(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.
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.
is not bioequivalent to Sandimmune
, conversion from Neoral
using a 1:1 ratio (mg/kg/day) may result in lower cyclosporine blood concentrations. Conversion from Neoral
should be made with increased monitoring to avoid the potential of underdosing.
Kidney, Liver, and Heart Transplant
Cyclosporine, the active ingredient of Neoral®, can cause nephrotoxicity and hepatotoxicity when used in high doses. It is not unusual for serum creatinine and BUN levels to be elevated during cyclosporine therapy. These elevations in renal transplant patients do not necessarily indicate rejection, and each patient must be fully evaluated before dosage adjustment is initiated.
Based on the historical Sandimmune® experience with oral solution, nephrotoxicity associated with cyclosporine had been noted in 25% of cases of renal transplantation, 38% of cases of cardiac transplantation, and 37% of cases of liver transplantation. Mild nephrotoxicity was generally noted 2-3 months after renal transplant and consisted of an arrest in the fall of the pre-operative elevations of BUN and creatinine at a range of 35-45 mg/dl and 2.0-2.5 mg/dl respectively. These elevations were often responsive to cyclosporine dosage reduction.
More overt nephrotoxicity was seen early after transplantation and was characterized by a rapidly rising BUN and creatinine. Since these events are similar to renal rejection episodes, care must be taken to differentiate between them. This form of nephrotoxicity is usually responsive to cyclosporine dosage reduction.
Although specific diagnostic criteria which reliably differentiate renal graft rejection from drug toxicity have not been found, a number of parameters have been significantly associated with one or the other. It should be noted however, that up to 20% of patients may have simultaneous nephrotoxicity and rejection.
||Donor >50 years old or hypotensive
Prolonged kidney preservation
Prolonged anastomosis time
Concomitant nephrotoxic drugs
|Anti-donor immune response
||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%)
||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
||Arteriolopathy (medial hypertrophy a, hyalinosis,
nodular deposits, intimal thickening, endothelial
vacuolization, progressive scarring)
Tubular atrophy, isometric vacuolization, isolated calcifications
Mild focal infiltratesc
Diffuse interstitial fibrosis, often striped form
|Endovasculitisc (proliferationa, intimal arteritisb,
Tubulitis with RBCb and WBCb casts, some irregular vacuolization
Interstitial edemac and hemorrhageb
Diffuse moderate to severe mononuclear infiltratesd
Glomerulitis (mononuclear cells)c
||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
||Tubular cells with vacuolization and granularization
||Degenerative tubular cells, plasma cells, and lymphocyturia > 20% of sediment
||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
||Loss of distinct corticomedullary junction, swelling image intensity of parachyma approaching that of psoas, loss of hilar fat
||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
||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 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)
Occasionally patients have developed a syndrome of thrombocytopenia and microangiopathic hemolytic anemia which may result in graft failure. The vasculopathy can occur in the absence of rejection and is accompanied by avid platelet consumption within the graft as demonstrated by Indium 111 labeled platelet studies. Neither the pathogenesis nor the management of this syndrome is clear. Though resolution has occurred after reduction or discontinuation of cyclosporine and 1) administration of streptokinase and heparin or 2) plasmapheresis, this appears to depend upon early detection with Indium 111 labeled platelet scans. (See ADVERSE REACTIONS)
Significant hyperkalemia (sometimes associated with hyperchloremic metabolic acidosis) and hyperuricemia have been seen occasionally in individual patients.
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.
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.
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.
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)
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 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)
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.
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)
During treatment with cyclosporine, vaccination may be less effective; and the use of live attenuated vaccines should be avoided.
Special Monitoring of Rheumatoid Arthritis
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
, 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%.
itoring 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.
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.
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.
Pregnancy Category C
Animal studies have shown reproductive toxicity in rats and rabbits. Cyclosporine gave no evidence of mutagenic or teratogenic effects in the standard test systems with oral application (rats up to 17 mg/kg and rabbits up to 30 mg/kg per day orally.) Only at dose levels toxic to dams, were adverse effects seen in reproduction studies in rats. Cyclosporine has been shown to be embryo- and fetotoxic in rats and rabbits following oral administration at maternally toxic doses. Fetal toxicity was noted in rats at 0.8 and rabbits at 5.4 times the transplant doses in humans of 6.0 mg/kg, where dose corrections are based on body surface area. Cyclosporine was embryo- and fetotoxic as indicated by increased pre- and postnatal mortality and reduced fetal weight together with related skeletal retardation.
There are no adequate and well-controlled studies in pregnant women therefore, Neoral® should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus.
In pregnant transplant recipients who are being treated with immunosuppressants the risk of premature birth is increased. The following data represent the reported outcomes of 116 pregnancies in women receiving cyclosporine during pregnancy, 90% of whom were transplant patients, and most of whom received cyclosporine throughout the entire gestational period. The only consistent patterns of abnormality were premature birth (gestational period of 28 to 36 weeks) and low birth weight for gestational age. Sixteen fetal losses occurred. Most of the pregnancies (85 of 100) were complicated by disorders; including, preeclampsia, eclampsia, premature labor, abruptio placentae, oligohydramnios, Rh incompatibility, and fetoplacental dysfunction. Pre-term delivery occurred in 47%. Seven malformations were reported in 5 viable infants and in 2 cases of fetal loss. Twenty-eight percent of the infants were small for gestational age. Neonatal complications occurred in 27%. Therefore, the risks and benefits of using Neoral® during pregnancy should be carefully weighed.
A limited number of observations in children exposed to cyclosporine in utero are available, up to an age of approximately 7 years. Renal function and blood pressure in these children were normal.
Because of the possible disruption of maternal-fetal interaction, the risk/benefit ratio of using Neoral® in psoriasis patients during pregnancy should carefully be weighed with serious consideration for discontinuation of Neoral®.
The alcohol content of the Neoral formulations should also be taken into account in pregnant women. (See WARNINGS, Special Excipients)
Cyclosporine is present in breast milk. Because of the potential for serious adverse drug reactions in nursing infants from Neoral, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Neoral contains ethanol. Ethanol will be present in human milk at levels similar to that found in maternal serum and if present in breast milk will be orally absorbed by a nursing infant (See WARNINGS).
Although no adequate and well-controlled studies have been completed in children, transplant recipients as young as one year of age have received Neoral® with no unusual adverse effects. The safety and efficacy of Neoral® treatment in children with juvenile rheumatoid arthritis or psoriasis below the age of 18 have not been established.
In rheumatoid arthritis clinical trials with cyclosporine, 17.5% of patients were age 65 or older. These patients were more likely to develop systolic hypertension on therapy, and more likely to show serum creatinine rises ≥50% above the baseline after 3-4 months of therapy.
Clinical studies of Neoral® in transplant and psoriasis patients did not include a sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experiences have not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.