Despite the increase in C_max and AUC seen in patients who are treated with NEORAL capsules and oral solution (cyclosporine), a similar safety profile to the conventional formulation of cyclosporine (SANDIMMUNE capsules and oral solution) has been observed. Studies have reported no significant difference between the two formulations in terms of renal safety, risk of adverse events, or laboratory parameters (eg blood pressure, creatinine clearance, serum levels of urea, creatinine, potassium, cholesterol, triglycerides). Furthermore, there is no indication of a correlation between peak cyclosporine concentration (C_max) and changes in renal function.

The following adverse reactions observed with SANDIMMUNE are also likely to occur with NEORAL.

Many side effects associated with cyclosporine therapy are dose-dependent and responsive to dose reduction. In the various indications, the overall spectrum of side effects is essentially the same. There are, however, differences in incidence and severity. As a consequence of the higher initial doses and longer maintenance therapy required after transplantation, side effects are more frequent and usually more severe in transplant patients than in patients treated for other indications.

Frequency estimate: very common ≥10%; common ≥1 to <10%; uncommon ≥0.1% to <1%; rare ≥0.01% to <0.1%; very rare <0.01%.

Very common: renal dysfunction

Very common: hypertension (particularly in heart transplant patients).

Very common: tremor, headache. Common: paresthesia. Uncommon: signs of encephalopathy such as convulsions, confusion, disorientation, decreased responsiveness, agitation, insomnia, visual disturbances, cortical blindness, coma, paresis, cerebellar ataxia. Rare: motor polyneuropathy. Very rare: optic disc edema including papilloedema, with possible visual impairment secondary to benign intracranial hypertension.

Common: anorexia, nausea, vomiting, abdominal pain, diarrhea, gingival hyperplasia, hepatic dysfunction. Rare: pancreatitis.

Very common: hyperlipidemia. Common: hyperuricemia, hyperkalemia, hypomagnesemia. Rare: hyperglycemia.

Common: muscle cramps, myalgia. Rare: muscle weakness, myopathy.

Uncommon: anemia, thrombocytopenia. Rare: micro-angiopathic hemolytic anemia, hemolytic uremic syndrome.

Common: hypertrichosis. Uncommon: allergic rashes.

Common: fatigue. Uncommon: edema, weight increase.

Rare: menstrual disturbances, gynecomastia.

Especially in liver transplant patients, signs of encephalopathy, vision and movement disturbances, and impaired consciousness are described. Whether these alterations are caused by cyclosporine, the underlying disease or other conditions remains to be established.In rare instances, thrombocytopenia, in some patients associated with micro-angiopathic hemolytic anemia and renal failure (hemolytic uremic syndrome), has been observed.

Malignancies and lymphoproliferative disorders have developed, but their incidence and distribution are similar to those in patients on conventional immunosuppressive therapy.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The following events occurred in patients involved in two clinical trials with NEORAL. The first column reports on a study in which stable renal transplant patients were switched to NEORAL; in the second, de novo renal transplant patients were treated with NEORAL. See Table 1.

Table 1: NEORAL

Adverse Events with NEORAL