Instructions for Sandimun Neoral soft capsules 50 mg No. 50
Composition
active ingredient: ciclosporin;
1 capsule contains 50 microemulsions of cyclosporine;
excipients: polyethoxylated castor oil, hydrogenated; corn oil mono- and di-triglycerides; anhydrous ethanol; propylene glycol; α-tocopherol;
capsule shell: gelatin, propylene glycol, glycerin (85%), residual solvents, titanium dioxide (E 171);
red food ink: carminic acid (E 120), aluminum chloride hexahydrate, sodium hydroxide, propylene glycol, hypromellose, isopropyl alcohol, purified water.
Dosage form
Soft capsules.
Main physicochemical properties:
50 mg capsules – oblong soft gelatin capsules of yellow-white color with red inscription NVR 50 mg;
Capsule contents:
clear, yellow to pale yellow or brownish yellow to pale brownish yellow liquid.
The liquid contains oily components of natural origin, which can harden at low temperatures. Gel-like formations may be observed at temperatures below 20 °C, which disappear at temperatures above 30 °C. Minor flakes or a slight precipitate may still be observed. This does not affect the quality of the capsules.
Pharmacotherapeutic group
Antineoplastic and immunomodulatory agents. Immunosuppressants. Calcineurin inhibitors. Cyclosporine.
ATX code L04A D01.
Pharmacological properties
Pharmacodynamics
Cyclosporine (also known as cyclosporine A) is a cyclic polypeptide of 11 amino acids. It is a potent immunosuppressive drug that prolongs the survival of skin, heart, kidney, pancreas, bone marrow, small intestine, and lung allografts in animals.
Studies have shown that cyclosporine inhibits the development of cell-mediated reactions, including allograft immunity, delayed-type cutaneous hypersensitivity, experimental allergic encephalomyelitis, Freund's adjuvant-induced arthritis, graft-versus-host disease (GVHD), and T-lymphocyte-dependent antibody production. Cyclosporine blocks resting lymphocytes in the G0 or early G1 phase of the cell cycle, inhibits antigen-dependent release of lymphokines by activated T-lymphocytes, and inhibits the production and release of lymphokines, including interleukin 2 (T-cell growth factor, TCGF), at the cellular level. All available data indicate a specific and reversible effect of cyclosporine on lymphocytes. It does not cause disorders of hematopoiesis and does not affect the function of phagocytes, unlike cytostatics. Thus, patients taking cyclosporine after transplantation are less prone to infectious diseases than those taking other immunosuppressive drugs.
Successful allogeneic solid organ and bone marrow transplantations have been performed using cyclosporine for the prevention and treatment of transplant rejection and graft-versus-host disease in humans. Cyclosporine has been used in both hepatitis C virus (HCV)-positive and HCV-negative liver transplant recipients. Positive effects of cyclosporine therapy have also been noted in the treatment of a number of pathologies with an established or possible autoimmune nature.
Sandimmun Neoral® is a microemulsion preconcentrate; a true microemulsion formed immediately upon contact of the solution with water (in the form of beverages or gastric juice) reduces the variability of pharmacokinetic parameters; a linear relationship between dose and exposure of cyclosporine is ensured.
Pharmacokinetics
Absorption
After oral administration of Sandimmune Neoral®, peak blood concentrations of cyclosporine are reached within 1–2 hours. The absolute oral bioavailability of cyclosporine with Sandimmune Neoral® is 20–50%. When Sandimmune Neoral® is taken with a high-fat meal, AUC and Cmax values are reduced by approximately 13% and 33%. The relationship between the prescribed dose and exposure (AUC) of cyclosporine is linear within the therapeutic dose range. The intersubject and intrasubject variability of AUC and Cmax values is approximately 10–20%. When Sandimmune Neoral® is used, Cmax values increase by approximately 59% and bioavailability increases by approximately 29% compared to the corresponding values with Sandimmune. Available data show that after switching from Sandimmun soft gelatin capsules to Sandimmun Neoral® in a 1:1 dose ratio, whole blood trough concentrations are comparable and remain within the target therapeutic range. Sandimmun Neoral® provides a more linear dose-to-exposure relationship for cyclosporine (AUCB). This medicinal product provides a more consistent absorption profile compared to Sandimmun, which is less dependent on food intake and circadian rhythm.
Distribution
Cyclosporine is distributed mainly in the extravascular space, the average apparent volume of distribution is 3.5 l/kg. In the blood, 33–47% of the drug is in the blood plasma,
4–9% in lymphocytes, 5–12% in granulocytes and 41–58% in erythrocytes. In blood plasma, approximately 90% of cyclosporine is bound to proteins, mainly lipoproteins.
Ciclosporin is extensively biotransformed to approximately 15 metabolites. Biotransformation generally occurs in the liver by cytochrome P450 3A4 (CYP3A4), with the main metabolic pathways being mono-, dihydroxylation, and N-demethylation of various sites on the molecule. All metabolites identified to date contain the full peptide structure of the parent compound; some have weak immunosuppressive activity (up to one-tenth the activity of the parent drug).
Breeding
The drug is excreted mainly in the bile, and only 6% of the oral dose is excreted in the urine, of which 0.1% of the dose is excreted in the urine as unchanged drug.
There is a high variability in the terminal half-life of ciclosporin, depending on the assay used and the target population. The terminal half-life ranges from 6.3 hours in healthy volunteers to 20.4 hours in patients with severe liver disease. The half-life in renal transplant patients was approximately 11 hours, with values ranging from 4 to 25 hours.
Special patient groups
Patients with renal impairment
In a study in patients with end-stage renal disease, systemic clearance was approximately two-thirds of the mean systemic clearance in patients with normal renal function. Less than 1% of the dose is removed by dialysis.
Patients with hepatic impairment
In patients with hepatic impairment, exposure to ciclosporin may be increased two- to three-fold. In a study in patients with severe liver disease and biopsy-proven cirrhosis, the terminal half-life was 20.4 hours (range 10.8 to 48 hours) compared with 7.4 to 11 hours in healthy volunteers.
Children
The pharmacokinetic data for Sandimmune Neoral® in children are very limited. In 15 renal transplant patients aged 3–16 years, the clearance of ciclosporin from whole blood after intravenous administration of Sandimmune was 10.6 ± 3.7 ml/min/kg (measured by Cyclo-trac RIA). In a study involving 7 renal transplant patients aged 2–16 years, the clearance of ciclosporin was 9.8–15.5 ml/min/kg. In 9 liver transplant patients aged 0.65–6 years, the clearance was 9.3 ± 5.4 ml/min/kg (measured by HPLC). The differences in bioavailability between Sandimmune Neoral® and Sandimmune in children are similar to those observed in adults.
Indication
Indications for transplants
Solid organ transplantation:
prevention of rejection of solid organ transplants; treatment of transplant rejection in patients previously treated with other immunosuppressive drugs.
Bone marrow transplantation:
prevention of allogeneic bone marrow and stem cell transplant rejection; prevention and treatment of graft-versus-host disease.
Indications not related to transplantation
Endogenous uveitis:
active intermediate or posterior uveitis, threatening vision loss, of non-infectious etiology in cases where alternative treatment has been ineffective or unacceptable due to adverse reactions; uveitis in Behçet's disease with repeated exacerbations of inflammation with retinal involvement without neurological symptoms.
Nephrotic syndrome:
steroid-dependent or steroid-resistant nephrotic syndrome due to minimal changes in primary glomerulonephritis, focal segmental glomerulosclerosis, or membranous glomerulonephritis.
Induction or maintenance of remission:
maintaining remission induced by corticosteroids, making their withdrawal possible.
Rheumatoid arthritis:
treatment of severe forms of active rheumatoid arthritis.
Psoriasis:
severe forms of psoriasis when standard treatment has been ineffective or unacceptable.
Atopic dermatitis:
treatment of severe forms of atopic dermatitis when systemic therapy is necessary.
Contraindication
Hypersensitivity to cyclosporine or to any of the excipients of the drug. Concomitant use with drugs containing Hypericum perforatum (St. John's wort) due to the risk of reducing the concentration of cyclosporine in the blood and, thus, reducing the therapeutic effect.
Concomitant use with medicinal products that are substrates of the multidrug efflux transporter P-glycoprotein (Pgp) or organic anion transport proteins (OATPs), increased plasma concentrations of which are associated with the development of serious and/or life-threatening adverse reactions, such as bosentan, dabigatran etexilate and aliskiren.
The following contraindications are also possible:
History of known or diagnosed malignancy of any type, except precancerous conditions or malignant skin lesions after treatment.
Interaction with other medicinal products and other types of interactions
Food interactions
Concomitant use of grapefruit or grapefruit juice has been shown to increase the bioavailability of cyclosporine.
Drug interactions
The following are drugs for which interactions are well documented and considered clinically significant.
Several drugs are known to increase or decrease plasma or whole blood concentrations of cyclosporine by inhibiting or inducing enzymes, particularly CYP3A4, involved in cyclosporine metabolism. Cyclosporine is also an inhibitor of CYP3A4, the multidrug efflux transporter P-glycoprotein, or organic anion transport proteins. This may increase the plasma concentrations of concomitantly administered drugs that are substrates of CYP3A4 and/or these transporters.
Drugs that reduce or increase the bioavailability of cyclosporine
Frequent determinations of cyclosporine blood levels should be performed in transplant recipients, especially at the beginning and end of treatment with another drug, and the dosage of Sandimmun Neoral® should be adjusted if necessary.
In patients treated for non-transplant indications, the relationship between blood concentrations and clinical effects is less well understood. Frequent assessment of renal function and close monitoring for ciclosporin-related adverse events may be more appropriate than blood level measurements when concomitant medications that increase ciclosporin concentrations are used.
Drugs that reduce cyclosporine concentrations
All inducers of CYP3A4 and/or P-glycoprotein are expected to decrease cyclosporine concentrations.
Examples of drugs that reduce cyclosporine concentrations: barbiturates, carbamazepine, oxcarbazepine, phenytoin, nafcillin, intravenous sulfadimidine, rifampicin, octreotide, orlistat, probucol, intravenous trimethoprim, drugs containing St. John's wort, ticlopidine, sulfinpyrazone, terbinafine, bosentan.
Rifampicin is an inducer of cyclosporine metabolism in the intestine and liver. Therefore, when used together, it may be necessary to increase the dose of cyclosporine in
3–5 times.
Octreotide reduces the oral absorption of cyclosporine, which may require a 50% increase in the cyclosporine dose or a switch to an intravenous formulation.
Drugs that increase cyclosporine concentrations
All CYP3A4 and/or P-glycoprotein inhibitors may increase cyclosporine concentrations. Examples of such drugs include: chloroquine, nicardipine, metoclopramide, oral contraceptives, methylprednisolone (high doses), allopurinol, cholic acid and its derivatives, protease inhibitors, imatinib, colchicine, nefazodone.
Macrolide antibiotics: Erythromycin may increase cyclosporine exposure 4-7-fold, sometimes resulting in nephrotoxicity. Clarithromycin has been reported to increase cyclosporine exposure by two-fold. Azithromycin increases cyclosporine concentrations by approximately 20%.
Azole antibiotics: ketoconazole, fluconazole, itraconazole, and voriconazole can increase cyclosporine exposure by more than twofold.
Verapamil increases the concentration of cyclosporine in the blood by 2–3 times.
Co-administration with telaprevir resulted in an approximately 4.64-fold increase in the normalized exposure (AUC) of ciclosporin.
Amiodarone significantly increases the plasma concentration of cyclosporine simultaneously
with an increase in serum creatinine concentration. This interaction is possible after a long period of time after discontinuation of amiodarone due to the very long half-life of this drug (about 50 days).
Danazol has been reported to increase the blood concentration of cyclosporine by approximately 50%.
Diltiazem (at a dose of 90 mg per day) is capable of increasing the plasma concentration of cyclosporine by 50%.
Imatinib may increase the exposure of cyclosporine and increase the Cmax of this medicinal product by approximately 20%.
Combinations with increased risk of nephrotoxicity
Caution is required when using cyclosporine concomitantly with other drugs that have a nephrotoxic synergistic effect, such as aminoglycosides (including gentamicin and tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+sulfamethoxazole), fibric acid derivatives (e.g. bezafibrate, fenofibrate), nonsteroidal anti-inflammatory drugs (including diclofenac, indomethacin, naproxen and sulindac), melphalan, histamine H2-receptor antagonists (e.g. cimetidine, ranitidine), methotrexate, tacrolimus.
Recommendations
If co-administration of medicinal products reported to interact with Sandimmun Neoral® cannot be avoided, the following basic recommendations should be followed:
In transplant recipients, isolated cases of significant but reversible renal dysfunction (with a corresponding increase in serum creatinine) have been observed after concomitant use of fibrates (e.g. bezafibrate, fenofibrate). Therefore, renal function should be closely monitored in such patients. In case of significant renal dysfunction, concomitant use should be discontinued.
Concomitant use of tacrolimus should be avoided due to increased risk of nephrotoxicity and pharmacokinetic interactions involving CYP3A4 and/or P-gp.
Effect of cyclosporine on other drugs
Cyclosporine may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins), etoposide, aliskiren, bosentan and dabigatran.
Severe digitalis toxicity has been observed within a few days of initiating cyclosporine therapy in some patients receiving digoxin. Cyclosporine has been reported to potentiate the toxic effects of colchicine, such as myopathy and neuropathy, particularly in patients with renal dysfunction.
In medical publications and post-marketing studies, cases of myotoxicity, including muscle pain and weakness, myositis and rhabdomyolysis, have been described in patients taking cyclosporine concomitantly with lovastatin, simvastatin, atorvastatin, pravastatin and, rarely, fluvastatin. With concomitant use
with cyclosporine, the dose of these statins should be reduced according to the instructions in the prescribing information. Statin therapy may be temporarily discontinued in patients with symptoms of myopathy or in patients with risk factors for severe renal impairment, including renal failure secondary to rhabdomyolysis.
Concomitant use of nifedipine with cyclosporine may lead to an increased incidence of gingival hyperplasia compared to cyclosporine alone.
After co-administration of cyclosporine and lercanidipine, the AUC of the latter increased 3-fold, and the AUC of cyclosporine increased by 21%. Therefore, the simultaneous use of cyclosporine with lercanidipine should be avoided. Taking cyclosporine 3 hours after lercanidipine did not change the AUC of the latter, but the AUC of cyclosporine increased by 27%. Therefore, this combination should be used with caution with an interval between taking the drugs of at least 3 hours.
Preference should be given to an antihypertensive agent that does not have pharmacokinetic interactions with cyclosporine.
After co-administration of ciclosporin and aliskiren, an increase in Cmax of aliskiren, a P-gp substrate, was observed by approximately 2.5-fold and an increase in AUC by approximately 5-fold. However, the pharmacokinetic profile of ciclosporin was not significantly altered.
Concomitant use of dabigatran etexilate is also not recommended due to the inhibitory activity of cyclosporine on P-gp. Dabigatran has a narrow therapeutic index and increased plasma concentrations are associated with an increased risk of bleeding.
It has been established that the simultaneous use of diclofenac and cyclosporine leads to a significant increase in the bioavailability of diclofenac with the possible development of reversible renal failure. This increase is most likely due to a decrease in the high first-pass effect of diclofenac. The simultaneous use of cyclosporine and NSAIDs with a low first-pass effect (such as acetylsalicylic acid) is usually not associated with an increase in their bioavailability.
Increases in serum creatinine have been observed in studies with the concomitant use of everolimus or sirolimus and full doses of ciclosporin microemulsion. This effect is often reversible with a reduction in the dose of ciclosporin. Everolimus and sirolimus have only a minor effect on the pharmacokinetics of ciclosporin. Concomitant use of ciclosporin significantly increases the blood concentrations of everolimus and sirolimus.
Caution should be exercised when prescribing cyclosporine and potassium-sparing drugs (e.g. potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists) or potassium-containing drugs, as this may lead to a significant increase in serum potassium levels.
Cyclosporine may also increase plasma levels of repaglinide, thereby increasing the risk of hypoglycemia.
Co-administration of bosentan with cyclosporine in healthy volunteers reduced cyclosporine exposure by 35%, while increasing bosentan exposure by approximately 2-fold. Therefore, co-administration of cyclosporine with bosentan is not recommended.
Administration of multiple doses of ambrisentan and ciclosporin to healthy volunteers resulted in an approximately 2-fold increase in ambrisentan exposure, while ciclosporin exposure was only slightly increased (approximately 10%).
Digoxin, colchicine, HMG-CoA reductase inhibitors. If any of these drugs are prescribed concomitantly with Sandimmun Neoral®, careful clinical monitoring is necessary to allow early detection of toxic effects and subsequent dose reduction or discontinuation of the drug.
Drug interactions are more common in elderly patients.
During cyclosporine therapy, the effectiveness of vaccination may be reduced. The use of live attenuated vaccines should be avoided.
Children
Drug interaction studies were conducted exclusively in adult patients.
Application features
Sandimmun Neoral® should only be prescribed by physicians experienced in immunosuppressive therapy and who can provide the necessary additional examinations (regular complete physical examination, blood pressure monitoring, laboratory tests). Transplant patients receiving Sandimmun Neoral® should only be treated in medical facilities that are equipped with the necessary laboratory and medical equipment. The physician responsible for supportive care should be provided with all the information necessary for proper patient care.
Absorption of calcineurin inhibitors may be impaired in patients with cystic fibrosis.
Like other immunosuppressants, cyclosporine increases the risk of lymphoma and other malignancies, including skin cancers. Regular examinations of patients receiving Sandimmun Neoral® for a long time are necessary to ensure early diagnosis. Treatment should be discontinued if a precancerous condition or tumor is diagnosed. There is reason to believe that the increased risk is associated with the degree and duration of immunosuppression, and not with the use of specific agents.
Therefore, treatment with a regimen that includes several immunosuppressants (including cyclosporine) should be used with caution, as it may lead to the development of lymphoproliferative disorders and solid organ tumors, sometimes with fatal outcome.
Given the potential risk of skin malignancies, patients taking Sandimmun Neoral®, particularly those treated for psoriasis or atopic dermatitis, should be advised to avoid excessive exposure to sunlight without adequate protection and not to receive concomitant ultraviolet B radiation or PUVA photochemotherapy.
Infections
As with other immunosuppressants, the use of ciclosporin has been associated with the development of a variety of bacterial, fungal, parasitic and viral infections, often involving opportunistic pathogens. Reactivation of latent polyomavirus infection has been reported in patients receiving ciclosporin, which can lead to polyomavirus-associated nephropathy (PVAN), including BK virus nephropathy (BKVN) or JC virus-associated progressive multifocal leukoencephalopathy (PML). These problems are often secondary to relatively high immunosuppression and should be considered in the differential diagnosis of immunosuppressed patients with worsening renal function or neurological symptoms. Serious and/or fatal outcomes have been reported. Effective preventive and therapeutic strategies should be used, especially in patients requiring multiple long-term immunosuppressive therapy. General immunosuppression should be reduced in patients with PVAN or PML, but reduced immunosuppression may also compromise the graft.
Toxic effect on kidneys
During the first few weeks of treatment with Sandimmun Neoral®, a common and potentially serious complication is an increase in serum creatinine and urea levels. These functional changes are dose-dependent and reversible, usually returning to normal values with dose reduction. In some patients, long-term use of the drug may lead to structural changes in the kidneys (e.g. interstitial fibrosis), which should be distinguished from signs of chronic rejection in patients with a kidney transplant. Therefore, frequent monitoring of renal function is necessary in accordance with local recommendations and taking into account the specific indications for prescribing the drug.
Hepatotoxicity
Sandimmun Neoral® may also cause dose-dependent reversible increases in serum bilirubin and occasionally elevations of liver enzymes. There have been solicited and spontaneous reports of hepatotoxicity and liver injury, including cholestasis, jaundice, hepatitis and hepatic failure, in patients treated with ciclosporin. Most reports have involved patients with significant comorbidities, underlying medical conditions and other concomitant factors, including infectious complications and concomitant medicinal products with the potential for hepatotoxicity. In some cases, mainly in transplant patients, fatalities have been reported.
It is necessary to regularly monitor the relevant liver function indicators and, if necessary, reduce the dose in case of deviations of these indicators from the norm.
Elderly patients (65 years and older)
Renal function should be monitored particularly carefully in elderly patients.
When Sandimmun Neoral® is used in transplant patients, systematic monitoring of cyclosporine blood levels is an important safety measure. Cyclosporine blood levels are best determined using specific monoclonal antibodies (determination of the amount of unchanged drug). However, high-performance liquid chromatography (HPLC) can also be used (also for the determination of the amount of unchanged drug). For quantification in plasma or serum, a standard separation method (time and temperature) should be used.
In liver transplant recipients, blood levels should be monitored at the start of treatment either with specific monoclonal antibodies alone or with concurrent determinations using specific and non-specific monoclonal antibodies to ensure an appropriate degree of immunosuppression.
It should also be remembered that the level of cyclosporine in blood, plasma or serum is only one of many factors that influence the clinical condition of the patient. Therefore, the results should be considered only in the context of a number of other clinical and biochemical parameters.
Blood pressure monitoring
During treatment with Sandimmun Neoral®, blood pressure should be monitored regularly. If hypertension is detected, appropriate treatment should be given to lower blood pressure. Preference should be given to antihypertensive drugs that do not affect the pharmacokinetics of cyclosporine, such as isradipine.
Increased blood lipid levels
There have been isolated reports of treatment with Sandimmun Neoral® associated with a slight increase in blood lipids, which was reversible; lipid levels should be measured before and 1 month after the start of treatment. If elevated lipid levels are detected, the proportion of fat in the diet should be reduced and, if necessary, the dose should be reduced.
Hyperkalemia
The risk of hyperkalemia is increased when taking cyclosporine, especially in patients with renal dysfunction. Cyclosporine should be administered with caution in combination with potassium-sparing drugs (e.g. potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists) or potassium-containing drugs, or in patients on a diet rich in potassium. In such cases, monitoring of potassium levels is recommended.
Hypomagnesemia
Cyclosporine increases magnesium excretion, which may lead to symptomatic hypomagnesemia, especially in the peritransplant period. Monitoring of serum magnesium levels is recommended during the peritransplant period, especially if neurological symptoms are observed. If deemed necessary, additional magnesium supplements should be administered.
Hyperuricemia
Caution is required when treating patients with hyperuricemia.
Live attenuated vaccines
Vaccination may be less effective during treatment with ciclosporin, and the use of live attenuated vaccines should be avoided.
Interactions
Caution should be exercised when prescribing cyclosporine concomitantly with medicinal products that significantly increase or decrease the plasma concentration of cyclosporine through inhibition or induction of CYP3A4 and/or P-glycoprotein (see section "Interaction with other medicinal products and other forms of interaction").
Nephrotoxicity should be monitored when ciclosporin is administered with active substances that increase ciclosporin concentrations or exhibit synergy in the development of nephrotoxic effects (see section "Interaction with other medicinal products and other types of interactions").
The concomitant use of ciclosporin and tacrolimus should be avoided (see section “Interaction with other medicinal products and other types of interactions”).
Ciclosporin is an inhibitor of CYP3A4, the multidrug efflux transporter P-glycoprotein and organic anion transport proteins (OATPs) and may increase plasma concentrations of concomitantly administered medicinal products that are substrates of this enzyme and/or transporter, such as dabigatran, aliskiren and bosentan. Caution should be exercised when co-administering ciclosporin with such medicinal products or their co-administration should be avoided (see section 4.5). Ciclosporin increases the exposure of HMG-CoA reductase inhibitors (statins). The dose of statins should be reduced when co-administered with ciclosporin; concomitant use with some statins should be avoided in accordance with the recommendations specified in the instructions for medical use of these medicinal products. Statin therapy should be temporarily or permanently discontinued in patients with signs and symptoms of myopathy or risk factors for severe renal injury, including renal failure secondary to rhabdomyolysis (see section 4.5).
Patients with psoriasis should avoid concomitant use of beta-blockers or diuretics.
Special excipients
Oral dosage forms of Sandimmune Neoral® contain approximately 12% (vol.) ethanol. A 500 mg dose of Sandimmune Neoral® contains 500 mg ethanol, which is equivalent to approximately 15 ml of beer or 5 ml of wine. This may be harmful to alcohol-dependent patients and should be taken into account when treating pregnant and breastfeeding women, patients with liver disease or epilepsy, and when administering the drug to children.
Additional precautions for non-transplant indications
Patients with impaired renal function (except patients with nephrotic syndrome with an acceptable degree of renal insufficiency), uncontrolled hypertension, uncontrolled infections, or malignancies of any type should not take cyclosporine.
A reliable assessment of baseline renal function should be performed prior to initiation of treatment by at least two measurements of estimated glomerular filtration rate (eGFR). Frequent assessment of renal function during therapy is necessary to ensure appropriate dose adjustment.
Additional precautions for endogenous uveitis
A possible association between cyclosporine and neurological manifestations of Behçet's syndrome has been reported. Sandimmun Neoral® should be administered with caution to patients with Behçet's syndrome who have neurological manifestations. The neurological status of such individuals should be closely monitored.
Additional precautions for nephrotic syndrome
Patients with impaired renal function at baseline should initially be given a dose of 2.5 mg/kg/day and monitored very closely.
In some patients, it may be difficult to detect Sandimmune Neoral®-induced renal dysfunction due to changes in renal function caused by the nephrotic syndrome itself. This explains why, in rare cases, Sandimmune Neoral®-associated structural changes in the kidneys are observed without an increase in serum creatinine. Renal biopsy should be considered in patients with minimal steroid-dependent nephropathy who have been on Sandimmune Neoral® therapy for more than 1 year.
There have been occasional reports of malignancies (including Hodgkin's lymphoma) in patients with nephrotic syndrome treated with immunosuppressants (including cyclosporine).
Additional precautions for rheumatoid arthritis
After 6 months of therapy, renal function should be determined every 4–8 weeks depending on the stability of the disease, concomitant medication and concomitant diseases. More frequent studies are necessary when the dose of Sandimmun Neoral® is increased or after the initiation of concomitant treatment with nonsteroidal anti-inflammatory drugs or in case of an increase in their dose.
Discontinuation of the drug may also be necessary if arterial hypertension that has arisen during Sandimmun Neoral® therapy is not controlled with appropriate antihypertensive therapy.
As with long-term use of other immunosuppressive drugs, the increased risk of lymphoproliferative disorders should be considered. Particular caution is required when Sandimmun Neoral® is used in combination with methotrexate due to synergistic nephrotoxic effects.
Additional precautions for psoriasis
Discontinuation of Sandimmun Neoral® therapy is recommended if arterial hypertension that has developed during treatment with Sandimmun Neoral® fails to respond to treatment.
