Wednesday, May 3, 2017

Medications of Cystinosis

When our older son Samuel was first diagnosed with cystinosis, we were overwhelmed by the many new medications that he was prescribed.  Here is a cheat sheet with some basic facts about many of the medications that you or your child may be prescribed for cystinosis.  I did not include transplant medications.  As always, if you have concerns or questions about medications prescribed to you, talk to your doctor or your pharmacist.

Cysteamine: This is the game-changing drug that was discovered in 1976 and approved by the FDA in 1994, that slows disease progression.  Cysteamine enters every cell of the body and binds to cystine molecules so that they can get out of the lysosome.  Cysteamine comes in two varieties, Cystagon and Procysbi.  Cystagon was the original form of the drug and must be taken every 6 hours to be effective.  Its common side effects include nausea, vomiting, abdominal pain and a sulfur smell.  Its absorption is decreased if taken with protein and fatty foods.

Procysbi was developed with funding from the Cystinosis Research Foundation and was approved by the FDA in 2013.  It contains the same active drug as Cystagon, but it is encapsulated in acid-resistant beads that do not dissolve until they arrive in the small intestine, where the pH is more alkaline.  This prevents the drug from being rapidly absorbed in the stomach.  The delayed absorption makes it possible to take every 12 hours.  Bypassing the stomach also tends to improve some of the side effects for some patients, including dyspepsia and nausea.  I’ve found that the smell is still there regardless of which drug you take, but some patients find one is better than the other.  The most important thing with Procysbi is that its absorption is affected by food, so you should take it on an empty stomach.  The package insert says to not eat for 2 hours before taking it, and to wait an additional thirty minutes before eating again.  You can take it with an acidic food like orange juice because the beads are resistant to acid.   You should not take the pills with alkaline foods like milk because the beads will dissolve prematurely and the drug will not have delayed absorption. 

Cysteamine eye drops:  These drops contain the same drug as the pills, but since the cornea does not have blood vessels, the oral version of the drug does not treat corneal crystals.  The drops should be administered every hour that the patient is awake to be most effective, but few patients are able to achieve this frequency.  Side effects include eye irritation, eye pain, and headaches.  Many people have reactions to the preservative in the drops, benzalkonium chloride.  It is currently the only approved therapy in the United States for corneal cystinosis.  Other countries have eye gels, and some pharmacies will compound eye drops. 

Potassium: People with cystinosis lose many electrolytes, including potassium, in their urine because of Fanconi syndrome.  Low potassium (hypokalemia) causes muscle weakness, muscle cramps and in severe cases can lead to cardiac arrhythmias.  Hypokalemia is made worse by vomiting and diarrhea.  Potassium can be replaced in a variety of formulations.  The most common form is potassium chloride, which is sold in its generic form or as Klor-Con, K-Tab or K-Sol (there are probably other names, too).  Every person needs a different amount of potassium replacement based on their labs.  Potassium is also available in combination with other essential medications, including citrate and phosphorus.  Side effects include nausea and abdominal discomfort.

Citrate: People with cystinosis lose bicarbonate in their urine, and this leads to more acid in the blood (acidosis).  The extra acid is buffered by bone, which leads to poor growth, bone resorption and soft bones (osteopenia).  This is corrected by taking a medication like citrate.  Citrate is taken up in the liver and converted to bicarbonate.  Citrate is combined with either potassium, sodium or both.  Potassium citrate is sold as Cytra-K, Virtrate-K, Polycitra-K and Urocit-K.  Some people get all of their potassium replacement from potassium citrate.  Sodium citrate is sold as Cytra-2, Virtrate-2, Oracit and Bicitra and does not have any potassium in it. Tricitrates, Polycitra and Cytra-3 have both potassium and sodium.   Citrate does bind calcium, so large doses can potentially lead to low calcium in the blood, which can cause tetany.  This may be exacerbated if taken with other medications that bind calcium, such as phosphorus.

Sodium bicarbonate: This is essentially baking soda, and can be taken as a tablet, or as actual baking soda in patients who cannot take or afford tablets.  Just like citrate, this medication increases serum bicarbonate levels to buffer the acids in the blood.  It may be used in place of citrate, or in addition to citrate.

Phosphorus: People with cystinosis lose phosphorus in their urine.  Phosphorus is essential for building bone, and low phosphorus (hypophosphatemia) leads to rickets, or soft bones.  Phosphorus is available in many formulations.  It is combined with sodium and potassium in Phos-NaK, K-Phos Neutral, K-Phos No. 2, Phospha 250 Neutral, Virt-Phos 250 Neutral and Av-Phos 250 Neutral.  It can also be prescribed as simply sodium phosphate or potassium phosphate.  Common side effects include diarrhea and nausea.  Large doses of phosphate taken at once can cause tetany by dropping serum calcium levels.

Carnitine: This is another molecule that is lost in the urine in people with cystinosis.  Carnitine is required for muscles to metabolize fat.  Lack of carnitine leads to accumulation of fat in muscle tissue and resultant myopathy (muscle disease).  Giving patients carnitine supplements reduces accumulation of fat in muscle tissue.  This drug is sold as Carnitor or Levocarnitine.

Vitamin D:  Normally we make vitamin D in our skin, with exposure to sunlight.  We can also get vitamin D from fortified foods, or from supplements.  If the supplement is from a plant, it's called ergocalciferol, or D2.  If it's from animals or our skin, it is called cholecalciferol, or D3.  Whether we make it in our skin or take a supplement, the vitamin D is modified by the liver to make 25-Vitamin D.  This form of vitamin D is then modified again by the kidneys, to make 1,25-Vitamin D, which is the active form.  This form is also called calcitriol, and it is required to maintain calcium and phosphate levels in the blood and promote bone growth and remodeling.  1,25-Vitamin D increases absorption of calcium and phosphate in the intestines.  Dr. Mak, a CRF funded researcher, has shown that 25-Vitamin D is important for muscle health.

Calcitriol: This is the activated form of vitamin D, also called 1,25-Vitamin D.  In people with chronic kidney disease, the kidneys lose the ability to convert 25-Vitamin D to the active form.  This drug may also be prescribed in patients with severe hypophosphatemia (low phosphorus) because it stimulates intestinal absorption of phosphorus.  

Iron: People with cystinosis may develop iron deficiency.  Iron is normally found in red meat, sea food, beans, spinach and peas.  Iron is an essential element for making hemoglobin, which is the protein in red blood cells that binds oxygen.  Lack of iron leads to anemia.  Iron may be taken as ferrous sulfate, ferrous fumarate and ferrous gluconate.   The most common side effect is constipation, and it may make stools darker. 

Thyroid hormone: Cystinosis causes thyroid disease through a few mechanisms, including cystine accumulation.  Symptoms of low thyroid (hypothyroidism) include fatigue, swelling, constipation, cold intolerance, coarse hair and skin.  Usually around age five to ten years, people with cystinosis require thyroid hormone replacement.  This is typically done with levothyroxine, which is an analog of thyroxine, or T4.  T4 is taken up by the body and converted to triiodothyronine, or T3, the active form of thyroid hormone. 

Growth hormone: Many people with cystinosis have growth failure and are treated with growth hormone.  This drug is usually given as a daily injection.  It must be given before the epiphyses (growth plates) fuse during puberty. 

Testosterone: Cystine accumulation and fibrosis in the testicles may lead to hypogonadism, and some boys may need testosterone replacement in order to progress through puberty.  This can be administered as an injection, implant, gel or patch.

Insulin: Insulin is a hormone produced by the pancreas to help cells take up glucose from the blood.  Many people with cystinosis develop diabetes mellitus as teenagers or later due to the effects of cystinosis on the pancreas.  These people have insufficient insulin production and require insulin therapy to maintain normal blood sugars.  Insulin is administered as an injection.  There are long acting forms of insulin, such as glargine, that are given once a day.  There are short-acting forms of insulin, such as lispro or aspart, that are given with meals.

Proton pump inhibitor: This class of medications includes esomeprazole, omeprazole, lansoprazole and pantoprazole, among others.  These medications lower the acidity of the stomach, which helps symptoms of acid reflux and stomach ulcers.  Many people are put on these medications to help with the side effects of other medications, including cysteamine.  Because these medications make the stomach less acidic, people taking Procysbi may want to avoid them.  Some research has shown that long term use of proton pump inhibitors is associated with increased risk of fractures, low magnesium levels, B12 deficiency and gastrointestinal infections.

ACE inhibitors: This class of medications includes lisinopril, benazepril, enalapril, fosinopril and others.  These medications affect the renin-angiotensin-aldosterone system, which regulates blood pressure, sodium and fluid status, and filtration through the kidneys.  These drugs are used primarily for high blood pressure and proteinuria (protein in the urine).  Most if not all people with cystinosis have protein in their urine.  Because of Fanconi syndrome, small proteins that are filtered through the glomerulus are not reabsorbed by the proximal tubule.  Research has shown that people with cystinosis also develop damage to the glomerulus, and this leads to leaking of larger proteins, like albumin, into the urine.  This usually manifests as foamy urine.  Over time this causes further damage to the kidneys.  ACE inhibitors can be used to reduce the amount of protein that leaks through the glomerulus by reducing the pressure on the filtering system.  Side effects include low blood pressure and high potassium levels.  Some people develop a chronic cough that usually resolves after stopping the medication.  Rarely people have a reaction in which the face or airway swells, called angioedema, and this is an emergency.  This drug should not be taken if you are dehydrated, as may occur with vomiting or diarrhea, because it can cause an acute kidney injury.  In patients who have proteinuria but cannot take an ACE inhibitor because of side effects or allergy, another class of medications, called angiotensin receptor blockers, or ARBs, can be used.  This class includes losartan, valsartan, irbesartan and others.

Spironolactone: This medication blocks the effects of a hormone called aldosterone.  It is a weak diuretic and can cause dehydration and low blood pressure.  Its main side effect is that it raises potassium levels, which may be beneficial in people with cystinosis.  It also reduces the amount of protein that leaks into the urine, and may be prescribed for this purpose.  Other side effects are related to its anti-androgen properties; it can cause menstrual irregularities and breast tenderness/enlargement in men and women.  Other related medications include amiloride and eplerenone. 

Indomethacin: This is a non-steroidal anti-inflammatory drug (NSAID) related to ibuprofen and naproxen.  Indomethacin reduces the amount of blood that filters through the kidneys, which results in less urine production.  The drug is used to reduce polyuria and improve electrolyte retention.  Its use is controversial in people with cystinosis because NSAIDs are toxic to the kidneys and can worsen renal failure.  There is some new data, however, that indomethacin may actually be protective in cystinosis.  You should not take this medication if you are dehydrated, as may occur with vomiting and diarrhea, because it can cause an acute kidney injury.  This drug can also cause ulcers in the stomach and duodenum, so a proton pump inhibitor is usually prescribed with it to reduce acidity in the stomach.

Ondansetron: This drug is also known as Zofran, and was developed to treat nausea and vomiting associated with chemotherapy.  Other drugs in this class include dolasetron and granisetron.  Many people with cystinosis take this medication to treat the side effects of medications they take, including cysteamine.  Common side effects include headache and constipation.  This medication is known to cause QT prolongation on ECGs, which can lead to arrhythmias, so it is important for your doctor to review possible medication interactions before starting this drug.


Erythropoiesis-Stimulating Agents (ESA): The kidneys are responsible for monitoring oxygen levels and telling the bone marrow when to make more red blood cells.  As kidney disease progresses, this function is lost, and many people develop anemia.  There are drugs, including Epoetin alfa (marketed as Procrit or Epogen) and Darbepoetin alfa (marketed as Aranesp) that can be given to stimulate red blood cell production in the bone marrow.  These drugs are given as an injection.    

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