration in Fruit Juice (except grapefruit juice): Pour approximately 4 ounces (½ cup) of fruit juice into a clean cup. Open the capsule(s) or packet(s). Sprinkle all the intact granules into the juice. Gently stir until mixed. Do not crush the granules. Drink the entire contents within 30 minutes of mixing. Do not chew the granules. Do not save the fruit juice and granules mixture for later use. Administration in Applesauce via a Gastrostomy (G) Tube (14 French or larger) A bolus (straight) feeding tube is recommended. Flush the gastrostomy tube button first with 5 mL of water to clear the button. Open the capsule(s) or packet(s) and empty the granules into a clean container with approximately 4 ounces (½ cup) of applesauce. Use only strained applesauce with no chunks. A minimum of 1 ounce (⅛cup) of applesauce may be used for children 25 kg or less starting PROCYSBI at a dose of 1 or 2 capsules or packets. Mix the intact granules into the applesauce. Do not crush the granules. Draw up the mixture into a syringe. Keep the feeding tube horizontal during administration and apply rapid and steady pressure (10 mL/10 seconds) to dispense the syringe contents into the tube within 30 minutes of preparation. Repeat step 3 until all of the mixture is administered. Do not save the applesauce and granule mixture for later use. Draw up a minimum of 10 mL of fruit juice or water into another syringe, swirl gently, and flush the tube.

Missed

Doses If a dose is missed, take the dose as soon as possible up to 8 hours after the scheduled time. However, if a dose is missed and the next scheduled dose is due in less than 4 hours, do not take the missed dose and take the next dose at the usual scheduled time. Do not take 2 doses at one time to make up for a missed dose.

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 )

REACTIONS 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 <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1) ]</span> . Skin : Erythema multiforme bullosa, toxic epidermal necrolysis, Ehlers-Danlos-like syndrome, molluscoid pseudotumors, skin striae, skin fragility <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1 , 5.2) ]</span>. Gastrointestinal: Fibrosing colonopathy reported with PROCYSBI <span class="opacity-50 text-xs">[see Warnings and Precautions (5.4) ]</span>.

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) ].

AND PRECAUTIONS 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.1 , 2.4) ]</span> .

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 <span class="opacity-50 text-xs">[see Contraindications (4) ]</span> .

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.1 , 2.4) ]</span> .

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.

PRECAUTIONS General Gastrointestinal tract symptoms including nausea, vomiting, anorexia and abdominal pain have been associated with cysteamine, sometimes severe. In addition, gastrointestinal ulceration and bleeding have been reported in patients on cysteamine therapy. If these develop, therapy may have to be interrupted and the dose adjusted. A cysteamine dose of 1.95 grams/m 2 /day (approximately 80 to 90 mg/kg/day) was associated with an increased number of withdrawals from treatment due to intolerance and an increased incidence of adverse events. Cysteamine has occasionally been associated with reversible leukopenia and abnormal liver function studies. Therefore, blood counts and liver function studies should be monitored. There have been reports of benign intracranial hypertension (or pseudotumor cerebri; PTC) and/or papilledema associated with CYSTAGON ® treatment that has resolved with the addition of diuretic therapy. PTC may be more common in cystinotic patients because of concurrent medication and renal transplantation. Although a causal relationship of PTC to CYSTAGON ® has not been established, physicians should monitor patients receiving CYSTAGON ® for this condition. Physicians should instruct patients to report any of the following symptoms: headache, tinnitus, dizziness, nausea, diplopia, blurry vision, loss of vision, pain behind the eye or pain with eye movement. A periodic eye examination is needed to identify this condition early and timely treatment should be provided when it occurs to prevent vision loss. There have been reports of serious skin lesions in patients treated with high doses of CYSTAGON ® or other cysteamine salts that have responded to cysteamine dose reduction. These skin lesions are purplish hemorrhagic lesions over the elbow area on both arms and have been described as molluscoid pseudotumors. Skin striae, bone lesions (that have been described as osteopenia, compression fractures, scoliosis and genu valgum) along with leg pain and joint hyperextension may also be present. One patient with serious skin lesions subsequently died of acute cerebral ischemia with marked vasculopathy. Physicians should routinely monitor the skin and bones of patients receiving CYSTAGON ® . If similar skin or bone abnormalities appear, the dose of CYSTAGON ® should be reduced. Information for Patients and Parents and/or Guardians See attached information for patients and parents and/or guardians.

Laboratory Tests

Leukocyte cystine measurements are useful to determine adequate dosage and compliance. When measured 5 to 6 hours after CYSTAGON ® administration, the goal should be a level < 1 nmol/½ cystine/mg protein. In some patients with poorer tolerability for CYSTAGON ® , patients may still receive benefit with a white cell cystine level of less than 2 nmol/½ cystine/mg protein. Measurements should be done every three months, more frequently when patients are transferred from cysteamine hydrochloride or phosphocysteamine solutions to CYSTAGON ® . Physicians should follow patients for signs and symptoms of gastrointestinal ulceration and bleeding, and should inform patients and/or guardians of the importance of this follow-up.

Drug Interactions

None have been described. CYSTAGON ® can be administered with electrolyte and mineral replacements necessary for management of the Fanconi Syndrome as well as vitamin D and thyroid hormone. Carcinogenesis, Mutagenesis, Impairment of Fertility Cysteamine has not been tested for its carcinogenic potential in long-term animal studies. Cysteamine 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/day (450 mg/m 2 /day, 0.4 times the recommended human dose based on body surface area). At an oral dose of 375 mg/kg/day (2,250 mg/m 2 /day, 1.7 times the recommended human dose based on body surface area), it reduced the fertility of the adult rats and the survival of their offspring.

Pregnancy

Teratology studies have been performed in rats at oral doses in a range of 37.5 to 150 mg/kg/day (about 0.2 to 0.7 times the recommended human maintenance dose on a body surface basis) and have revealed cysteamine bitartrate to be teratogenic and fetotoxic. Observed teratogenic findings were cleft palate, Kyphosis, heart ventricular septal defects, microcephaly and exencephaly. There are no adequate and well-controlled studies in pregnant women. CYSTAGON ® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing

Mothers It is not known whether cysteamine is excreted in human milk. Because many drugs are excreted in human milk and because of the manifested potential of cysteamine for developmental toxicity in suckling rat pups when it was administered to their lactating mothers at an oral dose of 375 mg/kg/day (2,250 mg/m 2 /day, 1.7 times the recommended human dose based on body surface area), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of CYSTAGON ® for cystinotic children have been established. Cysteamine therapy should be initiated as soon as the diagnosis of nephropathic cystinosis has been confirmed.

INTERACTIONS

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>. Monitor WBC cystine concentration when drugs that increase the gastric pH are concomitantly used <span class="opacity-50 text-xs">[see Dosage and Administration (2.5) ]</span>.

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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.6) ]</span>.

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.