How Effective Is Cyclosporine for Psoriasis?

Cyclosporine capsules for kidney, liver and heart transplantation: This product is suitable for preventing organ rejection in kidney, liver and heart allografts. This product can be used in combination with azathioprine and corticosteroids. Rheumatoid arthritis: This product is suitable for the treatment of severely active rheumatoid arthritis patients who do not respond adequately to methotrexate. For patients with rheumatoid arthritis who do not respond adequately to methotrexate alone, this product can be used in combination with methotrexate. Psoriasis: This product is suitable for the treatment of adult, severe non-immune damage (i.e. extensive disease and / or disability) that does not respond to at least one systemic treatment (e.g. radiotherapy (e.g. PUVA), resin or methotrexate) , Refractory, plaque psoriasis patients, or patients who are disabled (or intolerant) to other systemic treatments. This product rarely rebounds, and most patients are caused by discontinuation of medication.

Drug Name: Cyclosporine capsules

Drug type: Prescription medicines, essential medicines, medicines for medical workers' injuries
Use classification: Other immunosuppressants

Cyclosporine capsule ingredients

The main ingredient of this product is cyclosporine.

Cyclosporine Capsules

This product is an improved cyclosporine oral dosage form. The content is a white to yellow opaque semi-solid, which forms an aqueous dispersion in an aqueous environment.

Cyclosporine capsule specifications

(1) 25mg / capsule,
(2) 50mg / capsule,
(3) 100mg / capsule

Cyclosporine capsule dosage

This product (BID) should be given twice daily. It is recommended to do it on a consistent schedule, fixing the daily dosage and the relationship with the diet.
Grapefruit and grapefruit juice affect metabolism and increase the plasma concentration of cyclosporine, so it should be avoided.
Newly Transplanted Patients:
The initial dose of this product can be given 4 to 12 hours before or after transplantation. The starting dose of this product varies with the transplanted organ and other immunosuppressive agents included in the immunosuppressive regimen. For newly transplanted patients, the starting dose of this product is the same as the cyclosporine capsule (non-improved product). The initial dose of this product can be found in the 1994 Cyclosporine Capsule (non-improved) application survey by the American Transplant Center. The average starting dose for kidney transplant patients is 9 ± 3mg / kg (75 centers) per day, liver transplant patients are 8 ± 4mg / kg (30 centers) per day, and heart transplant patients are 7 ± 3mg / kg (24 centers) per day center). The total daily dose is divided into two equally. Then the dose of this product is adjusted to reach a predetermined cyclosporine blood concentration. If the cyclosporine valley concentration is used, the target range of this product is the same as that of the cyclosporine capsule (non-improved product). When this product and the cyclosporine capsule (non-improved product) use the same cyclosporine valley concentration target range, the degree of cyclosporine exposure after giving this product is greater (see [Pharmacokinetics]). Assessment of rejection and tolerance carefully adjusted doses. For maintenance therapy, lower doses of this product are sufficient.
A gradual reduction of prednisone with adrenal corticosteroids as an adjuvant treatment at the beginning seems to achieve similar results. A representative dosing regimen based on patient weight is: starting at 2.0 mg / kg per day for the first 4 days, gradually reducing to 1.0 mg / kg per day within the next week, and to 0.6 mg / kg per day after 2 weeks. After 1 month, it was reduced to 0.3 mg / kg per day, and after 2 months, it was reduced to 0.15 mg / kg per day, and this dose was used as the maintenance dose. The dose of steroid drugs should be based on the individualization of patient status and graft function Gradually decrease more slowly. The dose of prednisone must be adjusted according to the clinical status of the patient.
Transplant patients switched from cyclosporine capsules (non-improved) to Gingerford cyclosporine capsules (improved):
For patients who are considering switching from cyclosporine capsules (non-improved products), the same daily dose as cyclosporin capsules (non-improved products) previously used should be used to initiate treatment (1: 1 dose conversion). Subsequently, the dose of this product should be adjusted to obtain the cyclosporine blood valley concentration before the dressing change. When this product and the cyclosporine capsule (non-improved) use the same target range of cyclosporine valley concentration, the degree of cyclosporine exposure after this product is greater (see [Pharmacokinetics]). Patients suspected of poor absorption of cyclosporin capsules (non-improved products) require different dosing strategies (see Transplant patients with poor absorption of cyclosporin capsules (non-improved products)). For some patients, the increase in blood valley concentration is more significant and may have clinical significance.
Before the blood valley concentration reaches the pre-conversion level, it is strongly recommended to monitor the cyclosporine blood valley concentration every 4 to 7 days after switching to this product. In addition, clinical safety indicators should be monitored every two weeks within the first 2 months after conversion , Such as serum creatinine and blood pressure. If the blood valley concentration is outside the ideal range and / or the clinical safety index is deteriorated, the dose of this product must be adjusted accordingly.
Transplant patients with poor absorption of cyclosporine capsules (non-improved):
If the patients' cyclosporine blood trough concentration is lower than the expected oral dose corresponding to the cyclosporine capsule (non-improved product), they may have poor absorption of cyclosporine in the cyclosporine capsule (non-improved product) Or inconsistent. After switching to this product, the cyclosporine concentration in these patients is likely to be higher. Due to the increased bioavailability of cyclosporine after switching to this product, the blood concentration of cyclosporine may exceed the target range. If the patient's dose to this product is greater than 10 mg / kg per day, extra care must be taken. The dose of this product must be adjusted according to the cyclosporine valley concentration, tolerance, and individualized clinical response. For this population, the blood trough concentration of cyclosporine should be monitored more frequently, at least twice a week (if the initial dose exceeds 10 mg / kg per day, once a day) until the concentration stabilizes within the ideal range.
Rheumatoid arthritis:
The starting dose of this product is 2.5 mg / kg per day, orally (BID) twice. Salicylates, non-steroidal anti-inflammatory drugs, and oral corticosteroids can continue to be used (see [Drug Interactions]). The effect usually starts within 4 to 8 weeks. If the clinical effect is not sufficient and the tolerance is good (including the case where the serum creatinine is within 30% of the baseline), the dose can be increased by 0.5 to 0.75 mg / day after 8 weeks. kg, and increased again after 12 weeks, reaching the limit of 4 mg / kg per day. If no effect is seen after 16 weeks of treatment, the treatment of this product should be terminated.
At any time, in order to control adverse reactions, such as hypertension, elevated serum creatinine (more than 30% of the patient's pre-treatment level), or clinically significant laboratory tests, the dose should be reduced by 25% to 50% (see [ Precautions). If the reduction is not effective for abnormal control, or the adverse reaction is extremely serious, this product should be discontinued. When this product is used in combination with the recommended dose of methotrexate, the starting dose and dose range remain unchanged. When combined with methotrexate at a dose of up to 15 mg / kg per week, most patients can be treated with this product at a dose of 3 mg / kg per day.
Information on long-term treatment is limited. Generally speaking, within 4 weeks of discontinuation of cyclosporine, rheumatoid arthritis disease activity rebounded significantly.
Psoriasis:
The starting dose of this product should be 2.5 mg / kg daily, orally in two divided doses (1.25 mg / kg daily, BID). Patients should maintain this dose for at least 4 weeks to avoid adverse reactions. If the patient has not shown significant clinical improvement by that time, the patient's dose should be increased at 2-week intervals. Depending on the patient's response, the dose should be increased by approximately 0.5 mg / kg per day to a maximum of 4.0 mg / kg per day.
At any time, in order to control adverse reactions, such as hypertension, elevated serum creatinine (more than 25% of the patient's pre-treatment level), or clinically significant laboratory tests, the dose should be reduced by 25% to 50%. If the reduction is not effective for abnormal control, or the adverse reaction is very serious, this product should be discontinued (see [Precautions], special monitoring for patients with psoriasis).
Generally speaking, the clinical manifestations of patients with psoriasis show some improvement within 2 weeks. It takes 12 to 16 weeks to achieve satisfactory control and stabilization of the disease. The results of the dose-adjusting clinical trials of this product show that 51% of patients after 8 weeks, 79% of patients after 12 weeks, psoriasis improved by 75% or more (based on PASI calculation). If no effect is seen after 6 weeks of treatment at 4 mg / kg or the patient's maximum tolerated dose, the treatment of this product should be discontinued. Once the patient is adequately controlled and the performance is stable, the dose of this product should be reduced to treat the patient with the lowest dose that can maintain sufficient response. In clinical trials, cyclosporine at the lower end of the recommended dose range is effective in maintaining a satisfactory response in 60% of patients, and doses below 2.5 mg / kg per day may have the same effect.
After stopping cyclosporine treatment, relapse will occur between about 6 weeks (50% of patients) to 16 weeks (75% of patients), and most patients will not rebound after stopping cyclosporine treatment. It was reported that 13 patients changed from chronic plaque psoriasis to a more severe form of psoriasis, 9 cases of pustular psoriasis and 4 cases of erythrodermic psoriasis. This product has limited long-term treatment experience for patients with psoriasis. Long-term continuous treatment for more than one year is not recommended. Other treatments should be considered for long-term treatment of patients with this lifelong disease. Or as directed by your doctor.

Cyclosporine capsule adverse reactions

Kidney, liver and heart-liver transplants:
The main adverse effects of cyclosporine treatment were renal dysfunction, tremor, hairiness, hypertension, and gingival hyperplasia.
Generally mild to moderate hypertension can be seen in about 50% of kidney transplant patients and most heart transplant patients.
Glomerular capillary thrombosis has been found in cyclosporine-treated patients and may progress to graft failure. Pathological changes are similar to hemolytic uremia, including renal microvasculature thrombosis due to occlusion of glomerular capillaries and arterioles by platelet-fibrin thrombosis, microangiopathy hemolytic anemia, thrombocytopenia, and decreased renal function. Similar findings have been made with other immunosuppressive agents after transplantation.
Hypomagnesemia has been reported in some, but not all, patients with convulsions when treated with cyclosporine. Although the magnesium removal test in normal people suggests that hypomagnesemia is related to neurological disorders, it seems to be a variety of factors including hypertension, high-dose methylprednisolone, hypocholesterolemia, and high plasma concentrations of cyclosporine The associated neurotoxicity collectively leads to the neurological manifestations of cyclosporine toxicity.
In a controlled trial, the doses of cyclosporine capsules (improved) and cyclosporine capsules (non-improved) were adjusted to produce the same cyclosporine trough concentration. As a result, 493 patients were treated with cyclosporine capsules (improved) The nature, extent, and incidence of adverse reactions observed in transplant patients were similar to those observed in 208 transplant patients taking cyclosporine capsules (non-improved products).
Based on the historical experience of cyclosporine capsules (non-improved products), 3% of the 892 patients participating in clinical trials of kidney, heart and liver transplantation experienced the following reactions.

Among the 750 kidney transplant patients treated with a cyclosporine oral solution (non-improved product) in clinical trials, the percentage of patients who discontinued treatment for various reasons is as follows: reninic 5.4%, infection 0.9%, ineffective 1.4%, acute renal tubular loop Death was 1.0%, lymphoid hyperplasia disorder was 0.3%, hypertension was 0.3%, hypertension was 0.3%, and other causes were 0.7%.
The incidence of the following reactions in patients treated with cyclosporine capsules (non-improved products) 2%: allergic reactions, anemia, anorexia, blurred consciousness, conjunctivitis, edema, fever, fragile nails, gastritis, hearing loss, hiccups, Hyperglycemia, muscle pain, peptic ulcer, thrombocytopenia, tinnitus.
The following reactions are rare: anxiety, chest pain, constipation, depression, hair break, hematuria, joint pain, lethargy, oral ulcers, myocardial infarction, night sweats, pancreatitis, itching, difficulty swallowing, tingling, upper gastrointestinal bleeding, vision Obstacles, weakness, weight loss.

* Some patients also received ALG (anti-lymphocyte globulin) treatment.
Rheumatoid arthritis:
The main adverse reactions to cyclosporine in patients with rheumatoid arthritis are renal dysfunction, hypertension, headache, gastrointestinal dysfunction, and hairiness or excessive hairiness.
In clinical trials, patients with rheumatoid rheumatoid arthritis were treated with cyclosporine in the recommended dose range. As a result, 5.3% of patients discontinued due to hypertension and 7% of patients due to elevated creatinine. These changes are usually reversible if they are reduced or discontinued in time. The frequency and extent of serum creatinine increase with increasing dose and duration of cyclosporine treatment. If not reduced or discontinued, these increases are likely to become more severe.
The following adverse reactions occurred in controlled clinical trials:
Cyclosporine (improved product) / Cyclosporine (non-improved product) for rheumatoid arthritis The incidence of adverse reactions in the two cyclosporine treatment groups 3% of the total number of patients

Including only patients in the 2.5 mg / kg daily dose group, * NOS = Not Specific or Not Otherwise Specified.
In addition, 1% to <3% of rheumatoid arthritis patients in the cyclosporine-treated group in controlled clinical trials reported the following adverse reactions:
Autonomic nervous system: dry mouth and increased sweating;
Systemic: allergies, weakness, hot flushes, discomfort, overdose, non-specific (NOS *) processes, non-specific (NOS *) tumors, weight loss, weight gain;
Cardiovascular: abnormal heart sounds, heart failure, myocardial infarction, peripheral ischemia;
Central and peripheral nervous system: hyposensory, neurological disorders, dizziness;
Endocrine: goiter;
Gastrointestinal: constipation, dysphagia, mucosal rash, belching, esophagitis, gastric ulcer, gastritis, gastroenteritis, bleeding gums, glossitis, peptic ulcer, enlarged salivary glands, tongue disease, dental disease;
Infection: abscess, bacterial infection, cellulitis, folliculitis, fungal infection, herpes simplex, shingles, kidney abscess, candidiasis, tonsillitis, viral infection;
Hematology: anemia, epistaxis, leukopenia, lymphadenopathy;
Hepatobiliary system: bilirubinemia;
Metabolism and nutrition: diabetes, hyperkalemia, hyperuricemia, hypoglycemia;
Musculoskeletal system: arthralgia, fracture, bursitis, joint dislocation, myalgia, rigidity, synovial cyst, tendinopathy;
Tumors: fibrocystic breast disease, cancer;
Mental symptoms: anxiety, blurred consciousness, weakened sexual desire, changeable mood, inattention, increased sexual desire, nervousness, nightmares, drowsiness;
Reproductive system (female): breast pain, uterine bleeding;
Respiratory system: abnormal chest sounds, bronchospasm;
Skin and accessories: abnormal pigmentation, angioedema, dermatitis, dry skin, eczema, nail disease, pruritus, skin disorders, rubella;
Special sensations: abnormal vision, cataract, conjunctivitis, deafness, pain in the eyes, taste inversion, tinnitus, vestibular dysfunction;
Urinary system: abnormal urine, hematuria, increased BUN, urgency, nocturia, frequent urination, nephronephritis, urinary incontinence.
* NOS = Not Otherwise Specified
Psoriasis:
The main adverse reactions to cyclosporine in patients with psoriasis are renal dysfunction, headache, high blood pressure, hypertriglyceridemia, hairy / excessive hair, paresthesia or hypersensitivity, flu-like symptoms, nausea / vomiting, diarrhea, abdominal discomfort , Drowsiness and musculoskeletal or joint pain.
In clinical trials in the United States, 1.0% of patients with psoriasis treated with cyclosporine within the recommended dosage range discontinued treatment due to hypertension and 5.4% due to elevated creatinine. These changes were reversible in most cases after reduction or discontinuation of cyclosporine.
There has been a report of deaths in patients with psoriasis related to cyclosporine use. A 27-year-old man continued to use cyclosporine with deteriorating kidney function, which resulted in lethal progressive renal failure.
The frequency and extent of serum creatinine increase with increasing dose and duration of cyclosporine treatment. If not reduced or discontinued, these elevations are likely to become more severe and may cause irreversible kidney damage.
Adverse reactions in 3% of patients with psoriasis in controlled clinical trials

* Total percentage of events in the system ** Newly occurring hypertension SBP160mmHg and / or DBP90mmHg.
The following events occurred in 1% to <3% of patients with psoriasis treated with cyclosporine;
Whole body: fever, flushing, hot flushing;
Cardiovascular: chest pain;
Central and peripheral nervous system: increased appetite, insomnia, dizziness, nervousness, dizziness;
Gastrointestinal tract: bloating, constipation, bleeding gums;
Hepatobiliary system: hyperbilirubinemia;
Tumor: skin cancer [squamous cell carcinoma (0.9%) and basal cell carcinoma (0.4%)];
Reticuloendothelial system: platelet-bleeding, abnormal agglutination, and abnormal red blood cells;
Respiratory system: infections, viruses and other infections;
Skin and accessory organs: acne, folliculitis, keratosis, pruritus, rash, dry skin;
Urinary system: frequent urination;
Vision: abnormal vision.
Mild hypomagnesemia and hyperkalemia may occur, but asymptomatic. Uric acid may be elevated and rare cases of gout are not reported. Slight, dose-related hyperbilirubinemia has been observed without hepatocyte damage. Cyclosporine treatment may be associated with a slight increase in serum triglycerides or cholesterol. Approximately 15% of patients with psoriasis have elevated triglycerides (> 750 mg / dL); less than 3% of patients with psoriasis have elevated cholesterol (> 300 mg / dL). Generally, these laboratory abnormalities are reversible after cyclosporine is reduced or discontinued.

Cyclosporine capsules contraindications

General contraindications:
This product is contraindicated in patients who have an allergic reaction to cyclosporine or any of its ingredients.
Patients with rheumatoid arthritis:
Rheumatoid arthritis patients with abnormal renal function, uncontrolled hypertension or malignant tumors should not use this product.
Patients with psoriasis:
Patients with psoriasis treated with this product should not receive concurrent radiotherapy such as (PUVA or UVB), methotrexate or other immunosuppressive agents, coal tar or radiation therapy. Psoriasis patients with abnormal renal function, uncontrolled hypertension or malignant tumors should not use this product.

Precautions for cyclosporine capsules

Only experienced physicians who have systemic immunosuppressive treatment for this product's indications can use this product. This product must be prescribed by a physician with experience in immunosuppressive therapy and organ transplantation, and the dose must be carefully adjusted during parenchymal organ transplantation. Patients should be treated with this product in medical institutions with well-equipped laboratories and supportive medical resources. The physician responsible for maintenance treatment should have all the information needed to follow up the patient.
As a systemic immune preparation, this product may increase the chance of infection and cause tumor formation. For kidney, liver and heart transplant patients, this product can be given together with other immunosuppressants. As the degree of immunosuppression in transplant patients increases, it may lead to increased susceptibility to infection and may produce lymphomas and other tumors.
The active ingredient cyclosporine of this product can cause nephrotoxicity and liver toxicity. The risk increases when the cyclosporine dose is increased. Renal dysfunction, including structural (substantial) renal impairment, is a potential consequence of the use of this product, so renal function must be monitored during treatment. Caution should be exercised when using cyclosporine with nephrotoxic drugs.
Patients receiving this product need to monitor serum creatinine frequently (see special monitoring under [Dosage and Administration]). Special care should be taken in monitoring elderly patients as kidney function declines with age. If patients are not properly monitored and doses are not adjusted properly, cyclosporine treatment may cause structural kidney damage and persistent renal insufficiency.
Serum creatinine and BUN may increase during the treatment of this product, which indicates that the glomerular filtration rate is decreased. Renal impairment at any time requires close monitoring and frequent dose adjustments. The frequency and extent of serum creatinine increase with the increase in the dose and duration of cyclosporine treatment. If the dose is not reduced or discontinued, the increase is likely to worsen.
Because this product is not biologically equivalent to cyclosporine capsules (non-improved products), if you switch from this product to cyclosporine capsules (non-improved products) at a ratio of 1: 1, it will result in a decrease in cyclosporine blood concentration. Therefore, when switching from this product to cyclosporine capsules (non-improved products), monitoring should be strengthened to prevent the possibility of insufficient dosage.
Kidney, liver and heart transplants:
The active ingredient cyclosporine of this product can cause nephrotoxicity and liver toxicity at high doses. It is not uncommon for serum creatinine and BUN to increase during cyclosporine treatment. These elevations do not necessarily mean rejection in kidney transplant patients, and each patient must be fully evaluated before dose adjustment.
Based on the historical experience of cyclosporine oral solutions, cyclosporine nephrotoxicity has occurred in 25% of kidney transplant cases, 38% of heart transplant cases, and 37% of liver transplant cases. Generally, patients with mild renal toxicity 2 to 3 months after kidney transplantation, including those with higher BUN and creatinine before surgery, no longer decrease, ranging from 35 to 45 mg / dL and 2.0 to 2.5 mg / dL, respectively. These two elevated indicators are generally responsive to downsizing of cyclosporine.
The more pronounced renal toxicity in the early post-transplant period is marked by a rapid rise in BUN and creatinine. Because these phenomena behave similarly to renal rejection, they must be carefully distinguished. This form of nephrotoxicity usually responds to down-regulation of cyclosporine dose.
Although reliable diagnostic criteria for distinguishing renal graft rejection from drug poisoning have not yet been found, there are some parameters that are significantly related to each other. It must be noted, however, that up to 20% of patients may experience both nephrotoxicity and rejection.

Cyclosporine-induced nephropathy is characterized by continued deterioration of renal function and changes in kidney morphology. 5% to 15% of transplant recipients who received cyclosporine did not decrease their serum creatinine even if the cyclosporine dose was reduced or the drug was discontinued. Biopsies in these patients will show a change in tubule vacuole formation, microtubule calcification, pericytular capillary congestion, arterial disease, and band-like interstitial fibrosis with tubule atrophy. Although none of these morphological changes are completely specific, the diagnosis of cyclosporine-related structural nephrotoxicity requires these findings as evidence.
Considering the progression of cyclosporine-induced nephropathy Sometimes, it should be noted the correlation between the appearance of interstitial fibrosis reported by several researchers and the higher cumulative dose of cyclosporine or the high circulating trough concentration. This correlation was particularly evident during the first 6 months after the highest dose of transplantation, when the kidney recipient's organs were the most vulnerable and were susceptible to cyclosporine toxicity. Other factors that cause interstitial fibrosis in these patients include prolonged perfusion time, prolonged warm ischemia time, onset of acute toxicity, and acute and chronic rejection. The reversibility of interstitial fibrosis and its relationship with renal function have not been determined. Arterial disease is reported to be reversible after cyclosporine is discontinued or the dose is reduced.
Impairment of renal function at any time requires close monitoring and frequent dose adjustments.
For severe and persistent rejection, when rescue treatment with pulsed steroids and monoclonal antibodies cannot reverse its onset, it is best to switch to other immunosuppressive treatments rather than excessively increasing the dose of this product.
Occasionally patients have thrombocytopenia and microangiopathic hemolytic anemia syndrome, which can lead to graft failure. Vascular disease may occur in the absence of rejection and is accompanied by avid platelet depletion inside the graft, as confirmed by the Indium 111-labeled platelet institute. The pathogenesis and management of this syndrome are unclear. Although the symptoms subsided after cyclosporine was reduced or discontinued and 1) streptokinase and heparin were administered or 2) plasma was removed, it appears that this relies on the early detection of platelet scans labeled with indium 111 (see [Adverse Reactions] ).
Significant hyperkalemia (sometimes associated with hyperchloric metabolic acidosis) and hyperuricemia are occasionally seen in individual patients.
Hepatotoxicity associated with the use of cyclosporine was observed in 4% of kidney transplant cases, 7% of heart transplant cases, and 4% of liver transplant cases. This is usually seen during the first month of treatment with high-dose cyclosporine and manifests with elevated liver enzymes and bilirubin. The increase in the chemical index usually decreases after the drug is reduced.
As with patients receiving other immunosuppressants, patients taking cyclosporine have an increased risk of developing lymphoma and other cancers, especially skin cancer. The increased risk appears to be related to the intensity and duration of immunosuppression rather than the drug used. Because over-suppressing the immune system can increase the risk of infection or cancer, care must be taken when using multiple immunosuppressive treatment regimens.
Convulsions have been reported in adult and pediatric patients who received cyclosporine, especially in patients who received high-dose methylprednisolone.
Use caution with cyclosporine in combination with nephrotoxic drugs.
Rheumatoid arthritis:
Renal biopsies were performed in 60 rheumatoid arthritis patients after an average of 19 months of treatment with cyclosporine, and 6 (10%) had cyclosporine nephropathy. Of these 6 patients, only 1 used a dose of 4 mg / kg per day. After cyclosporine was discontinued, the serum muscle grafts of patients except one improved. The "maximum increase in creatinine" appears to be a factor predicting cyclosporine nephropathy.
Like other immunosuppressive agents, the incidence of malignant lymphoma may increase with cyclosporine. Whether cyclosporine is at greater risk than rheumatoid arthritis patients or rheumatoid arthritis patients treated with cytotoxic drugs is unclear. Five lymphomas were found: four were seen in a survey of 2,300 patients treated with cyclosporine for rheumatoid arthritis, and another was found in clinical trials. Although this investigation also reported other tumors (12 cases of skin cancer, 24 cases of various types of parenchymal tumors, and 1 case of multiple myeloma), with the exception of malignant lymphoma, epidemiological analysis does not support their association with Correlation of cyclosporine.
Patients must be thoroughly examined for cancer development before and during treatment with this product. In addition, when used with other immunosuppressants, this product may cause excessive immunosuppression, which is known to increase the risk of cancer.
Special monitoring for rheumatoid arthritis patients:
Before starting treatment, a careful physical examination should be performed, including measuring blood pressure (at least twice) and measuring creatinine twice to estimate the baseline value. Blood pressure and serum creatinine concentration should be measured every two weeks for the first three months, and if the patient is stable, then monthly. During the treatment with this product, it is best to monitor the serum creatinine concentration and blood pressure after each increase of the non-steroidal anti-inflammatory drug dose and before starting the new non-steroidal anti-inflammatory drug treatment. If combined with methotrexate, it is recommended to monitor CBC (complete blood cell count) and liver function once a month.
If patients receiving cyclosporine develop hypertension, the dose of this product should be reduced by 25% to 50%. If hypertension persists, the dose of this product should be further reduced, or blood pressure should be controlled with antihypertensive drugs. In most cases, blood pressure drops to baseline after cyclosporine is discontinued.
Psoriasis:
Because cyclosporine is a potent immunosuppressant that may cause some serious side effects, the risks and benefits of using this product must be considered before starting treatment for psoriasis patients. Cyclosporine, the active ingredient of this product, can cause nephrotoxicity and hypertension, and its risk increases with dose and course of treatment. Patients at high risk of using cyclosporine, such as patients with abnormal kidney function and uncontrolled hypertension or cancer, should not take this product.
Renal dysfunction is a potential consequence of this product, so renal function must be monitored during treatment.
Patients taking this product need to monitor serum creatinine frequently. Elderly patients need to be carefully monitored, as kidney function also decreases with age. If the patient is not properly monitored or the dose is not adjusted properly, cyclosporine treatment can lead to kidney damage and persistent renal dysfunction.
Serum creatinine and BUN may increase during the treatment of this product, which reflects the decrease in glomerular filtration rate.
Patients with psoriasis treated with cyclosporine have an increased risk of skin and lymphoid tissue hyperplasia malignancies. The relative risk of developing cancer is similar to those of patients with psoriasis treated with other immunosuppressants.
Due to the potential for excessive immunosuppression and the risk of malignant tumors, patients should not be treated with cyclosporine and radiotherapy such as PUVA or UVB, other radiotherapy or other immunosuppressants (see [Contraindications]). Patients should also be warned to protect themselves properly in the sun and to avoid excessive sun exposure. Patients should be thoroughly examined for cancer before and during treatment. Keep in mind during the examination that malignant lesions may be covered by psoriasis spots. Before beginning treatment, a biopsy of skin lesions that are not typical of psoriasis should be performed. This product can only be used to treat patients after the suspicious damage has completely subsided and there are no other treatment options.
Special surveillance for psoriasis patients:
Before starting treatment, a careful skin and physical examination should be performed, including taking blood pressure (at least twice). Because this product is an immunosuppressant, patients should be checked for recessive infections and early tumors during the first physical examination and throughout the treatment of this product. Before starting treatment with this product, a biopsy of non-psoriasis-specific skin damage should be performed. Patients with malignant skin or precancerous changes in the skin can only be treated with this product after appropriate treatment of these injuries and when there are no other treatment options.
Baseline laboratory tests should include serum creatinine (twice), BUN, CBC, serum magnesium, potassium, uric acid, and lipid tests.
If the starting dose is low (2.5 mg / kg per day) and the maximum dose does not exceed 4 mg / kg per day, and serum creatinine is regularly monitored when cyclosporine is administered, even if the creatinine rise is greater than or equal to 25% of the patient's pre-treatment level, Then the risk of cyclosporine nephropathy will be reduced. If the dose of this product is reduced or the drug is stopped in time, the increase in creatinine is usually reversible.
Serum creatinine and BUN should be measured every two weeks for the first three, and if the patient is stable, then monthly. If the serum creatinine rise is greater than or equal to 25% of the patient's pre-treatment level, the serum creatinine should be repeated within two weeks. If the change in serum creatinine is greater than or equal to 25% of the patient before treatment, the amount of this product should be reduced by 25% to 50%. Any time the serum creatinine rise is greater than or equal to 50% of the pre-treatment level, the dose of this product should be reduced by 25% to 50%. If serum creatinine is still irreversible after two dose adjustments (within 25% of baseline), this product should be discontinued. During treatment, it is best to monitor the serum creatinine concentration after each increase in the NSAID dose and before starting a new NSAID treatment.
Blood pressure should be measured every 2 weeks for the first three months, and if the patient is stable, and then measured monthly, monitoring should be more frequent when adjusting the dose. Patients without a history of hypertension before starting treatment with this product should reduce the dose of this product by 25 to 50% if hypertension is found. If the patient's blood pressure is still high after reducing the dose of this product multiple times, this product should be discontinued. For patients who have undergone hypertension treatment, before starting the treatment of this product, their antihypertensive drugs should be adjusted to control blood pressure when taking this product. If changes in hypertension management are ineffective or intolerable, this product should be discontinued.
In the first 3 months of treatment, CBC, uric acid, potassium, lipids and magnesium should be monitored every 2 weeks. If the patient is stable, then the monthly measurement should be performed. Monitoring should be more frequent when adjusting the agent. If there are any abnormalities in clinical events, the dose should be reduced by 25% to 50%.
In a cyclosporine controlled trial in patients with psoriasis, the correlation between cyclosporine blood concentration and side effects such as improved symptoms or renal dysfunction was not good.
Vaccination:
Vaccination may be less effective during treatment with cyclosporine; live attenuated vaccines should be avoided.
Monitoring of plasma concentrations in transplant patients:
The transplant center found that monitoring cyclosporine blood levels was a vital element in patient management. When analyzing plasma concentrations, important considerations are the type of assay used, what organs are transplanted, and other immunosuppressants used at the same time. Although a fixed relationship has not been established, plasma concentration analysis can help clinically evaluate rejection and toxicity, make dose adjustments, and assess compliance.
Various methods have been used to determine the blood concentration of cyclosporine. Older studies using non-specific assays often cite concentrations that are about twice that of specific assays. Therefore, when comparing concentrations in the literature with specific patient concentrations measured with current methods, it is necessary to have a thorough understanding of the measurement methods used in each of them. The results of current assays are also not interchangeable and should be used under the guidance of their recognized label. Annals of Clinical Biochemistry 1994; 31: 420-446 discusses different assay methods. Although several assays and assay matrices are available, it is generally accepted that assays that are specific to the parent compound are most relevant to clinical events. Of these methods, HPLC is the standard reference, but the monoclonal antibody RIA and monoclonal antibody FP IA methods also provide sensitivity, reproducibility, and convenience. Most clinicians base their monitoring on cyclosporine valley concentrations. "Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring (Applied Pharmacokinetics, Principles of Therapeutic Drug Monitoring)" (1992) discusses the pharmacokinetics and pharmacokinetics of cyclosporine extensively. But blood concentration monitoring is not a substitute for renal function monitoring and tissue biopsy.

Cyclosporine capsules for pregnant and lactating women

There are no adequate, well-controlled studies in pregnant women. This product should only be used during pregnancy if the potential benefits outweigh the potential danger to the fetus.
Because cyclosporine is excreted from human milk, breastfeeding should be avoided.

Cyclosporine capsules for children

Although adequate, well-controlled trials have not been completed in children, transplant patients as young as one year old have no unusual adverse effects after taking cyclosporine capsules (improved). The safety and effectiveness of cyclosporine capsules (improved) in children under 18 years of age with juvenile rheumatoid arthritis or psoriasis have not been established.

Cyclosporine capsules for elderly

In cyclosporine rheumatoid arthritis clinical trials, 17.5% of patients were over 65 years of age. These patients are more likely to develop systolic hypertension during treatment, and their serum creatinine levels have increased by 50% from baseline levels after 3 to 4 months of treatment. Blood concentrations should be monitored regularly.

Cyclosporine capsule drug interactions

When patients with rheumatoid arthritis take diclofenac or methotrexate and cyclosporine at the same time, the AUC of diclofenac and methotrexate are significantly increased (see [Notes], [Drug Interactions]). There are no supervised pharmacokinetic interactions between cyclosporine and aspirin, ketoprofen, piroxicam, or indomethacin.
All drugs listed below are likely to interact with cyclosporine. In addition, taking non-steroidal anti-inflammatory drugs at the same time, especially in dehydrated environments, may strengthen renal dysfunction.
Antibiotics that may strengthen renal dysfunction: gentamicin, tobramycin, vancomycin, trimethoprim, sulfamethoxazole. Antitumor drugs: melphalan antifungal drugs: amphotericin B, ketoconazole Anti-inflammatory drugs: Azaprom, diclofenac, naproxen, sulindac, colchicine Gastrointestinal drugs: Cimetidine, Ranitidine Immunosuppressants: Tacrolimus changes cyclosporine concentration Drug:
Avoid compounds that reduce cyclosporine absorption, such as orlistat. Cyclosporine is metabolized by cytochrome P-450 3A. Drugs that inhibit this enzyme can reduce cyclosporine metabolism and increase its concentration. Substances that induce cytochrome P-450 3A activity can increase cyclosporine metabolism and reduce its concentration. When used in combination with these drugs, it is important to monitor cyclosporine blood concentrations and properly adjust the dose of this product.
Drugs that increase the concentration of cyclosporine: calcium channel blockers: diltiazem, nicardipine, verapamil. Antibiotics: clarithromycin, erythromycin, quinopudine, dafamptin. Itraconazole, ketoconazole glucocorticoids: methylprednisolone other drugs: allopurinol, bromocriptine, danazol, metoclopramide, colchicine, amiodarone known HIV protease inhibitors ( (Such as indinavir, nelfinavir, ritonavir, and saquinavir) can inhibit cytochrome P-450 3A and may increase the concentration of cyclosporine, but there are no official related reports. Be careful when using these drugs in combination.
Grapefruit and grapefruit juice affect metabolism and increase cyclosporine blood concentrations and should be avoided.
Antibiotics that reduce cyclosporine concentration: nafcillin, rifampicin Anticonvulsants: carbamazepine, phenobarbital, phenytoin Other drugs: ticlopidine, octreotide, orlistat, St. John's Wort
The severity of the interaction between cyclosporine and herbal dietary supplements, St. John's Wort, has been reported. The report suggests that the decrease in cyclosporine blood concentration after combined use can lead to a decrease in the level of treatment, rejection of the transplanted tissue, and even the result of transplantation failure.
Rifabutin is known to enhance the metabolism of other drugs metabolized by the cytochrome P-450 system. There are no studies on the interaction of rifabutin and cyclosporine. Use caution when combining these two drugs.
Interactions with non-steroidal anti-inflammatory drugs (NSAID):
When cyclosporine and non-steroidal anti-inflammatory drugs are combined in patients with rheumatoid arthritis, clinical status and serum creatinine should be closely monitored (see Warning).
There have been reports of pharmacodynamic interactions between cyclosporine and naproxen and sulindac. When they are used concurrently, 99m-Tc diethylenetriamine (DTPA) and (p-aminomaleic acid) Cumulative decline in renal function measured by PAH clearance. Although co-administration of diclofenac did not affect the blood concentration of cyclosporine, it was related to individual reports of doubling blood levels of diclofenac and decreased reversibility of renal function. Therefore, the dose of diclofenac should be close to the lower limit of the therapeutic range.
Interaction with methotrexate:
Preliminary data suggest that when methotrexate and cyclosporine were administered to patients with rheumatoid arthritis (N = 20), methotrexate concentrations (AUCs) increased by approximately 30%, and their metabolite 7-hydroxymethyl Chloropterin concentrations (AUCs) decreased by about 80%. The clinical significance of this interaction is unclear. The cyclosporine concentration did not seem to change (N = 6).
Interaction with other drugs:
When prednisone, digoxin, and HMG-CoA reductase inhibitors were given at the same time as cyclosporine, the clearance of these drugs decreased. In addition, after cyclosporine administration, the apparent volume of distribution of digoxin decreased. Several patients taking digoxin had severe digoxin poisoning within days of starting cyclosporine treatment. Cyclosporine should not be used in combination with potassium-sparing diuretics because it produces hyperkalemia.
During treatment with cyclosporine, immunization may be less effective. The use of live vaccines should be avoided. Used with HMG-CoA reductase inhibitors, it has caused myositis and occasional rhabdomyolysis; used with nifedipine, frequent gingival hyperplasia; combined with high-dose methylprednisolone can cause seizures.
Patients with psoriasis receiving other immunosuppressive agents and radiotherapy (including PUVA and UVB) should not take cyclosporine at the same time because it may cause excessive immunosuppression.

Cyclosporine capsule overdose

Cyclosporine overdose is rare. Forced vomiting 2 hours after giving this product is still helpful for detoxification. Transient hepatotoxicity and nephrotoxicity may occur, and these toxicity should resolve after discontinuation. In all cases of overdose, general supportive and symptomatic treatment should be performed. Cyclosporine has a low dialysis rate and cannot be completely removed by blood perfusion of charcoal. Test animals (mouse, rat, and rabbit) are expected to have an oral dose of 31 times, 39 times, and 54 times the maintenance dose (6 mg / kg; corrected for body surface area) of the transplant patient.

Cyclosporine capsule pharmacology and toxicology

Cyclosporine is a potent immunosuppressant that prolongs the survival time of animals that have been transplanted with skin, kidney, liver, heart, pancreas, bone marrow, small intestine and lung. Cyclosporine has been shown to inhibit humoral immunity and has a stronger inhibitory effect on cell-mediated immune responses, such as: allograft rejection, delayed hypertension, experimental allergic encephalomyelitis, Freund's Adjuvant arthritis, as well as graft-recipient disease, occurs in various organs when transplanted in many animal species.
Cyclosporine works by selectively and reversibly suppressing immune-active lymphocytes during the G0- and G1- phases of the cell cycle. The strongest inhibition of T cells. Although T suppressor cells may also be suppressed, T helper cells are the primary target. Cyclosporine can also inhibit the production and release of lymphokines including interleukin-2.
No effect of cyclosporine on phagocytic function (enzymatic secretion, mitochondrial migration, macrophage migration, carbon body clearance change) of animals was found to be affected. Cyclosporine did not show bone marrow suppression in animal models or humans.
Carcinogenicity, mutagenicity and fertility impairment:
Carcinogenicity experiments were performed with male and female rats and mice. In a 78-week mouse experiment, the incidence of lymphocytic lymphoma in female mice was statistically different from that in the control group, and the incidence of hepatocellular tumors in middle-dose male mice was significantly higher than that in the control group. In a 24-month rat experiment, the incidence of low-dose islet cell adenoma was significantly higher than that of the control group. The dose for mouse and rat research is 0.01 to 0.16 times of the clinical maintenance dose (6 mg / kg). Hepatocellular tumors and islet cell adenomas were not dose-related. Published reports have shown that skin irradiation with UV radiation and the use of cyclosporine or other immunosuppressive agents in synergistic treatment in nude mice results in skin cancer formation in a shorter period of time than UV radiation alone.
In appropriate experimental systems, cyclosporine is not mutagenic. In Ames experiment, V79-HGPRT experiment, mouse and Chinese hamster micronucleus experiment, chromosome aberration experiment using Chinese hamster bone marrow, mouse dominant allele lethal experiment and drug-treated rat sperm DNA repair experiment No mutagenicity / genotoxicity was found in cyclosporine. A recent experiment using human lymphocytes analyzed in vitro the cyclosporine-induced sister chromatid exchange (SCE), and the results suggest that high concentrations in this system have a positive effect (ie, induce SCE).
Male and female rats experiments showed no impaired fertility.
Long-term treatment of dogs at a dose of 2.5 mg / kg (calculated based on body surface area), which was 9 times the early therapeutic dose of human psoriasis, showed widespread skin papilloma. After cyclosporine was discontinued, the papilloma resolved on its own.
It has been recognized that the increased incidence of malignant tumors is a complication of immunosuppression in organ transplant recipients and patients with rheumatoid arthritis and psoriasis. The most common tumors are non-Hodgkin's lymphoma and skin cancer. Patients receiving cyclosporine are at a higher risk of developing a malignancy than normal healthy people, but they are similar to patients receiving other immunosuppressants. Decreasing or discontinuing immunosuppressants can make the damage subside.
Malignancies-especially skin cancer-have been reported in patients with psoriasis taking cyclosporine (see Precautions). Before treatment with cyclosporine, biopsies of non-psoriasis-specific skin lesions should be performed. Patients with malignant skin or precancerous changes of the skin should only be treated with cyclosporine after appropriate treatment of these injuries and when no other treatment options are available.
Pregnancy:
Pregnancy toxicity level C. Cyclosporine is not teratogenic in appropriate experimental systems. In rat reproduction experiments, adverse effects were seen only at doses that were toxic to the fetus. Oral administration of cyclosporine to rats and rabbits at maternal toxicity doses showed embryo and fetal toxicity. Based on body surface area calculations, the fetal toxicity doses in rats and rabbits were 0.8 and 5.4 times the doses for human transplantation (6.0 mg / kg), respectively. The embryo and fetal toxicity of cyclosporine can also be confirmed by increased prenatal and postnatal mortality, reduced fetal weight, and related skeletal developmental block.

Pharmacokinetics of cyclosporine capsules

Note: Cyclosporine capsule (improved product) and cyclosporine capsule (non-improved product)
Cyclosporine capsules (non-improved products) refer to products that were used earlier in clinical practice. The 25th edition of the United States Pharmacopoeia has received cyclosporine capsules. The content of such non-improved cyclosporine capsules is emulsified. Drug solution.
Cyclosporine capsule (improved product) means relative to non-improved product. Adopt a certain preparation process to improve clinical efficacy. The clinical application of this kind of product is relatively late, and it has not been included in the United States Pharmacopoeia, such as semi-solid preparation process, micro-emulsion preparation process, and so on.
The content of Jingefu cyclosporine capsule is a white to yellow opaque semi-solid, which belongs to cyclosporine capsule (improved product).
After oral administration, cyclosporine was not completely absorbed. The degree of cyclosporine absorption depends on the individual patient, the patient population, and the preparation. Cyclosporine is eliminated primarily through the biliary tract, and only 6% of the dose (parent drug and metabolites) is excreted through the urine. The treatment of cyclosporine in blood is generally two-phase, and the terminal half-life is about 8.4 hours (5-18 hours). After intravenous administration, the cyclosporine blood clearance rate (measured by HPLC) of adult patients with kidney or liver allografts is about 5-7 mL / min / Kg. Cyclosporine blood clearance appears to be slightly slower in heart transplant patients.
Within the therapeutic dose range, the administered dose and exposure (area under the concentration-time curve, AUC) have a linear relationship. Renal transplant patients are given cyclosporine capsules (improved products) or cyclosporine capsules (non-improved products), and the individual variation (total,% CV) of cyclosporine exposure (AUC) is between 20% and 50% . Due to inter-individual variation, in order to achieve the best results, it is necessary to individualize the administration (see Dosage and Administration). The variation (% CV) of cyclosporine capsules (improved) and cyclosporine capsules (non-improved) in AUC individuals of renal transplant patients was 9% to 21% and 19% to 26%, respectively. In these studies, the intra-individual variation (% CV) of the trough concentration of cyclosporine capsules (improved) and cyclosporin capsules (non-improved) was 17% to 30% and 16% to 38%, respectively.
absorb:
Compared with cyclosporine capsules (non-improved products), cyclosporine capsules (improved products) have higher bioavailability. The absolute bioavailability of cyclosporine given in cyclosporine capsules (non-improved products) depends on the patient population. It is estimated that less than 10% of liver transplant patients and 89% of certain kidney transplant patients.()()()AUC20%50%(C _max )40%106%28()AUC()50%C _max90%()AUCC _max()()AUCC _max()()
()(T _max )1.52.0()AUCC _max()(66945g)AUC13%C _max33%(66715g)
11TT()TT6.9±41%(-55%68%)

1.12
2.AUC
3.()12
4.TDx
5.Cyclo-trac
6.INCSTAR
distributed:
35L/kg33%47%4%9%5%12%41%58%90%()()
metabolism:
P-450A()25(M1M9M4N)1-9-4-N-()M1M9M4NAUCAUC70%21%7.5%(()()13)(4()3())M1M9M4N()()
excretion:
0.1%6%()

()()1531610.6±3.7mL/min/kg(Cyclo-tracRIA)72169.815.5mL/min/kg90.65.69.3±5.4mL/min/kg(HPLC)
()()71.410()43%(30%68%)()28%(17%42%)

1.AUC
2.Cyclo-trac
3.TDx
Seniors:
(N=1869)(N=1668)(N=1626)

1530(5986F)

30/50/

24 months ^[1]