What is the treatment for nephropathic cystinosis?

1.

Elsevier ClinicalKey Drug Monograph

Content last updated: April 1, 2024.

Description Cystaran is used orally to treat nephropathic cystinosis. Cystaran ophthalmic solutions are used to treat the corneal cystine crystal accumulation that occurs in patients with cystinosis. Nephropathic cystinosis is a rare autosomal recessive disease involving the defective transport of cystine across the lysosomal membrane. The defective transport of cystine out of lysosomes results in free cystine accumulation and crystallization within the lysosomes, which destroys various tissues and damages organs, especially the kidney. An example of kidney damage includes renal tubular Fanconi Syndrome, which is characterized by polyuria, polydipsia, electrolyte imbalance, dehydration, rickets, and growth failure. If left untreated, progressive glomerular failure and end-stage renal failure, usually occurring by 10 years of age, also are possible. Other sequelae of untreated cystinosis include photophobia, retinal blindness, hypothyroidism, pulmonary dysfunction, and male hypogonadism. For patients with cystinosis, treatment with cystaran early in life has been shown to slow the rate of renal failure progression, increase growth in affected patients, obviate the need for levothyroxine replacement, and decrease corneal cystine deposits.

Indications And Dosage **For the treatment of cystinosis** NOTE: The FDA has granted procysbi orphan drug status for this indication. **for the systemic treatment of nephropathic cystinosis** Oral dosage (immediate-release capsules) Adults: Initiate therapy at one-fourth to one-sixth the maintenance dose and gradually escalate over 4 to 6 weeks. The recommended maintenance dose is 500 mg procysbi free base every 6 hours (2 g/day). The dosage may be further increased to achieve a therapeutic target WBC cystine concentration; Max: 1.95 g/m2/day. If intolerance occurs, temporarily stop therapy, re-institute at a lower dose, and gradually increase to the proper dose. Adolescents weighing 50.5 kg or more: Initiate therapy at one-fourth to one-sixth the maintenance dose and gradually escalate over 4 to 6 weeks. The recommended maintenance dose is 500 mg procysbi free base every 6 hours (2 g/day). The dosage may be further increased to achieve a therapeutic target WBC cystine concentration; Max: 1.95 g/m2/day. If intolerance occurs, temporarily stop therapy, re-institute at a lower dose, and gradually increase to the proper dose. Children and Adolescents weighing 41.4 to 50.4 kg: Initiate therapy at one-fourth to one-sixth the maintenance dose and gradually escalate over 4 to 6 weeks. The recommended maintenance dose is 450 mg procysbi free base every 6 hours (1.3 g/m2/day). The dosage may be further increased to achieve a therapeutic target WBC cystine concentration; Max: 1.95 g/m2/day. If intolerance occurs, temporarily stop therapy, re-institute at a lower dose, and gradually increase to the proper dose. Children and Adolescents weighing 32.3 to 41.3 kg: Initiate therapy at one-fourth to one-sixth the maintenance dose and gradually escalate over 4 to 6 weeks.

Indications And Dosage **for the treatment of corneal cystine crystal accumulation in patients with cystinosis** Ophthalmic dosage (0.44% ophthalmic solution) Adults: Instill 1 drop in each eye, every waking hour. Infants, Children, and Adolescents: Instill 1 drop in each eye, every waking hour. Neonates: Instill 1 drop in each eye, every waking hour. Ophthalmic dosage (0.37% ophthalmic solution) Adults: Instill 1 drop in each eye 4 times daily during waking hours. Infants, Children, and Adolescents: Instill 1 drop in each eye 4 times daily during waking hours. Neonates: Instill 1 drop in each eye 4 times daily during waking hours. **for the systemic treatment of nephropathic cystinosis** Oral dosage (immediate-release capsules) Adults: Initiate therapy at one-fourth to one-sixth the maintenance dose and gradually escalate over 4 to 6 weeks. The recommended maintenance dose is 500 mg procysbi free base every 6 hours (2 g/day). The dosage may be further increased to achieve a therapeutic target WBC cystine concentration; Max: 1.95 g/m2/day. If intolerance occurs, temporarily stop therapy, re-institute at a lower dose, and gradually increase to the proper dose. Adolescents weighing 50.5 kg or more: Initiate therapy at one-fourth to one-sixth the maintenance dose and gradually escalate over 4 to 6 weeks. The recommended maintenance dose is 500 mg procysbi free base every 6 hours (2 g/day). The dosage may be further increased to achieve a therapeutic target WBC cystine concentration; Max: 1.95 g/m2/day. If intolerance occurs, temporarily stop therapy, re-institute at a lower dose, and gradually increase to the proper dose. Children and Adolescents weighing 41.4 to 50.4 kg: Initiate therapy at one-fourth to one-sixth the maintenance dose and gradually escalate over 4 to 6 weeks.

Indications And Dosage Adults: Instill 1 drop in each eye, every waking hour. Infants, Children, and Adolescents: Instill 1 drop in each eye, every waking hour. Neonates: Instill 1 drop in each eye, every waking hour. Ophthalmic dosage (0.37% ophthalmic solution) Adults: Instill 1 drop in each eye 4 times daily during waking hours. Infants, Children, and Adolescents: Instill 1 drop in each eye 4 times daily during waking hours. Neonates: Instill 1 drop in each eye 4 times daily during waking hours. **for the systemic treatment of nephropathic cystinosis** Oral dosage (immediate-release capsules) Adults: Initiate therapy at one-fourth to one-sixth the maintenance dose and gradually escalate over 4 to 6 weeks. The recommended maintenance dose is 500 mg cysteamine free base every 6 hours (2 g/day). The dosage may be further increased to achieve a therapeutic target WBC cystine concentration; Max: 1.95 g/m2/day. If intolerance occurs, temporarily stop therapy, re-institute at a lower dose, and gradually increase to the proper dose. Adolescents weighing 50.5 kg or more: Initiate therapy at one-fourth to one-sixth the maintenance dose and gradually escalate over 4 to 6 weeks. The recommended maintenance dose is 500 mg cysteamine free base every 6 hours (2 g/day). The dosage may be further increased to achieve a therapeutic target WBC cystine concentration; Max: 1.95 g/m2/day. If intolerance occurs, temporarily stop therapy, re-institute at a lower dose, and gradually increase to the proper dose. Children and Adolescents weighing 41.4 to 50.4 kg: Initiate therapy at one-fourth to one-sixth the maintenance dose and gradually escalate over 4 to 6 weeks. The recommended maintenance dose is 450 mg cysteamine free base every 6 hours (1.3 g/m2/day).

Mechanism Of Action Cysteamine, an aminothiol, decreases the amount of cystine in the lysosomes of patients with cystinosis. Exogenous cysteamine enters the cell and converts cystine to cysteine and a cysteine-cysteamine complex. Both cysteine and the cysteine-cysteamine complex are more readily transported out of the lysosome than cystine, resulting in a long-term depletion of lysosomal cystine. Clinically, the administration of cysteamine early in life slows the progression of renal failure, improves growth, obviates the need for levothyroxine replacement, and decreases corneal cystine deposits.

2.

Guay-Woodford, Lisa M. (2024). In Goldman-Cecil Medicine (pp. 815). DOI: 10.1016/B978-0-323-93038-3.00113-1

The mainstay of therapy is oral cysteamine (dose: 60 to 90 mg/kg/day or 1.35 to 1.90 g/m2/day, divided every 6 hours), which is an aminothiol that can lower intracellular cystine content by 90%.In well-treated patients, cysteamine delays renal functional decline, enhances growth, prevents hypothyroidism, and lowers muscle cystine content. Therefore, early diagnosis and prompt, proper treatment are critical for preventing or significantly delaying the complications of cystinosis. Twice-daily dosing with delayed-release cysteamine bitartrate (at approximately 70% of the patient’s usual dose) is as efficacious as cysteamine for reducing white blood cell cystine levels in patients with nephropathic cystinosis.

3.

Food and Drug Administration (DailyMed).

Publish date: August 1, 2021.

Mechanism Of Action Mechanism of Action Cystinosis is an autosomal recessive inborn error of metabolism in which the transport of cystine out of lysosomes is abnormal; in the nephropathic form, accumulation of cystine and formation of crystals damage various organs, especially the kidney, leading to renal tubular Fanconi Syndrome and progressive glomerular failure, with end stage renal failure by the end of the first decade of life. In four studies of cystinosis patients before cysteamine was available, renal death (need for transplant or dialysis) occurred at median age of less than 10 years. Patients with cystinosis also experience growth failure, rickets, and photophobia due to cystine deposits in the cornea. With time most organs are damaged, including the retina, muscles and central nervous system. Cysteamine is an aminothiol that participates within lysosomes in a thiol-disulfide interchange reaction converting cystine into cysteine and cysteine-cysteamine mixed disulfide, both of which can exit the lysosome in patients with cystinosis.

Indications And Usage INDICATIONS AND USAGE Cystagon (cysteamine bitartrate) ® is indicated for the management of nephropathic cystinosis in children and adults.

Clinical Pharmacology Doses could be raised if white cell cystine levels were approximately 2 nmol/½ cystine/mg protein and lowered due to intolerance. Mean doses were 1.27 g/m 2 /day and 1.87 g/m 2 /day in the two groups and white cell cystine levels averaged 1.72 ± 1.65 nmol/½ cystine/mg protein and 1.86 ± 0.92 nmol/½ cystine/mg protein in the 1.3 and 1.95 g/m 2 /day groups, respectively. In new patients, a group similar in age to the NCCS group, serum creatinine was essentially unchanged over the period of follow-up (about half of the patients were followed for 24 months) and phosphocysteamine and cysteamine HCl had similar effects. The long-term follow-up group, about nine years old on average at entry, stayed in the study (almost 80% were followed at least 2 years) and had essentially no change in renal function. In four studies of untreated cystinosis, renal death (need for transplant or dialysis) occurred at median age of less than 10 years. Both groups maintained height (although they did not catch up from baseline). There was no apparent difference between the two doses.