PROCYSBI

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

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 )

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 [see Dosage and Administration (2.5) ] . Adjust the PROCYSBI dosage as needed to achieve the therapeutic target WBC cystine concentration [see Dosage and Administration (2.4) ] . 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 [see Dosage and Administration (2.5) ] . 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 [see Warnings and Precautions (5) , Adverse Reactions (6.1) ]. 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 [see Clinical Pharmacology (12.2) ] . 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'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 [see Drug Interactions (7.1) ]. 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 [see Drug Interactions (7.2) ]. 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 )

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.

Storage and Handling Prior to dispensing, store PROCYSBI delayed-release capsules and PROCYSBI delayed-release oral granules in a refrigerator, 2°C to 8°C (36°F to 46°F). Dispense PROCYSBI delayed-release capules and PROCYSBI delayed-release oral granules with a 4 month discard date. Dispense in original packaging. Do not subdivide or repackage. Do not remove desiccant or oxygen absorber(s) from the bottle of PROCYSBI delayed-release capsules. Keep bottles tightly closed in a dry place. Protect from light and moisture.