Sandimmune® Soft Gelatin Capsules
(cyclosporine
capsules, USP)
Sandimmune® Oral Solution
(cyclosporine
oral solution, USP)
Sandimmune® Injection
(cyclosporine
injection, USP)
FOR INFUSION ONLY
Rx only
WARNING: Only
physicians experienced in immunosuppressive therapy and management of
organ
transplant patients should prescribe Sandimmune® (cyclosporine).
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.
Sandimmune® (cyclosporine) should be administered with adrenal
corticosteroids but not with
other
immunosuppressive agents. Increased susceptibility to infection and the
possible
development
of lymphoma may result from immunosuppression.
Sandimmune® soft gelatin capsules (cyclosporine capsules, USP)
and Sandimmune® oral
solution
(cyclosporine oral solution, USP) have decreased bioavailability in comparison
to
Neoral® soft gelatin capsules (cyclosporine capsules, USP)
MODIFIED and Neoral® oral
solution
(cyclosporine oral solution, USP) MODIFIED.
Sandimmune® and Neoral® are
not bioequivalent and cannot be used interchangeably without
physician
supervision.
The
absorption of cyclosporine during chronic administration of Sandimmune® soft gelatin
capsules
and oral solution was found to be erratic. It is recommended that patients
taking the
soft
gelatin capsules or oral solution over a period of time be monitored at
repeated intervals
for
cyclosporine blood levels and subsequent dose adjustments be made in order to
avoid
toxicity
due to high levels and possible organ rejection due to low absorption of
cyclosporine.
This
is of special importance in liver transplants. Numerous assays are being
developed to
measure
blood levels of cyclosporine. Comparison of levels in published literature to
patient
levels
using current assays must be done with detailed knowledge of the assay methods
employed.
(See Blood Level Monitoring under DOSAGE AND ADMINISTRATION)
DESCRIPTION: Cyclosporine,
the active principle in Sandimmune® (cyclosporine)
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-Nmethyl-
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).
Sandimmune® Soft Gelatin Capsules (cyclosporine
capsules, USP) are available in 25 mg
and
100 mg strengths.
Each
25 mg capsule contains:
cyclosporine,
USP............................................................................................................25
mg
alcohol,
USP
dehydrated........................................................................max
12.7% by volume
Each
100 mg capsule contains:
cyclosporine,
USP..........................................................................................................
100 mg
alcohol,
USP
dehydrated........................................................................max
12.7% by volume
Inactive
Ingredients: corn oil, gelatin, glycerol, Labrafil M 2125 CS
(polyoxyethylated
glycolysed
glycerides), red iron oxide (25 mg and 100 mg capsule only), sorbitol, titanium
dioxide,
and other ingredients.
Sandimmune® Oral Solution (cyclosporine
oral solution, USP) is available in 50 mL bottles.
Each
mL contains:
cyclosporine,
USP..........................................................................................................
100 mg
alcohol,
Ph.
Helv............................................................................................12.5%
by volume
dissolved
in an olive oil, Ph. Helv./Labrafil M 1944 CS (polyoxyethylated oleic
glycerides)
vehicle
which must be further diluted with milk, chocolate milk, or orange juice before
oral
administration.
Sandimmune® Injection (cyclosporine
injection, USP) is available in a 5 mL sterile ampul
for
I.V. administration.
Each
mL contains:
cyclosporine,
USP ........................
...................................................................................50
mg
*Cremophor® EL (polyoxyethylated castor
oil).............................................................650 mg
alcohol,
Ph.
Helv............................................................................................32.9%
by volume
nitrogen
.................................................................................................................................
qs
which
must be diluted further with 0.9% Sodium Chloride Injection or 5% Dextrose
Injection
before
use.
The
chemical structure of cyclosporine (also known as cyclosporin A) is:
CLINICAL PHARMACOLOGY: Sandimmune® (cyclosporine) is a potent
immunosuppressive
agent which in animals prolongs survival of allogeneic transplants
involving
skin, heart, kidney, pancreas, bone marrow, small intestine, and lung.
Sandimmune®
(cyclosporine)
has been demonstrated to suppress some humoral immunity and to a greater
extent,
cell-mediated 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.
Successful
kidney, liver, and heart allogeneic transplants have been performed in man
using
Sandimmune® (cyclosporine).
The
exact mechanism of action of Sandimmune® (cyclosporine)
is not known. Experimental
evidence
suggests that the effectiveness of cyclosporine is due to specific and
reversible
inhibition
of immunocompetent lymphocytes in the G0- or
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. Sandimmune® (cyclosporine)
also inhibits
lymphokine
production and release including interleukin-2 or T-cell growth factor (TCGF).
No
functional effects on phagocytic (changes in enzyme secretions not altered,
chemotactic
migration
of granulocytes, macrophage migration, carbon clearance in vivo) or
tumor cells
(growth
rate, metastasis) can be detected in animals. Sandimmune® (cyclosporine) does not
cause
bone marrow suppression in animal models or man.
The
absorption of cyclosporine from the gastrointestinal tract is incomplete and
variable. Peak
concentrations
(Cmax) in blood and plasma are achieved at about 3.5
hours. Cmax and area
under
the plasma or blood concentration/time curve (AUC) increase with the
administered
dose;
for blood the relationship is curvilinear (parabolic) between 0 and 1400 mg. As
determined
by a specific assay, Cmax is
approximately 1.0 ng/mL/mg of dose for plasma and
2.7-1.4
ng/mL/mg of dose for blood (for low to high doses). Compared to an intravenous
infusion,
the absolute bioavailability of the oral solution is approximately 30% based
upon the
results
in 2 patients. The bioavailability of Sandimmune® soft
gelatin capsules (cyclosporine
capsules,
USP) is equivalent to Sandimmune® oral solution, (cyclosporine
oral solution, USP).
Cyclosporine
is distributed largely outside the blood volume. 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
uptake by
leukocytes
and erythrocytes becomes saturated. In plasma, approximately 90% is bound to
proteins,
primarily lipoproteins.
The
disposition of cyclosporine from blood is biphasic with a terminal half-life of
approximately
19 hours (range: 10-27 hours). Elimination is primarily biliary with only 6% of
the
dose excreted in the urine.
Cyclosporine
is extensively metabolized but there is no major metabolic pathway. Only 0.1%
of
the dose is excreted in the urine as unchanged drug. Of 15 metabolites
characterized in
human
urine, 9 have been assigned structures. The major pathways consist of
hydroxylation of
the
Cγ-carbon of 2 of the leucine residues, Cη-carbon hydroxylation, and
cyclic ether
formation
(with oxidation of the double bond) in the side chain of the amino acid
3-hydroxyl-
N,4-dimethyl-L-2-amino-6-octenoic
acid and N-demethylation of N-methyl leucine residues.
Hydrolysis
of the cyclic peptide chain or conjugation of the aforementioned metabolites do
not
appear
to be important biotransformation pathways.
INDICATIONS AND USAGE: Sandimmune® (cyclosporine) is indicated for the prophylaxis
of
organ rejection in kidney, liver, and heart allogeneic transplants. It is always
to be used with
adrenal
corticosteroids. The drug may also be used in the treatment of chronic
rejection in
patients
previously treated with other immunosuppressive agents.
Because
of the risk of anaphylaxis, Sandimmune® injection
(cyclosporine injection, USP)
should
be reserved for patients who are unable to take the soft gelatin capsules or
oral
solution.
CONTRAINDICATIONS: Sandimmune® injection (cyclosporine injection, USP) is
contraindicated
in patients with a hypersensitivity to Sandimmune® (cyclosporine)
and/or
Cremophor® EL (polyoxyethylated castor oil).
WARNINGS: (See
boxed WARNINGs): Sandimmune® (cyclosporine),
when used in high
doses,
can cause hepatotoxicity and nephrotoxicity.
It
is not unusual for serum creatinine and BUN levels to be elevated during
Sandimmune®
(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.
Nephrotoxicity
has 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 transplant and consisted of an arrest in the fall of the
preoperative
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 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 rejection episodes
care
must
be taken to differentiate between them. This form of nephrotoxicity is usually
responsive
to
Sandimmune® (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
to
one or the other. It should be noted however, that up to 20% of patients may
have
simultaneous
nephrotoxicity and rejection.
A
form of chronic progressive cyclosporine-associated nephrotoxicity is
characterized by
serial
deterioration in renal function and morphologic changes in the kidneys. From
5%-15%
of
transplant recipients will fail to show a reduction in a rising serum
creatinine despite a
decrease
or discontinuation of cyclosporine therapy. Renal biopsies from these patients
will
demonstrate
an interstitial fibrosis with tubular atrophy. In addition, toxic tubulopathy,
peritubular
capillary congestion, arteriolopathy, and a striped form of interstitial
fibrosis with
tubular
atrophy may be present. Though none of these morphologic changes is entirely
specific,
a histologic diagnosis of chronic progressive cyclosporine-associated
nephrotoxicity
requires
evidence of these.
When
considering the development of chronic nephrotoxicity 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 posttransplant 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 must be included, 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.
Impaired
renal function at any time requires close monitoring, and frequent dosage
adjustment
may
be indicated. In patients with persistent high elevations of BUN and creatinine
who are
unresponsive
to dosage adjustments, consideration should be given to switching to other
immunosuppressive
therapy. In the event of severe and unremitting rejection, it is preferable
to
allow the kidney transplant to be rejected and removed rather than increase the
Sandimmune® (cyclosporine) dosage to a very high level in an
attempt to reverse the rejection.
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
Sandimmune® (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
has 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 Sandimmune® (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
Sandimmune®
(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, which can also increase susceptibility to infection,
Sandimmune® (cyclosporine) should not be administered with
other immunosuppressive
agents
except adrenal corticosteroids. The efficacy and safety of cyclosporine in
combination
with
other immunosuppressive agents have not been determined.
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.
Rarely
(approximately 1 in 1000), patients receiving Sandimmune® injection (cyclosporine
injection,
USP) have experienced anaphylactic reactions. Although the exact cause of these
reactions
is unknown, it is believed to be due to the Cremophor® EL (polyoxyethylated castor
oil)
used as the vehicle for the I.V. formulation. These reactions have consisted of
flushing of
the
face and upper thorax, acute respiratory distress with dyspnea and wheezing,
blood
pressure
changes, and tachycardia. One patient died after respiratory arrest and
aspiration
pneumonia.
In some cases, the reaction subsided after the infusion was stopped.
Patients receiving Sandimmune® Injection (cyclosporine
injection, USP) should be under
continuous observation for at
least the first 30 minutes following the start of the infusion
and at frequent intervals
thereafter. If anaphylaxis occurs, the infusion should be
stopped. An aqueous solution of
epinephrine 1:1000 should be available at the bedside as
well as a source of oxygen.
Anaphylactic
reactions have not been reported with the soft gelatin capsules or oral
solution
which
lack Cremophor® EL (polyoxyethylated castor oil). In fact,
patients experiencing
anaphylactic
reactions have been treated subsequently with the soft gelatin capsules or oral
solution
without incident.
Care
should be taken in using Sandimmune® (cyclosporine)
with nephrotoxic drugs. (See
PRECAUTIONS)
Because
Sandimmune® is not bioequivalent to Neoral®, conversion from
Neoral® to
Sandimmune® using a 1:1 ratio (mg/kg/day) may result in a
lower cyclosporine blood
concentration.
Conversion from Neoral® to Sandimmune® should be made with increased
blood
concentration monitoring to avoid the potential of underdosing.
PRECAUTIONS: General: Patients
with malabsorption may have difficulty in achieving
therapeutic
levels with Sandimmune® soft gelatin capsules or oral
solution.
Hypertension
is a common side effect of Sandimmune® (cyclosporine)
therapy. (See
ADVERSE
REACTIONS) Mild or moderate hypertension is more frequently
encountered than
severe
hypertension and the incidence decreases over time. Antihypertensive therapy
may be
required.
Control of blood pressure can be accomplished with any of the common
antihypertensive
agents. However, since cyclosporine may cause hyperkalemia, potassiumsparing
diuretics
should not be used. While calcium antagonists can be effective agents in
treating
cyclosporine-associated hypertension, care should be taken since interference
with
cyclosporine
metabolism may require a dosage adjustment. (See Drug Interactions)
During
treatment with Sandimmune® (cyclosporine), vaccination may
be less effective; and
the
use of live attenuated vaccines should be avoided.
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
the drug. They should be given careful dosage instructions, advised of the
potential
risks
during pregnancy, and informed of the increased risk of neoplasia.
Patients
using cyclosporine oral solution with its accompanying syringe for dosage
measurement
should be cautioned not to rinse the syringe either before or after use.
Introduction
of water into the product by any means will cause variation in dose.
Laboratory Tests: Renal
and liver functions should be assessed repeatedly by measurement
of
BUN, serum creatinine, serum bilirubin, and liver enzymes.
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 Alter Cyclosporine
Concentrations:
Compounds
that decrease cyclosporine absorption such as orlistat should be avoided.
Cyclosporine
is extensively metabolized by 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
Sandimmune® dosage adjustment are essential when these drugs
are used
concomitantly.
(See Blood Concentration Monitoring)
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
Antibiotics Anticonvulsants Other Drugs/Dietary Supplements
nafcillin carbamazepine octreotide
rifampin phenobarbital ticlopidine
phenytoin orlistat
St. John’s Wort
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
antiinflammatory
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 99mTc-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: Cyclosporine gave no evidence
of
mutagenic or teratogenic effects in appropriate test systems. Only at dose
levels toxic to
dams,
were adverse effects seen in reproduction studies in rats. (See Pregnancy)
Carcinogenicity
studies were carried out in male and female rats and mice. In the 78-week
mouse
study, at doses of 1, 4, and 16 mg/kg/day, 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,
conducted at 0.5, 2, and 8 mg/kg/day, pancreatic islet cell adenomas
significantly
exceeded
the control rate in the low dose level. The hepatocellular carcinomas and
pancreatic
islet
cell adenomas were not dose related.
No
impairment in fertility was demonstrated in studies in male and female rats.
Cyclosporine
has not been found 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.
An
increased incidence of malignancy is a recognized complication of
immunosuppression in
recipients
of organ transplants. 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. It has been reported that reduction or discontinuance of
immunosuppression
may cause the lesions to regress.
Pregnancy: Pregnancy
Category C. Sandimmune® oral
solution (cyclosporine oral solution,
USP)
has been shown to be embryo- and fetotoxic in rats and rabbits when given in
doses 2-5
times
the human dose. At toxic doses (rats at 30 mg/kg/day and rabbits at 100
mg/kg/day),
Sandimmune® oral solution (cyclosporine oral solution, USP)
was embryo- and fetotoxic as
indicated
by increased pre- and postnatal mortality and reduced fetal weight together
with
related
skeletal retardations. In the well-tolerated dose range (rats at up to 17
mg/kg/day and
rabbits
at up to 30 mg/kg/day), Sandimmune® oral
solution (cyclosporine oral solution, USP)
proved
to be without any embryolethal or teratogenic effects.
There
are no adequate and well-controlled studies in pregnant women. Sandimmune®
(cyclosporine)
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
Sandimmune® (cyclosporine) during pregnancy, 90% of whom were
transplant patients, and
most
of whom received Sandimmune® (cyclosporine) throughout the
entire gestational period.
Since
most of the patients were not prospectively identified, the results are likely
to be biased
toward
negative outcomes. The only consistent patterns of abnormality were premature
birth
(gestational
period of 28 to 36 weeks) and low birth weight for gestational age. It is not
possible
to separate the effects of Sandimmune® (cyclosporine)
on these pregnancies from the
effects
of the other immunosuppressants, the underlying maternal disorders, or other
aspects
of
the transplantation milieu. 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.
Preterm
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%. In a report of 23 children followed up to 4 years,
postnatal
development was said to be normal. More information on cyclosporine use in
pregnancy
is available from Novartis Pharmaceuticals Corporation.
Nursing Mothers: Since
Sandimmune® (cyclosporine) is excreted in human milk, nursing
should
be avoided.
Pediatric Use: Although
no adequate and well controlled studies have been conducted in
children,
patients as young as 6 months of age have received the drug with no unusual
adverse
effects.
ADVERSE REACTIONS: The
principal adverse reactions of Sandimmune® (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 resemble those seen in the
hemolytic-uremic
syndrome
and include 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 posttransplantation.
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.
The
following reactions occurred in 3% or greater of 892 patients involved in
clinical trials of
kidney,
heart, and liver transplants:
The
following reactions occurred in 2% or less of 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.
Cremophor® EL (polyoxyethylated castor oil) is known to cause
hyperlipemia and
electrophoretic
abnormalities of lipoproteins. These effects are reversible upon
discontinuation
of treatment but are usually not a reason to stop treatment.
OVERDOSAGE: There
is a minimal experience with overdosage. Because of the slow
absorption
of Sandimmune® soft gelatin capsules or oral solution, forced
emesis would be of
value
up to 2 hours after administration. 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. Sandimmune®
(cyclosporine)
is not dialyzable to any great extent, nor is it cleared well by charcoal
hemoperfusion.
The oral LD50 is 2329 mg/kg in mice, 1480 mg/kg in rats, and
> 1000 mg/kg
in
rabbits. The I.V. LD50 is
148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.
DOSAGE AND ADMINISTRATION:
Sandimmune®
Soft Gelatin
Capsules (cyclosporine
capsules, USP) and Sandimmune® Oral Solution (cyclosporine oral
solution, USP):
Sandimmune® soft gelatin capsules (cyclosporine capsules, USP)
and Sandimmune® oral
solution
(cyclosporine oral solution, USP) have decreased bioavailability in comparison
to
Neoral® soft gelatin capsules (cyclosporine capsules, USP)
MODIFIED and Neoral® oral
solution
(cyclosporine oral solution, USP) MODIFIED. Sandimmune® and Neoral® are
not
bioequivalent
and cannot be used interchangeably without physician supervision.
The
initial oral dose of Sandimmune® (cyclosporine) should be given
4-12 hours prior to
transplantation
as a single dose of 15 mg/kg. Although a daily single dose of 14-18 mg/kg was
used
in most clinical trials, few centers continue to use the highest dose, most
favoring the
lower
end of the scale. There is a trend towards use of even lower initial doses for
renal
transplantation
in the ranges of 10-14 mg/kg/day. The initial single daily dose is continued
postoperatively
for 1-2 weeks and then tapered by 5% per week to a maintenance dose of 5-10
mg/kg/day.
Some centers have successfully tapered the maintenance dose to as low as 3
mg/kg/day
in selected renal transplant patients without an apparent rise in
rejection rate.
(See
Blood Level Monitoring below)
In
pediatric usage, the same dose and dosing regimen may be used as in adults
although in
several
studies children have required and tolerated higher doses than those used in
adults.
Adjunct
therapy with adrenal corticosteroids is recommended. Different tapering dosage
schedules
of prednisone appear to achieve similar results. A 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. Another center started with an initial dose
of 200 mg
tapered
by 40 mg/day until reaching 20 mg/day. After 2 months at this dose, a further
reduction
to 10 mg/day was made. Adjustments in dosage of prednisone must be made
according
to the clinical situation.
To
make Sandimmune® oral solution (cyclosporine oral solution, USP)
more palatable, the
oral
solution may be diluted with milk, chocolate milk, or orange juice preferably
at room
temperature.
Patients should avoid switching diluents frequently. Sandimmune® soft gelatin
capsules
and oral solution should be administered on a consistent schedule with regard
to time
of
day and relation to meals.
Take
the prescribed amount of Sandimmune® (cyclosporine)
from the container using the
dosage
syringe supplied after removal of the protective cover, and transfer the
solution to a
glass
of milk, chocolate milk, or orange juice. Stir well and drink at once. Do not
allow to
stand
before drinking. It is best to use a glass container and rinse it with more
diluent to ensure
that
the total dose is taken. After use, replace the dosage syringe in the
protective cover. Do
not
rinse the dosage syringe with water or other cleaning agents either before or
after use. If
the
dosage syringe requires cleaning, it must be completely dry before resuming
use.
Introduction
of water into the product by any means will cause variation in dose.
Sandimmune® Injection (cyclosporine
injection, USP)
FOR INFUSION ONLY
Note:
Anaphylactic reactions have occurred with Sandimmune® injection (cyclosporine
injection,
USP). (See WARNINGS)
Patients
unable to take Sandimmune® soft gelatin capsules or oral
solution pre- or
postoperatively
may be treated with the I.V. concentrate. Sandimmune® Injection
(cyclosporine injection, USP) is
administered at 1/3 the oral dose. The initial dose of
Sandimmune® injection (cyclosporine injection, USP) should be
given 4-12 hours prior to
transplantation
as a single I.V. dose of 5-6 mg/kg/day. This daily single dose is continued
postoperatively
until the patient can tolerate the soft gelatin capsules or oral solution.
Patients
should
be switched to Sandimmune® soft gelatin capsules or oral
solution as soon as possible
after
surgery. In pediatric usage, the same dose and dosing regimen may be used,
although
higher
doses may be required.
Adjunct
steroid therapy is to be used. (See aforementioned)
Immediately
before use, the I.V. concentrate should be diluted 1 mL Sandimmune® injection
(cyclosporine
injection, USP) in 20 mL-100 mL 0.9% Sodium Chloride Injection or 5%
Dextrose
Injection and given in a slow intravenous infusion over approximately 2-6
hours.
Diluted
infusion solutions should be discarded after 24 hours.
The
Cremophor® EL (polyoxyethylated castor oil) contained in the
concentrate for intravenous
infusion
can cause phthalate stripping from PVC.
Parenteral
drug products should be inspected visually for particulate matter and
discoloration
prior
to administration, whenever solution and container permit.
Blood Level Monitoring: Several
study centers have found blood level monitoring of
cyclosporine
useful in patient management. While no fixed relationships have yet been
established,
in one series of 375 consecutive cadaveric renal transplant recipients, dosage
was
adjusted
to achieve specific whole blood 24-hour trough levels of 100-200 ng/mL as
determined
by high-pressure liquid chromatography (HPLC).
Of
major importance to blood level analysis is the type of assay used. The above
levels are
specific
to the parent cyclosporine molecule and correlate directly to the new
monoclonal
specific
radioimmunoassays (mRIA-sp). Nonspecific assays are also available which detect
the
parent compound molecule and various of its metabolites. Older studies often
cited levels
using
a nonspecific assay which were roughly twice those of specific assays. Assay
results are
not
interchangeable and their use should be guided by their approved labeling. If
plasma
specimens
are employed, levels will vary with the temperature at the time of separation
from
whole
blood. Plasma levels may range from 1/2-1/5 of whole blood levels. Refer to
individual
assay
labeling for complete instructions. In addition, Transplantation Proceedings
(June
1990)
contains position papers and a broad consensus generated at the Cyclosporine-
Therapeutic
Drug Monitoring conference that year. Blood level monitoring is not a
replacement
for renal function monitoring or tissue biopsies.
HOW SUPPLIED: Sandimmune® Soft Gelatin Capsules
(cyclosporine capsules, USP)
25 mg: Oblong,
pink, branded “ 78/240”. Unit dose packages of 30 capsules, 3 blister
cards
of 10 capsules (NDC 0078-0240-15).
100 mg: Oblong,
dusty rose, branded “ 78/241”. Unit dose packages of 30 capsules, 3
blister
cards of 10 capsules (NDC 0078-0241-15).
Store and Dispense: Store
at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F).
[See
USP Controlled Room Temperature] An odor may be detected upon opening the unit
dose
container, which will dissipate shortly thereafter. This odor does not affect
the quality of
the
product.
Sandimmune® Oral Solution (cyclosporine oral
solution, USP): Supplied in 50 mL bottles
containing
100 mg of cyclosporine per mL (NDC 0078-0110-22). A dosage syringe is
provided
for dispensing.
Store and Dispense: In
the original container at temperatures below 86°F (30°C). Do not store
in
the refrigerator. Protect from freezing. Once opened, the contents must be used
within 2
months.
Sandimmune® Injection (cyclosporine
injection, USP)
FOR INTRAVENOUS INFUSION
Supplied
as a 5 mL sterile ampul containing 50 mg of cyclosporine per mL, in boxes of 10
ampuls
(NDC 0078-0109-01).
Store and Dispense: At
temperatures below 86°F (30°C) and protected from light.
Sandimmune® Soft Gelatin Capsules
(cyclosporine capsules, USP)
Manufactured
by
R.P.
Scherer GmbH, EBERBACH/BADEN, GERMANY
Manufactured
for
Novartis
Pharmaceuticals Corporation, East Hanover, NJ 07936
Sandimmune® Oral Solution (cyclosporine oral
solution, USP) and
Sandimmune® Injection (cyclosporine
injection, USP)
FOR INFUSION ONLY
Manufactured
by
NOVARTIS
PHARMA AG, Basle, Switzerland
Manufactured
for
Novartis
Pharmaceuticals Corporation, East Hanover, NJ 07936
Novartis
Pharmaceuticals Corporation
East
Hanover, New Jersey 07936
T2001-50
REV:
JUNE 2001 PRINTED IN USA 89005205
©
2001 Novartis