Sandimmune neoral®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SANGDIMUN NEORAL® (SANDIMMUN NEORAL®)

Composition:

Active substance: ciclosporin;

1 ml of solution contains 100 mg of cyclosporin microemulsion;

Excipients: DL-alpha-tocopherol; anhydrous ethanol; propylene glycol; corn oil; polyoxyl 35 hydrogenated castor oil.

Pharmaceutical form. Oral solution.

Main physicochemical properties: clear solution, color ranging from yellow to light yellow or from amber-yellow to light amber-yellow. Since the preparation contains oily components of natural origin which tend to solidify at low temperatures, the product may become gel-like at temperatures below 20 °C, reverting to liquid form upon warming to 30 °C. However, a slight amount of flakes or slight sediment may remain. These phenomena do not affect the efficacy and safety of the preparation, and dosing using the provided syringe remains accurate.

Pharmaco-therapeutic group. Antineoplastic and immunomodulating agents. Immunosuppressants. Calcineurin inhibitors. Cyclosporin.

ATC code: L04AD01.

Pharmacological properties.

Pharmacodynamics.

Cyclosporine (also known as cyclosporine A) is a cyclic polypeptide composed of 11 amino acids. It is a potent immunosuppressive agent that prolongs the survival of allogeneic transplants of skin, heart, kidney, pancreas, bone marrow, small intestine, and lungs in animals.

Studies demonstrate that cyclosporine suppresses cell-mediated reactions, including immune responses against allografts, delayed-type skin hypersensitivity, experimental allergic encephalomyelitis, adjuvant-induced arthritis, graft-versus-host reaction (GVHR), and T-lymphocyte-dependent antibody production. Cyclosporine arrests lymphocytes in the resting state at phase G0 or early G1 phase of the cell cycle, inhibits antigen-dependent release of lymphokines by activated T-lymphocytes, and suppresses at the cellular level the production and release of lymphokines, including interleukin-2 (T-cell growth factor, TCGF). All available evidence indicates a specific and reversible effect of cyclosporine on lymphocytes. It does not impair hematopoiesis and does not affect phagocyte function, unlike cytostatic agents. Thus, patients receiving cyclosporine after transplantation are less susceptible to infectious diseases than those receiving other immunosuppressive drugs.

Successful allogeneic transplantation of solid organs and bone marrow has been performed in humans using cyclosporine for the prevention and treatment of graft rejection and graft-versus-host disease. Cyclosporine has been used in both hepatitis C virus (HCV)-positive and HCV-negative liver transplant recipients. Positive therapeutic effects of cyclosporine have also been observed in the treatment of several conditions with established or suspected autoimmune etiology.

Sandimmun Neoral® is a microemulsion preconcentrate; the true microemulsion formed immediately upon contact of the solution with water (as beverages or gastric juice) reduces variability in pharmacokinetic parameters and provides a linear relationship between dose and cyclosporine exposure.

Pharmacokinetics.

Absorption

After oral administration of Sandimmun Neoral®, peak blood concentrations of cyclosporine are reached within 1–2 hours. Absolute oral bioavailability of cyclosporine with Sandimmun Neoral® ranges from 20% to 50%. When Sandimmun Neoral® is taken with a high-fat meal, AUC and Cmax values decrease by approximately 13% and 33%, respectively. The relationship between administered dose and cyclosporine exposure (AUC) is linear within the therapeutic dose range. Inter- and intra-subject variability in AUC and Cmax values is approximately 10–20%. After administration of Sandimmun Neoral®, Cmax values increase by approximately 59%, and bioavailability increases by approximately 29% compared to Sandimmun. Available data indicate that after switching from Sandimmun soft gelatin capsules to Sandimmun Neoral® at a 1:1 dose ratio, trough concentrations in whole blood are comparable and remain within the target therapeutic range. Sandimmun Neoral® provides a more pronounced linear relationship between dose and cyclosporine exposure (AUC). Compared to Sandimmun, this medicinal product ensures a more stable absorption profile, less influenced by concomitant food intake and circadian rhythm.

Distribution

Cyclosporine is distributed predominantly in the extravascular space, with a mean apparent volume of distribution of 3.5 L/kg. In blood, 33–47% of the drug is located in plasma, 4–9% in lymphocytes, 5–12% in granulocytes, and 41–58% in erythrocytes. In plasma, approximately 90% of cyclosporine is protein-bound, primarily to lipoproteins.

Biotransformation

Cyclosporine undergoes extensive biotransformation, forming approximately 15 metabolites. Biotransformation primarily occurs in the liver via cytochrome P450 3A4 (CYP3A4), with main metabolic pathways being mono- and dihydroxylation and N-demethylation at various sites of the molecule. All identified metabolites retain the complete peptide structure of the parent compound; some exhibit weak immunosuppressive activity (up to one-tenth the activity of the unchanged drug).

Elimination

The drug is excreted predominantly in bile, with only 6% of the orally administered dose eliminated in urine, of which 0.1% is excreted unchanged in urine.

There is high variability in terminal half-life data of cyclosporine depending on the analytical method and target population. Terminal half-life ranges from 6.3 hours in healthy volunteers to 20.4 hours in patients with severe liver disease. In kidney transplant patients, the half-life was approximately 11 hours, ranging from 4 to 25 hours.

Special patient groups

Patients with impaired renal function

In a study involving patients with end-stage renal failure, systemic clearance of the drug was approximately two-thirds of the average systemic clearance observed in patients with normal renal function. Less than 1% of the administered dose is removed by dialysis.

Patients with impaired hepatic function

In patients with impaired liver function, cyclosporine exposure may increase two- to threefold. In a study of patients with severe liver disease and biopsy-confirmed cirrhosis, terminal half-life was 20.4 hours (ranging from 10.8 to 48 hours) compared to 7.4–11 hours in healthy volunteers.

Children

Pharmacokinetic data for Sandimmun Neoral® in pediatric patients are very limited. In 15 kidney transplant patients aged 3–16 years, whole blood clearance of cyclosporine after intravenous administration of Sandimmun was 10.6 ± 3.7 mL/min/kg (determination method: RIA Cyclo-trac). In a study of 7 kidney transplant patients aged 2–16 years, cyclosporine clearance ranged from 9.8 to 15.5 mL/min/kg. In 9 liver transplant patients aged 0.65–6 years, clearance was 9.3 ± 5.4 mL/min/kg (determination method: HPLC). Differences in bioavailability between Sandimmun Neoral® and Sandimmun in children are similar to those observed in adults.

Clinical characteristics.

Indications.

Indications in transplantation

Organ transplantation:

• prevention of rejection of solid organ transplants;
• treatment of transplant rejection in patients previously treated with other immunosuppressive agents.

Bone marrow transplantation:

• prevention of rejection of allogeneic bone marrow and stem cell transplants;
• prevention and treatment of graft-versus-host disease.

Non-transplant indications

Endogenous uveitis:

• active intermediate or posterior uveitis threatening vision loss, of non-infectious etiology, when alternative treatments have proven ineffective or unacceptable due to adverse reactions;
• uveitis in Behçet’s disease with recurrent inflammatory episodes involving the retina without neurological symptoms.

Nephrotic syndrome:

• steroid-dependent or steroid-resistant nephrotic syndrome due to minimal change disease in primary glomerulonephritis, focal segmental glomerulosclerosis, or membranous glomerulonephritis.

Induction or maintenance of remission:

• maintenance of remission induced by corticosteroids, enabling their discontinuation.

Rheumatoid arthritis:

• treatment of severe active rheumatoid arthritis.

Psoriasis:

• severe forms of psoriasis when standard treatment has proven ineffective or unacceptable.

Atopic dermatitis:

• treatment of severe forms of atopic dermatitis requiring systemic therapy.

Contraindications.

Hypersensitivity to cyclosporine or to any of the excipients of the medicinal product. Concomitant use with medicinal products containing Hypericum perforatum (St. John’s wort) due to the risk of reduced cyclosporine blood concentration and, consequently, diminished therapeutic effect.

Concomitant use with medicinal products that are substrates of the multidrug efflux transporter P-glycoprotein (Pgp) or organic anion transporting polypeptides (OATPs), whose increased plasma concentrations are associated with the development of serious adverse reactions and/or life-threatening adverse reactions, such as bosentan, dabigatran etexilate, and aliskiren.

Other possible contraindications:

• Renal insufficiency, except in patients with nephrotic syndrome and moderately elevated baseline creatinine concentrations up to 200 µmol/L in adults and 140 µmol/L in children. In nephrotic syndrome, cautious treatment with doses not exceeding 2.5 mg/kg/day may be permitted only if cyclosporine use contributes to normalization of creatinine levels elevated due to the disease.
• Poorly controlled hypertension.
• Poorly controlled infection.

History of known or diagnosed malignant tumors of any type, except premalignant conditions or skin malignancies following treatment.

Interaction with other medicinal products and other types of interactions.

Food interactions

An increase in cyclosporine bioavailability has been observed when grapefruit or grapefruit juice is consumed concomitantly.

Drug interactions

The following medicinal products have well-documented and clinically significant interactions.

Various drugs are known to increase or decrease cyclosporine concentrations in plasma or whole blood by inhibiting or inducing enzymes, particularly CYP3A4, involved in cyclosporine metabolism. Cyclosporine is an inhibitor of CYP3A4, the multidrug efflux transporter P-glycoprotein, and organic anion transporting proteins. This may increase plasma concentrations of concomitantly administered medicinal products that are substrates of CYP3A4 and/or these transporters.

Medicinal products that decrease or increase cyclosporine bioavailability
Frequent monitoring of cyclosporine blood levels should be performed in transplant recipients, especially at the beginning and end of treatment with another medicinal product, and dosing of Sandimmun Neoral® should be adjusted as necessary.

In patients treated for non-transplant indications, the relationship between blood concentration and clinical effects is less well studied. When co-administering medicinal products that increase cyclosporine concentration, frequent assessment of renal function and careful monitoring of cyclosporine-related adverse effects may be more appropriate than measuring blood levels.

Medicinal products that decrease cyclosporine concentrations

All CYP3A4 and/or P-glycoprotein inducers are expected to reduce cyclosporine concentrations.

Examples of medicinal products that decrease cyclosporine concentration: barbiturates, carbamazepine, oxcarbazepine, phenytoin, nafcillin, intravenous sulfadimidine, rifampicin, octreotide, orlistat, probucol, intravenous trimethoprim, products containing St. John’s wort, ticlopidine, sulfinpyrazone, terbinafine, bosentan.

Rifampicin is an inducer of cyclosporine metabolism in the intestine and liver. Therefore, when used concomitantly, a 3–5-fold increase in cyclosporine dose may be required.

Octreotide reduces oral absorption of cyclosporine, potentially requiring a 50% increase in cyclosporine dose or switching to an intravenous formulation.

Medicinal products that increase cyclosporine concentrations

All CYP3A4 and/or P-glycoprotein inhibitors may increase cyclosporine concentration. Examples of such medicinal products: 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 times, sometimes causing nephrotoxicity. Clarithromycin has been reported to double cyclosporine exposure. Azithromycin increases cyclosporine concentration by approximately 20%.

Azole antifungals: ketoconazole, fluconazole, itraconazole, and voriconazole can increase cyclosporine exposure by more than two-fold.

Verapamil increases cyclosporine blood concentration 2–3 times.

Concomitant administration with telaprevir resulted in an approximately 4.64-fold increase in normalized exposure (AUC) of cyclosporine.

Amiodarone significantly increases cyclosporine plasma concentration along with increased serum creatinine. This interaction may persist for a prolonged period after amiodarone discontinuation due to its very long elimination half-life (approximately 50 days).

Danazol has been reported to increase cyclosporine blood concentration by approximately 50%.

Diltiazem (at a dose of 90 mg/day) may increase cyclosporine plasma concentration by 50%.

Imatinib may enhance cyclosporine exposure and increase its Cmax by approximately 20%.

Combinations with increased risk of nephrotoxicity

Caution is required when cyclosporine is used concomitantly with other agents exhibiting synergistic nephrotoxic effects, 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 concomitant use of medicinal products known to interact with Sandimmun Neoral® cannot be avoided, the following general recommendations should be followed:

When used concomitantly with medicinal products that may exhibit synergistic nephrotoxic effects, careful monitoring of renal function is required. In case of pronounced renal dysfunction, the dose of the concomitantly administered medicinal product should be reduced or alternative therapy considered.

In transplant recipients, isolated cases of significant but reversible renal dysfunction (with 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. If significant renal dysfunction occurs, concomitant use of the products 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 medicinal products

Cyclosporine may reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins), etoposide, aliskiren, bosentan, and dabigatran.

Severe digitalis intoxication was observed within several days after initiation of cyclosporine therapy in some patients receiving digoxin. Cyclosporine has been reported to potentiate the toxic effects of colchicine, such as myopathy and neuropathy, especially in patients with renal dysfunction.

Cases of myotoxicity, including muscle pain and weakness, myositis, and rhabdomyolysis, have been described in medical publications and post-marketing studies in patients taking cyclosporine concomitantly with lovastatin, simvastatin, atorvastatin, pravastatin, and also fluvastatin (rarely). When used concomitantly with cyclosporine, the dose of these statins should be reduced according to the instructions provided in their prescribing information. Statin therapy may be temporarily discontinued in patients with symptoms of myopathy or in patients with risk factors for severe renal dysfunction, including secondary renal failure developed due to rhabdomyolysis.

Concomitant use of nifedipine with cyclosporine may lead to an increased frequency 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, concomitant use of cyclosporine with lercanidipine should be avoided. Administration of cyclosporine 3 hours after lercanidipine did not alter the AUC of the latter, but the AUC of cyclosporine increased by 27%. Therefore, this combination should be used cautiously with an interval of at least 3 hours between administration of the medicinal products.

An antihypertensive agent without pharmacokinetic interactions with cyclosporine should be preferred.

After concomitant administration of cyclosporine and aliskiren, an increase in Cmax of aliskiren, a P-gp substrate, by approximately 2.5-fold and an increase in AUC by approximately 5-fold were observed. However, the pharmacokinetic profile of cyclosporine was not significantly altered.

Concomitant use of dabigatran etexilate is also not recommended due to cyclosporine’s inhibitory activity on P-gp. Dabigatran has a narrow therapeutic index, and increased plasma concentration is associated with an increased risk of bleeding.

It has been established that concomitant use of diclofenac and cyclosporine leads to a significant increase in diclofenac bioavailability, potentially causing reversible renal insufficiency. This increase is most likely due to reduced high first-pass effect of diclofenac. Concomitant use of cyclosporine with NSAIDs having low first-pass effect (such as acetylsalicylic acid) is generally not associated with increased bioavailability.

Increased serum creatinine has been observed in studies during concomitant use of everolimus or sirolimus and full doses of cyclosporine in microemulsion form. This effect is often reversible upon reduction of cyclosporine doses. Everolimus and sirolimus have only minimal effects on cyclosporine pharmacokinetics. Concomitant use of cyclosporine significantly increases blood concentrations of everolimus and sirolimus.

Cyclosporine should be prescribed with caution together with potassium-sparing agents (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists) or potassium-containing products, 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.

Concomitant administration of bosentan with cyclosporine in healthy volunteers decreased cyclosporine exposure by 35%, while bosentan exposure increased approximately 2-fold. Therefore, concomitant use of cyclosporine with bosentan is not recommended.

Repeated doses of ambrisentan and cyclosporine in healthy volunteers led to an approximately 2-fold increase in ambrisentan exposure, while cyclosporine exposure was only slightly increased (approximately 10%).

In oncology patients, concomitant use of intravenous forms of anthracycline antibiotics (e.g., doxorubicin, mitoxantrone, daunorubicin) and very high doses of cyclosporine resulted in a significant increase in anthracycline antibiotic exposure.

Digoxin, colchicine, HMG-CoA reductase inhibitors. If any of these medicinal products are prescribed concomitantly with Sandimmun Neoral®, careful clinical monitoring is required to enable early detection of toxic effects and subsequent dose reduction or discontinuation of the medicinal product.

Drug interactions occur more frequently in elderly patients.

During cyclosporine therapy, vaccine efficacy may be reduced. Use of live attenuated vaccines should be avoided.

Children

Drug interaction studies were conducted exclusively in adult patients.

Special precautions for use

Sandimmun Neoral® should be prescribed only by physicians experienced in immunosuppressive therapy who can provide the necessary monitoring (regular comprehensive physical examinations, blood pressure control, laboratory tests). Patients who have undergone transplantation and are receiving Sandimmun Neoral® must be treated only in medical facilities equipped with appropriate laboratory and medical infrastructure. The physician responsible for maintenance therapy should be provided with all necessary information for proper patient management.

Absorption of calcineurin inhibitors may be impaired in patients with cystic fibrosis.

Like other immunosuppressants, cyclosporine increases the risk of developing lymphomas and other malignancies, including skin tumors. Regular monitoring of patients receiving long-term Sandimmun Neoral® therapy is essential to ensure early diagnosis. Treatment should be discontinued if a premalignant condition or tumor is diagnosed. Evidence suggests that the increased risk is related to the degree and duration of immunosuppression, rather than to the use of specific agents.

Therefore, treatment regimens involving multiple immunosuppressive agents (including cyclosporine) should be used with caution, as they may lead to lymphoproliferative disorders and solid organ tumors, sometimes with fatal outcomes.

Due to the potential risk of skin malignancies, patients receiving Sandimmun Neoral®, particularly those being treated for psoriasis or atopic dermatitis, should be advised to avoid excessive sun exposure without adequate protection and should not undergo UVB irradiation or PUVA photochemotherapy concurrently.

Infections

As with other immunosuppressants, the use of cyclosporine may lead to various bacterial, fungal, parasitic, and viral infections, often involving opportunistic pathogens. Reactivation of latent polyomavirus infection has been observed in patients receiving cyclosporine, potentially leading to polyomavirus-associated nephropathy (PVAN), including BK virus nephropathy (BKVN), or progressive multifocal leukoencephalopathy associated with JC virus (PML). These complications are often secondary to high levels of 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 prophylactic and therapeutic strategies should be employed, especially in patients requiring repeated long-term immunosuppressive therapy. Overall immunosuppression should be reduced in patients with PVAN or PML, although reduced immunosuppression may also jeopardize graft survival.

Renal toxicity

Elevated serum creatinine and urea levels are common and potentially serious complications during the first few weeks of Sandimmun Neoral® therapy. These functional changes are dose-dependent and usually reversible, with values returning to normal upon dose reduction. In some patients, prolonged treatment may lead to structural kidney changes (e.g., interstitial fibrosis), which should be differentiated from signs of chronic rejection in kidney transplant recipients. Frequent monitoring of renal function is therefore necessary, in accordance with local guidelines and specific indications for drug use.

Hepatotoxicity

Sandimmun Neoral® may cause dose-dependent, reversible increases in serum bilirubin levels and, occasionally, elevated liver enzymes. There have been case reports and spontaneous reports of hepatotoxicity and liver injury, including cholestasis, jaundice, hepatitis, and liver failure, in patients receiving cyclosporine. Most reports involved patients with significant comorbidities, underlying pathological conditions, and other concurrent factors, including infectious complications and concomitant medications with hepatotoxic potential. Fatal outcomes have been reported, primarily in transplant patients.

Regular monitoring of relevant liver function parameters is required, and dose reduction should be considered if abnormalities are detected.

Elderly patients (aged 65 years and older)

Renal function should be monitored particularly carefully in elderly patients.

Monitoring of cyclosporine levels

When administering Sandimmun Neoral® to post-transplant patients, regular monitoring of blood cyclosporine concentrations is an essential safety measure. Cyclosporine levels in blood are best determined using specific monoclonal antibodies (measuring unchanged drug). However, high-performance liquid chromatography (HPLC) may also be used (also for measuring unchanged drug). A standardized sample separation method (time and temperature) must be applied when quantifying cyclosporine in plasma or serum.

In liver transplant recipients, initial blood level monitoring should be performed either using specific monoclonal antibodies alone or by parallel measurements with both specific and non-specific monoclonal antibodies to ensure adequate immunosuppression.

It should also be remembered that cyclosporine blood, plasma, or serum levels are only one of many factors influencing the patient's clinical status. Therefore, results should be interpreted only in the context of other clinical and biochemical parameters.

Monitoring of blood pressure

Blood pressure should be monitored regularly during Sandimmun Neoral® therapy. If arterial hypertension is detected, appropriate antihypertensive treatment should be initiated. Antihypertensive drugs that do not affect cyclosporine pharmacokinetics, such as isradipine, should be preferred.

Increased blood lipid levels

Isolated reports have linked Sandimmun Neoral® treatment with mild, reversible increases in blood lipids. Lipid levels should be measured before and one month after starting treatment. If elevated lipid levels are detected, dietary fat intake should be reduced and, if necessary, the dose of Sandimmun Neoral® should be decreased.

Hyperkalemia

The risk of hyperkalemia increases during cyclosporine therapy, especially in patients with renal dysfunction. Cyclosporine should be used with caution in combination with potassium-sparing agents (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists) or potassium-containing medications, or in patients on a potassium-rich diet. Potassium levels should be monitored in such cases.

Hypomagnesemia

Cyclosporine increases magnesium excretion, potentially leading to symptomatic hypomagnesemia, particularly in the peri-transplant period. Serum magnesium levels should be monitored during the peri-transplant period, especially if neurological symptoms occur. If necessary, magnesium supplementation should be administered.

Hyperuricemia

Caution is required when treating patients with hyperuricemia.

Live attenuated vaccines

Vaccination during cyclosporine therapy may be less effective, and the use of live attenuated vaccines should be avoided.

Interactions

Cyclosporine should be administered with caution in combination with medicinal products that significantly increase or decrease cyclosporine plasma concentrations through inhibition or induction of CYP3A4 and/or P-glycoprotein (see section "Interaction with other medicinal products and other forms of interaction").

Monitoring for nephrotoxicity is required when cyclosporine is administered with substances that increase cyclosporine concentration or exhibit synergism in nephrotoxic effects (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of cyclosporine and tacrolimus should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Cyclosporine is an inhibitor of CYP3A4, the multidrug efflux transporter P-glycoprotein, and organic anion transporting polypeptides (OATPs) and may increase plasma concentrations of concomitantly administered drugs that are substrates of these enzymes and/or transporters, such as dabigatran, aliskiren, and bosentan. Caution should be exercised when using cyclosporine concomitantly with such medicinal products, or their combined use should be avoided (see section "Interaction with other medicinal products and other forms of interaction"). Cyclosporine enhances exposure to HMG-CoA reductase inhibitors (statins). When used concomitantly with cyclosporine, statin doses should be reduced; combined use with certain statins should be avoided according to recommendations specified in the product information for these medicinal products. Statin therapy should be temporarily or permanently discontinued in patients showing signs and symptoms of myopathy or at risk of severe renal injury, including renal failure due to rhabdomyolysis (see section "Interaction with other medicinal products and other forms of interaction").

Patients with psoriasis should avoid concomitant use of beta-blockers or diuretics.

Special excipients

Sandimmun Neoral® contains hydrogenated castor oil "Polyoxyl 40," which may cause gastrointestinal disturbances and diarrhea.

Oral dosage forms of Sandimmun Neoral® contain approximately 12% (v/v) ethanol. A 500 mg dose of Sandimmun Neoral® contains 500 mg of ethanol, equivalent to approximately 15 ml of beer or 5 ml of wine. This may be harmful to alcohol-dependent patients and requires consideration when treating pregnant and breastfeeding women, patients with liver disease or epilepsy, and in pediatric use.

Additional precautions for non-transplant indications

Cyclosporine should not be administered to patients with impaired renal function (except patients with nephrotic syndrome with acceptable degree of renal insufficiency), uncontrolled arterial hypertension, uncontrolled infections, or any type of malignant tumor.

Prior to initiating treatment, a reliable assessment of baseline renal function should be performed by at least two measurements of estimated glomerular filtration rate (eGFR). Frequent monitoring of renal function during therapy is necessary for appropriate dose adjustment.

Additional precautions in endogenous uveitis

A possible association between cyclosporine and neurological manifestations of Behçet's syndrome has been reported. Sandimmun Neoral® should be used with caution in patients with Behçet's syndrome who have neurological manifestations. Close monitoring of neurological status in such patients is required.

Additional precautions in nephrotic syndrome

Patients with baseline renal dysfunction should initially receive a dose of 2.5 mg/kg/day and require very careful monitoring.

In some patients, it may be difficult to distinguish cyclosporine-induced renal dysfunction from changes caused by nephrotic syndrome itself. This explains why, in rare cases, Sandimmun Neoral®-associated structural kidney changes may occur without elevated serum creatinine levels. Renal biopsy should be considered in patients with steroid-dependent minimal change nephropathy who have received Sandimmun Neoral® therapy for more than one year.

Occasional reports have described the development of malignancies (including Hodgkin's lymphoma) in patients with nephrotic syndrome receiving immunosuppressants (including cyclosporine).

Additional precautions in rheumatoid arthritis

After 6 months of therapy, renal function should be assessed every 4–8 weeks, depending on disease stability, concomitant medication, and comorbidities. More frequent evaluations are required if the dose of Sandimmun Neoral® is increased or if concomitant nonsteroidal anti-inflammatory drugs are initiated or their doses increased.

Discontinuation of the drug may also be necessary if arterial hypertension induced by Sandimmun Neoral® therapy cannot be controlled with appropriate antihypertensive treatment.

As with long-term use of other immunosuppressive agents, an increased risk of lymphoproliferative disorders should be considered. Particular caution is required when using Sandimmun Neoral® in combination with methotrexate due to synergistic nephrotoxic effects.

Additional precautions in psoriasis

Discontinuation of Sandimmun Neoral® therapy is recommended if arterial hypertension induced by the drug cannot be controlled with appropriate therapy.

Treatment of elderly patients should be initiated only in cases of disabling forms of psoriasis and with particularly careful monitoring of renal function.

Malignant tumors (including skin) have been reported in patients with psoriasis receiving cyclosporine as standard immunosuppressive therapy. Atypical skin lesions suspicious for malignancy or premalignant changes should undergo biopsy before initiating Sandimmun Neoral® therapy. Patients with malignant or premalignant skin changes should receive Sandimmun Neoral® only after appropriate treatment of skin lesions and if no other effective treatment options are available.

Lymphoproliferative disorders have occurred in some patients with psoriasis receiving Sandimmun Neoral®. These resolved after rapid discontinuation of the drug.

Patients receiving Sandimmun Neoral® should not undergo UVB irradiation or PUVA photochemotherapy concurrently.

Additional precautions in atopic dermatitis

Discontinuation of Sandimmun Neoral® therapy is recommended if arterial hypertension induced by the drug cannot be controlled with appropriate therapy.

Treatment of elderly patients should be initiated only in cases of disabling forms of atopic dermatitis and with particularly careful monitoring of renal function.

Benign lymphadenopathy is often associated with exacerbations of atopic dermatitis and resolves spontaneously or with general improvement of the disease.

Lymphadenopathy occurring during cyclosporine therapy requires regular monitoring.

If lymphadenopathy persists despite reduced disease activity, a biopsy should be performed as a precautionary measure to rule out lymphoma.

Before initiating Sandimmun Neoral® therapy, patients should recover from active herpes simplex virus infection. However, such infection does not necessarily require discontinuation of the drug if it occurs during treatment (except in severe cases).

Skin infections caused by Staphylococcus aureus do not constitute an absolute contraindication to Sandimmun Neoral® therapy but require treatment with appropriate antibacterial agents. Oral erythromycin, known to increase cyclosporine blood concentrations, should be avoided; if no alternative is available, careful monitoring of cyclosporine blood levels, renal function, and cyclosporine-related adverse effects is recommended.

Patients receiving Sandimmun Neoral® should be advised to avoid excessive sun exposure without adequate protection and should not undergo UVB irradiation or PUVA photochemotherapy concurrently.

Use in pediatric patients for non-transplant indications

Except for the treatment of nephrotic syndrome, adequate experience with Sandimmun Neoral® is lacking; its use in children under 16 years of age for non-transplant indications other than nephrotic syndrome cannot be recommended.

Do not use after the expiry date stated on the packaging.

Use during pregnancy or breastfeeding

Animal studies have demonstrated reproductive toxicity in rats and rabbits.

Clinical experience with Sandimmun Neoral® in pregnant women is limited. Pregnant women receiving immunosuppressants after transplantation, including cyclosporine, or treatment regimens containing cyclosporine, have an increased risk of preterm delivery (<37 weeks).

A limited number of observations have been made in children up to 7 years of age exposed to cyclosporine in utero. These children had normal renal function and blood pressure.

However, no adequately controlled studies in pregnant women have been conducted. Sandimmun Neoral® should not be used during pregnancy except when the potential benefit to the mother outweighs the potential risk to the fetus. The presence of ethanol in Sandimmun Neoral® formulations should also be considered during pregnancy.

Cyclosporine passes into breast milk. The presence of ethanol in Sandimmun Neoral® formulations should be considered for breastfeeding women. Women using Sandimmun Neoral® should not breastfeed due to the potential for serious adverse reactions in breastfed newborns/infants. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from the drug, taking into account the importance of the drug to the mother.

Data on the effect of Sandimmun Neoral® on human fertility are limited.

Ability to affect reaction speed when driving vehicles or operating machinery

Data on the effect of Sandimmun Neoral® on the ability to drive vehicles or operate machinery are lacking.

Method of Administration and Dosage.

The dosage ranges indicated for oral administration should be considered only as recommended. The daily dose of Sandimmun Neoral® should always be divided into two doses with equal time intervals between administrations. It is recommended to administer Sandimmun Neoral® according to a strict schedule considering time of day and dietary regimen. If the prescribed dosing regimen cannot be achieved with capsules, particularly in patients with low body weight, the use of the oral solution is recommended.

Sandimmun Neoral® may be prescribed only by a physician experienced in immunosuppressive therapy and/or organ transplantation.

Transplantation Indications

Regular monitoring of cyclosporine blood levels using a radioimmunoassay with monoclonal antibodies is required. The results obtained serve as the basis for determining the dose necessary to achieve target concentrations.

Organ Transplantation

The initial dose is 10–15 mg/kg body weight, divided into two doses and administered up to 12 hours before transplantation. For 1–2 weeks after surgery, the drug is administered daily at the same dose, after which the dose is gradually reduced under the control of cyclosporine blood concentration according to local immunosuppressive therapy protocols until reaching a maintenance dose of 2–6 mg/kg/day (in two divided doses).

Sandimmun Neoral® may be used in combination with other immunosuppressants/corticosteroids, as well as part of a combined triple or quadruple therapy regimen. At the beginning of treatment, lower doses may be used (e.g., an oral dose of 3–6 mg/kg/day, divided into two doses).

Bone Marrow Transplantation / Prevention and Treatment of Graft-versus-Host Reaction

The recommended dose should be initiated one day before transplantation.

Sandimmun, concentrate for solution for infusion, is generally preferred at the beginning of therapy. The recommended intravenous dose is 3–5 mg/kg/day. Infusion at this dose should be continued during the early post-transplant period for up to 2 weeks, after which transition to oral maintenance therapy with Sandimmun Neoral® at a daily dose of approximately 12.5 mg/kg, divided into two doses, should be made.

Maintenance therapy should be continued for 3–6 months (preferably 6 months). The dose should be gradually reduced to zero within one year after transplantation. If Sandimmun Neoral® is used at the beginning of therapy, the recommended dose is 12.5–15 mg/kg/day in two divided doses, starting the day before transplantation.

In patients with gastrointestinal disorders leading to reduced absorption, higher doses of capsules or concentrate for intravenous infusion (Sandimmun) may be required.

In some patients, graft-versus-host reaction (GVHR) may occur after discontinuation of Sandimmun Neoral®, which usually resolves after resuming therapy. In such cases, an initial oral loading dose of 10–12.5 mg/kg should be prescribed, followed by oral maintenance therapy at the dose effective during previous treatment. For treatment of chronic, mild forms of this condition, Sandimmun Neoral® should be used at low doses.

Non-Transplantation Indications

When using Sandimmun Neoral® for any approved non-transplantation indications, the following general rules should be observed.

Before initiating treatment, an objective baseline renal function should be established based on at least two measurements. Estimated glomerular filtration rate (eGFR), calculated using the MDRD formula, may be used to assess renal function in adults. An appropriate formula should be used to estimate eGFR in children. Since Sandimmun Neoral® may impair renal function, frequent monitoring is necessary. If eGFR decreases by more than 25% compared to baseline in more than one measurement, the dose of Sandimmun Neoral® should be reduced by 25–50%. If the reduction in eGFR compared to baseline exceeds 35%, further dose reduction of Sandimmun Neoral® should be considered. These recommendations apply even if the obtained values fall within the normal laboratory reference range. If dose reduction does not restore eGFR within one month, treatment with Sandimmun Neoral® should be discontinued.

Regular monitoring of arterial blood pressure is essential.

Before starting therapy, bilirubin concentration and other liver function parameters should be determined. Careful monitoring of these parameters is recommended during treatment.

Serum lipid levels, potassium, magnesium, and uric acid concentrations should be measured before starting therapy and periodically during treatment.

Periodic monitoring of cyclosporine blood concentration may be useful when used for non-transplantation indications, for example, when Sandimmun Neoral® is co-administered with drugs that may affect cyclosporine pharmacokinetics, or in cases of unusual clinical response (e.g., insufficient efficacy or increased sensitivity to the drug, manifested as impaired renal function).

The standard route of administration is oral. When using the concentrate for infusion solution, careful calculations should be performed to determine the appropriate intravenous dose equivalent to the oral dose. Consultation with a physician experienced in cyclosporine use is recommended.

The total daily dose should not exceed 5 mg/kg, except for use in patients with endogenous uveitis threatening vision and children with nephrotic syndrome.

For maintenance therapy, the lowest effective and well-tolerated dose should be individually determined.

Treatment with Sandimmun Neoral® should be discontinued in patients who do not achieve an adequate response within a defined time period (for detailed information, see below) or when the effective dose does not comply with established safety recommendations.

Endogenous Uveitis

The recommended initial dose to promote remission is 5 mg/kg/day orally in two divided doses until remission of active uveitic inflammation and improvement in visual acuity. In refractory cases, the dose may be temporarily increased to 7 mg/kg/day.

To achieve initial remission or prevent exacerbation of ocular inflammation when adequate control cannot be achieved with Sandimmun Neoral® monotherapy, combination with systemic corticosteroids, e.g., prednisone at 0.2–0.6 mg/kg or equivalent, may be considered. After 3 months of treatment, the corticosteroid dose may be reduced to the lowest effective dose.

Treatment with Sandimmun Neoral® should be discontinued if no improvement is observed after three months of therapy.

During maintenance therapy, the dose should be gradually reduced to the lowest effective dose, which during remission should not exceed 5 mg/kg/day.

Before initiating immunosuppressive therapy, infectious causes of uveitis should be ruled out.

The daily dose should be reduced by 25–50% if plasma creatinine concentration exceeds the baseline level by more than 30% in more than one measurement, even if this concentration is within the normal range.

Nephrotic Syndrome

The recommended daily dose to promote remission is 5 mg/kg for adults and 6 mg/kg for children, divided into two doses, provided renal function is normal except for proteinuria. For patients with impaired renal function, the initial dose should not exceed 2.5 mg/kg/day orally.

In cases of inadequate monotherapy with Sandimmun Neoral®, particularly in steroid-resistant patients, combination therapy with Sandimmun Neoral® and low-dose oral corticosteroids may be beneficial.

Time to improvement ranges from 3 to 6 months, depending on the type of glomerulopathy. If no improvement is observed within this period, treatment with Sandimmun Neoral® should be discontinued.

Doses should be individually adjusted based on efficacy (proteinuria) and safety, and should not exceed 5 mg/kg/day for adults and 6 mg/kg/day for children.

For maintenance therapy, doses should be gradually and individually reduced to the lowest effective level.

Rheumatoid Arthritis

During the first 6 weeks of treatment, the recommended dose is 3 mg/kg/day orally, divided into two doses. If the response is inadequate, the daily dose may be gradually increased, if tolerated, but should not exceed 5 mg/kg/day. Treatment with Sandimmun Neoral® may be continued for up to 12 weeks to achieve maximum efficacy.

For maintenance therapy, the dose should be individually titrated to the lowest effective dose based on tolerability.

Sandimmun Neoral® may be prescribed in combination with low-dose corticosteroids and/or nonsteroidal anti-inflammatory drugs (NSAIDs).

Sandimmun Neoral® may also be used in combination with low weekly doses of methotrexate in cases of inadequate response to methotrexate monotherapy. In such cases, Sandimmun Neoral® is prescribed at an initial dose of 2.5 mg/kg/day, divided into two doses, with the possibility of dose escalation within tolerability limits.

Psoriasis

Treatment with Sandimmun Neoral® should be initiated by a physician experienced in the diagnosis and treatment of psoriasis. Due to the variability of this disease, treatment should be individualized. The recommended initial dose for induction of remission is 2.5 mg/kg/day, divided into two doses; if no improvement is observed after 1 month of treatment, the dose may be gradually increased up to a maximum of 5 mg/kg/day. Treatment should be discontinued if an adequate response is not achieved within one month of daily administration of 5 mg/kg/day or if the effective dose is inconsistent with established safety recommendations.

For patients requiring particularly rapid improvement, an initial dose of 5 mg/kg/day may be justified. Treatment with Sandimmun Neoral® may be discontinued after achieving a satisfactory response and restarted with the previous effective dose in case of relapse. Some patients may require continuous maintenance therapy.

For maintenance therapy, the dose should be individually adjusted to the lowest effective level and should not exceed 5 mg/kg/day.

Treatment with Sandimmun Neoral® should be gradually discontinued if remission persists for more than 6 months. However, the risk of relapse after discontinuation is very high.

Atopic Dermatitis

Treatment with Sandimmun Neoral® should be initiated by a physician experienced in the diagnosis and treatment of atopic dermatitis. Due to the variability of this disease, treatment should be individually tailored. For adults and adolescents aged 16 years and older, the recommended dose is 2.5–5 mg/kg/day, divided into two doses.

If the response to treatment at the initial dose of 2.5 mg/kg/day is not satisfactory after 2 weeks, the daily dose may be rapidly increased to the maximum dose of 5 mg/kg/day. In very severe cases, rapid and adequate disease control may be achieved by using an initial dose of 5 mg/kg/day.

Treatment should be discontinued if patients with atopic dermatitis do not show sufficient improvement after one month of treatment with Sandimmun Neoral® at a dose of 5 mg/kg/day.

Current data on the long-term use of Sandimmun Neoral® for atopic dermatitis are limited; therefore, the recommended duration of individual treatment cycles is no more than 8 weeks.

Switching from Sandimmun to Sandimmun Neoral®

Available data confirm that switching from Sandimmun to Sandimmun Neoral® at a 1:1 ratio results in comparable minimum cyclosporine concentrations in whole blood. In many patients, higher maximum (peak) concentrations (Cmax) and increased drug exposure (AUC) may be observed. In a small percentage of patients, these changes may be more pronounced and clinically significant. Additionally, cyclosporine absorption from Sandimmun Neoral® shows less variability, and the correlation between trough cyclosporine concentrations and drug exposure (expressed as AUC) is stronger than with Sandimmun.

Since switching from Sandimmun to Sandimmun Neoral® may lead to increased cyclosporine exposure, the following rules should be observed.

In post-transplant patients, treatment with Sandimmun Neoral® should be initiated at the same daily dose previously used with Sandimmun. Initial monitoring of trough cyclosporine blood concentrations should be performed 4–7 days after switching to Sandimmun Neoral®. Additionally, clinical safety parameters such as renal function and blood pressure should be monitored during the first 2 months after the switch. If trough cyclosporine blood concentrations fall outside the therapeutic range and/or clinical safety parameters worsen, appropriate dose adjustments should be made.

When treating non-transplantation indications, Sandimmun Neoral® should be prescribed at the same daily dose as Sandimmun. Renal function and blood pressure should be monitored 2, 4, and 8 weeks after the switch. If more than one blood pressure measurement significantly exceeds pre-switch levels or eGFR decreases by more than 25% compared to pre-Sandimmun therapy values, the dose should be reduced. In case of unexpected toxic effects or cyclosporine inefficacy, monitoring of trough cyclosporine blood concentrations should also be performed.

Switching Between Oral Cyclosporine Formulations

Switching from one oral cyclosporine formulation to another should be done cautiously and under specialist supervision. Initiation of a new cyclosporine formulation should be accompanied by monitoring of cyclosporine blood levels in post-transplant patients.

Administration

Soft gelatin capsules should be swallowed whole, without chewing. If a cyclosporine dose less than 10 mg is required, the drug should be administered in an appropriate dosage strength or pharmaceutical form.

Special Populations

Patients with Impaired Renal Function

All Indications

Cyclosporine is minimally excreted by the kidneys, and its pharmacokinetics are not significantly affected by impaired renal function. However, due to its nephrotoxic potential, careful monitoring of renal function is recommended.

Non-Transplantation Indications

Cyclosporine should not be prescribed to patients with impaired renal function, except for those being treated for nephrotic syndrome. For patients with nephrotic syndrome and impaired renal function, the initial dose should not exceed 2.5 mg/kg/day.

Patients with Impaired Hepatic Function

Cyclosporine is extensively metabolized in the liver. In patients with impaired hepatic function, cyclosporine exposure may increase approximately two- to threefold. In cases of severe hepatic impairment, dose reduction may be necessary to maintain drug blood concentrations within the recommended target range. In such cases, monitoring of cyclosporine blood concentrations is recommended until stable levels are achieved.

Patients with severe hepatic impairment require regular monitoring of plasma creatinine levels and, if possible, cyclosporine levels, with dose adjustments as needed.

Elderly Patients

Experience with Sandimmun Neoral® in elderly patients is limited.

In clinical trials of cyclosporine use in rheumatoid arthritis, patients aged 65 years and older showed a higher incidence of systolic hypertension and an increase in serum creatinine levels exceeding baseline values by 50% or more after 3–4 months of therapy.

In general, dose selection for elderly patients should be cautious, considering the higher frequency of decreased hepatic, renal, or cardiac function, the presence of concomitant diseases, or concomitant therapies that may increase susceptibility to infections. Treatment should usually be initiated with a dose at the lower end of the dosage range.

Children.

Clinical studies have included children as young as 1 year of age. In several studies, pediatric patients required and tolerated higher doses of cyclosporine per unit of body weight than adults.

Except for the treatment of nephrotic syndrome, adequate experience with Sandimmun Neoral® is lacking; its use in children under 16 years of age for non-transplantation indications, other than nephrotic syndrome, cannot be recommended.

Overdose.

The oral LD50 of cyclosporine is 2,329 mg/kg in mice, 1,480 mg/kg in rats, and >1,000 mg/kg in rabbits. The intravenous LD50 of cyclosporine is 148 mg/kg in mice, 104 mg/kg in rats, and 46 mg/kg in rabbits.

Symptoms

Data on acute cyclosporine overdose are limited. Oral intake of doses up to 10 g (approximately 150 mg/kg) has led to relatively minor clinical consequences such as vomiting, somnolence, headache, tachycardia, and in some patients, relatively significant reversible renal function impairment. However, accidental parenteral overdose in premature infants has resulted in severe intoxication.

Treatment

In all cases of overdose, symptomatic treatment and general supportive measures should be implemented. Inducing vomiting and gastric lavage may be beneficial within the first hours after overdose. The drug is practically not removed by hemodialysis and is inadequately removed by hemoperfusion using activated charcoal.

Adverse reactions.

Summary of safety profile

The main adverse reactions observed during clinical trials and associated with cyclosporine use include renal dysfunction, tremor, hirsutism, arterial hypertension, diarrhea, anorexia, nausea, and vomiting.

Many adverse reactions associated with cyclosporine are dose-dependent and reversible upon dose reduction. The spectrum of adverse reactions is generally similar across different indications, although differences in frequency and severity exist. In transplant recipients, adverse effects occur more frequently and are usually more pronounced than in patients with other indications, due to the need for higher initial doses and longer duration of maintenance therapy.

Infections and infestations

Patients receiving immunosuppressive therapy, including cyclosporine, or treatment regimens containing cyclosporine, are at increased risk of developing viral, bacterial, fungal, and parasitic infections. Both localized and systemic infections may occur, as well as reactivation or exacerbation of pre-existing infections. Reactivation of polyomavirus infections may lead to polyomavirus-associated nephropathy (PVAN) or progressive multifocal leukoencephalopathy associated with JC virus (PML). Serious and/or fatal cases have been reported.

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Patients receiving immunosuppressive agents, including cyclosporine, or treatment regimens containing cyclosporine, are at increased risk of developing lymphomas or lymphoproliferative disorders and other malignancies, particularly of the skin. The incidence of malignancies increases with increasing intensity and duration of therapy. Some malignancies may be fatal.

Summary of adverse reactions observed in clinical trials

Adverse reactions identified during clinical trials are grouped by system organ class according to MedDRA. Within each group, reactions are listed in descending order of severity. Adverse effects are listed according to frequency of occurrence (starting with the most frequent): very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000), including isolated case reports.

Blood and lymphatic system disorders:

Common: leucopenia;
Uncommon: anemia, thrombocytopenia;
Rare*: thrombotic microangiopathy (including thrombotic thrombocytopenic purpura, microangiopathic hemolytic anemia, hemolytic uremic syndrome).

Metabolism and nutrition disorders:

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

Nervous system disorders:

Very common: tremor (10–20%), headache, including migraine (up to 15%);
Common: paresthesia;
Uncommon: signs of encephalopathy, including reversible posterior encephalopathy syndrome, such as seizures, confusion, disorientation, psychomotor retardation, excitement, insomnia, visual disturbances, cortical blindness, coma, paresis, cerebellar ataxia;
Rare: motor polyneuropathy;
Very rare: optic disc edema, including papilledema, with possible visual loss due to benign intracranial hypertension.

Cardiac disorders:

Very common: arterial hypertension (15–40%);
Common: flushing.

Gastrointestinal disorders:

Very common: nausea, vomiting, abdominal discomfort, abdominal pain, diarrhea, gingival hyperplasia;
Common: peptic ulcer;
Rare: pancreatitis.

Hepatobiliary disorders:

Common: hepatic function abnormalities;
Not known*: hepatotoxicity and liver injury, including cholestasis; jaundice, hepatitis, hepatic failure, sometimes fatal.

Skin and subcutaneous tissue disorders:

Very common: hirsutism;
Common: rash, acne;
Uncommon: allergic rash.

Musculoskeletal and connective tissue disorders:

Common: muscle spasms, myalgia;
Rare: muscle weakness, myopathy, limb pain.

Renal and urinary disorders:

Very common: renal function abnormalities.

Reproductive system and breast disorders:

Rare: menstrual disorders, gynecomastia.

General disorders and administration site conditions:

Common: fatigue, edema, pyrexia;
Uncommon: weight increased.

*Adverse reactions identified from post-marketing experience, frequency unknown due to lack of precise population denominator.

Other adverse reactions reported from post-marketing surveillance

Spontaneous and solicited reports have been received regarding cases of hepatotoxicity and liver injury, including cholestasis, jaundice, hepatitis, and hepatic failure in patients receiving cyclosporine. Most reports involved patients with significant comorbidities, underlying pathological conditions, and other risk factors, including infectious complications and concomitant use of hepatotoxic drugs. Fatal outcomes have been reported, particularly in transplant patients.

Acute and chronic nephrotoxicity

Patients receiving calcineurin inhibitors, including cyclosporine, or treatment regimens containing cyclosporine, are at increased risk of acute or chronic nephrotoxicity. Such reports have been received during clinical trials and post-marketing use of Sandimmun Neoral®. Electrolyte imbalances such as hyperkalemia, hypomagnesemia, and hypouricemia have been reported. In some cases, chronic morphological changes such as arteriolar hyalinosis, tubular atrophy, and interstitial fibrosis have been observed.

Paediatric population

Clinical trials included children aged 1 year and older. The safety profile observed with standard doses of cyclosporine was similar to that in adults.

Shelf life. 3 years.

The solution should be used within 2 months after first opening of the vial.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of reach of children.

Packaging.

50 mL in a vial with a rubber stopper and an aluminum cap with a rubber closure. The vial, together with a dosing set (dosing syringe and syringe adapter), is packed in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

1. Novartis Pharma GmbH (batch release).
2. Novartis Farmacéutica, S.A. (batch release).

Manufacturer's name and address.

1. Roonstrasse 25, Roonstrasse, Nuremberg, Bavaria, 90429, Germany.
2. Gran Vía de les Corts Catalanes 764, Barcelona, 08013, Spain.