Questions About Cyclosporine
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by Mark D Grebenau, MBA,MD, PhD
For further information about Novartis and Cyclosporine, please see:
- Neoral Product Information: Neoral Product Information by Novartis
What is Novartis?
Novartis Pharmaceuticals is the result of a merger of Sandoz Pharmaceuticals and Ciba-Geigy Pharmaceuticals. Among the many products manufactured by Novartis are Sandimmune (cyclosporine, UPS), Neoral® (cyclosporine capsules and oral solution for microemulsion), and Simulect (basiliximab).
What is the difference between Sandimmune and Neoral?
Sandimmune and Neoral are two different dosage forms of the same drug, cyclosporine. But, because of the differences in how fast and well they are absorbed, they cannot be interchanged without close physician supervision.
The difference in dosage form of the two products affects the way they are absorbed by the body. The Neoral microemulsion dosage form is more readily absorbed than the original Sandimmune form. Parents should be sure that their child receives the dosage form specified by their doctor.
Will Sandimmune always be available, or is it being phased out?
We strongly believe that Neoral is a better drug than Sandimmune in that it provides increased bioavailability and decreased variability of cyclosporine exposure. However, Novartis recognizes its responsibility to patients and their physicians who depend on our products and therefore, will not withdraw Sandimmune until the market dictates that we should do so.
Does the dose have to be changed when switching from Sandimmune to Neoral?
This depends greatly on the patient. People who absorb Sandimmune well are likely to absorb Neoral similarly well — so they will probably not need a dosage adjustment. Those who do not absorb the original dosage form well, however, can often benefit from using Neoral because they may be able to take a lower dose and still get the same degree of exposure to the medication.
Are the side effects worse with Sandimmune or with Neoral?
In clinical trials, the side effects were the same for both drugs. There was a tendency to see a slightly higher rate of adverse reactions like headache or upset stomach and a mild compromise of kidney function soon after starting Neoral, possibly due to an increase in blood levels of cyclosporine. However, these problems regularly resolved after a short period of time or with a dose adjustment.
What foods and/or drinks affect absorption the most?
Cyclosporine, being insoluble in water, needs to be formulated in lipids (i.e., fat). The body has special ways of breaking down fats in the diet and this can affect the absorption of Sandimmune. For example, a fatty meal can cause bile to be secreted from the gall bladder, which in turn can increase absorption of Sandimmune.
One of the advantages of Neoral is its formulation: Neoral is less dependent on factors such fat-rich meals and production of bile. Neoral provides greater consistency of absorption and less variation of drug exposure in any given individual because of changes in the diet.
Can my child be weaned from cyclosporine?
The immune system, which is responsible for rejecting transplanted organs, is controlled, but not eliminated, by cyclosporine. It has been reported that in rare cases, a few children (and adults) appear to have developed immunological tolerance to their transplanted organ. This means that the immune system no longer rejects the organ and has "accepted" it as its own. A few of these children have been weaned from all of the drugs they were taking to control the immune system. Scientists do not fully understand how tolerance takes place and do not have a test that can determine if someone is tolerant or will become tolerant. Therefore, there is currently no way to predict who will and who will not be able to stop taking drugs.
Will long-term cyclosporine use affect my child’s physical and/or mental development?
In contrast to drugs like corticosteroids, no clear effect on physical or mental development has been seen in growing children treated with cyclosporine.
What can be done about extra (unwanted) hair growth?
This is a peculiar side effect of cyclosporine. We do not understand how it occurs and unfortunately don’t have a means of stopping it. However, patients often find that cosmetic approaches including bleaching, use of depilatories, or electrolysis can provide satisfactory results.
What can be done about the overgrowth of gum tissue caused by cyclosporine?
Consistent and vigorous oral hygiene, with regular dental care, seems to help to control this problem. Certain drugs taken concomitantly can exacerbate this effect. If gum overgrowth becomes excessive, it can be removed surgically. Recent evidence suggests that a short course of azithromycin, a common antibiotic, may be helpful.
Why is cyclosporine so expensive?
As with most drugs, the need to recover research and development costs and reinvest in development of future products is the primary reason for the cost of cyclosporine. According to the Pharmaceutical Research and Manufacturers of America, on average, it takes about $500 million and 14 years to develop and bring a new drug to market. Through a three-phase, 15-year development program we have continually improved cyclosporine therapy through advances in drug delivery. Novartis remains committed to studying Neoral through a $100 million commitment to phase IV research for transplant, psoriasis and rheumatoid arthritis patients over the next five years.
To develop new drugs that will improve outcomes and reduce side effects for transplant recipients, the company has also invested hundreds of millions of dollars in researching other new anti-rejection candidates. This resulted in the recent introduction of the orphan drug Simulect, a monoclonal antibody for the prevention of acute organ rejection in kidney transplantation. Globally, Novartis reinvests 19% of all sales dollars into research.
What can be done for children whose parents can’t afford cyclosporine?
Novartis has a patient assistance program for those who cannot afford Sandimmune or Neoral. Please call 1-888-455-6655.
Why are other immunosuppression drugs sometimes used in addition to cyclosporine?
While cyclosporine acts on the T helper cell, which is the "master cell" of the immune system, there are other cells that participate in the rejection process. Those cells must be controlled through the use of other drugs. Also, by using smaller amounts of several drugs, it may be possible to lessen the side effects that would result from using a large amount of a single drug.
How many children will get kidney damage from long-term cyclosporine use?
Cyclosporine may affect kidney function with long-term use. However, in most patients the effect of the drug on kidney function usually levels off after approximately a year and remains steady thereafter. If sudden toxic effects to the kidney do occur, they have been found to be reversible with a reduction in the drug dose in the majority of cases. Only a few patients experience structural changes of the blood vessels in the kidney, which cannot be reversed.
What should I do if my child accidentally misses a dose of cyclosporine?
Call your transplant team immediately. Do not try to double the next dose or otherwise change your child’s dosage regimen unless you are told to do so by a medical professional. Of course, while it is better not to miss doses, it is unlikely that a single missed dose will have grave consequences. So don’t panic, but do try to do everything possible to avoid missing a dose.
Do I need to wait until time for my child’s dose to open the foil Neoral packages, or can I open enough for a week, or a month at a time?
It is strongly recommended that the capsules only be removed from the foil pack just prior to dosing. If one wants to open up a day’s worth of Neoral, it is unlikely that it will affect the drug adversely. However, for drug stability reasons, it is not recommended that you keep capsules out of their foil pack beyond a week.
Is the medication still good if I accidentally leave it in the car and it gets very hot? What if it freezes?
It is best to avoid extremes of temperature. If Sandimmune or Neoral becomes too cool or too hot, the drug should be restored to room temperature, in order to allow it to revert to its original appearance. It can be difficult to visualize this with gel capsules but studies show that as long as the gel capsules are not ruptured (no leak or breakage of the capsule), the drug substance remains stable.
Is it true that grapefruit juice increases the absorption of cyclosporine?
Patients should not take cyclosporine (either Neoral or Sandimmune) with grapefruit juice because it can impact the absorption of the drug and reduce the effectiveness of therapy. Patients can, however, drink grapefruit juice at other times of the day.
Grapefruit juice doesn’t increase absorption. It inhibits the activity of an enzyme in the wall of the gastrointestinal tract that is responsible for breaking down cyclosporine before it can even enter the body. This effect will vary, depending on the amount of this enzyme in a given person’s intestines, and on the amount of the inhibiting substances, called flavonoids, in a given container of grapefruit juice (the amount of such substances is not regulated by the FDA or USDA).
What commonly prescribed prescriptions and over-the-counter medications interfere with cyclosporine?
There are a wide variety of drugs that can affect cyclosporine. It is recommended that you ask your physician, pharmacist or transplant team before taking any prescription or over-the-counter medications.
What should my child’s cyclosporine level be?
Cyclosporine levels are individually tailored to a specific patient and therefore, there is no one target level for everyone.
Mark D Grebenau, MBA,MD, PhD is the Director of Immunology/Transplantation at Novartis Pharmaceuticals.