Sandimmune neoral capsules 25mg N50.
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Active ingredients
Cyclosporine
Release form
Capsules
Composition
Soft gelatin capsules, composition (1 capsule): active substance: cyclosporine - 25 mg adjuvants: DL-a-tocopherol - 0.25 mg, ethanol - 25 mg, propylene glycol - 25 mg, mono-di-triglycerides of corn oil - 86 mg, polyoxyl 40 hydrogenated castor oil - 101.25 mg shell: titanium dioxide (E171), glycerol 85%, propylene glycol, gelatin, residual solvents (consisting of ethanol and water), ferrous oxide black (E172)
Pharmacological effect
immunosuppressive
Pharmacokinetics
When taking the drug Sandimmune Neoral, a more clear linear relationship between the dose and the effect of cyclosporine (AUCB) is provided, a more constant absorption profile and a lesser dependence on simultaneous food intake and daily rhythm, which is characteristic of the drug Sandimmune. These properties combined due to the low variability of the pharmacokinetics of cyclosporine in the same patient and a more pronounced correlation between basal concentration and bioavailability (AUCB). Due to these additional benefits in the dosing regimen of Sandimmune Neoral, it is no longer necessary to take into account meal times. In addition, the use of the drug Sandymun Neoral provides a more uniform exposure to cyclosporine both during the day and during the course of maintenance therapy. Soft gelatin capsules and oral solution are bioequivalent. The absolute bioavailability of cyclosporine varies in different patient populations. Tmax is 1.5 –2 h, absorption of the drug Sandimmune Neoral occurs quickly, the average Cmax value is 59% more and bioavailability is 29% higher than Sandimmune. The cyclosporin is distributed more frequently. Stew outside the bloodstream. In the blood, 33–47% of cyclosporine is found in plasma, 4–9% in lymphocytes, 5–12% in granulocytes, and 41–58% in erythrocytes. Plasma protein binding (predominantly lipoproteins) is approximately 90%. Cyclosporine is largely biotransformed by the cytochrome P4503A enzyme system, and, to a lesser extent, in the gastrointestinal tract and kidneys, with the formation of about 15 metabolites. There is no single major metabolic pathway.The drug is excreted mainly with bile and only 6% of the dose ingested is excreted in the urine (and only 0.1% is excreted unchanged). The values of the final T1 / 2 of cyclosporine are very variable, which depends on the method of determination and the patient population being examined. The final T1 / 2 with unchanged liver function is approximately 6.3 hours; in patients with severe liver disease - approximately 20.4 hours
Indications
TransplantationSlide organs transplantation: prevention of allograft rejection of the kidney, liver, heart, lung, pancreas, as well as a combined cardiopulmonary transplant; treatment of transplant rejection in patients previously treated with other immunosuppressants. Bone marrow transplantation preventing implant transplantation. graft versus host disease (DTP). Indications non-transplant. Endogenous uveitac willow-threatening middle or posterior uveitis of non-infectious etiology in cases where traditional treatment had no effect or in cases of severe side effects, Behcet's uveitis with repeated bouts of inflammation with retinal involvement. Nephrotic steroids-dependent and steroid-resistant nephrotic syndrome in adults and children caused by a pathologist such as minimal changes nephropathy, focal and segmental glomerulosclerosis, membranous glomerulonephritis. The drug Sandimmune Neoral can be used to induce and maintain remission. It can also be used to maintain remission caused by the GCS, which allows them to be canceled. Rheumatoid arthritis of severe forms of active rheumatoid arthritis. Psoriasis of severe forms of psoriasis when conventional therapy is ineffective or impossible. Atopic dermatitis is severe atopic dermatitis when systemic therapy is required.
Contraindications
Hypersensitivity to cyclosporine or any other component of the drug. For indications not related to transplantation, renal dysfunction (except for patients with nephrotic syndrome with an acceptable degree of these disorders); uncontrolled arterial hypertension; infectious diseases,not amenable to adequate therapy; malignant neoplasms. With caution: pregnancy; period of breastfeeding.
Use during pregnancy and lactation
In experimental studies showed the toxic effect of the drug on reproductive function. Experience with the use of the drug Sandimmune Neoral in pregnant women is limited. Pregnant women who have undergone organ transplantation and are receiving immunosuppressive treatment with cyclosporine or combination therapy, including cyclosporine, have a risk of premature birth (occurring during the gestation period up to 37 weeks). There are a limited number of observations of children (until they reach the age of 7 years), exposed to cyclosporine in the period of prenatal development. Kidney function and blood pressure in these children were normal. However, adequate and well-controlled studies in pregnant women have not been conducted, so you should not use the drug during pregnancy, except in cases where the expected benefit to the mother justifies the potential risk to the fetus. Cyclosporine enters breast milk. Mothers receiving the drug Sandimmune Neoral should not breastfeed.
Dosage and administration
Inside, regardless of the meal. The daily dose of Sandimmune Neoral should always be divided into 2 doses. The transition from Sandimmune to Sandimmune Neoral The available data show that when switching from Sandimmune to taking Sandimmune Neoral while maintaining the 1: 1 dose ratio of basal concentrations of cyclosporine, determined in whole blood counts are comparable. In many patients, however, higher Cmax values and an increase in the duration of exposure (AUC) may be observed. In a small percentage of patients, these changes are more noticeable and may be clinically significant. Their magnitude depends largely on the individual differences in the absorption of cyclosporine from the originally used drug Sandimmune, whose bioavailability is characterized by high variability. In patients with variable values of basal concentrations, or receiving the drug Sandimmune in very high doses (includingin patients with cystic fibrosis, patients with a transplanted liver with concomitant cholestasis or poor bile secretion, in children or some patients with a transplanted kidney), cyclosporine absorption may be low or inconsistent, however, when switching to Sandimmune Neoral, absorption may improve. As a result, in this population of patients after switching from Sandimmune to taking Sandimmune Neoral, while maintaining the 1: 1 dose ratio, an increase in the bioavailability of cyclosporine may be more pronounced than is usually observed. Given this, the dose of Sandimmune Neoral should be reduced by individual selection, depending on the range of basal concentrations and appropriate indications. The absorption of cyclosporine from Sandimmune Neoral is less variable and the correlation between basal concentration and bioavailability (by AUC values) is much more pronounced than with Sandimmune. This makes the basal level of concentration of cyclosporine in the blood a clearer and more reliable parameter for the therapeutic control of the drug. switching from Sandimmune to Sandimmune Neoral can lead to an increase in drug exposure, the following rules should be observed. In patients after transplantation, treatment with Sandimmune Neoral should be started with the same daily dose as during previous use of Sandimmune. The basal concentration of cyclosporine in whole blood should be monitored within 4–7 days after switching to Sandimmune Neoral. In addition, clinical safety parameters such as serum creatinine and blood pressure should be monitored during the first 2 months after the transition. If the basal concentration of cyclosporine in the blood is outside the therapeutic range and / or there is a deterioration in clinical safety parameters, the dose should be adjusted accordingly. In patients treated for indications not related to transplantation, treatment with Sandimmune Neoral should be started with the same dose that was when using the drug Sandimmune. After 2, 4 and 8 weeks after the transition should be monitored concentration of creatinine in serum and blood pressure.If serum creatinine concentrations or blood pressure levels rise markedly compared to those before the transition, or if creatinine concentrations increased by more than 30% compared to the pre-treatment values of Sandimmune in more than one dimension, then the dose should be reduced (see also “Additional Instructions”) by 25–50%. If the serum concentration increases by more than 50%, then it is necessary to reduce the dose by 50%. In the case of the development of a toxic effect or with the ineffectiveness of the drug, the basal concentrations of cyclosporine in the blood should also be monitored. The oral dose ranges given below should be considered only as recommendations. The generally accepted monitoring of the concentration of cyclosporine in the blood should be carried out, for which a radio-immunological method based on the use of monoclonal antibodies can be applied. Based on the results, determine the dose required to achieve the desired concentration of cyclosporine in different patients. Transplantation Transplantation of glide organs Treatment with Sandimmune Neoral should be started 12 hours before surgery at a dose of 10 to 15 mg / kg, divided into 2 doses. Within 1-2 weeks after surgery, the drug is prescribed daily in the same dose, after which the dose is gradually reduced, under the control of the concentration of cyclosporine in the blood, until a supporting dose of 2-6 mg / kg / day is achieved, divided into 2 doses. Sandymmun Neoral prescribed in combination with other immunosuppressants (including those with GCS, as well as as part of a combined three-component (Sandimmun Neoral + GCS + azathioprine) or four-component (Sandimmun Neoral + GCS + azathioprine + monoclonal antibodies) therapy The four-component scheme is used in patients with a high risk of rejection.In the case of the use of the drug Sandimmune Neoral as part of combination therapy schemes, its dose may be reduced at the initial stage of therapy (3–6 mg / kg / day in 2 doses) or adjusted to treatment process, taking into account the concentration of cyclosporine in the blood plasma and the dynamics of safety indicators (concentration of urea, serum creatinine, blood pressure). Bone marrow transplantationThe initial dose should be administered on the day preceding the transplant.In most cases, it is preferable to / in the introduction; The recommended dose is 3-5 mg / kg / day. Infusion administration in the same dose is continued for 2 weeks immediately after transplantation, then transferred to oral maintenance therapy with Sandimmune Neoral in a daily dose of about 12.5 mg / kg, divided into 2 doses. Maintenance therapy is carried out for at least 3 months (preferably 6 months), after which the dose is gradually reduced to complete withdrawal of the drug within 1 year after transplantation. If Sandimmune Neoral is prescribed for the initial stage of therapy, then the recommended daily dose is 12.5–15 mg / kg (in 2 doses), starting from the day before the transplantation. In the presence of gastrointestinal diseases, leading to decreased absorption, more high doses of the drug Sandimmune Neoral or the use of intravenous infusions of the drug Sandimmune. After stopping the introduction of the drug Sandimmune, some patients may develop a graft versus host disease (TSH), which usually regresses after resuming rapii. For the treatment of this condition in its chronic course in a weakly expressed form, the drug Sandimmune Neoral should be used in low doses. Indications not related to transplantation Endogenous uveitis Inside. To induce remission, the drug is prescribed in an initial daily dose of 5 mg / kg in 2 doses until the signs of active inflammation disappear and visual acuity improves. In cases that are difficult to treat, the dose can be increased to 7 mg / kg / day for a short period. If the situation cannot be controlled with a single drug, Sandimmune Neoral, then systemic GCS can be attached to achieve initial remission or to relieve an inflammation attack in a daily dose of 0.2–0.6 mg / kg or another GCS equivalent dose). During maintenance therapy, the dose should be slowly reduced until the lowest effective dose is reached, which should not exceed during the remission of the disease 5 mg / kg / day. Nephrotic syndrome For induction of remission, the recommended daily dose is 5 mg / kg for adults and 6 mg / kg for children in 2 doses, provided that the kidney function is normal, not counting proteinuria. In patients with impaired renal function, the initial dose should not exceed 2.5 mg / kg / day.If the use of a single drug Sandimmune Neoral fails to achieve a satisfactory effect, especially in steroid-resistant patients, then it is recommended to combine it with low doses of oral GCS. If after 3 months of treatment no improvement was achieved, Sandimmune Neoral should be discontinued. Doses should be selected individually, taking into account the indicators of efficacy (proteinuria) and safety (serum creatinine concentration), but the dose of 5 mg / kg / day should not be exceeded for adults and 6 mg / kg / day - for children. For maintenance therapy, the dose should be gradually reduced to the minimum effective. Rheumatoid arthritis. During the first 6 weeks of treatment, the recommended dose is 3 mg / kg / day in 2 doses. In case of insufficient effect, the daily dose can be gradually increased, if tolerance allows, but it should not exceed 5 mg / kg. To achieve full efficacy, it may take up to 12 weeks of therapy with Sandimmune Neoral. For maintenance therapy, the dose should be adjusted individually depending on the tolerability of the drug. Sandimmune Neoral can be prescribed in combination with low doses of GCS and / or NSAIDs. The drug Sandimmune Neoral can also be combined with a weekly course of methotrexate in low doses in patients with an unsatisfactory response to methotrexate monotherapy. The initial dose of Sandimmune Neoral is 2.5 mg / kg / day in 2 divided doses, and the dose can be increased to a level that is limited by tolerability. Psoriasis Dosing regimen should be selected individually. For induction of remission, the recommended initial dose is 2.5 mg / kg / day in 2 doses. In the absence of 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 a satisfactory response from the manifestations of psoriasis after 6 weeks of treatment with a dose of 5 mg / kg / day has not been achieved, or if the effective dose does not meet the established safety parameters. A higher initial dose of 5 mg / kg / day may be justified. in patients whose condition requires early improvement. If a satisfactory response is achieved, then the drug Sandimmune Neoral can be canceled, and the subsequent relapse can be treated by re-administering the drug Sandimmune Neoral in the previous effective dose.Some patients may require long-term maintenance therapy. For maintenance therapy, doses should be selected individually at the minimum effective level, they should not exceed 5 mg / kg / day. Atopic dermatitis Dosing regimens should be selected individually. The recommended initial dose is 2.5–5 mg / kg / day in 2 doses. If the initial dose of 2.5 mg / kg / day does not allow a satisfactory response to be achieved within two weeks, then the daily dose can be quickly increased to a maximum of 5 mg / kg. In very severe cases, rapid and adequate disease control can be achieved by initially applying a dose of 5 mg / kg / day. When a satisfactory response is achieved, the dose should be gradually reduced and, if possible, the preparation Sandimmune Neoral should be discontinued. In the event of a relapse, a repeated course of the drug Sandimmune Neoral may be conducted. Despite the fact that a course of treatment for 8 weeks may be sufficient to cleanse the skin, it has been shown that therapy with a duration of up to 1 year is effective and well tolerated, subject to mandatory monitoring of all necessary indicators. The use of elderly patients is limited to the use of the drug Sandimmune Neoral in elderly patients. In clinical studies on the use of cyclosporine for treating aoid arthritis, the proportion of patients aged 65 years and older was 17.5%. It was shown that these patients are more likely to develop systolic hypertension, and also more likely to increase serum creatinine concentration by more than 50% higher than baseline after 3-4 months of cyclosporine therapy. The number of patients 65 years of age and older included in clinical studies in patients with grafts, as well as in patients with psoriasis, Sandimmune Neoral was not sufficient to determine whether the response to treatment in this category of patients differs from the response to treatment in younger patients ENTOV. Based on other available information on the use of cyclosporine in clinical practice, it can be concluded that the response to treatment in elderly and younger patients is no different. Dose selection in elderly patients should be carried out carefully; usually, treatment begins with the lowest dose, given the greater frequency of liver dysfunction,kidney or heart, as well as taking into account concomitant diseases or other concomitant therapy. Additional instructions on dosing regimen for endogenous uveitis, psoriasis and atopic dermatitis Since Sandimmune Neoral may interfere with kidney function, a reliable initial serum creatinine concentration in at least two dimensions must be established prior to treatment. Creatinine concentration should be monitored at 2-week intervals during the first 3 months of therapy. Further, if the creatinine concentration remains stable, measurements should be taken monthly. If the serum creatinine concentration increases and remains elevated by more than 30% from baseline values in more than one dimension, then the dose should be reduced by 25–50%. These recommendations should be followed, even if the creatinine concentrations continue to be within the laboratory norm. If a dose reduction does not lead to a decrease in creatinine concentration within one month, then treatment with Sandimmune Neoral should be discontinued. Discontinuation of treatment is also necessary when an uncontrolled increase in blood pressure occurs during treatment with Sandimmune Neoral. Additional instructions on the dosage regimen for nephrotic SyndromeSince the drug Sandimmune Neoral can cause renal dysfunction, it is often necessary to control it. If the serum creatinine concentration remains elevated by more than 30% from baseline values and in more than one dimension, a reduction in the dose of Sandimmune Neoral by 25–50% is required. For patients with initially impaired renal function, the initial dose should be 2.5 mg / kg / day. It is necessary to ensure close monitoring of the condition of these patients. Additional instructions on the dosage regimen for rheumatoid arthritis Since Sandimmune Neoral may interfere with kidney function, a reliable initial serum creatinine concentration must be established in at least two dimensions prior to treatment. The concentration of creatinine should be monitored at 2-week intervals during the first 3 months of therapy and then monthly.After 6 months of therapy, serum creatinine concentration should be determined every 4–8 weeks, depending on the stability of the underlying disease, simultaneously applied therapy and concomitant diseases. More frequent monitoring is needed when increasing the dose of Sandimmune Neoral, when adding concomitant NSAID therapy or increasing their dose. If the serum creatinine concentration remains elevated by more than 30% from baseline values and in more than one dimension, it is necessary to reduce the dose. If the serum creatinine concentration increases by more than 50%, then it is necessary to reduce the dose by 50%. These recommendations should be followed, even if the creatinine concentrations continue to be within the laboratory norm. If a dose reduction does not lead to a decrease in creatinine concentration within one month, then treatment with Sandimmune Neoral should be discontinued. Termination of treatment is also necessary when an uncontrolled increase in blood pressure occurs during treatment with Sandimmune Neoral. Features of the use and storage of Sandimmune Neoral Capsules Sandimmune Neoral should be left in a blister pack until needed. After opening the blister pack, there is a characteristic smell. This is normal. Capsules should be swallowed whole. Instructions for using the drug Sandimmune Neoral in the form of oral solution I. With initial use1. Remove the plastic cover. Completely tear off the sealing ring.3. Remove the black plug and discard it. Push the tube with a white cork into the neck of the bottle with force. Insert a measuring syringe into a white stopper. Dial into the measuring syringe the volume of the solution corresponding to the prescribed dose. To expel all large bubbles, moving the piston several times back and forth, before separating the syringe containing the volume of solution in accordance with the prescribed dose, and the vial. The presence of several very small bubbles does not matter and in no way affects the dose. After use, wipe the outside syringe with only a dry cloth from the outside and place it in a protective case. The white tube and tube should remain in the bottle. Close the bottle cap.II.For subsequent use, start with step 5. Immediately before taking the solution of the drug Sandimmune Neoral should be taken from the vial using a measuring syringe (as indicated above), transferred to a glass or cup and mixed with orange or apple juice. You can also use other soft drinks (in accordance with the individual taste). The added drink and solution should be mixed well. Do not use grapefruit juice, given the possibility of its interaction with the cytochrome P450 enzyme system. Do not allow the measuring syringe to touch the beverage to be mixed. Do not rinse the syringe with water or any other liquid. Sandymmun Neoral should be used in the form of a solution for 2 months after opening the vial and stored at a temperature of 15 to 30 ° C, preferably at a temperature not lower than 20 ° C for long periods of storage, since the preparation contains oil components of natural origin, which tend to harden at low temperature. At temperatures below 20 ° C, the preparation can take on a jelly-like consistency, which disappears when the temperature rises to 30 ° C. However, there may be a small amount of flakes or light sedimentation. These phenomena do not affect the efficacy and safety of the drug, and dosing using a measuring syringe remains accurate.
Side effects
Many of the side effects associated with the use of cyclosporine, dose-dependent and reversible with decreasing dose. The spectrum of side effects is generally the same for different indications, although the frequency and severity of side effects may vary. In patients who have undergone transplantation, because of the higher dose and longer duration of treatment, side effects are more common and usually more pronounced than in patients with other indications. When i / v administration of cyclosporine, there were cases of anaphylactoid reactions. Patients receiving immunosuppressive treatment with cyclosporine or combination therapy, including cyclosporine, increase the risk of developing local and generalized infections (viral, bacterial, fungal etiology) and parasitic invasions. Exacerbation of previously existing infectious diseases is also possible. It has been reported cases of the development of infectious lesions with a fatal outcome.Patients receiving immunosuppressive treatment with cyclosporine or combination therapy, including cyclosporine, increase the risk of developing lymphomas, lymphoproliferative diseases and malignant neoplasms, especially of the skin. The incidence of malignant neoplasms increases with increasing intensity and duration of immunosuppressive therapy. The incidence of adverse events was estimated as follows: occurring very often (≥1 / 10), often (≥1 / 100; <1/10), sometimes (≥1 / 1000; <1/100), rarely (≥1 / 10000 ; <1/1000), very rarely (<1/10000), including separate messages. From the urinary system: very often - a renal failure (see "Special instructions"). From the side of the cardiovascular system: very often - increase in blood pressure. From the nervous system: very often - tremor, headache; often - paresthesias; sometimes signs of encephalopathy, such as convulsions, lethargy, disorientation, slow reactions, agitation, sleep disturbance, visual disturbances, cortical blindness, coma, paresis, cerebellar ataxia; rarely, motor polyneuropathy; very rarely - swelling of the optic nerve head, including the nipple of the optic nerve, secondary to benign intracranial hypertension. From the alimentary system: often anorexia, nausea, vomiting, abdominal pain, diarrhea, gingival hyperplasia, impaired liver function; rarely - pancreatitis. Metabolism: very often - hyperlipidemia; often - hyperuricemia, hyperkalemia, hypomagnesemia; rarely - hyperglycemia. From the musculoskeletal system: often - muscle spasms, myalgia; rarely - muscle weakness, myopathy. From the hematopoietic system: sometimes - anemia, thrombocytopenia; rarely - microangiopathic hemolytic anemia, hemolytic uremic syndrome. Dermatological reactions: often - hypertrichosis; sometimes an allergic rash. On the whole body: often fatigue; sometimes - swelling, weight gain. From the endocrine system: rarely - menstrual disorders, gynecomastia.
Overdose
Symptoms: Experience with regard to acute overdose with Sandimmune Neoral is limited. When ingested cyclosporine in a dose of up to 10 g (about 150 mg / kg) in most cases there were slightly pronounced clinical manifestations, such as vomiting, dizziness, headache, tachycardia. In some cases, reversible impaired renal function of a moderate degree was observed.However, in the case of an accidental parenteral overdose of cyclosporine in premature infants, severe toxic complications were reported in the neonatal period. Treatment: symptomatic therapy, a specific antidote does not exist. During the first 2 hours after ingestion, the drug can be removed from the body by causing vomiting or by washing the stomach. Cyclosporine is practically not excreted by hemodialysis and hemoperfusion using activated carbon.
Interaction with other drugs
The following are the drugs for which interaction with cyclosporine is confirmed and clinically significant. Various drugs can increase or decrease the concentration of cyclosporine in plasma or whole blood, usually by suppressing or inducing enzymes involved in the metabolism of cyclosporine, in particular the cytochrome CYP3A4 isoenzymes. Since cyclosporine is an inhibitor of cytochrome CYP3A4 and a membrane carrier of P-glycoprotein molecules, with simultaneous use with Sandimmune Neoral, it is possible to increase the concentration of drugs that are substrates of cytochrome CYP3A4 and / or the membrane carrier of P-glycoprotein. oxcarbazepine, phenytoin; nafcillin, sulfadimidine with its on / in the introduction; rifampicin; octreotide; probucol; orlistat; preparations containing St. John's wort Hypericum perforatum; Ticlopidine, sulfinpirazon, terbinafine, bozentan. Preparations that increase the concentration of cyclosporine: some macrolide antibiotics (for example, 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 drug interactions. Care should be taken with the simultaneous use of the drug Sandimmune Neoral and drugs with nephrotoxic effects: aminoglycosides (including gentamicin, tobramycin), amphotericin B, ciprofloxacin, vancomycin, trimethoprim (+ sulfamethoxazole); NSAIDs (includingdiclofenac, naproxen, sulindac); melphalan, H2-histamine receptor antagonists (for example, cimetidine, ranitidine), methotrexate. The combined use of cyclosporine with tacrolimus should be avoided, since this may lead to an increased risk of nephrotoxicity. The combined use of nifedipine and cyclosporine can lead to more pronounced gingival hyperplasia than with cyclosporine monotherapy. With the simultaneous appointment of cyclosporine and lercanidipine, an increase in the AUC of lercanidipine by 3 times and the AUC of cyclosporine by 21% is noted. Caution must be exercised when using cyclosporine and lercanidipine in combination. It has been found that the combined use of diclofenac and cyclosporine can significantly increase the bioavailability of diclofenac, with the possible development of reversible kidney function. The increase in bioavailability of diclofenac is most likely associated with a decrease in its metabolism during the first passage through the liver. When used in conjunction with cyclosporine, NSAIDs with a less pronounced effect of the first passage (for example, acetylsalicylic acid), their bioavailability is not expected to increase. Cyclosporin can reduce the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins) and etoposide. Several cases of severe glycosidic intoxication have been reported for several days after starting treatment with cyclosporin in patients receiving digoxin. There are also reports that cyclosporine may enhance the toxic effects of colchicine, for example, the development of myopathy or neuropathy, especially in patients with impaired renal function. With simultaneous use of cyclosporine with digoxin or colchicine, careful clinical observation is necessary for the timely detection of the toxic effects of these drugs and for deciding whether to reduce the dose or cancel treatment. including muscle pain