2.1 Starting Dose

        PROCYSBI therapy should be initiated promptly once the diagnosis is confirmed (i.e., increased white blood cell (WBC) cystine concentration). Cysteamine-naïve patients should be started on ⅙ to ¼ of the maintenance dose of PROCYSBI. The dose should be raised gradually over 4 to 6 weeks to help reduce the risk of side-effects. WBC cystine level and/or cysteamine concentration measurements, taken 30 minutes after dose administration, are recommended for new patients after the maintenance dose is achieved.

2.2 Maintenance Dose

        The recommended PROCYSBI maintenance dose is 1.3 gram/m2/day, in two divided doses given every 12 hours. [see Administration Options (2.3)] The dose can be increased up to 1.95 grams/m2/day if the white blood cell cystine level remains higher than the target WBC cystine level and/or the target cysteamine concentration has not been achieved. [see Dose Titration (2)]

2.3 Administration Options

PROCYSBI - Oral Administration

• PROCYSBI should be swallowed whole. Patients should not crush or chew capsules or capsule contents.
• Alternatively, for patients who have difficulty swallowing capsules, PROCYSBI can be opened and administered as follows:
  • Open capsule.
  • Sprinkle intact granules on approximately 4 ounces (½ cup) of applesauce or berry jelly.
  • Eat mixture within 30 minutes of preparation.
• PROCYSBI may also be emptied into a small volume of either orange juice or apple juice:
  • Mix or sprinkle intact granules into a small volume of either orange juice or apple juice (approximately 4 ounces (½cup)).
  • Shake gently for 5 minutes then administer by spoon or cup within 30 minutes.

PROCYSBI - Feeding Tube Administration

• For patients who have a 12 French or larger gastrostomy (G)-tube in place, PROCYSBI can be administered as follows:
  • Open capsule.
  • Mix intact granules into approximately 4 ounces (½ cup) of applesauce.
  • Administer mixture via feeding tube within 30 minutes.
  • Flush with approximately 8 ounces (1 cup) of orange juice or apple juice to clear the tube.

USE IN OTHER FOODS AND LIQUIDS HAS NOT BEEN STUDIED CLINICALLY AND IS THEREFORE NOT RECOMMENDED.

2.4 Administration with Food

        Patients should not eat for at least 2 hours before taking PROCYSBI and at least 30 minutes after taking PROCYSBI. Patients who are unable to take PROCYSBI without eating should eat only a small amount (approximately 4 ounces (½ cup)) of food between 1 hour before taking PROCYSBI and 1 hour after taking PROCYSBI. Patients should take PROCYSBI in a consistent manner in regard to food.

2.5 Missed Doses

        Patients should be instructed that if a dose is missed, it should be taken as soon as possible. However, if a patient has missed a dose and the next scheduled dose is due in less than 4 hours, the patient should be instructed to not take the missed dose, and to take the next dose on time. Patients should be instructed not to take 2 doses at one time to make up for a missed dose.

2.6 Dose Titration

        Titration Based on WBC Cystine: Adjust the PROCYSBI dosage to produce the target WBC cystine level. Measured concentrations of cystine in WBCs vary according to analytical techniques for WBC protein levels. Therefore, target concentrations of cystine in WBC should be determined by individual analytical laboratories using local methodology and calibration of protein assay.
        Titration Based on Plasma Cysteamine: If WBC cystine measurements are not available, plasma cysteamine measurement may be used to help guide PROCYSBI dose titration. Titrate the PROCYSBI dosage to maintain a cysteamine concentration >0.1 mg/L, 30 minutes after dosing. WBC cystine levels (or plasma cysteamine concentration if adequate WBC cystine testing is not available) should be measured as follows:

• Monthly for 3 months, then quarterly for 1 year, then twice yearly at a minimum for patients never treated with immediate-release cysteamine before.
• Two weeks, then quarterly for 6 months, then twice yearly at a minimum for patients switching from immediate-release cysteamine to PROCYSBI.
  Measurement Timing: WBC cystine and/or plasma cysteamine measurements must be obtained 12.5 hours after the evening dose the day before, and therefore 30 minutes after the following morning dose is given.
  Measurement Interpretation:
• In well-controlled and adherent patients with nephropathic cystinosis, the plasma cysteamine is >0.1 mg/L, and the WBC cystine is <1.0 nmol ½ cystine/mg protein.
• If the plasma cysteamine is >0.1 mg/L, but the WBC cystine is >1.0 nmol ½ cystine/mg protein, the physician is advised to investigate the following parameters: adherence to dosing interval, adherence to medication, or the relationship between administration of PROCYSBI and fasted/fed state.
  PROCYSBI dosing may need to be increased to achieve the target WBC cystine concentration (or plasma cysteamine concentration) or decreased if there is evidence of intolerance to PROCYSBI. [see Warnings and Precautions (5) and Adverse Reactions (6)]) If a dose adjustment is required, it is recommended to adjust the dose by 10%. The dose of PROCYSBI can be increased to a maximum of 1.95 grams/m2/day to achieve the target WBC cystine concentration (or plasma cysteamine concentration). The dose of 1.95 grams/m2/day of immediate-release cysteamine bitartrate has been associated with an increased rate of withdrawal from treatment due to intolerance and an increased incidence of adverse reactions.
  Patients who initially tolerate PROCYSBI poorly should temporarily stop taking PROCYSBI, then re-start PROCYSBI at a lower dose and gradually increase the dose to the proper dose. [see Warnings and Precautions (5)] Some patients may be unable to achieve their therapeutic target due to poorer tolerability of PROCYSBI.

2.7 Transferring Patients from Immediate-release Cysteamine Bitartrate Capsules

        Patients with cystinosis taking immediate-release cysteamine bitartrate may be transferred to a total daily dose of PROCYSBI equal to their previous total daily dose of immediate-release cysteamine bitartrate. Patients being transferred from immediate-release cysteamine bitartrate to PROCYSBI should have their WBC cystine levels and/or plasma cysteamine concentration measured in 2 weeks, and quarterly for 6 months, then twice yearly at a minimum.

5.1 Ehlers-Danlos like Syndrome

        Skin and bone lesions that resemble clinical findings for Ehlers-Danlos 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 increased to the appropriate therapeutic dose.

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, discontinue use of any cysteamine product permanently. [see Dosage and Administration (2)]

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.

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 eva luate and monitor patients who develop CNS symptoms. Interrupt or adjust the dose as necessary for patients with severe symptoms or with symptoms that persist or progress. Patients should exercise caution when driving or engaging in other hazardous activities when taking cysteamine.

5.5 Leukopenia and Elevated Alkaline Phosphatase Levels

        Cysteamine has been associated with reversible leukopenia and elevated alkaline phosphatase levels. Therefore, blood counts and alkaline phosphatase levels should be monitored.

5.6 Benign Intracranial Hypertension

        Benign intracranial hypertension (pseudotumor cerebri; PTC) and/or papilledema has been reported in patients receiving immediate-release cysteamine bitartrate treatment. A causal relationship between PTC and cysteamine has not been established. Physicians should 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.