Cyclosporine (oral)

Cyclosporine (oral)
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Deepika Beereddy, MBBS [2]

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Black Box Warning

WARNING See full prescribing information for complete Boxed Warning. *Only physicians experienced in management of systemic immunosuppressive therapy for the indicated disease should prescribe Neoral®. At doses used in solid organ transplantation, only physicians experienced in immunosuppressive therapy and management of organ transplant recipients should prescribe Neoral®. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Neoral®, a systemic immunosuppressant, may increase the susceptibility to infection and the development of neoplasia. In kidney, liver, and heart transplant patients Neoral® may be administered with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma and other neoplasms may result from the increase in the degree of immunosuppression in transplant patients. Neoral® Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Neoral® Oral Solution (cyclosporine oral solution, USP) MODIFIED have increased bioavailability in comparison to Sandimmune® Soft Gelatin Capsules (cyclosporine capsules, USP) and Sandimmune® Oral Solution (cyclosporine oral solution, USP). Neoral® and Sandimmune® are not bioequivalent and cannot be used interchangeably without physician supervision. For a given trough concentration, cyclosporine exposure will be greater with Neoral® than with Sandimmune®. If a patient who is receiving exceptionally high doses of Sandimmune® is converted to Neoral®, particular caution should be exercised. Cyclosporine blood concentrations should be monitored in transplant and rheumatoid arthritis patients taking Neoral® to avoid toxicity due to high concentrations. Dose adjustments should be made in transplant patients to minimize possible organ rejection due to low concentrations. Comparison of blood concentrations in the published literature with blood concentrations obtained using current assays must be done with detailed knowledge of the assay methods employed. For Psoriasis Patients: 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.

Overview

Cyclosporine (oral) is a that is FDA approved for the {{{indicationType}}} of . There is a Black Box Warning for this drug as shown here. Common adverse reactions include .

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

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Off-Label Use and Dosage (Adult)

Guideline-Supported Use

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There is limited information regarding Off-Label Guideline-Supported Use of Cyclosporine (oral) in adult patients.

Non–Guideline-Supported Use

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There is limited information regarding Off-Label Non–Guideline-Supported Use of Cyclosporine (oral) in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

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There is limited information regarding FDA-Labeled Use of Cyclosporine (oral) in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition1

• Developed by:

• Class of Recommendation:

• Strength of Evidence:

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Condition2

There is limited information regarding Off-Label Guideline-Supported Use of Cyclosporine (oral) in pediatric patients.

Non–Guideline-Supported Use

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• Dosing Information

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There is limited information regarding Off-Label Non–Guideline-Supported Use of Cyclosporine (oral) in pediatric patients.

Contraindications

• General

Neoral® is contraindicated in patients with a hypersensitivity to cyclosporine or to any of the ingredients of the formulation.

Rheumatoid Arthritis

Rheumatoid arthritis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive Neoral®.

Psoriasis

Psoriasis patients who are treated with Neoral® should not receive concomitant PUVA or UVB therapy, methotrexate or other immunosuppressive agents, coal tar or radiation therapy. Psoriasis patients with abnormal renal function, uncontrolled hypertension, or malignancies should not receive Neoral®.

Warnings

WARNING See full prescribing information for complete Boxed Warning. *Only physicians experienced in management of systemic immunosuppressive therapy for the indicated disease should prescribe Neoral®. At doses used in solid organ transplantation, only physicians experienced in immunosuppressive therapy and management of organ transplant recipients should prescribe Neoral®. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient. Neoral®, a systemic immunosuppressant, may increase the susceptibility to infection and the development of neoplasia. In kidney, liver, and heart transplant patients Neoral® may be administered with other immunosuppressive agents. Increased susceptibility to infection and the possible development of lymphoma and other neoplasms may result from the increase in the degree of immunosuppression in transplant patients. Neoral® Soft Gelatin Capsules (cyclosporine capsules, USP) MODIFIED and Neoral® Oral Solution (cyclosporine oral solution, USP) MODIFIED have increased bioavailability in comparison to Sandimmune® Soft Gelatin Capsules (cyclosporine capsules, USP) and Sandimmune® Oral Solution (cyclosporine oral solution, USP). Neoral® and Sandimmune® are not bioequivalent and cannot be used interchangeably without physician supervision. For a given trough concentration, cyclosporine exposure will be greater with Neoral® than with Sandimmune®. If a patient who is receiving exceptionally high doses of Sandimmune® is converted to Neoral®, particular caution should be exercised. Cyclosporine blood concentrations should be monitored in transplant and rheumatoid arthritis patients taking Neoral® to avoid toxicity due to high concentrations. Dose adjustments should be made in transplant patients to minimize possible organ rejection due to low concentrations. Comparison of blood concentrations in the published literature with blood concentrations obtained using current assays must be done with detailed knowledge of the assay methods employed. For Psoriasis Patients: 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.

(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

Nephrotoxicity

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.

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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 concentrations 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 blood concentrations.

Due to the potential for additive or synergistic impairment of renal function, caution should be exercised when coadministering Neoral with other drugs that may impair renal function. (See PRECAUTIONS, Drug Interactions)

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 co-morbidities, 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)

Polyoma Virus Infections

Patients receiving immunosuppressants, including Neoral, are at increased risk for opportunistic infections, including polyoma virus 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, including Posterior Reversible Encephalopathy Syndrome (PRES), 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)

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 WARNING 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)

Special Excipients

Alcohol (ethanol)

The alcohol content (See DESCRIPTION) of Neoral should be taken into account when given to patients in whom alcohol intake should be avoided or minimized, e.g., pregnant or breastfeeding women, in patients presenting with liver disease or epilepsy, in alcoholic patients, or pediatric patients. For an adult weighing 70 kg, the maximum daily oral dose would deliver about 1 gram of alcohol which is approximately 6% of the amount of alcohol contained in a standard drink.

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 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 coadministered 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.

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.

Adverse Reactions

Clinical Trials Experience

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.

IMG-CT

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Cyclosporine (oral) in the drug label.

Body as a Whole

Cardiovascular

Digestive

Endocrine

Hematologic and Lymphatic

Metabolic and Nutritional

Musculoskeletal

Neurologic

Respiratory

Skin and Hypersensitivy Reactions

Special Senses

Urogenital

Miscellaneous

Drug Interactions

A. Effect of Drugs and Other Agents on Cyclosporine Pharmacokinetics and/or Safety

All of the individual drugs cited below are well substantiated to interact with cyclosporine. In addition, concomitant use of non-steroidal anti-inflammatory drugs with cyclosporine, particularly in the setting of dehydration, may potentiate renal dysfunction. Caution should be exercised when using other drugs which are known to impair renal function. (See WARNINGS, Nephrotoxicity)

IMG00

During the concomitant use of a drug that may exhibit additive or synergistic renal impairment with cyclosporine, close monitoring of renal function (in particular serum creatinine) should be performed. If a significant impairment of renal function occurs, the dosage of the coadministered drug should be reduced or an alternative treatment considered.

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 concentrations of cyclosporine usually by inhibition or induction of CYP3A4 or P-glycoprotein transporter or both. Compounds that decrease cyclosporine absorption such as orlistat should be avoided. Appropriate Neoral® dosage adjustment to achieve the desired cyclosporine concentrations is essential when drugs that significantly alter cyclosporine concentrations are used concomitantly. (See Blood Concentration Monitoring)

IMG01

HIV Protease inhibitors

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 juice

Grapefruit and grapefruit juice affect metabolism, increasing blood concentrations of cyclosporine, thus should be avoided.

IMG02

Bosentan

Coadministration of bosentan (250–1000 mg every 12 hours based on tolerability) and cyclosporine (300 mg every 12 hours for 2 days then dosing to achieve a Cmin of 200–250 ng/mL) for 7 days in healthy subjects resulted in decreases in the cyclosporine mean dose-normalized AUC, Cmax, and trough concentration of approximately 50%, 30%, and 60%, respectively, compared to when cyclosporine was given alone (See also Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents).

Boceprevir

Coadministration of boceprevir (800 mg three times daily for 7 days) and cyclosporine (100 mg single dose) in healthy subjects resulted in increases in the mean AUC and Cmax of cyclosporine approximately 2.7-fold and 2-fold, respectively, compared to when cyclosporine was given alone.

Telaprevir

Coadministration of telaprevir (750 mg every 8 hours for 11 days) with cyclosporine (10 mg on day 8) in healthy subjects resulted in increases in the mean dose-normalized AUC and Cmax of cyclosporine approximately 4.5-fold and 1.3-fold, respectively, compared to when cyclosporine (100 mg single dose) was given alone.

St. John’s Wort

There have been reports of a serious drug interaction between cyclosporine and the herbal dietary supplement St. John’s Wort. This interaction has been reported to produce a marked reduction in the blood concentrations of cyclosporine, resulting in subtherapeutic levels, rejection of transplanted organs, and graft loss.

Rifabutin

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.

B. Effect of Cyclosporine on the Pharmacokinetics and/or Safety of Other Drugs or Agents

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, aliskiren, repaglinide, NSAIDs, sirolimus, etoposide, and other drugs. See the full prescribing information of the other drug for further information and specific recommendations. The decision on coadministration of cyclosporine with other drugs or agents should be made by the physician following the careful assessment of benefits and risks.

Digoxin

Severe digitalis toxicity has been seen within days of starting cyclosporine in several patients taking digoxin. If digoxin is used concurrently with cyclosporine, serum digoxin concentrations should be monitored.

Colchicine

There are reports on the potential of cyclosporine to enhance the toxic effects of colchicine such as myopathy and neuropathy, especially in patients with renal dysfunction. Concomitant administration of cyclosporine and colchicine results in significant increases in colchicine plasma concentrations. If colchicine is used concurrently with cyclosporine, a reduction in the dosage of colchicine is recommended.

HMG-CoA reductase inhibitors (statins)

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.

Repaglinide

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.

Ambrisentan

Coadministration of ambrisentan (5 mg daily) and cyclosporine (100–150 mg twice daily initially, then dosing to achieve Cmin 150–200 ng/mL) for 8 days in healthy subjects resulted in mean increases in ambrisentan AUC and Cmax of approximately 2-fold and 1.5–fold, respectively, compared to ambrisentan alone.

Anthracycline antibiotics

High doses of cyclosporine (e.g., at starting intravenous dose of 16 mg/kg/day) may increase the exposure to anthracycline antibiotics (e.g., doxorubicin, mitoxantrone, daunorubicin) in cancer patients.

Aliskiren

Cyclosporine alters the pharmacokinetics of aliskiren, a substrate of P-glycoprotein and CYP3A4. In 14 healthy subjects who received concomitantly single doses of cyclosporine (200 mg) and reduced dose aliskiren (75 mg), the mean Cmax of aliskiren was increased by approximately 2.5 fold (90% CI: 1.96-3.17) and the mean AUC by approximately 4.3 fold (90% CI: 3.52-5.21), compared to when these subjects received aliskiren alone. The concomitant administration of aliskiren with cyclosporine prolonged the median aliskiren elimination half-life (26 hours versus 43 to 45 hours) and the Tmax (0.5 hours versus 1.5 to 2.0 hours). The mean AUC and Cmax of cyclosporine were comparable to reported literature values. Coadministration of cyclosporine and aliskiren in these subjects also resulted in an increase in the number and/or intensity of adverse events, mainly headache, hot flush, nausea, vomiting, and somnolence. The coadministration of cyclosporine with aliskiren is not recommended.

Bosentan

In healthy subjects, coadministration of bosentan and cyclosporine resulted in mean increases in dose-normalized bosentan trough concentrations on day 1 and day 8 of approximately 21-fold and 2-fold , respectively, compared to when bosentan was given alone as a single dose on day 1. (See also Effect of Drugs and Other Agents on Cyclosporine Pharmacokinetics and/or Safety)

Potassium-Sparing Diuretics

Cyclosporine should not be used with potassium-sparing diuretics because hyperkalemia can occur. Caution is also required when cyclosporine is coadministered 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.

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 99mTc-diethylenetriaminepentaacetic acid (DTPA) and (p-aminohippuric acid) PAH clearances. Although concomitant administration of diclofenac does not affect blood concentrations of cyclosporine, it has been associated with approximate doubling of diclofenac blood concentrations and occasional reports of reversible decreases in renal function. Consequently, the dose of diclofenac should be in the lower end of the therapeutic range.

Methotrexate Interaction

Preliminary data indicate that when methotrexate and cyclosporine were coadministered 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).

Sirolimus

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 coadministration 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.

Nifedipine

Frequent gingival hyperplasia when nifedipine is given concurrently with cyclosporine has been reported. The concomitant use of nifedipine should be avoided in patients in whom gingival hyperplasia develops as a side effect of cyclosporine.

Methylprednisolone

Convulsions when high dose methylprednisolone is given concurrently with cyclosporine have been reported.

Other Immunosuppressive Drugs and Agents

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.

C. Effect of Cyclosporine on the Efficacy of Live Vaccines

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

For additional information on Cyclosporine Drug Interactions please contact Novartis Medical Affairs Department at 888-NOW-NOVA [888-669-6682].

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Cyclosporine (oral) in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Cyclosporine (oral) during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Cyclosporine (oral) with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Cyclosporine (oral) with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Cyclosporine (oral) with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Cyclosporine (oral) with respect to specific gender populations.

Race

There is no FDA guidance on the use of Cyclosporine (oral) with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Cyclosporine (oral) in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Cyclosporine (oral) in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Cyclosporine (oral) in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Cyclosporine (oral) in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

• Intravenous

Monitoring

There is limited information regarding Monitoring of Cyclosporine (oral) in the drug label.

• Description

IV Compatibility

There is limited information regarding IV Compatibility of Cyclosporine (oral) in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Cyclosporine (oral) in the drug label.

Pharmacology

There is limited information regarding Cyclosporine (oral) Pharmacology in the drug label.

Mechanism of Action

Cyclosporine is a potent immunosuppressive agent that in animals prolongs survival of allogeneic transplants involving skin, kidney, liver, heart, pancreas, bone marrow, small intestine, and lung. Cyclosporine has been demonstrated to suppress some humoral immunity and to a greater extent, cell-mediated immune reactions such as allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, Freund’s adjuvant arthritis, and graft vs. host disease in many animal species for a variety of organs.

The effectiveness of cyclosporine results from specific and reversible inhibition of immunocompetent lymphocytes in the G0- and G1-phase of the cell cycle. T-lymphocytes are preferentially inhibited. The T-helper cell is the main target, although the T-suppressor cell may also be suppressed. Cyclosporine also inhibits lymphokine production and release including interleukin-2.

No effects on phagocytic function (changes in enzyme secretions, chemotactic migration of granulocytes, macrophage migration, carbon clearance in vivo) have been detected in animals. Cyclosporine does not cause bone marrow suppression in animal models or man.

Structure

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:

IMG-structure

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Cyclosporine (oral) in the drug label.

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 (Cmax) was approximately 40% to 106% greater following administration of Neoral® compared to following administration of Sandimmune®. The dose normalized AUC in de novo liver transplant patients administered Neoral® 28 days after transplantation was 50% greater and Cmax was 90% greater than in those patients administered Sandimmune®. AUC and Cmax are also increased (Neoral® relative to Sandimmune®) in heart transplant patients, but data are very limited. Although the AUC and Cmax values are higher on Neoral® relative to Sandimmune®, the predose trough concentrations (dose-normalized) are similar for the two formulations.

Following oral administration of Neoral®, the time to peak blood cyclosporine concentrations (Tmax) ranged from 1.5-2.0 hours. The administration of food with Neoral® decreases the cyclosporine AUC and Cmax. A high fat meal (669 kcal, 45 grams fat) consumed within one-half hour before Neoral® administration decreased the AUC by 13% and Cmax by 33%. The effects of a low fat meal (667 kcal, 15 grams fat) were similar.

The effect of T-tube diversion of bile on the absorption of cyclosporine from Neoral® was investigated in eleven de novo liver transplant patients. When the patients were administered Neoral® with and without T-tube diversion of bile, very little difference in absorption was observed, as measured by the change in maximal cyclosporine blood concentrations from pre-dose values with the T-tube closed relative to when it was open: 6.9±41% (range -55% to 68%).

IMG-PK

Distribution

Cyclosporine is distributed largely outside the blood volume. The steady state volume of distribution during intravenous dosing has been reported as 3-5 L/kg in solid organ transplant recipients. In blood, the distribution is concentration dependent. Approximately 33%-47% is in plasma, 4%-9% in lymphocytes, 5%-12% in granulocytes, and 41%-58% in erythrocytes. At high concentrations, the binding capacity of leukocytes and erythrocytes becomes saturated. In plasma, approximately 90% is bound to proteins, primarily lipoproteins. Cyclosporine is excreted in human milk. (See PRECAUTIONS, Nursing Mothers)

Metabolism

Cyclosporine is extensively metabolized by the cytochrome P-450 3A enzyme system in the liver, and to a lesser degree in the gastrointestinal tract, and the kidney. The metabolism of cyclosporine can be altered by the coadministration of a variety of agents. (See PRECAUTIONS, Drug Interactions) At least 25 metabolites have been identified from human bile, feces, blood, and urine. The biological activity of the metabolites and their contributions to toxicity are considerably less than those of the parent compound. The major metabolites (M1, M9, and M4N) result from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively. At steady state following the oral administration of Sandimmune®, the mean AUCs for blood concentrations of M1, M9, and M4N are about 70%, 21%, and 7.5% of the AUC for blood cyclosporine concentrations, respectively. Based on blood concentration data from stable renal transplant patients (13 patients administered Neoral® and Sandimmune® in a crossover study), and bile concentration data from de novo liver transplant patients (4 administered Neoral®, 3 administered Sandimmune®), the percentage of dose present as M1, M9, and M4N metabolites is similar when either Neoral® or Sandimmune® is administered.

Excretion

Only 0.1% of a cyclosporine dose is excreted unchanged in the urine. Elimination is primarily biliary with only 6% of the dose (parent drug and metabolites) excreted in the urine. Neither dialysis nor renal failure alters cyclosporine clearance significantly.

Drug Interactions

(See PRECAUTIONS, Drug Interactions) When diclofenac or methotrexate was coadministered 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.

Specific Populations

Renal Impairment

In a study performed in 4 subjects with end-stage renal disease (creatinine clearance <5 mL/min), an intravenous infusion of 3.5 mg/kg of cyclosporine over 4 hours administered at the end of a hemodialysis session resulted in a mean volume of distribution (Vdss) of 3.49 L/kg and systemic clearance (CL) of 0.369 L/hr/kg. This systemic CL (0.369 L/hr/kg) was approximately two thirds of the mean systemic CL (0.56 L/hr/kg) of cyclosporine in historical control subjects with normal renal function. In 5 liver transplant patients, the mean clearance of cyclosporine on and off hemodialysis was 463 mL/min and 398 mL/min, respectively. Less than 1% of the dose of cyclosporine was recovered in the dialysate.

Hepatic Impairment

Cyclosporine is extensively metabolized by the liver. Since severe hepatic impairment may result in significantly increased cyclosporine exposures, the dosage of cyclosporine may need to be reduced in these patients.

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%).

IMG-PK2

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.

Nonclinical Toxicology

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.

Clinical Studies

There is limited information regarding Clinical Studies of Cyclosporine (oral) in the drug label.

How Supplied

Storage

There is limited information regarding Cyclosporine (oral) Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Cyclosporine (oral) in the drug label.

Precautions with Alcohol

• Alcohol-Cyclosporine (oral) interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• ®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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