NEORAL NEORAL

NEORAL

Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED

NEORAL

Oral Solution (cyclosporine oral solution, USP) MODIFIED

Rx only

Prescribing Information

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

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.

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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-

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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 G

- and G

-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. Neoral

Oral Solution diluted with

orange juice or apple juice is bioequivalent to Neoral Oral Solution diluted with water. The effect of milk

on the bioavailability of cyclosporine when administered as Neoral Oral Solution has not been evaluated.

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 (C

max

) 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 C

max

was 90% greater than in

those patients administered Sandimmune

. AUC and C

max

are also increased (Neoral

relative to

Sandimmune

) in heart transplant patients, but data are very limited. Although the AUC and C

max

values

are higher on Neoral

relative to Sandimmune

, the pre-dose trough concentrations (dose-normalized) are

similar for the two formulations.

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Following oral administration of Neoral

, the time to peak blood cyclosporine concentrations (T

max

)

ranged from 1.5-2.0 hours. The administration of food with Neoral

decreases the cyclosporine AUC and

max

. A high fat meal (669 kcal, 45 grams fat) consumed within one-half hour before Neoral

administration decreased the AUC by 13% and C

max

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%).

Pharmacokinetic Parameters (mean±SD)

Dose/day

Dose/weight AUC

max

Trough

CL/F CL/F

Patient Population (mg/d) (mg/kg/d) (ng·hr/mL) (ng/mL) (ng/mL) (mL/min) (mL/min/kg)

De novo renal

transplant

597±174 7.95±2.81 8772±2089 1802±428 361±129 593±204 7.8±2.9

Week 4 (N=37)

Stable renal

transplant

344±122 4.10±1.58 6035±2194 1333±469 251±116 492±140 5.9±2.1

(N=55)

De novo liver

transplant

458±190 6.89±3.68 7187±2816 1555±740 268±101 577±309 8.6±5.7

Week 4 (N=18)

De novo rheumatoid

arthritis

182±55.6 2.37±0.36 2641±877 728±263 96.4±37.7 613±196 8.3±2.8

(N=23)

De novo psoriasis

189±69.8 2.48±0.65 2324±1048 655±186 74.9±46.7 723±186 10.2±3.9

Week 4 (N=18)

Total daily dose was divided into two doses administered every 12 hours

AUC was measured over one dosing interval

Trough concentration was measured just prior to the morning Neoral

dose, approximately 12 hours after the previous dose

Assay: TDx specific monoclonal fluorescence polarization immunoassay

Assay: Cyclo-trac specific monoclonal radioimmunoassay

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%-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 co-administration 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

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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%).

Pediatric Pharmacokinetic Parameters (mean±SD)

Dose/day Dose/weight AUC

max

CL/F CL/F

Patient Population (mg/d) (mg/kg/d) (ng·hr/mL) (ng/mL) (mL/min) (mL/min/kg)

Stable liver transplant

Age 2-8, Dosed TID (N=9) 101±25 5.95±1.32 2163±801 629±219 285±94 16.6±4.3

Age 8-15, Dosed BID (N=8) 188±55 4.96±2.09 4272±1462 975±281 378±80 10.2±4.0

Stable liver transplant

Age 3, Dosed BID (N=1) 120 8.33 5832 1050 171 11.9

Age 8-15, Dosed BID (N=5) 158±55 5.51±1.91 4452±2475 1013±635 328±121 11.0±1.9

Stable renal transplant

Age 7-15, Dosed BID (N=5) 328±83 7.37±4.11 6922±1988 1827±487 418±143 8.7±2.9

AUC was measured over one dosing interval

Assay: Cyclo-trac specific monoclonal radioimmunoassay

Assay: TDx specific monoclonal fluorescence polarization immunoassay

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.

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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 0.5 mg/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.

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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

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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.

Nephrotoxicity vs. Rejection

Parameter Nephrotoxicity Rejection

History

Donor >50 years old or hypotensive

Prolonged kidney preservation

Anti-donor immune response

Retransplant patient

Prolonged anastomosis time

Concomitant nephrotoxic drugs

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Clinical

Often >6 weeks postop

Prolonged initial nonfunction (acute tubular

necrosis)

Often < 4 weeks postop

Fever > 37.5°C

Weight gain > 0.5 kg

Graft swelling and tenderness

Decrease in daily urine volume > 500 mL (or 50%)

Laboratory

CyA serum trough level > 200 ng/mL

Gradual rise in Cr (< 0.15 mg/dl/day)

Cr plateau < 25% above baseline

BUN/Cr ≥ 20

CyA serum trough level < 150 ng/mL

Rapid rise in Cr (> 0.3 mg/dl/day)

Cr > 25% above baseline

BUN/Cr < 20

Biopsy

Arteriolopathy (medial hypertrophy

, hyalinosis,

nodular deposits, intimal thickening, endothelial

vacuolization, progressive scarring)

Tubular atrophy, isometric vacuolization, isolated

calcifications

Minimal edema

Mild focal infiltrates

Endovasculitis

(proliferation

, intimal arteritis

necrosis, sclerosis)

Tubulitis with RBC

and WBC

casts, some

irregular vacuolization

Interstitial edema

and hemorrhage

Diffuse moderate to severe mononuclear

infiltrates

Aspiration Cytology

Diffuse interstitial fibrosis, often striped form

CyA deposits in tubular and endothelial cells

Fine isometric vacuolization of tubular cells

Glomerulitis (mononuclear cells)

Inflammatory infiltrate with mononuclear

phagocytes, macrophages, lymphoblastoid cells,

and activated T-cells

These strongly express HLA-DR antigens

Urine Cytology

Tubular cells with vacuolization and

granularization

Degenerative tubular cells, plasma cells, and

lymphocyturia > 20% of sediment

Manometry

Ultrasonography

Intracapsular pressure < 40 mm Hg

Unchanged graft cross sectional area

Intracapsular pressure > 40 mm Hg

Increase in graft cross sectional area

AP diameter ≥ Transverse diameter

Magnetic Resonance

Imagery

Normal appearance

Loss of distinct corticomedullary junction, swelling

image intensity of parachyma approaching that of

psoas, loss of hilar fat

Radionuclide Scan Normal or generally decreased perfusion

Decrease in tubular function

(

131

I-hippuran) > decrease in perfusion (

99m

DTPA)

Patchy arterial flow

Decrease in perfusion > decrease in tubular

function

Increased uptake of Indium 111 labeled platelets

or Tc-99m in colloid

Therapy Responds to decreased cyclosporine

Responds to increased steroids or antilymphocyte

globulin

a b d

p < 0.05, p < 0.01,

p < 0.001, p < 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%-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.

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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. Patients taking

cyclosporine should be warned to avoid excess ultraviolet light exposure. 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.

Some malignancies may be fatal. Transplant patients receiving cyclosporine are at increased risk for

serious infection with fatal outcome.

Latent Viral Infections

Immunosuppressed patients are at increased risk for opportunistic infections, including activation of latent

viral infections. These include BK virus-associated nephropathy which has been observed in patients

receiving immunosuppressants, including Neoral. This infection is associated with serious outcomes,

including deteriorating renal function and renal graft loss. Patient monitoring may help detect patients at

risk for BK virus-associated nephropathy. Reduction in immunosuppression should be considered for

patients who develop evidence of BK virus-associated nephropathy.

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. Another rare manifestation of

cyclosporine-induced neurotoxicity, occurring in transplant patients more frequently than in other

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indications, is optic disc edema including papilloedema, with possible visual impairment, secondary to

benign intracranial hypertension.

Care should be taken in using cyclosporine with nephrotoxic drugs. (See PRECAUTIONS)

Rheumatoid Arthritis

Cyclosporine nephropathy was detected in renal biopsies of 6 out of 60 (10%) rheumatoid arthritis

patients after the average treatment duration of 19 months. Only one patient, out of these 6 patients, was

treated with a dose ≤4 mg/kg/day. Serum creatinine improved in all but one patient after discontinuation

of cyclosporine. The “maximal creatinine increase” appears to be a factor in predicting cyclosporine

nephropathy.

There is a potential, as with other immunosuppressive agents, for an increase in the occurrence of

malignant lymphomas with cyclosporine. It is not clear whether the risk with cyclosporine is greater than

that in rheumatoid arthritis patients or in rheumatoid arthritis patients on cytotoxic treatment for this

indication. Five cases of lymphoma were detected: four in a survey of approximately 2,300 patients

treated with cyclosporine for rheumatoid arthritis, and another case of lymphoma was reported in a

clinical trial. Although other tumors (12 skin cancers, 24 solid tumors of diverse types, and 1 multiple

myeloma) were also reported in this survey, epidemiologic analyses did not support a relationship to

cyclosporine other than for malignant lymphomas.

Patients should be thoroughly evaluated before and during Neoral

treatment for the development of

malignancies. Moreover, use of Neoral

therapy with other immunosuppressive agents may induce an

excessive immunosuppression which is known to increase the risk of malignancy.

Psoriasis

(See also Boxed WARNINGS for Psoriasis)

Since cyclosporine is a potent immunosuppressive agent with a number of potentially serious side effects,

the risks and benefits of using Neoral

should be considered before treatment of patients with psoriasis.

Cyclosporine, the active ingredient in Neoral

, can cause nephrotoxicity and hypertension (see

PRECAUTIONS) and the risk increases with increasing dose and duration of therapy. Patients who may

be at increased risk such as those with abnormal renal function, uncontrolled hypertension or

malignancies, should not receive Neoral

Renal dysfunction is a potential consequence of Neoral

therefore renal function must be monitored

during therapy.

Patients receiving Neoral

require frequent monitoring of serum creatinine. (See Special Monitoring

under DOSAGE AND ADMINISTRATION) Elderly patients should be monitored with particular care,

since decreases in renal function also occur with age. If patients are not properly monitored and doses are

not properly adjusted, cyclosporine therapy can cause structural kidney damage and persistent renal

dysfunction.

An increase in serum creatinine and BUN may occur during Neoral

therapy and reflects a reduction in

the glomerular filtration rate.

Kidney biopsies from 86 psoriasis patients treated for a mean duration of 23 months with 1.2-7.6

mg/kg/day of cyclosporine showed evidence of cyclosporine nephropathy in 18/86 (21%) of the patients.

The pathology consisted of renal tubular atrophy and interstitial fibrosis. On repeat biopsy of 13 of these

patients maintained on various dosages of cyclosporine for a mean of 2 additional years, the number with

cyclosporine induced nephropathy rose to 26/86 (30%). The majority of patients (19/26) were on a dose

of ≥5.0 mg/kg/day (the highest recommended dose is 4 mg/kg/day). The patients were also on

cyclosporine for greater than 15 months (18/26) and/or had a clinically significant increase in serum

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creatinine for greater than 1 month (21/26). Creatinine levels returned to normal range in 7 of 11 patients

in whom cyclosporine therapy was discontinued.

There is an increased risk for the development of skin and lymphoproliferative malignancies in

cyclosporine-treated psoriasis patients. The relative risk of malignancies is comparable to that observed in

psoriasis patients treated with other immunosuppressive agents.

Tumors were reported in 32 (2.2%) of 1439 psoriasis patients treated with cyclosporine worldwide from

clinical trials. Additional tumors have been reported in 7 patients in cyclosporine postmarketing

experience. Skin malignancies were reported in 16 (1.1%) of these patients; all but 2 of them had

previously received PUVA therapy. Methotrexate was received by 7 patients. UVB and coal tar had been

used by 2 and 3 patients, respectively. Seven patients had either a history of previous skin cancer or a

potentially predisposing lesion was present prior to cyclosporine exposure. Of the 16 patients with skin

cancer, 11 patients had 18 squamous cell carcinomas and 7 patients had 10 basal cell carcinomas.

There were two lymphoproliferative malignancies; one case of non-Hodgkin’s lymphoma which required

chemotherapy, and one case of mycosis fungoides which regressed spontaneously upon discontinuation of

cyclosporine. There were four cases of benign lymphocytic infiltration: 3 regressed spontaneously upon

discontinuation of cyclosporine, while the fourth regressed despite continuation of the drug. The

remainder of the malignancies, 13 cases (0.9%), involved various organs.

Patients should not be treated concurrently with cyclosporine and PUVA or UVB, other radiation

therapy, or other immunosuppressive agents, because of the possibility of excessive

immunosuppression and the subsequent risk of malignancies. (See CONTRAINDICATIONS) Patients

should also be warned to protect themselves appropriately when in the sun, and to avoid excessive sun

exposure. Patients should be thoroughly evaluated before and during treatment for the presence of

malignancies remembering that malignant lesions may be hidden by psoriatic plaques. Skin lesions not

typical of psoriasis should be biopsied before starting treatment. Patients should be treated with Neoral

only after complete resolution of suspicious lesions, and only if there are no other treatment options. (See

Special Monitoring for Psoriasis Patients)

PRECAUTIONS

General

Hypertension

Cyclosporine is the active ingredient of Neoral

. Hypertension is a common side effect of cyclosporine

therapy which may persist. (See ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION for

monitoring recommendations) Mild or moderate hypertension is encountered more frequently than severe

hypertension and the incidence decreases over time. In recipients of kidney, liver, and heart allografts

treated with cyclosporine, antihypertensive therapy may be required. (See Special Monitoring of

Rheumatoid Arthritis and Psoriasis Patients) However, since cyclosporine may cause hyperkalemia,

potassium-sparing diuretics should not be used. While calcium antagonists can be effective agents in

treating cyclosporine-associated hypertension, they can interfere with cyclosporine metabolism. (See

Drug Interactions)

Vaccination

During treatment with cyclosporine, vaccination may be less effective; and the use of live attenuated

vaccines should be avoided.

Special Monitoring of Rheumatoid Arthritis Patients

Before initiating treatment, a careful physical examination, including blood pressure measurements (on at

least two occasions) and two creatinine levels to estimate baseline should be performed. Blood pressure

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and serum creatinine should be evaluated every 2 weeks during the initial 3 months and then monthly if

the patient is stable. It is advisable to monitor serum creatinine and blood pressure always after an

increase of the dose of nonsteroidal anti-inflammatory drugs and after initiation of new nonsteroidal anti-

inflammatory drug therapy during Neoral

treatment. If co-administered with methotrexate, CBC and

liver function tests are recommended to be monitored monthly. (See also PRECAUTIONS, General,

Hypertension)

In patients who are receiving cyclosporine, the dose of Neoral

should be decreased by 25%-50% if

hypertension occurs. If hypertension persists, the dose of Neoral

should be further reduced or blood

pressure should be controlled with antihypertensive agents. In most cases, blood pressure has returned to

baseline when cyclosporine was discontinued.

In placebo-controlled trials of rheumatoid arthritis patients, systolic hypertension (defined as an

occurrence of two systolic blood pressure readings >140 mmHg) and diastolic hypertension (defined as

two diastolic blood pressure readings >90 mmHg) occurred in 33% and 19% of patients treated with

cyclosporine, respectively. The corresponding placebo rates were 22% and 8%.

Special Monitoring for Psoriasis Patients

Before initiating treatment, a careful dermatological and physical examination, including blood pressure

measurements (on at least two occasions) should be performed. Since Neoral

is an immunosuppressive

agent, patients should be evaluated for the presence of occult infection on their first physical examination

and for the presence of tumors initially, and throughout treatment with Neoral

. Skin lesions not typical

for psoriasis should be biopsied before starting Neoral

. Patients with malignant or premalignant changes

of the skin should be treated with Neoral

only after appropriate treatment of such lesions and if no other

treatment option exists.

Baseline laboratories should include serum creatinine (on two occasions), BUN, CBC, serum magnesium,

potassium, uric acid, and lipids.

The risk of cyclosporine nephropathy is reduced when the starting dose is low (2.5 mg/kg/day), the

maximum dose does not exceed 4.0 mg/kg/day, serum creatinine is monitored regularly while

cyclosporine is administered, and the dose of Neoral

is decreased when the rise in creatinine is greater

than or equal to 25% above the patient’s pretreatment level. The increase in creatinine is generally

reversible upon timely decrease of the dose of Neoral

or its discontinuation.

Serum creatinine and BUN should be evaluated every 2 weeks during the initial 3 months of therapy and

then monthly if the patient is stable. If the serum creatinine is greater than or equal to 25% above the

patient’s pretreatment level, serum creatinine should be repeated within two weeks. If the change in serum

creatinine remains greater than or equal to 25% above baseline, Neoral

should be reduced by 25%-50%.

If at any time the serum creatinine increases by greater than or equal to 50% above pretreatment level,

Neoral

should be reduced by 25%-50%. Neoral

should be discontinued if reversibility (within 25% of

baseline) of serum creatinine is not achievable after two dosage modifications. It is advisable to monitor

serum creatinine after an increase of the dose of nonsteroidal anti-inflammatory drug and after initiation

of new nonsteroidal anti-inflammatory therapy during Neoral

treatment.

Blood pressure should be evaluated every 2 weeks during the initial 3 months of therapy and then

monthly if the patient is stable, or more frequently when dosage adjustments are made. Patients without a

history of previous hypertension before initiation of treatment with Neoral

, should have the drug reduced

by 25%-50% if found to have sustained hypertension. If the patient continues to be hypertensive despite

multiple reductions of Neoral

, then Neoral

should be discontinued. For patients with treated

hypertension, before the initiation of Neoral

therapy, their medication should be adjusted to control

hypertension while on Neoral

. Neoral

should be discontinued if a change in hypertension management

is not effective or tolerable.

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CBC, uric acid, potassium, lipids, and magnesium should also be monitored every 2 weeks for the first 3

months of therapy, and then monthly if the patient is stable or more frequently when dosage adjustments

are made. Neoral

dosage should be reduced by 25%-50% for any abnormality of clinical concern.

In controlled trials of cyclosporine in psoriasis patients, cyclosporine blood concentrations did not

correlate well with either improvement or with side effects such as renal dysfunction.

Information for Patients: Patients should be advised that any change of cyclosporine formulation

should be made cautiously and only under physician supervision because it may result in the need

for a change in dosage.

Patients should be informed of the necessity of repeated laboratory tests while they are receiving

cyclosporine. Patients should be advised of the potential risks during pregnancy and informed of the

increased risk of neoplasia. Patients should also be informed of the risk of hypertension and renal

dysfunction.

Patients should be advised that during treatment with cyclosporine, vaccination may be less effective and

the use of live attenuated vaccines should be avoided.

Patients should be given careful dosage instructions. Neoral

Oral Solution (cyclosporine oral solution,

USP) MODIFIED should be diluted, preferably with orange or apple juice that is at room temperature.

The combination of Neoral

Oral Solution (cyclosporine oral solution, USP) MODIFIED with milk can

be unpalatable.

Patients should be advised to take Neoral

on a consistent schedule with regard to time of day and

relation to meals. Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of

cyclosporine, thus should be avoided.

Laboratory Tests

In all patients treated with cyclosporine, renal and liver functions should be assessed repeatedly by

measurement of serum creatinine, BUN, serum bilirubin, and liver enzymes. Serum lipids, magnesium,

and potassium should also be monitored. Cyclosporine blood concentrations should be routinely

monitored in transplant patients (see DOSAGE AND ADMINISTRATION, Blood Concentration

Monitoring in Transplant Patients), and periodically monitored in rheumatoid arthritis patients.

Drug Interactions

All of the individual drugs cited below are well substantiated to interact with cyclosporine. In addition,

concomitant non-steroidal anti-inflammatory drugs, particularly in the setting of dehydration, may

potentiate renal dysfunction.

Drugs That May Potentiate Renal Dysfunction

Anti-

Antibiotics

Antineoplastics

Antifungals

inflammatory

Drugs

Gastrointestinal

Agents

Immunosuppressives Other Drugs

fibric acid

ciprofloxacin melphalan amphotericin B azapropazon cimetidine tacrolimus derivatives

gentamicin ketoconazole colchicine ranitidine

(e.g., bezafibrate,

fenofibrate)

methotrexate

tobramycin

diclofenac

vancomycin naproxen

trimethoprim with

sulfamethoxazole

sulindac

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Drugs That Alter Cyclosporine Concentrations

Cyclosporine is extensively metabolized by CYP 3A isoenzymes, in particular CYP3A4, and is a

substrate of the multidrug efflux transporter P-glycoprotein. Various agents are known to either increase

or decrease plasma or whole blood of cyclosporine levels usually by inhibition or induction of CYP3A4

or P-glycoprotein transporter or both. Compounds that decrease cyclosporine absorption such as orlistat

should be avoided. Monitoring of circulating cyclosporine concentrations and appropriate Neoral

dosage

adjustment are essential when these drugs are used concomitantly. (See Blood Concentration Monitoring)

Drugs That Increase Cyclosporine Concentrations

Calcium Channel Blockers Antifungals Antibiotics Glucocorticoids Other Drugs

diltiazem fluconazole azithromycin methylprednisolone Allopurinol

nicardipine itraconazole clarithromycin Amiodarone

verapamil ketoconazole erythromycin Bromocriptine

voriconazole quinupristin/ dalfopristin colchicine

danazol

imatinib

metoclopramide

nefazodone

oral contraceptives

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 bosentan St. John’s Wort

rifampin oxcarbazepine octreotide

phenobarbital orlistat

phenytoin sulfinpyrazone

terbinafine

ticlopidine

There have been reports of a serious drug interaction between cyclosporine and the herbal dietary

supplement, St. John’s Wort. This interaction has been reported to produce a marked reduction in

the blood concentrations of cyclosporine, resulting in subtherapeutic levels, rejection of

transplanted organs, and graft loss.

Rifabutin is known to increase the metabolism of other drugs metabolized by the cytochrome P-450

system. The interaction between rifabutin and cyclosporine has not been studied. Care should be exercised

when these two drugs are administered concomitantly.

Nonsteroidal Anti-inflammatory Drug (NSAID) Interactions

Clinical status and serum creatinine should be closely monitored when cyclosporine is used with

nonsteroidal anti-inflammatory agents in rheumatoid arthritis patients. (See WARNINGS)

Pharmacodynamic interactions have been reported to occur between cyclosporine and both naproxen and

sulindac, in that concomitant use is associated with additive decreases in renal function, as determined by

99m

Tc-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

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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

Cyclosporine is an inhibitor of CYP3A4 and of the multidrug efflux transporter P-glycoprotein and

may increase plasma concentrations of comedications that are substrates of CYP3A4 or P-

glycoprotein or both.

Cyclosporine may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase

inhibitors (statins) and etoposide. Severe digitalis toxicity has been seen within days of starting

cyclosporine in several patients taking digoxin. There are also reports on the potential of

cyclosporine to enhance the toxic effects of colchicine such as myopathy and neuropathy, especially

in patients with renal dysfunction. If digoxin or colchicine are used concurrently with cyclosporine,

close clinical observation is required in order to enable early detection of toxic manifestations of

digoxin or colchicine, followed by reduction of dosage or its withdrawal.

Literature and postmarketing cases of myotoxicity, including muscle pain and weakness, myositis,

and rhabdomyolysis, have been reported with concomitant administration of cyclosporine with

lovastatin, simvastatin, atorvastatin, pravastatin, and, rarely fluvastatin. When concurrently

administered with cyclosporine, the dosage of these statins should be reduced according to label

recommendations. Statin therapy needs to be temporarily withheld or discontinued in patients with

signs and symptoms of myopathy or those with risk factors predisposing to severe renal injury,

including renal failure, secondary to rhabdomyolysis.

Cyclosporine may increase the plasma concentrations of repaglinide and thereby increase the risk of

hypoglycemia. In 12 healthy male subjects who received two doses of 100mg cyclosporine capsule

orally 12 hours apart with a single dose of 0.25mg repaglinide tablet (one half of a 0.5mg tablet)

orally 13 hours after the cyclosporine initial dose, the repaglinide mean Cmax and AUC were

increased 1.8 fold (range: 0.6 - 3.7 fold) and 2.4 fold (range 1.2 - 5.3 fold), respectively. Close

monitoring of blood glucose level is advisable for a patient taking cyclosporine and repaglinide

concomitantly.

Cyclosporine should not be used with potassium-sparing diuretics because hyperkalemia can occur.

Caution is also required when cyclosporine is co-administered with potassium sparing drugs (e.g.

angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists), potassium containing

drugs as well as in patients on a potassium rich diet. Control of potassium levels in these situations is

advisable.

Elevations in serum creatinine were observed in studies using sirolimus in combination with full-dose

cyclosporine. This effect is often reversible with cyclosporine dose reduction. Simultaneous co-

administration of cyclosporine significantly increases blood levels of sirolimus. To minimize increases in

sirolimus concentrations, it is recommended that sirolimus be given 4 hours after cyclosporine

administration.

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During treatment with cyclosporine, vaccination may be less effective. The use of live vaccines should be

avoided. Frequent gingival hyperplasia with nifedipine, and convulsions with high dose

methylprednisolone have been reported.

Psoriasis patients receiving other immunosuppressive agents or radiation therapy (including PUVA and

UVB) should not receive concurrent cyclosporine because of the possibility of excessive

immunosuppression.

For additional information on Cyclosporine Drug Interactions please contact Novartis Medical Affairs

Department at 888-NOW-NOVA [888-669-6682].

Carcinogenesis, Mutagenesis, and Impairment of Fertility

Carcinogenicity studies were carried out in male and female rats and mice. In the 78-week mouse study,

evidence of a statistically significant trend was found for lymphocytic lymphomas in females, and the

incidence of hepatocellular carcinomas in mid-dose males significantly exceeded the control value. In the

24-month rat study, pancreatic islet cell adenomas significantly exceeded the control rate in the low dose

level. Doses used in the mouse and rat studies were 0.01 to 0.16 times the clinical maintenance dose (6

mg/kg). The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related.

Published reports indicate that co-treatment of hairless mice with UV irradiation and cyclosporine or other

immunosuppressive agents shorten the time to skin tumor formation compared to UV irradiation alone.

Cyclosporine was not mutagenic in appropriate test systems. Cyclosporine has not been found to be

mutagenic/genotoxic in the Ames Test, the V79-HGPRT Test, the micronucleus test in mice and Chinese

hamsters, the chromosome-aberration tests in Chinese hamster bone-marrow, the mouse dominant lethal

assay, and the DNA-repair test in sperm from treated mice. A recent study analyzing sister chromatid

exchange (SCE) induction by cyclosporine using human lymphocytes in vitro gave indication of a

positive effect (i.e., induction of SCE), at high concentrations in this system. In two published research

studies, rabbits exposed to cyclosporine in utero (10 mg/kg/day subcutaneously) demonstrated reduced

numbers of nephrons, renal hypertrophy, systemic hypertension and progressive renal insufficiency up to

35 weeks of age. Pregnant rats which received 12 mg/kg/day of cyclosporine intravenously (twice the

recommended human intravenous dose) had fetuses with an increased incidence of ventricular septal

defect. These findings have not been demonstrated in other species and their relevance for humans is

unknown.

No impairment in fertility was demonstrated in studies in male and female rats.

Widely distributed papillomatosis of the skin was observed after chronic treatment of dogs with

cyclosporine at 9 times the human initial psoriasis treatment dose of 2.5 mg/kg, where doses are

expressed on a body surface area basis. This papillomatosis showed a spontaneous regression upon

discontinuation of cyclosporine.

An increased incidence of malignancy is a recognized complication of immunosuppression in recipients

of organ transplants and patients with rheumatoid arthritis and psoriasis. The most common forms of

neoplasms are non-Hodgkin’s lymphoma and carcinomas of the skin. The risk of malignancies in

cyclosporine recipients is higher than in the normal, healthy population but similar to that in patients

receiving other immunosuppressive therapies. Reduction or discontinuance of immunosuppression may

cause the lesions to regress.

In psoriasis patients on cyclosporine, development of malignancies, especially those of the skin has been

reported. (See WARNINGS) Skin lesions not typical for psoriasis should be biopsied before starting

cyclosporine treatment. Patients with malignant or premalignant changes of the skin should be treated

with cyclosporine only after appropriate treatment of such lesions and if no other treatment option exists.

This label may not be the latest approved by FDA.

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Pregnancy:

Pregnancy Category C

Animal studies have shown reproductive toxicity in rats and rabbits. Cyclosporine gave no evidence of

mutagenic or teratogenic effects in the standard test systems with oral application (rats up to 17 mg/kg

and rabbits up to 30 mg/kg per day orally.) Only at dose levels toxic to dams, were adverse effects seen in

reproduction studies in rats. Cyclosporine has been shown to be embryo- and fetotoxic in rats and rabbits

following oral administration at maternally toxic doses. Fetal toxicity was noted in rats at 0.8 and rabbits

at 5.4 times the transplant doses in humans of 6.0 mg/kg, where dose corrections are based on body

surface area. Cyclosporine was embryo- and fetotoxic as indicated by increased pre- and postnatal

mortality and reduced fetal weight together with related skeletal retardation.

There are no adequate and well-controlled studies in pregnant women therefore, Neoral

should not be

used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus.

In pregnant transplant recipients who are being treated with immunosuppressants the risk of premature

birth is increased. The following data represent the reported outcomes of 116 pregnancies in women

receiving cyclosporine during pregnancy, 90% of whom were transplant patients, and most of whom

received cyclosporine throughout the entire gestational period. The only consistent patterns of

abnormality were premature birth (gestational period of 28 to 36 weeks) and low birth weight for

gestational age. Sixteen fetal losses occurred. Most of the pregnancies (85 of 100) were complicated by

disorders; including, pre-eclampsia, eclampsia, premature labor, abruptio placentae, oligohydramnios, Rh

incompatibility, and fetoplacental dysfunction. Pre-term delivery occurred in 47%. Seven malformations

were reported in 5 viable infants and in 2 cases of fetal loss. Twenty-eight percent of the infants were

small for gestational age. Neonatal complications occurred in 27%. Therefore, the risks and benefits of

using Neoral

during pregnancy should be carefully weighed.

A limited number of observations in children exposed to cyclosporine in utero are available, up to an age

of approximately 7 years. Renal function and blood pressure in these children were normal.

Because of the possible disruption of maternal-fetal interaction, the risk/benefit ratio of using Neoral

psoriasis patients during pregnancy should carefully be weighed with serious consideration for

discontinuation of Neoral

Nursing Mothers

Cyclosporine passes into breast milk. Mothers receiving treatment with Neoral

should not breast-feed.

Pediatric Use

Although no adequate and well-controlled studies have been completed in children, transplant recipients

as young as one year of age have received Neoral

with no unusual adverse effects. The safety and

efficacy of Neoral

treatment in children with juvenile rheumatoid arthritis or psoriasis below the age of

18 have not been established.

Geriatric Use

In rheumatoid arthritis clinical trials with cyclosporine, 17.5% of patients were age 65 or older. These

patients were more likely to develop systolic hypertension on therapy, and more likely to show serum

creatinine rises ≥50% above the baseline after 3-4 months of therapy.

Clinical studies of Neoral

in transplant and psoriasis patients did not include a sufficient number of

subjects aged 65 and over to determine whether they respond differently from younger subjects. Other

reported clinical experiences have not identified differences in response between the elderly and younger

patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end

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of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and

of concomitant disease or other drug therapy.

ADVERSE REACTIONS

Kidney, Liver, and Heart Transplantation

The principal adverse reactions of cyclosporine therapy are renal dysfunction, tremor, hirsutism,

hypertension, and gum hyperplasia.

Hypertension, which is usually mild to moderate, may occur in approximately 50% of patients following

renal transplantation and in most cardiac transplant patients.

Glomerular capillary thrombosis has been found in patients treated with cyclosporine and may progress to

graft failure. The pathologic changes resembled those seen in the hemolytic-uremic syndrome and

included thrombosis of the renal microvasculature, with platelet-fibrin thrombi occluding glomerular

capillaries and afferent arterioles, microangiopathic hemolytic anemia, thrombocytopenia, and decreased

renal function. Similar findings have been observed when other immunosuppressives have been employed

post-transplantation.

Hypomagnesemia has been reported in some, but not all, patients exhibiting convulsions while on

cyclosporine therapy. Although magnesium-depletion studies in normal subjects suggest that

hypomagnesemia is associated with neurologic disorders, multiple factors, including hypertension, high

dose methylprednisolone, hypocholesterolemia, and nephrotoxicity associated with high plasma

concentrations of cyclosporine appear to be related to the neurological manifestations of cyclosporine

toxicity.

In controlled studies, the nature, severity, and incidence of the adverse events that were observed in 493

transplanted patients treated with Neoral

were comparable with those observed in 208 transplanted

patients who received Sandimmune

in these same studies when the dosage of the two drugs was adjusted

to achieve the same cyclosporine blood trough concentrations.

Based on the historical experience with Sandimmune

, the following reactions occurred in 3% or greater

of 892 patients involved in clinical trials of kidney, heart, and liver transplants.

Randomized Kidney Patients Cyclosporine Patients (Sandimmune

)

Sandimmune

Azathioprine Kidney Heart Liver

Body System Adverse Reactions (N=227)% (N=228)% (N=705)% (N=112)% (N=75)%

Genitourinary Renal Dysfunction 32 6 25 38 37

Cardiovascular Hypertension 26 18 13 53 27

Cramps 4 <1 2 <1 0

Skin Hirsutism 21 <1 21 28 45

Acne 6 8 2 2 1

Central Nervous System Tremor 12 0 21 31 55

Convulsions 3 1 1 4 5

Headache 2 <1 2 15 4

Gastrointestinal Gum Hyperplasia 4 0 9 5 16

Diarrhea 3 <1 3 4 8

Nausea/Vomiting 2 <1 4 10 4

Hepatotoxicity <1 <1 4 7 4

Abdominal Discomfort <1 0 <1 7 0

Autonomic Nervous

System Paresthesia 3 0 1 2 1

Flushing <1 0 4 0 4

Hematopoietic Leukopenia 2 19 <1 6 0

Lymphoma <1 0 1 6 1

Respiratory Sinusitis <1 0 4 3 7

Miscellaneous Gynecomastia <1 0 <1 4 3

Among 705 kidney transplant patients treated with cyclosporine oral solution (Sandimmune

)

in clinical

trials, the reason for treatment discontinuation was renal toxicity in 5.4%, infection in 0.9%, lack of

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For current labeling information, please visit https://www.fda.gov/drugsatfda

efficacy in 1.4%, acute tubular necrosis in 1.0%, lymphoproliferative disorders in 0.3%, hypertension in

0.3%, and other reasons in 0.7% of the patients.

The following reactions occurred in 2% or less of Sandimmune

-treated patients: allergic reactions,

anemia, anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails, gastritis, hearing loss,

hiccups, hyperglycemia, muscle pain, peptic ulcer, thrombocytopenia, tinnitus.

The following reactions occurred rarely: anxiety, chest pain, constipation, depression, hair breaking,

hematuria, joint pain, lethargy, mouth sores, myocardial infarction, night sweats, pancreatitis, pruritus,

swallowing difficulty, tingling, upper GI bleeding, visual disturbance, weakness, weight loss.

Patients receiving immunosuppressive therapies, including cyclosporine and cyclosporine -containing

regimens, are at increased risk of infections (viral, bacterial, fungal, parasitic). Both generalized and

localized infections can occur. Pre-existing infections may also be aggravated. Fatal outcomes have been

reported. (see Warnings)

Infectious Complications in Historical Randomized Studies

in Renal Transplant Patients Using Sandimmune®

Cyclosporine Treatment Azathioprine with Steroids*

(N=227) (N=228)

Complication % of Complications % of Complications

Septicemia 5.3 4.8

Abscesses 4.4 5.3

Systemic Fungal Infection 2.2 3.9

Local Fungal Infection 7.5 9.6

Cytomegalovirus 4.8 12.3

Other Viral Infections 15.9 18.4

Urinary Tract Infections 21.1 20.2

Wound and Skin Infections 7.0 10.1

Pneumonia 6.2 9.2

*Some patients also received ALG.

Postmarketing Experience, Kidney, Liver and Heart Transplantation

BK virus associated nephropathy has been observed in patients receiving immunosuppressants, including

Neoral. This infection is associated with serious outcomes, including deteriorating renal function and

renal graft loss. (see WARNINGS, Kidney, Liver and Heart Transplant).

Rheumatoid Arthritis

The principal adverse reactions associated with the use of cyclosporine in rheumatoid arthritis are renal

dysfunction (see WARNINGS), hypertension (see PRECAUTIONS), headache, gastrointestinal

disturbances, and hirsutism/hypertrichosis.

In rheumatoid arthritis patients treated in clinical trials within the recommended dose range, cyclosporine

therapy was discontinued in 5.3% of the patients because of hypertension and in 7% of the patients

because of increased creatinine. These changes are usually reversible with timely dose decrease or drug

discontinuation. The frequency and severity of serum creatinine elevations increase with dose and

duration of cyclosporine therapy. These elevations are likely to become more pronounced without dose

reduction or discontinuation.

The following adverse events occurred in controlled clinical trials:

Neoral

/Sandimmune

Rheumatoid Arthritis

Percentage of Patients with Adverse Events ≥3% in any Cyclosporine Treated Group

Studies Study Study Study Study Studies

651+652+2008 302 654 654 302 651+652+2008

Methotrexate & Methotrexate

Body

System

Preferred

Term

Sandimmune

†

(N=269)

Sandimmune

(N=155)

Sandimmune

(N=74)

& Placebo

(N=73)

Neoral

(N=143)

Placebo

(N=201)

Autonomic Nervous System Disorders

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Flushing 2% 2% 3% 0% 5% 2%

Body As A Whole–General Disorders

Accidental

Trauma 0% 1% 10% 4% 4% 0%

Edema NOS* 5% 14% 12% 4% 10% <1%

Fatigue 6% 3% 8% 12% 3% 7%

Fever 2% 3% 0% 0% 2% 4%

Influenza-like

symptoms <1% 6% 1% 0% 3% 2%

Pain 6% 9% 10% 15% 13% 4%

Rigors 1% 1% 4% 0% 3% 1%

Cardiovascular Disorders

Arrhythmia 2% 5% 5% 6% 2% 1%

Chest Pain 4% 5% 1% 1% 6% 1%

Hypertension 8% 26% 16% 12% 25% 2%

Central and Peripheral Nervous System Disorders

Dizziness 8% 6% 7% 3% 8% 3%

Headache 17% 23% 22% 11% 25% 9%

Migraine 2% 3% 0% 0% 3% 1%

Paresthesia 8% 7% 8% 4% 11% 1%

Tremor 8% 7% 7% 3% 13% 4%

Gastrointestinal System Disorders

Abdominal Pain 15% 15% 15% 7% 15% 10%

Anorexia 3% 3% 1% 0% 3% 3%

Diarrhea 12%

12% 18% 15% 13% 8%

Dyspepsia 12% 12% 10% 8% 8% 4%

Flatulence 5% 5% 5% 4% 4% 1%

Gastrointestinal

Disorder NOS* 0% 2% 1% 4% 4% 0%

Gingivitis 4% 3% 0% 0% 0% 1%

Gum Hyperplasia 2% 4% 1% 3% 4% 1%

Nausea 23% 14% 24% 15% 18% 14%

Rectal

Hemorrhage 0% 3% 0% 0% 1% 1%

Stomatitis 7% 5% 16% 12% 6% 8%

Vomiting 9% 8% 14% 7% 6% 5%

Hearing and Vestibular Disorders

Ear Disorder

NOS* 0% 5% 0% 0% 1% 0%

Metabolic and Nutritional Disorders

Hypomagnesemia

Musculoskeletal System Disorders

0% 4% 0% 0% 6% 0%

Arthropathy 0% 5% 0% 1% 4% 0%

Leg Cramps /

Involuntary

Muscle

Contractions 2% 11% 11% 3% 12% 1%

Psychiatric Disorders

Depression 3% 6% 3% 1% 1% 2%

Insomnia 4% 1% 1% 0% 3% 2%

Renal

Creatinine

elevations ≥30% 43% 39% 55% 19% 48% 13%

Creatinine

elevations ≥50%

24% 18% 26% 8% 18%

Reproductive Disorders, Female

Leukorrhea 1% 0% 4% 0% 1% 0%

Menstrual

Disorder 3% 2% 1% 0% 1% 1%

Respiratory System Disorders

Bronchitis 1% 3% 1% 0% 1% 3%

Coughing 5% 3% 5% 7% 4% 4%

Dyspnea 5% 1% 3% 3% 1% 2%

Infection NOS* 9% 5% 0% 7% 3% 10%

Pharyngitis 3% 5% 5% 6% 4% 4%

Pneumonia 1% 0% 4% 0% 1% 1%

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Rhinitis 0% 3% 11% 10% 1% 0%

Sinusitis 4% 4% 8% 4% 3% 3%

Upper Respiratory

Tract

0% 14% 23% 15% 13% 0%

Skin and Appendages Disorders

Alopecia 3% 0% 1% 1% 4% 4%

Bullous Eruption 1% 0% 4% 1% 1% 1%

Hypertrichosis 19% 17% 12% 0% 15% 3%

Rash 7% 12% 10% 7% 8% 10%

Skin Ulceration 1% 1% 3% 4% 0% 2%

Urinary System Disorders

Dysuria

Micturition

0% 0% 11% 3% 1% 2%

Frequency

2% 4% 3% 1% 2% 2%

NPN, Increased 0% 19% 12% 0% 18% 0%

Urinary Tract

Infection 0% 3% 5% 4% 3% 0%

Vascular (Extracardiac) Disorders

Purpura 3% 4% 1% 1% 2% 0%

† Includes patients in 2.5 mg/kg/day dose group only. *NOS = Not Otherwise Specified.

In addition, the following adverse events have been reported in 1% to <3% of the rheumatoid arthritis

patients in the cyclosporine treatment group in controlled clinical trials.

Autonomic Nervous System: dry mouth, increased sweating;

Body as a Whole: allergy, asthenia, hot flushes, malaise, overdose, procedure NOS*, tumor NOS*,

weight decrease, weight increase;

Cardiovascular: abnormal heart sounds, cardiac failure, myocardial infarction, peripheral ischemia;

Central and Peripheral Nervous System: hypoesthesia, neuropathy, vertigo;

Endocrine: goiter;

Gastrointestinal: constipation, dysphagia, enanthema, eructation, esophagitis, gastric ulcer, gastritis,

gastroenteritis, gingival bleeding, glossitis, peptic ulcer, salivary gland enlargement, tongue disorder,

tooth disorder;

Infection: abscess, bacterial infection, cellulitis, folliculitis, fungal infection, herpes simplex, herpes

zoster, renal abscess, moniliasis, tonsillitis, viral infection;

Hematologic: anemia, epistaxis, leukopenia, lymphadenopathy;

Liver and Biliary System: bilirubinemia;

Metabolic and Nutritional: diabetes mellitus, hyperkalemia, hyperuricemia, hypoglycemia;

Musculoskeletal System: arthralgia, bone fracture, bursitis, joint dislocation, myalgia, stiffness,

synovial cyst, tendon disorder;

Neoplasms: breast fibroadenosis, carcinoma;

Psychiatric: anxiety, confusion, decreased libido, emotional lability, impaired concentration, increased

libido, nervousness, paroniria, somnolence;

Reproductive (Female): breast pain, uterine hemorrhage;

Respiratory System: abnormal chest sounds, bronchospasm;

Skin and Appendages: abnormal pigmentation, angioedema, dermatitis, dry skin, eczema, nail

disorder, pruritus, skin disorder, urticaria;

Special Senses: abnormal vision, cataract, conjunctivitis, deafness, eye pain, taste perversion, tinnitus,

vestibular disorder;

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Urinary System: abnormal urine, hematuria, increased BUN, micturition urgency, nocturia, polyuria,

pyelonephritis, urinary incontinence.

*NOS = Not Otherwise Specified.

Psoriasis

The principal adverse reactions associated with the use of cyclosporine in patients with psoriasis are renal

dysfunction, headache, hypertension, hypertriglyceridemia, hirsutism/hypertrichosis, paresthesia or

hyperesthesia, influenza-like symptoms, nausea/vomiting, diarrhea, abdominal discomfort, lethargy, and

musculoskeletal or joint pain.

In psoriasis patients treated in US controlled clinical studies within the recommended dose range,

cyclosporine therapy was discontinued in 1.0% of the patients because of hypertension and in 5.4% of the

patients because of increased creatinine. In the majority of cases, these changes were reversible after dose

reduction or discontinuation of cyclosporine.

There has been one reported death associated with the use of cyclosporine in psoriasis. A 27-year-old

male developed renal deterioration and was continued on cyclosporine. He had progressive renal failure

leading to death.

Frequency and severity of serum creatinine increases with dose and duration of cyclosporine therapy.

These elevations are likely to become more pronounced and may result in irreversible renal damage

without dose reduction or discontinuation.

Adverse Events Occurring in 3% or More of Psoriasis Patients in Controlled Clinical Trials

Body System* Preferred Term Neoral

(N=182) Sandimmune

(N=185)

Infection or Potential Infection 24.7% 24.3%

Influenza-Like Symptoms 9.9% 8.1%

Upper Respiratory Tract Infections 7.7% 11.3%

Cardiovascular System 28.0% 25.4%

Hypertension** 27.5% 25.4%

Urinary System 24.2% 16.2%

Increased Creatinine 19.8% 15.7%

Central and Peripheral Nervous

System 26.4% 20.5%

Headache 15.9% 14.0%

Paresthesia 7.1% 4.8%

Musculoskeletal System 13.2% 8.7%

Arthralgia 6.0% 1.1%

Body As a Whole–General 29.1% 22.2%

Pain 4.4% 3.2%

Metabolic and Nutritional 9.3% 9.7%

Reproductive, Female 8.5% (4 of 47 females) 11.5% (6 of 52 females)

Resistance Mechanism 18.7% 21.1%

Skin and Appendages 17.6% 15.1%

Hypertrichosis 6.6% 5.4%

Respiratory System

Bronchospasm, Coughing, Dyspnea,

5.0% 6.5%

Rhinitis

5.0% 4.9%

Psychiatric

5.0% 3.8%

Gastrointestinal System 19.8% 28.7%

Abdominal Pain 2.7% 6.0%

Diarrhea 5.0% 5.9%

Dyspepsia 2.2% 3.2%

Gum Hyperplasia 3.8% 6.0%

Nausea 5.5% 5.9%

White cell and RES 4.4% 2.7%

*Total percentage of events within the system

**Newly occurring hypertension = SBP≥160 mm Hg and/or DBP≥90 mm Hg

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The following events occurred in 1% to less than 3% of psoriasis patients treated with cyclosporine:

Body as a Whole: fever, flushes, hot flushes;

Cardiovascular: chest pain;

Central and Peripheral Nervous System: appetite increased, insomnia, dizziness, nervousness,

vertigo;

Gastrointestinal: abdominal distention, constipation, gingival bleeding;

Liver and Biliary System: hyperbilirubinemia;

Neoplasms: skin malignancies [squamous cell (0.9%) and basal cell (0.4%) carcinomas];

Reticuloendothelial: platelet, bleeding, and clotting disorders, red blood cell disorder;

Respiratory: infection, viral and other infection;

Skin and Appendages: acne, folliculitis, keratosis, pruritus, rash, dry skin;

Urinary System: micturition frequency;

Vision: abnormal vision.

Mild hypomagnesemia and hyperkalemia may occur but are asymptomatic. Increases in uric acid may

occur and attacks of gout have been rarely reported. A minor and dose related hyperbilirubinemia has

been observed in the absence of hepatocellular damage. Cyclosporine therapy may be associated with a

modest increase of serum triglycerides or cholesterol. Elevations of triglycerides (>750 mg/dL) occur in

about 15% of psoriasis patients; elevations of cholesterol (>300 mg/dL) are observed in less than 3% of

psoriasis patients. Generally these laboratory abnormalities are reversible upon dose reduction or

discontinuation of cyclosporine.

OVERDOSAGE

There is a minimal experience with cyclosporine overdosage. Forced emesis and gastric lavage can be of

value up to 2 hours after administration of Neoral

. Transient hepatotoxicity and nephrotoxicity may

occur which should resolve following drug withdrawal. Oral doses of cyclosporine up to 10 g (about 150

mg/kg) have been tolerated with relatively minor clinical consequences, such as vomiting, drowsiness,

headache, tachycardia and, in a few patients, moderately severe, reversible impairment of renal function.

However, serious symptoms of intoxication have been reported following accidental parenteral

overdosage with cyclosporine in premature neonates. General supportive measures and symptomatic

treatment should be followed in all cases of overdosage. Cyclosporine is not dialyzable to any great

extent, nor is it cleared well by charcoal hemoperfusion. The oral dosage at which half of experimental

animals are estimated to die is 31 times, 39 times, and >54 times the human maintenance dose for

transplant patients (6mg/kg; corrections based on body surface area) in mice, rats, and rabbits.

DOSAGE AND ADMINISTRATION

Neoral

Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Neoral

Oral Solution

(cyclosporine oral solution, USP) MODIFIED

Neoral

has increased bioavailability in comparison to Sandimmune

. Neoral

and Sandimmune

are not bioequivalent and cannot be used interchangeably without physician supervision.

The daily dose of Neoral

should always be given in two divided doses (BID). It is recommended that

Neoral

be administered on a consistent schedule with regard to time of day and relation to meals.

Grapefruit and grapefruit juice affect metabolism, increasing blood concentration of cyclosporine, thus

should be avoided.

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Newly Transplanted Patients

The initial oral dose of Neoral

can be given 4-12 hours prior to transplantation or be given

postoperatively. The initial dose of Neoral

varies depending on the transplanted organ and the other

immunosuppressive agents included in the immunosuppressive protocol. In newly transplanted patients,

the initial oral dose of Neoral

is the same as the initial oral dose of Sandimmune

. Suggested initial

doses are available from the results of a 1994 survey of the use of Sandimmune

in US transplant centers.

The mean ± SD initial doses were 9±3 mg/kg/day for renal transplant patients (75 centers), 8±4

mg/kg/day for liver transplant patients (30 centers), and 7±3 mg/kg/day for heart transplant patients

(24 centers). Total daily doses were divided into two equal daily doses. The Neoral

dose is subsequently

adjusted to achieve a pre-defined cyclosporine blood concentration. (See Blood Concentration Monitoring

in Transplant Patients, below) If cyclosporine trough blood concentrations are used, the target range is the

same for Neoral

as for Sandimmune

. Using the same trough concentration target range for Neoral

for Sandimmune

results in greater cyclosporine exposure when Neoral

is administered. (See

Pharmacokinetics, Absorption) Dosing should be titrated based on clinical assessments of rejection and

tolerability. Lower Neoral

doses may be sufficient as maintenance therapy.

Adjunct therapy with adrenal corticosteroids is recommended initially. Different tapering dosage

schedules of prednisone appear to achieve similar results. A representative dosage schedule based on the

patient’s weight started with 2.0 mg/kg/day for the first 4 days tapered to 1.0 mg/kg/day by 1 week, 0.6

mg/kg/day by 2 weeks, 0.3 mg/kg/day by 1 month, and 0.15 mg/kg/day by 2 months and thereafter as a

maintenance dose. Steroid doses may be further tapered on an individualized basis depending on status of

patient and function of graft. Adjustments in dosage of prednisone must be made according to the clinical

situation.

Conversion from Sandimmune

to Neoral

in Transplant Patients

In transplanted patients who are considered for conversion to Neoral

from Sandimmune

, Neoral

should be started with the same daily dose as was previously used with Sandimmune

(1:1 dose

conversion). The Neoral

dose should subsequently be adjusted to attain the pre-conversion cyclosporine

blood trough concentration. Using the same trough concentration target range for Neoral

as for

Sandimmune

results in greater cyclosporine exposure when Neoral

is administered. (See

Pharmacokinetics, Absorption) Patients with suspected poor absorption of Sandimmune

require different

dosing strategies. (See Transplant Patients with Poor Absorption of Sandimmune

, below) In some

patients, the increase in blood trough concentration is more pronounced and may be of clinical

significance.

Until the blood trough concentration attains the pre-conversion value, it is strongly recommended

that the cyclosporine blood trough concentration be monitored every 4 to 7 days after conversion to

Neoral

. In addition, clinical safety parameters such as serum creatinine and blood pressure should be

monitored every two weeks during the first two months after conversion. If the blood trough

concentrations are outside the desired range and/or if the clinical safety parameters worsen, the dosage of

Neoral

must be adjusted accordingly.

Transplant Patients with Poor Absorption of Sandimmune

Patients with lower than expected cyclosporine blood trough concentrations in relation to the oral dose of

Sandimmune

may have poor or inconsistent absorption of cyclosporine from Sandimmune

. After

conversion to Neoral

, patients tend to have higher cyclosporine concentrations. Due to the increase in

bioavailability of cyclosporine following conversion to Neoral

, the cyclosporine blood trough

concentration may exceed the target range. Particular caution should be exercised when converting

patients to Neoral

at doses greater than 10 mg/kg/day. The dose of Neoral

should be titrated

individually based on cyclosporine trough concentrations, tolerability, and clinical response. In this

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population the cyclosporine blood trough concentration should be measured more frequently, at least

twice a week (daily, if initial dose exceeds 10 mg/kg/day) until the concentration stabilizes within the

desired range.

Rheumatoid Arthritis

The initial dose of Neoral

is 2.5 mg/kg/day, taken twice daily as a divided (BID) oral dose. Salicylates,

nonsteroidal anti-inflammatory agents, and oral corticosteroids may be continued. (See WARNINGS and

PRECAUTIONS, Drug Interactions) Onset of action generally occurs between 4 and 8 weeks. If

insufficient clinical benefit is seen and tolerability is good (including serum creatinine less than 30%

above baseline), the dose may be increased by 0.5-0.75 mg/kg/day after 8 weeks and again after 12 weeks

to a maximum of 4 mg/kg/day. If no benefit is seen by 16 weeks of therapy, Neoral

therapy should be

discontinued.

Dose decreases by 25%-50% should be made at any time to control adverse events, e.g., hypertension

elevations in serum creatinine (30% above patient’s pretreatment level) or clinically significant laboratory

abnormalities. (See WARNINGS and PRECAUTIONS)

If dose reduction is not effective in controlling abnormalities or if the adverse event or abnormality is

severe, Neoral

should be discontinued. The same initial dose and dosage range should be used if Neoral

is combined with the recommended dose of methotrexate. Most patients can be treated with Neoral

doses of 3 mg/kg/day or below when combined with methotrexate doses of up to 15 mg/week. (See

CLINICAL PHARMACOLOGY, Clinical Trials)

There is limited long-term treatment data. Recurrence of rheumatoid arthritis disease activity is generally

apparent within 4 weeks after stopping cyclosporine.

Psoriasis

The initial dose of Neoral

should be 2.5 mg/kg/day. Neoral

should be taken twice daily, as a divided

(1.25 mg/kg BID) oral dose. Patients should be kept at that dose for at least 4 weeks, barring adverse

events. If significant clinical improvement has not occurred in patients by that time, the patient’s dosage

should be increased at 2-week intervals. Based on patient response, dose increases of approximately 0.5

mg/kg/day should be made to a maximum of 4.0 mg/kg/day.

Dose decreases by 25%-50% should be made at any time to control adverse events, e.g., hypertension,

elevations in serum creatinine (≥25% above the patient’s pretreatment level), or clinically significant

laboratory abnormalities. If dose reduction is not effective in controlling abnormalities, or if the adverse

event or abnormality is severe, Neoral

should be discontinued. (See Special Monitoring of Psoriasis

Patients)

Patients generally show some improvement in the clinical manifestations of psoriasis in 2 weeks.

Satisfactory control and stabilization of the disease may take 12-16 weeks to achieve. Results of a dose-

titration clinical trial with Neoral

indicate that an improvement of psoriasis by 75% or more (based on

PASI) was achieved in 51% of the patients after 8 weeks and in 79% of the patients after 16 weeks.

Treatment should be discontinued if satisfactory response cannot be achieved after 6 weeks at 4

mg/kg/day or the patient’s maximum tolerated dose. Once a patient is adequately controlled and appears

stable the dose of Neoral

should be lowered, and the patient treated with the lowest dose that maintains

an adequate response (this should not necessarily be total clearing of the patient). In clinical trials,

cyclosporine doses at the lower end of the recommended dosage range were effective in maintaining a

satisfactory response in 60% of the patients. Doses below 2.5 mg/kg/day may also be equally effective.

Upon stopping treatment with cyclosporine, relapse will occur in approximately 6 weeks (50% of the

patients) to 16 weeks (75% of the patients). In the majority of patients rebound does not occur after

cessation of treatment with cyclosporine. Thirteen cases of transformation of chronic plaque psoriasis to

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more severe forms of psoriasis have been reported. There were 9 cases of pustular and 4 cases of

erythrodermic psoriasis. Long term experience with Neoral

in psoriasis patients is limited and

continuous treatment for extended periods greater than one year is not recommended. Alternation with

other forms of treatment should be considered in the long term management of patients with this life long

disease.

Neoral

Oral Solution (cyclosporine oral solution, USP) MODIFIED–

Recommendations for Administration

To make Neoral

Oral Solution (cyclosporine oral solution, USP) MODIFIED more palatable, it should

be diluted with orange or apple juice that is at room temperature. Patients should avoid switching diluents

frequently. Grapefruit juice affects metabolism of cyclosporine and should be avoided. The combination

of Neoral

solution with milk can be unpalatable. The effect of milk on the bioavailability of cyclosporine

when adminstered as Neoral Oral Solution has not been evaluated.

Take the prescribed amount of Neoral

Oral Solution (cyclosporine oral solution, USP) MODIFIED from

the container using the dosing syringe supplied, after removal of the protective cover, and transfer the

solution to a glass of orange or apple juice. Stir well and drink at once. Do not allow diluted oral solution

to stand before drinking. Use a glass container (not plastic). Rinse the glass with more diluent to ensure

that the total dose is consumed. After use, dry the outside of the dosing syringe with a clean towel and

replace the protective cover. Do not rinse the dosing syringe with water or other cleaning agents. If the

syringe requires cleaning, it must be completely dry before resuming use.

Blood Concentration Monitoring in Transplant Patients

Transplant centers have found blood concentration monitoring of cyclosporine to be an essential

component of patient management. Of importance to blood concentration analysis are the type of assay

used, the transplanted organ, and other immunosuppressant agents being administered. While no fixed

relationship has been established, blood concentration monitoring may assist in the clinical evaluation of

rejection and toxicity, dose adjustments, and the assessment of compliance.

Various assays have been used to measure blood concentrations of cyclosporine. Older studies using a

nonspecific assay often cited concentrations that were roughly twice those of the specific assays.

Therefore, comparison between concentrations in the published literature and an individual patient

concentration using current assays must be made with detailed knowledge of the assay methods

employed. Current assay results are also not interchangeable and their use should be guided by their

approved labeling. A discussion of the different assay methods is contained in Annals of Clinical

Biochemistry 1994;31:420-446. While several assays and assay matrices are available, there is a

consensus that parent-compound-specific assays correlate best with clinical events. Of these, HPLC is the

standard reference, but the monoclonal antibody RIAs and the monoclonal antibody FPIA offer

sensitivity, reproducibility, and convenience. Most clinicians base their monitoring on trough

cyclosporine concentrations. Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring

(1992) contains a broad discussion of cyclosporine pharmacokinetics and drug monitoring techniques.

Blood concentration monitoring is not a replacement for renal function monitoring or tissue biopsies.

HOW SUPPLIED

Neoral

Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED

25 mg

Oval, blue-gray imprinted in red, “Neoral” over “25 mg.”

Packages of 30 unit-dose blisters (NDC 0078-0246-15).

100 mg

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Oblong, blue-gray imprinted in red, “NEORAL” over “100 mg.”

Packages of 30 unit-dose blisters (NDC 0078-0248-15).

Store and Dispense

In the original unit-dose container at controlled room temperature 68°-77°F (20°-25°C).

Neoral

Oral Solution (cyclosporine oral solution, USP) MODIFIED

A clear, yellow liquid supplied in 50 mL bottles containing 100 mg/mL (NDC 0078-0274-22).

Store and Dispense

In the original container at controlled room temperature 68°-77°F (20°-25°C). Do not store in the

refrigerator. Once opened, the contents must be used within two months. At temperatures below 68°F

(20°C) the solution may gel; light flocculation or the formation of a light sediment may also occur. There

is no impact on product performance or dosing using the syringe provided. Allow to warm to room

temperature 77°F (25°C) to reverse these changes.

Neoral

Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED

Neoral

Oral Solution (cyclosporine oral solution, USP) MODIFIED

Distributed by:

Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936

REV: October 2009 T2009-16

This label may not be the latest approved by FDA.

For current labeling information, please visit https://www.fda.gov/drugsatfda