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NEORALŽ SANDIMMUNEŽ I.V.
Novartis
Cyclosporine
Immunosuppressant
Caution: Transplantation: Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Neoral and Sandimmune I.V. Patients receiving the drug should be managed in centres staffed with professionals experienced in transplantation and the use of immunosuppressants and equipped with adequate laboratory facilities to monitor cyclosporine levels. The ability to measure cyclosporine blood levels facilitates the management of the patient. The radioimmunoassay (RIA) method has been used most often in clinical trials.
For long-term follow-up, the attending physician should receive complete information from the transplant centre on the patient, to include: recommended Neoral dosage, target trough levels of cyclosporine and frequency of determination of these levels. The attending physician should consult with the transplant centre when making dose adjustments to ensure that toxicity is minimized while maintaining adequate immunosuppression.
Sandimmune and Neoral, which are different in formulation, should not be used interchangeably.
Following initiation of treatment with Neoral, due to the different bioavailabilities of the different oral cyclosporine formulations, patients should not be converted to any other oral formulation of cyclosporine without appropriate monitoring of cyclosporine blood concentrations, serum creatinine levels and blood pressure. This does not apply to the conversion between Neoral soft gelatin capsules and Neoral oral solution as these two dosage forms are bioequivalent.
It is therefore important that prescribers, pharmacists and patients be aware that substitution of Neoral with any other oral formulation of cyclosporine is not recommended as this may lead to alterations in cyclosporine blood concentrations. For this reason, it might be appropriate to prescribe by brand.
Psoriasis/Rheumatoid Arthritis/Nephrotic Syndrome: Careful monitoring of Neoral treated patients is mandatory. Neoral should only be prescribed for psoriasis, rheumatoid arthritis or nephrotic syndrome by physicians experienced with its use. Neoral is indicated: In patients with severe psoriasis in whom conventional therapy is ineffective or inappropriate and when the psoriasis is of such severity that the risks inherent in treatment with cyclosporine are justified for that patient; for the treatment of severe, active rheumatoid arthritis in patients for whom classical slow-acting antirheumatic agents are inappropriate or ineffective; in patients with steroid dependent and steroid resistant nephrotic syndrome.
 
Action And Clinical Pharmacology: 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. When compared to Sandimmune capsules and oral solution, Neoral provides a more complete and consistent absorption profile and is less influenced by concomitant food intake or by diurnal rhythm than is Sandimmune. 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 (AUCB) 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.

Because of these differences in bioavailability parameters, caution is advised in switching patients from Sandimmune oral formulations to Neoral. The two should not be used interchangeably.

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.

Indications And Clinical Uses: Solid Organ Transplantation: Neoral capsules and oral solution and Sandimmune I.V. are indicated in the prevention of graft rejection following solid organ transplantation and treatment of transplant rejection in patients previously receiving other immunosuppressive agents.

Bone Marrow Transplantation: Neoral capsules and oral solution and Sandimmune I.V. are indicated in the prevention of graft rejection following bone marrow transplantation and prevention or treatment of graft-versus-host disease (GVHD).

Psoriasis: Neoral capsules and oral solution are indicated for the treatment of severe psoriasis in patients for whom conventional therapy is ineffective or inappropriate.

Rheumatoid Arthritis: Neoral capsules and oral solution are also indicated for the treatment of severe active rheumatoid arthritis in patients for whom classical slow-acting antirheumatic agents are inappropriate or ineffective.

Nephrotic Syndrome: Neoral capsules and oral solution 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.

Contra-Indications: Patients with a hypersensitivity to cyclosporine, or any of its excipients.

Neoral is also contraindicated in the treatment of psoriasis and rheumatoid arthritis patients under the following circumstances: abnormal renal function; uncontrolled hypertension; malignancy (except nonmelanoma skin cancer); uncontrolled infection; primary or secondary immunodeficiency excluding autoimmune disease.

Manufacturers' Warnings In Clinical States: Transplantation: Neoral capsules and oral solution and Sandimmune I.V. 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 i.v. 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 Precautions, Patient Management Transplants).

Psoriasis: 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 pretreatment physical examination to include blood pressure, renal function and careful examination for tumors, 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 premalignant conditions.

Rheumatoid Arthritis: Patients with abnormal renal function, abnormal liver function, uncontrolled hypertension, uncontrolled infections or any kind of malignancy should not receive Neoral. 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.

Nephrotic Syndrome: Neoral should only be prescribed by physicians experienced with its use. All patients to be treated with Neoral for nephrotic syndrome must have a pretreatment physical examination to include blood pressure, renal function (see Dosage) and screening for malignancies.

For All Patients: 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 (see Precautions).

Pregnancy: 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.

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, 2 291 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, 5 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.

Neoral or Sandimmune I.V. should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation: As cyclosporine is transferred into breast milk of lactating females, mothers receiving treatment with Neoral or Sandimmune I.V. should not breast-feed.

Children: 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.

Precautions: For All Patients: Because of the difference in bioavailability parameters, caution is advised in switching patients from Sandimmune oral formulations to Neoral. The two should not be used interchangeably.

Nephrotoxicity: 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 patients who are treated with cyclosporine for nontransplant 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.

Hepatotoxicity: 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.

Hypertension: 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).

Lipoprotein Abnormalities: 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 dose may also be considered.) Caution is advised in the coadministration 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 Effects).

Neurotoxicity: 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.

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

Infection/Immunization: Since cyclosporine is an immunosuppressive drug, patients will be at increased risk for infections. Vaccination may be less effective and the use of live attenuated vaccines should be avoided.

Hyperkalemia/Hyperuricemia: Since cyclosporine occasionally causes hyperkalemia or may aggravate pre-existing hyperkalemia, monitoring of serum potassium is recommended, especially in patients with marked renal dysfunction.

Patients receiving cyclosporine should avoid high dietary potassium intake and the use of potassium-containing medications or potassium-sparing diuretics is not recommended.

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

Geriatrics: 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.

Drug Interactions: See Table II. Caution should be exercised in patients receiving drug treatment with: nephrotoxic drugs; cytotoxic drugs; immunosuppressants or radiation (including PUVA or UVB); drug affecting metabolism/absorption of cyclosporine.

If combined administration is unavoidable, careful monitoring of blood cyclosporine concentration and appropriate modification of Neoral or Sandimmune I.V. dosage are essential.

Nonsteroidal Anti-inflammatory Drugs: NSAID 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.

Grapefruit juice should be avoided owing to its possible interference with the P450 enzyme system which may result in an increase in the bioavailability of Neoral.

HMG-CoA Reductase Inhibitors: 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 also enhance the potential of lovastatin and colchicine to induce muscular toxicity including muscle pain and weakness. The concomitant use of these drugs with Neoral capsules and oral solution or Sandimmune I.V. should be carefully considered.

Prednisolone and Methylprednisolone: 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.

Transplant Patient Management: Clinical: The concentrate for i.v. infusion contains polyoxyethylated castor oil which has been reported to cause anaphylactoid reactions. These reactions consist of flushing of the face and upper thorax, acute respiratory distress with dyspnea and wheezing, blood pressure changes and tachycardia.

Special caution is therefore necessary in patients who have previously received, by i.v. injection or infusion, preparations containing polyoxyethylated castor oil, or in patients with an allergic predisposition. Thus, patients receiving Sandimmune I.V. should be observed continuously for at least the first 30 minutes following the start of the infusion and at frequent intervals therafter. If anaphylaxis occurs, the infusion should be discontinued. An aqueous solution of epinephrine 1:1 000 and a source of oxygen should be available at the bedside. Prophylactic administration of an antihistamine (H1+H2 blocker) prior to Sandimmune I.V. has also been successfully employed to reduce the severity and prevent the occurrence of anaphylactoid reactions. The oral forms of Neoral do not contain polyoxyethylated castor oil.

Laboratory: Accurate and regular monitoring of cyclosporine blood levels in conjunction with other laboratory and clinical parameters is regarded as an essential aid to maintain the trough concentrations within the relatively narrow therapeutic window between efficacy and toxicity.

During the immediate postoperative period, levels should be monitored every 2 to 3 days.

Monitoring schedules should continue until the patient's clinical condition and Neoral or Sandimmune I.V. dosage are stable. Following discharge from hospital, cyclosporine levels are determined at each clinic visit, which is usually twice weekly for the first 2 months, weekly until 4 months and monthly thereafter for the first year.

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

Two methods are available for the specific assay of cyclosporine parent compound: radioimmunoassay (RIA) and high-performance liquid chromatography (HPLC). Comparative findings for the analysis of blood samples by both the RIA method (based on specific monoclonal antibody) and the HPLC method has established that the specific antibody gives a selective measure of the cyclosporine parent compound without significant interference from drug metabolites. Therefore, 12-hour trough levels of the cyclosporine parent compound should routinely be measured using the radioimmunoassay (RIA) kit for cyclosporine based on the specific monoclonal antibody.

Because there is a temperature and time-dependent uptake of cyclosporine by erythrocytes, the concentration of cyclosporine in plasma separated at room temperature and 37°C will differ substantially, the latter being higher. For this reason, it is not recommended to use plasma or serum as the matrix of choice. However, if plasma or serum are used, a standard separation protocol (time and temperature) should be followed.

Whole blood is the matrix of choice. Specimens should be collected into tubes containing ethylene diamine tetraacetic acid (EDTA) anticoagulant. Heparin anticoagulation is not recommended because of the tendency to form clots on storage. Samples which are not to be analyzed immediately should be stored in a refrigerator (4°C) and assayed within 7 days; if the samples are to be kept longer they should be deep frozen (-20°C) for up to 6 months.

Psoriasis/Rheumatoid Arthritis/Nephrotic Syndrome Patient Management: Prior to initiation of Neoral Therapy: Clinical: Before treatment, the patient should undergo a history and physical examination with investigations as warranted. An initial blood pressure reading should be made on at least 2 occasions within 2 weeks to establish a baseline. As Neoral is immunosuppressive, a search should be made for tumors of all kinds, particularly of the skin. Any persistent previously undiagnosed skin lesion should be biopsied for a confirmed diagnosis prior to starting therapy. Female patients should have an examination of the cervix within the first 6 months of therapy, and periodically thereafter, to exclude malignancy.

Laboratory: Prior to therapy, a 12-hour fasting serum creatinine should be measured on at least 3 occasions within 2 weeks to give an accurate baseline value. A baseline creatinine clearance is also suggested, if possible. It is recommended that initial investigations should include urinalysis, complete blood count, liver function tests, serum uric acid and serum potassium.

Follow-up during Neoral Therapy: Clinical: 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 Hodgkin's 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.

Laboratory: 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). 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 an NSAID 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.

Nephrotic Syndrome: Since cyclosporine can impair renal function, it is necessary to assess renal function frequently and, if the serum creatinine 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. This may explain why, in rare cases, cyclosporine-associated structural kidney alterations have been observed without changes in serum creatinine. Renal biopsy should be considered for patients with steroid-dependent minimal change nephropathy in whom cyclosporine therapy has been maintained for more than 1 year.

Periodic monitoring of cyclosporine trough levels is recommended.

Adverse Reactions: Despite the increase in Cmax and AUC seen in patients who are treated with Neoral capsules and oral solution, 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 2 formulations in terms of renal safety, risk of adverse events, or laboratory parameters (e.g., blood pressure, creatinine clearance, serum levels of urea, creatinine, potassium, cholesterol, triglycerides). Furthermore, there is no indication of a correlation between peak cyclosporine concentration (Cmax) and changes in renal function.

The following adverse reactions observed with Sandimmune are also likely to occur with Neoral. In some cases, adverse reactions are dose-dependent and responsive to dose reduction. See Table IV.

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.

Transplantation: The adverse events shown in Table V occurred in patients involved in 2 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.

Psoriasis: In clinical trials, the most frequent side effects associated with the use of cyclosporine in psoriasis were renal dysfunction, hypertension, gastrointestinal disorders, hypertrichosis, paresthesia, headache, influenza-like symptoms, upper respiratory tract infections, gum hyperplasia, fatigue, hyperuricemia, hypomagnesemia and increase in plasma liquids.

The adverse events (excluding renal dysfunction, hypertension and malignancies) shown in Table VI occurred in 3% or greater of 631 psoriatic patients involved in clinical trials.

In psoriasis in 1 439 patients treated with Sandimmune the following were reported: 21 cases of skin cancer, 17 cases of solid malignant tumors 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. Rheumatoid Arthritis: In clinical trials, the most frequent side effects associated with the use of cyclosporine in rheumatoid arthritis were hypertrichosis; hypertension; nausea; abdominal pain; paresthesia; headache and gum disorders (see Table VII).

Nephrotic Syndrome: In clinical trials, the most frequent side effects associated with the use of cyclosporine in nephrotic syndrome were: renal dysfunction, hypertrichosis, gingival hyperplasia, hypertension, tremor and paresthesia, and gastrointestinal symptoms.

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

Symptoms And Treatment Of Overdose: Symptoms and Treatment: No experience of acute overdosage of Neoral capsules and oral solution is available. Documented cases include both single and multiple overdoses of Sandimmune capsules and oral solution to a maximum overdose of 25 000 mg. High blood levels of cyclosporine result in acute toxic symptoms which may include: nausea, headache, hyperesthesia in the hands and feet, flushing of face, gum soreness and bleeding, and sensation of increased abdominal girth. Although high levels may cause transient hepato- and nephrotoxicity, no permanent residual or long-term sequelae have been reported. If indicated, general supportive measures should follow. Elimination can be achieved only by nonspecific measures including gastric lavage, as cyclosporine is not dialyzable to any great extent nor is it cleared well by charcoal hemoperfusion. tag_DosageDosage

Dosage And Administration: The dose ranges of Neoral capsules and oral solution and Sandimmune I.V. given below are intended to serve as a guideline only. Routine monitoring of cyclosporine blood levels is required; this can be carried out by means of 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.

Solid Organ Transplantation: Treatment with Neoral may be initiated within 12 hours prior to surgery at a dose of 10 to 15 mg/kg given in 2 divided doses. This dose should be maintained as the daily dose for 1 to 2 weeks post-operatively before being gradually reduced in accordance with blood levels until a maintenance dose of about 2 to 6 mg/kg given in 2 divided doses is reached. Table IX outlines the recommended steady-state therapeutic ranges of cyclosporine 12-hour trough levels (the level immediately before the next dose).

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 2 divided doses for the initial treatment) may be used.

Recommended Dosage of Concentrate for I.V. Infusion: 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 postoperatively 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 Precautions).

Bone Marrow Transplantation: The initial dose should be given on the day before transplantation. In most cases i.v. infusion of Sandimmune is preferred for this purpose (see previous section). Maintenance treatment with Neoral is at a daily dose of about 12.5 mg/kg given in 2 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 1 year after transplantation. If Neoral is used to initiate therapy, the recommended daily dose is 12.5 to 15 mg/kg given in 2 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 favorably to re-introduction of therapy. Low doses of Neoral should be used to treat mild, chronic GVHD.

Psoriasis: Recommended Dosage: Dose Titration for Induction of Remission: The recommended initial dose is 2.0 mg/kg/day given in 2 divided oral doses. If there is no improvement after 1 month, the daily dose may be gradually increased. Dose adjustments should be made in increments of 0.5 to 1.0 mg/kg/day body weight/month and total daily dose, depending on monitoring of drug tolerance, should not exceed 5 mg/kg/day.

Treatment Discontinuation: Treatment should be discontinued in patients in whom psoriatic lesions do not respond sufficiently within 6 weeks on 5.0 mg/kg/day, or in whom the effective dose is not compatible with the safety guidelines given below under Monitoring. As skin lesions improve the dose should be reduced in increments of 0.5 to 1 mg/kg/day/month.

Long-term Goals of Therapy: 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.

Maintenance Dose: After reaching a relatively disease-free state, the patient should be given the minimum effective maintenance dose. For maintenance treatment, doses should be titrated individually to the lowest effective level, and, depending on monitoring of drug tolerance, should not exceed 5.0 mg/kg/day.

If a patient experienced a worsening of the condition during maintenance, therapy can be changed to a dose that is sufficient to control psoriasis while remaining compatible with the safety guidelines, i.e., maximum 5.0 mg/kg/day. An attempt should then be made to reduce the dose to the lowest effective level. Dosage adjustments should follow the guidelines for inducing remission. If no relapse occurs within 6 months, an attempt should be made to wean the patient off Neoral.

Monitoring for Psoriasis Patients: 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 to 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 tumors 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.

Rheumatoid Arthritis: Recommended Dosage: For the first 6 weeks of treatment, the recommended initial dose is 2.0 mg/kg/day orally given in 2 divided doses. If necessary, the daily dose may then be increased gradually as tolerability permits (see Warnings) 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 nonsteroidal anti-inflammatory drugs (see Precautions).

Monitoring for Rheumatoid Arthritis Patients: Since cyclosporine can impair renal function, a reliable baseline level of serum creatinine should be established by at least 2 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 nonsteroidal 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 1 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 1 month, Neoral treatment should be discontinued.

Nephrotic Syndrome: Recommended Dosage: Dose Titration for Induction of Remission: The recommended initial daily dose, given in 2 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 Sandimmune Neoral is not satisfactory, especially in steroid-resistant patients.

Treatment Discontinuation: Treatment should be discontinued if no improvement has been observed after 3 months of Neoral therapy.

Maintenance Dose: 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.

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 creatinine remains increased by more than 30% above baseline at more than 1 measurement, the dosage of Sandimmune 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 1 year.

Periodic monitoring of cyclosporine trough levels is recommended.

Switch from Sandimmune oral formulations to Neoral: Caution is advised in switching patients from Sandimmune oral formulations to Neoral. The two should not be used interchangeably.

Transplant Indications: For converting patients from Sandimmune oral formulations to Neoral, an initial mg for mg conversion from Sandimmune to Neoral is recommended, with subsequent dose titration if required. Available data confirm that following this initial mg for mg conversion, comparable trough concentrations of cyclosporine in whole blood are achieved, maintaining in most patients adequate immunosuppression. In many patients, higher peak concentrations (Cmax) and an increased exposure to the drug (AUC) may occur. No additional adverse events, including renal dysfunction were observed due to these changes in pharmacokinetic parameters during long-term treatment. In a small percentage of patients, these changes may be more marked and of clinical significance. Their magnitude depends largely on the individual ability to absorb cyclosporine from the originally used Sandimmune oral formulations. (For example, in specific clinical situations like early after transplantation, in recipients of liver grafts or patients who were transplanted for cystic fibrosis, the absorption of cyclosporine from Sandimmune is even more markedly variable). In these patients, dose reduction should be undertaken to achieve the appropriate trough concentration range.

Clinical data in renal transplant patients have demonstrated that a large proportion of patients previously on Sandimmune therapy can be maintained at the same dose of Neoral as with Sandimmune oral formulations.

Moreover, all patients should be monitored according to the following recommendations: a) Preconversion (i.e., on Sandimmune): Measure cyclosporine trough concentration, serum creatinine and blood pressure. b) Day 1: Convert the patient to the same daily dose of Neoral as was previously used with oral Sandimmune (i.e., on a mg to mg basis). c) Days 4 to 7 post conversion: Follow-up visit to measure cyclosporine trough concentration, serum creatinine and blood pressure. d) Subsequent follow-up: Depending on the findings on review at days 4 to 7, subsequent follow-up visits may need to be arranged (e.g., week 2 and week 4) in the first 2-month period after conversion to Neoral. During these visits, cyclosporine trough concentrations, serum creatinine and blood pressure should be measured and dependent on these measurements the dose of Neoral adjusted accordingly.

Caution is advised in switching patients from Sandimmune oral formulations to Neoral. The two should not be used interchangeably.

Nontransplant Indications: In psoriasis, rheumatoid arthritis or nephrotic syndrome patients, the clinical status of each patient should be assessed prior to initiating Neoral therapy. Initial conversion from Sandimmune oral formulations to Neoral should be conducted on a 1:0.7 basis with monitoring for dose-dependent side effects as outlined below. The dose of Neoral should be subsequently adjusted according to each patient's response.

If, on more than 1 measurement, the serum creatinine increases more than 30% above the pre-Sandimmune (oral formulations) baseline, the dose of Neoral should be decreased (see Precautions).

All patients should be monitored according to the following recommendations: a) Preconversion: Measure serum creatinine and blood pressure prior to conversion from oral Sandimmune to Neoral. b) Day 1: Initiate Neoral therapy. c) Week 2, 4 and 8: Measure serum creatinine and blood pressure. If serum creatinine levels increase to more than 30% above the pre-Sandimmune baseline level at more than one measurement, the dose of Neoral should be reduced. In addition, if either parameter exceeds the level at the time of conversion, consider reducing the dose of Neoral. d) For nephrotic syndrome patients, monitoring of cyclosporine trough levels is recommended.

Administration: Neoral should always be given in 2 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 I.V. Infusion) is diluted to 1:20 to 1:100, immediately prior to use, with 5% glucose or normal saline and administered by slow i.v. infusion over a period of 2 to 6 hours (see Precautions).

If available, glass containers should be used. Plastic bottles should only be used if they conform to the requirements for "plastic containers for blood" of the European pharmacopoeia, since polyoxyethylated castor oil contained in the concentrate can cause phthalate stripping from PVC. Containers and stoppers should be free of silicon oil and fatty substances.



Availability And Storage: Sandimmune I.V. (concentrate for i.v. infusion): Each mL of sterile ampul in a polyoxyethylated castor oil/ethanol vehicle contains: cyclosporine 50 mg. Ampuls of 1 and 5 mL. Dilution: The concentrate for i.v. infusion should be diluted to between 1:20 and 1:100 in 5% glucose or normal saline only, immediately prior to use (see Dosage).

Store the i.v. product, protected from light, at temperatures not exceeding 30°C. Do not store in the refrigerator and protect from freezing.

Neoral: Capsules: 10 mg: Each soft gelatin capsule contains: cyclosporine for microemulsion 10 mg. Nonmedicinal ingredients: dl-a-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).

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

50 mg: Each soft gelatin capsule contains: cyclosporine for microemulsion 50 mg. Nonmedicinal ingredients: dl-a-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).

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

The 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.

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

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