Cystaran（cysteamine ophthalmic，半胱胺 滴眼液0.44% ）

美国初次批准：1994
适应症和用途
CYSTARAN是一种胱氨酸-耗竭剂适用于有胱氨酸贮积症患者中为治疗角膜胱氨酸结晶积蓄。
剂量和给药方法
每只眼一滴CYSTARAN，每醒着小时。
剂型和规格
无菌眼溶液含6.5 mg/mL盐酸盐酸半胱胺 等同于4.4 mg/mL的半胱胺(0.44%)。
美国FDA批准Cystaran(cysteamine,半胱胺眼溶液)0.44%为治疗胱氨酸贮积症
FDA批准Sigma-Tau公司的Cystaran（cysteamine）滴眼液用于治疗胱氨酸病患者的角膜胱氨酸结晶堆积。胱氨酸病是一种罕见的遗传性溶酶体贮积病。该公司曾表示Cystaran有望今年在美国上市，但价格尚未确定。Cystaran是一种半胱胺眼用制剂，是半胱氨酸的降解产物。2010年5月FDA接受了该药的申请并给予优先审评权
NIH的国家人类基因研究所临床主任William A. Gahl，M.D.，Ph.D 说：“这是对遭受胱氨酸贮积症儿童和成年的重要进展”“FDA批准这个药物代表国家眼科研究所，Eunice Kennedy Shriver国立儿童健康和人类发展研究所，美国国家人类基因组研究所和Sigma-Tau Pharmaceuticals公司之间的长期合作的一个高潮它也涉及来自胱氨酸贮积症宣传组—胱氨酸贮积症研究网络，胱氨酸贮积症基金会和胱氨酸贮积症研究基金会宝贵的合作。”
Cystaran计划得到FDA的孤儿药补助金的部分支持。
关于胱氨酸贮积症
胱氨酸贮积症，在美国影响约300个儿童和年轻成年和世界范围2,000名个体，是一种罕见，遗传性溶酶体贮积病，特征为氨基酸，胱氨酸的异常积蓄，这个疾病引起胱氨酸结晶在机体各个器官建立，包括角膜，肾，肝，胰腺，肌肉，脑和白细胞。角膜胱氨酸积蓄可能导致眼并发症例如眯眼，外来物感觉，视力变化，角膜朦胧和畏光(即，对光敏感)。胱氨酸贮积症的其他并发症包括肌肉软弱，糖尿病，甲状腺机能低下，吞咽困难和佝偻病。
Cystaran Dosage and Administration
Instill one drop of Cystaran in each eye, every waking hour.
Do not touch dropper tip to any surface, as this may contaminate the solution.
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Discard after 1 week of use.
Dosage Forms and Strengths
Sterile ophthalmic solution containing 6.5 mg/mL of cysteamine hydrochloride equivalent to 4.4 mg/mL of cysteamine (0.44%).
Contraindications
None.
Warnings and Precautions
Contamination of Tip and Solution
To minimize contaminating the dropper tip and solution, care should be taken not to touch the eyelids or surrounding areas with the dropper tip of the bottle. Keep bottle tightly closed when not in use.
Benign Intracranial Hypertension
There have been reports of benign intracranial hypertension (or pseudotumor cerebri) associated with oral cysteamine treatment that has resolved with the addition of diuretic therapy.
There have also been reports associated with ophthalmic use of cysteamine; however, all of these patients were on concurrent oral cysteamine.
Use with Contact Lenses
Cystaran contains benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to application of solution and may be reinserted 15 minutes following its administration [see Patient Counseling Information(17.3)].
Topical Ophthalmic Use Only
Cystaran is for topical ophthalmic use only.
Adverse Reactions
Clinical Studies 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 practice.
The safety data described below reflect exposure in controlled clinical trials of six months to 19 years duration in approximately 300 patients.
The most frequently reported ocular adverse reactions occuring in ≥10% of patients were sensitivity to light, redness, and eye pain/irritation, headache and visual field defects.
USE IN SPECIFIC POPULATIONS
Pregnancy
There are no adequate and well-controlled studies of ophthalmic cysteamine in pregnant women. Cystaran should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Teratogenic Effects: Pregnancy Category C.
Teratology studies have been performed in rats at oral doses in a range of 37.5 mg/kg/day 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. Observed teratogenic findings were cleft palate, kyphosis, heart ventricular septal defects, microcephaly, and exencephaly.
Nonteratogenic Effects: Cysteamine was fetotoxic, resulting in intrauterine death and growth retardation in rats at oral doses of 0.2 to 0.7 times the recommended human maintenance dose on a body surface basis.
Nursing Mothers
It is not known whether oral 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/m2/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. The incremental increase in systemic cysteamine levels derived from drug applied topically to the eye in patients treated with oral cysteamine is negligible.
Pediatric Use
The safety and effectiveness of Cystaran (cysteamine ophthalmic solution) 0.44% have been established.
Geriatric Use
When the clinical studies with Cystaran were conducted, the reduced life expectancy from cystinosis did not make it possible to include patients in the geriatric age range.
Renal Impairment
The effect of renal impairment on the pharmacokinetics of cysteamine following ophthalmic administration of cysteamine ophthalmic solution has not been eva luated because ophthalmic exposure compared to systemic exposure is negligible. The majority of the patients in the ophthalmic clinical studies are assumed to have had some degree of renal impairment due to their underlying systemic disease. The total daily ophthalmic dose is less than 2% of the recommended oral daily dose of cysteamine; thus, the systemic exposure following ophthalmic administration is expected to be negligible compared to oral administration.
Cystaran Description
Cystaran is a sterile ophthalmic solution containing 6.5 mg/mL of cysteamine hydrochloride, equivalent to 4.4 mg/mL of cysteamine (0.44%) as the active ingredient. Cysteamine is a cystine-depleting agent which lowers the cystine content of cells in patients with cystinosis.
Molecular Formula: C2H7NS HCl
Molecular Weight: 113.61
Each milliliter of Cystaran contains: Active: cysteamine 4.4 mg (equivalent to cysteamine hydrochloride 6.5 mg); Preservative: benzalkonium chloride 0.1 mg; Inactive Ingredients: sodium chloride, hydrochloric acid and/or sodium hydroxide (to adjust pH to 4.1-4.5), and purified water.
Cystaran - Clinical Pharmacology
Mechanism of Action
Cysteamine acts as a cystine-depleting agent by converting cystine to cysteine and cysteine-cysteamine mixed disulfides and reduces corneal cystine crystal accumulation.
Pharmacokinetics
The peak plasma concentration of cysteamine following ocular administration of cysteamine ophthalmic solution in humans is unknown, but it is expected to be substantially less than the peak plasma concentration following oral administration of cysteamine bitartrate.
Nonclinical Toxicology
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/m2/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/m2/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.
Clinical Studies
Clinical efficacy was eva luated in controlled clinical trials in approximately 300 patients. The primary efficacy end point was the response rate of eyes that had a reduction of at least 1 unit in the photo-rated Corneal Cystine Crystal Score (CCCS) at some time point during the study when baseline CCCS ≥1, or a lack of an increase of more than 1 unit in CCCS throughout the study when baseline CCCS <1.
Study 1 combined the data from three smaller studies. For eyes with a lower baseline of CCCS <1, the response rate was 13% (4/30) [95% CI: (4, 32)]. For eyes with a higher baseline of CCCS ≥1, the response rate was 32% (94/291) [95% CI: (27, 38)].
Study 2 eva luated ocular cystinosis patients who had a baseline of CCCS ≥1. The response rate was 67% (10/15) [95% CI: (38, 88)].
Study 3 also eva luated ocular cystinosis patients; for eyes with a baseline of CCCS ≥1, the response rate was 33% (3/9) [95% CI: (8, 70)].
Corneal crystals accumulate if Cystaran is discontinued.
How Supplied/Storage and Handling
Cystaran (cysteamine ophthalmic solution) 0.44% is supplied in a 15 mL, opaque, white, low-density polyethylene (LDPE) bottle with a 15 mm white, LDPE controlled dropper tip and closed with a white, polypropylene screw cap.
Storage: Store in freezer at -25°C to -15°C (-13°F to 5°F). Thaw for approximately 24 hours before use. Store thawed bottle at 2°C to 25°C (36°F to 77°F) for up to 1 week. Do not refreeze. Discard after 1 week of use.