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

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/m² 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/m² 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):

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/m² 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/m² 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 interchangeable. 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 (1∕2 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 capules 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 packets(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 (1/8 cup) 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.

One case of overdosing with PROCYSBI has been reported. A 16-year old male patient suffered nausea and vomiting after he mistakenly took a second dose of PROCYSBI 30 minutes after his usual dose.

Two cases of overdosing with immediate-release cysteamine bitartrate have been reported in two patients. In the first case, the patient immediately vomited after ingesting an unknown dose and did not develop any symptoms. The second case involved an accidental ingestion of a 200 to 250 mg/kg dose by a healthy 13-month-old child. Vomiting and dehydration were experienced. The child was hospitalized and fluids were administered. The patient fully recovered from the overdosing.

Should overdosing occur, the respiratory and cardiovascular systems should be supported appropriately. No specific antidote is known. Hemodialysis may be considered since cysteamine is poorly bound to plasma proteins.

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.

Instructions for the Patient:

• Store PROCYSBI delayed-release capsules and PROCYSBI delayed-relase oral granules at room temperature, 20°C to 25°C (68°F to 77°F) in the original packaging. Do not subdivide or repackage.
• Protect from light and moisture.
• Do not store PROCYSBI delayed-release oral granules in opened packets.