Sandimmun

Composition:

Active substance: cyclosporine;

1 ml of concentrate for solution for infusion contains 50 mg of cyclosporine;

Excipients: polyoxyl 40 hydrogenated castor oil, ethanol 94% m/m.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: the content of the ampoule – clear, brownish-yellow, oily liquid.

Pharmacotherapeutic group. Immunosuppressive agents. Calcineurin inhibitors.

ATC code L04AD01.

Pharmacological Properties.

Pharmacodynamics.

Cyclosporine is a cyclic polypeptide composed of eleven amino acids. It is a highly effective immunosuppressive agent that, in animal studies, prolongs survival of allografts of skin, heart, kidney, pancreas, bone marrow, small intestine, and lungs. Cyclosporine suppresses cell-mediated immune reactions, including immunity against allografts, delayed-type skin hypersensitivity, experimental allergic encephalomyelitis, adjuvant-induced arthritis, graft-versus-host disease (GVHD), and T-lymphocyte-dependent antibody production. It inhibits the synthesis and release of lymphokines, including interleukin-2 (T-lymphocyte growth factor). Cyclosporine arrests lymphocytes in the resting state at the G0 or G1 phase of the cell cycle and inhibits the release of lymphokines from activated T-cells in response to antigen contact.

In patients treated with cyclosporine for prevention and treatment of transplant rejection and GVHD, allogeneic transplantation of solid organs and bone marrow has been successfully performed. Cyclosporine has been used in both HCV-positive and HCV-negative liver transplant recipients. A significant positive effect of cyclosporine treatment has also been observed in patients with severe forms of psoriasis, atopic dermatitis, and rheumatoid arthritis—conditions that may be considered to have an immunological mechanism of origin.

All available data indicate that cyclosporine acts specifically and reversibly on lymphocytes. Unlike cytostatic agents, it does not suppress hematopoiesis and does not affect phagocyte function. Transplanted patients receiving cyclosporine are less susceptible to infections than those receiving other immunosuppressive therapies.

Pharmacokinetics.

Sandimmun, concentrate for solution for infusion, has demonstrated bioequivalence to Sandimmun, oral solution.

Distribution

Absolute bioavailability at steady state ranges from 25–50%, with peak blood concentrations achieved within 1–6 hours.

Cyclosporine A is predominantly distributed outside the vascular compartment, with a mean volume of distribution of 3.5 L/kg. In blood, distribution depends on the concentration of the active substance: 33–47% of cyclosporine is found in plasma, 4–9% in lymphocytes, 5–12% in granulocytes, and 41–58% in erythrocytes. At high leukocyte and erythrocyte concentrations, uptake becomes saturated. Binding to plasma proteins (predominantly lipoproteins) reaches approximately 90%.

Metabolism

Cyclosporine is actively metabolized, primarily by the cytochrome P450 (CYP450 3A4)-dependent monooxygenase system. More than 15 metabolites have been identified to date. Metabolites are mainly formed via monohydroxylation, dihydroxylation, and N-demethylation at various molecular sites. It has been established that drugs affecting the cytochrome P450 (CYP450 3A4)-dependent enzyme system may increase or decrease cyclosporine levels. All metabolites identified so far retain the intact peptide structure of the parent drug. Some of these metabolites exhibit weak immunosuppressive activity (up to 10% of that of cyclosporine).

Excretion

Elimination half-life values of cyclosporine vary significantly depending on the study method and population. They range from 6.3 hours in healthy volunteers to 7–16 hours in kidney transplant patients, and 20.4 hours in patients with severe liver disease.

The drug is excreted predominantly via bile, and only 6% of the orally administered dose is excreted in urine (of which only 1% is excreted unchanged).

The terminal elimination half-life of cyclosporine is 19 hours, independent of dose and route of administration.

Elderly Patients

The distribution of cyclosporine in elderly patients does not differ from that in middle-aged patients.

Children

On average, cyclosporine elimination is slightly faster in children than in adults. Therefore, higher doses (relative to body weight) may be required to achieve the same blood concentrations.

Renal Impairment

Renal impairment does not have a clinically significant effect on pharmacokinetics, as cyclosporine is primarily excreted via bile.

Hepatic Impairment

Hepatic impairment slows the elimination of cyclosporine. Therefore, careful monitoring of serum creatinine and blood cyclosporine levels with appropriate dose adjustment is required in patients with severe liver dysfunction.

Clinical Characteristics.

Indications.

Transplantation of Solid Organs

• Prevention of rejection of transplanted kidneys, liver, heart, lungs, pancreatic allografts, as well as combined heart-lung transplantation.
• Treatment of transplant rejection in patients previously treated with other immunosuppressive agents.

Bone Marrow Transplantation

• Prevention of graft rejection and graft-versus-host disease (GVHD) following bone marrow transplantation.
• Treatment of established GVHD.

Contraindications.

Hypersensitivity to cyclosporine or any of the excipients of the medicinal product, including hypersensitivity to polyoxethylated castor oil.

Interactions with Other Medicinal Products and Other Forms of Interactions.

Interactions with Food

Concomitant intake of grapefruit juice has been reported to increase the bioavailability of cyclosporine.

Drug-Drug Interactions

Various drugs may increase or decrease cyclosporine plasma or blood concentrations by competitively inhibiting or inducing liver enzymes involved in cyclosporine metabolism, particularly cytochrome P450 isoenzymes CYP3A4. Cyclosporine is an inhibitor of CYP3A4 and also a potent inhibitor of P-glycoprotein for many drugs, which may increase plasma levels of concomitant medications that are substrates of this enzyme and/or transported by it.

Drugs that decrease cyclosporine concentrations: barbiturates, carbamazepine, oxcarbazepine, phenytoin, nafcillin, sulfadimidine when administered intravenously; rifampicin, octreotide; probucol; orlistat; St. John’s wort (Hypericum perforatum) preparations; ticlopidine, sulfinpyrazone, terbinafine, bosentan.

Drugs that increase cyclosporine concentrations: certain macrolide antibiotics (primarily erythromycin, azithromycin, and clarithromycin); ketoconazole, fluconazole, itraconazole; voriconazole; diltiazem, nicardipine, verapamil; metoclopramide; oral contraceptives; danazol; methylprednisolone (high doses); allopurinol; amiodarone; cholic acid and its derivatives; protease inhibitors: imatinib, colchicine, nefazodone.

Other Significant Interactions

Caution should be exercised when co-administering Sandimmun with drugs exhibiting nephrotoxic effects, such as aminoglycosides (gentamicin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim with sulfamethoxazole; nonsteroidal anti-inflammatory drugs (including diclofenac, indomethacin, naproxen, sulindac); melphalan, histamine H2-receptor antagonists (e.g., cimetidine, ranitidine); methotrexate, tacrolimus.

Concomitant use of nifedipine and cyclosporine may result in more pronounced gingival hyperplasia than with cyclosporine monotherapy.

Concomitant administration of cyclosporine and lercanidipine increases the AUC of lercanidipine by threefold and the AUC of cyclosporine by 21%. Caution should be exercised when co-administering cyclosporine and lercanidipine. Antihypertensive agents without pharmacokinetic interaction with cyclosporine should be preferred.

Concomitant administration of diclofenac and cyclosporine has been shown to significantly increase the bioavailability of diclofenac, potentially leading to reversible renal function impairment. The increased bioavailability is most likely due to reduced first-pass effect of diclofenac. Concomitant use of cyclosporine with nonsteroidal anti-inflammatory drugs having low first-pass effect (such as acetylsalicylic acid) is generally not associated with increased bioavailability.

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

Serious digitalis intoxication has been observed in patients receiving digoxin within several days after initiation of cyclosporine therapy. Cyclosporine may potentially enhance colchicine-related toxic effects such as myopathy and neuropathy, particularly in patients with impaired renal function. If digoxin or colchicine is co-administered with cyclosporine, careful clinical monitoring is required to enable early detection of digoxin or colchicine toxicity, followed by dose reduction or discontinuation if necessary.

Significant increases in exposure to anthracycline antibiotics (e.g., doxorubicin, mitoxantrone, daunorubicin) have been observed in oncology patients who received anthracyclines intravenously concomitantly with high-dose cyclosporine.

Cases of myotoxicity, including muscle pain and weakness, myositis, and rhabdomyolysis, have been reported during post-marketing surveillance and in the literature in patients receiving cyclosporine concomitantly with lovastatin, simvastatin, atorvastatin, pravastatin, and rarely fluvastatin. When co-administered with cyclosporine, the dose of these statins should be reduced according to prescribing information. Statin therapy may be temporarily discontinued or suspended in patients with symptoms of myopathy or in patients with risk factors for severe renal dysfunction, including secondary renal failure resulting from rhabdomyolysis.

Elevated serum creatinine has been observed in studies when everolimus or sirolimus was co-administered with full doses of cyclosporine in microemulsion form. This effect is often reversible upon reduction of cyclosporine dose. Everolimus and sirolimus have only minimal effects on the pharmacokinetics of cyclosporine. However, 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 preparations, as this may lead to a significant increase in serum potassium levels.

Cyclosporine may increase plasma levels of repaglinide, thereby increasing the risk of hypoglycemia.

Concomitant administration of bosentan and cyclosporine in healthy volunteers resulted in approximately a twofold increase in bosentan exposure and a 35% decrease in cyclosporine exposure.

Concomitant use of cyclosporine and aliskiren increases Cmax of aliskiren by 2.5 times and AUC by 5 times. In contrast, the pharmacokinetic profile of cyclosporine is not significantly altered.

Concomitant administration of dabigatran and cyclosporine increases dabigatran plasma concentrations due to inhibition of P-glycoprotein. Dabigatran has a narrow therapeutic index; therefore, increased plasma concentrations are associated with an elevated risk of bleeding.

Repeated concomitant administration of ambrisentan and cyclosporine in healthy volunteers led to approximately a twofold increase in ambrisentan exposure and a slight increase in cyclosporine exposure (approximately 10%).

Recommendations

If therapy is necessary despite potential interaction with cyclosporine, the following recommendations should be followed:

• When using drugs causing nephrotoxic synergy, renal parameters (serum creatinine level) should be closely monitored. In case of inadequate renal function, the dose of the co-administered drug should be promptly adjusted or discontinued, followed by initiation of alternative therapy;
  • isolated reports indicate reversible renal function impairment (with corresponding increases in serum creatinine levels) in transplant recipients after concomitant use of cyclosporine with fibric acid derivatives (e.g., bezafibrate, fenofibrate). Therefore, renal function should be carefully monitored in such patients. Combined therapy should be discontinued in case of significant renal impairment;
  • drugs that decrease or increase cyclosporine bioavailability: transplant recipients should undergo frequent monitoring of blood cyclosporine levels; dose adjustment may be necessary, particularly at the start of treatment and during discontinuation of the concomitant drug. When co-administering drugs known to increase cyclosporine blood levels, frequent monitoring of renal function and careful observation for adverse effects of cyclosporine may be more important than measuring cyclosporine blood levels;
  • concomitant use of nifedipine should be avoided in patients who develop gingival hyperplasia as a side effect of cyclosporine;
• nonsteroidal anti-inflammatory drugs with pronounced first-pass hepatic metabolism (e.g., diclofenac) should be administered at lower doses than in patients not receiving cyclosporine;
• when prescribing digoxin, colchicine, or HMG-CoA reductase inhibitors (statins) concomitantly with cyclosporine, clinical monitoring for toxic manifestations of these drugs is required, with appropriate dose reduction or discontinuation if such toxic effects occur.

Drug interactions are more frequently observed in elderly patients.

Special precautions for use.

Sandimmune may be administered only by physicians experienced in immunosuppressive therapy who are able to provide adequate patient monitoring, including regular comprehensive examinations, blood pressure measurements, and laboratory monitoring. Patients who have undergone transplantation and are receiving the drug should be monitored only in facilities staffed by specially trained medical personnel and equipped with appropriate laboratories and other necessary resources. The physician responsible for supportive therapy must be fully informed about patient management.

Regarding polyoxyethylated castor oil contained in Sandimmune, anaphylactoid reactions have been reported after intravenous administration, manifesting as facial and upper trunk flushing, non-cardiogenic pulmonary edema with acute respiratory distress syndrome, dyspnea and stridorous breathing, blood pressure fluctuations, and tachycardia. Patients predisposed to allergic reactions and those previously administered intravenous infusions or injections of products containing polyoxyethylated castor oil (e.g., products containing Cremophor® EL) should be closely monitored. Patients receiving Sandimmune concentrate for infusion solution must be under continuous observation during the first 30 minutes after initiation of infusion and throughout the entire infusion period. Infusion must be discontinued at the first signs of an anaphylactoid reaction. Appropriate resuscitation equipment must be readily available. An aqueous solution of epinephrine 1:1000 and an oxygen source should be kept at the patient's bedside.

Due to the risk of anaphylactic reactions, Sandimmune concentrate for infusion solution should be used only when oral administration is not feasible. Patients should be switched to oral Sandimmune Neoral® as soon as possible.

To prevent anaphylactoid reactions, antihistamines (H1- and H2-receptor blockers) may be administered prior to intravenous infusion of Sandimmune.

Like other immunosuppressants, cyclosporine increases the risk of developing lymphomas and other malignancies, particularly of the skin. The increased risk is more likely related to the degree and duration of immunosuppression than to the use of specific agents.

Therefore, treatment involving multiple immunosuppressive agents (including cyclosporine) should be used with caution, as it may lead to lymphoproliferative disorders and solid organ tumors, some of which have been reported as fatal.

Due to the potential risk of skin malignancies, patients receiving Sandimmune, particularly those treated for psoriasis or atopic dermatitis, should be warned about the dangers of excessive sun exposure without adequate protection and must not receive concurrent UVB or PUVA therapy.

As with other immunosuppressants, cyclosporine use predisposes patients to various bacterial, fungal, parasitic, and viral infections, often involving opportunistic pathogens.

In patients receiving cyclosporine, reactivation of latent polyomavirus infection has been observed, potentially leading to polyomavirus-associated nephropathy (PVAN), including BK virus-associated nephropathy (BKVN), or progressive multifocal leukoencephalopathy (PML) associated with JC virus. These conditions are often secondary to high levels of overall immunosuppression and should be considered in the differential diagnosis of immunosuppressed patients with worsening renal function or neurological symptoms. Serious, including fatal, outcomes have been reported. BK virus-associated nephropathy may lead to graft loss. Effective preventive and therapeutic strategies should be employed, especially in patients requiring repeated long-term immunosuppressive therapy. Immunosuppression reduction should be considered in patients with polyomavirus-associated nephropathy or JC virus-associated PML, although reducing immunosuppression may also jeopardize the transplant.

During the first few weeks of Sandimmune therapy, a frequent and potentially dangerous complication—elevated serum creatinine and urea levels—may occur. These functional changes are transient and dose-dependent, usually responding to dose reduction. With prolonged treatment, structural kidney changes (e.g., interstitial fibrosis) may develop in some patients, which in kidney transplant recipients should be differentiated from changes due to chronic rejection.

Sandimmune may cause dose-dependent, reversible increases in serum bilirubin levels and, rarely, liver enzymes. There are solicited and spontaneous reports of hepatotoxicity and liver injury, including cholestasis, jaundice, hepatitis, and hepatic failure, which may result in fatal outcomes in patients treated with cyclosporine. Most reports involved patients with concomitant diseases, underlying conditions, and predisposing factors, including infectious complications and concomitant use of hepatotoxic drugs. Fatal outcomes have occasionally been reported, particularly in post-transplant patients. Close monitoring of renal and hepatic function parameters is required. Dose reduction may be necessary if these parameters deviate from normal.

In kidney transplant recipients receiving Sandimmune therapy, perfusion duration exceeding 24 hours using an automated system and reanastomosis duration exceeding 45 minutes may significantly affect graft function. Both factors are likely to increase the incidence of acute tubular necrosis.

In elderly patients receiving Sandimmune therapy, renal function parameters should be closely monitored.

For monitoring cyclosporine levels in whole blood, specific monoclonal antibodies are preferred (measuring unchanged drug concentration). High-performance liquid chromatography (HPLC) may also be used, which similarly measures unchanged drug concentration. If plasma or serum is used, standard separation techniques (time and temperature) must be followed. For initial cyclosporine concentration monitoring in liver transplant patients, either specific monoclonal antibodies or parallel determinations using specific and non-specific monoclonal antibodies may be used to achieve a dose ensuring adequate immunosuppression.

It should also be remembered that cyclosporine concentration in blood, plasma, or serum is only one of many factors influencing the patient's clinical condition. Therefore, results should be interpreted only as guidance for treatment decisions within the context of various other clinical and laboratory parameters.

During cyclosporine therapy, blood pressure should be regularly monitored, and appropriate antihypertensive therapy should be initiated if elevated. Antihypertensive agents without pharmacokinetic interaction with cyclosporine should be preferred.

In isolated cases, Sandimmune may slightly and reversibly increase serum lipid parameters; therefore, lipid levels should be measured before treatment initiation and one month after starting therapy. If lipid levels increase, a low-fat diet and cyclosporine dose reduction should be considered.

Cyclosporine increases the risk of hyperkalemia, especially in patients with renal dysfunction. Cyclosporine should also be used cautiously in combination with potassium-sparing agents (particularly potassium-sparing diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists) or potassium-containing preparations, or if patients are on a potassium-rich diet. In such cases, potassium level monitoring is recommended.

Cyclosporine increases magnesium clearance, potentially leading to symptomatic hypomagnesemia, especially in the peri-transplant period. Monitoring of serum magnesium levels is recommended during the peri-transplant period in relation to neurological symptoms. Magnesium supplementation should be administered if necessary.

Caution is required when treating patients with hyperuricemia.

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

Caution is required when co-administering lercanidipine and cyclosporine.

Cyclosporine may increase blood levels of concurrently administered drugs that are substrates of P-glycoprotein (Pgp) or organic anion transporting polypeptide, such as aliskiren, dabigatran, and bosentan. Concomitant use of cyclosporine with aliskiren, dabigatran, or bosentan should be avoided.

Cyclosporine use may increase the risk of benign intracranial hypertension. Patients with signs of increased intracranial pressure should be evaluated, and if benign intracranial hypertension is diagnosed, cyclosporine should be discontinued due to the risk of permanent vision loss.

Sandimmune concentrate for infusion solution contains 34.4% ethanol. A 100 mg dose of Sandimmune concentrate contains 556 mg of ethanol, equivalent to approximately 15 mL of beer or 5 mL of wine. This may be harmful to patients with alcoholism and should also be considered when prescribing the drug to pregnant women or breastfeeding women, patients with liver disease or epilepsy, or pediatric patients.

Use during pregnancy or breastfeeding.

Animal studies have demonstrated reproductive toxicity in rats and rabbits.

Clinical experience with Sandimmune use in pregnant women is currently limited. Pregnant women receiving immunosuppressive therapy after transplantation with cyclosporine or cyclosporine-containing products should be monitored by specialists due to an increased risk of preterm delivery (< 37 weeks).

A limited number of observations have been conducted on children up to approximately 7 years of age exposed to cyclosporine.

Since adequate and well-controlled studies in pregnant women have not been conducted, Sandimmune should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Cyclosporine is excreted in breast milk. Sandimmune may cause serious adverse effects in breastfed infants; therefore, women taking Sandimmune should not breastfeed.

Ability to affect reaction speed when driving or operating machinery.

The effect of the drug on the ability to drive vehicles or operate machinery is unknown.

Method of Administration and Dosage.

The dosage ranges indicated for oral administration should be considered only as recommended guidelines.

The recommended dose is 3 to 5 mg/kg, which corresponds approximately to one-third of the oral dose. Regular monitoring of cyclosporine blood levels using a radioimmunoassay with monoclonal antibodies is required. The results obtained should guide dose adjustments to achieve target concentrations.

Intravenous administration of the drug.

Sandimmun, concentrate for solution for infusion, must be diluted before use in a ratio of 1:20 to 1:100 with physiological saline or 5% glucose solution and administered intravenously slowly over 2 to 6 hours. Any unused prepared solution must be discarded after 24 hours.

Organ transplantation.

When Sandimmun is used in combination with other immunosuppressive agents (e.g., corticosteroids or as part of triple or quadruple drug therapy), lower doses of the drug may be used (e.g., 1–2 mg/kg/day intravenously, followed by 3–6 mg/kg/day orally as initial therapy). However, it is recommended that patients switch to oral therapy as soon as clinical circumstances permit.

Bone marrow transplantation / prevention and treatment of graft-versus-host reaction (GVHR).

The recommended dose for intravenous administration is 3–5 mg/kg/day, starting one day before transplantation, followed by continued administration during the early post-transplant period for up to two weeks until initiation of oral maintenance therapy at a dose of 12.5 mg/kg/day.

In some cases, due to gastrointestinal disorders that may reduce drug absorption, patients may require intravenous administration of the drug.

In some cases, graft-versus-host reaction (GVHR) may develop after discontinuation of Sandimmun, which typically resolves upon re-administration of the drug.

Use in children.

Experience with the use of cyclosporine in children is limited. Studies involving children aged 1 year and older have been conducted. No unusual complications have been reported in children aged 1 year and older receiving standard doses of Sandimmun. In several studies, pediatric patients required and tolerated higher doses of cyclosporine per unit of body weight than those used in adults. Patients with severe hepatic disorders require careful monitoring of plasma creatinine levels and, if possible, cyclosporine blood levels, with dose adjustments as needed.

Elderly patients.

In clinical trials of cyclosporine use in rheumatoid arthritis, patients aged 65 years and older comprised 17.5% of the study population. After three to four months of therapy, these patients were more prone to develop systolic hypertension and showed serum creatinine levels exceeding baseline values by 50% or more.

Clinical trials of Sandimmun in post-transplant patients and patients with psoriasis did not include a sufficient number of individuals aged 65 years and older to allow conclusions regarding differences in response compared to younger patients. In general, dose selection for elderly patients should be cautious, taking into account the higher prevalence of impaired hepatic, renal, or cardiac function, concomitant diseases, and concomitant medications, which may increase susceptibility to infections. Therapy should generally be initiated with a dose at the lower end of the dosage range.

Children. Experience with the use of the drug in children is limited. Studies involving children aged 1 year and older have been conducted.

Overdose.

Symptoms. Data on acute cyclosporine overdose are limited. Clinical consequences of oral cyclosporine administration at doses up to 10 g (approximately 150 mg/kg) are relatively mild: for example, vomiting, drowsiness, headache, tachycardia, and in some patients, moderate renal dysfunction, which was reversible. However, serious symptoms of intoxication have been reported following accidental parenteral overdose of cyclosporine in premature infants.

Treatment. As indicated, general supportive measures and symptomatic treatment should be implemented. Induction of vomiting and gastric lavage may be beneficial within the first few hours after oral ingestion. Cyclosporine is practically not eliminated by hemodialysis or charcoal hemoperfusion.

Adverse reactions.

Many adverse effects associated with the use of cyclosporine are dose-dependent and vary according to dosage. The spectrum of adverse effects is generally similar across different indications for use.

Anaphylactoid reactions may occur with intravenous administration of the drug.

Infections and infestations

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

Benign and malignant neoplasms and neoplasms of uncertain origin (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 malignant neoplasms, particularly of the skin. The incidence of malignant neoplasms increases with increasing intensity and duration of therapy. Some malignant tumors may be fatal.

Adverse reactions, listed starting with the most common, are classified by frequency: 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.

Blood and lymphatic system disorders:

Common – leukopenia;
Uncommon – anemia, thrombocytopenia;
Rare – microangiopathic hemolytic anemia, hemolytic uremic syndrome, thrombotic microangiopathy, thrombotic thrombocytopenic purpura.

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, mental slowing, agitation, insomnia, visual disturbances, cortical blindness, coma, paresis, ataxia;
Rare – motor polyneuropathy;
Very rare – optic disc edema with possible visual loss due to benign intracranial hypertension.

Cardiac and vascular disorders:

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

Gastrointestinal disorders:

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

Hepatobiliary disorders:

Common – liver function abnormalities.

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 impairment.

Reproductive system and breast disorders:

Rare – menstrual disorders, gynecomastia.

General disorders and administration site conditions:

Common – fatigue, pyrexia, edema;
Uncommon – weight increase.

Other adverse reactions reported during post-marketing use:

Cases of hepatotoxicity and liver injury, including cholestasis, jaundice, hepatitis, and hepatic failure, have been reported in patients receiving cyclosporine. In most cases, reports involved patients with significant underlying conditions, including pathological states and other concomitant factors such as infectious complications and concomitant use of drugs with hepatotoxic potential. Fatal outcomes have occasionally been reported, primarily in post-transplant patients.

Shelf life. 4 years.

Storage conditions.

Store in a place inaccessible to children, at a temperature not exceeding 30 °C.

Incompatibilities.

Sandimmun, concentrate for solution for infusion, contains polyoxylated castor oil, which may cause desorption of phthalates upon contact with PVC. Therefore, glass containers are recommended for infusion solutions whenever possible. Plastic bottles should only be used if they meet the requirements for "Sterile plastic containers intended for storage of human blood and blood components." If polyvinyl chloride bags are used for infusion solutions, they must comply with the requirements for "Empty sterile poly(vinyl chloride) containers intended for storage of human blood and blood components" as defined in the European Pharmacopoeia. Containers and stoppers must not contain silicone oil or fatty substances.

Packaging. 1 ml in a vial, 10 vials in a cardboard box.

Prescription category. Prescription only.

Manufacturer.

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

Manufacturer's address and location of business operations.

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