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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-leucylN-methyl-L-leucyl-N-methyl-L-valyl-3-hydroxy-N,4-dimethyl-L-2-amino-6-octenoyl-L-α -aminobutyryl-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:
alcohol, USP dehydrated.............................11.9% v/v (9.5% wt/vol.)
Each 100 mg capsule contains:
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-αtocopherol 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:
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:
Neoral® Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED25 mg
Oval, blue-gray imprinted in red, “Neoral” over “25 mg.”
Packages of 30 unit-dose blisters (NDC 0078-0246-15).
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.
Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936. REV: August 2012.
(See also BOXED WARNING)
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 TransplantNephrotoxicity
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.
|Parameter||Nephrotoxicity vs. Rejection|
|History||Donor > 50 years old or hypotensive Prolonged kidney preservation |
Prolonged anastomosis time
Concomitant nephrotoxic drugs
|Anti-donor immune response |
|Clinical||Often > 6 weeks postopb |
Prolonged initial nonfunction (acute tubular necrosis)
|Often < 4 weeks postopb |
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)a |
Cr plateau < 25% above baseline
BUN/Cr > 20
|CyA serum trough level < 150 ng/mL Rapid rise in Cr ( > 0.3 mg/dl/day)a |
Cr > 25% above baseline
BUN/Cr < 20
|Biopsy||Arteriolopathy (medial hypertrophya, hyalinosis, nodular deposits, intimal thickening, endothelial vacuolization, progressive scarring) |
Tubular atrophy, isometric vacuolization, isolated calcifications
Mild focal infiltratesc
|Endovasculitisc (proliferationa, intimal arteritisb, necrosis, sclerosis) |
Tubulitis with RBCb and WBCb casts, some irregular vacuolization
Interstitial edemac and hemorrhageb
Diffuse moderate to severe mononuclear infiltratesd
Glomerulitis (mononuclear cells)c
|Aspiration Cytology||Diffuse interstitial fibrosis, often striped form |
CyA deposits in tubular and endothelial cells
Fine isometric vacuolization of tubular 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 Hgb Unchanged graft cross sectional area||Intracapsular pressure > 40 mm Hgb 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 Tc 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|
|ap < 0.05, |
bp < 0.01,
cp < 0.001,
dp < 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.
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.Thrombotic Microangiopathy
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)Hyperkalemia
Significant hyperkalemia (sometimes associated with hyperchloremic metabolic acidosis) and hyperuricemia have been seen occasionally in individual patients.Hepatotoxicity
Cases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis, and liver failure have been reported in patients treated with cyclosporine. Most reports included patients with significant comorbidities, underlying conditions and other confounding factors including infectious complications and comedications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported (see ADVERSE REACTIONS, Postmarketing Experience, Kidney, Liver and Heart Transplantation).
Hepatotoxicity, usually manifested by elevations in hepatic enzymes and bilirubin, was reported in patients treated with cyclosporine in clinical trials: 4% in renal transplantation, 7% in cardiac transplantation, and 4% in liver transplantation. This was usually noted during the first month of therapy when high doses of cyclosporine were used. The chemistry elevations usually decreased with a reduction in dosage.Malignancies
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.Serious Infections
Patients receiving immunosuppressants, including Neoral, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes [See BOXED WARNING, and ADVERSE REACTIONS].Polyomavirus Infections
Patients receiving immunosuppressants, including Neoral, are at increased risk for opportunistic infections, including polyomavirus infections. Polyoma virus infections in transplant patients may have serious, and sometimes, fatal outcomes. These include cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), and polyoma virus-associated nephropathy (PVAN), especially due to BK virus infection, which have been observed in patients receiving cyclosporine.
PVAN is associated with serious outcomes, including deteriorating renal function and renal graft loss, (see ADVERSE REACTIONS/Postmarketing Experience, Kidney, Liver and Heart Transplantation). Patient monitoring may help detect patients at risk for PVAN.
Cases of PML have been reported in patients treated with Neoral. PML, which is sometimes fatal, commonly presents with hemiparesis, apathy, confusion, cognitive deficiencies and ataxia. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis in patients reporting neurological symptoms and consultation with a neurologist should be considered as clinically indicated.
Consideration should be given to reducing the total immunosuppression in transplant patients who develop PML or PVAN. However, reduced immunosuppression may place the graft at risk.Neurotoxicity
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 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)
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.
(See also BOXED WARNINGS for Psoriasis)
Since cyclosporine is a potent immunosuppressive agent with a number of potentially serious side effects, the risks and benefits of using Neoral® should be considered before treatment of patients with psoriasis. Cyclosporine, the active ingredient in Neoral®, can cause nephrotoxicity and hypertension (see PRECAUTIONS) and the risk increases with increasing dose and duration of therapy. Patients who may be at increased risk such as those with abnormal renal function, uncontrolled hypertension or malignancies, should not receive Neoral®.
Renal dysfunction is a potential consequence of Neoral® therefore renal function must be monitored during therapy.
Patients receiving Neoral® require frequent monitoring of serum creatinine. (See Special Monitoring under DOSAGE AND ADMINISTRATION) Elderly patients should be monitored with particular care, since decreases in renal function also occur with age. If patients are not properly monitored and doses are not properly adjusted, cyclosporine therapy can cause structural kidney damage and persistent renal dysfunction.
An increase in serum creatinine and BUN may occur during Neoral® therapy and reflects a reduction in the glomerular filtration rate.
Kidney biopsies from 86 psoriasis patients treated for a mean duration of 23 months with 1.2-7.6 mg/kg/day of cyclosporine showed evidence of cyclosporine nephropathy in 18/86 (21%) of the patients. The pathology consisted of renal tubular atrophy and interstitial fibrosis. On repeat biopsy of 13 of these patients maintained on various dosages of cyclosporine for a mean of 2 additional years, the number with cyclosporine induced nephropathy rose to 26/86 (30%). The majority of patients (19/26) were on a dose of ≥ 5.0 mg/kg/day (the highest recommended dose is 4 mg/kg/day). The patients were also on cyclosporine for greater than 15 months (18/26) and/or had a clinically significant increase in serum creatinine for greater than 1 month (21/26). Creatinine levels returned to normal range in 7 of 11 patients in whom cyclosporine therapy was discontinued.
There is an increased risk for the development of skin and lymphoproliferative malignancies in cyclosporine-treated psoriasis patients. The relative risk of malignancies is comparable to that observed in psoriasis patients treated with other immunosuppressive agents.
Tumors were reported in 32 (2.2%) of 1439 psoriasis patients treated with cyclosporine worldwide from clinical trials. Additional tumors have been reported in 7 patients in cyclosporine postmarketing experience. Skin malignancies were reported in 16 (1.1%) of these patients; all but 2 of them had previously received PUVA therapy. Methotrexate was received by 7 patients. UVB and coal tar had been used by 2 and 3 patients, respectively. Seven patients had either a history of previous skin cancer or a potentially predisposing lesion was present prior to cyclosporine exposure. Of the 16 patients with skin cancer, 11 patients had 18 squamous cell carcinomas and 7 patients had 10 basal cell carcinomas.
There were two lymphoproliferative malignancies; one case of non-Hodgkin's lymphoma which required chemotherapy, and one case of mycosis fungoides which regressed spontaneously upon discontinuation of cyclosporine. There were four cases of benign lymphocytic infiltration: 3 regressed spontaneously upon discontinuation of cyclosporine, while the fourth regressed despite continuation of the drug. The remainder of the malignancies, 13 cases (0.9%), involved various organs.
Patients should not be treated concurrently with cyclosporine and PUVA or UVB, other radiation therapy, or other immunosuppressive agents, because of the possibility of excessive immunosuppression and the subsequent risk of malignancies. (See CONTRAINDICATIONS) Patients should also be warned to protect themselves appropriately when in the sun, and to avoid excessive sun exposure. Patients should be thoroughly evaluated before and during treatment for the presence of malignancies remembering that malignant lesions may be hidden by psoriatic plaques. Skin lesions not typical of psoriasis should be biopsied before starting treatment. Patients should be treated with Neoral® only after complete resolution of suspicious lesions, and only if there are no other treatment options. (See Special Monitoring for Psoriasis Patients)
Uses of Neoral
Neoral is a prescription medication used to prevent transplant rejection in those who have received kidney, liver, and heart transplants.
Neoral may also be used to treat psoriasis symptoms of rheumatoid arthritis.
This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.
Neoral Drug Class
Neoral is part of the drug class:
Side Effects of Neoral
Common side effects of Neoral include:
- kidney dysfunction
- hirsutism (excessive growth of hair in women in a male-like pattern)
- high blood pressure
- gum tissue overgrowth
Tell your doctor if any side effect is bothersome or does not go away. Neoral may cause other side effects. Call your doctor if you have any unusual problems while using this medication.
Neoral Food Interactions
Grapefruit and grapefruit juice may interact with Neoral and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor.
Your doctor may tell you to limit the amount of potassium in your diet. Follow these instructions carefully. Talk to your doctor about the amount of potassium-rich foods such as bananas, prunes, raisins, and orange juice you may have in your diet. Many salt substitutes contain potassium, so talk to your doctor about using them during your treatment.
Neoral and Pregnancy
Tell your doctor if you are pregnant or plan to become pregnant.
The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.
Neoral falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.
Neoral and Lactation
Tell your doctor if you are breastfeeding or plan to breastfeed. It is not known if Neoral is excreted in human breast milk or if it will harm your nursing baby.
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.