Ecoral, 100 mg/ml 50 ml

Pharmacotherapeutic group

Immunosuppressive agent

Pharmacodynamics:

Ecoral® (cyclosporine A) is a cyclic polypeptide consisting of 11 amino acids and is a powerful immunosuppressive agent.

At the cellular level, cyclosporine inhibits the formation and release of lymphokines including interleukin-2 (T-lymphocyte growth factor). Cyclosporine blocks resting lymphocytes in the G0 or G1 phase of the cell cycle and inhibits antigen-dependent release of lymphokines by activated T lymphocytes. All these data indicate that cyclosporine acts on lymphocytes specifically and reversibly.

Cyclosporine does not inhibit hematopoiesis and does not affect the function of phagocytic cells.

Pharmacokinetics:

After oral administration of cyclosporine, its maximum concentration in the blood is observed between 1 and 6 hours, with bioavailability averaging 30% (20 to 50%) and increasing with increasing dose and duration of treatment. Absorption decreases after liver transplantation in liver disease or gastrointestinal pathology (diarrhea vomiting ileus).

It is intensively bound to proteins and blood cells (concentration in whole blood is 2-9 times higher than in plasma). Protein binding is 90% (mainly with lipoproteins). It is distributed mainly outside the bloodstream; it is present in plasma – 33-47%; lymphocytes – 4-9% in granulocytes – 5-12% in erythrocytes – 41-58%. Time of reaching maximum concentration (TSmax) in plasma is 15-35 hours after oral administration. Metabolized by the liver by P450 3A enzyme and to a lesser extent by the gastrointestinal system by the kidneys. Excreted with the bile; by the kidneys – 6% of the administered oral dose. Excreted with breast milk. Cyclosporine is extensively metabolized to form 15 identified metabolites.

The T½ (half-life) is 19 hours in adults and 7 hours in children regardless of dose or route of administration.

Indications

Transplantation

Solid organ transplantation: prevention of graft rejection after allogeneic kidney liver heart lung pancreatic transplantation of the heart-lung complex. Treatment of transplant rejection in patients previously treated with other immunosuppressive agents.

Bone marrow transplantation: prevention of graft rejection after bone marrow transplantation; prevention and treatment of graft vs. host reaction (GVHD).

Non-transplant indications

Endogenous uveitis (active vision-threatening uveitis of middle and posterior regions of the eye of non-infectious etiology if conventional therapy fails or leads to severe adverse reactions); Behcet’s uveitis (with recurrent bouts of inflammation affecting the retina).

Nephrotic syndrome: Steroid-dependent and steroid-resistant nephrotic syndrome due to glomerular pathology such as minimal change nephropathy focal and segmental glomerulosclerosis or membranous glomerulonephritis (to achieve and maintain remission and to support glucocorticosteroid-induced remission to allow reversal of glucocorticosteroid therapy).

Rheumatoid arthritis: severe forms of highly active rheumatoid arthritis when traditionally slow-acting antirheumatic drugs are ineffective or impossible to use.

Psoriasis: severe forms of psoriasis when traditional therapy is ineffective or impossible.

Atopic dermatitis: severe forms of atopic dermatitis when conventional therapy is ineffective or impossible.

Active ingredient

Composition

One ml of 10% solution contains:

Active ingredient: Cyclosporine 100 mg;

Excipients: Ethyl alcohol 120 mg, Polyglyceryl (3) oleate 310 mg, Polyglyceryl (10) oleate 190 mg, Macrogol glyceryl hydroxystearate 280 mg.

How to take, the dosage

The daily dose of Ecoral® should be divided into 2 doses. The following dose ranges for oral administration of Ecoral® should only be considered as recommendations. Routine monitoring of cyclosporine blood concentrations should be performed. Based on the results, determine the dose required to achieve the desired level of cyclosporine concentration in different patients. Capsules of the drug Ekoral® should be taken with water and swallowed whole.

Because of a possible interaction with the P450-dependent enzyme system, grapefruit or grapefruit juice should not be consumed one hour before taking a dose of the drug.

Transplantation

In case of transplantation of solid organs the treatment by Ekoral® should be started 12 hours before the surgery in dose of 10-15 mg/kg divided into two doses. During 1-2 weeks after the operation the drug is prescribed daily in the same dose after which the dose is gradually reduced under control of cyclosporine blood concentrations up to a maintenance dose of 2-6 mg/kg/day (in 2 doses).

. When the drug Ekoral® is prescribed in combination with glucocorticosteroids and also as part of tricomponent or quadruple therapy the dose of the drug can be decreased even in initial therapy (3-6 mg/kg/day in 2 doses) or corrected during treatment with regard to cyclosporine blood concentration and changes in safety parameters (serum creatinine urea concentration and blood pressure).

In case of bone marrow transplantation, the initial dose should be administered one day before surgery. The daily dose of the drug Ekoral® should be 125 mg/kg divided into 2 doses. Maintenance therapy is carried out for at least 3 months (6 months is preferable) after which the dose of cyclosporine is gradually reduced to zero for 1 year.

Non-transplant indications

In endogenous uveitis to achieve remission, the drug is prescribed at an initial daily dose of 5 mg/kg orally in 2 doses until the signs of active inflammation disappear and visual acuity improves. In cases of difficult to treat the dose may be increased to 7 mg/kg/day for a short period.

If it is not possible to control the situation by Ekoral® monotherapy then in order to achieve initial remission or to stop inflammatory attack systemic glucocorticosteroids in daily dose of 02- 06 mg/kg of prednisolone (or other glucocorticosteroid medicine in equivalent dose) can be added in combination therapy.

In maintenance therapy, the dose should be slowly reduced until the lowest effective dose is achieved, which should not exceed 5 mg/kg/day during remission of the disease.

In nephrotic syndrome to achieve remission, the recommended daily dose is 5 mg/kg for adults and 6 mg/kg for children (in 2 doses) with normal renal function. In patients with impaired renal function, the initial dose should not exceed 25 mg/kg/day.

If a satisfactory effect cannot be achieved with Ekoral® alone, especially in steroid resistant patients, it is recommended to combine it with low doses of oral glucocorticoids. If after 3 months of treatment no improvement has been achieved Ekoral® should be discontinued.

In rheumatoid arthritis during the first 6 weeks of treatment the recommended dose is 3 mg/kg/day in 2 intakes. In case of insufficient effect, the daily dose may be gradually increased if tolerability allows, but should not exceed 5 mg/kg. It may take 12 weeks of treatment with Ekoral® to achieve full efficacy.

For maintenance therapy, the dose should be adjusted individually depending on tolerance to the drug.

Ecoral® may be prescribed in combination with low doses of glucocorticoids and/or NSAIDs (non-steroidal anti-inflammatory drugs). Ecoral® can also be combined with a weekly course of low-dose methotrexate in patients with an unsatisfactory response to methotrexate monotherapy. The starting dose of Ecoral® is 25 mg/kg/day (in 2 doses) and the dose may be increased to a tolerance limit.

In psoriasis, because of the variability of this disease, treatment must be tailored individually. For induction of remission, the recommended starting dose is 25 mg/kg/day in 2 doses. If there is no improvement after 1 month of therapy, the daily dose may be gradually increased, but should not exceed 5 mg/kg. Treatment should be discontinued if satisfactory response of psoriasis manifestations has not been achieved after 6 weeks of treatment with a dose of 5 mg/kg/day or if the effective dose meets the established safety parameters.

The initial dose of 5 mg/kg/day is justified in patients whose condition requires urgent improvement. If a satisfactory response is achieved, Eko-ral® may be discontinued and subsequent relapse treated with a second administration of the drug at the previous effective dose. Some patients may require long-term maintenance therapy.

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

In atopic dermatitis, because of the variability of this condition, treatment must be tailored individually. The recommended starting dose range is 25-5 mg/kg/day in 2 doses. If the initial dose of 25 mg/kg/day does not allow achieving a satisfactory response within 2 weeks, the daily dose can be quickly increased to a maximum of 5 mg/kg. In very severe cases, rapid and adequate control of the disease can be achieved by initially using a dose of 5 mg/kg/day. When a satisfactory response is achieved, the dose should be gradually reduced and, if possible, the drug should be withdrawn. If a relapse occurs, a second course may be given.

While a treatment course of 8 weeks may be sufficient to clear the skin it has been shown that therapy of up to 1 year is effective and well tolerated with monitoring of all relevant parameters.

Interaction

The following are drugs for which interactions with cyclosporine have been confirmed and are clinically significant.

The various drugs can increase or decrease concentrations of cyclosporine in plasma or whole blood usually through inhibition or induction of enzymes involved in cyclosporine metabolism in particular the CYP3A4 isoenzyme of the cytochrome P450 system. Since cyclosporine is an inhibitor of CYP3A4 isoenzyme and membrane messenger of P-glycoprotein molecules, concomitant use of cyclosporine may increase concentration of drugs being substrates of CYP3A4 isoenzyme and/or membrane messenger of P-glycoprotein.

Drugs decreasing concentrations of cyclosporine in plasma due to inhibition of CYP3A4 isoenzyme

Carbamazepine oxcarbazepine phenytoin nafcillin sulfadimidine for intravenous administration rifampicin octreotide probucol orlistat preparations containing Hypericum perforatum ticlopidine sulfinpyrazone terbinafine bozentan.

Drugs that increase the concentration of cyclosporine in blood plasma by inhibiting the CYP3A4 isoenzyme

Macrolide antibiotics (mainly erythromycin azithromycin and clarithromycin) ketoconazole fluconazole itraconazole voriconazole diltiazem nicardipine verapamil metoclopramide oral contraceptives danazol methylprednisolone (high dose) allopurinol amiodarone cholic acid and its derivatives HIV protease inhibitors imatinib colchicine nefazodone.

Other drug interactions

Caution should be exercised when using concomitantly with drugs that increase the risk of nephrotoxic effects, including aminoglycosides (gentamicin tobramycin) amphotericin B ciprofloxacin vancomycin trimethoprim (+ sulfamethoxazole) nonsteroidal anti-inflammatory drugs (NSAIDs) (diclofenac naproxen sulindac) melphalan H2- histamine receptor blockers (cimetidine ranitidine) methotrexate.

The concomitant use with tacrolimus should be avoided due to increased risk of nephrotoxicity.

In case of concomitant use with drugs with nephrotoxic effect the renal function parameters should be monitored carefully (in particular, serum creatinine concentration should be determined regularly). If marked renal dysfunction is detected, the dose of this drug should be reduced or the possibility of alternative treatment should be considered.

There have been isolated reports of significant but reversible impairment of renal function (with a corresponding increase in creatinine concentrations) in transplant patients when cyclosporine is used simultaneously with fibric acid derivatives (e.g., bezafibrate fenofibrate). Therefore, renal function should be monitored in this category of patients. In case of marked renal dysfunction, concomitant use of the above mentioned drugs should be discontinued.

The concomitant use with nifedipine may lead to more severe gingival hyperplasia than with cyclosporine monotherapy. In patients with gingival hyperplasia on cyclosporine therapy, concomitant use of nifedipine should be avoided.

In concomitant use with lercanidipine there is a 3-fold increase in the area under the curve “concentration-time” (AUC) of lercanidipine and 21% increase in the AUC of cyclosporine. Caution should be exercised when concomitant use with lercanidipine.

Cyclosporine is a highly active inhibitor of P-glycoprotein and can increase plasma concentrations of drugs that are substrates of glycoprotein such as aliskiren. After concomitant use of cyclosporine and aliskiren, the maximum concentration of aliskiren increases by a factor of approximately 25 and the AUC by a factor of 5. The pharmacokinetic profile of cyclosporine does not change significantly. It was found that concomitant use with diclofenac can significantly increase bioavailability of diclofenac with possible development of reversible renal dysfunction. Increased bioavailability of diclofenac is most likely due to a decrease in its metabolism during “first passage” through the liver. When concomitant use with NSAIDs with less pronounced “first pass” effect (e.g. acetylsalicylic acid), no increase in their bioavailability is expected. NSAIDs with a pronounced “first pass” effect through the liver (including diclofenac) should be used in lower doses than in patients not receiving cyclosporine.

Cyclosporine may decrease clearance of digoxin colchicine prednisolone HMG-CoA reductase inhibitors (statins) and etoposide. Several cases of severe glycoside intoxication have been reported within a few days after initiation of cyclosporine treatment in patients receiving digoxin. There are also reports that cyclosporine may increase the toxic effects of colchicine, including the development of myopathy or neuropathy especially in patients with impaired renal function. When concomitant use of cyclosporine with digoxin or colchicine, careful clinical monitoring is necessary to identify the toxic effects of these drugs in a timely manner and to decide whether to reduce the dose or cancel treatment.

The literature describes cases of muscle toxicity including muscle pain weakness myositis and rhabdomyolysis with concomitant use of cyclosporine with lovastatin simvastatin atorvastatin pravastatin and in rare cases with fluvastatin that were observed in the postmarketing period. If it is necessary to use the above drugs simultaneously with cyclosporine, their dose should be reduced. Statin therapy should be temporarily discontinued or withdrawn altogether in patients with symptoms of myopathy and in patients with predisposition factors for severe renal dysfunction including renal failure secondary to rhabdomyolysis.

An increase in creatinine concentrations has been observed in clinical trials in which concomitant use of everolimus or sirolimus with high doses of cyclosporine in the form of a microemulsion has been studied. This effect is often reversible after reducing the dose of cyclosporine. Everolimus and sirolimus have little effect on the pharmacokinetic parameters of cyclosporine. Concomitant use of cyclosporine with everolimus or sirolimus leads to a significant increase in plasma concentrations of the latter. Caution should be exercised when using cyclosporine together with potassium-saving drugs (potassium-saving diuretics angiotensin converting enzyme (ACE) inhibitors angiotensin II receptor antagonists) or potassium drugs to prevent the possible development of severe hyperkalemia. Cyclosporine may increase the concentration of repaglinide and increase the risk of hypoglycemia.

In transplant patients with concomitant use of drugs that decrease or increase bioavailability of cyclosporine, cyclosporine concentrations should be determined regularly and, if necessary, cyclosporine doses should be adjusted especially at the initial stage of combined treatment or during withdrawal.

In patients without a transplant, monitoring of cyclosporine concentrations is not as significant because for these patients the relationship between plasma concentrations and clinical effects has not been proven with complete certainty. When concomitant use of cyclosporine and drugs that increase its concentration, frequent monitoring of renal function and monitoring of cyclosporine side effects is more important than determination of plasma cyclosporine concentration.

Food interactions

The use of cyclosporine against the use of grapefruit juice and fatty foods may be accompanied by an increase in its bioavailability.

Vaccination should not be performed during treatment with cyclosporine because the effectiveness of live attenuated vaccines may be reduced.

Special Instructions

Ecoral® should only be used by a physician experienced in immunosuppressive therapy and able to arrange for appropriate monitoring of the patient, including regular complete physical examination, blood pressure measurement and serum creatinine monitoring. Follow-up of transplant patients receiving the drug should only be performed in facilities that have trained medical personnel and adequate laboratory resources.

Please note that cyclosporine, like other immunosuppressive medications, increases the risk of lymphoma and other malignancies, particularly in the skin. The increased risk of these complications depends more on the degree and duration of immunosuppression than on the specific drug. Thus, caution should be exercised when using combined immunosuppressive regimens, keeping in mind the possibility of lymphoproliferative disease and solid malignancies, sometimes leading to death.

In view of the potential risk of malignancies of the skin, patients receiving cyclosporine treatment should avoid excessive exposure to direct sunlight exposure to ultraviolet radiation (UVB) PUVA therapy (photochemotherapy).

The use of cyclosporine as well as other immunosuppressive drugs predisposes to the development of various bacterial fungal parasitic and viral infections and often with the participation of conditionally pathogenic pathogens. Reactivation of polyomavirus from a latent state can lead to the development of PVAN or PMLEP. These conditions are often associated with a high degree of immunosuppression and should be considered in the differential diagnosis of the causes of renal and nervous system dysfunction in patients receiving immunosuppressive therapy. Given the potential life-threatening danger of these infections, an effective system of prophylactic and therapeutic measures should be used, especially in cases of long-term use of combined immunosuppressive therapy.

In the first few weeks of the therapy by Ekoral® a frequent and potentially dangerous complication – increase of serum creatinine and urea concentration may occur. These functional changes are reversible and dose-dependent and usually normalize with dose lowering. During long-term treatment some patients may develop structural changes in kidneys (e.g. interstitial fibrosis) that in patients with renal transplants should be differentiated with changes in chronic rejection. Ekoral® may also cause a dose-dependent reversible increase in bilirubin concentrations and rarely an increase in hepatic transaminases. During clinical practice, there were reports about cyclosporine hepatotoxicity, which manifested as cholestasis hepatic jaundice and hepatic failure. In most cases, the condition of patients was aggravated by comorbidities and other aggravating factors (infectious complications and simultaneous use of drugs with hepatotoxic effect). In these cases, close monitoring of renal and liver function parameters is required. In the case of deviations of these parameters from the norm it may be necessary to reduce the dose of cyclosporine.

In elderly patients renal function should be monitored particularly closely.

When using Ekoral® in patients after transplantation, plasma cyclosporine concentrations should be determined.

The use of specific monoclonal antibodies (measurement of the amount of unchanged drug) is preferable for monitoring cyclosporine concentrations in blood. High performance liquid chromatography can also be used to measure the concentration of unchanged substance. If plasma or serum is used, standard separation techniques (time and temperature) must be followed. Specific monoclonal antibodies should be used for the initial determination of cyclosporine concentrations in patients with liver transplants. Parallel determinations using specific and non-specific monoclonal antibodies may also be performed to achieve a dose that provides adequate immunosuppression.

Please remember that cyclosporine concentrations in plasma or serum are only one of many factors that characterize a patient’s clinical condition. Cyclosporine results are only one factor in determining the dosing regimen and are considered in conjunction with various clinical and laboratory parameters.

In the course of treatment with Ekoral® it is necessary to monitor BP regularly. In case of BP increase adequate hypotensive therapy should be used. Preference should be given to such hypotensive drugs which do not influence pharmacokinetics of cyclosporine.

Since in rare cases the preparation Ekoral® causes slight reversible hyperlipidemia it is recommended to determine plasma lipid concentration before the treatment and in a month after the beginning of therapy. In case of increased lipid concentration, the question about restriction of fat intake with food and, if necessary, about reduction of the dose of Ekoral® preparation should be considered. The use of Ecoral® may increase the risk of hyperkalemia especially in patients with impaired renal function. Caution should be also observed when concomitant use of cyclosporine with potassium-saving diuretics, ACE angiotensin II receptor antagonists and potassium-containing drugs as well as in cases of using potassium-enriched diet. In these cases, monitoring of plasma potassium concentration is recommended.

Cyclosporine increases magnesium excretion that may lead to clinically significant hypomagnesemia especially in the peritransplant period. Therefore, in the peritransplantation period it is recommended to monitor plasma magnesium concentrations especially if neurological symptoms occur. Magnesium preparations are used if necessary. Monitoring of serum uric acid concentrations is recommended, especially in patients with previous hyperuricemia.

In order to prevent anaphylactoid reactions the administration of antihistamine drugs (H1-histamine receptor blocker) may be used before the use of Eko-ral®.

Additional precautions for non-transplant indications

Cyclosporine should not be used in patients with impaired renal function (except for patients with nephrotic syndrome and acceptable degrees of these impairments) uncontrolled arterial hypertension infectious diseases not adequately treated malignant neoplasms.

Because Ekoral® preparation can cause renal dysfunction it is necessary to determine reliable initial concentration of creatinine in serum in at least 2 measurements before the treatment. Creatinine concentration should be controlled at 2-week intervals during the first 3 months of the therapy and monthly thereafter. After 6 months of therapy creatinine concentration should be determined every 4-8 weeks depending on stability of basic disease and concomitant therapy. More frequent monitoring is necessary when the dose of Ecoral® medicine is increased during concomitant therapy with NSAIDs or increasing of their dose. Additional precautions for endogenous uveitis

If creatinine concentration in serum remains elevated more than 30% compared to the initial concentration (before treatment with Ekoral®) in more than one measurement, it is necessary to decrease the dose by 25-50%. These recommendations should be followed even if the creatinine concentration continues to be within the laboratory normal range.

The experience with the use of Ecoral® in children for endogenous uveitis is limited.

Additional precautions in nephrotic syndrome

If creatinine concentration remains elevated more than 30% compared to the baseline concentration (before starting treatment with Ecoral®) in more than one measurement then a dose reduction of 25 to 50% is required. In patients with baseline impaired renal function the initial dose should be 25 mg/kg/day. Careful monitoring of these patients should be ensured.

Because of changes in renal function due to nephrotic syndrome in some patients it may be difficult to detect renal dysfunction caused by immunosuppressive medications. This explains the fact that in some cases immunosuppressive medication-related structural changes in the kidneys have not been accompanied by an increase in creatinine concentrations. Kidney biopsy is indicated in patients with steroid-dependent nephropathy of minimal change who have received maintenance therapy with Ekoral® for more than 1 year. In rare cases, patients with nephrotic syndrome treated with immunosuppressive drugs have shown the occurrence of malignancies, including Hodgkin’s lymphoma.

Additional precautions in rheumatoid arthritis

If creatinine concentrations remain elevated more than 30% of baseline and in more than one dimension, the dose should be reduced. If the creatinine concentration increases by more than 50% then the dose should be reduced by 50%. These recommendations should be followed even if the creatinine concentration continues to be within laboratory limits. If the dose lowering does not lead to creatinine concentration decreasing within 1 month Ecoral® treatment should be stopped.

Discontinuation of treatment is also necessary if uncontrolled arterial hypertension occurs during treatment with Ecoral®.

As with other long-term immunosuppressive treatments, the increased risk of lymphoproliferative disorders should be kept in mind. Particular caution should be exercised when using Ecoral® in combination with methotrexate.

Additional precautions in psoriasis

If creatinine concentration increases and remains elevated by more than 30% of the baseline values and in more than one measurement, the dose should be reduced by 25 to 50%. These recommendations should be followed even if creatinine concentrations continue to be within laboratory normal limits. If the dose lowering does not lead to creatinine concentration decrease within 1 month Ecoral® treatment should be discontinued.

Discontinuation of treatment is also necessary if uncontrolled arterial hypertension occurs during the treatment with Ekoral®.

The use of Ecoral® in elderly patients is possible only in cases of disabling psoriasis and close monitoring of renal function is necessary.

The experience of using Ecoral® in children in psoriasis is limited.

It is known that psoriasis patients treated with cyclosporine as well as other common immunosuppressive therapies may develop malignancies, particularly in skin. In case of skin lesions not typical for psoriasis and in case of suspicion of malignant or pre-cancerous disease, a biopsy should be performed before starting treatment with Ekoral®. Treatment with Ecoral® in patients with malignant or precancerous lesions is possible only after appropriate treatment of these diseases and in absence of alternative effective therapy. Patients with psoriasis who were treated with cyclosporine may develop lymphoproliferative diseases. In these cases, the drug should be discontinued immediately. Patients treated with Ecoral® should not simultaneously receive UVB or PUVA therapy.

Additional precautions for atopic dermatitis

If creatinine concentration increases and remains elevated by more than 30% of baseline values in more than one measurement, the dose should be reduced by 25 to 50%. These recommendations should be followed even if creatinine concentrations continue to be within normal laboratory limits. If the dose reduction does not lead to creatinine reduction within one month, treatment with Ecoral® should be discontinued.

Discontinuation of treatment is also necessary if uncontrolled arterial hypertension occurs during treatment with Ecoral®.

Because there is still limited experience with the use of Ecoral® in children with atopic dermatitis, its use in this patient population is not recommended.

The use of Ecoral® in elderly patients is possible only in cases of disabling disease course and close monitoring of renal function is necessary.

Benign lymphadenopathy is usually associated with sudden exacerbations of atopic dermatitis. It either disappears on its own or with a general improvement in the course of the disease. Lymphadenopathy resulting from cyclosporine treatment should be monitored regularly.

Lymphadenopathy persisting despite decreased disease activity should be biopsied to rule out lymphoma.

Cases of herpes simplex in the acute period should be treated before initiating treatment with Ecoral® but recurrence of herpes simplex is not a reason to withdraw the drug if treatment has already started except in severe cases.

Skin infectious diseases caused by Staphylococcus aureus are not an absolute contraindication for the therapy with Ekoral® but should be controlled using appropriate antibacterial drugs.

Because of the potential risk of skin malignancies during treatment with Ecoral® patients should be warned to avoid direct exposure to sunlight and UVB radiation or PUVA therapy.

Perform caution when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and quick psychomotor reactions due to possible adverse reactions to the nervous system, such as confusion, disorientation, and slowing of vision.

Contraindications

Side effects

Many side effects associated with the use of cyclosporine are dose-dependent and reversible with dose reduction. The spectrum of side effects is generally similar for different indications; however, the frequency and severity of side effects may vary. In post-transplant patients, due to higher doses and longer duration of treatment, side effects are more common and usually more severe than in patients taking cyclosporine for non-transplant indications.

In patients receiving immunosuppressive treatment with cyclosporine or combined therapy including cyclosporine there is an increased risk of local and generalized infections (viral bacterial and fungal etiology) and parasitic infestations. There may also be exacerbation of pre-existing infectious diseases and reactivation of polyomavirus infection leading to the development of polyomavirus-associated nephropathy (PVAN) (especially associated with VC) or progressive multifocal leukoencephalopathy (PMLEP) (associated with JC virus). The development of severe infectious disease has been reported in some cases with a fatal outcome.

In patients receiving immunosuppressive treatment with cyclosporine or combined therapy including cyclosporine, the risk of lymphoproliferative diseases and solid malignancies, especially of the skin, increases. The incidence of malignancies increases with increasing intensity and duration of immunosuppressive therapy.

The incidence of side effects is classified according to the recommendations of the World Health Organization: very common – at least 10%; common – at least 1% but less than 10%; infrequent – at least 01% but less than 1%; rare – at least 001% but less than 01%; very rare – 001% including individual reports.

Infections: frequent – upper respiratory tract infection lower respiratory tract infection including bronchiolitis urinary tract infection cytomegalovirus infection; infrequent – sepsis herpes infection candida infection.

New growths: rare – skin papilloma basalioma squamous cell skin cancer Bowen’s disease lymphoproliferative diseases including lymphoma; very rare – seborrheic keratosis melanoma.

Blood and lymphatic system disorders: infrequent anemia thrombocytopenia; rarely – microangiopathic anemia hemolytic-uremic syndrome.

Nervous system disorders: very common – tremor headache including migraine; common – paresthesias; infrequent – encephalopathy seizures confusion disorientation lethargy psychomotor agitation sleep disturbance cortical blindness coma paresis cerebellar ataxia; rare – motor polyneuropathy; very rare – optic disc edema including optic nipple edema secondary to benign intracranial hypertension.

Cardiovascular system disorders: very common – increase in blood pressure (BP).

The digestive system: frequently – anorexia nausea vomiting abdominal pain diarrhea gum hyperplasia; infrequent – liver disorders (increased “hepatic” transaminases activity and concentration of bilirubin in serum); rarely – pancreatitis.

Skin and subcutaneous tissue: frequently – hypertrichosis; infrequent – allergic skin rash.

Skeletal, muscular and connective tissue: often – muscle spasms myalgia; rarely – muscle weakness myopathy.

Perior urinary system disorders: very common – renal dysfunction.

Urogenital system disorders: rarely – dysmenorrhea gynecomastia.

Laboratory parameters: very often – hyperlipidemia; often – hypercholesterolemia hyperuricemia hypomagnesaemia; rarely – hyperglycaemia.

Others: common – fatigue; infrequent – weight gain edema.

Overdose

To date there are no data on acute overdose with the drug and there is limited experience with overdose with other cyclosporines.

Symptoms: Renal dysfunction, which is likely reversible and will disappear when the drug is withdrawn.

Treatment: general supportive measures should be taken when indicated. The drug can only be eliminated from the body using non-specific measures, including gastric lavage, because cyclosporine is almost never eliminated by hemodialysis and activated charcoal hemoperfusion.

Pregnancy use

There is limited experience with the use of cyclosporine in pregnant women. Pregnant transplant recipients taking immunosuppressive medications, including cyclosporine, have an increased risk of preterm delivery (less than 37 weeks). There are limited observations of children up to the age of 7 years whose mothers took cyclosporine during pregnancy. The kidney function and blood pressure of these children were within the age range. However, there are no data on the efficacy and safety of cyclosporine use in pregnant women, so cyclosporine should not be used in pregnancy unless the expected benefit to the mother exceeds the potential risk to the fetus.

Cyclosporine penetrates into breast milk. Breastfeeding should be discontinued if it is necessary to use cyclosporine.

Similarities