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Cyclosporine Softgels Instructions
Please read the instructions carefully and use under the guidance of a physician. span>
Warning
Only physicians experienced in systemic immunosuppressive therapy should prescribe this product. When used in organ transplantation, this product should be prescribed only by physicians experienced in immunosuppressive therapy and transplant patient management. Transplant patients receiving drug therapy should be treated in a hospital with adequate medical care. The physician responsible for maintenance therapy should have the complete information necessary for patient follow-up.
This product is a systemic immunosuppressant and may put patients at increased risk for infection and tumor development. It may be used in combination with other immunosuppressive agents in patients undergoing organ transplantation. The increased risk of infection and lymphoma and other tumors in transplant patients may be due to an increased level of immunosuppression.
Emulsified cyclosporine softgels as well as oral solution and non-emulsified cyclosporine softgels as well as oral solution are not bioequivalent and should not be exchanged without physician monitoring. The exposure to cyclosporine is higher in this product than in the latter if the same trough concentration is used. Use special caution if switching to this product in patients receiving high doses of non-emulsifying cyclosporine therapy.
The transplant and rheumatoid arthritis patients taking this product should be cyclosporine blood concentrations should be monitored to avoid toxic reactions due to high concentrations. Dose modulation should be performed in transplant patients to reduce organ rejection due to low concentrations. Comparison of blood concentrations of cyclosporine in the published literature with those obtained in the current trial must be performed with detailed knowledge of the assay used.
For patients with psoriasis (see also “Warnings” above)
Patients with psoriasis previously treated with photochemotherapy (PUVA), followed by methotrexate or other immunosuppressive agents, medium-wave ultraviolet (UVB), coal tar, or radiation therapy, are at increased risk of skin malignancies when taking this product. There is an increased risk of occurrence.
Cyclosporine, the active ingredient in this product, causes hypertension and nephrotoxicity at the recommended dose of administration. This risk increases with increasing dose and duration of cyclosporine therapy. Cyclosporine therapy has the potential to cause renal insufficiency, including structural kidney damage, and therefore renal function must be monitored during therapy.
[Drug Name].
Generic name: Cyclosporine softgels
Trade name: Tianke
English Name: Ciclosporin Soft Capsules
Hanyu Pinyin: Huanbaosu Ruanjiaonang
[Ingredients] The main ingredient of this product is cyclosporine.
Chemical name: cyclic [[(E)-(2S,3R,4R)-3-hydroxy-4-methyl-2-(methylamino)-6-octenyl]-L-2aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-leucyl alanyl-N-methyl-L-valyl]
Chemical structural formula.
Molecular formula: C62H111N11O12
Molecular weight: 1202.63
[Properties
This product is a soft capsule with yellow to slightly yellow or brown to slightly brownish-yellow oily liquid content.
[Indications
1. Transplantation
a. Organ transplantation
—Prevention of rejection of allografts, including renal, hepatic, cardiac, pulmonary, combined cardiopulmonary and pancreatic transplants.
–Treatment of graft rejection in patients who have received other immunosuppressive agents.
b. Bone marrow transplantation
–Prevention of bone marrow transplant rejection.
–Prevention and treatment of graft-versus-host disease (GVHD).
2. Non-transplant indications
The person who diagnoses and decides to prescribe this product should be a physician with experience in the use of immunosuppressive agents, particularly cyclosporine (see [Precautions]).
a. Endogenous uveitis
–Active central or posterior noninfectious uveitis with risk of blindness in which conventional therapy is ineffective or produces unacceptable adverse effects.
– Behcet’s uveitis with recurrent retinitis in patients aged 7-70 years with normal renal function.
b. Psoriasis
Severe cases in which alternate therapies have failed or are not indicated.
c. Atopic dermatitis
Severe cases where conventional therapies are ineffective or inapplicable.
d. Rheumatoid arthritis
e. Nephrotic syndrome
–Patients with idiopathic corticosteroid-dependent and antagonistic nephrotic syndrome (biopsy-proven microdegenerative nephropathy [MCD] or focal segmental glomerulosclerosis [FSGS] in most cases) who have failed conventional cytostatic therapy but have at least 50% normal renal function remaining. The application of this product may provide remission or maintain the remission produced by other drugs, including corticosteroids, thereby discontinuing other drugs.
[SIZE] 25 mg; 50 mg.
[Dosage].
Oral treatment with this product is recommended for most cases, except in some cases where intravenous cyclosporine concentrate is required. It is more rapidly absorbed than cyclosporine non-microemulsified oral solution (mean time to peak is 1 hour earlier, mean peak concentration is 59% higher), and its bioavailability (AUC) is on average 29% higher in renal transplant patients receiving maintenance doses. In patients with very poor absorption of oral non-microemulsified cyclosporine (especially those taking large oral doses), the increase in cyclosporine bioavailability they obtained after conversion of this product in equal doses may exceed 100%.
The total daily dose of this product should be divided into two doses (morning and evening).
See the specific requirements for dosing and renal function monitoring in patients treated with cyclosporine non-microemulsifiable prior to conversion in “Conversion of Cyclosporine Non-microemulsifiable Formulations to this product.
Transplantation
The following dose ranges are intended as a guide for dosing only. Routine monitoring of cyclosporine blood levels is important and can be determined by monoclonal antibody methods. This result can be used to determine the dose of this product to achieve the desired blood concentration (see [Precautions]).
1.1 Organ transplantation
Treatment with this product should be initiated 12 hours prior to transplantation with 10 to 15 mg/kg/day administered in two divided doses. This dosage should be maintained until 1-2 weeks postoperatively. The dosage is then tapered to 2-6 mg/kg/day in two oral doses according to blood levels.
– In renal transplant recipients, the risk of rejection can be increased by cyclosporine blood concentrations below 50-100 ng/ml when receiving lower doses than 3 to 4 mg/kg/day.
-When this product is used in combination with other immunosuppressive drugs (e.g., in combination with corticosteroids as part of a triple or quadruple dose), the starting dose is 3 to 6 mg/kg/day in two oral doses.
1.2 Bone marrow transplantation
Dosing is initiated the day before transplantation, preferably by intravenous drip. If oral administration of this product is being prepared at the time of initiation, it should be administered the day before transplantation at a recommended dosage of 12.5 to 15 mg/kg/day. The maintenance dose is approximately 12.5 mg/kg/day and should be continued for 3-6 months (preferably 6 months). The dose is then gradually reduced until it is discontinued 1 year after transplantation. Gastrointestinal disorders may reduce drug absorption, and this group of patients requires higher doses of this product or intravenous administration.
-The total daily dose of this product should be taken orally in two divided doses (morning and evening).
-Some patients may develop GVHD after stopping cyclosporine, but usually respond well to re-dosing. In this case, an initial oral loading dose of 10 to 12.5 mg/kg should be given, followed by a previously appropriate daily maintenance dose. A smaller dose of this product is appropriate for the treatment of chronic mild GVHD.
2. Non-organ transplant indications
When using this product in non-transplant indications, the following general principles should be followed.
– Reliable baseline serum creatinine levels should be determined by at least two determinations prior to initiation of therapy, and renal function should be assessed periodically during therapy to allow for real-time dose adjustments.
-Oral administration is the only acceptable route of administration (intravenous infusion concentrates should not be used), and the daily dose should be divided into two doses.
-The total daily dose should not exceed 5 mg/kg, except in pediatric patients with endogenous uveitis and nephrotic syndrome, which can cause vision loss.
-The lowest effective and well-tolerated dose for maintenance therapy should be determined on an individual basis.
– Treatment should be discontinued if appropriate efficacy is not demonstrated within a given time frame (see below for specific information) or if the effective dose does not meet established safety guidelines.
There is no experience with non-intestinal administration in patients with non-transplant indications.
2.1 Endogenous uveitis
Dose
–The starting dose is 5 mg/kg/day orally in two divided doses until the inflammation resolves and vision improves. Its short-term dose can be increased to 7 mg/kg/day for those who do not have significant efficacy.
– If the condition is not effectively controlled with this product alone, systemic administration of corticosteroids (e.g., prednisone 0.2 to 0.6 mg/kg/day) may be used to accelerate remission and/or control of ocular inflammation. If the condition does not improve within 3 months, discontinue the product.
– To maintain efficacy, the dose of this product should be tapered to the minimum effective dose. During the remission period, the dose of this product should not exceed 5 mg/kg/day.
Renal Function Monitoring
–This product may impair renal function. Therefore, serum creatinine should be measured at least twice before the start of therapy to obtain a reliable baseline serum creatinine value, and then the corresponding creatinine clearance should be calculated from each of the two serum creatinine values by an appropriate method (e.g., DETTLI), and both values should be within the normal range. Serum creatinine and blood pressure should be measured weekly during the first 4 weeks of treatment and monthly thereafter. If the dose of this product is increased, the frequency of measurement should be increased. If the patient’s serum creatinine value exceeds 30% of the baseline value, the dose should be reduced by 25%-50%, even if the value is still within the normal range. If this creatinine value does not decrease within 1 month, discontinue the product. Short-term creatinine values above 20%-30% of baseline should be repeated to exclude the possibility of temporary non-nephrogenic increase in serum creatinine. If blood pressure significantly exceeds the baseline value, antihypertensive therapy should be given. If uncontrolled, the product should be discontinued.
2.2 Dermatologic indications
Psoriasis
Dose.
–For remission, the recommended initial dose is 2.5 mg/kg/day in two oral doses. If there is no improvement after 4 weeks of treatment, the dose may be gradually increased by 0.5 to 1.0 mg/kg/month, but should not exceed 5 mg/kg/day. 5 mg/kg/day should be discontinued if the lesions do not improve after 4 weeks of use or if the effective dose does not meet the following safety guidelines (see [Precautions]). The initial dose may be adjusted to 5 mg/kg/day in some cases where rapid improvement is needed.
–To maintain efficacy, the dose should be adjusted separately to the minimum effective dose for each patient, but should not exceed 5 mg/kg/day. If symptoms persist in remission for more than 6 months, the drug should be discontinued, although relapse may increase after discontinuation.
Atopic dermatitis
Dosage.
–In adults and young adults 16 years of age and older, the recommended dose range is 2.5 to 5.0 mg/kg/day in two oral doses. If satisfactory efficacy is not achieved within 2 weeks with the initial dose of 2.5 mg/kg/day, the maximum dose of 5 mg/kg/day may be rapidly increased. In very severe cases, an initial dose of 5 mg/kg/day may be required for rapid and effective control of the disease.
– There is little experience with the long-term use of cyclosporine in the treatment of atopic dermatitis. Therefore, it is recommended that the maximum duration of treatment should not exceed 8 weeks.
If a dose of 5 mg/kg/day is used and satisfactory results are not achieved within 1 month, discontinue this product.
Warnings.
– Prior to treatment, patients should be fully informed about the therapeutic benefits and possible risks of this product, as well as the greater susceptibility to relapse after discontinuation of the drug.
–Patients with renal insufficiency, uncontrolled hypertension or infection, and any other malignancy other than skin should not receive this product. And this product should be used with caution in patients with hyperuricemia (see [Precautions]).
—This product should also be discontinued if hypertension occurs during the use of this product and is not controlled with antihypertensive therapy.
—Renal function monitoring: see “Endogenous Uveitis” above.
—Schoriasis and skin tumors: In cases treated with cyclosporine, malignancies (especially skin cancer) have been reported, as in those treated with conventional therapy. Prior to application of this product, biopsies should be performed if the patient has skin lesions that are not typical of psoriasis or if cancerous or precancerous lesions are suspected. It should be used only after treatment of such lesions and when no other effective therapy is available for those with concomitant skin cancer or precancerous lesions (see [Precautions]).
– Atopic dermatitis and skin infections: For active herpes simplex infections, the skin should be cleared before starting this product. If these occur during the use of this product, it is not necessary to discontinue the drug unless the infection is severe. Staphylococcus aureus skin infections are not an absolute contraindication to this product, but appropriate antibiotic therapy is required. However, erythromycin should not be given orally because it can increase the blood concentration of cyclosporine (see [Drug Interactions]). If no other antibiotic is available to replace erythromycin, close monitoring of cyclosporine blood concentrations, renal function, and symptoms of adverse reactions is necessary.
2.3 Rheumatoid arthritis
Dose.
The recommended dose for the first 6 weeks is 3 mg/kg/day in two oral doses.
If efficacy is not evident, the dose may be gradually increased to a maximum of 5 mg/kg/day. If the efficacy is still not significant within 3 months after dose adjustment, discontinue the product.
In addition, the maintenance dose must be adjusted individually to the lowest effective dose, depending on the degree of tolerance of each individual. It can be combined with low-dose corticosteroids and/or nonsteroidal anti-inflammatory drugs.
Warnings.
–Patients should be fully informed about the therapeutic benefits and possible risks of this product prior to treatment.
–Patients with renal insufficiency, uncontrolled hypertension or infection, and any malignancy should not receive this product. And this product should be used with caution in patients with hyperuricemia or hyperkalemia (see [Precautions]).
Renal function monitoring
–Cyclosporine may impair renal function. Therefore, serum creatinine should be measured at least twice prior to initiation of therapy to obtain reliable baseline serum creatinine values, and the corresponding creatinine clearance should be calculated from each of the two serum creatinine values by an appropriate method (e.g., DETTLI), both of which should be within the normal range. Serum creatinine and blood pressure should be measured weekly during the first 4 weeks of treatment and monthly thereafter. However, if the dose of this product is increased, if it is started in combination with NSAIDs or if the dose is increased, it may be necessary to increase the frequency of measurement. If a patient’s serum creatinine value exceeds 30% of the baseline value more than once, the dose should be reduced even if the value remains within the normal range.
Serum creatinine exceeding 20%-30% of baseline in some cases should be measured repeatedly to rule out a temporary non-nephrogenic increase in serum creatinine. If 50% of the baseline value is exceeded, the dose should be reduced by 50%. If no improvement is seen within 1 month of dose reduction, the product should be discontinued.
If blood pressure significantly exceeds baseline values, antihypertensive therapy should be given. If it is not controlled, then the product should be reduced or discontinued.
As with other long-term immunosuppressive agents, there is an increased risk of proliferative lymphoid lesions, which should be taken into account (see [Precautions]).
2.4 Nephrotic syndrome
Dose.
–For symptomatic relief, the recommended dose is 5 mg/kg/day in adults and 6 mg/kg/day in children, divided into two oral doses. The initial dose should not exceed 2.5 mg/kg/day in patients with renal insufficiency yet at a permissible level (the product is contraindicated in adults with serum creatinine above 200 micromol/liter and in children above 140 micromol/liter).
–If the efficacy of this product alone is not satisfactory, especially in corticosteroid-tolerant patients, a combination of this product with low-dose corticosteroids is recommended. If the efficacy is still unsatisfactory after 3 months, discontinue the product.
The dose used in patients should be adjusted individually based on efficacy (proteinuria) and safety (mainly based on serum creatinine). However, the dose should not exceed 5 mg/kg/day in adults and 6 mg/kg/day in children.
–To maintain efficacy, the dose should be tapered to the minimum effective dose.
Renal function monitoring.
–Cyclosporine may impair renal function. Therefore, serum creatinine should be measured at least twice before the start of therapy to obtain reliable serum creatinine values. Serum creatinine and blood pressure should be measured weekly during the first 4 weeks of treatment and monthly thereafter. If the dose of this product is increased, the frequency of measurement should be increased. If a patient’s serum creatinine value exceeds 30% of the baseline value, the dose should be reduced by 25%-50%. In some patients, serum creatinine values above 20%-30% of baseline should be measured repeatedly to exclude the possibility of a temporary non-renal creatinine increase.
– If blood pressure significantly exceeds baseline values, antihypertensive therapy should be given. If uncontrolled, the product should be reduced or discontinued.
–In patients with renal insufficiency yet at a permissible level, their initial dose should not exceed 2.5 mg/kg/day and they should be closely monitored. This product is contraindicated if serum creatinine exceeds 200 micromol/L in adults and 140 micromol/L in children (see [Precautions]).
In patients with nephrotic syndrome who have pre-existing renal impairment, it is difficult to determine whether the changes in renal tissue are due to this product. This is why reports of “structural changes in renal tissue without elevated serum creatinine” are rare. Therefore, renal biopsy should be considered in patients with corticosteroid-resistant microscopic nephropathy who have been on this product for more than a year.
There is no information on the use of this product in young children. There is also limited information on the use of cyclosporine non-microemulsifiable formulations in this age group, although some reports suggest that it is safe for children over 1 year of age to receive standard doses. Several pediatric studies have shown that children require and can tolerate higher doses per kilogram of body weight than adults. In addition, serum creatinine values (preferably along with cyclosporine blood concentrations) should be closely monitored in patients with severe hepatic dysfunction. If necessary, make dose adjustments.
Conversion of cyclosporine non-microemulsifiable formulations to this product
The available data suggest that the lowest concentrations of cyclosporine in whole blood are similar after 1:1 conversion of non-emulsified cyclosporine softgels to emulsified cyclosporine softgels. However, many patients may experience elevated peak concentrations (Cmax) as well as increased drug exposure (AUC). In a small number of patients, these changes are more pronounced and may be clinically significant. The amount of variation depends to a large extent on individual differences in cyclosporine absorption with the original use of nonemulsified cyclosporine softgels, which are known to have a high degree of variability in bioavailability. Patients with variable minimum levels of non-emulsified cyclosporine softgels or very high doses administered may have poor or inconsistent absorption of cyclosporine (e.g., patients with cystic fibrosis, liver transplant patients with cholestasis or poor bile secretion, children, or some renal transplant recipients) who may be well absorbed when switching to emulsified cyclosporine softgels. Therefore, the increase in cyclosporine bioavailability in this group of patients following a 1:1 conversion from non-emulsified cyclosporine softgels to emulsified cyclosporine softgels may be greater than the results normally seen. Therefore, the dose of emulsified cyclosporine softgels should be reduced individually according to their target minimum level range.
It is important to emphasize that there is less variability in cyclosporine absorption following administration of emulsified cyclosporine softgels compared with non-emulsified cyclosporine softgels, and the correlation between the lowest cyclosporine concentration and exposure (AUC) is more pronounced. This makes cyclosporine minimum blood concentration a more stable and reliable parameter for therapeutic drug monitoring.
Because switching from non-emulsified cyclosporine softgels to this product may result in increased drug exposure, the following outcomes must be observed.
The daily dose of emulsified cyclosporine softgels administered to transplant patients should be the same as the previously used non-emulsified cyclosporine softgels. Monitoring of minimum concentrations of cyclosporine in whole blood should be initiated within the first 4 to 7 days after conversion to emulsified cyclosporine softgels. In addition, clinical safety parameters (e.g., serum creatinine and blood pressure) should be monitored during the first 2 months following the switch. If the minimum blood concentration of cyclosporine is outside the therapeutic range and/or clinical safety parameters deteriorate, the dose must be adjusted accordingly.
Patients undergoing treatment for non-transplant indications should have the same daily dose of cyclosporine softgels administered as non-emulsified cyclosporine softgels. Serum creatinine levels and blood pressure should be monitored during the 2, 4, and 8 weeks after conversion. If serum creatinine levels are significantly higher than pre-conversion levels in more than 1 measurement, or if blood pressure is significantly higher than pre-conversion levels, or if serum creatinine levels are more than 30% higher than before treatment with non-emulsified cyclosporine softgels, the dose should be reduced (see [Precautions]). Minimum blood levels should also be monitored if unexpected toxicity or cyclosporine ineffectiveness occurs.
Conversion of oral cyclosporine products
Conversion from one oral cyclosporine to another needs to be done with caution and under the supervision of a physician. Switching to a new oral cyclosporine must involve monitoring blood levels to ensure that they reach the levels that were present with the original oral cyclosporine.
3. Dosing guidelines
See General Instructions.
The daily dose of this product should be taken by mouth in two divided doses (morning and evening).
When opening the capsule foil package, a distinctive odor may be detected, which is normal and not a problem with the capsule.
Capsules should be swallowed whole (see “General Instructions”).
Other information
General information
The capsule may be removed from the foil package before you are ready to take it. In some cases (especially in light-weight individuals), where their total all-day dose cannot be divided precisely into morning and evening portions, the following method is used.
-give different doses in the morning and evening
– If the above approach is unsuccessful, the patient may need to be switched to an oral solution.
[Adverse effects
The major adverse reactions observed in clinical trials and associated with the use of cyclosporine include renal insufficiency, tremor, hirsutism, hypertension, diarrhea, anorexia, nausea, and vomiting.
Many of the adverse reactions associated with cyclosporine therapy are dose-dependent and diminish with dose reduction. The range of adverse reactions was generally consistent across all indications and varied only in incidence and severity. Because of the higher starting dose and longer duration of maintenance therapy required for the indications used for transplantation, adverse reactions were more common and more severe in transplant recipients than in patients treated for other indications.
Allergic reactions have been reported after intravenous administration.
Infection
Patients receiving immunosuppressive therapy, including cyclosporine and cyclosporine-containing dosing regimens, are at increased risk of infection (viral, bacterial, fungal, parasitic) (see [PRECAUTIONS]). Both systemic and localized infections may occur. Pre-existing infections may also be exacerbated. Polyomavirus infection may lead to polyomavirus-associated nephropathy (PVAN) or JC virus-associated progressive multifocal leukoencephalopathy (PML). Serious or fatal events have been reported.
Tumors: benign, malignant, and undetermined (including cysts and polyps)
Patients receiving immunosuppressive therapy, including cyclosporine and cyclosporine-containing dosing regimens, are at increased risk of developing lymphoma or lymphoproliferative disorders and other malignancies, particularly skin cancer. The frequency of malignancies may be increased with increased intensity and duration of drug therapy (see [Precautions]). Some malignancies may be fatal. However, their incidence and distribution in transplant patients is similar to that of patients receiving conventional immunosuppression.
Adverse drug reactions observed in clinical trials are listed according to the MedDRA organ classification system. Within each organ system category, adverse drug reactions were ranked in order of frequency of occurrence, with the most common ranked first. Within each frequency grouping, adverse drug reactions were ranked in order of severity from most to least severe. The following conventional classification of adverse drug reaction frequency was used (CIOMS III): very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000) rare (< 1/10,000), including isolated case reports.
Table 1 Adverse drug reactions observed in clinical trials
hematologic and lymphatic lesions commonLeukopeniaMetabolic and nutritional disorders very commonAnorexiaNeurological disorders very commonTremors, headachesCommon CommonConvulsions. Sensory abnormalitiesDiseases of the vascular system very commonhypertensionCommonFlushingGastrointestinal Disorders very commonNausea, vomiting, abdominal discomfort, diarrhea, gum enlargementCommonPeptic UlcerHepatobiliary Disease CommonHepatotoxicityDermal and subcutaneous tissue lesions Very commonHirsutismCommonAcne, rashKidney and urinary tract lesions very commonRenal dysfunctionReproductive and Breast Diseases Rarely seenMenstrual disordersSystemic disease and site reactions to medication CommonFever, edema
Post-marketing adverse drug reactions
The following post-marketing adverse drug reactions were spontaneously reported and reported in the literature. Because they originated from spontaneous reports of uncertain population size, their frequency cannot be accurately estimated. Adverse drug reactions were categorized by MedDRA organ system. Within each organ system category, they are ranked in order of severity from most to least severe.
Table 2 Spontaneous reports and adverse drug reactions reported in the literature (frequency of occurrence unknown)
hematologic and lymphatic lesionsThrombotic microangiopathy, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, anemia, thrombocytopeniaMetabolic and Nutritional DiseasesHyperlipidemia Neurological DisordersEncephalopathies, including reversible posterior encephalopathy syndrome (PRES), signs and symptoms such as convulsions, confusion, disorientation, decreased reactivity, agitation, insomnia, visual disturbances, cortical blindness, coma, light paralysis, cerebellar ataxia; optic disc edema including optic nerve papilledema, possible visual impairment secondary to benign intracranial pressure increase; peripheral neuropathy; migraineGastrointestinal DisordersAcute pancreatitis Liver and gallbladder diseaseHepatotoxicity and liver injury including cholestasis, jaundice; hepatitis and liver failure (some leading to lethal outcomes)Dermal and subcutaneous tissue disordersMultiple hairsSkeletal muscle and connective tissue disordersMyopathy, muscle spasms, myalgia, muscle weakness, lower extremity painReproductive and breast disordersMale breast developmentSystemic disease and administration site reactions Fatigue, weight gainThere are active and post-marketing spontaneous reports of cyclosporine treatment patients with hepatotoxicity and liver injury, including cholestasis, jaundice, hepatitis, and liver failure. Most were reported in patients with severe co-morbidities, underlying diseases and other confounding factors, including infectious complications and coadministration of potentially hepatotoxic drugs. In some cases, death has been reported, primarily in transplant patients.
Patients treated with calcium-regulated phosphatase inhibitors (CNIs) including cyclosporine and cyclosporine-containing regimens are at increased risk of acute or chronic nephrotoxicity. Such reports have been reported in clinical trials and with post-marketing use of this product. Cases of acute nephrotoxicity were reported as impaired ion dynamic balance, such as hyperkalemia, hypomagnesemia, and hyperuricemia, with most cases occurring during the first month of treatment. Chronic morphologic changes reported in cases include hyaline degeneration of small arteries, tubular atrophy, and interstitial fibrosis.
BK viral nephropathy has been seen in patients treated with immunosuppressive agents, including cyclosporine. Such infections can lead to serious consequences including worsening renal function and loss of function of the kidney graft.
Isolated cases of lower extremity pain associated with cyclosporine use have been reported. As described in the literature, lower extremity pain has been annotated as part of calcium-modulated neurophosphatase inhibitor-induced pain syndrome (CIPS).
[Contraindicated]
Cyclosporine and any of its excipients are contraindicated in individuals with hypersensitivity to cyclosporine.
Contraindicated in children under 3 years of age and in patients with rheumatoid arthritis under 18 years of age.
Cyclosporine should not be taken concomitantly with tacrolimus.
Patients with rheumatoid arthritis
This product is contraindicated in patients with rheumatoid arthritis who have abnormal renal function, uncontrolled hypertension, or malignancy.
Patients with psoriasis
Patients with psoriasis treated with this product should not be treated with combination PUVA or UVB therapy, methotrexate or other immunosuppressive therapy, coal tar, or radiation therapy. This product is contraindicated in patients with psoriasis who have abnormal renal function, uncontrolled hypertension, or malignancy.
Warning
(See black box warning)
All patients
Cyclosporine may cause nephrotoxicity and hepatotoxicity. The risk increases with increasing cyclosporine dose. Treatment with this product has the potential to cause renal insufficiency, including structural renal damage, so renal function must be monitored during treatment. Caution should be exercised when cyclosporine is combined with nephrotoxic drugs. Cyclosporine
Patients treated with this product require frequent monitoring of serum creatinine. Older patients may have declining renal function due to age, so their monitoring should be especially careful. If patients are not monitored properly and doses are not adjusted appropriately, cyclosporine therapy may lead to structural renal damage, as well as persistent renal insufficiency.
Elevated serum creatinine and urea nitrogen (BUN) may occur during this treatment, suggesting a decrease in glomerular filtration rate. Frequent dose adjustments are required in addition to close monitoring once renal decompensation occurs. The frequency and severity of serum creatinine elevation increases with the dose and duration of cyclosporine therapy. If the dose is not adjusted downward or discontinued, serum creatinine is likely to rise further.
Because this product is not bioequivalent to non-emulsified cyclosporine softgels, switching from this product to non-emulsified cyclosporine softgels at a dose of 1:1 (mg/kg/day) may result in a decrease in cyclosporine blood concentrations. During the conversion process, monitoring should be increased to avoid underdosing.
Kidney, liver, and heart transplantation
Nephrotoxicity
Cyclosporine may cause nephrotoxicity and hepatotoxicity at high doses. It is not uncommon for increased serum creatinine and BUN concentrations to occur during cyclosporine therapy. The presence of elevations in these markers in renal transplant patients is not necessarily indicative of rejection, and a thorough analysis of each patient’s condition must be performed before dose adjustment.
According to previous experience with oral cyclosporine dosing, the incidence of cyclosporine-related nephrotoxicity was 25% in renal transplant cases, 38% in cardiac transplant cases, and 37% in liver transplant cases. Mild nephrotoxicity usually occurs 2 to 3 months after renal transplantation, when the preoperative elevated BUN and creatinine no longer fall back and levels remain at 35 to 45 mg/dl and 2.0 to 2.5 mg/dl, respectively. these indicators are further reduced by downward adjustment of cyclosporine dose.
A more pronounced nephrotoxic response is seen early after transplantation, usually in the form of rapid increases in BUN and creatinine. Because these events are similar to the manifestations of renal rejection, they must be carefully differentiated. Such nephrotoxicity usually resolves with cyclosporine dose downregulation.
While there are no definitive diagnostic criteria to reliably distinguish renal rejection from drug toxicity, there are parameters that may provide a valuable diagnostic reference. It is important to note that up to 20% of patients may have a combination of both nephrotoxicity and rejection.
Table 3 List of nephrotoxicity and rejection reactions
Nephrotoxicity and rejectionParametersNephrotoxicityExclusionMedical historyDonor age> 50 years old or with hypotension
Kidney kept for too long
Anastomosis time is too long
Combined use of nephrotoxic drugsAnti-donor immune response
re-transplant patientsClinicaloften occurs at >6 weeks postoperativelyb
Prolonged time to first nonfunction (acute tubular necrosis)Often occurs at <4 weeks postoperativelyb Fever> 37.5°C
Weight gain> 0.5 kg
Graft enlargement, pressure pain
Decreased daily urine output> 500 mL (or 50%)LabsCyclosporine A (CyA) serum trough concentration> 200 ng/mL
Cr slowly increasing (< 0.15 mg/dl/day)a
Cr ping table exceeds baseline value proportionally< 25%
BUN/Cr ≥ 20
CyA serum trough concentration< 150 ng/mL
Rapidly elevated Cr (> 0.3 mg/dl/day)a
Cr exceeds baseline value proportionally > 25%
BUN/Cr < 20Biopsysmall arteriopathy (mesenteric hypertrophya, hyaline degeneration, nodular deposits, endothelial thickening, endothelial vacuolization, progressive scar formation)
Nephron tubular atrophy, uniformly sized vacuoles, isolated foci of calcification
Mild edema
mild focal infiltratesc
Diffuse interstitial fibrosis, often streakyEndarteritisc ( hyperplasia, endarteritisb, necrosis, sclerosis)
tubulitis with RBCb and WBCb tubular pattern, scattered irregular vacuoles
Interstitial edemac and hemorrhageb
Diffuse moderate to severe mononuclear cell infiltrationd
Glomerulonephritis (mononuclear cell)cPuncture CytologyCyA deposition in renal tubules and endothelial cells
Tiny uniform vacuoles are seen in renal tubular cellsInflammatory infiltrates formed by mononuclear phagocytes, macrophages, lymphoblasts, and activated T inflammatory infiltrates formed by mononuclear phagocytes, macrophages, lymphoblasts and activated T cells
These cells abundantly express HLA-DR antigensUrine cytologyRenal tubular cells with vacuoles and granulesDenatured renal tubular cells, plasma cells and lymphocytes in the urine sediment>20%Pressure measurement
Ultrasound
Intracapsular pressure< 40 mm Hgb
No change in graft cross-sectional volumeIntracapsular pressure> 40 mm Hgb
Graft cross-sectional volume increase
Anteroposterior diameter ≥ Transverse diameterMagnetic Resonance Imagingnormal imageUnclear renal dermal medullary junction, swollen renal parenchymal signal intensity close to psoas muscle, loss of hilar fat Radionuclide scanNormal or mostly reduced perfusion
Amplitude of decrease in renal tubular function (131I-hippuran)> magnitude of decrease in perfusion (99mTc DTPA) Lamellar artery blood flow
Amplitude of reduction in perfusion> amplitude of reduction in renal tubular function
indium111-labeled platelets or increased colloidal Tc-99m uptakeTreatmentDownward adjustment of cyclosporine dose is effectiveIncreasing the dose of steroids or anti-lymphocyte globulin therapy is effectiveap< 0.05, bp< 0.01, cp< 0.001, dp< 0.0001Sequential deterioration of renal function and altered renal morphology are characteristic of cyclosporine-associated nephropathy when it occurs. Five to 15% of transplant recipients with elevated serum creatinine do not experience a decrease in creatinine levels after cessation of cyclosporine therapy. Renal biopsies in this subset of patients may reveal the following changes: tubular vacuolization, foci of tubular microcalcifications, peritubular capillary congestion, small arteriopathy, and striated interstitial fibrosis with tubular atrophy. Although these morphological changes lack specificity, they are still essential for the diagnosis of cyclosporine-associated structural nephrotoxicity.
In the context of studies on the pathogenesis of cyclosporine-associated nephropathy, some authors have claimed an association between interstitial fibrosis and increased cumulative doses of cyclosporine or sustained high trough concentrations. This observation applies particularly to the 6 months following transplantation, when doses are near their highest and organs in the kidney recipient are most sensitive to the toxic effects of cyclosporine. Other factors contributing to the development of interstitial fibrosis in these patients include duration of perfusion, prolonged thermal ischemia, as well as acute toxic reactions, acute and chronic rejection. The reversibility of interstitial fibrosis and the relationship to renal function are currently unclear. Small arteriopathies have been reported to be reversed with discontinuation of cyclosporine or dose reduction.
Once renal hypofunction occurs, frequent dose adjustments are required in addition to close monitoring.
When severe and persistent rejection occurs and steroid shock and monoclonal antibody remedial therapy fail to reverse the rejection, consider switching to other immunosuppressive therapy rather than overincreasing the dose of emulsified cyclosporine.
Vascular embolic microangiopathy
Sometimes patients may already have a syndrome consisting of thrombocytopenia and microangiopathic hemolytic anemia, which can lead to graft failure. The development of vasculopathy is not necessarily accompanied by rejection, but a large platelet depletion within the graft can be detected by indium111-labeled platelet examination. The pathogenesis of this syndrome is unclear, and there is no definitive management. Although the disease may resolve after discontinuation of cyclosporine or downward dose adjustment plus 1) streptokinase and heparin 2) plasma exchange, this is not possible without early detection of the disease by indium111-labeled platelet scans. (See Adverse Reactions)
Hyperkalemia
Severe hyperkalemia (sometimes combined with hyperchloremic metabolic acidosis) and hyperuricemia have occasionally occurred in individual patients.
Hepatotoxicity
Cyclosporine-treated patients have reported cases of hepatotoxicity and liver injury (including cholestasis, jaundice, hepatitis, and liver failure). Most reports included the presence of significant co-morbidities, underlying diseases and other confounding factors, including infectious complications and concomitant use of potentially hepatotoxic drugs. Lethal outcomes were reported in some cases, primarily in organ transplant patients (see Adverse Reactions, Postmarketing Experience, Kidney, Liver, and Heart Transplantation).
Hepatotoxicity has been reported in cyclosporine-treated patients in clinical trials, usually in the form of elevated liver enzymes and bilirubin: The incidence of cyclosporine-associated hepatotoxicity was 4% in renal transplant cases, 7% in cardiac transplant cases, and 4% in liver transplant cases. Hepatotoxicity usually occurs in the first month of treatment with higher doses of cyclosporine and manifests as elevated liver enzymes and bilirubin. These assays often decrease after dose downregulation.
Malignancy
Like patients on other immunosuppressive drugs, patients treated with cyclosporine are at increased risk for lymphoma and other malignancies, especially cutaneous malignancies. Physicians should caution cyclosporine-treated patients to avoid excessive exposure to ultraviolet light. The degree of increased risk may be related to the intensity and duration of immunosuppression, independent of the specific drug used. Given the increased risk of infection and malignancy associated with excessive immune system suppression, combination regimens of multiple immunosuppressive agents should be used with caution. Some malignancies can lead to patient death. Transplant patients treated with cyclosporine are more likely to develop lethal serious infections.
Severe infections
Patients receiving immunosuppressive therapy, including cyclosporine, are at elevated risk for bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections can lead to serious and sometimes fatal outcomes (see black box for warnings and adverse reactions).
Polyomavirus infections
Patients receiving immunosuppressive therapy, including cyclosporine, are at increased risk for opportunistic infections, including polyomavirus infections. Polyomavirus infections in transplant patients may produce serious and sometimes fatal outcomes. These include cases of JC virus-associated progressive multifocal leukoencephalopathy (PML) and polyomavirus-associated nephropathy (PVAN), particularly caused by BK virus infection, which has been observed in patients treated with cyclosporine.
PVAN is associated with serious outcomes, including worsening renal function and transplant kidney failure (see Adverse Reactions/Postmarketing Experience, Kidney, Liver, and Heart Transplantation). Patient monitoring may help detect patients at risk for PVAN.
Cyclosporine-treated patients have reported cases of PML, which is sometimes fatal and often associated with hemiparesis, apathy, confusion, cognitive impairment, and ataxia. risk factors for PML include immunosuppressive therapy and impaired immune function. In immunosuppressed patients, physicians should consider PML in the differential diagnosis of patients reporting neurologic symptoms and should consider a neurologist consultation when clinically indicated.
Transplant patients who develop PML or PVAN should be considered for reduction in overall immunosuppression intensity.
However, reducing the intensity of immunosuppression may cause graft risk.
Neurotoxicity
Convulsions have been reported in adult and pediatric patients during the use of cyclosporine, especially in combination with high-dose methylprednisolone.
Encephalopathy has been reported in post-marketing reports and in the journal literature. Its manifestations include impaired consciousness, convulsions, visual disturbances (which can be blinding), loss of motor function, movement disorders, and psychiatric disorders. Imaging and pathological diagnoses in many cases show white matter changes. Predisposing factors such as hypertension, hypomagnesemia, hypercholesterolemia, high doses of corticosteroids, high cyclosporine blood levels, and graft-versus-host disease are present in many cases, but predisposing factors are not found in every case report. These changes are usually reversed after cyclosporine discontinuation, and in some cases, improvement is observed with only a downward dose adjustment. From the data, liver transplant patients are more susceptible to encephalopathy than renal transplant patients. Another rarer manifestation of cyclosporine-induced neurotoxicity is optic disc edema and optic nerve papilloedema secondary to benign intracranial hypertension, in which vision may be affected, which occurs more frequently in transplant patients than in other indications.
Caution should be exercised when combining cyclosporine with nephrotoxic drugs (see [Precautions]).
[Precautions].
This product should be prescribed by a physician experienced in immunosuppressive therapy with adequate follow-up (including periodic systemic physical examinations, blood pressure measurements, and control of laboratory safety parameters). Transplant patients receiving drug therapy should be treated in a hospital with adequate medical care. The physician responsible for maintenance therapy should have complete information necessary for patient follow-up.
As with other immunosuppressive agents, cyclosporine increases the risk of lymphoma and other malignancies, particularly skin cancer. This increased risk is shown to be related to the degree and duration of immunosuppression and not to the use of specific agents. Because this can lead to lymphoproliferative disorders and organ solid tumors, in which isolated deaths have been reported, regimens that include multiple immunosuppressive agents, including cyclosporine, should be used with caution.
Considering the potential risk of skin malignancies, patients using this product should be cautioned to avoid excessive exposure to UV light.
Like other immunosuppressive agents, cyclosporine can predispose patients to a variety of bacterial, fungal, parasitic, and viral infections, often with conditionally pathogenic bacteria. Potential polyomavirus infections that may lead to polyomavirus-associated nephropathy (PVAN), particularly BK virus-associated nephropathy (BKVN), or JC virus-associated progressive multifocal leukoencephalopathy (PML), have been reported in patients receiving cyclosporine. These are usually associated with excessive immunosuppression and should also be differentially diagnosed from the deterioration of renal function and neurological symptoms associated with the use of immunosuppression. Serious or fatal outcomes have been reported. Effective prevention and treatment strategies should be implemented, especially in patients on long-term multiple immunosuppressive therapy.
A common and potentially serious complication, increased serum creatinine and urea nitrogen levels, may occur during the first few weeks of treatment with this product. These functional changes are dose-dependent and reversible, and usually diminish with lower doses administered. During long-term treatment, structural changes in the kidney (e.g., interstitial fibrosis) may occur in some patients, and such changes must be distinguished from changes in renal transplant patients due to the development of chronic rejection. This product may also cause a dose-dependent and reversible increase in serum bilirubin and liver enzymes. There are active and spontaneous postmarketing reports of hepatotoxicity and liver injury in cyclosporine-treated patients, including cholestasis, jaundice, hepatitis, and liver failure. Most were reported in patients with serious co-morbidities, underlying diseases, and other confounding factors, including infectious complications and coadministration of potentially hepatotoxic drugs. Death has been reported in some cases, primarily in transplant patients. Close monitoring of hepatic and renal function parameters is required. The dose administered should be reduced when abnormal values occur.
In elderly patients, special attention should be paid to monitoring of renal function.
For monitoring cyclosporine levels in whole blood, a specific monoclonal antibody (to measure the parent drug) is preferred, or an HPLC method that also measures the parent drug may be used. If plasma or serum is used, a standard isolation protocol (time and temperature) should be used. For initial monitoring of liver transplant patients, specific monoclonal antibodies should be used or a parallel assay of specific and nonspecific monoclonal antibodies should be used to ensure that an adequate dose of immunosuppression is provided.
It is important to remember that cyclosporine concentrations in whole blood, plasma, or serum are only one of many factors that affect the clinical status of a patient. Therefore, these results should only be used in combination with other clinical and laboratory parameters to guide dosing.
Monitor blood pressure regularly during treatment with this product and provide appropriate antihypertensive therapy if hypertension develops. Prioritize antihypertensive agents that do not affect cyclosporine pharmacokinetics, such as ilaridipine. .
Mildly reversible elevations in lipids have been reported with nonemulsifying cyclosporine, so lipid measurements are recommended before and after 1 month of treatment. If elevated lipids are found, consideration should be given to limiting fat-containing foods or reducing the dose administered.
Cyclosporine can increase the risk of hyperkalemia, especially in patients with renal dysfunction. Therefore caution should also be exercised when cyclosporine is used in combination with potassium-preserving agents (e.g., potassium-preserving diuretics, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists) and potassium-containing drugs, and in patients consuming potassium-rich foods (see Interactions with Other Drugs). Potassium level control is recommended in these situations.
Cyclosporine increases the clearance of magnesium. This can lead to symptomatic hypomagnesemia, especially during transplantation. Therefore, control of serum magnesium levels during transplantation is recommended, especially in the presence of neurologic signs/symptoms. If deemed necessary, magnesium should be supplemented.
Caution should be exercised in the treatment of patients with hyperuricemia.
The effectiveness of vaccination may be reduced during treatment with cyclosporine; live attenuated vaccines should be avoided.
Cyclosporine should be observed in combination with lercanidipine (see Interactions with Other Drugs).
Cyclosporine may increase blood levels of cotrimoxazole efflux transporter P glycoprotein or organic anion transport protein (OATP) substrates such as aliskiren, dabigatran, or bosentan. The combination of cyclosporine with aliskiren is not recommended. The combination of cyclosporine with dabigatran or bosentan should be avoided. These recommendations are based on the potential clinical impact of these interactions (see [Drug Interactions]).
The effects of ethanol contained in this product should be considered when used by pregnant or nursing women, patients with liver disease or epilepsy, patients with alcoholism, or children.
Other considerations for non-transplant indications
Cyclosporine should not be used in patients with renal impairment (except in patients with renal disease with permissive renal impairment), uncontrolled hypertension, uncontrolled infection, or any other type of malignancy.
Other considerations for endogenous uveitis
Because this product can impair renal function, renal function must be assessed frequently and the dose of this product should be reduced by 25% to 50% if serum creatinine is consistently more than 30% above baseline in more than 1 measurement. If serum creatinine increases by more than 50% of the baseline value, a further dose reduction should be considered. These recommendations apply even if the patient’s test values remain within normal laboratory values.
Patients with leukoaraiosis (Behcet’s syndrome) who have neurologic impairment should be noted for emulsified cyclosporine use. The neurologic status of these patients should be carefully monitored.
There is limited experience with this product in the treatment of endogenous uveitis in children.
Other considerations in nephrotic syndrome
Because this product can impair renal function, renal function must be evaluated frequently. If serum creatinine is consistently more than 30% above baseline on more than 1 measurement, the dose of this product should be reduced by 25% to 50%. If serum creatinine increases by more than 50% of the baseline value, a further dose reduction should be considered. Patients with abnormal baseline renal function should be initiated on a dose of 2.5 mg/kg/day and should be monitored closely.
Some patients may have difficulty detecting renal dysfunction caused by this product due to the occurrence of renal function changes related to the nephrotic syndrome itself. This explains why very few cases have developed renal structural changes associated with this product without elevated serum creatinine levels. Renal tissue biopsy should be considered in patients with steroid-dependent microdegenerative nephropathy who have been treated with this product for more than 1 year.
Malignancies (including Hodgkin’s lymphoma) have occasionally been reported in patients with nephrotic syndrome treated with immunosuppressive agents, including cyclosporine injection.
Other considerations for rheumatoid arthritis
Because this product can impair renal function, reliable baseline serum creatinine levels should be determined by at least 2 measurements prior to treatment and monitored weekly during the first 3 months of treatment and monthly thereafter. After 6 months of treatment, serum creatinine levels should be measured every 4 to 8 weeks depending on disease stability, co-morbidities and concomitant disease. The frequency of testing must be increased when the dose of this product is increased or when concomitant therapy with NSAIDs or increased doses of NSAIDs are administered.
If serum creatinine is consistently more than 30% higher than baseline in more than 1 measurement, the dose of this product should be reduced. If serum creatinine increases by 50%, the dose administered must be reduced by 50%. These recommendations apply even if the patient’s test values remain within normal laboratory values. If lowering the administered dose does not result in a reduction in serum creatinine levels within 1 month, treatment with this product should be discontinued.
Therapy with this drug may also be discontinued if hypertension that develops during treatment with this drug is not controlled by appropriate antihypertensive therapy.
Like other long-term immunosuppressive (including cyclosporine) therapies, the increased risk of lymphoproliferative disorders must be considered. Particular caution should be exercised when combining this product with methotrexate.
Other considerations for psoriasis
Because this product can impair renal function, reliable baseline serum creatinine levels should be established by at least 2 determinations before treatment and monitored weekly for the first 3 months of treatment. Thereafter, if serum creatinine levels remain stable, they should be measured at 1-month intervals. If serum creatinine levels are elevated and consistently more than 30% above baseline in more than 1 measurement, the dose of this product should be reduced by 25% to 50%. If serum creatinine increases by more than 50% of the baseline value, a further dose reduction should be considered. These recommendations apply even if the patient’s test values remain within the normal range of laboratory values. If lowering the administered dose fails to reduce serum creatinine levels within 1 month, treatment with this product should be discontinued.
Treatment with this product is also recommended to be discontinued if hypertension that develops during treatment with this product is not controlled by appropriate antihypertensive therapy.
Older patients should be treated only if they develop psoriasis disability, and renal function should be specifically monitored.
Experience with this product for the treatment of psoriasis in children is limited.
Patients with psoriasis treated with cyclosporine have been reported to develop malignancies (especially skin cancer) similar to those treated with conventional immunosuppressive therapy . Therefore, skin lesions that are not typical signs of psoriasis but are suspected to be malignant or pre-malignant should be biopsied before starting treatment with this product. Patients with malignant or pre-malignant skin changes that have no other successful treatment options should be treated with this product only after appropriate treatment of such skin lesions.
There have been several cases of lymphoproliferative disease in patients with psoriasis treated with non-emulsifying cyclosporine. Immediate discontinuation of the drug is effective.
Patients treated with this product should not receive concomitant UV-B segment irradiation or PUVA photochemotherapy.
Other considerations for atopic dermatitis
Because this product can impair renal function, reliable baseline serum creatinine levels should be determined by at least 2 determinations prior to treatment and monitored every 2 weeks for the first 3 months of treatment. Thereafter, if serum creatinine levels remain stable, they should be measured at 1-month intervals. If the serum creatinine level increases and is consistently more than 30% higher than baseline in more than 1 measurement, the dose of this product must be reduced by 25% to 50%. If serum creatinine increases by more than 50% of the baseline value, a further dose reduction should be considered. These recommendations apply even if the patient’s test values remain within normal laboratory values. If lowering the administered dose fails to reduce serum creatinine levels within 1 month, treatment with this product should be discontinued.
Treatment with this product is also recommended to be discontinued if hypertension that develops during treatment with this product is not controlled by appropriate antihypertensive therapy.
There is still limited experience to date with the use of this drug in children with atopic dermatitis, and therefore its use is not recommended in this patient population.
Elderly patients should be treated only if they develop atopic dermatitis disability and should be specifically monitored for renal function.
Benign lymphadenopathy is usually associated with the development of atopic dermatitis and resolves spontaneously or with improvement of the disease. Regular monitoring should be performed for lymphadenopathy that develops as a result of treatment with cyclosporine. As a preventive measure, lymphadenopathy that improves with disease but still persists should be biopsied to ensure the absence of lymphoma.
Active herpes simplex infection should be cleared before starting treatment with this product, but if the herpes occurs during treatment, it is not necessary to discontinue the drug unless the infection is severe.
The occurrence of a Staphylococcus aureus skin infection is not an absolute contraindication to treatment with this product, but should be controlled with appropriate antibacterial agents. Oral erythromycin, which is known to increase cyclosporine blood levels (see [Drug Interactions]), should be avoided, and close monitoring of cyclosporine blood levels, renal function, and its side effects is recommended if no alternative drug is available.
In view of the potential for skin cancer, patients treated with this product should avoid excessive unprotected sun exposure and should not receive concomitant UV-B band exposure or PUVA photochemotherapy.
Impact on ability to drive and use machines
No information is available on the effects of this product on the ability to drive and use machines.
[For pregnant and lactating women
Pregnancy
Animal tests have demonstrated reproductive toxicity in rats and rabbits (see [Pharmacology and Toxicology]).
There is a modest amount of data on the use of lactated cyclosporine in pregnant patients. Pregnant transplant recipients being treated with immunosuppressive agents are at increased risk of preterm delivery. Pregnant transplant recipients being treated with immunosuppressive agents (including cyclosporine and cyclosporine-containing combination regimens) are at increased risk of preterm delivery (<37 weeks).
The limited clinical observational data currently available on cyclosporine exposure in children from fetal to approximately 7 years of age suggest normal renal function and blood pressure in these children.
Because there are insufficient data in pregnant women, cyclosporine should not be used during pregnancy unless it can be demonstrated that the benefits to the mother outweigh the potential risks to the fetus. The effects of the ethanol content of this product should also be considered in pregnant women.
Lactation
Cyclosporine can be excreted into breast milk. The effect of the ethanol content of this product should also be taken into consideration. Therefore, lactating women on cyclosporine therapy should not lactate. Cyclosporine may cause serious adverse drug reactions in breastfeeding neonates/infants and the decision to stop breastfeeding or discontinue the drug should be based on the importance of the drug to the mother.
Fertility
There are limited data on the effects of this product on human fertility. Studies in male and female rats have shown no effect of cyclosporine on fertility.
[Pediatric Dosage].
Experience with cyclosporine treatment in pediatric patients remains limited. However, no specific problems have been seen in children over 1 year of age given non-emulsified cyclosporine at standard doses. In several trials, children required and tolerated higher doses of nonemulsified cyclosporine by weight than adults.
This product is not recommended for pediatric patients with non-transplant indications other than nephrotic syndrome.
[Geriatric Use].
Experience with cyclosporine therapy in elderly patients is limited, but no specific problems have been reported after dosing as recommended.
In clinical trials of oral use of cyclosporine for rheumatoid arthritis, 17.5% of patients ³ were 65 years old. These patients were more likely to develop systolic hypertension during treatment and their serum creatinine levels were more likely to be ³50% higher than baseline values at 3 to 4 months after treatment.
Adequate numbers of subjects aged ³ 65 years were not included in clinical trials of patients with transplantation and psoriasis treated with this product, designed to identify differences in response with younger subjects. Other reported clinical experience has also not shown a response difference between older and younger patients. In general, dose selection in older patients should be cautious, and dosing should generally be started at the lower end of the dosing range, as older patients are more likely to have decreased hepatic, renal, or cardiac function and concomitant disease or other drug therapy.
[Drug Interactions].
Food Interactions
Concurrent administration with grapefruit juice has been reported to increase the bioavailability of cyclosporine.
Drug interactions
A. Effects of Drugs and Other Substances on the Pharmacokinetics and/or Safety of Cyclosporine
The interactions between the drugs listed below and cyclosporine are well established. In addition, the combination of NSAIDs, especially when dehydrated, may promote the development of renal insufficiency.
Drugs that may cause renal insufficiency
AntibioticsAnti-tumor drugsAntifungalsAnti-inflammatory drugsGastroenterologyImmunosuppressantsOther drugsCiprofloxacin
Gentamicin
Tubocin
Vancomycin
Methomyl plus sulfamethiothiazoleMefalen
Gender-neutral B
Ketoconazole
Azaprizone
Colchicine
Diclofenac
Naproxen
SulforaphaneCimetidine
Renitidine
Tacrolimus
Cellulose derivatives
(e.g., benzofibrate, fenofibrate)
Methotrexate
CYP 3A isozymes, represented by CYP3A4, are widely involved in cyclosporine metabolism, and cyclosporine is also a substrate for the multidrug efflux pump P-glycoprotein. A variety of drugs are known to increase or decrease cyclosporine concentrations in plasma or whole blood by inhibiting or inducing CYP3A4 and/or the P-glycoprotein transporter. Drugs such as orlistat inhibit the absorption of cyclosporine and should be avoided in combination. When combined with these drugs, the blood concentration of cyclosporine should be monitored and the dose of this product should be adjusted as appropriate (see Blood Concentration Monitoring). .
1. Drugs that increase cyclosporine concentrations
Calcium channel blockersAntifungals AntibioticsGlucocorticoidsGlucocorticoidsOther drugsDiltiazem
Nicardipine
VerapamilFluconazole
Itraconazole
Ketoconazole
VoriconazoleAzithromycin
Clarithromycin
Erythromycin
Quinupristin/DafopristinMethylprednisoloneMethylprednisolone >Allopurinol
Amiodarone
Bromocriptine
Colchicine
Danazol
Imatinib
Metoclopramide
Naphthazodone
Oral contraceptivesHIV protease inhibitors
HIV protease inhibitors (eg, indinavir, nelfinavir, ritonavir, and saquinavir) are known to inhibit cytochrome P-450 3A and therefore may increase cyclosporine concentrations, although rigorous drug interaction studies have not been conducted. Caution should be exercised when combining these drugs.
Grapefruit juice
Grapefruit and grapefruit juice can affect metabolism and increase cyclosporine blood levels and should be avoided.
2. Drugs/dietary supplements that lower cyclosporine concentrations
.
AntibioticsAnticonvulsantsOther drugs/dietary supplementsNafcillin
MeperidineCarbamazepine
Oxcarbazepine
Phenobarbital
PhenytoinBosentan
Oxytocin
Olestat
Phenylsulfonazone
Tebuprofen
TiclopidineGuangyelianthus ExtractGonophyllum Extract
Serious drug interactions have been reported between cyclosporine and the herbal dietary supplement Ganoderma lucidum extract. This interaction can significantly reduce cyclosporine blood levels to subtherapeutic levels and lead to graft rejection and graft failure.
Rifabutin
Rifabutin is known to be a metabolic enhancer of other drugs that are metabolized by the cytochrome P-450 system. Drug interactions between rifabutin and cyclosporine have not been studied. Caution should be exercised when combining these two drugs.
B. Effect of cyclosporine on the pharmacokinetics and/or safety of other drugs or substances
Cyclosporine is an inhibitor of CYP3A4 and multiple drug transporter P-glycoproteins. Blood levels may increase if the concomitant drug is CYP3A4 or P-glycoprotein or both acting as substrates.
Cyclosporine may decrease the clearance of digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (statins) and repaglinide, NSAIDs, sirolimus, etoposide, aliskiren, bosentan, or dabigatran. Additional information and specific recommendations can be found in the instructions for other drugs. The decision to give cyclosporine and other drugs or substances in combination should be made by the physician only after careful evaluation of the benefits and risks.
Dabigatran
When given in combination with dabigatran, cyclosporine causes elevated plasma levels of dabigatran due to the P-glycoprotein inhibitory activity of cyclosporine (see [Precautions]). Dabigatran has a narrow therapeutic index and elevated plasma levels can cause an increased risk of bleeding. The combination of cyclosporine and dabigatran should be avoided.
Digoxin
Several patients taking digoxin developed severe digitalis toxicity within days of cyclosporine administration. If digoxin is administered concomitantly with cyclosporine, serum concentrations of digoxin should be monitored.
Colchicine
Cyclosporine has also been reported to potentiate the toxic effects of colchicine, such as myopathy and neuropathy, and the toxicity is more pronounced in patients with renal insufficiency. The combined administration of cyclosporine and colchicine results in a significant increase in colchicine plasma concentrations. If colchicine is given in combination with cyclosporine, a lower dose of colchicine is recommended.
HMG-CoA reductase inhibitors (statins)
From the literature and cases of muscle toxicity collected post-marketing, muscle toxicity includes myalgia, muscle weakness, myositis, and rhabdomyolysis. Drugs used in combination with cyclosporine include lovastatin, simvastatin, atorvastatin, pravastatin, and more rarely when combined with fluvastatin. When these statins are combined with cyclosporine, the statin dose should be adjusted downward according to the instructions. Statin therapy should be suspended or discontinued in patients who present with signs and symptoms of myopathy and in patients with severe renal impairment such as renal failure secondary to rhabdomyolysis in the presence of certain risk factors.
Reglanol
Cyclosporine increases the plasma concentration of repaglinide, thereby increasing the risk of hypoglycemia. 12 healthy male subjects received two oral doses of cyclosporine capsules 100 mg at 12-hour intervals and one dose of repaglinide tablets 0.25 mg (0.5 mg size half tablet) 13 hours after the first dose of cyclosporine, resulting in an increase in the mean Cmaxand AUC were increased by 1.8-fold (range: 0.6 to 3.7-fold) and 2.4-fold (range 1.2 to 5.3-fold), respectively. Patients on the combination of cyclosporine and repaglinide should have their blood glucose levels monitored closely.
Aliskiren
Aliskiren is a substrate for p-glycoprotein and CYP3A4, and cyclosporine alters the pharmacokinetics of aliskiren. In 14 healthy subjects given a combined single dose of cyclosporine (200 mg) and a low dose of aliskiren (75 mg), the mean Cmax was approximately 2.5-fold (90% CI: 1.96 to 3.17) and the mean AUC was approximately 4.3-fold (90% CI: 3.52 to 5.21) higher with aliskiren compared with aliskiren alone . Combined administration of aliskiren with cyclosporine prolonged the elimination half-life (26 hours vs 43 to 45 hours) as well as Tmax (0.5 hours vs 1.5 to 2.0 hours) of aliskiren. The mean AUC and Cmax of cyclosporine were comparable to values reported in the literature. Combined administration of cyclosporine and aliskiren also resulted in an elevated number and/or intensity of adverse events, primarily headache, hot flashes, nausea, vomiting, and drowsiness. Combined administration of cyclosporine and aliskiren is not recommended.
Potassium-preserving diuretics
Cyclosporine should not be combined with a potassium-preserving diuretic to avoid hyperkalemia. Similarly, cyclosporine should be used with caution when patients are on potassium-preserving drugs (e.g., angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists), potassium-containing drugs, or potassium-rich diets. When a combination is necessary, control of potassium concentration is recommended.
Drug interactions with nonsteroidal anti-inflammatory drugs (NSAIDs)
Patients with rheumatoid arthritis should be closely monitored clinically and serum creatinine concentrations should be closely monitored (see WARNINGS) when combining cyclosporine and NSAIDs.
Pharmacodynamic interactions between cyclosporine and both naproxen and sulforaphane have been reported and can lead to hyperalgesia if combined, as confirmed by 99mTc-diethylenetriaminepentaacetic acid (DTPA) and (para-amino-malic acid) PAH clearance assays. Although co-administration with diclofenac does not affect cyclosporine blood levels, diclofenac doubles blood levels and can occasionally cause reversible renal hypoperfusion. Therefore, the dose of diclofenac should be taken at the lower limit of the therapeutic range.
Drug interactions with methotrexate
Preliminary results showed that in patients with rheumatoid arthritis (N=20) treated concomitantly with methotrexate and cyclosporine, methotrexate concentrations (AUC) increased by approximately 30% and its metabolite 7-hydroxymethotrexate concentrations (AUC) decreased by approximately 80%. The clinical significance of this drug interaction is unclear. There was no significant change in cyclosporine concentrations (N=6).
Sirolimus
Serum creatinine was observed to be elevated in the combination study of sirolimus with full dose cyclosporine. This effect was often reversed after cyclosporine dose downregulation. Concomitant administration of cyclosporine and sirolimus resulted in a significant increase in sirolimus blood concentrations. To avoid excessive increases in sirolimus concentrations, a 4-hour interval between cyclosporine administration and sirolimus administration is recommended.
Nifedipine
Nifedipine administered concomitantly with cyclosporine has been reported to frequently occur as gingival hyperplasia.
Methylprednisolone
Convulsions have been reported with high-dose methylprednisolone coadministered with cyclosporine.
Other immunosuppressive drugs and substances
Patients with psoriasis should not be treated with other immunosuppressive or radiotherapy (including PUVA and UVB) in combination with cyclosporine to avoid excessive immunosuppression.
C. Effect of cyclosporine on the efficacy of live vaccines
Vaccination effectiveness may be reduced during cyclosporine therapy. Live vaccines should be avoided.
[Drug overdose].
Symptoms
There is limited experience with acute cyclosporine overdose. The maximum tolerated oral dose of cyclosporine of 10 g (approximately 150 mg/kg) is accompanied by some relatively mild clinical consequences, such as vomiting, drowsiness, headache, tachycardia, and, in a few patients, moderately severe reversible renal impairment. However, severe toxic symptoms have been reported in premature neonates following incidental cyclosporine overdose.
Therapeutic management
In all cases of overdose, general supportive measures and symptomatic treatment should be instituted. Emetic and gastric lavage within a few hours of oral administration may be effective. Cyclosporine is not completely dialyzable and cannot be completely removed by activated carbon hemoperfusion.
[Pharmacologic Toxicology
Pharmacological effects
Cyclosporine is an immunosuppressive agent that selectively blocks the cell cycle of immunoreactive lymphocytes, keeping them in the G0 or G1 phase. Cyclosporine primarily blocks helper T lymphocytes and also inhibits the production and release of lymphokines, including interleukin-2etc. Cyclosporine does not affect phagocytosis and does not produce myelosuppressive effects.
Toxicological studies
Genotoxicity
The results of the cyclosporine Ames test, the V79-HGPRT test, the micronucleus test in mice and Chinese hamsters, the chromosomal aberration test in the bone marrow of Chinese hamsters, the dominant lethal test in mice, and the DNA repair test in mouse sperm were all negative, but an analysis of cyclosporine-induced sister chromatid exchange (SCE) using human exolymphocytes The test showed that cyclosporine induced sister chromatid exchange in human lymphocytes.
Reproductive toxicity
No effect of cyclosporine on fertility was seen in rats.
No teratogenicity was seen in pregnant rats given 17 mg/kg/day or pregnant rabbits given 30 mg/kg/day by oral administration. Increased prenatal and postnatal mortality, decreased fetal body weight, and delayed skeletal development were seen in pregnant rats given 30 mg/kg/day or pregnant rabbits given 100 mg/kg/day orally, equivalent to 0.8 or 5.4 times the recommended human dose of 6 mg/kg, respectively, based on body surface area conversion.
In two published research trials, reduced renal units, renal hypertrophy, systemic hypertension, and progressive renal insufficiency were seen in rabbits after intrauterine exposure to cyclosporine (10 mg/kg/day, subcutaneously) up to 35 weeks of age. The incidence of fetal ventricular septal defects was increased in pregnant rats given cyclosporine 12 mg/kg/day intravenously, equivalent to two times the recommended human dose.
Carcinogenicity
The incidence of lymphocytic lymphoma was increased in female mice given cyclosporine 1, 4, and 16 mg/kg/day for 78 weeks. In addition, at a dose of 4 mg/kg/day (0.05 times the clinically indicated dose of 6 mg/kg) male mice had an increased incidence of hepatocellular carcinoma. The incidence of islet cell adenocarcinoma was increased in rats given cyclosporine at 0.5, 2 and 8 mg/kg/day for 24 months, and at 2 mg/kg/day (0.05 times the proposed clinical dose of 6 mg/kg). No dose correlation was seen for the incidence of hepatocellular carcinoma and islet cell adenocarcinoma.
Literature studies have shown that cyclosporine shortens the duration of UV irradiation-induced skin cancer in nude mice.
[Pharmacokinetics].
Compared with administration of nonemulsified cyclosporine, administration of this product improves the dose linearity of cyclosporine exposure (AUCB), has a more consistent absorption profile, and is less affected by food co-administration and circadian rhythms. Based on the nature of these combinations, it can be seen that there is less intrapatient variability in cyclosporine pharmacokinetics and a stronger correlation between lowest concentration and total exposure (AUCB). Because of these added advantages, the timing of meals no longer needs to be considered when giving this product. In addition, exposure to this product cyclosporine was more consistent throughout the day on the day of administration as well as each day of maintenance therapy.
This product is bioequivalent to emulsified cyclosporine oral solution. The available data indicate that the minimum concentration in whole blood is similar after 1:1 conversion of non-emulsified cyclosporine to this product, so the required range of minimum therapeutic levels remains unchanged. Compared with nonemulsified cyclosporine (peak blood concentrations 1 to 6 hours after administration), emulsified cyclosporine softgels are more rapidly absorbed (mean tmax 1 hour earlier, mean Cmax 59% higher), and bioavailability is on average 29% higher.
The distribution of cyclosporine greatly exceeds the blood volume. In the blood, 33% to 47% is distributed in plasma, 4% to 9% in lymphocytes, 5% to 12% in granulocytes and 41% to 58% in erythrocytes. In the plasma, about 90% is bound to proteins (mainly lipoproteins).
Cyclosporine is extensively biotransformed to about 15 metabolites. There is no single major metabolic pathway. Cyclosporine is primarily eliminated by bile, and only 6% of the orally administered dose is excreted in the urine; only 0.1% of the prototype drug is excreted in the urine.
There is a high degree of variability in cyclosporine end-of-life data reported based on the assay method used and the target population. The terminal half-life ranged from 6.3 hours in healthy volunteers to 20.4 hours in patients with severe liver disease.
Special Populations
Children
Pharmacokinetic data are limited after administration of emulsified cyclosporine or non-emulsified cyclosporine in children. 15 renal transplant patients aged 3 to 16 years had a cyclosporine plasma clearance of 10.6±3.7 ml/min/kg after intravenous cyclosporine administration (assay. Cycto-trac specific monoclonal release assay). In a study of 7 renal transplant patients aged 2 to 16 years, cyclosporine plasma clearance ranged from 9.8 to 15.5 ml/min/kg. In 9 liver transplant patients aged 0.6 to 5.6 years, cyclosporine plasma clearance was 9.3±5.4 ml/min/kg (assay: HPLC).
The biological utilization of this product has been shown to be higher than that of non-emulsified cyclosporine in children. The absolute bioavailability of this product was 43% (range 30% to 68%) in 7 first-time liver transplant patients aged 1.4 to 10 years, compared with 28% (range 17% to 42%) for the same individual non-emulsified cyclosporine.
Children’s Pharmacokinetics ( mean±SD) Dose/day Dose/weightAUC1CmaxCL/FCL/FPatient population(mg/d)(mg/ kg/d)(ng-hr/mL)(ng/mL)(mL/min)(mL/min/kg)Stable liver transplant patients2 Age 2 to 8, TID dosing (N=9) 101±255.95±1.32 2163±801629±219285 ±9416.6±4.3Age 8-15, BID dosing (N=8) 188±55 4.96±2.094272±1462975±281378±8010.2±4.0Stable liver transplant patients3 Age 3, BID dosing (N=1) 1208.33