CYCLOSPORINE
WARNING
Only physicians experienced in management
of systemic immunosuppressive therapy for
the indicated disease should prescribe
Sandimmun neoral. At doses used in solid organ
transplantation, only physicians
experienced in immunosuppressive therapy
and management of organ transplant
recipients should prescribe Sandimmun 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.
Sandimmun neoral, a systemic immunosuppressant,
may increase the susceptibility to
infection and the development of neoplasia.
In kidney, liver, and heart transplant
patients Sandimmun 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.
Sandimmun neoral Soft Gelatin Capsules
(cyclosporine capsules for microemulsion)
and Sandimmun neoral Oral Solution (cyclosporine
oral solution for micro emulsion) have
increased bioavailability in comparison to
Sandimmune(R) Soft Gelatin Capsules
(cyclosporine capsules, USP) and
Sandimmune(R) Oral solution (cyclosporine
oral solution, USP). Sandimmun neoral and
Sandimmune(R) are not bioequivalent and
cannot be used interchangeably without
physician supervision. For a given trough
concentration, cyclosporine exposure will
be greater with Sandimmun neoral than with
Sandimmune(R). If a patient who is
receiving exceptionally high doses of
Sandimmune(R) is converted to Sandimmun neoral,
particular caution should be exercised.
Cyclosporine blood concentrations should be
monitored in transplant and rheumatoid
arthritis patients taking Sandimmun 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 Sandimmun neoral.
Cyclosporine, the active ingredient in
Sandimmun 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: Sandimmun neoral is an oral formulation of cyclosporine that immediately
forms a microemulsion in an aqueous environment. Cyclosporine, the active
principle in Sandimmun 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+ACo-,R+ACo--(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- (alpha)-amino-butyryl-N-methylglycyl-N-methyl-
L- leucyl-L-valyl-N-methyl-L-leucyl).
SANDIMMUN NEORAL SOFT GELATIN CAPSULES (cyclosporine capsules for microemulsion) are
available in 25 mg and 100 mg strengths.
Each 25 mg capsule contains:
cyclosporine25 mg
alcohol, USP 11.9+ACU- v/v (9.5+ACU- wt/vol.)
Each 100 mg capsule contains:
cyclosporine100 mg
alcohol, USP dehydrated 11.9+ACU- v/v (9.5+ACU- wt/vol.)
INACTIVE INGREDIENTS: Corn oil-mono-di- triglycerides, polyoxyl 40 hydrogenated
castor oil NF, DL-(alpha)-tocopherol USP, gelatin NF, glycerol, iron oxide
black, propylene glycol USP, titanium dioxide USP, carmine, and other
ingredients.
ACTIONS/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+ACU- 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 Sandimmun neoral Soft Gelatin Capsules (cyclosporine capsules for microemulsion)
and Sandimmun neoral Oral Solution (cyclosporine oral solution for microemulsion) 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, +ACU-CV) of cyclosporine exposure (AUC)
when Sandimmun neoral or Sandimmune(R) is administered ranges from approximately 20+ACU- to
50+ACU- 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 (+ACU-CV) was 9+ACU--21+ACU- for Sandimmun neoral and 19+ACU--26+ACU- for Sandimmune(R). In the
same studies, Intrasubject variability of trough concentrations (+ACU-CV) was 17+ACU--
30+ACU- for Sandimmun neoral and 16+ACU--38+ACU- for Sandimmune(R).
ABSORPTION: Sandimmun neoral has increased bioavailability compared to Sandimmune(R).
The absolute bioavailability of cyclosporine administered as Sandimmune(R) is
dependent on the patient population, estimated to be less than 10+ACU- in liver
transplant patients and as great as 89+ACU- in some renal transplant patients. The
absolute bioavailability of cyclosporine administered as Sandimmun neoral has not been
determined in adults. In studies of renal transplant, rheumatoid arthritis and
psoriasis patients, the mean cyclosporine AUC was approximately 20+ACU- to 50+ACU-
greater and the peak blood cyclosporine concentration (Cmax) was approximately
40+ACU- to 106+ACU- greater following administration of Sandimmun neoral compared to following
administration of Sandimmune(R). The dose normalized AUC in DE NOVO liver
transplant patients administered Sandimmun neoral 28 days after transplantation was 50+ACU-
greater and Cmaxwas 90+ACU- greater than in those patients administered
Sandimmune(R). AUC and Cmax are also increased (Sandimmun neoral relative to
Sandimmune(R)) in heart transplant patients, but data are very limited. Although
the AUC and Cmax values are higher on Sandimmun neoral relative to Sandimmune(R), the
+AAQ-pre- +AAg- dose trough concentrations (dose-normalized) are
similar for the two formulations.
Following oral administration of Sandimmun neoral, the time to peak blood cyclosporine
concentrations (Tmax) ranged from 1.5-2.0 hours. The administration of food with
Sandimmun neoral decreases the cyclosporine AUC and Cmax. A high fat meal (669 kcal, 45
grams fat) consumed within one-half hour before Sandimmun neoral administration
decreased the AUC by 13+ACU- and Cmax by 33+ACU-. 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
Sandimmun neoral was investigated in eleven DE NOVO liver transplant patients. When
the patients were administered Sandimmun 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: 6.941+ACU- (range -55+ACU- to 68+ACU-).
+AAg- PHARMACOKINETIC PARAMETERS (MEANSD)
------------------------------------------------------------------------------
DOSE/
+AAg- DOSE/DAY(REF.1) +AAQ-WEIGHT AUC(REF. 2) CMAX
PATIENT POPULATION (MG/D) (MG/KG/D) (NG+ACo-HR/ML) (NG/ML
-------------------- --------------- ----------- ------------ ---------
DE NOVO renal
transplant (REF. 4)
Week 4 (N+AD0-37) 597174 7.952.81 87722089 1802428
------------------------------------------------------------------------------
Stable renal
transplant (REF. 4)
(N+AD0-55) 344122 4.101.58 60352194 1333469
------------------------------------------------------------------------------
DE NOVO liver
transplant (REF. 5)
Week 4 (N+AD0-18) 458190 6.893.68 71872816 1555740
------------------------------------------------------------------------------
DE NOVO rheumatoid
arthritis (REF. 6)
(N+AD0-23) 18255.6 2.370.36 2641877 728263
------------------------------------------------------------------------------
DE NOVO psoriasis
(REF. 6)
Week 4 (N+AD0-18) 18969.8 2.480.65 23241048 655186
------------------------------------------------------------------------------
TROUGH(REF. 3) CL/F CL/F
PATIENT POPULATION (NG/ML) (ML/MIN) (ML/MIN/KG)
------------------ -------------- ------------ ------------
DE NOVO renal
transplant (REF. 4)
Week 4 (N+AD0-37) 361129 593204 7.82.9
-------------------------------------------------------------------
Stable renal
transplant (REF. 4)
(N+AD0-55) 251116 492140 5.92.1
-------------------------------------------------------------------
DE NOVO liver
transplant (REF. 5)
Week 4 (N+AD0-18) 268101 577309 8.65.7
-------------------------------------------------------------------
DE NOVO rheumatoid
arthritis (REF. 6)
(N+AD0-23) 96.437.7 613196 8.32.8
-------------------------------------------------------------------
DE NOVO psoriasis
(REF. 6)
Week 4 (N+AD0-18) 74.946.7 723186 10.23.9
-------------------------------------------------------------------
REF. 1 Total daily dose was divided into two doses administered every 12 hours
REF. 2 AUC was measured over one dosing interval
REF. 3 Trough concentration was measured just prior to the morning Sandimmun neoral
dose, approximately 12 hours after the previous dose
REF. 4 Assay: TDx specific monoclonal fluorescence polarization immunoassay
REF. 5 Assay: Cyclo-trac specific monoclonal radioimmunoassay
REF. 6 Assay: INCSTAR specific monoclonal radioimmunoassay
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+ACU--47+ACU- is in plasma, 4+ACU--9+ACU- in
lymphocytes, 5+ACU--12+ACU- in granulocytes, and 41+ACU--58+ACU- in erythrocytes. At high
concentrations, the binding capacity of leukocytes and erythrocytes becomes
saturated. In plasma, approximately 90+ACU- 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
III-A 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(R), the mean AUCs for blood concentrations of M1,
M9, and M4N are about 70+ACU-, 21+ACU-, and 7.5+ACU- of the AUC for blood cyclosporine
concentrations, respectively. Based on blood concentration data from stable
renal transplant patients (13 patients administered Sandimmun neoral and Sandimmune(R)
in a crossover study), and bile concentration data from DE NOVOliver transplant
patients (4 administered Sandimmun neoral, 3 administered Sandimmune(R)), the
percentage of dose present as M1, M9, and M4N metabolites is similar when either
Sandimmun neoral or Sandimmune(R) is administered.
EXCRETION: Only 0.1+ACU- of a cyclosporine dose is excreted unchanged in the urine.
Elimination is primarily biliary with only 6+ACU- 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 Sandimmun neoral or Sandimmune(R) are very limited. In 15 renal
transplant patients aged 3-16 years, cyclosporine whole blood clearance after IV
administration of Sandimmune(R) was 10.63.7 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 9.35.4 mL/min/kg (assay: HPLC).
In the pediatric population, Sandimmun neoral also demonstrates an increased
bioavailability as compared to Sandimmune(R). In 7 liver DE NOVO transplant
patients aged 1.4-10 years, the absolute bioavailability of Sandimmun neoral was 43+ACU-
(range 30+ACU--68+ACU-) and for Sandimmune(R) in the same individuals absolute
bioavailability was 28+ACU- (range 17+ACU--42+ACU-).
+AAg- PEDIATRIC PARMACOKINETIC PARAMETERS (MEANSD)
-----------------------------------------------------------------------------
DOSE/DAY DOSE/WEIGHT AUC(REF. 1)
PATIENT POPULATION (MG/D) (MG/KG/D) (NG+ACo-HR/ML)
--------------------------- ----------- -------------- -------------
Stable liver transplant
(REF. 2)
Age 2-8,
Dosed TID (N+AD0-9) 10125 5.951.32 2163801
Age 8-15,
Dosed BID (N+AD0-8) 18855 4.962.09 42721462
------------------------------------------------------------------------------
Stable liver transplant
(REF. 3)
Age 3,
Dosed BID (N+AD0-1) 120 8.33 5832
Age 8-15,
Dosed BID (N+AD0-5) 15855 5.511.91 44522475
------------------------------------------------------------------------------
Stable renal transplant
(REF. 3)
Age 7-15,
Dosed BID (N+AD0-5) 32883 7.374.11 69221988
------------------------------------------------------------------------------
CMAX CL/F CL/F
PATIENT POPULATION (NG/ML) (ML/MIN) (ML/MIN/KG)
--------------------------- ------------- ------------ ------------
Stable liver transplant
(REF. 2)
Age 2-8,
Dosed TID (N+AD0-9) 629219 28594 16.64.3
Age 8-15,
Dosed BID (N+AD0-8) 975281 37880 10.24.0
------------------------------------------------------------------------------
Stable liver transplant
(REF. 3)
Age 3,
Dosed BID (N+AD0-1) 1013635 328121 11.01.9
Age 8-15,
Dosed BID (N+AD0-5) 1827487 418143 8.72.9
------------------------------------------------------------------------------
Stable renal transplant
(REF. 3)
Age 7-15,
Dosed BID (N+AD0-5) 1050 171 11.9
------------------------------------------------------------------------------
REF. 1 - AUC was measured over one dosing interval
REF. 2 - Assay: Cyclo-trac specific monoclonal radioimmunoassay
REF. 3 - Assay: TDx specific monoclonal fluorescence polarization immunoassay
GERIATRIC POPULATION: Comparison of single dose data from both normal elderly
volunteers (N+AD0-18, mean age 69 years) and elderly rheumatoid arthritis patients
(N+AD0-16, mean age 68 years) to single dose data in young adult volunteers (N+AD0-16,
mean age 26 years) showed no significant difference in the pharmacokinetic
parameters.
CLINICAL STUDIES:
CLINICAL TRIALS
RHEUMATOID ARTHRITIS: The effectiveness of Sandimmune(R) (cyclosporine) and
Sandimmun neoral (cyclosporine for microemulsion) in the treatment of severe rheumatoid
arthritis was evaluated in 5 clinical studies involving a total of 728
cyclosporine treated patients and 273 placebo +AAg- treated
patients.
A summary of the results is presented for the +ACI-responder+ACI- rates per treatment
group, with a responder being defined as a patient having COMPLETED the trial
with a 20+ACU- improvement in the tender and the swollen joint count and a 20+ACU-
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 +AD4-6 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 +AD4-6 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 +ADw-30+ACU- decrease in active joint count occurred without any
significant toxicity+ADs- dose decreases could be made at any time for toxicity or
(2) placebo. +AAg- 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+ACU- of whom were
unresponsive or intolerant to at least one prior major RA drug. Patients were
randomized to 1 of 2 treatment +AAg- groups (1) Sandimmun 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 2.91mg/kg/day (range: 0.72-5.17)
for Sandimmun neoral and 3.27 mg/kg/day (range: 0.73-5.68) for cyclosporine. See Graph
below.
Click here for illustration(s).
INDICATIONS AND USAGE:
KIDNEY, LIVER, AND HEART TRANSPLANTATION: Sandimmun neoral is indicated for the
prophylaxis of organ rejection in kidney, liver, and heart allogeneic
transplants. Sandimmun neoral has been used in combination with azathioprine and
corticosteroids.
RHEUMATOID ARTHRITIS: Sandimmun neoral is indicated for the treatment of patients with
severe active, rheumatoid arthritis where the disease has not adequately
responded to methotrexate. Sandimmun neoral can be used in combination with
methotrexate in rheumatoid arthritis patients who do not respond adequately to
methotrexate alone.
PSORIASIS: Sandimmun 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
Sandimmun neoral as with other therapies upon cessation of treatment.
CONTRAINDICATIONS:
GENERAL: Sandimmun 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
Sandimmun neoral.
PSORIASIS: Psoriasis patients who are treated with Sandimmun 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 Sandimmun neoral.
WARNINGS:
Only physicians experienced in management
of systemic immunosuppressive therapy for
the indicated disease should prescribe
Sandimmun neoral. At doses used in solid organ
transplantation, only physicians
experienced in immunosuppressive therapy
and management of organ transplant
recipients should prescribe Sandimmun 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.
Sandimmun neoral, a systemic immunosuppressant,
may increase the susceptibility to
infection and the development of neoplasia.
In kidney, liver, and heart transplant
patients Sandimmun 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.
Sandimmun neoral Soft Gelatin Capsules
(cyclosporine capsules for microemulsion)
and Sandimmun neoral Oral Solution (cyclosporine
oral solution for microemulsion) have
increased bioavailability in comparison to
Sandimmune(R) Soft Gelatin Capsules
(cyclosporine capsules, USP) and
Sandimmune(R) Oral solution (cyclosporine
oral solution, USP). Sandimmun neoral and
Sandimmune(R) are not bioequivalent and
cannot be used interchangeably without
physician supervision. For a given trough
concentration, cyclosporine exposure will
be greater with Sandimmun neoral than with
Sandimmune(R). If a patient who is
receiving exceptionally high doses of
Sandimmune(R) is converted to Sandimmun neoral,
particular caution should be exercised.
Cyclosporine blood concentrations should be
monitored in transplant and rheumatoid
arthritis patients taking Sandimmun 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
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 Sandimmun neoral.
Cyclosporine, the active ingredient in
Sandimmun neoral, in recommended dosages, can
cause systemic hypertension and
nephrotixicity. 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.
ALL PATIENTS: Cyclosporine, the active ingredient of Sandimmun 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 Sandimmun neoral and therefore renal function must be
monitored during therapy. CARE SHOULD BE TAKEN IN USING CYCLOSPORINE WITH
NEPHROTOXIC DRUGS. (SEE PRECAUTIONS)
Patients receiving Sandimmun 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 Sandimmun 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 SANDIMMUN NEORAL IS NOT BIOEQUIVALENT TO SANDIMMUNE(R), CONVERSION FROM
SANDIMMUN NEORAL TO SANDIMMUNE(R) USING A 1:1 RATIO (MG/KG/DAY) MAY RESULT IN LOWER
CYCLOSPORINE BLOOD CONCENTRATIONS. CONVERSION FROM SANDIMMUN NEORAL TO SANDIMMUNE(R)
SHOULD BE MADE WITH INCREASED MONITORING TO AVOID THE POTENTIAL OF UNDERDOSING.
KIDNEY, LIVER, AND HEART TRANSPLANT:
Cyclosporine, the active ingredient of Sandimmun 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(R) experience with oral solution,
nephrotoxicity associated with cyclosporine had been noted in 25+ACU- of cases of
renal transplantation, 38+ACU- of cases of cardiac transplantation, and 37+ACU- 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+ACU- of patients may have simultaneous nephrotoxicity and rejection.
+AAg- NEPHROTOXICITY VS. REJECTION
------------------------------------------------------------------------------
PARAMETER NEPHROTOXICITY REJECTION
----------------- ----------------------------- ----------------------------
History Donor +AD4-50 years old or Anti-donor immune response
hypotensive
Prolonged kidney preservation Retransplant patient
Prolonged anastomosis time
Concomitant nephrotoxic drugs
Clinical Often +AD4-6 weeks postop(REF. b) Often +ADw-4 weeks postop(REF.b)
Prolonged initial nonfunction Fever +AD4-37.5degC
(acute tubular necrosis) Weight gain +AD4-0.5 kg
Graft swelling and
tenderness
Decrease in daily urine
volume +AD4-500 mL (or 50+ACU-)
Laboratory CyA serum trough level CyA serum trough level
+AD4-200 ng/mL +ADw-150 ng/mL
Gradual rise in Cr Rapid rise in Cr
(+ADw- 0.15 mg/dl/day)(REF. a) (+AD4-0.3 mg/dl/day)(REF. a)
Cr plateau +ADw-25+ACU- above baseline Cr +AD4-25+ACU- above baseline
BUN/Cr (+AD4-/+AD0-) 20 BUN/Cr +ADw-20
Biopsy Arteriolopathy (medial Endovasculitis(REF. c)
hypertrophy(REF.a),hyalinosis, (proliferation(REF. a),
nodular deposits, intimal initmal arteritis(REF. b),
thickening, endothelial necrosis, sclerosis)
vacuolization, progressive
scarring)
Tubular atrophy, isometric Tubulitis with RBC(REF. b)
vacuolization, isolated and WBC(REF. b) casts,
calcifications some irregular
vacuolization
Minimal edema Interstitial edema(REF. c)
and hemorrhage(REF. b)
Mild focal infiltrates(REF c) Diffuse moderate to severe
mononuclear infiltrates
(REF. d)
Diffuse interstitial fibrosis, Glomerulitis (mononuclear
often striped form cells)(REF. c)
Aspiration
Cytology CyA deposits in tubular and Inflammatory infiltrate
endothelial cells with mononuclear
Fine isometric vacuolization phagocytes, macrophages,
of tubular cells lymphoblastoid cells, and
activated T-cells
These strongly express
HLA-DR antigens
Urine Cytology Tubular cells with Degenerative tubular cells,
vacuolization and plasma cells, and
granularization lymphocyturia +AD4-20 +ACU- of
sediment
Manometry Intracapsular pressure Intracapsular pressure
+ADw- 40 mm Hg(REF. b) +AD4-40 mm Hg(REF. b)
Ultrasonography Unchanged graft cross Increase in graft cross
sectional area sectional area
AP diameter (+AD4-/+AD0-)
Transverse diameter
Magnetic Resonance Normal appearance Loss of distinct
Imagery corticomedullary junction,
swelling image intensity
of parachyma approaching
that of psoas, loss of hilar
fat
Radionuclide Scan Normal or generally decreased Patchy arterial flow
perfusion
Decrease in tubular function Decrease in perfusion
(131 raised) I-hippuran) +AD4-decrease in
+AD4-decrease in perfusion tubular function
(99m raised)Tc DTPA) Increased uptake of Indium
111 labeled platelets or
Tc-99m in colloid
Therapy Responds to decreased Responds to increased
cyclosporine steroids or
antilymphocyte globulin
------------------------------------------------------------------------------
REF. (a) p +ADw- 0.05
REF. (b) p +ADw- 0.01
REF. (c) p +ADw- 0.001
REF. (d) p +ADw- 0.0001
A form of a cyclosporine-associated nephropathy is characterized by serial
deterioration in renal function and morphologic changes in the kidneys. From 5+ACU--
15+ACU- 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 Sandimmun 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+ACU- of cases of
renal transplantation, 7+ACU- of cases of cardiac transplantation, and 4+ACU- 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.
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+ACU-)
rheumatoid arthritis patients after the average treatment duration of 19 months.
Only one patient, out of these 6 patients, was treated with a dose (+ADw-/+AD0-)4
mg/kg/day. Serum creatinine improved in all but one patient after
discontinuation of cyclosporine. The +ACI-maximal creatinine increase+ACI- 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 Sandimmun neoral treatment
for the development of malignancies. Moreover, use of Sandimmun 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 Sandimmun neoral should be considered before treatment of
patients with psoriasis. Cyclosporine, the active ingredient in Sandimmun 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 Sandimmun neoral.
Renal dysfunction is a potential consequence of Sandimmun neoral therefore renal
function must be monitored during therapy.
Patients receiving Sandimmun 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 Sandimmun 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+ACU-) 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+ACU-). The majority of patients (19/26) were on a dose of (+AD4-/+AD0-)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+ACU-) 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+ACU-) of these patients+ADs- 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+ADs- 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+ACU-), 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 Sandimmun neoral
only after complete resolution of suspicious lesions, and only if there are no
other treatment options. (SEE SPECIAL MONITORING FOR PSORIASIS PATIENTS)