Ciclosporin 💊

COMPOSITION
Active substance: ciclosporin;
Each soft capsule contains ciclosporin 25 mg, 50 mg, or 100 mg
Excipients: ethanol; tocopherol acetate; diethylene glycol monoethyl ether; oleoyl macrogolglycerides; hydrogenated castor oil
Capsule shell: gelatin, glycerol, propylene glycol, titanium dioxide (E 171), iron oxide black (E 172) (in capsules of 25 mg and 100 mg).

PHARMACODYNAMICS

Ciclosporin (also known as ciclosporin A) is a cyclic polypeptide consisting of 11 amino acids. Ciclosporin is an immunosuppressive agent that increases the lifespan of allogeneic transplants in animals, including skin, heart, kidney, pancreas, bone marrow, small intestine, and lungs. Studies show that ciclosporin also suppresses cellular reactions towards the allograft, delayed-type hypersensitivity skin reactions, experimental allergic encephalomyelitis, Freund’s adjuvant arthritis, BTPH, and T-lymphocyte-dependent antibody formation.

Ciclosporin acts selectively on lymphocytes, inhibiting the activation of lymphocyte calcineurin in the G0 or G1 phase of the cell cycle, thereby preventing T-lymphocyte activation and, at a cellular level, antigen-dependent release of lymphokines, including interleukin-2 (T-lymphocyte growth factor).

PHARMACOKINETICS
Peak blood concentration (Cmax) is reached within 1-2 hours (Tmax). The bioavailability is 30-60%. The interindividual variability of ciclosporin pharmacokinetics and the variability of ciclosporin pharmacokinetics within the same patient is 10-20% for AUC and Cmax in healthy volunteers. Ciclosporin can be taken regardless of food intake.

Distribution:
Ciclosporin is primarily distributed outside the bloodstream. In blood, 33-47% of ciclosporin is found in plasma, 4-9% in lymphocytes, 5-12% in granulocytes, and 41-58% in erythrocytes. Plasma protein binding (predominantly to lipoproteins) is approximately 90%.

Metabolism:
Ciclosporin undergoes biotransformation to approximately 15 metabolites via several metabolic pathways.

Excretion:
Ciclosporin is mainly excreted via bile, with only 6% of the administered dose excreted in the urine (with only 0.1% unchanged). The final half-life of ciclosporin varies considerably depending on the method of determination and the patient population studied. The final half-life with unchanged liver function is approximately 6.3 hours; in patients with severe liver disease, it is approximately 20.4 hours.

Pharmacokinetics in special patient groups:
Elderly patients:
Data on the absorption of the drug in elderly patients are not available. However, the distribution of ciclosporin in these patients does not differ from that in middle-aged patients.

Children:
On average, the elimination of ciclosporin in children is somewhat faster than in adults. Therefore, higher doses (relative to body weight) may be necessary to achieve similar blood levels of the drug.

Renal impairment:
The presence of renal impairment does not have a significant clinical impact on pharmacokinetics, as ciclosporin is mainly excreted via bile.

Hepatic impairment:
Hepatic impairment slows the elimination of ciclosporin. Therefore, patients with severe liver dysfunction require careful monitoring of serum creatinine levels and ciclosporin blood levels with appropriate dose adjustments.

Nephrotic syndrome:
Oral administration of the drug to patients with nephrotic syndrome does not alter pharmacokinetics. Dose adjustment is not required in such cases.

INDICATIONS
Indications for Transplantation:
Solid Organ Transplantation:

• Prevention of kidney, liver, heart, combined heart-lung, lung, and pancreatic allograft rejection
• Treatment of allograft rejection in patients previously treated with other immunosuppressive agents.

Bone Marrow Transplantation:

• Prevention of graft rejection
• Prevention and treatment of graft-versus-host reaction.

Indications Not Related to Transplantation:
Endogenous Uveitis:

• Active intermediate or posterior uveitis threatening vision loss, of non-infectious etiology in cases where alternative treatment has been ineffective or unacceptable.
• Uveitis in Behcet’s disease with recurrent inflammation spreading to the retina.

Nephrotic Syndrome:

• Idiopathic steroid-dependent or steroid-resistant nephrotic syndrome or segmental glomerulosclerosis in adults and children, not responding to traditional cytostatic therapy, but only when kidney function indicators are less than 50% of normal.
• Induction or maintenance of remission
• Maintenance of remission induced by corticosteroids, making their withdrawal possible.

Rheumatoid Arthritis:

• Treatment of severe forms of rheumatoid arthritis when standard specific therapy for this condition has proven ineffective or unacceptable.

Psoriasis:

• Severe forms of psoriasis when alternative treatment has proven ineffective or unacceptable.

Atopic Dermatitis:

• Severe forms of atopic dermatitis when alternative treatment has proven ineffective or unacceptable.

CONTRAINDICATIONS:

• Hypersensitivity to ciclosporin or any of the excipients of the drug.
• Impaired kidney function, except for nephrotic syndrome and renal insufficiency, when there is a moderate increase in serum creatinine levels due to the disease (not exceeding 200 µmol/l in adults and not exceeding 140 µmol/l in children), which improves and is treated as allowed (not more than 2.5 mg/kg/day).
• Uncontrolled arterial hypertension.
• Uncontrolled infectious diseases.
• History of known or diagnosed malignant neoplasms of any type, except for precancerous or malignant changes of the skin.
• Concurrent use with tacrolimus.
• Concurrent use of ciclosporin and rosuvastatin. Statin therapy should be temporarily discontinued in patients with signs or symptoms of myopathy, as well as in patients with risk factors for developing serious kidney damage, including renal insufficiency, and acute muscle necrosis.
• Concurrent use with medicinal products containing Hypericum perforatum (St. John’s wort).
• Concurrent use with medicinal products that are substrates of the multidrug efflux transporter P-glycoprotein (Pgp) or organic anion transport proteins (OATPs), for which an increase in plasma concentration is associated with the development of serious adverse reactions and/or life-threatening adverse reactions, such as bosentan, dabigatran etexilate, and aliskiren.

METHOD OF ADMINISTRATION AND DOSAGE:

The drug is taken orally. Capsules should be swallowed whole.
The daily dose of ciclosporin should always be divided into 2 doses.
Patients undergoing transplantation should monitor ciclosporin blood concentration levels to avoid the risk of side effects (if blood levels are too high) and organ rejection (if blood levels are too low).
Considering the differences in bioavailability of different forms of ciclosporin for oral administration, patients cannot be switched from one form of the drug to another without proper monitoring of ciclosporin and serum creatinine levels and blood pressure.
For monitoring ciclosporin blood levels, a method using specific monoclonal antibodies is predominantly used.
In the presence of gastrointestinal tract diseases leading to reduced absorption, higher doses of ciclosporin may be required, and in some cases, intravenous infusions of ciclosporin may be used.

Solid Organ Transplantation:
Treatment with ciclosporin should be initiated from 12:00 before surgery at a dose of 10 to 15 mg/kg body weight, divided into 2 doses. 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 ciclosporin blood concentration) to achieve a maintenance dose of 2-6 mg/kg/day (in 2 doses).
It has been established that in recipients of kidney transplants, doses below 3-4 mg/kg/day, resulting in minimum blood levels below 50-100 ng/ml, are associated with an increased risk of rejection.
When ciclosporin is used in combination with other immunosuppressants, including glucocorticoids (GCs) or as part of combined three-component (ciclosporin + glucocorticoids + azathioprine) or four-component (ciclosporin + GCs + azathioprine + monoclonal or polyclonal antibody preparations) therapy, it is administered at a reduced dose (3-6 mg/kg/day in 2 doses).
Dosing recommendation for oral ciclosporin in combination with everolimus in kidney transplantation:
If ciclosporin is used concomitantly with everolimus for an extended period, efforts should be made to reduce ciclosporin exposure. Reduction of ciclosporin exposure should start 1 month after transplantation.
The following target exposure levels for ciclosporin [ciclosporin blood concentrations determined 2 hours after administration (C2)] are recommended: weeks 0-4: 1000-1400 ng/ml, weeks 5-8: 700-900 ng/ml, weeks 9-12: 550-650 ng/ml, weeks 13-52: 250-450 ng/ml.
Before reducing ciclosporin doses, ensure that minimum everolimus levels in steady-state (C0) are ≥ 3 ng/ml. If reducing ciclosporin concentration leads to signs of transplant rejection, reconsider the appropriateness of continuing everolimus therapy.
To minimize the risk of reduced efficacy, it is important that neither everolimus concentration nor ciclosporin blood concentration after transplantation fall below the therapeutic range.
Information on everolimus dosage in patients with minimum ciclosporin levels (C0) below 50 ng/ml or C2 levels below 350 ng/ml during long-term therapy is limited (i.e., when the treatment period exceeds 12 months).

DOSE RECOMMENDATIONS FOR NON-ORAL ADMINISTRATION OF CYCLOSPORIN IN COMBINATION WITH EVEROLIMUS IN HEART TRANSPLANTATION:
To improve kidney function in heart transplant patients with renal impairment during the stabilization phase (i.e., after 1 month), the ciclosporin dose should be reduced as much as possible. If renal function deteriorates or calculated creatinine clearance drops to <60 ml/min, dose adjustment is required.
For heart transplant patients, the ciclosporin dose should be based on specific minimum blood ciclosporin levels. Dosage information for everolimus in combined therapy in heart transplant patients with minimum ciclosporin levels (C0) below 175 ng/ml for the first 3 months, below 135 ng/ml for 6 months, and below 100 ng/ml after 6 months is limited. Before reducing ciclosporin doses, ensure that minimum everolimus blood levels in steady-state are ≥ 3 ng/ml.

Bone Marrow Transplantation:
The initial dose should be taken one day before transplantation, with a recommended dose of 12.5-15 mg/kg/day divided into 2 doses, starting from the day before transplantation. Then, maintenance therapy is continued at a dose of 12.5 mg/kg/day divided into 2 doses. Maintenance therapy should be carried out for at least 3 months (preferably 6 months), after which the dose is gradually reduced to zero within 1 year after transplantation.
In the presence of gastrointestinal diseases leading to reduced absorption, higher doses of ciclosporin or the use of intravenous forms of ciclosporin may be required.
After discontinuation of ciclosporin administration, some patients may develop graft-versus-host reaction, which usually regresses after resuming therapy. For the treatment of this condition in its mildly expressed chronic form, ciclosporin should be administered in low doses.

Endogenous Uveitis:
To promote remission, the drug is prescribed initially at a dose of 5 mg/kg orally in 2 doses until signs of active inflammation of the eye’s vascular membrane disappear and visual acuity improves. In cases where the disease is difficult to treat, the dose can be increased to 7 mg/kg/day.
If ciclosporin is not providing sufficient efficacy, systemic glucocorticoids (prednisolone at a dose of 0.2-0.6 mg/kg or equivalent) can be added to achieve particularly rapid remission.
Ciclosporin should be discontinued if there is no improvement in the patient’s condition after 3 months of treatment.
During maintenance therapy, the dose should be gradually reduced to achieve the lowest effective dose, which during disease remission should not exceed 5 mg/kg/day. The daily dose can be reduced by 25-50% if the serum creatinine level exceeds the baseline value by more than 30% on more than one determination, even if this value remains within normal limits. If dose reduction has no effect within one month, the drug should be discontinued.

Control of Kidney Function:
Cyclosporine may impair kidney function, so reliable baseline serum creatinine levels should be established before starting treatment, based on at least two determinations. Both determinations should indicate normal kidney function. Using an appropriate formula, creatinine clearance can be calculated based on serum creatinine levels (e.g., Dettli). Serum creatinine levels should be monitored weekly during the first month of treatment, then monthly or more frequently if the dose is increased. In cases where serum creatinine levels exceed the initial value by 20-30%, repeat determinations should be performed to rule out temporary increases unrelated to kidney function.

Blood Pressure Control:
If elevated blood pressure develops during treatment and cannot be normalized with appropriate antihypertensive therapy, the cyclosporine dose should be reduced, or if necessary, the drug should be discontinued.

Dermatologic Indications:
Special Instructions:
Before initiating treatment, patients should be fully informed about the benefits and possible risks of Cyclosporine Alkaloid therapy and the common problem of recurrence after discontinuation of the drug. Patients with renal insufficiency, uncontrolled arterial hypertension, infectious diseases, or any type of malignancy except skin cancer should not use Cyclosporine Alkaloid. Caution should be exercised when prescribing to patients with hyperkalemia or hyperuricemia.

Nephrotic Syndrome:
For induction of remission in nephrotic syndrome, the recommended daily dose is 5 mg/kg, or 6 mg/kg for children (in 2 divided doses), assuming normal kidney function. For patients with impaired kidney function, the initial dose should not exceed 2.5 mg/kg/day (serum creatinine level >200 µmol/L in adults and >140 µmol/L in children is a contraindication for drug use). When adjusting the new dose, appropriate monitoring of cyclosporine levels is recommended to avoid overdosing in children. Doses should be individually tailored, taking into account effectiveness (proteinuria) and safety (serum creatinine concentration), but should not exceed 5 mg/kg/day for adults and 6 mg/kg/day for children. During maintenance therapy, the dose should be gradually reduced to achieve the lowest effective dose. The dose should be reduced by 25-50% if the serum creatinine level exceeds the baseline value by more than 30%. If satisfactory effect is not achieved after 3 months of treatment, cyclosporine therapy should be discontinued. Combination therapy of cyclosporine and corticosteroids may be beneficial in central segmental glomerulosclerosis. Combined use of Cyclosporine Alkaloid with oral corticosteroids in low doses is recommended for patients who have not responded adequately to treatment with Cyclosporine Alkaloid alone, especially in cases of steroid-resistant nephrotic syndrome. The initial dose for patients with pre-existing kidney dysfunction (serum creatinine level >200 µmol/L in adults and >140 µmol/L in children) should not exceed 2.5 mg/kg/day, and careful monitoring is required for such patients. Some patients may have difficulty detecting kidney dysfunction caused by the use of Cyclosporine Alkaloid because nephrotic syndrome itself causes changes in kidney function. Therefore, in rare cases, structural changes in the kidneys caused by the use of Cyclosporine Alkaloid may be observed in the absence of any increase in serum creatinine levels. Therefore, patients with steroid-dependent minimal change nephropathy who have been taking Cyclosporine Alkaloid for more than one year should undergo kidney biopsy.

Rheumatoid Arthritis:
Patients with renal insufficiency, uncontrolled arterial hypertension, or infectious, malignant, or any type of new growths should not use cyclosporine. Caution should be exercised when prescribing to patients with hyperkalemia or hyperuricemia.
For rheumatoid arthritis, the recommended dose for the first 6 weeks of treatment is 3 mg/kg/day in 2 divided doses. The dose can be reduced based on tolerability. If there is inadequate response, the daily dose can be gradually increased if tolerated, but should not exceed 5 mg/kg/day. Up to 12 weeks of therapy may be needed for full effectiveness of the drug. If the dose is increased too rapidly, there is a risk of overdose.
Capsules of 100 mg are not suitable for dose titration in patients weighing less than 80 kg.
For maintenance therapy, the dose should be individually adjusted to achieve the lowest effective dose.
Cyclosporine therapy should be discontinued if there is no improvement in the patient’s condition after 3 months of treatment.
Cyclosporine can be prescribed in combination with low doses of corticosteroids and/or nonsteroidal anti-inflammatory drugs (NSAIDs) (see “Interaction with Other Medications and Other Types of Interactions”). The daily dose of the drug should be reduced if the serum creatinine level exceeds the mean baseline value by more than 30%, even if this value is within the normal range. If the baseline value is exceeded by more than 50%, the dose should be halved. If dose reduction is not effective within 1 month, the drug should be discontinued.
Regular monitoring of serum creatinine levels may be necessary when NSAIDs are prescribed or when an increased dose of such a drug is prescribed.
As with prolonged use of other immunosuppressive drugs, it should be noted that the risk of lymphoproliferative disorders increases with the use of the drug.
Cyclosporine can be combined with a weekly course of low-dose methotrexate for patients with an unsatisfactory response to methotrexate monotherapy. The initial dose of cyclosporine is 2.5 mg/kg/day (in 2 divided doses), with the dose being increased to a level limited by tolerability.
Psoriasis:
For psoriasis, the dosing regimen should be individually tailored. For induction of remission, the recommended initial dose is 2.5 mg/kg/day (in 2 divided doses). If there is no improvement after 1 month of therapy, the daily dose can be gradually increased, but should not exceed 5 mg/kg. Treatment should be discontinued if satisfactory results in terms of psoriasis manifestations are not achieved after 6 weeks of treatment with a dose of 5 mg/kg/day, or if the effective dose does not meet established safety parameters.
The use of an initial dose of 5 mg/kg/day may be justified for patients whose condition requires rapid improvement. If satisfactory results are achieved, cyclosporine can be discontinued, and subsequent relapses treated with re-administration of cyclosporine at the previous effective dose. Some patients may require long-term maintenance therapy.
For maintenance therapy, the dose should be individually adjusted to the minimum effective level and should not exceed 5 mg/kg/day in 2 divided doses.

Atopic Dermatitis:
For atopic dermatitis, the dosing regimen should be individually tailored. The recommended dose is 2.5-5 mg/kg/day orally in 2 divided doses. If the initial dose of 2.5 mg/kg/day does not achieve satisfactory results within 2 weeks, the daily dose can be increased to a maximum of 5 mg/kg/day. In severe cases of the disease, control can be achieved with an initial dose of 5 mg/kg/day. Once satisfactory results are achieved, the dose should be gradually reduced, and cyclosporine should be discontinued if possible. In the event of recurrence, a repeat course of cyclosporine treatment may be conducted.
Treatment should be discontinued for patients who do not respond adequately to treatment with a dose of 5 mg/kg/day within 1 month.
Experience with long-term use of cyclosporine in the treatment of atopic dermatitis is insufficient, so the recommended duration of individual treatment cycles should not exceed 8 weeks.
Skin Infections:
Before starting cyclosporine treatment, active infections caused by the herpes simplex virus should be treated. However, infections caused by the herpes simplex virus, if they occur during treatment, may not necessarily be a reason for discontinuing the drug if the infection is not severe.
The presence of skin infections caused by Staphylococcus aureus is not an absolute contraindication to cyclosporine treatment, but they should be treated with appropriate antibiotics. Oral erythromycin should be avoided as it may lead to an increase in cyclosporine concentration in the blood. If there is no alternative, the cyclosporine blood level, renal function, and signs of side effects should be constantly monitored.

Skin Tumors:
The development of malignant neoplasms (especially of the skin) has been reported in patients with psoriasis receiving cyclosporine treatment, as well as in those undergoing conventional immunosuppressive therapy. Therefore, before starting cyclosporine treatment, a biopsy of skin lesions that are atypical for psoriasis and may be malignant or precancerous should be performed. Patients with detected malignant or precancerous skin changes may use cyclosporine only after appropriate treatment, and in cases where another potentially effective type of treatment cannot be applied.
Administration Method:
To achieve optimal therapeutic concentrations, the cyclosporine blood concentration should be monitored using the radioimmunoassay method, which is based on the use of monoclonal antibodies.
The daily dose of cyclosporine should be divided into two separate doses, taken at the same time with the same interval (morning and evening).
Cyclosporine should be taken orally, regardless of food intake.
Capsules should be swallowed whole with liquid.
Switching from Other Oral Medications to Cyclosporine:
When switching from other oral medications containing cyclosporine to Cyclosporin Alkaloid, the cyclosporine blood concentration, serum creatinine concentration, and blood pressure of patients should be monitored before the switch. Cyclosporine treatment should be initiated at the same daily dose that was used in the previous cyclosporine treatment.
Cyclosporine blood concentration, serum creatinine concentration, and blood pressure should be monitored after 4-7 days of drug administration. If necessary, the dose of cyclosporine should be adjusted accordingly. Additional monitoring should be conducted during the first 2 months after the switch (e.g., at 2, 4, and 8 weeks), and the dose should be adjusted accordingly.

Method of Administration:
To achieve optimal concentrations of cyclosporine in the blood in different patients, it is necessary to conduct a standard control using a radioimmunological method with monoclonal antibodies.
The daily dose of cyclosporine should be divided into two separate doses, taken at the same time with an equal interval (morning and evening).
Cyclosporine should be taken orally, regardless of food intake.
Capsules should be swallowed whole, with liquid.
Transition from Other Oral Preparations to Cyclosporine:
Before transitioning from other oral preparations containing cyclosporine to Cyclosporin Alkaloid, it is necessary to monitor the level of cyclosporine in the blood, serum creatinine concentration, and blood pressure. Treatment with cyclosporine should begin with the same daily dose that was used in the previous cyclosporine treatment.
Cyclosporine concentration in the blood, serum creatinine concentration, and blood pressure should be monitored 4-7 days after starting the medication. If necessary, the cyclosporine dose should be adjusted accordingly. Additional monitoring is required for the first 2 months after transition (e.g., at 2, 4, and 8 weeks), and the dose should be adjusted accordingly.
Dosage in Renal Impairment:
Special caution should be exercised with rapid increases in serum creatinine levels (even within the normal range) after starting cyclosporine therapy. Considering the increase in serum creatinine concentration or decrease in creatinine clearance, especially after kidney transplantation, and the possibility of rejection reactions, the dose should be adjusted, taking into account the risk and benefit with full control of the disease and mandatory determination of cyclosporine levels in the blood.
Patients with nephrotoxic syndrome and moderately impaired renal function (initial serum creatinine values in adults <200 μmol/L, in children <140 μmol/L) should not exceed the initial cyclosporine dose of 2.5 mg/kg/day. Careful monitoring of patients is required.

Dosage in Liver Impairment:

Significant changes in cyclosporine pharmacokinetics may occur in patients with liver impairment. In such cases, the cyclosporine blood level should be constantly monitored, and the dose should be adjusted if necessary.
In psoriasis, cyclosporine should be discontinued if liver enzyme levels and bilirubin increase twofold compared to baseline values.
In patients with nephrotic syndrome and severe liver impairment, the initial cyclosporine dose should be reduced by 25-50%.
Use in Children:
Clinical studies with children aged 1 year and older have shown that pediatric patients may require and tolerate higher doses of cyclosporine per body weight than adults. An exception is the treatment of nephrotic syndrome. In other cases, the use of cyclosporine in children under 16 years of age for indications not related to transplantation should be cautious.

Overdose💊💊💊:
Symptoms: Data on acute cyclosporine overdose are limited. Ingestion of cyclosporine orally at doses up to 10 grams (approximately 150 mg/kg) typically resulted in vomiting, drowsiness, headache, and tachycardia. In some cases, reversible renal function disturbances were observed.

However, accidental parenteral overdose of cyclosporine in preterm infants during the neonatal period has been reported to lead to severe toxic complications. Nephrotoxicity may develop, which is likely reversible upon discontinuation of the drug.

Treatment: Symptomatic supportive therapy. Cyclosporine is practically not removed by hemodialysis and hemoperfusion using activated charcoal. The drug can only be eliminated from the body through nonspecific measures, including gastric lavage. However, activated charcoal removes only a small amount of cyclosporine from hepatic circulation. The drug can be removed from the body within the first few hours after oral ingestion by inducing vomiting.

Storage Conditions and Shelf Life:
Store in the original packaging at a temperature not exceeding 25°C.
Keep out of reach of children.
Shelf life: 3 years.