C.L.A.S.S. Asks 20 Questions
About Cyclosporine
Answers provided by Mark D Grebenau, MBA,MD, PhD,
Director, Immunology/Transplantation
Novartis
Pharmaceuticals
1. 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).
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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).
19. 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.
20. 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.
