英文药名：Procysbi（Cysteamine bitartrate delayed-release capsules）

中文药名：半胱胺重酒石酸氢盐缓释胶囊

生产厂家：Raptor Pharmaceuticals
药品介绍
2013年4月30日，美国FDA批准Procysbi（cysteamine bitartrate，酒石酸半胱胺）用于治疗儿童和成人胱氨酸肾病。Procysbi被给予罕用药待遇。
胱氨酸病是一种罕见的遗传性疾病，据估计在美国有500名此症患者和世界各地患者人数也仅约3000名。如果在儿时不及时治疗，它可能致命。胱氨酸病导致胱氨酸在身体的每一个细胞蓄积。胱氨酸的积累会引起肾脏问题，从而可能通过排尿使身体失去过多的糖、蛋白质和盐。胱氨酸病可能导致机体生长发育缓慢和身材纤细、骨骼脆弱，引发肾功能衰竭并使恶化。有三种类型胱氨酸病，其中胱氨酸肾​​病最严重，会严重损害肾脏。
迄今FDA批准用于治疗胱氨酸病的药物有Cystagon（cysteamine bitartrate，酒石酸半胱胺），1994年获准的速释片剂，Cystaran（cysteamine ophthalmic solution，半胱胺滴眼液），去年获准用于治疗角膜胱氨酸结晶体积聚。
Procysbi是一种缓释胶囊，用于年龄在6岁及以上患者。Cystagon需每6个小时左右服用一次，控制胱氨酸的水平，而Procysbi为长效的配方，可每12小时服用一次。
FDA药品评价和研究中心胃肠道和先天性疾病药品部门副主任Andrew E. Mulberg 博士指出：“Procysbi是FDA批准的治疗胱氨酸肾病的唯一缓释制剂，为这种罕见病患者提供一种重要的治疗选择。”
一项涉及43名胱氨酸肾病的成人和儿童患者的重要研究结果支持Procysbi的安全性和有效性。患者被随机分配接受Cystagon或Procysbi为时3周，切换另一药品持续另外3周。血液测试显示Procysbi与Cystagon对控制胱氨酸水平同样有效。
以半胱胺治疗的患者最常见的副作用包括恶心、口臭、腹痛、便秘、消化不良或肠胃不适、头痛、嗜睡和头晕。其它少见但严重的副作用包括胃或小肠溃疡或出血、精神状态改变、癫痫发作、严重皮疹和过敏性反应。
Procysbi由加州Raptor医药公司销售。Cystagon则由宾夕法尼亚州的Mylan公司销售，Cystaran的销售总部Sigma-Tau制药公司位于美国马里兰州.
PROCYSBI(CYSTEAMINE BITARTRATE)

PROCYSBI DELAYED-RELEASE- cysteamine bitartrate capsule, delayed release pellets
RAPTOR THERAPEUTICS INC.
1. DESCRIPTION 
Cysteamine bitartrate delayed-release capsules for oral administration, is a cystine depleting agent which lowers the cystine content of cells in patients with nephropathic cystinosis, an inherited defect of lysosomal transport.
Cysteamine bitartrate contains the bitartrate salt of cysteamine. The chemical name for cysteamine bitartrate is ethanethiol, 2-amino, (2R,3R)-2,3-dihydroxybutanedioate (1:1) (salt). Cysteamine bitartrate is a highly water soluble white powder. It has the following chemical structure:

Empirical formula: C2H7NS • C4H6O6 - Molecular weight: 227.24
Each 25 mg delayed-release capsule contains 74 mg cysteamine bitartrate, equivalent to 25 mg cysteamine. Each 75 mg delayed-release capsule contains 221 mg cysteamine bitartrate, equivalent to 75 mg cysteamine. Cysteamine bitartrate delayed-release capsules contain the following inactive ingredients: microcrystalline cellulose, Eudragit® L 30 D-55, hypromellose, talc, triethyl citrate, sodium lauryl sulfate, and purified water. Capsule shell ingredients are gelatin, titanium dioxide, blue ink and white ink.
2. INDICATIONS AND USAGE 
Cysteamine bitartrate is indicated for the management of nephropathic cystinosis in adults and children ages 6 years and older.
3. DOSAGE AND ADMINISTRATION 
Cysteamine bitartrate is available as a capsule in 25 mg and 75 mg strengths. Directions for use specific to the route and available methods of administration are presented below. Cysteamine bitartrate should be taken at least 2 hours after and at least 30 min before eating.
3.1 Starting Dose
Cysteamine bitartrate 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 1/6 to 1/4 of the maintenance dose of cysteamine bitartrate. 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 ½ hour after dose administration, are recommended for new patients after the maintenance dose is achieved.
3.2 Maintenance Dose
The recommended cysteamine bitartrate maintenance dose is 1.3 gram/m2/day, in two divided doses given every 12 hours. (3.3) The dose can be increased up to1.95 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 Dosage and Administration (3.6)]
TABLE 1: Approximation of 1.3 gram/m2/day dose of cysteamine bitartrate

TABLE 1: Approximation of 1.3 gram/m² /day dose of PROCYSBI

Weight in Pounds	mg of PROCYSBI Every 12 hours
0-10	200
11-20	300
21-30	400
31-40	500
41-50	600
51-70	700
71-90	800
91-110	900
>110	1000

3.3 Administration Options
Oral Administration
• Cysteamine bitartrate should be swallowed whole. Patients should not crush or chew capsules or capsule contents.
• Alternatively, for patients who have difficulty swallowing capsules, cysteamine bitartrate delayed-release capsules can be opened and administered as follows:
• Open capsule.
• Sprinkle intact granules on approximately 4 ounces (1/2 cup) of applesauce or berry jelly.
• Eat mixture within 30 minutes of preparation.
• Cysteamine bitartrate 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 (½ cup)).
• Shake gently for 5 minutes then administer by spoon or cup within 30 minutes.
Feeding Tube Administration
• For patients who have a 12 French or larger gastrostomy (G)-tube in place, cysteamine bitartrate delayed-release capsules can be administered as follows:
• Open capsule.
• Mix intact granules into approximately 4 ounces (1/2 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.
3.4 Administration with Food
Patients should not eat for at least 2 hours before taking cysteamine bitartrate and at least 30 minutes after taking cysteamine bitartrate. Patients who are unable to take cysteamine bitartrate without eating should eat only a small amount (approximately 4 ounces (½ cup)) of food between 1 hour before taking cysteamine bitartrate and 1 hour after taking cysteamine bitartrate. Patients should take cysteamine bitartrate in a consistent manner in regard to food.
3.5 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.
3.6 Dose Titration
Titration Based on WBC Cystine: Adjust the cysteamine bitartrate 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 cysteamine bitartrate dose titration. Titrate the cysteamine bitartrate dosage to maintain a cysteamine concentration > 0.1 mg/L, 30 min 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 one 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 to cysteamine bitartrate.
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 cysteamine bitartrate and fasted/fed state.
Cysteamine bitartrate 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 cysteamine bitartrate [see Warnings and Precautions (5) and Adverse Reactions (6.2)]). If a dose adjustment is required, it is recommended to adjust the dose by 10%. The dose of cysteamine bitartrate 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 cysteamine bitartrate poorly should temporarily stop taking cysteamine bitartrate, then re-start cysteamine bitartrate 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 cysteamine bitartrate.
3.7 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 cysteamine bitartrate equal to their previous total daily dose of immediate-release cysteamine bitartrate. Patients being transferred from immediate-release cysteamine bitartrate to cysteamine bitartrate 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 .
4. CONTRAINDICATIONS 
The use of cysteamine bitartrate delayed-release capsules is contraindicated in patients who are hypersensitive to penicillamine.
5. WARNINGS AND PRECAUTIONS 
5.1 Ehler-Danlos like Syndrome
Skin and bone lesions that resemble clinical findings for Ehler-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 cysteamine bitartrate dosing if patients develop these lesions. Cysteamine bitartrate 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 (3.6)]
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 cysteamine bitartrate.
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 evaluate 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.
6. ADVERSE REACTIONS 
The following adverse reactions are also discussed in other sections of the labeling: gastrointestinal ulceration and bleeding, somnolence, encephalopathy, seizures, interstitial nephritis, elevated alkaline phosphatase, and leukopenia [see Warnings and Precautions (5)].
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 to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Causality of side effects is sometimes difficult to determine because adverse effects may result from the underlying disease.
Clinical Trials Experience with Immediate-release Cysteamine
Cysteamine or phosphocysteamine have been administered to 246 children with cystinosis in three clinical trials (the National Collaborative Cysteamine Trial [NCCS], the Long Term Trial, and a trial in the United Kingdom).
The most frequent adverse reactions involved the gastrointestinal and central nervous systems. These were especially prominent at the initiation of cysteamine therapy. Most patients were able to resume therapy at lower doses without incident of adverse reactions.
Adverse reactions were not collected systematically in the NCCS trial that treated 93 children but were often listed by investigators. The following rates may therefore be underestimated. The most common reactions (>5%) were vomiting 35%, anorexia 31%, fever 22%, diarrhea 16%, lethargy 11%, and rash 7%. Other adverse reactions included nausea, bad breath, abdominal pain, headache, dizziness, and urticaria.
Withdrawals due to intolerance, vomiting associated with medication, anorexia, lethargy, and fever occurred more frequently in those patients receiving 1.95 grams/m2/day as compared to 1.30 grams/m2/day of immediate-release cysteamine bitartrate.
Clinical Trials Experience with Delayed-release Cysteamine
The data described below reflect exposure to DR cysteamine in 40 healthy volunteers in 3 clinical trials (Trials 2, 5, and 6) and 72 patients with nephropathic cystinosis in 3 clinical trials (Trials 1, 3 and 4). Healthy volunteers ranged in age from 19 to 64 years old and patients with nephropathic cystinosis ranged in age from 2 to 32 years old. Patients received DR cysteamine at doses ranging 0.5 grams/m2/day to 2.23 grams/m2/day and included 45 males and 27 females. The frequency of adverse reactions was similar across trials noting abdominal pain, nausea, and headache as the most commonly reported events in ≥ 5% of individuals in all trials.
The most commonly reported adverse reactions (≥5%) in healthy volunteers were diarrhea and nausea, abdominal pain /discomfort, headache, vomiting and abnormal urine odor. The most commonly reported adverse reactions (≥5%) in patients with nephropathic cystinosis, were vomiting, abdominal pain/discomfort, headaches, nausea, diarrhea, anorexia/decreased appetite, breath odor, fatigue, dizziness, skin odor and rash.
There have not been any unexpected serious adverse events (SAEs) reported by patients in clinical trials attributable to cysteamine bitartrate delayed-release capsules. In Trial 3, the pivotal clinical trial comparing DR cysteamine to the immediate-release cysteamine bitartrate, a higher incidence of adverse reactions were reported in patients during the DR cysteamine treatment period compared to the immediate-release cysteamine treatment period (see Table 2). Other significant adverse reactions reported during clinical trials included anaphylaxis and allergic reaction.
TABLE 2: Comparison of adverse reactions that occurred in 5% or more patients while receiving IR cysteamine or DR cysteamine during Trial 3

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

IR = Immediate-release
DR = Delayed-release
_______________________________________________________
Trial 4 includes patients continuing treatment from Trial 3. In Trial 4, 40 patients have been treated for longer than one year and 3 patients have been treated for at least 19 months. The most commonly reported adverse reactions (≥5%) were vomiting, abdominal pain, nausea, breath odor, diarrhea, skin odor, and decreased appetite.

6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of immediate-release cysteamine bitartrate: benign intracranial hypertension (or PTC) with papilledema; skin lesions, molluscoid pseudotumors, skin striae, skin fragility; joint hyperextension, leg pain, genu valgum, osteopenia, compression fracture and scoliosis [see Warnings and Precautions (5.1, 5.7)].
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.
Following the pivotal Phase 3 trial, 40 subjects have been treated for at least one year with DR cysteamine in an Extension Trial. There were no unexpected or serious safety concerns experienced by subjects attributable to DR cysteamine. Based on the average number of gastro-intestinal AEs per subject per month that went slightly downward from 0.11 gastrointestinal disorder AEs/subject/month to ~ 0.09 gastrointestinal disorder AEs/subject/month, there was a gradual decrease in gastrointestinal disorder AEs with long term DR cysteamine therapy (p < 0.05). This decrease was also seen in the average number of total AEs/subject/month; from ~ 0.15 total AEs/subject/month at the beginning of the trial to ~ 0.08 total AEs/subject/month (p< 0.05, post-hoc analysis).
In two randomized clinical trials with healthy volunteers, there were no unexpected serious adverse events reported that were attributable to DR cysteamine. The most frequent adverse events (AEs) reported by the subjects related to DR cysteamine were GI symptoms (16%). The AE profile for healthy subjects was similar to the AE profile in patients relative to gastro-intestinal disorders (diarrhea and abdominal pain).
7. DRUG INTERACTIONS 
Cysteamine bitartrate delayed-release capsules can be administered with electrolyte (except bicarbonate) and mineral replacements necessary for management of Fanconi Syndrome as well as vitamin D and thyroid hormone.
An in vitro study indicates cysteamine bitartrate is not an inhibitor of CYP enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4). The potential for cysteamine to affect the pharmacokinetics of other drugs via these enzymes is low.
8. USE IN SPECIFIC POPULATIONS 
8.1 Usage in Pregnancy
Pregnancy Category C
Risk Summary
There are no adequate and well-controlled studies in pregnant women. Cysteamine (administered as cysteamine bitartrate) was teratogenic and fetotoxic in rats at doses less than the recommended human maintenance dose.
DR cysteamine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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/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 Nursing Mothers
It is not known whether cysteamine is present in human milk. A decrease in survival occurred in neonatal rats nursed by mothers receiving cysteamine. Because many drugs are present in human milk and because of the potential for serious adverse reactions in nursing infants from cysteamine, nursing is not recommended.
8.3 Pediatric Use
DR cysteamine therapy should be initiated as soon as the diagnosis of nephropathic cystinosis has been confirmed in children greater than 6 years and adults. The risks and benefits of treatment with DR cysteamine in children under 6 years old are not yet established.
9. OVERDOSAGE 
A single oral dose of cysteamine at 660 mg/kg was lethal to rats. Symptoms of acute toxicity were reduction of motor activity and generalized hemorrhage in gastrointestinal tract and kidneys.
Two cases of human over-dosing with immediate-release cysteamine bitartrate have been reported. In one case, the patient immediately vomited the drug and did not develop any symptoms. The second incident 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. A full recovery was made.
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.
10. MECHANISM OF ACTION 
Cysteamine is an aminothiol that participates within lysosomes in a thiol-disulfide interchange reaction converting cystine into cysteine and cysteinecysteamine mixed disulfide, both of which can exit the lysosome in patients with cystinosis.
11. PHARMACODYNAMICS  
Normal individuals and persons heterozygous for cystinosis have white blood cell cystine levels of < 0.2 and usually below 1 nmol ½ cystine/mg protein, respectively. Untreated patients with nephropathic cystinosis have elevations of white cell cystine above 2 nmol ½ cystine/mg protein. White blood cell cystine is monitored in these patients to determine adequacy of dosing, levels being measured 1/2 hour after dosing when treated with DR cysteamine. In a Long-Term Study entry white blood cell cystine levels were 3.73 nmol ½ cystine/mg protein (range 0.13 to 19.80 nmol ½ cystine/mg protein) and were maintained close to 1 nmol ½ cystine/mg protein with an immediate-release cysteamine dose range of 1.3 to 1.95 g/m2/day. (See Section 3.6 Dose Titration)
12. PHARMACOKINETICS  
Pharmacokinetic (PK) and pharmacodynamic (PD) relationships following a single dose of cysteamine bitartrate delayed-release capsules was first studied in comparison to a single dose of immediate-release cysteamine bitartrate in a study with nine (9) patients. Following normalization to a 450 mg dose, the maximum plasma levels Cmax, AUC0-6h and AUC0-12h (calculated directly from the plasma level data for DR cysteamine and from doubling the AUC0-6h value for immediate-release cysteamine to represent two doses) were lower for DR cysteamine (27.70 ± 14.99 μmol/L, 75.93 ± 39.22 μmol*h/L and 99.26 ± 44.21 μmol*h/L respectively) than for immediate-release cysteamine bitartrate (37.72 ± 12.10 μmol/L, 96.00 ± 37.81 μmol*h/L and 192.00 ± 75.62 μmol*h/L respectively.
The pharmacokinetics of DR cysteamine is consistent with a delayed-release formulation showing a Tmax of 2.78 ± 1.56 h for DR cysteamine. Cysteamine was moderately bound to human plasma proteins, predominantly to albumin, with mean protein binding of about 52%. Plasma protein binding was independent of concentration over the concentration range achieved clinically with the recommended doses.
After each dose of DR cysteamine the cysteamine concentration in the blood continues to decline for ~ ½ hour and the level of WBC cystine increases accordingly.
An exploratory study suggested that administering the contents of cysteamine bitartrate delayed-release capsules mixed with a small amount (4 ounces) of applesauce had no effect on the rate and extent of cysteamine absorption as compared to administration of intact capsules.
An additional bioequivalence trial (n=20) was conducted in fasted healthy volunteers. In this bioequivalence trial, intact capsules were taken with orange juice instead of applesauce. Analysis showed bioequivalence between whole capsule and sprinkle administration in the fasted state.
An exploratory trial shows that food can reduce the systemic exposure of cysteamine, therefore, it is recommended that DR cysteamine be administered at least 30 minutes before or 2 hours after a meal with a high-fat meal.
13. HOW SUPPLIED/STORAGE AND HANDLING 
1) How Available:
a) Brand name: PROCYSBI, by Raptor Pharma.
b) Generic drugs: None.
2) How Supplied:
• 25 mg Delayed-release Capsule: A hard gelatin capsule with light blue opaque cap imprinted with Raptor Logo in white ink and light blue opaque body imprinted with “25 mg” in white ink, supplied as bottle of 60 capsules (NDC 4966-3001-06).

• 75 mg Delayed-release Capsule: A hard gelatin capsule with dark blue opaque cap imprinted with Raptor Logo in white ink and light blue opaque body imprinted with “75 mg” in white ink, supplied as bottle of 250 capsules (NDC 4966-3002-25).
3) Storage and Handling:

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature].
Protect from light and moisture.
Dispense only in original packaging. Do not subdivide or repackage. Do not remove desiccant or oxygen absorber from the container. Keep bottles tightly closed in a dry place.