NEORAL
Soft Gelatin
Capsules (cyclosporine capsules, USP) MODIFIED
NEORAL
Oral Solution
(cyclosporine oral solution, USP) MODIFIED
Rx only
WARNING
Only
physicians experienced in management of systemic immunosuppressive therapy for
the
indicated
disease should prescribe Neoral. At doses used in solid organ transplantation,
only
physicians
experienced in immunosuppressive therapy and
management of organ
transplant
recipients
should prescribe Neoral. Patients receiving the drug should be managed
in
facilities
equipped and staffed with adequate laboratory and supportive medical resources.
The
physician
responsible for maintenance therapy should have complete information requisite
for
the
follow-up of the patient.
Neoral,
a systemic immunosuppressant, may increase the susceptibility to infection and
the
development
of neoplasia. In kidney, liver, and
heart transplant patients
Neoral may be
administered
with other immunosuppressive agents. Increased susceptibility to infection and
the
possible development of lymphoma and other neoplasms may result from the
increase in
the
degree of immunosuppression in transplant patients.
Neoral Soft
Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and
Neoral Oral
Solution
(cyclosporine oral solution, USP) MODIFIED have increased bioavailability in
comparison to
Sandimmune Soft Gelatin
Capsules (cyclosporine capsules,
USP) and
Sandimmune
Oral Solution (cyclosporine oral solution, USP). Neoral and Sandimmune are
not bioequivalent and cannot be used interchangeably without physician
supervision. For a
given
trough concentration, cyclosporine exposure will be greater with Neoral than
with
Sandimmune.
If a patient who is receiving exceptionally high doses of
Sandimmune is
converted
to Neoral, particular caution should be exercised. Cyclosporine blood
concentrations
should be monitored in transplant and rheumatoid arthritis patients taking
Neoral to
avoid toxicity due to high
concentrations. Dose adjustments should be made in
transplant patients
to minimize possible
organ rejection due
to low concentrations.
Comparison of
blood concentrations in the
published literature with blood concentrations
obtained
using current assays must be done with detailed knowledge of the assay methods
employed.
For Psoriasis
Patients (See also Boxed WARNINGS above)
Psoriasis
patients previously treated with PUVA and to a lesser extent, methotrexate or
other
immunosuppressive
agents, UVB, coal tar, or radiation therapy, are at an increased risk of
developing
skin malignancies when taking Neoral.
Cyclosporine,
the active ingredient in Neoral, in recommended dosages, can cause systemic
hypertension and
nephrotoxicity. The risk
increases with increasing dose and duration of
cyclosporine
therapy. Renal dysfunction, including structural kidney damage, is
a potential
consequence
of cyclosporine, and therefore, renal function must be monitored during
therapy.
DESCRIPTION:
Neoral is an oral formulation
of cyclosporine that
immediately forms a
microemulsion
in an aqueous environment.
Cyclosporine,
the active principle in Neoral, is a cyclic polypeptide
immunosuppressant
agent consisting
of 11 amino acids. It
is produced as
a metabolite by
the fungus species
Beauveria
nivea.
Chemically,
cyclosporine is designated as [R-[R*,R*-(E)]]-cyclic-(L-alanyl-D-alanyl-N-
methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6-
octenoyl-L-α-amino-butyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl).
Neoral Soft Gelatin Capsules
(cyclosporine capsules, USP) MODIFIED are available in
25
mg and 100 mg strengths.
Each
25 mg capsule contains:
cyclosporine
......................................................................................................................
25 mg
alcohol,
USP
dehydrated.....................................................................11.9%
v/v (9.5% wt/vol.)
Each
100 mg capsule contains:
cyclosporine
....................................................................................................................
100 mg
alcohol,
USP
dehydrated.....................................................................11.9%
v/v (9.5% wt/vol.)
Inactive
Ingredients: Corn oil-mono-di-triglycerides, polyoxyl 40
hydrogenated castor oil NF,
DL-α-tocopherol
USP, gelatin NF, glycerol, iron oxide black, propylene glycol USP, titanium
dioxide
USP, carmine, and other ingredients.
Neoral Oral Solution
(cyclosporine oral solution, USP) MODIFIED is available in 50 mL
bottles.
Each
mL contains:
cyclosporine
..............................................................................................................100
mg/mL
alcohol,
USP dehydrated.....................................................................11.9%
v/v (9.5% wt/vol.)
Inactive
Ingredients: Corn oil-mono-di-triglycerides, polyoxyl 40
hydrogenated castor oil NF,
DL-α-tocopherol
USP, propylene glycol USP.
The
chemical structure of cyclosporine (also known as cyclosporin A) is:
CLINICAL PHARMACOLOGY:
Cyclosporine is a potent immunosuppressive agent that in
animals prolongs
survival of allogeneic transplants involving skin, kidney, liver, heart,
pancreas, bone
marrow, small intestine,
and lung. Cyclosporine has been demonstrated to
suppress some
humoral immunity and to a greater extent, cell-mediated
immune reactions
such
as allograft rejection, delayed hypersensitivity, experimental allergic
encephalomyelitis,
Freund.s
adjuvant arthritis, and graft vs. host disease in many animal species for a
variety of
organs.
The effectiveness of cyclosporine results from specific and reversible
inhibition of
immunocompetent
lymphocytes in the G0- and G1-phase of the cell cycle. T-lymphocytes are
preferentially inhibited. The T-helper cell is the main
target, although the T-suppressor cell
may also be suppressed. Cyclosporine also
inhibits lymphokine production and release
including
interleukin-2.
No
effects on phagocytic function (changes
in enzyme secretions, chemotactic migration of
granulocytes,
macrophage migration, carbon clearance in vivo) have been detected in
animals.
Cyclosporine
does not cause bone marrow suppression in animal models or man.
Pharmacokinetics: The
immunosuppressive activity of
cyclosporine is primarily due to
parent drug. Following oral administration,
absorption of cyclosporine is incomplete. The
extent
of absorption of cyclosporine is dependent on the individual patient, the
patient
population,
and the formulation. Elimination of cyclosporine is primarily biliary with only
6%
of
the dose (parent drug and metabolites) excreted in urine. The
disposition of cyclosporine
from blood
is generally biphasic,
with a terminal half-life of approximately 8.4 hours
(range
5-18 hours). Following intravenous administration, the blood clearance of
cyclosporine
(assay:
HPLC) is approximately 5-7 mL/min/kg in adult recipients of renal or liver
allografts.
Blood
cyclosporine clearance appears to be slightly slower in cardiac transplant
patients.
The
Neoral Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Neoral
Oral
Solution (cyclosporine oral solution, USP) MODIFIED are bioequivalent.
The
relationship between administered dose and exposure (area under the
concentration versus
time curve,
AUC) is linear
within the therapeutic
dose range. The
intersubject variability
(total,
%CV) of cyclosporine exposure (AUC) when Neoral or Sandimmune is administered
ranges from
approximately 20% to
50% in renal transplant patients.
This intersubject
variability contributes
to the need for individualization of the dosing
regimen for optimal
therapy (see DOSAGE AND ADMINISTRATION). Intrasubject variability
of AUC in renal
transplant
recipients (%CV) was 9%-21% for Neoral and 19%-26% for Sandimmune. In the
same studies,
intrasubject variability of
trough concentrations (%CV)
was 17%-30% for
Neoral
and 16%-38% for Sandimmune.
Absorption:
Neoral has increased bioavailability compared to Sandimmune. The absolute
bioavailability of
cyclosporine administered as
Sandimmune is dependent on the patient
population,
estimated to be less than 10% in liver transplant patients and as great as 89%
in
some renal
transplant patients. The
absolute bioavailability of
cyclosporine administered as
Neoral
has not been determined in adults. In studies of renal transplant, rheumatoid
arthritis
and psoriasis
patients, the mean cyclosporine
AUC was approximately 20% to 50% greater
and
the peak blood cyclosporine concentration (Cmax)
was approximately 40% to 106% greater
following
administration of Neoral compared to following administration of Sandimmune.
The
dose normalized AUC in de novo liver transplant patients administered
Neoral 28 days
after transplantation was 50% greater and Cmax was
90% greater than in those patients
administered Sandimmune. AUC and Cmax are also increased (Neoral relative
to
Sandimmune)
in heart transplant patients, but data are very limited. Although the AUC and
Cmax values are higher on Neoral relative
to Sandimmune, the pre-dose trough
concentrations
(dose-normalized) are similar for the two formulations.
Following
oral administration of Neoral, the time to peak blood cyclosporine
concentrations
(Tmax)
ranged from 1.5-2.0 hours. The
administration of food with Neoral decreases the
cyclosporine
AUC and Cmax. A high
fat meal (669 kcal, 45 grams fat) consumed within
one-half
hour before Neoral administration decreased the AUC by 13% and Cmax by 33%.
The
effects of a low fat meal (667 kcal, 15 grams fat) were similar.
The
effect of T-tube diversion of bile on the absorption of cyclosporine from
Neoral was
investigated
in eleven de novo liver transplant patients. When the patients were
administered
Neoral
with and without T-tube diversion of bile, very little difference in
absorption was
observed,
as measured by the change in maximal cyclosporine blood concentrations from
pre-dose
values with the T-tube closed relative to when it was open: 6.9±41% (range -55%
to
68%).
Distribution:
Cyclosporine is distributed largely outside the blood volume. The steady state
volume
of distribution during intravenous dosing has been reported as 3-5 L/kg in
solid organ
transplant recipients. In blood, the distribution is
concentration dependent. Approximately
33%-47%
is in plasma, 4%-9% in lymphocytes, 5%-12% in
granulocytes, and 41%-58% in
erythrocytes. At
high concentrations, the binding capacity of leukocytes and
erythrocytes
becomes
saturated. In plasma, approximately 90% is bound to proteins, primarily
lipoproteins.
Cyclosporine
is excreted in human milk. (See PRECAUTIONS, Nursing Mothers)
Metabolism:
Cyclosporine is extensively metabolized by the cytochrome P-450 3A enzyme
system in
the liver, and
to a lesser degree in
the gastrointestinal tract,
and the kidney.
The
metabolism
of cyclosporine can be altered by the coadministration of a variety of agents.
(See
PRECAUTIONS,
Drug Interactions) At least 25 metabolites have been identified from
human
bile,
feces, blood, and urine. The biological activity of the metabolites and their
contributions
to toxicity are considerably less than those of
the parent compound. The major metabolites
(M1,
M9, and M4N) result from oxidation at the 1-beta, 9-gamma, and
4-N-demethylated
positions,
respectively. At steady state following the oral administration of Sandimmune,
the
mean
AUCs for blood concentrations of M1, M9, and M4N are about 70%, 21%, and 7.5%
of
the
AUC for blood cyclosporine
concentrations, respectively. Based on blood concentration
data
from stable renal transplant patients (13 patients administered Neoral and
Sandimmune
in a
crossover study), and bile concentration data from de novo liver transplant
patients
(4
administered Neoral, 3
administered Sandimmune), the percentage of dose present as
M1, M9,
and M4N metabolites
is similar when
either Neoral or
Sandimmune is
administered.
Excretion:
Only 0.1% of a cyclosporine dose is excreted unchanged in the urine.
Elimination
is primarily
biliary with only 6%
of the dose (parent drug
and metabolites) excreted
in the
urine.
Neither dialysis nor renal failure alter cyclosporine clearance significantly.
Drug Interactions: (See PRECAUTIONS, Drug Interactions)
When diclofenac or
methotrexate
was co-administered with cyclosporine in rheumatoid arthritis patients, the AUC
of
diclofenac and methotrexate, each was significantly increased. (See
PRECAUTIONS, Drug
Interactions) No
clinically significant pharmacokinetic interactions
occurred between
cyclosporine
and aspirin, ketoprofen, piroxicam, or indomethacin.
Special Populations: Pediatric
Population: Pharmacokinetic data from pediatric
patients administered Neoral or Sandimmune
are very limited.
In 15 renal transplant
patients
aged 3-16 years, cyclosporine whole blood clearance after IV
administration of
Sandimmune
was 10.6±3.7 mL/min/kg (assay: Cyclo-trac specific RIA). In a study of 7 renal
transplant
patients aged 2-16, the cyclosporine clearance ranged from 9.8-15.5 mL/min/kg.
In
9
liver transplant patients aged 0.6-5.6 years, clearance was
9.3±5.4 mL/min/kg
(assay:
HPLC).
In
the pediatric population, Neoral
also demonstrates an
increased bioavailability as
compared to
Sandimmune. In 7 liver de
novo transplant patients aged 1.4-10 years, the
absolute
bioavailability of Neoral was 43% (range 30%-68%) and for Sandimmune in the
same
individuals absolute bioavailability was 28% (range 17%-42%).
Geriatric Population:
Comparison of single dose data from both normal elderly volunteers
(N=18,
mean age 69 years) and elderly rheumatoid arthritis patients (N=16, mean age
68
years) to single dose data in young adult volunteers (N=16, mean age 26 years)
showed no
significant
difference in the pharmacokinetic parameters.
CLINICAL TRIALS: Rheumatoid Arthritis: The effectiveness of Sandimmune and
Neoral in
the treatment of
severe rheumatoid arthritis
was evaluated in 5 clinical
studies
involving
a total of 728 cyclosporine treated patients and 273 placebo treated patients.
A
summary of the results is presented for the .responder. rates per treatment
group, with a
responder
being defined as a patient having completed the trial with a 20% improvement in
the
tender and the swollen joint count and a 20% improvement in 2 of 4 of
investigator global,
patient
global, disability, and erythrocyte sedimentation rates (ESR) for the Studies
651 and
652
and 3 of 5 of investigator global, patient global, disability, visual analog
pain, and ESR
for
Studies 2008, 654 and 302.
Study
651 enrolled 264 patients with active rheumatoid arthritis with at
least 20 involved
joints,
who had failed at least one major RA drug, using a 3:3:2 randomization to one
of the
following
three groups: (1) cyclosporine dosed at 2.5-5 mg/kg/day, (2) methotrexate at
7.5-15
mg/week, or (3) placebo. Treatment duration was 24 weeks. The mean cyclosporine
dose
at the last visit was 3.1 mg/kg/day. See Graph below.
Study
652 enrolled 250 patients with active RA with >6 active painful
or tender joints who
had
failed at least one major RA drug. Patients were randomized using a 3:3:2
randomization
to 1
of 3 treatment arms: (1) 1.5-5 mg/kg/day
of cyclosporine, (2)
2.5-5 mg/kg/day of
cyclosporine,
and (3) placebo. Treatment duration was 16 weeks. The mean cyclosporine dose
for
group 2 at the last visit was 2.92 mg/kg/day. See Graph below.
Study
2008 enrolled 144 patients with active RA and >6 active joints who had
unsuccessful
treatment
courses of aspirin and gold or Penicillamine. Patients were randomized to 1
of 2
treatment
groups (1) cyclosporine 2.5-5 mg/kg/day with adjustments after the first month
to
achieve
a target trough level and (2) placebo. Treatment duration was 24 weeks. The mean
cyclosporine
dose at the last visit was 3.63 mg/kg/day. See Graph below.
Study
654 enrolled 148 patients who remained with active joint counts of 6 or more
despite
treatment with
maximally tolerated methotrexate doses for at
least three months.
Patients
continued to
take their current
dose of methotrexate and were
randomized to receive, in
addition,
one of the following medications: (1) cyclosporine 2.5 mg/kg/day with
dose
increases
of 0.5 mg/kg/day at weeks 2 and 4 if there was no evidence of toxicity and
further
increases
of 0.5mg/kg/day at weeks 8 and 16 if a <30% decrease in active joint count
occurred
without any
significant toxicity; dose
decreases could be made at any
time for toxicity or
(2)
placebo. Treatment duration was 24 weeks. The mean cyclosporine dose at the
last visit
was
2.8 mg/kg/day (range: 1.3-4.1). See Graph below.
Study
302 enrolled 299 patients with severe active RA, 99% of whom were unresponsive
or
intolerant
to at least one prior major RA drug. Patients were randomized to 1 of 2
treatment
groups
(1) Neoral and (2) cyclosporine, both of which were started at 2.5 mg/kg/day
and
increased
after 4 weeks for inefficacy in increments of 0.5 mg/kg/day to a maximum of
5
mg/kg/day and decreased at any
time for toxicity.
Treatment duration was
24 weeks. The
mean
cyclosporine dose at the last visit was
2.91 mg/kg/day (range: 0.72-5.17)
for Neoral
and
3.27 mg/kg/day (range: 0.73-5.68) for cyclosporine. See Graph below.
INDICATIONS AND USAGE: Kidney, Liver, and Heart
Transplantation: Neoral is
indicated
for the prophylaxis of organ rejection in kidney, liver, and heart
allogeneic
transplants.
Neoral has been used in combination with azathioprine and corticosteroids.
Rheumatoid Arthritis:
Neoral is indicated for the treatment of patients with severe active,
rheumatoid
arthritis where the disease has not adequately responded to methotrexate.
Neoral
can be
used in combination
with methotrexate in
rheumatoid arthritis patients
who do not
respond
adequately to methotrexate alone.
Psoriasis:
Neoral is indicated for the treatment of adult, nonimmunocompromised
patients
with
severe (i.e., extensive and/or disabling), recalcitrant, plaque psoriasis who
have failed to
respond
to at least one systemic therapy (eg., PUVA, retinoids, or methotrexate) or in
patients
for
whom other systemic therapies are contraindicated, or cannot be tolerated.
While
rebound rarely occurs, most patients will experience relapse with Neoral as
with other
therapies
upon cessation of treatment.
CONTRAINDICATIONS:
General:
Neoral is contraindicated in patients
with a
hypersensitivity
to cyclosporine or to any of the ingredients of the formulation.
Rheumatoid Arthritis:
Rheumatoid arthritis patients with abnormal
renal function,
uncontrolled
hypertension, or malignancies should not receive Neoral.
Psoriasis:
Psoriasis patients who are treated with Neoral
should not receive concomitant
PUVA
or UVB therapy, methotrexate or other immunosuppressive agents, coal tar or
radiation
therapy.
Psoriasis patients with abnormal renal function, uncontrolled hypertension, or
malignancies
should not receive Neoral.
WARNINGS: (See
also Boxed WARNING)
All Patients:
Cyclosporine, the active ingredient
of
Neoral, can cause nephrotoxicity and hepatotoxicity. The risk increases
with increasing
doses
of cyclosporine. Renal dysfunction including structural kidney damage is
a potential
consequence
of Neoral and therefore renal function must be monitored during therapy. Care
should be taken in using
cyclosporine with nephrotoxic drugs. (See PRECAUTIONS)
Patients
receiving Neoral require frequent monitoring of serum creatinine. (See Special
Monitoring
under DOSAGE AND ADMINISTRATION) Elderly patients should be
monitored
with
particular care, since decreases in renal function also occur with age. If
patients are not
properly
monitored and doses are not properly adjusted,
cyclosporine therapy can be
associated
with the occurrence of structural kidney damage and persistent renal
dysfunction.
An
increase in serum creatinine and BUN may occur during Neoral therapy and
reflect a
reduction
in the glomerular filtration rate. Impaired renal function at any time requires
close
monitoring,
and frequent dosage adjustment may be indicated. The frequency and severity of
serum
creatinine elevations increase with dose and duration of cyclosporine therapy.
These
elevations
are likely to become more pronounced without dose reduction or discontinuation.
Because Neoral is not bioequivalent to
Sandimmune, conversion from Neoral to
Sandimmune using a 1:1 ratio (mg/kg/day)
may result in lower cyclosporine blood
concentrations. Conversion from
Neoral
to
Sandimmune
should be
made with
increased monitoring to avoid
the potential of underdosing.
Kidney, Liver, and Heart
Transplant: Cyclosporine, the active ingredient of Neoral,
can
cause
nephrotoxicity and hepatotoxicity when used in high doses. It is not unusual
for serum
creatinine
and BUN levels to be elevated during cyclosporine therapy. These
elevations in
renal
transplant patients do not necessarily indicate rejection, and each patient
must be fully
evaluated
before dosage adjustment is initiated.
Based
on the historical Sandimmune experience with oral solution, nephrotoxicity
associated
with
cyclosporine had been noted in 25% of cases of renal transplantation, 38% of
cases of
cardiac
transplantation, and 37% of cases of liver
transplantation. Mild nephrotoxicity was
generally
noted 2-3 months after renal transplant and consisted of an arrest in the fall
of the
pre-operative
elevations of BUN and creatinine at a range of 35-45 mg/dl and 2.0-2.5 mg/dl
respectively.
These elevations were often responsive to cyclosporine dosage reduction.
More
overt nephrotoxicity was seen early after transplantation and
was characterized by a
rapidly
rising BUN and creatinine. Since these events are similar to renal rejection
episodes,
care must
be taken to
differentiate between them. This
form of nephrotoxicity is usually
responsive
to cyclosporine dosage reduction.
Although
specific diagnostic criteria which reliably
differentiate renal graft
rejection from
drug
toxicity have not been found, a number of parameters have been significantly
associated
with one
or the other. It should
be noted however, that up to 20%
of patients may have
simultaneous
nephrotoxicity and rejection.
A form
of a cyclosporine-associated
nephropathy is characterized by serial deterioration in
renal
function and morphologic changes in the kidneys. From 5%-15% of transplant
recipients
who
have received cyclosporine will fail to show a reduction in rising serum
creatinine despite
a
decrease or discontinuation of cyclosporine therapy. Renal biopsies from these
patients will
demonstrate
one or several of the following alterations: tubular vacuolization, tubular
microcalcifications,
peritubular capillary congestion, arteriolopathy, and a striped form
of
interstitial
fibrosis with tubular atrophy. Though none of these morphologic changes is
entirely
specific,
a diagnosis of cyclosporine-associated structural nephrotoxicity requires
evidence of
these
findings.
When
considering the development of cyclosporine-associated nephropathy, it is
noteworthy
that
several authors have reported an association between the appearance of
interstitial fibrosis
and higher
cumulative doses or persistently
high circulating trough levels of cyclosporine.
This
is particularly true during the first 6 post-transplant months when the dosage
tends to be
highest
and when, in kidney recipients, the organ appears to be most vulnerable to the
toxic
effects of
cyclosporine. Among other
contributing factors to
the development of
interstitial
fibrosis in
these patients are
prolonged perfusion time,
warm ischemia time,
as well as
episodes of
acute toxicity, and acute and
chronic rejection. The reversibility of interstitial
fibrosis and
its correlation to
renal function have
not yet been
determined. Reversibility of
arteriolopathy
has been reported after stopping cyclosporine or lowering the dosage.
Impaired
renal function at any time requires close monitoring, and frequent dosage
adjustment
may
be indicated.
In
the event of severe and unremitting rejection, when rescue therapy with pulse
steroids and
monoclonal
antibodies fail to reverse the rejection episode, it may be preferable to
switch to
alternative
immunosuppressive therapy rather than increase the Neoral dose to excessive
levels.
Occasionally
patients have developed a syndrome of thrombocytopenia and microangiopathic
hemolytic
anemia which may result in graft failure. The vasculopathy can occur in the
absence
of
rejection and is accompanied by avid platelet consumption within the graft as
demonstrated
by
Indium 111 labeled platelet studies. Neither the pathogenesis nor the
management of this
syndrome
is clear. Though resolution has occurred
after reduction or
discontinuation of
cyclosporine
and 1) administration of streptokinase and heparin or 2) plasmapheresis, this
appears
to depend upon early detection with Indium 111 labeled platelet scans.
(See
ADVERSE REACTIONS
Significant
hyperkalemia (sometimes associated with hyperchloremic metabolic acidosis) and
hyperuricemia
have been seen occasionally in individual patients.
Hepatotoxicity
associated with cyclosporine use had been noted in 4% of cases of
renal
transplantation,
7% of cases of cardiac transplantation, and 4%
of cases of
liver
transplantation.
This was usually noted during the first month of therapy when high doses of
cyclosporine were
used and consisted
of elevations of
hepatic enzymes and
bilirubin. The
chemistry
elevations usually decreased with a reduction in dosage.
As
in patients receiving other immunosuppressants, those patients receiving
cyclosporine are
at
increased risk for development of lymphomas and other malignancies,
particularly those of
the skin.
The increased risk
appears related to
the intensity and
duration of
immunosuppression
rather than to the use of specific
agents. Because of
the danger of
oversuppression
of the immune system resulting in increased risk of infection or malignancy,
a
treatment regimen containing multiple immunosuppressants should be used with
caution.
There
have been reports of convulsions in adult and pediatric patients receiving
cyclosporine,
particularly
in combination with high dose methylprednisolone.
Encephalopathy has
been described both
in post-marketing reports
and in the literature.
Manifestations
include impaired consciousness, convulsions, visual disturbances (including
blindness),
loss of motor function, movement disorders and psychiatric disturbances. In
many
cases,
changes in the white matter have been detected using imaging techniques and
pathologic specimens.
Predisposing factors such as
hypertension, hypomagnesemia,
hypocholesterolemia, high-dose
corticosteroids, high
cyclosporine blood concentrations, and
graft-versus-host
disease have been noted in many but not all of the reported cases. The
changes
in most cases have been reversible upon discontinuation of cyclosporine, and in
some
cases
improvement was noted after reduction of dose. It appears that patients
receiving liver
transplant
are more susceptible to encephalopathy than those receiving kidney transplant.
Care
should be taken in using cyclosporine with nephrotoxic drugs. (See
PRECAUTIONS)
Rheumatoid Arthritis:
Cyclosporine nephropathy was detected in renal biopsies of 6 out of
60
(10%) rheumatoid arthritis patients after the average treatment duration of 19
months. Only
one
patient, out of these 6 patients, was treated with a dose ≤4
mg/kg/day. Serum creatinine
improved
in all but one patient after discontinuation of cyclosporine. The .maximal
creatinine
increase.
appears to be a factor in predicting cyclosporine nephropathy.
There
is a potential, as with other immunosuppressive agents, for an increase in the
occurrence
of
malignant lymphomas with cyclosporine. It is not clear whether the risk with
cyclosporine
is greater
than that in
Rheumatoid Arthritis patients
or in Rheumatoid Arthritis patients
on
cytotoxic
treatment for this indication. Five cases of lymphoma were detected: four in a
survey
of
approximately 2,300 patients treated with cyclosporine for rheumatoid
arthritis, and another
case
of lymphoma was reported in a clinical trial. Although other tumors (12 skin
cancers, 24
solid tumors
of diverse types,
and 1 multiple myeloma) were
also reported in
this survey,
epidemiologic
analyses did not support a relationship to cyclosporine other than for
malignant
lymphomas.
Patients
should be thoroughly evaluated before and during Neoral treatment for
the
development
of malignancies. Moreover, use of Neoral
therapy with other
immunosuppressive
agents may induce an excessive immunosuppression which is known to
increase
the risk of malignancy.
Psoriasis: (See also Boxed WARNINGS for Psoriasis)
Since cyclosporine is a potent
immunosuppressive agent
with a number of potentially
serious side effects, the risks and
benefits of using Neoral should be considered before
treatment of patients with psoriasis.
Cyclosporine,
the active ingredient in Neoral, can cause nephrotoxicity and hypertension (see
PRECAUTIONS)
and the risk increases with increasing dose and duration of therapy.
Patients
who may
be at increased risk such as those with abnormal renal function,
uncontrolled
hypertension
or malignancies, should not receive Neoral.
Renal
dysfunction is a potential consequence of Neoral therefore renal function must
be
monitored
during therapy.
Patients
receiving Neoral require frequent monitoring of serum creatinine. (See Special
Monitoring
under DOSAGE AND ADMINISTRATION) Elderly patients should be
monitored
with
particular care, since decreases in renal function also occur with age. If
patients are not
properly monitored
and doses are not properly adjusted, cyclosporine therapy can cause
structural
kidney damage and persistent renal dysfunction.
An
increase in serum creatinine and BUN may occur during Neoral therapy and reflects a
reduction
in the glomerular filtration rate.
Kidney
biopsies from 86 psoriasis patients treated for a mean duration of 23 months
with
1.2-7.6
mg/kg/day of cyclosporine showed evidence of cyclosporine nephropathy in
18/86
(21%) of the patients. The pathology consisted of renal tubular atrophy and
interstitial
fibrosis. On
repeat biopsy of
13 of these patients maintained on various dosages of
cyclosporine
for a mean of 2 additional years, the number with cyclosporine induced
nephropathy
rose to 26/86 (30%). The majority of patients
(19/26) were on a dose
of
≥5.0
mg/kg/day (the highest recommended dose is 4 mg/kg/day). The
patients were also
on
cyclosporine
for greater than 15 months (18/26) and/or had a clinically significant increase
in
serum
creatinine for greater than 1 month (21/26). Creatinine levels returned to
normal range
in 7
of 11 patients in whom cyclosporine therapy was discontinued.
There
is an increased risk for the development of skin and lymphoproliferative
malignancies
in
cyclosporine-treated psoriasis patients. The relative risk of malignancies is comparable to
that
observed in psoriasis patients treated with other immunosuppressive agents.
Tumors were
reported in 32 (2.2%) of 1439 psoriasis patients treated with
cyclosporine
worldwide from
clinical trials. Additional
tumors have been
reported in 7
patients in
cyclosporine
postmarketing experience. Skin malignancies were reported in 16 (1.1%) of these
patients;
all but 2 of them had previously received PUVA therapy. Methotrexate was
received
by 7
patients. UVB and coal tar had been used by 2 and 3 patients, respectively.
Seven patients
had
either a history of previous skin cancer or a potentially predisposing lesion
was present
prior to cyclosporine exposure. Of the 16 patients
with skin cancer, 11 patients had 18
squamous
cell carcinomas and 7 patients had 10 basal cell carcinomas.
There
were two lymphoproliferative malignancies; one case of non-Hodgkin.s lymphoma
which
required chemotherapy, and one case of
mycosis fungoides which
regressed
spontaneously
upon discontinuation of cyclosporine. There were four cases of benign
lymphocytic
infiltration: 3 regressed spontaneously upon discontinuation of
cyclosporine,
while
the fourth regressed despite continuation of the drug. The remainder of the
malignancies,
13 cases (0.9%), involved various organs.
Patients should not be treated
concurrently with cyclosporine and PUVA or UVB, other
radiation therapy, or other
immunosuppressive agents, because of the possibility of
excessive immunosuppression and
the subsequent risk of malignancies. (See
CONTRAINDICATIONS Patients should also be warned to protect
themselves appropriately
when
in the sun, and to avoid excessive sun exposure. Patients should be thoroughly
evaluated
before and
during treatment for
the presence of
malignancies remembering that
malignant
lesions
may be hidden by psoriatic plaques. Skin lesions not typical of psoriasis
should be
biopsied
before starting treatment. Patients should be treated with Neoral only after
complete
resolution
of suspicious lesions, and only if there are no other treatment options.
(See Special
Monitoring
for Psoriasis Patients)
PRECAUTIONS: General: Hypertension: Cyclosporine is the active
ingredient of
Neoral.
Hypertension is a common side effect of cyclosporine therapy which may
persist.
(See
ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION for monitoring
recommendations)
Mild or moderate hypertension is encountered more frequently than
severe
hypertension
and the incidence decreases
over time. In recipients of
kidney, liver, and heart
allografts
treated with cyclosporine, antihypertensive therapy may be required. (See Special
Monitoring
of Rheumatoid Arthritis and Psoriasis Patients) However,
since cyclosporine may
cause
hyperkalemia, potassium-sparing diuretics should not be used. While calcium
antagonists
can be effective agents in treating cyclosporine-associated hypertension, they
can
interfere
with cyclosporine metabolism. (See Drug Interactions)
Vaccination:
During treatment with cyclosporine, vaccination may be less effective; and the
use
of live attenuated vaccines should be avoided.
Special Monitoring of Rheumatoid
Arthritis Patients: Before
initiating treatment, a
careful
physical examination, including blood pressure measurements (on
at least two
occasions)
and two creatinine levels to estimate baseline should be performed. Blood
pressure
and
serum creatinine should be evaluated every 2 weeks during the initial 3 months
and then
monthly
if the patient is stable. It is advisable to monitor serum creatinine and blood
pressure
always
after an increase of the dose of nonsteroidal anti-inflammatory drugs and
after
initiation
of new nonsteroidal anti-inflammatory drug therapy during Neoral treatment.
If
co-administered with
methotrexate, CBC and
liver function tests
are recommended to
be
monitored
monthly. (See also PRECAUTIONS, General, Hypertension)
In
patients who are receiving cyclosporine, the dose of Neoral should be decreased by
25%-50%
if hypertension occurs. If hypertension persists, the dose of
Neoral should be
further
reduced or blood pressure should be controlled with antihypertensive agents. In
most
cases,
blood pressure has returned to baseline when cyclosporine was discontinued.
In
placebo-controlled trials of rheumatoid arthritis patients, systolic
hypertension (defined as
an
occurrence of two systolic blood pressure readings >140mmHg) and diastolic
hypertension
(defined
as two diastolic blood pressure readings >90 mmHg) occurred in 33% and 19%
of
patients
treated with cyclosporine, respectively. The corresponding placebo rates were
22%
and
8%.
Special Monitoring for Psoriasis
Patients:
Before initiating treatment,
a careful
dermatological
and physical examination, including blood pressure measurements (on at least
two
occasions) should be performed. Since Neoral is an immunosuppressive agent,
patients
should
be evaluated for the presence of occult infection on their first physical
examination and
for
the presence of tumors initially, and throughout treatment with Neoral. Skin
lesions not
typical
for psoriasis should be biopsied
before starting Neoral.
Patients with malignant
or
premalignant
changes of the skin should be treated with Neoral only after appropriate
treatment
of such lesions and if no other treatment option exists.
Baseline
laboratories should include serum creatinine (on two occasions), BUN, CBC,
serum
magnesium,
potassium, uric acid, and lipids.
The
risk of cyclosporine nephropathy is reduced when the starting dose is
low
(2.5
mg/kg/day), the maximum
dose does not exceed 4.0 mg/kg/day, serum creatinine
is
monitored
regularly while cyclosporine is administered, and the dose of Neoral is
decreased
when the rise in creatinine is greater than or
equal to 25% above the patients pretreatment
level.
The increase in creatinine is generally reversible upon timely decrease of
the dose of
Neoral
or its discontinuation.
Serum
creatinine and BUN should be evaluated every 2 weeks during the initial 3
months of
therapy
and then monthly if the patient is stable. If the serum creatinine is greater
than or equal
to
25% above the patient.s pretreatment level, serum creatinine should be repeated
within two
weeks.
If the change in serum creatinine remains greater than or equal to 25% above
baseline,
Neoral
should be reduced by 25%-50%. If
at any time the
serum creatinine increases by
greater than
or equal to 50% above pretreatment level, Neoral
should be reduced by
25%-50%.
Neoral should be discontinued if reversibility (within 25% of baseline) of
serum
creatinine
is not achievable after two dosage modifications. It is advisable to monitor
serum
creatinine
after an increase of the dose of nonsteroidal anti-inflammatory drug and
after
initiation
of new nonsteroidal anti-inflammatory therapy during Neoral treatment.
Blood
pressure should be evaluated every 2 weeks during the initial 3 months of
therapy and
then
monthly if the patient is stable, or more frequently when dosage adjustments
are made.
Patients
without a history of previous hypertension before initiation of treatment with
Neoral,
should
have the drug reduced by 25%-50% if found to have sustained hypertension. If
the
patient continues
to be hypertensive despite multiple
reductions of Neoral, then Neoral
should
be discontinued. For patients with treated hypertension, before the initiation
of Neoral
therapy, their
medication should be adjusted to
control hypertension while on Neoral.
Neoral
should be discontinued if a change in hypertension management is not effective
or
tolerable.
CBC,
uric acid, potassium, lipids, and magnesium should also be monitored every 2
weeks for
the
first 3 months of therapy, and then monthly if the patient is stable or more
frequently when
dosage
adjustments are made. Neoral dosage should be reduced by 25%-50% for any
abnormality
of clinical concern.
In
controlled trials of cyclosporine in psoriasis patients, cyclosporine blood
concentrations did
not
correlate well with either improvement or with side effects such as renal
dysfunction.
Information for Patients:
Patients should be advised that any change of cyclosporine
formulation should be made
cautiously and only under physician supervision because it
may result in the need for a
change in dosage.
Patients should
be informed of
the necessity of repeated
laboratory tests while they are
receiving
cyclosporine. Patients should be advised of the potential risks during
pregnancy and
informed
of the increased risk of neoplasia. Patients should also be
informed of the
risk of
hypertension
and renal dysfunction.
Patients
should be advised that during treatment with cyclosporine, vaccination may
be less
effective
and the use of live attenuated vaccines should be avoided.
Patients
should be given careful dosage instructions. Neoral Oral Solution (cyclosporine
oral
solution,
USP) MODIFIED should be diluted, preferably with orange or apple juice that is
at
room
temperature. The combination of Neoral
Oral Solution (cyclosporine oral solution,
USP)
MODIFIED with milk can be unpalatable.
Patients
should be advised to take Neoral on a consistent schedule with regard to time
of day
and relation
to meals. Grapefruit
and grapefruit juice
affect metabolism, increasing
blood
concentration
of cyclosporine, thus should be avoided.
Laboratory Tests: In
all patients treated with cyclosporine, renal and liver functions should
be
assessed repeatedly by measurement of serum creatinine, BUN, serum bilirubin,
and liver
enzymes. Serum
lipids, magnesium, and
potassium should also
be monitored. Cyclosporine
blood
concentrations should be routinely monitored in transplant patients (see
DOSAGE AND
ADMINISTRATION,
Blood Concentration Monitoring in Transplant Patients),
and
periodically
monitored in rheumatoid arthritis patients.
Drug Interactions: All
of the individual drugs cited below are well substantiated to interact
with
cyclosporine. In addition, concomitant non-steroidal anti-inflammatory drugs,
particularly
in the setting of dehydration, may potentiate renal dysfunction.
Drugs That May Potentiate Renal
Dysfunction
Drugs That Alter Cyclosporine
Concentrations: Compounds that
decrease
cyclosporine
absorption such as orlistat should be avoided. Cyclosporine is extensively
metabolized
cytochrome P-450 3A. Substances that inhibit this enzyme could decrease
metabolism and
increase cyclosporine concentrations. Substances that are inducers
of
cytochrome P-450
activity could increase metabolism and decrease cyclosporine
concentrations.
Monitoring of circulating cyclosporine concentrations and appropriate Neoral
dosage adjustment
are essential when
these drugs are
used concomitantly. (See Blood
Concentration
Monitoring)
Drugs That Increase Cyclosporine
Concentrations
The
HIV protease inhibitors (e.g., indinavir, nelfinavir, ritonavir, and
saquinavir) are known to
inhibit cytochrome
P-450 3A and thus could
potentially increase the concentrations of
cyclosporine,
however no formal studies of the interaction are available. Care should
be
exercised
when these drugs are administered concomitantly.
Grapefruit
and grapefruit juice affect metabolism, increasing blood concentrations of
cyclosporine,
thus should be avoided.
Drugs/Dietary Supplements That
Decrease Cyclosporine Concentrations
There have been reports of a
serious drug interaction between cyclosporine and the
herbal dietary supplement, St.
John’s Wort. This interaction has been reported to
produce a marked reduction in
the blood concentrations of cyclosporine, resulting in
subtherapeutic levels, rejection
of transplanted organs, and graft loss.
Rifabutin
is known to increase the metabolism of other drugs metabolized by the
cytochrome
P-450
system. The interaction between rifabutin and cyclosporine has not been
studied. Care
should
be exercised when these two drugs are administered concomitantly.
Nonsteroidal Anti-inflammatory
Drug (NSAID) Interactions: Clinical status and
serum
creatinine should be closely monitored when cyclosporine is used with nonsteroidal
anti-inflammatory
agents in rheumatoid arthritis patients. (See WARNINGS)
Pharmacodynamic
interactions have been reported to occur between cyclosporine and
both
naproxen
and sulindac, in that concomitant use is associated with additive decreases in
renal
function,
as determined by 99 mTc-diethylenetriaminepentaacetic acid
(DTPA) and
(p-aminohippuric acid)
PAH clearances. Although concomitant administration of diclofenac
does
not affect blood levels of cyclosporine, it has been associated with
approximate doubling
of
diclofenac blood levels and occasional reports of reversible decreases in
renal function.
Consequently,
the dose of diclofenac should be in the lower end of the therapeutic range.
Methotrexate Interaction: Preliminary
data indicate that
when methotrexate and
cyclosporine were
co-administered to rheumatoid
arthritis patients (N=20),
methotrexate
concentrations
(AUCs) were increased approximately 30% and the concentrations (AUCs) of
its metabolite,
7-hydroxy methotrexate,
were decreased by
approximately 80%. The clinical
significance of
this interaction is
not known. Cyclosporine concentrations do not appear to
have
been altered (N=6).
Other Drug Interactions:
Reduced clearance of prednisolone, digoxin, and lovastatin has
been
observed when these drugs are administered with cyclosporine. In addition, a
decrease in
the apparent
volume of distribution of
digoxin has been reported after cyclosporine
administration.
Severe digitalis toxicity has been seen within days of starting cyclosporine in
several
patients taking digoxin. Cyclosporine should not be used with potassium-sparing
diuretics
because hyperkalemia can occur.
During
treatment with cyclosporine, vaccination may be less effective. The use of
live
vaccines
should be avoided. Myositis has occurred
with concomitant lovastatin,
frequent
gingival
hyperplasia with nifedipine, and convulsions with high dose methylprednisolone.
Psoriasis
patients receiving other immunosuppressive agents or radiation therapy
(including
PUVA
and UVB) should not receive concurrent cyclosporine because of the possibility
of
excessive
immunosuppression.
For
additional information on Cyclosporine Drug Interactions please contact
Novartis Medical
Affairs
Department at 888-NOW-NOVA [888-669-6682].
Carcinogenesis, Mutagenesis, and
Impairment of Fertility: Carcinogenicity studies
were
carried out in male and female rats and mice. In the 78-week mouse study,
evidence of a
statistically
significant trend was found for lymphocytic
lymphomas in females,
and the
incidence
of hepatocellular carcinomas in mid-dose males significantly exceeded the
control
value. In
the 24-month rat
study, pancreatic islet
cell adenomas significantly exceeded the
control
rate in the low dose level. Doses used in the mouse and rat studies were 0.01
to 0.16
times
the clinical maintenance dose (6 mg/kg). The hepatocellular carcinomas and
pancreatic
islet cell adenomas were not dose related.
Published reports indicate that co-treatment of
hairless mice
with UV irradiation and cyclosporine or other
immunosuppressive agents
shorten
the time to skin tumor formation compared to UV irradiation alone.
Cyclosporine
was not mutagenic in appropriate test systems. Cyclosporine has not been found
to
be mutagenic/genotoxic in the Ames Test, the V79-HGPRT Test, the micronucleus
test in
mice
and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone-
marrow, the
mouse dominant lethal
assay, and the
DNA-repair test in
sperm from treated
mice.
A recent study analyzing sister chromatid exchange (SCE) induction by
cyclosporine
using
human lymphocytes in vitro gave indication of a positive effect (i.e.,
induction of SCE),
at
high concentrations in this system.
No
impairment in fertility was demonstrated in studies in male and female rats.
Widely distributed
papillomatosis of the
skin was observed
after chronic treatment
of dogs
with
cyclosporine at 9 times the human initial psoriasis treatment dose of
2.5 mg/kg, where
doses
are expressed on a body surface area basis. This papillomatosis showed a
spontaneous
regression
upon discontinuation of cyclosporine.
An
increased incidence of malignancy is a recognized complication of
immunosuppression in
recipients
of organ transplants and patients with rheumatoid arthritis and psoriasis. The
most
common
forms of neoplasms are non-Hodgkin.s lymphoma and carcinomas of the skin. The
risk
of malignancies in cyclosporine recipients is higher than in the normal,
healthy population
but
similar to that in patients receiving other immunosuppressive therapies.
Reduction or
discontinuance
of immunosuppression may cause the lesions to regress.
In psoriasis patients on cyclosporine,
development of malignancies, especially those of the
skin
has been reported. (See WARNINGS) Skin
lesions not typical
for psoriasis should
be
biopsied before
starting cyclosporine treatment. Patients with malignant or
premalignant
changes of the skin should be treated with
cyclosporine only after appropriate treatment of
such
lesions and if no other treatment option exists.
Pregnancy: Pregnancy Category
C. Cyclosporine was not teratogenic in appropriate
test
systems.
Only at dose levels toxic to dams, were adverse effects seen in reproduction
studies
in
rats. Cyclosporine has been shown to be embryo- and fetotoxic in rats and
rabbits following
oral
administration at maternally toxic doses. Fetal toxicity was noted in rats at
0.8 and rabbits
at
5.4 times the transplant doses in humans of 6.0 mg/kg, where dose corrections
are based on
body
surface area. Cyclosporine was embryo- and fetotoxic as indicated by increased
pre- and
postnatal
mortality and reduced fetal weight together with related skeletal retardation.
There
are no adequate and well-controlled studies in pregnant women. Neoral should be
used
during
pregnancy only if the potential benefit justifies the potential risk to the
fetus.
The
following data represent the reported outcomes of 116 pregnancies in women receiving
cyclosporine
during pregnancy, 90% of whom were transplant patients, and
most of whom
received
cyclosporine throughout the entire gestational period. The only consistent
patterns of
abnormality
were premature birth (gestational period of 28 to 36 weeks) and low birth
weight
for
gestational age. Sixteen fetal losses occurred. Most of the pregnancies (85
of 100) were
complicated by
disorders; including, pre-eclampsia, eclampsia, premature labor,
abruptio
placentae, oligohydramnios, Rh incompatibility, and
fetoplacental dysfunction. Pre-term
delivery occurred in 47%. Seven malformations were
reported in 5 viable infants and in
2
cases of fetal loss. Twenty-eight percent of the
infants were small
for gestational age.
Neonatal
complications occurred in 27%. Therefore, the risks and benefits of
using Neoral
during
pregnancy should be carefully weighed.
Because
of the possible disruption of maternal-fetal interaction, the risk/benefit
ratio of using
Neoral in
psoriasis patients during
pregnancy should carefully be weighed with serious
consideration
for discontinuation of Neoral.
Nursing Mothers:
Since cyclosporine is excreted in human milk, breast-feeding should be
avoided.
Pediatric Use:
Although no adequate and well-controlled studies have been completed in
children, transplant
recipients as young as one year of age have received
Neoral with no
unusual
adverse effects. The safety and efficacy of Neoral treatment in children with
juvenile
rheumatoid
arthritis or psoriasis below the age of 18 have not been established.
Geriatric Use: In rheumatoid arthritis clinical trials with
cyclosporine, 17.5% of patients
were
age 65 or older. These patients were more likely to develop systolic
hypertension on
therapy, and
more likely to
show serum creatinine rises ≥50% above the baseline after 3-4
months
of therapy.
ADVERSE REACTIONS: Kidney, Liver, and Heart Transplantation: The
principal
adverse
reactions of cyclosporine therapy are
renal dysfunction, tremor,
hirsutism,
hypertension,
and gum hyperplasia.
Hypertension,
which is usually mild to moderate, may occur in approximately 50% of patients
following
renal transplantation and in most cardiac transplant patients.
Glomerular
capillary thrombosis has been found in patients treated with cyclosporine and
may
progress to
graft failure. The
pathologic changes resembled
those seen in
the hemolytic-
uremic
syndrome and included thrombosis of the renal microvasculature, with
platelet-fibrin
thrombi
occluding glomerular capillaries and
afferent arterioles, microangiopathic hemolytic
anemia,
thrombocytopenia, and decreased renal function. Similar findings have been
observed
when
other immunosuppressives have been employed post-transplantation.
Hypomagnesemia
has been reported in some, but not all, patients exhibiting convulsions while
on cyclosporine therapy. Although
magnesium-depletion studies in normal subjects suggest
that hypomagnesemia is associated with
neurologic disorders, multiple
factors, including
hypertension,
high dose methylprednisolone, hypocholesterolemia, and nephrotoxicity
associated with
high plasma concentrations of cyclosporine appear to be related to the
neurological
manifestations of cyclosporine toxicity.
In
controlled studies, the nature, severity, and incidence of
the adverse events
that were
observed in 493 transplanted patients treated with
Neoral were comparable with those
observed
in 208 transplanted patients who received Sandimmune in these same studies when
the
dosage of the two drugs was adjusted to achieve the same cyclosporine blood
trough
concentrations.
Based
on the historical experience with Sandimmune, the following reactions occurred
in 3%
or
greater of 892 patients involved in clinical trials of kidney, heart, and liver
transplants.
Among
705 kidney transplant patients treated with cyclosporine oral solution
(Sandimmune)
in
clinical trials, the reason for treatment
discontinuation was renal toxicity in 5.4%, infection
in
0.9%, lack of efficacy in
1.4%, acute tubular necrosis in
1.0%, lymphoproliferative
disorders
in 0.3%, hypertension in 0.3%, and other reasons in 0.7% of the patients.
The
following reactions occurred in 2% or
less of Sandimmune-treated patients: allergic
reactions, anemia,
anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails,
gastritis, hearing
loss, hiccups, hyperglycemia, muscle pain,
peptic ulcer, thrombocytopenia,
tinnitus.
The following
reactions occurred rarely: anxiety, chest pain, constipation,
depression, hair
breaking, hematuria, joint pain, lethargy, mouth
sores, myocardial infarction, night sweats,
pancreatitis,
pruritus, swallowing difficulty, tingling, upper GI bleeding, visual disturbance,
weakness,
weight loss.
Rheumatoid Arthritis: The
principal adverse reactions associated with the use of
cyclosporine
in rheumatoid arthritis are renal dysfunction (see WARNINGS),
hypertension (see
PRECAUTIONS),
headache, gastrointestinal disturbances, and hirsutism/hypertrichosis.
In
rheumatoid arthritis patients treated in clinical trials within the recommended
dose range,
cyclosporine
therapy was discontinued in 5.3% of the patients because of hypertension and in
7%
of the patients because of increased creatinine. These changes are usually
reversible with
timely
dose decrease or drug discontinuation. The frequency and severity of serum
creatinine
elevations
increase with dose and duration of cyclosporine therapy. These elevations are
likely
to
become more pronounced without dose reduction or discontinuation.
The
following adverse events occurred in controlled clinical trials:
In
addition, the following adverse events have been reported in 1% to <3% of
the rheumatoid
arthritis
patients in the cyclosporine treatment group in controlled clinical trials.
Autonomic Nervous System: dry
mouth, increased sweating;
Body as a Whole:
allergy, asthenia, hot flushes, malaise, overdose, procedure NOS*, tumor
NOS*,
weight decrease, weight increase;
Cardiovascular: abnormal
heart sounds, cardiac failure, myocardial
infarction, peripheral
ischemia;
Central and Peripheral Nervous
System: hypoesthesia, neuropathy, vertigo;
Endocrine: goiter;
Gastrointestinal: constipation,
dysphagia, enanthema, eructation, esophagitis, gastric ulcer,
gastritis,
gastroenteritis, gingival bleeding, glossitis, peptic ulcer, salivary gland
enlargement,
tongue
disorder, tooth disorder;
Infection: abscess,
bacterial infection, cellulitis, folliculitis, fungal infection, herpes
simplex,
herpes
zoster, renal abscess, moniliasis, tonsillitis, viral infection;
Hematologic: anemia,
epistaxis, leukopenia, lymphadenopathy;
Liver and Biliary System:
bilirubinemia;
Metabolic and Nutritional:
diabetes mellitus, hyperkalemia, hyperuricemia, hypoglycemia;
Musculoskeletal System: arthralgia,
bone fracture, bursitis, joint dislocation, myalgia,
stiffness,
synovial cyst, tendon disorder;
Neoplasms: breast
fibroadenosis, carcinoma;
Psychiatric: anxiety,
confusion, decreased libido, emotional lability, impaired concentration,
increased
libido, nervousness, paroniria, somnolence;
Reproductive (Female):
breast pain, uterine hemorrhage;
Respiratory System:
abnormal chest sounds, bronchospasm;
Skin and Appendages:
abnormal pigmentation, angioedema, dermatitis, dry skin, eczema,
nail
disorder, pruritus, skin disorder, urticaria;
Special Senses:
abnormal vision, cataract, conjunctivitis, deafness, eye pain, taste
perversion,
tinnitus, vestibular disorder;
Urinary System:
abnormal urine, hematuria, increased BUN, micturition urgency, nocturia,
polyuria,
pyelonephritis, urinary incontinence.
*NOS
= Not Otherwise Specified.
Psoriasis: The
principal adverse reactions associated with the use of cyclosporine in patients
with psoriasis
are renal dysfunction, headache, hypertension, hypertriglyceridemia,
hirsutism/hypertrichosis,
paresthesia or hyperesthesia,
influenza-like symptoms,
nausea/vomiting,
diarrhea, abdominal discomfort, lethargy, and musculoskeletal or joint pain.
In psoriasis
patients treated in
US controlled clinical
studies within the
recommended dose
range,
cyclosporine therapy was discontinued in 1.0% of the patients because of
hypertension
and
in 5.4% of the patients because of increased creatinine. In the majority of
cases, these
changes
were reversible after dose reduction or discontinuation of cyclosporine.
There has
been one reported
death associated with the use of cyclosporine in psoriasis. A
27-year-old male
developed renal deterioration
and was continued on cyclosporine. He had
progressive
renal failure leading to death.
Frequency
and severity of serum creatinine increases with dose and duration of
cyclosporine
therapy.
These elevations are likely to become more pronounced and may result in
irreversible
renal
damage without dose reduction or discontinuation.
The following
events occurred in
1% to less than 3%
of psoriasis patients
treated with
cyclosporine:
Body as a Whole:
fever, flushes, hot flushes; Cardiovascular: chest pain; Central and
Peripheral Nervous System:
appetite increased, insomnia, dizziness, nervousness,
vertigo;
Gastrointestinal:
abdominal distention, constipation, gingival bleeding; Liver and
Biliary System: hyperbilirubinemia; Neoplasms: skin malignancies
[squamous cell
(0.9%)
and basal cell (0.4%) carcinomas]; Reticuloendothelial:
platelet, bleeding, and
clotting
disorders, red blood cell disorder; Respiratory: infection, viral and other
infection;
Skin and Appendages: acne,
folliculitis, keratosis, pruritus,
rash, dry skin;
Urinary
System:
micturition frequency; Vision:
abnormal vision.
Mild
hypomagnesemia and hyperkalemia may occur but are asymptomatic. Increases
in uric
acid
may occur and attacks of gout have been rarely reported. A minor and
dose related
hyperbilirubinemia
has been observed in the absence of hepatocellular damage. Cyclosporine
therapy
may be associated with a modest increase of serum triglycerides or cholesterol.
Elevations
of triglycerides (>750 mg/dL) occur in about 15% of psoriasis patients;
elevations
of
cholesterol (>300mg/dL) are observed in less than 3% of psoriasis patients.
Generally these
laboratory
abnormalities are reversible upon dose
reduction or discontinuation of
cyclosporine.
OVERDOSAGE:
There is a minimal experience with
cyclosporine overdosage. Forced
emesis
can be of value up to 2 hours after administration of Neoral. Transient
hepatotoxicity
and
nephrotoxicity may occur which should resolve following drug
withdrawal. General
supportive
measures and symptomatic treatment should be followed in all cases of
overdosage.
Cyclosporine is not dialyzable to any great extent, nor is it
cleared well by
charcoal
hemoperfusion. The oral dosage at which half of experimental animals are
estimated
to
die is 31 times, 39 times, and >54 times the human maintenance dose for
transplant patients
(6mg/kg;
corrections based on body surface area) in mice, rats, and rabbits.
DOSAGE AND ADMINISTRATION:
Neoral
Soft Gelatin
Capsules (cyclosporine
capsules, USP) MODIFIED and
Neoral
Oral
Solution (cyclosporine oral solution, USP)
MODIFIED
Neoral has increased bioavailability in
comparison to Sandimmune. Neoral and
Sandimmune are not bioequivalent and cannot
be used interchangeably without
physician supervision.
The
daily dose of Neoral should always be given in two divided doses (BID). It is
recommended
that Neoral be administered on a
consistent schedule with
regard to time
of
day
and relation to meals. Grapefruit and grapefruit juice affect metabolism,
increasing blood
concentration
of cyclosporine, thus should be avoided.
Newly Transplanted Patients: The
initial oral dose of Neoral can be given 4-12 hours
prior to
transplantation or be
given postoperatively. The
initial dose of
Neoral varies
depending
on the transplanted organ and the other immunosuppressive agents included in
the
immunosuppressive
protocol. In newly transplanted patients, the initial oral dose of Neoral is
the
same as the initial oral dose of Sandimmune. Suggested initial doses are
available from
the
results of a 1994 survey of the use of Sandimmune in US transplant centers. The
mean ±
SD
initial doses were 9±3 mg/kg/day for renal transplant patients (75 centers),
8±4mg/kg/day
for
liver transplant patients (30 centers), and 7±3 mg/kg/day for heart
transplant patients
(24
centers). Total daily doses were divided into two equal daily doses. The Neoral
dose is
subsequently
adjusted to achieve a pre-defined cyclosporine blood concentration. (See
Blood
Concentration
Monitoring in Transplant Patients, below) If cyclosporine trough
blood
concentrations
are used, the target range is the same for Neoral as for Sandimmune. Using
the
same trough concentration target range for Neoral as for Sandimmune results in
greater
cyclosporine
exposure when Neoral is administered. (See Pharmacokinetics, Absorption)
Dosing should be titrated based on clinical
assessments of rejection and tolerability. Lower
Neoral
doses may be sufficient as maintenance therapy.
Adjunct therapy
with adrenal corticosteroids is recommended initially.
Different tapering
dosage schedules
of prednisone appear
to achieve similar
results. A representative dosage
schedule
based on the patient.s weight started with 2.0 mg/kg/day for the first 4 days
tapered
to
1.0 mg/kg/day by 1 week, 0.6 mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1
month, and
0.15
mg/kg/day by 2 months and thereafter as a maintenance dose. Steroid doses may
be
further
tapered on an individualized basis depending on status of patient and function
of graft.
Adjustments
in dosage of prednisone must be made according to the clinical situation.
Conversion from Sandimmune to Neoral in Transplant Patients: In
transplanted
patients
who are considered for conversion to Neoral from Sandimmune, Neoral should be
started with
the same daily
dose as was
previously used with
Sandimmune (1:1 dose
conversion).
The Neoral dose should subsequently be adjusted to attain the
pre-conversion
cyclosporine
blood trough concentration. Using the same trough concentration target range
for
Neoral
as for Sandimmune results in greater cyclosporine exposure when Neoral is
administered.
(See Pharmacokinetics, Absorption) Patients with suspected poor
absorption of
Sandimmune
require different dosing strategies. (See
Transplant Patients with Poor
Absorption
of Sandimmune, below) In some patients, the increase in blood trough
concentration
is more pronounced and may be of clinical significance.
Until the blood trough
concentration attains the pre-conversion value, it is strongly
recommended that the cyclosporine
blood trough concentration be monitored every 4 to
7 days after conversion to
Neoral. In addition, clinical safety parameters such as
serum
creatinine and
blood pressure should be monitored every two weeks during
the first two
months after
conversion. If the blood trough concentrations are outside the desired
range
and/or
if the clinical safety parameters
worsen, the dosage
of Neoral must
be adjusted
accordingly.
Transplant Patients with Poor
Absorption of Sandimmune:
Patients with lower
than
expected cyclosporine blood trough concentrations in relation to the
oral dose of
Sandimmune
may have poor or inconsistent absorption of cyclosporine from Sandimmune.
After
conversion to Neoral, patients tend to have higher cyclosporine concentrations.
Due to
the increase in bioavailability
of cyclosporine following conversion to Neoral, the
cyclosporine blood trough
concentration may exceed the target range. Particular caution
should be exercised when
converting patients to Neoral at doses greater than
10 mg/kg/day. The
dose of Neoral should be titrated individually based on cyclosporine
trough
concentrations, tolerability, and clinical response. In this population
the cyclosporine
blood
trough concentration should be measured more frequently, at least twice a week
(daily,
if initial
dose exceeds 10 mg/kg/day) until the concentration
stabilizes within the desired
range.
Rheumatoid Arthritis: The
initial dose of Neoral is 2.5 mg/kg/day, taken twice daily as a
divided (BID)
oral dose. Salicylates, nonsteroidal anti-inflammatory agents, and oral
corticosteroids
may be continued. (See WARNINGS and PRECAUTIONS: Drug Interactions)
Onset
of action generally occurs between 4 and 8 weeks. If insufficient clinical
benefit is seen
and
tolerability is good (including serum creatinine less than 30% above
baseline), the dose
may
be increased by 0.5-0.75 mg/kg/day after 8 weeks and again after 12
weeks to a
maximum
of 4 mg/kg/day. If no benefit is seen by 16 weeks of therapy, Neoral therapy
should
be discontinued.
Dose decreases
by 25%-50% should be made at any time to control adverse events,
e.g.,
hypertension elevations in serum creatinine (30% above patient.s pretreatment
level) or
clinically
significant laboratory abnormalities. (See WARNINGS and PRECAUTIONS)
If
dose reduction is not effective in controlling abnormalities or if the
adverse event or
abnormality
is severe, Neoral should be discontinued. The same initial dose and dosage
range
should
be used if Neoral is combined
with the recommended
dose of methotrexate. Most
patients
can be treated with Neoral doses of 3
mg/kg/day or below when combined with
methotrexate
doses of up to 15 mg/week. (See CLINICALPHARMACOLOGY, Clinical Trials)
There
is limited long-term treatment data. Recurrence of rheumatoid arthritis disease
activity
is
generally apparent within 4 weeks after stopping cyclosporine.
Psoriasis: The
initial dose of
Neoral should be 2.5 mg/kg/day. Neoral should be taken
twice
daily, as a divided (1.25 mg/kg BID) oral dose. Patients should be kept at that
dose for at
least
4 weeks, barring adverse events. If significant clinical improvement has not
occurred in
patients
by that time, the patient.s dosage should be increased at 2 week intervals.
Based on
patient
response, dose increases of approximately 0.5 mg/kg/day should be made
to a
maximum
of 4.0 mg/kg/day.
Dose decreases
by 25%-50% should be made at any time to control adverse events,
e.g.,
hypertension, elevations in serum
creatinine (≥25%
above the patient.s pretreatment
level), or
clinically significant laboratory abnormalities. If dose reduction
is not effective in
controlling
abnormalities, or if the adverse event or abnormality is severe, Neoral should
be
discontinued.
(See Special Monitoring of Psoriasis Patients)
Patients generally
show some improvement
in the clinical
manifestations of psoriasis
in
2
weeks. Satisfactory control and stabilization of the disease may take 12-16
weeks to achieve.
Results
of a dose-titration clinical trial with Neoral indicate that an improvement of
psoriasis
by
75% or more (based on PASI) was achieved in 51% of the patients after 8 weeks
and in
79%
of the patients after 12 weeks. Treatment should be discontinued if
satisfactory response
cannot
be achieved after 6 weeks at 4 mg/kg/day or the patient.s maximum
tolerated dose.
Once
a patient is adequately controlled and appears stable the dose of
Neoral should be
lowered,
and the patient treated with the lowest dose that maintains an adequate
response (this
should
not necessarily be total clearing of the patient). In clinical trials,
cyclosporine doses at
the
lower end of the recommended dosage range were effective in maintaining a
satisfactory
response
in 60% of the patients. Doses below 2.5 mg/kg/day may also be equally
effective.
Upon
stopping treatment with cyclosporine, relapse will occur in approximately 6
weeks (50%
of
the patients) to 16 weeks (75% of the patients). In the majority of patients
rebound does not
occur after
cessation of treatment
with cyclosporine. Thirteen cases of transformation of
chronic
plaque psoriasis to more severe forms of psoriasis have been reported. There
were 9
cases
of pustular and 4 cases of erythrodermic psoriasis. Long term experience with Neoral
in
psoriasis patients is limited and continuous treatment for extended periods
greater than one
year
is not recommended. Alternation with other forms of treatment should be
considered in
the
long term management of patients with this life long disease.
Neoral Oral Solution (cyclosporine oral
solution, USP) MODIFIED–
Recommendations for
Administration: To make Neoral
Oral Solution (cyclosporine
oral
solution, USP) MODIFIED more palatable, it should be diluted preferably with
orange or
apple
juice that is at room temperature. Grapefruit juice affects metabolism of
cyclosporine
and
should be avoided. The combination of Neoral solution with milk can be
unpalatable.
Take
the prescribed amount of Neoral
Oral Solution (cyclosporine oral solution, USP)
MODIFIED from
the container using the dosing syringe supplied, after
removal of the
protective
cover, and transfer the solution to a glass of orange or apple juice. Stir well
and
drink at
once. Do not
allow diluted oral solution to stand before drinking. Use
a glass
container (not
plastic). Rinse the
glass with more
diluent to ensure
that the total
dose is
consumed.
After use, dry the outside of the dosing syringe with a clean towel and replace
the
protective
cover. Do not rinse the dosing syringe with water or other cleaning
agents. If the
syringe
requires cleaning, it must be completely dry before resuming use.
Blood Concentration Monitoring
in Transplant Patients: Transplant centers have
found
blood concentration monitoring of cyclosporine to be an essential component of
patient
management. Of
importance to blood concentration analysis are the type of assay used,
the
transplanted
organ, and other immunosuppressant agents being administered. While no fixed
relationship
has been established, blood concentration monitoring may assist in the clinical
evaluation
of rejection and toxicity, dose adjustments, and the assessment of compliance.
Various
assays have been used to measure blood concentrations of cyclosporine. Older studies
using
a nonspecific assay often cited concentrations that were roughly
twice those of
the
specific
assays. Therefore, comparison between concentrations in the published
literature and
an individual
patient concentration using current assays must be made with
detailed
knowledge
of the assay methods employed. Current assay results are also not
interchangeable
and
their use should be guided by their approved labeling. A discussion of the
different assay
methods
is contained in Annals of Clinical
Biochemistry 1994;31:420-446. While several
assays
and assay matrices are available, there is a
consensus that parent-compound-specific
assays correlate
best with clinical events. Of these, HPLC is the standard
reference, but the
monoclonal
antibody RIAs and the monoclonal
antibody FPIA offer
sensitivity,
reproducibility,
and convenience. Most clinicians base their
monitoring on trough
cyclosporine
concentrations. Applied
Pharmacokinetics, Principles of Therapeutic Drug
Monitoring
(1992) contains a broad discussion of cyclosporine pharmacokinetics and drug
monitoring
techniques. Blood concentration monitoring is not a replacement for renal
function
monitoring
or tissue biopsies.
HOW SUPPLIED: Neoral Soft Gelatin Capsules
(cyclosporine capsules, USP)
MODIFIED
25 mg
Oval,
blue-gray imprinted in red, .Neoral. over .25 mg..
Packages
of 30 unit-dose blisters (NDC 0078-0246-15).
100 mg
Oblong,
blue-gray imprinted in red, .NEORAL. over .100 mg..
Packages
of 30 unit-dose blisters (NDC 0078-0248-15).
Store and Dispense: In
the original unit-dose container
at controlled room temperature
68°-77°F
(20°-25°C).
Neoral Oral Solution (cyclosporine oral
solution, USP) MODIFIED: A clear,
yellow
liquid supplied in 50 mL bottles containing 100 mg/mL (NDC 0078-0274-22).
Store and Dispense: In
the original container at controlled room temperature 68°-77°F
(20°-25°C).
Do not store in the refrigerator. Once opened, the contents must be used within
two
months. At temperatures below 68°F (20°C) the solution may gel; light
flocculation or the
formation
of a light sediment may also occur. There is no impact on product performance
or
dosing
using the syringe provided. Allow to warm to room temperature 77°F (25°C) to
reverse
these
changes.
Neoral Soft Gelatin Capsules
(cyclosporine capsules, USP) MODIFIED
Manufactured
by R.P. Scherer GmbH, EBERBACH/BADEN, GERMANY
Manufactured
for Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936
Neoral Oral Solution (cyclosporine oral
solution, USP) MODIFIED
Manufactured
by NOVARTIS PHARMA AG, Basle, Switzerland
Manufactured
for Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936
Novartis
Pharmaceuticals Corporation, East Hanover, New Jersey 07936