About nephropathic cystinosis

What is nephropathic cystinosis?

Nephropathic cystinosis is the most common form of cystinosis, a rare, inherited condition that affects every cell of the body by causing buildup of the amino acid cystine. The buildup of cystine causes kidney and other problems throughout the body. These problems cause the body to lose too much sugar (glucose), proteins, and salts (electrolytes) through the urine. Nephropathic cystinosis may lead to slow body growth and small stature, weak bones, hypothyroidism, blindness, muscle weakness, pulmonary dysfunction, and developing and worsening kidney failure.1-5

It is estimated that there are currently about 500 people in the United States—and 2,000 worldwide—diagnosed with this disorder.6 Nephropathic cystinosis is classically associated with blond-haired, blue-eyed children of European descent, although all races and ethnic backgrounds may be affected.3 The disease tends to affect more males than females, 1:4:1 according to one study.4

How nephropathic cystinosis affects the body

Although nephropathic cystinosis affects the entire body, the kidneys and eyes are typically affected first.3 Nephropathic cystinosis is the leading cause of Fanconi syndrome, a disorder of the kidney tubules in which important nutrients and minerals are released into the urine and must be replaced.3,7 Before the availability of cystine-depleting medication, nephropathic cystinosis would progress to kidney failure, usually between 9 and 10 years of age.5,7 Today, cystine-depleting medication may delay the progression of cystinosis and certain complications of the disease.4

In the eyes, cystine crystals form on the cornea. This can cause people with cystinosis to experience severe light sensitivity, which means that a bright sunny day can be painful; they may want to avoid bright lights or wear sunglasses to be more comfortable. Sometimes they may need to wear sunglasses indoors.3,8 Cystine-depleting eyedrops are used to dissolve corneal crystals.3 In addition to forming in the kidneys and eyes, cystine crystals can also form in such organs and tissue as the liver, spleen, lymph nodes, thyroid, intestines, muscle, brain, and bone marrow.3

Over time, nephropathic cystinosis can lead to damage to the heart, central nervous system, and muscle tissue.3 Ongoing, regular treatment is needed to continuously lower cystine concentration in the cells, which may delay or prevent irreversible organ damage.7 To determine how effectively treatment is working, people with nephropathic cystinosis should monitor their cystine concentration via frequent white blood cell cystine testing.11

Cystinosis and the cells6,9

Normal Lysosome

In a normal lysosome, cystine and lysine are produced and then transported away through the lysosomal membrane by their own transporters.

Untreated Cystinotic Lysosome

In people with nephropathic cystinosis, the transport system doesn’t work properly. While lysine is able to pass through the lysosome membrane, cystine is not.

In an untreated cystinotic lysosome, cystine is unable to exit the lysosome, and its accumulation leads to irreversible cell damage.

As toxic accumulation of cystine continues, crystals may form within the lysosome. Increased and sustained cystine concentration eventually leads to cell destruction. Although nephropathic cystinosis affects the entire body, the kidneys and eyes are typically affected first.3 Patients with nephropathic cystinosis usually show symptoms of Fanconi syndrome, a disorder of the kidney tubules that causes patients to lose important nutrients and minerals in the urine, between 6 and 12 months of age.

Treated Cystinotic Lysosome

Fortunately, cystine-depleting medications are available to treat nephropathic cystinosis. These medications effectively “modify” cystine, allowing it to pass through the membrane, which slows accumulation and crystallization. This may help delay disease progression.

In a treated cystinotic lysosome, cystine-depleting medications modify cystine to resemble lysine, thus enabling it to go through the lysine transporter. Cystine-depleting medications do not appear to remove previously accumulated crystals in the body or reverse previous damage to the cells.

The importance of white blood cell cystine testing

Along with careful adherence to a treatment plan, white blood cell (WBC) cystine testing can play an important part in helping your patients manage cystinosis. Measuring your patient’s WBC cystine concentration is the best way to determine the effectiveness of a given cystine-depletion medication and decide if any dosage adjustments are necessary.10

The goal of cystine-depleting medications is to keep cystine concentration to less than 1 nmol ½ cystine/mg of protein. To achieve continuous cystine control, regular WBC cystine tests may be needed.11,12 Patients taking PROCYSBI should undergo frequent WBC cystine-concentration tests.

Managing nephropathic cystinosis

The importance of continuous cystine control

Nephropathic cystinosis is a relentless, progressive disorder that leads to toxic concentration of cystine within cells. Without treatment, this elevation of cystine to toxic concentration will cause severe and irreversible organ damage. Even brief interruptions in treatment allow cystine to accumulate to toxic levels.1,3-7

Keeping cystine concentration under control is the only way to limit or prevent the irreversible damage caused by excessive cystine accumulation. Cysteamine, a cystine-depleting therapy, is critical to the management of cystinosis.1,3,4 Cysteamine helps by effectively reducing the toxic concentration of cystine in cells.3

In a clinical trial, PROCYSBI provided continuous cystine control when dosed every 12 hours and was proven noninferior to immediate-release cysteamine (dosed every 6 hours).8,11

Common challenges

Common cystinosis treatment challenges

Expand the fields below to learn more about some common issues patients with cystinosis and their caretakers and healthcare providers may face.

  • Despite the effectiveness of timely cystine-depletion therapies, some patients with cystinosis will eventually require a kidney transplant.7 Some patients may need more than one transplant surgery. Even though patients may feel better after renal transplantation, cystine accumulation continues and can lead to additional extrarenal complications.7 Thus, it is essential to continue cysteamine treatment even after transplantation surgery.5 Dietary changes may also be recommended.13

    Learn more about kidney transplants ›

  • Patients who do not receive timely and adequate cysteamine treatment may eventually require dialysis.3 This can be an emotionally difficult experience, and it presents dietary challenges because patients are placed on dialysis diets, which generally attempt to limit the amount of potassium and phosphorous.14

    Because of these restrictions, which sometimes even include foods like fruits and vegetables, patients may complain that they are unhealthy.13 Portion sizes and proper supplementation will help patients on dialysis diets eat foods they like and receive important nutrients without compromising their treatment goals.13

    Learn more about dialysis ›

  • The prognosis for patients with cystinosis has improved dramatically over the past 20 years when treatment is initiated early.3 Regardless, patients with cystinosis and their caregivers still face a lifetime of unique challenges. Transitional periods, such as those from childhood to adolescence and again from adolescence to adulthood, can be particularly difficult. Having strategies for handling these periods can limit the stress felt by both patients and caregivers.15

    Learn more about transition of care › 

References

1. Brodin-Sartorius A, Tète M-J, Niaudet P, et al. Cysteamine therapy delays the progression of nephropathic cystinosis in late adolescents and adults. Kidney Int. 2012;81:179-189.

2. Cooper GM. The Cell: A Molecular Approach. 2nd edition. Sunderland (MA): Sinauer Associates; 2000. Available at http://www.ncbi.nlm.nih.gov/books/NBK9953. Accessed July 22, 2015.

3. Gahl WA, Thoene JG, Schneider JA. Cystinosis. N Engl J Med. 2002;347(2):111-121.

4. Gahl WA, Balog JZ, Kleta R. Nephropathic cystinosis in adults: Natural history and effects of oral cysteamine therapy. Ann Intern Med. 2007;147:242-250.

5. Levtchenko EN, van Dael CM, de Graaf-Hess AC, et al. Strict cysteamine dose regimen is required to prevent nocturnal cystine accumulation in cystinosis. Pediatr Nephrol. 2006;21:110-113.

6. Cystinosis Research Foundation. “About Cystinosis.” Available at http://www.cystinosisresearch.org/About-Cystinosis. Accessed December 4, 2015.

7. Nesterova G, Gahl WA. Cystinosis: The evolution of a treatable disease. Pediatr Nephrol. 2013;28:51-59.

8. Langman CB, Greenbaum LA, Sarwal M, et al. A randomized controlled crossover trial with delayed-release cysteamine bitartrate in nephropathic cystinosis: Effectiveness on white blood cell cystine levels and comparison of safety. Clin J Am Soc Nephrol. 2012;7:1112-1120.

9. Genetics Home Reference. “What is a cell?” Available at http://ghr.nlm.nih.gov/handbook/basics/cell. Accessed December 4, 2015.

10. Dalton, Neil. The importance of accurate cystine level testing. Cystinosis Research Network. Available at https://cystinosis.org/images/research/article-library/cystagon/2009_01_Cystine_Level_Testing.pdf. Accessed December 4, 2015.

11. PROCYSBI [package insert]. Lake Forest, IL: Horizon Pharma USA, Inc; 2017.

12. CYSTAGON [package insert]. Morgantown, WV: Mylan Pharmaceuticals Inc.; 2007.

13. Data on file, Horizon Pharma USA, Inc.

14. “Kidney diet: Dialysis patients overview.” New York Times. Available at http://www.nytimes.com/health/guides/nutrition/kidney-diet-dialysis-patients/overview.html?print=1#Food-Sources. Accessed July 21, 2015.

15. Cystinosis Research Network. “Building bridges to the future: A transition guide for teens and young adults with cystinosis and their families.” Available at https://cystinosis.org/images/research/article-library/transition/CRNtransit06152011.pdf. Accessed December 4, 2015.

IMPORTANT SAFETY INFORMATION

INDICATIONS AND USAGE: PROCYSBI® (cysteamine bitartrate) delayed-release capsules is a cystine depleting agent indicated for the treatment of nephropathic cystinosis in adult and pediatric patients 1 year of age and older.

CONTRAINDICATIONS:

  • Serious hypersensitivity reaction, including anaphylaxis to penicillamine or cysteamine.

WARNINGS AND PRECAUTIONS:

  • Ehlers-Danlos-like Syndrome: Skin and bone lesions that resemble clinical findings for Ehlers-Danlos-like 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 increase to the appropriate therapeutic dose.
  • 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, permanently discontinue use of PROCYSBI.
  • 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.
  • 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 medication or adjust the dose as necessary for patients with severe symptoms or with symptoms that persist or progress.
    • Inform patients that PROCYSBI may impair their ability to perform tasks such as driving or operating machinery.
  • Leukopenia and/or Elevated Alkaline Phosphatase Levels: Cysteamine has been associated with reversible leukopenia and elevated alkaline phosphatase levels. Monitor white blood cell counts and alkaline phosphatase levels. If tests values remain elevated, consider decreasing the dose or discontinuing the drug until values revert to normal.
  • Benign Intracranial Hypertension: Benign intracranial hypertension (pseudotumor cerebri; PTC) and/or papilledema has been reported in patients receiving immediate-release cysteamine bitartrate treatment.
    • 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. If signs/symptoms persist, interrupt dosing or decrease the dose and refer the patient to an ophthalmologist. If the diagnosis is confirmed, permanently discontinue use of PROCYSBI.

ADVERSE REACTIONS:

The most common adverse reactions (≥5%) in patients treated in clinical trials are vomiting, nausea, gastroenteritis / viral gastroenteritis, abdominal pain, breath odor, diarrhea, skin odor, fatigue, rash, headache, and electrolyte imbalance.

To report SUSPECTED ADVERSE REACTIONS, contact Horizon Pharma USA, Inc. at 1-855-888-4004 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

 

DRUG INTERACTIONS:

  • Drugs that Increase Gastric pH: Administer PROCYSBI at least 1 hour before or 1 hour after medications containing bicarbonate or carbonate.
  • Consumption of alcohol with PROCYSBI may increase the rate of cysteamine release and/or adversely alter the pharmacokinetic properties, as well as the effectiveness and safety of PROCYSBI.
  • PROCYSBI can be administered with electrolyte (except bicarbonate) and mineral replacements necessary for management of Fanconi Syndrome as well as vitamin D and thyroid hormone.

USE IN SPECIFIC POPULATIONS

Lactation:

  • Breastfeeding is not recommended while taking PROCYSBI.

Part No.: P-PYB-00033                     Derived from Full Prescribing Information December 2017