CYCLOSPORINE

The mean ± SD initial doses were 9 ± 3 mg/kg/day for renal transplant patients (75 centers), 8 ± 4 mg/kg/day for liver transplant patients (30 centers), and 7 ± 3 mg/kg/day for heart transplant patients (24 centers). Total daily doses were divided into two equal daily doses.

The cyclosporine capsules (modified) dose is subsequently adjusted to achieve a pre-defined cyclosporine blood concentration (see Blood Concentration Monitoring in Transplant Patients , below). If cyclosporine trough blood concentrations are used, the target range is the same for cyclosporine capsules (modified) as for Sandimmune ® .

Using the same trough concentration target range for cyclosporine capsules (modified) as for Sandimmune ® results in greater cyclosporine exposure when cyclosporine capsules (modified) is administered (see Pharmacokinetics, Absorption ).

Dosing should be titrated based on clinical assessments of rejection and tolerability. Lower cyclosporine capsules (modified) doses may be sufficient as maintenance therapy. Adjunct therapy with adrenal corticosteroids is recommended initially.

Different tapering dosage schedules of prednisone appear to achieve similar results. 15 mg/kg/day by 2 months and thereafter as a maintenance dose. Steroid doses may be further tapered on an individualized basis depending on status of patient and function of graft.

Adjustments in dosage of prednisone must be made according to the clinical situation. Conversion from Sandimmune® to cyclosporine capsules (modified) in Transplant Patients In transplanted patients who are considered for conversion to cyclosporine capsules (modified) from Sandimmune ® , cyclosporine capsules (modified) should be started with the same daily dose as was previously used with Sandimmune ® (1:1 dose conversion).

The cyclosporine capsules (modified) dose should subsequently be adjusted to attain the pre-conversion cyclosporine blood trough concentration. Using the same trough concentration target range for cyclosporine capsules (modified) as for Sandimmune ® results in greater cyclosporine exposure when cyclosporine capsules (modified) is administered (see Pharmacokinetics, Absorption ).

Patients with suspected poor absorption of Sandimmune ® require different dosing strategies (see Transplant Patients with Poor absorption of Sandimmune ® , below). In some patients, the increase in blood trough concentration is more pronounced and may be of clinical significance.

Until the blood trough concentration attains the pre-conversion value, it is strongly recommended that the cyclosporine blood trough concentration be monitored every 4 to 7 days after conversion to cyclosporine capsules, (modified).

In addition, clinical safety parameters such as serum creatinine and blood pressure should be monitored every two weeks during the first two months after conversion. If the blood trough concentrations are outside the desired range and/or if the clinical safety parameters worsen, the dosage of cyclosporine capsules (modified) must be adjusted accordingly.

Transplant Patients with Poor Absorption of Sandimmune Patients with lower than expected cyclosporine blood trough concentrations in relation to the oral dose of Sandimmune may have poor or inconsistent absorption of cyclosporine from Sandimmune.

After conversion to cyclosporine capsules, (modified), patients tend to have higher cyclosporine concentrations. Due to the increase in bioavailability of cyclosporine following conversion to cyclosporine capsules, (modified), the cyclosporine blood trough concentration may exceed the target range.

Particular caution should be exercised when converting patients to cyclosporine capsules (modified) at doses greater than 10 mg/kg/day. The dose of cyclosporine capsules (modified) should be titrated individually based on cyclosporine trough concentrations, tolerability, and clinical response.

In this population the cyclosporine blood trough concentration should be measured more frequently, at least twice a week (daily, if initial dose exceeds 10 mg/kg/day) until the concentration stabilizes within the desired range. 5 mg/kg/day, taken twice daily as a divided (BID) oral dose.

Salicylates, NSAIDs, and oral corticosteroids may be continued (see WARNINGS and PRECAUTIONS, Drug Interactions ). Onset of action generally occurs between 4 and 8 weeks. 75 mg/kg/day after 8 weeks and again after 12 weeks to a maximum of 4 mg/kg/day.

If no benefit is seen by 16 weeks of therapy, cyclosporine capsules (modified) therapy should be discontinued. , hypertension elevations in serum creatinine (30% above patient's pretreatment level) or clinically significant laboratory abnormalities (see WARNINGS and PRECAUTIONS ).

If dose reduction is not effective in controlling abnormalities or if the adverse event or abnormality is severe, cyclosporine capsules (modified) should be discontinued. The same initial dose and dosage range should be used if cyclosporine capsules (modified) is combined with the recommended dose of methotrexate.

Most patients can be treated with cyclosporine capsules (modified) doses of 3 mg/kg/day or below when combined with methotrexate doses of up to 15 mg/week (see CLINICAL PHARMACOLOGY, Clinical Trials ). There is limited long-term treatment data.

Recurrence of rheumatoid arthritis disease activity is generally apparent within 4 weeks after stopping cyclosporine. 5 mg/kg/day. 25 mg/kg BID) oral dose. Patients should be kept at that dose for at least 4 weeks, barring adverse events.

If significant clinical improvement has not occurred in patients by that time, the patient's dosage should be increased at 2-week intervals. 0 mg/kg/day. , hypertension, elevations in serum creatinine (≥ 25% above the patient's pretreatment level), or clinically significant laboratory abnormalities.

If dose reduction is not effective in controlling abnormalities, or if the adverse event or abnormality is severe, cyclosporine capsules (modified) should be discontinued (see Special Monitoring of Psoriasis Patients ) Patients generally show some improvement in the clinical manifestations of psoriasis in 2 weeks.

Satisfactory control and stabilization of the disease may take 12 to 16 weeks to achieve. Results of a dose-titration clinical trial with cyclosporine capsules (modified) indicate that an improvement of psoriasis by 75% or more (based on PASI) was achieved in 51% of the patients after 8 weeks and in 79% of the patients after 16 weeks.

Treatment should be discontinued if satisfactory response cannot be achieved after 6 weeks at 4 mg/kg/day or the patient's maximum tolerated dose. Once a patient is adequately controlled and appears stable the dose of cyclosporine capsules (modified) should be lowered, and the patient treated with the lowest dose that maintains an adequate response (this should not necessarily be total clearing of the patient).

In clinical trials, cyclosporine doses at the lower end of the recommended dosage range were effective in maintaining a satisfactory response in 60% of the patients. 5 mg/kg/day may also be equally effective. Upon stopping treatment with cyclosporine, relapse will occur in approximately 6 weeks (50% of the patients) to 16 weeks (75% of the patients).

In the majority of patients rebound does not occur after cessation of treatment with cyclosporine. Thirteen cases of transformation of chronic plaque psoriasis to more severe forms of psoriasis have been reported. There were 9 cases of pustular and 4 cases of erythrodermic psoriasis.

Long term experience with cyclosporine capsules (modified) in psoriasis patients is limited and continuous treatment for extended periods greater than one year is not recommended. Alternation with other forms of treatment should be considered in the long term management of patients with this life long disease.

Blood Concentration Monitoring in Transplant Patients Transplant centers have found blood concentration monitoring of cyclosporine to be an essential component of patient management. Of importance to blood concentration analysis are the type of assay used, the transplanted organ, and other immunosuppressant agents being administered.

While no fixed relationship has been established, blood concentration monitoring may assist in the clinical evaluation of rejection and toxicity, dose adjustments, and the assessment of compliance. Various assays have been used to measure blood concentrations of cyclosporine.

Older studies using a nonspecific assay often cited concentrations that were roughly twice those of the specific assays. Therefore, comparison between concentrations in the published literature and an individual patient concentration using current assays must be made with detailed knowledge of the assay methods employed.

Current assay results are also not interchangeable and their use should be guided by their approved labeling. A discussion of the different assay methods is contained in Annals of Clinical Biochemistry 1994; 31:420 to 446. While several assays and assay matrices are available, there is a consensus that parent-compound-specific assays correlate best with clinical events.

Of these, HPLC is the standard reference, but the monoclonal antibody RIAs and the monoclonal antibody FPIA offer sensitivity, reproducibility, and convenience. Most clinicians base their monitoring on trough cyclosporine concentrations.

Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring (1992) contains a broad discussion of cyclosporine pharmacokinetics and drug monitoring techniques. Blood concentration monitoring is not a replacement for renal function monitoring or tissue biopsies.

Based on the historical experience with Sandimmune ® , the following reactions occurred in 3% or greater of 892 patients involved in clinical trials of kidney, heart, and liver transplants. 7% of the patients. The following reactions occurred in 2% or less of cyclosporine-treated patients: allergic reactions, anemia, anorexia, confusion, conjunctivitis, edema, fever, brittle fingernails, gastritis, hearing loss, hiccups, hyperglycemia, migraine (cyclosporine capsules, (modified)), muscle pain, peptic ulcer, thrombocytopenia, tinnitus.

The following reactions occurred rarely: anxiety, chest pain, constipation, depression, hair breaking, hematuria, joint pain, lethargy, mouth sores, myocardial infarction, night sweats, pancreatitis, pruritus, swallowing difficulty, tingling, upper GI bleeding, visual disturbance, weakness, weight loss.

Patients receiving immunosuppressive therapies, including cyclosporine and cyclosporine -containing regimens, are at increased risk of infections (viral, bacterial, fungal, parasitic). Both generalized and localized infections can occur.

Pre-existing infections may also be aggravated. Fatal outcomes have been reported (see WARNINGS ). 2 *Some patients also received ALG. Postmarketing Experience, Kidney, Liver and Heart Transplantation Hepatotoxicity Cases of hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure; serious and/or fatal outcomes have been reported (see WARNINGS, Hepatotoxicity ).

Increased Risk of Infections Cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), sometimes fatal; and polyoma virus-associated nephropathy (PVAN), especially BK virus resulting in graft loss have been reported (see WARNINGS, Polyoma Virus Infection ) Headache, including Migraine Cases of migraine have been reported.

In some cases, patients have been unable to continue cyclosporine, however, the final decision on treatment discontinuation should be made by the treating physician following the careful assessment of benefits versus risks. Pain of lower extremities Isolated cases of pain of lower extremities have been reported in association with cyclosporine.

Pain of lower extremities has also been noted as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS) as described in the literature. Rheumatoid Arthritis The principal adverse reactions associated with the use of cyclosporine in rheumatoid arthritis are renal dysfunction (see WARNINGS ), hypertension (see PRECAUTIONS ), headache, gastrointestinal disturbances, and hirsutism/hypertrichosis.

3% of the patients because of hypertension and in 7% of the patients because of increased creatinine. These changes are usually reversible with timely dose decrease or drug discontinuation. The frequency and severity of serum creatinine elevations increase with dose and duration of cyclosporine therapy.

These elevations are likely to become more pronounced without dose reduction or discontinuation. 5 mg/kg/day dose group only. *NOS = Not Otherwise Specified. In addition, the following adverse events have been reported in 1% to <3% of the rheumatoid arthritis patients in the cyclosporine treatment group in controlled clinical trials.

Autonomic Nervous System: dry mouth, increased sweating Body as a Whole: allergy, asthenia, hot flushes, malaise, overdose, procedure NOS*, tumor NOS*, weight decrease, weight increase Cardiovascular: abnormal heart sounds, cardiac failure, myocardial infarction, peripheral ischemia Central and Peripheral Nervous System: hypoesthesia, neuropathy, vertigo Endocrine: goiter Gastrointestinal: constipation, dysphagia, enanthema, eructation, esophagitis, gastric ulcer, gastritis, gastroenteritis, gingival bleeding, glossitis, peptic ulcer, salivary gland enlargement, tongue disorder, tooth disorder Infection: abscess, bacterial infection, cellulitis, folliculitis, fungal infection, herpes simplex, herpes zoster, renal abscess, moniliasis, tonsillitis, viral infection Hematologic: anemia, epistaxis, leukopenia, lymphadenopathy Liver and Biliary System: bilirubinemia Metabolic and Nutritional: diabetes mellitus, hyperkalemia, hyperuricemia, hypoglycemia Musculoskeletal System: arthralgia, bone fracture, bursitis, joint dislocation, myalgia, stiffness, synovial cyst, tendon disorder Neoplasms: breast fibroadenosis, carcinoma Psychiatric: anxiety, confusion, decreased libido, emotional lability, impaired concentration, increased libido, nervousness, paroniria, somnolence Reproductive (Female): breast pain, uterine hemorrhage Respiratory System: abnormal chest sounds, bronchospasm Skin and Appendages: abnormal pigmentation, angioedema, dermatitis, dry skin, eczema, nail disorder, pruritus, skin disorder, urticaria Special Senses: abnormal vision, cataract, conjunctivitis, deafness, eye pain, taste perversion, tinnitus, vestibular disorder Urinary System: abnormal urine, hematuria, increased BUN, micturition urgency, nocturia, polyuria, pyelonephritis, urinary incontinence *NOS = Not Otherwise Specified Psoriasis The principal adverse reactions associated with the use of cyclosporine in patients with psoriasis are renal dysfunction, headache, hypertension, hypertriglyceridemia, hirsutism/hypertrichosis, paresthesia or hyperesthesia, influenza-like symptoms, nausea/vomiting, diarrhea, abdominal discomfort, lethargy, and musculoskeletal or joint pain.

4% of the patients because of increased creatinine. In the majority of cases, these changes were reversible after dose reduction or discontinuation of cyclosporine. There has been one reported death associated with the use of cyclosporine in psoriasis.

A 27-year-old male developed renal deterioration and was continued on cyclosporine. He had progressive renal failure leading to death. Frequency and severity of serum creatinine increases with dose and duration of cyclosporine therapy.

These elevations are likely to become more pronounced and may result in irreversible renal damage without dose reduction or discontinuation. 7% *Total percentage of events within the system. **Newly occurring hypertension = SBP ≥ 160 mm Hg and/or DBP ≥ 90 mm Hg.

4%) carcinomas] Reticuloendothelial: platelet, bleeding, and clotting disorders, red blood cell disorder Respiratory: infection, viral and other infection Skin and Appendages: acne, folliculitis, keratosis, pruritus, rash, dry skin Urinary System: micturition frequency Vision: abnormal vision Mild hypomagnesemia and hyperkalemia may occur but are asymptomatic.

Increases in uric acid may occur and attacks of gout have been rarely reported. A minor and dose related hyperbilirubinemia has been observed in the absence of hepatocellular damage. Cyclosporine therapy may be associated with a modest increase of serum triglycerides or cholesterol.

Elevations of triglycerides (> 750 mg/dL) occur in about 15% of psoriasis patients; elevations of cholesterol (> 300 mg/dL) are observed in less than 3% of psoriasis patients. Generally these laboratory abnormalities are reversible upon dose reduction or discontinuation of cyclosporine.

Postmarketing Experience, Psoriasis Cases of transformation to erythrodermic psoriasis or generalized pustular psoriasis upon either withdrawal or reduction of cyclosporine in patients with chronic plaque psoriasis have been reported.

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.

5 mg/dL, respectively. These elevations were often responsive to cyclosporine dosage reduction. More overt nephrotoxicity was seen early after transplantation and was characterized by a rapidly rising BUN and creatinine. Since these events are similar to renal rejection episodes, care must be taken to differentiate between them.

This form of nephrotoxicity is usually responsive to cyclosporine dosage reduction. Although specific diagnostic criteria which reliably differentiate renal graft rejection from drug toxicity have not been found, a number of parameters have been significantly associated with one or the other.

It should be noted however, that up to 20% of patients may have simultaneous nephrotoxicity and rejection. Nephrotoxicity vs. 0001 A form of a cyclosporine-associated nephropathy is characterized by serial deterioration in renal function and morphologic changes in the kidneys.

From 5% to 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 cyclosporine capsules (modified) dose to excessive blood concentrations.

Due to the potential for additive or synergistic impairment of renal function, caution should be exercised when coadministering cyclosporine capsules (modified) 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 cyclosporine capsules, (modified), 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 cyclosporine capsules, (modified), 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 cyclosporine capsules, (modified). 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 cyclosporine capsules (modified) treatment for the development of malignancies. Moreover, use of cyclosporine capsules (modified) 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 cyclosporine capsules (modified) should be considered before treatment of patients with psoriasis.

Cyclosporine, the active ingredient in cyclosporine capsules, (modified), 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 cyclosporine capsules, (modified).

Renal dysfunction is a potential consequence of cyclosporine capsules (modified) therefore renal function must be monitored during therapy. Patients receiving cyclosporine capsules (modified) 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 cyclosporine capsules (modified) therapy and reflects a reduction in the glomerular filtration rate. 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%).

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.

2%) of 1439 psoriasis patients treated with cyclosporine worldwide from clinical trials. Additional tumors have been reported in 7 patients in cyclosporine postmarketing experience. 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. 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 cyclosporine capsules (modified) only after complete resolution of suspicious lesions, and only if there are no other treatment options (see Special Monitoring for Psoriasis Patients ).

, 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 (See DESCRIPTION for alcohol content of each formulation ).