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