Neoral

Following concomitant administration of cyclosporine and lercanidipine, the AUC of lercanidipine was increased threefold and the AUC of cyclosporine was increased 21%.

Grapefruit juice should be avoided owing to its interference with the P450 enzyme system which has been reported to increase the bioavailability of NEORAL.

It has been noted that cyclosporine reduces the clearance of prednisolone and conversely, high dose therapy with methylprednisolone can increase the blood concentration of cyclosporine.

During treatment with cyclosporine, vaccination may be less effective; the use of live-attenuated vaccines should be avoided.

Nonsteroidal anti-inflammatory drug therapy should be discontinued where possible. As nonsteroidal anti-inflammatory drugs alone can have an adverse effect on renal function, addition of these drugs to NEORAL or SANDIMMUNE I.V. therapy or an increase in their dosage should be accompanied by particular close monitoring of renal function.

In transplant patients who received the HMG-CoA reductase inhibitor lovastatin in combination with cyclosporine and other immunosuppressive drugs, there have been reports of severe rhabdomyolysis that precipitated acute renal failure. The potential for NEORAL or SANDIMMUNE I.V. to interact with drugs in this class should be considered.

Cyclosporine may reduce the clearance of digoxin{*If digoxin, colchicine, or HMG-CoA reductase inhibitors (statins), are used concurrently with cyclosporine, close clinical observation is required in order to enable early detection of toxic manifestations of the drug, followed by reduction of its dosage or its withdrawal.}, colchicine*, prednisolone* , HMG-CoA reductase inhibitors (statins) and etoposide.

Severe digitalis toxicity has been seen within days of starting cyclosporine in several patients taking digoxin. There are also reports on the potential of cyclosporine to enhance the toxic effects of colchicine such as myopathy and neuropathy, especially in patients with renal dysfunction. If digoxin or colchicine are used concurrently with cyclosporine, close clinical observation is required in order to enable early detection of toxic manifestations of digoxin or colchicine, followed by reduction of dosage or its withdrawal.

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.

Elevations in serum creatinine were observed in the studies using sirolimus in combination with full-dose cyclosporine for microemulsion. This effect is often reversible with cyclosporine dose reduction. Sirolimus had only a minor influence on cyclosporine pharmacokinetics. Co-administration of cyclosporin significantly increases blood levels of sirolimus.

The concomitant use of these drugs with NEORAL capsules and oral solution or SANDIMMUNE I.V. (cyclosporine) should be carefully considered.

In graft recipients there have been isolated reports of considerable but reversible impairment of kidney function (with corresponding increase in serum creatinine) following concomitant administration of fibric acid derivatives (e.g. bezafibrate, fenofibrate). Kidney function must therefore be closely monitored in these patients. In the event of significant impairment of kidney function the comedication should be withdrawn.

Caution is required for concomitant use of potassium sparing drugs (e.g. potassium sparing diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists) or potassium containing drugs since they may lead to significant increases in serum potassium (see Warnings and Precautions).

Cyclosporine may increase the plasma concentrations of repaglinide and thereby increase the risk of hypoglycaemia.

Of the many drugs reported to interact with cyclosporine, those for which the interactions are adequately substantiated and considered to have clinical implications are listed below.

Various agents are known to either increase or decrease plasma or whole blood cyclosporine levels usually by inhibition or induction of enzymes involved in the metabolism of cyclosporine, in particular CYP3A4. Cyclosporine is also an inhibitor of CYP3A4 and of the multidrug efflux transporter P-glycoprotein and may increase plasma levels of comedications that are substrates of this enzyme and/or transporter.

The initial dose should be given on the day before transplantation. In most cases i.v. infusion of SANDIMMUNE is preferred for this purpose (please refer to previous Section). Maintenance treatment with NEORAL is at a daily dose of about 12.5 mg/kg given in two divided doses, and should be continued for at least 3 months (and preferably for 6 months) before the dose is gradually decreased to zero by one year after transplantation. If NEORAL is used to initiate therapy, the recommended daily dose is 12.5 to 15 mg/kg given in two divided doses, starting on the day before transplantation.

Higher doses of NEORAL, or the use of i.v. therapy, may be necessary in the presence of gastrointestinal disturbances which might decrease drug absorption. In some patients, GVHD occurs after discontinuation of cyclosporine treatment, but usually responds favourably to re-introduction of therapy.

Low doses of NEORAL should be used to treat mild, chronic GVHD.

Treatment should be discontinued if no improvement has been observed after three months' of NEORAL therapy.

NEORAL should always be given in two divided doses.

NEORAL soft gelatin capsules: When the blister package is opened, a characteristic smell is noticeable. This is normal and does not mean that there is anything wrong with the capsule.

Capsules should be swallowed whole.

NEORAL solution should be diluted with preferably orange juice or apple juice. Grapefruit juice should be avoided for dilution owing to its possible interference with the P450 enzyme system. Immediately before taking the solution, it should be stirred well. Other drinks such as soft drinks can be used according to individual taste.

The syringe should not come into contact with the diluent. If the syringe is to be cleaned, do not rinse it but wipe the outside with a dry tissue.

SANDIMMUNE I.V. (50 mg/mL Concentrate for Solution for Infusion) is diluted to l:20 to l:l00, immediately prior to use, with 5% glucose or normal saline and administered by slow intravenous infusion over a period of two to six hours (see Warnings and Precautions).

If available, glass containers should be used. Plastic bottles should only be used if they conform to the requirements for “sterile plastic containers for human blood and blood components” respectively to “empty sterile containers of plasticized poly(vinyl chloride) for human blood and blood components” of the current european pharmacopoeia, since polyoxyethylated castor oil contained in the concentrate can cause phathalate stripping from PVC. Containers and stoppers should be free of silicone oil and fatty substances.

Since cyclosporine can impair renal function, a reliable baseline level of serum creatinine should be established by at least two measurements prior to treatment, and serum creatinine should be monitored every 2 weeks during the first 3 months of therapy. Thereafter, if creatinine remains stable, measurements can be made every 4 weeks. More frequent checks are necessary when the dose of NEORAL is increased or concomitant treatment with a non-steroidal anti-inflammatory drug is initiated or its dosage increased. The same precaution applies to the introduction of any drug known to increase cyclosporine blood levels.

Dose adjustment based on creatinine values: If serum creatinine remains increased by more than 30% above baseline at more than one measurement, the dosage of NEORAL should be reduced. If serum creatinine increases by more than 50%, a dosage reduction by 50% is mandatory. These recommendations apply even if the patient's values still lie within the laboratory normal range. If dose reduction is not successful in reducing levels within one month, NEORAL treatment should be discontinued.

Since NEORAL can impair renal function, serum creatinine should be measured every 2 weeks for the first 3 months of therapy. Thereafter, if creatinine remains stable, measurements should be done every 2 months in patients who are on up to 2.5 mg/kg/day, and at monthly intervals in patients who require higher doses. The dose must be reduced by 25-50% when serum creatinine increases by more than 30% above the patient's own baseline, even if the values are still within the normal range. If dose reduction is not successful within 1 month, NEORAL treatment should be discontinued.

Discontinuation of NEORAL therapy is also recommended if hypertension developing during NEORAL therapy cannot be controlled with appropriate therapy.

As cyclosporine is an immunosuppressive agent, search should be made for tumours of all kinds, in particular the skin, oral mucosa and major lymph nodes. This physical examination should be made initially at least every 3 months and any skin lesion not typical for psoriasis should be biopsied. NEORAL treatment should be discontinued if a malignancy occurs, and appropriate treatment of the malignancy instituted.

The dose must be adjusted individually according to efficacy (proteinuria) and safety (primarily serum creatinine), but, depending on monitoring of drug tolerance, should not exceed 5 mg/kg a day in adults and 6 mg/kg a day in children.

Psoriasis generally recurs when NEORAL treatment is stopped. The goal of maintenance therapy is to optimize therapy and achieve sustained improvement. That is, to keep the patient's disease controlled with the minimal dose of NEORAL in order to avoid adverse effects. Total clearing of the skin should not always be the ultimate goal.

Patients unable to take NEORAL soft gelatin capsules or oral solution pre- or postoperatively, may be treated with the SANDIMMUNE I.V. at one-third the oral dose.

The initial dose of SANDIMMUNE I.V. is 3 to 5 mg/kg/day. This daily dose is continued post-operatively for up to 2 weeks until the patient can tolerate the NEORAL soft gelatin capsules or oral solution. Patients should be switched to NEORAL as soon as possible after surgery. In pediatric usage, the adult dose and dosing regimen have been used initially and adjusted to target blood levels (see Warnings and Precautions).

Dose Titration for Induction of Remission, the recommended initial dose is 2 mg/kg/day given in two divided oral doses.

If there is no improvement after one month, the daily dose may be gradually increased. Dose adjustments should be made in increments of 0.5 to 1 mg/kg/day body weight per month and total daily dose, depending on monitoring of drug tolerance, should not exceed 5 mg/kg/day.

The dose ranges of NEORAL capsules and oral solution and SANDIMMUNE I.V. given below are intended to serve as guideline only. Routine monitoring of cyclosporine blood levels is required; this can be carried out by means of an RIA method based on monoclonal antibodies. The results obtained will serve as a guide for determining the actual dosage required to achieve the desired target concentration in individual patients.

When NEORAL is given with other immunosuppressants (e.g. with corticosteroids or as part of a triple or quadruple drug therapy), lower doses (e.g. 3 to 6 mg/kg given in two divided doses for the initial treatment) may be used.

For inducing remission, the recommended initial daily dose, given in two divided oral doses, is 3.5 mg/kg for adults and 4.2 mg/kg for children if, except for proteinuria, renal function is normal. In patients with impaired renal function, the initial dose should not exceed 2.5 mg/kg/day.

The combination of NEORAL with low doses of oral corticosteroids is recommended if the effect of NEORAL is not satisfactory, especially in steroid-resistant patients.

For maintenance treatment, the dose should be slowly reduced to the lowest effective level. Monitoring for Nephrotic Syndrome Patients.

Since NEORAL can impair renal function, it is necessary to assess renal function frequently and if serum creatine remains increased by more than 30% above baseline at more than one measurement, the dosage of NEORAL must be reduced by 25% to 50%.

In some patients it may be difficult to detect cyclosporine-induced renal dysfunction because of changes in renal function related to the nephrotic syndrome itself. Renal biopsy should be considered for patients with steroid-dependent minimal change nephropathy in whom NEORAL therapy has been maintained for more than one year.

Periodic monitoring of cyclosporine trough levels is recommended.

For the first 6 weeks of treatment, the recommended initial dose is 2 mg/kg/day orally given in two divided doses. If necessary, the daily dose may then be increased gradually as tolerability permits (see Warnings and Precautions) but, depending on monitoring of drug tolerance, should not exceed 5 mg/kg/day. Up to 12 weeks of NEORAL therapy may be required before full effectiveness is achieved.

For maintenance therapy, the dose must be titrated individually according to tolerability.

NEORAL may be given in combination with low-dose corticosteroids and/or non-steroidal anti-inflammatory drugs (see Warnings and Precautions).

Rare: menstrual disturbances, gynecomastia.

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.

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

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.

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

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

Common: fatigue. Uncommon: edema, weight increase.

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.

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.

Very common: renal dysfunction (see Warnings and Precautions).

Common: hypertrichosis. Uncommon: allergic rashes.

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

Patients receiving immunosuppressive therapies, including cyclosporine and cyclosporine- containing regimens, are at increased risk of infections (viral, bacterial, fungal, parasitic) (see Warnings and Precautions). Both generalised and localised infections can occur. Pre-existing infections may also be aggravated. Fatal outcomes have been reported.

Patients receiving immunosuppressive therapies, including cyclosporine and cyclosporine- containing regimens, are at increased risk of developing lymphomas or lymphoproliferative disorders and other malignancies, particularly of the skin. The frequency of malignancies increases with the intensity and duration of therapy (see Warnings and Precautions).

Frequency estimate: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10 000, <1/1000) very rare (<1/10 000), including isolated reports.

Common: hepatic dysfunction.

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.

Anaphylactoid reactions have been observed following i.v. administration (see Warnings and Precautions).

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

In psoriasis in 1439 patients treated with SANDIMMUNE the following were reported: 21 cases of skin cancer, 17 cases of solid malignant tumours and 6 cases of lymphoproliferative disorders (2 lymphomas).

There is an increased risk of malignancies, particularly skin cancer in psoriasis patients especially when the psoriasis has been previously treated with carcinogens, such as PUVA treatment.

In nephrotic syndrome of 660 patients treated with Sandimmune, malignancies occurred in 5 patients (3 carcinomas, 2 Hodgkins lymphomas).

NEORAL capsules and oral solution (cyclosporine) are indicated in adults and children for steroid dependent and steroid resistant nephrotic syndrome due to glomerular diseases such as minimal change nephropathy; focal and segmental glomerulosclerosis, or membranous glomerulonephritis. NEORAL can be used to induce remissions and to maintain them. It can also be used for maintenance of steroid induced remissions, allowing withdrawal of, or reduction in the dosage of steroids.

NEORAL capsules and oral solution and SANDIMMUNE I.V. (cyclosporine) are indicated in the prevention of graft rejection following bone marrow transplantation and the prevention or treatment of graft-versus-host disease (GVHD).

NEORAL capsules and oral solution (cyclosporine) are indicated for the treatment of severe psoriasis in patients for whom conventional therapy is ineffective or inappropriate.

NEORAL capsules and oral solution (cyclosporine) are also indicated for the treatment of severe active rheumatoid arthritis in patients for whom classical slow-acting antirheumatic agents are inappropriate or ineffective.

NEORAL capsules and oral solution and SANDIMMUNE I.V. (cyclosporine) are indicated in the prevention of graft rejection following solid organ transplantation and in the treatment of transplant rejection in patients previously receiving other immunosuppressive agents.

Each soft gelatin capsule with the imprint NVR 50 mg contains: cyclosporine for microemulsion 50 mg. Nonmedicinal ingredients: dl-α-tocopherol, ethanol, hydrogenated castor oil, maize oil and propylene glycol; shell: gelatin, glycerol and propylene glycol; coloring agents: aluminum chloride, hydroxypropyl methylcellulose, sodium hydroxide and titanium dioxide. Packs of 30 (6 full aluminum blister strips of 5 capsules each).

Each mL of sterile ampul in a polyoxyethylated castor oil/ethanol vehicle contains: cyclosporine 50 mg. Ampuls of 1 and 5 mL.

Each soft gelatin capsule with the imprint NVR 10 mg contains: cyclosporine for microemulsion 10 mg. Nonmedicinal ingredients: dl-α-tocopherol, ethanol, hydrogenated castor oil, maize oil and propylene glycol; shell: gelatin, glycerol and propylene glycol; coloring agents: aluminum chloride, hydroxypropyl methylcellulose, sodium hydroxide and titanium dioxide. Packs of 60 (6 full aluminum blister strips of 10 capsules each).

Each mL contains: cyclosporine for microemulsion 100 mg dissolved. Nonmedicinal ingredients: dl-α-tocopherol, ethanol, hydrogenated castor oil, maize oil and propylene glycol. Bottles of 50 mL. A graduated syringe for dispensing is provided.

Each soft gelatin capsule with the imprint NVR 100 mg contains: cyclosporine for microemulsion 100 mg. Nonmedicinal ingredients: dl-α-tocopherol, ethanol, hydrogenated castor oil, maize oil and propylene glycol; shell: gelatin, glycerol and propylene glycol; coloring agents: aluminum chloride, carminic acid, hydroxypropyl methylcellulose, iron oxide black, sodium hydroxide and titanium dioxide. Packs of 30 (6 full aluminum blister strips of 5 capsules each).

Each soft gelatin capsule with the imprint NVR 25 mg contains: cyclosporine for microemulsion 25 mg. Nonmedicinal ingredients: dl-α-tocopherol, ethanol, hydrogenated castor oil, maize oil and propylene glycol; shell: gelatin, glycerol and propylene glycol; coloring agents: aluminum chloride, carminic acid, hydroxypropyl methylcellulose, iron oxide black, sodium hydroxide and titanium dioxide. Packs of 30 (6 full aluminum blister strips of 5 capsules each).

Caution should be exercised in patients receiving drug treatment with:

• Nephrotoxic Drugs

  
  

• Cytotoxic Drugs

  
  

• Immunosuppressants or radiation (including PUVA or UVB)

  
  

• Drugs affecting metabolism/absorption of cyclosporine.

  
  

• Lercanidipine

  
  

• Methotrexate

Cyclosporine may cause increases in serum creatinine and urea levels, even at recommended doses as a result of reduced glomerular filtration rate (GFR). The mechanism leading to these increases is not fully understood. These functional changes are dose dependent and reversible, and usually respond to dose reduction. Although less frequent, some patients may develop structural changes in the kidney (e.g. interstitial fibrosis) during long term treatment. Although these renal changes are less common, they may be irreversible. In renal transplant patients, structural changes in the kidney must be differentiated from organ rejection.

Close monitoring of parameters that assess renal function is required. Abnormal values may necessitate dose reduction.

In elderly patients (>65 years of age), renal function should be monitored more closely. Kidney changes occur both structurally and functionally with aging leading to a natural decrease of renal function. Cyclosporine whole blood concentrations should be closely monitored in this patient group to ensure maximum safety and optimal clinical outcome.

In patients who are treated with cyclosporine for non-transplant indications, the risk of renal structural changes is greater if the serum creatinine level increases more than 30% from the patient's own baseline value. Thus regular measurements of serum creatinine levels must be made (see also Monitoring and Laboratory Tests, Psoriasis/Rheumatoid Arthritis/Nephrotic Syndrome Patient Management).

Like other immunosuppressants, cyclosporine, predisposes patients to the development of a variety of bacterial, fungal, parasitic and viral infections, often with opportunistic pathogens. As this can lead to a fatal outcome, effective pre-emptive and therapeutic strategies should be employed particularly in patients on multiple long-term immunosuppressive therapy.

Vaccination may be less effective and the use of live attenuated vaccines should be avoided.

Cyclosporine enhances the risk of hyperkalemia, especially in patients with renal dysfunction. Caution is also required when cyclosporine is co-administered with potassium sparing diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists and potassium containing drugs as well as in patients on a potassium rich diet (see Drug Interactions). Control of potassium levels in these situations is advisable.

Caution is required in treating patients with hyperuricemia (see Drug Interactions).

Cyclosporine enhances the clearance of magnesium. This can lead to symptomatic hypomagnesemia, especially in the peri-transplant period. Control of serum magnesium levels is therefore recommended in the peri-transplant period, particularly in the presence of neurological symptoms/signs. If considered necessary, magnesium supplementation should be given.

Many transplant patients have hyperlipidemia and cyclosporine may contribute to the genesis of this problem. It is advisable to perform lipid determination before treatment and after the first month of therapy. If lipids are increased, restriction of dietary fat should be considered. (If the risk benefit ratio warrants, a reduction of NEORAL capsules and oral solution (cyclosporine) dose may also be considered.) Caution is advised in the co-administration of NEORAL or SANDIMMUNE I.V. and the HMG-CoA reductase inhibitor, lovastatin due to the risk of myocyte necrosis. The potential for interaction with other drugs in this class should be considered (see Drug Interactions and Adverse Reactions).

Cyclosporine is not teratogenic in animals, but was shown to be both embryo- and feto-toxic in rats and rabbits at 2 to 5 times the human dose.

To date, information has been received on 514 pregnancies with exposure to SANDIMMUNE. In most patients, the indication for cyclosporine therapy was organ transplantation.

Pregnant women receiving immunosuppressive therapies after transplantation, including cyclosporine and cyclosporine-containing regimens, are at risk of premature delivery (<37 weeks).

Most patients who became pregnant continued cyclosporine therapy throughout pregnancy, usually in combination with other immunosuppressive drugs and further medication.

Fetal loss occurred in 9.1% of the patients, which is within the range found in a normal population. In 4.9% of the patients, the pregnancy was interrupted, either for medical considerations or at the wish of the patient.

The course of pregnancy was often complicated by disorders specific to pregnancy, in particular in renal transplant patients, or by disorders relating to the underlying disease. A large proportion of the pregnancies ended in preterm delivery. Accordingly, the main problems seen in the neonates relate to prematurity, best exemplified by the short median gestation duration of 35.7 weeks in the 439 pregnancies completed, and the low median birth weight, 2291 g, of the 446 babies delivered, including 10 twins.

It appears that premature delivery and the delivery of infants small for their age occur more often in patients who have undergone a renal transplantation.

Out of 102 babies born to mothers treated with SANDIMMUNE, five were born with malformations. It is not clear what role cyclosporine has played in the complications of pregnancy.

Males treated with cyclosporine have fathered normal children.

In pregnant transplant recipients who are being treated with immunosupressants the risks of premature births is increased.

A limited number of observations in children exposed to cyclosporine in utero is available, up to an age of approximately 7 years. Renal function and blood pressure in these children were normal.

However there are no adequate and well-controlled studies in pregnant women and, therefore, NEORAL or SANDIMMUNE I.V. should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the foetus.

Experience with cyclosporine in the elderly is limited, but no particular problems have been reported following the use of the drug at the recommended dose. However, factors sometimes associated with aging, in particular impaired renal function, necessitate careful supervision and may necessitate dosage adjustment.

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.

Cyclosporine has the potential to induce tremor, convulsions and paresthesia in post-transplant recipients. Rarely, more complex neurological abnormalities including motor spinal cord and cerebellar syndromes have been reported in post-transplant patients.

Cyclosporine may also cause dose-dependent, reversible increases in serum bilirubin and, occasionally, in liver enzymes.

Close monitoring of parameters that assess hepatic function is required. Abnormal values may necessitate dose reduction.

Patients receiving cyclosporine may develop hypertension, and regular monitoring of blood pressure is required. Caution is advised in choosing an agent to treat this hypertension. Diuretics are not recommended (see Drug Interactions).

In addition, in psoriasis patients; beta-blockers are not generally recommended due to their propensity to exacerbate psoriasis. Only calcium channel blockers which do not interfere with cyclosporine pharmacokinetics are recommended (see Drug Interactions).

Discontinuation of the drug is recommended if hypertension developing during NEORAL therapy cannot be controlled with appropriate antihypertensive therapy. As with other long-term immunosuppressive treatments, an increased risk of lymphoproliferative disorders must be borne in mind.

Malignancy and lymphoproliferative disorders have developed, but their incidence and distribution are similar to those in patients on conventional immuno-suppressive therapy. In psoriatic patients on cyclosporine therapy, development of malignancies (in particular of the skin) has been reported. Skin lesions, not typical of psoriasis, but suspected to be malignant or premalignant should be biopsied before starting cyclosporine treatment. Patients with malignant or premalignant alterations of the skin should be treated with cyclosporine only after appropriate treatment of such lesions and if no other option for successful therapy exists. Cyclosporine should be discontinued if malignancy occurs.

In view of the potential risk of skin malignancy, patients on NEORAL or SANDIMMUNE I.V., should be warned to avoid excess ultraviolet light exposure.

Psoriasis and rheumatoid arthritis: A complete blood count including, differential WBC, platelet counts, liver function tests, urinalysis, serum potassium, uric acid should be measured periodically during treatment with NEORAL. Serum creatinine should be measured every 2 weeks for the initial 3 months (see Dosage and Administration). Thereafter, if creatinine levels remain stable, measurements should be made every 2 months in patients who are receiving up to 2.5 mg/kg/day and every 4 weeks in patients who are receiving higher doses.

More frequent checks are necessary when the NEORAL dose is increased or concomitant treatment with a non-steroidal anti-inflammatory drug is initiated or the dosage is increased. The same precaution applies to the introduction of any drug known to increase cyclosporine blood levels.

Routine measurements of cyclosporine blood levels are not necessary because of their poor predictive value, but may be useful in special cases where drug interactions or altered bioavailability are suspected.

Regular clinical examinations are necessary during treatment with NEORAL. Follow-up assessment of blood pressure should be performed every 2 weeks during the initial 3 months and every month thereafter.

Should hypertension occur, in the majority of patients, elevated blood pressure can be adequately controlled by dose reduction. Should antihypertensive therapy be necessary, diuretics are not recommended. In addition, in psoriasis patients, beta-blockers are not generally recommended due to their propensity to exacerbate psoriasis. Only calcium channel blockers which do not interfere with NEORAL pharmacokinetics are recommended (see Drug Interactions). If hypertension is uncontrolled with antihypertensive treatment, NEORAL should be discontinued. When NEORAL is discontinued, blood pressure returns to normal within 3 months. Development of malignancies has been reported in patients when treated with cyclosporine. In patients with nephrotic syndrome treated with immunosuppressants (including cyclosporine) the occurrence of malignancies (including Hodgkins lymphoma) has occasionally been reported. Careful physical examination should thus be made for malignancies, notably of skin, oral mucosa, major lymph nodes. Psoriatic patients should avoid direct sun exposure as this will increase the risk of skin cancer.

NEORAL should only be prescribed by physicians experienced with its use. All patients to be treated with NEORAL for nephrotic syndrome must have a pre-treatment physical examination to include blood pressure, renal function (see Dosage and Administration) and screening for malignancies.

Experience with NEORAL in children is still limited. Experience in children is almost entirely based on SANDIMMUNE. In several studies pediatric patients required and tolerated higher doses of SANDIMMUNE per kg body weight than those used in adults.

NEORAL should only be prescribed for psoriatic patients by physicians experienced with its use. All patients to be treated with NEORAL for psoriasis must have a pre-treatment physical examination to include blood pressure, renal function and careful examination for tumours, particularly of the skin, to establish accurate baseline values and clinical status.

Skin lesions not typical of psoriasis should be biopsied to exclude skin cancers, mycosis fungoides or other pre-malignant conditions.

Patients with impaired renal function (except in nephrotic syndrome patients with a permissible degree of renal impairment), abnormal liver function, uncontrolled hypertension, uncontrolled infections or any kind of malignancy should not receive NEORAL.

Appropriate patient and laboratory monitoring is essential to prevent, reverse or minimize the following adverse events: nephrotoxicity; hypertension; the development of malignancies and lymphoproliferative disorders; increased risk of infections; hepatotoxicity; lipoprotein abnormalities; neurotoxicity.

Cyclosporine absorption has significant inter-and intra-patient variability. Cyclosporine whole blood concentrations as well as the effectiveness and the adverse events related to cyclosporine should be appropriately monitored in all patients, particularly in de novo patients undergoing any change in their treatment regimen, to ensure maximum safety and optimal clinical outcome.

NEORAL capsules and oral solution and SANDIMMUNE I.V. (cyclosporine) should be prescribed only by physicians who are experienced in immunosuppressive therapy and management of transplant patients and can provide adequate follow-up, including regular full physical examination, measurement of blood pressure and control of laboratory safety parameters. Patients receiving the drug should be managed in facilities with adequate laboratory and supportive medical resources.

The concentrate for solution for infusion contains polyoxyethylated castor oil which has been reported to cause anaphylactoid reactions. Patients receiving SANDIMMUNE I.V. should be observed continuously for at least 30 minutes following the start of the infusion and at frequent intervals thereafter. (See also Monitoring and Laboratory Tests, Transplant Patient Management.)

As cyclosporine is transferred into breast milk of lactating females, mothers receiving treatment with NEORAL or SANDIMMUNE I.V. should not breast-feed.

Animal studies have shown reproductive toxicity in rats and rabbits.

NEORAL capsules should be stored at temperatures between 15 and 25°C and should not be removed from the blister packs until required for use. Occasional increases in temperature up to 30°C do not affect the quality of the product.

Store the intravenous product, protected from light, between 15 and 30°C. Do not store in the refrigerator and protect from freezing.

The concentrate for solution for infusion should be diluted to between 1:20 and 1:100 in 5% glucose or normal saline only, immediately prior to use (see Administration).

Once opened, the contents must be used within 2 months.

NEORAL solution should be stored and dispensed in the original container. Store between 15 and 30°C, preferably not below 20°C for prolonged periods, as it contains oily components of natural origin which tend to solidify at low temperatures. Do not store in the refrigerator and protect from freezing.

A jelly-like formation may occur below 20°C, which is however reversible at temperatures up to 30°C. Minor flakes or a slight sediment may still be observed. These phenomena do not affect the efficacy and safety of the product, and the dosing by means of the syringe remains accurate.

Following intravenous (I.V.) administration, SANDIMMUNE exhibits multi-compartment behaviour. The initial rapid distribution half-life is 0.10 hours, followed by a second slower distribution half-life of 1.1 hours. Continuous administration of the drug leads to eventual saturation of the peripheral compartment. This is reflected clinically by a decreased dosage requirement with long-term administration to maintain constant cyclosporine levels.

In blood, cyclosporine is highly bound to erythrocytes and plasma lipoprotein. However, all cyclosporine metabolites are less bound to plasma lipoprotein than cyclosporine itself. The relative distribution of cyclosporine in blood is a function of drug concentration, hematocrit, temperature and lipoprotein concentration. At a blood concentration of 500 mg/mL, 58 % of the drug is associated with erythrocytes, 4% with granulocytes, 5% with lymphocytes and the remaining 33% is distributed within the plasma. The plasma concentration of cyclosporine increased linearly with whole blood concentrations up to 1000 ng/mL. Above this concentration, the distribution of cyclosporine between blood and plasma is non-linear. Blood cells appear saturated by cyclosporine at concentrations above 500 ng/mL. Above this concentration there is a sharp decrease in the fraction of cyclosporine absorbed by erythrocytes, with a corresponding increase in the fraction of drug in the plasma.

In transplant recipients, low hematocrit (due to chronic disease or intraoperative blood loss) alters cyclosporine distribution between blood and plasma, resulting in higher levels of the drug in the plasma. This effect is temperature-dependent.

In plasma, more than 80% of cyclosporine is bound to lipoproteins. The major lipoprotein fractions involved are high-(HDL) and low-(LDL) density lipoprotein, which bind more than 80% of cyclosporine in plasma. The binding of cyclosporine to plasma protein is independent of concentration between 20 and 20×10³ ng/mL. However, binding is markedly influenced by temperature; about 70% of the drug is bound at 4°C, 93% at 20°C and 98% at 37°C.

With a temperature decrease from 37° to 21°C, approximately 50% of cyclosporine diffuses from the plasma to the red blood cells, where it binds to hemoglobin; this process is reversible upon re-equilibration at 37°C for 2 hours.

Consistent with the lipophilic nature of cyclosporine, body fat contains the highest concentration of the drug. Accumulation also occurs in liver, pancreas, lungs, kidneys, adrenal glands, spleen and lymph nodes. Very low levels are found in brain tissues and cerebrospinal fluid suggesting that cyclosporine does not readily cross the blood brain barrier. The large tissue distribution of cyclosporine is consistent with the large apparent volume of distribution of 3.5-9 litres/kg and results from the high lipid solubility of cyclosporine and its ability to diffuse easily through biological membranes.

When NEORAL is given, it provides improved dose linearity in cyclosporine exposure (AUC_B), a more consistent absorption profile and less influence from concomitant food intake and from diurnal rhythm than does SANDIMMUNE. These properties combined yield a lower within-patient variability in pharmacokinetics of cyclosporine and a stronger correlation between trough concentration and total exposure (AUC). As a consequence of these additional advantages, the time schedule of NEORAL administration does not require that meals be considered. In addition, NEORAL produces a more uniform exposure to cyclosporine throughout the day and from day to day on a maintenance regimen.

Compared to other oral forms of SANDIMMUNE, NEORAL capsules and solution is more quickly absorbed (resulting in a 1 hour earlier mean T_max and a 59% higher mean C_max) and exhibits, on average, a 29 % higher bioavailability.

Cyclosporine is a potent immunosuppressive agent with a narrow therapeutic range which has been shown in man to prolong the survival of allogenic transplants.

NEORAL capsules and oral solution include a microemulsion formulation of cyclosporine. NEORAL provides a more complete and consistent absorption profile and is less influenced by concomitant food intake or by diurnal rhythm than the previously marketed conventional formulation of cyclosporine (SANDIMMUNE capsules and oral solution). These properties combined yield a lower intra-patient variability, as well as in some cases, a lower inter-patient variability in pharmacokinetics of cyclosporine and a stronger correlation between trough concentration and total exposure (AUC_Β) for a more accurate targeting of the level of immunosuppression.

As a consequence of these properties, the time schedule of NEORAL administration does not require that meals be considered. In addition, NEORAL produces a more even exposure to cyclosporine throughout the day and from day to day on a maintenance regimen, thereby helping to avoid periods of either under-immunosuppression or over-exposure to the drug.

Cyclosporine is distributed largely outside the blood volume. In the blood, 33 to 47 % is present in plasma, 4 to 9 % in lymphocytes, and 41 to 58 % in erythrocytes. In plasma, approximately 90% is bound to proteins, mostly lipoproteins.

Cyclosporine is extensively biotransformed to approximately 15 metabolites. There is no single major metabolic pathway. Elimination is primarily biliary, with only 6% of the oral dose excreted in the urine; only 0.1 % is excreted in the urine as unchanged drug. The distribution of cyclosporine appears to conform to a multicompartmental model in which continued administration leads to eventual saturation of the peripheral compartment.

The half-life of cyclosporine is approximately 18 hours (range 7.7 to 26.9). However there is a high variability in the data reported on the terminal half-life of cyclosporine depending on the assay applied and on the target population. For example, the terminal half-life ranged from 6.3 hours in healthy volunteers to 20.4 hours in patients with severe liver disease.

The recommended therapeutic range for 12-hour trough (C₀) levels from whole blood which appear to minimize side effects and rejection episodes is between 100-400 ng/mL as measured by the RIA method based on the specific monoclonal antibody (see Dosage and Administration).

It has however been reported that monitoring with the area under the time concentration curve for the first 4 hours (AUC_0-4) may provide for a more accurate prediction of optimal Neoral immunosuppression than trough (C₀) monitoring, thereby minimizing the risk of rejection, nephrotoxicity, neurotoxicity, hepatoxicity, and lowering serum creatinine levels.

Reports in the literature further indicate that using a single sampling point at 2 hours post-dose (C₂) best correlates with AUC_0-4 and provides for accurate assessment of Neoral absorption and immunosuppression in organ transplant recipients. When compared to C₀ monitoring, Neoral C₂ monitoring provided lower rates of rejection and toxicity in liver and renal transplant patients who attained C₂ target levels.

NEORAL and SANDIMMUNE I.V. (cyclosporine) strongly suppress cell mediated immunity and are therefore highly effective in preventing allograft rejection. However, interference with the primary activation of T-helper/inducer lymphocytes through the suppression of IL-2 production may be only one of several mechanisms contributing to an immunosuppressed state.

The major route of elimination of cyclosporine is through the bile. Less than 1 % of an administered dose of cyclosporine is excreted in the bile as parent drug. More than 44% of a cyclosporine dose appears in the bile as metabolites when measured by RIA.

Enterohepatic recirculation of parent drug is thus very low. Hepatic functional impairment can reduce total clearance of parent drug and/or metabolite. Renal excretion is a minor pathway with only 6 % of an oral dose excreted in urine; only 0. 1 % is excreted as unchanged drug.

In a study of 24 healthy male volunteers it was demonstrated that NEORAL soft gelatin capsules and NEORAL solution are bioequivalent.

Cyclosporine is primarily metabolized by the hepatic mono-oxygenase multiple forms of cytochrome P-450. Metabolites and unchanged drug are excreted into bile. Of the 17 suspected metabolites of cyclosporine, 9 have been isolated and identified. All the identified metabolites have the intact cyclic oligopeptide structure of the parent drug. Structural modifications during metabolism include mono- and dihydroxylation as well as N-demethylation, mainly at the N-methyl leucines. Both cyclosporine clearance and half-life are highly variable among patients and seem to be influenced by the type of transplant, age, disease state and concurrent drug therapy.

Since cyclosporine is primarily eliminated by hepatic metabolism, its clearance is impaired in patients with liver disease and in liver transplant recipients in the early post-operative phase. On a bodyweight basis, pediatric patients appear to clear the drug more rapidly as compared to adults. Therefore, children may require more frequent and larger doses of cyclosporine to achieve therapeutic blood levels. The metabolism of cyclosporine is also significantly influenced by changes in the activity of the hepatic drug metabolising system; for example, the induction of the cytochrome P-450 enzyme system by barbiturates, phenytoin and rifampicin markedly accelerated the elimination of cyclosporine, potentially causing inadequate immunosuppression and acute rejection. In contrast, ketoconazole increases cyclosporine levels by inhibiting its metabolism and/or active transport into the bile. A similar interaction is observed with erythromycin.

The administration of high dose methylprednisolone (for acute rejection) and long term steroid therapy may also affect the pharmacokinetics of cyclosporine.