Cipol-N

Cyclosporin.

Each 25 mg capsule contains cyclosporine (USP) (INN: Ciclosporin) 25 mg.
Each 100 mg capsule contains cyclosporine (USP) (INN: Ciclosporin) 100 mg.
Cyclosporine is a potent immunosuppressive agent which prevents graft rejection following allogenic transplantations, which improves success rates of transplantations and survival rates of patients.
This drug is a state-of-the-art microemulsion formulation of cyclosporine. The original formulation has interpatient and intrapatient variability in cyclosporine absorption owing to bile dependent absorption.
This drug is developed to overcome the variability associated with the original formulation by virtually bile-independent absorption. Therefore, the improved oral bioavailability and dose linearity see n with this drug can facilitate patient management: the new formulation allows more accurate dose titration in the clinical setting and reduces the risk of over exposure or under exposure to the drug and maintain optimal immunosuppression of patients.

Pharmacology: Pharmacodynamics: Cyclosporine (cyclosporine A) is a cyclosporine immunosuppressive agent. The drug is a nonpolar, cyclic polypeptide antibiotic consisting of 11 amino acids. In vivo studies in animals have shown that cyclosporine inhibits cell-mediated immune responses such as allograft rejection, delayed hypersensitivity (e.g., tuberculin-induced), experimental allergic encephalomyelitis, Freund's adjuvant-induced arthritis, and graft-vs-host disease.
Cyclosporine has also been shown to inhibit primary and secondary responses to T cell-dependent antigens. Increased survival of allogeneic (homologous) transplants involving skin, heart, kidney, liver, pancreas, bone marrow, small intestine, and lung has been shown in animals receiving the drug.
It has been suggested that the immunosuppressive action of cyclosporine results from specific and reversible inhibition of immunocompetent T cells (T-lymphocytes) in the G₀ or G₁ phase of the cell cycle. Cyclosporine inhibits production and/or release of lymphokines including interleukin-2 (T-cell growth factor) and interleukin-1 (lymphocyte-activating factor).
Cyclosporine inhibits the release of interleukin-2 from activated T cells and also inhibits interleukin-2-induced activation of resting T cells; the drug does not appear to inhibit activation of resting T cells that is induced by exogenous interleukin-2. Cyclosporine does not affect the function of phagocytic cells or that of tumor cells. In one study following administration of high dosages of cyclosporine, bone marrow cell counts showed only slight reductions in cell numbers; proliferation of bone marrow stem cells was normal or enhanced.
Pharmacokinetics: Absorption: Following oral administration, cyclosporine is variably and incompletely absorbed. The extent of absorption depends on the individual patient, patient population (e.g., transplant type), post-transplantation time (e.g. increasing during the early post-transplantation period in renal transplant recipients), bile flow (micellar absorption of the drug involving bile), GI state (e.g., decreased with diarrhea), and the formulation administered. Although the absolute oral bioavailability of cyclosporine administered as the modified oral formulations has not been determined in adults, these formulations have greater bioavailability than the conventional oral formulations of cyclosporine. The higher bioavailability of the modified oral formulations relative to the conventional oral formulation varies across patient populations. Food decreases the AUC and peak blood concentration of cyclosporine attained with the modified oral formulations.
Distribution: Cyclosporine is widely distributed into body fluids and tissues, with most of the drug being distributed outside the blood volume. Approximately 90-98% of cyclosporine in plasma is protein bound, mainly to lipoproteins (85-90% of total protein binding). Of lipoprotein binding, 43-57% is to high density lipoproteins (HDLs), 25% to low density lipoproteins (LDLs), and 2% to very-low-density lipoproteins (VLDLs). Distribution of the drug in blood is dose dependent; in vitro in blood, 33-47% of the drug is distributed into plasma, 4-9% into lymphocytes, 4-12% into granulocytes, and 41-58% into erythrocytes. At high concentrations, distribution of cyclosporine into leukocytes and erythrocytes becomes saturated. Concentrations of the drug achieved in mononuclear cells have been reported to be 1000 times greater than those achieved in erythrocytes. Cyclosporine crosses the placenta in animals and humans and is distributed into milk.
Metabolism: Cyclosporine is extensively metabolized in the liver via the cytochrome P-450 enzyme system, principally by the CYP3A isoenzyme, and less extensively in the GI tract and the kidney to at least 30 metabolites found in bile, feces, blood and urine. The drug undergoes extensive first-pass metabolism following oral administration. Several major metabolic pathways, including hydroxylation of the Cγ-carbon of 2 leucine residues, Cλ-carbon hydroxylation and cyclic ether formation (with oxidation of the double bond) in the side chain of the amino acid 3-hydroxyl-N,4-dimethyl-1-2 amino-6-octenoic acid, and N-demethylation of N-methyl leucine residues, are involved. Conjugation of these metabolites or hydrolysis of the cyclic peptide chain does not appear to be an important pathway for cyclosporine metabolism. Oxidation of cyclosporine at its 1-λ, 4-N-desmethylated, and 9-γ positions yields the major metabolites known as AM1 (M17), AM4N (M21), AM9 (M1), respectively.
Elimination: Cyclosporine is principally excreted via bile, almost entirely as metabolites. Only about 6% of a dose of the drug is excreted in urine, with 0.1% of a dose being excreted unchanged. However, urinary excretion of unchanged drug may be increased in certain patient populations (e.g., early posttransplant period in bone marrow allograft recipients) and in younger patients. The clearance of cyclosporine reportedly is not changed substantially by renal failure or dialysis.

Transplantation indications: Solid organ transplantation: Prevention of graft rejection following kidney, liver, heart, combined heart lung, lung or pancreas allogeneic transplantations. Treatment of transplant rejection in patients previously receiving other immunosuppressive agents.
Bone marrow transplantation: Prevention of graft rejection following bone marrow transplantation. Prevention or treatment of graft-versus-host disease (GVHD).
Non-transplantation indications: Endogenous uveitis: Treatment of active sight-threatening intermediate or posterior uveitis of non-infectious aetiology in patients where conventional therapy fails, or cause unacceptable side effects.
Treatment of Behçet uveitis with repeated inflammatory attacks involving the retina.
Nephrotic syndrome: Steroid-dependent and steroid-resistant nephrotic syndrome in adults and children, due to glomerular diseases such as minimal change nephropathy, focal and segmental glomerulosclerosis, or membranous glomerulonephritis. Cipol-N can be used to induce remissions and to maintain them. It can also be used to maintain steroid-induced remission, allowing withdrawal of steroids.
Rheumatoid arthritis: Treatment of severe, active rheumatoid arthritis.
Psoriasis: Treatment of severe psoriasis in patients in whom conventional therapy is ineffective or inappropriate.
Atopic dermatitis: Cipol-N is indicated in patients with severe atopic dermatitis when systemic therapy is required.

Recommended Dose: The daily doses of Cipol-N should always be given in two divided doses.
Because of considerable inter- and intraindividual variations in absorption and elimination and the possibility of pharmacokinetic drug interactions, doses should be titrated individually according to clinical response and tolerability.
In transplant patients, routine monitoring of cyclosporine trough blood levels is required to avoid adverse effects due to high levels and to prevent organ rejection due to low levels.
In patients treated for non-transplant indications, monitoring of cyclosporine blood levels is of limited value except in the case of unexpected treatment failure or relapse, where it may be appropriate to establish the possibility of very low levels caused by non-compliance, impaired gastrointestinal absorption, or pharmacokinetic interactions.
General target population: Transplantation indications: Solid organ transplantation: Treatment with this drug should be initiated 12 hours before surgery at a dose of 10 to 15 mg/kg given in two divided doses. This dose should be maintained as the daily dose for 1 to 2 weeks postoperatively before being gradually reduced in accordance with blood levels until a maintenance dose of about 2 to 6 mg/kg given in two divided doses is reached. When this drug is given with other immunosuppressants (e.g. with corticosteroids or as part of a triple or quadruple drug therapy) lower doses (e.g. 3 to 6 mg/kg given in two divided doses for the initial treatment) may be used.
Bone marrow transplantation: The initial dose should be given on the day before transplantation. If this drug is used to initiate therapy, the recommended daily dose is 12.5 to 15 mg/kg given in two divided doses, starting on the day before transplantation. Maintenance treatment at daily doses of about 12.5 mg/kg should be continued for at least 3 months (and preferably for 6 months) before the dose is gradually decreased zero by 1 year after transplantation. Higher doses of this drug, or the use of IV therapy, may be necessary in the presence of gastrointestinal disturbances which might decrease drug absorption. In some patients, GVHD occurs after discontinuation of this drug treatment, but usually responds favourably to reintroduction of therapy. Low doses of this drug should be used to treat mild, chronic GVHD.
Non-transplantation indications: When using Cipol-N in any of the established non-transplant indications, the following general rules should be adhered to: Before initiation of treatment a reliable baseline level of serum creatinine should be established by at least two measurements, and renal function must be assessed regularly throughout therapy to allow dosage adjustment.
The only accepted route of administration is by mouth (the concentrate for intravenous infusion must not be used), and the daily dose should be given in two divided doses.
Except in patients with sight-threatening endogenous uveitis and in children with nephrotic syndrome, the total daily dose must never exceed 5 mg/kg.
For maintenance treatment the lowest effective and well tolerated dosage should be determined individually.
In patients in whom within a given time no adequate response is achieved or the effective dose is not compatible with the established safety guidelines, treatment with this drug should be discontinued.
Endogenous uveitis: For inducing remission, initially 5 mg/kg per day orally given in two divided doses are recommended until remission of active uveal inflammation and improvement in visual acuity are achieved. In refractory cases, the dose can be increased to 7 mg/kg per day for a limited period.
To achieve initial remission, or to counteract inflammatory ocular attacks, systemic corticosteroid treatment with daily doses of 0.2 to 0.6 mg/kg prednisolone or an equivalent may be added if this drug alone does not control the situation sufficiently.
For maintenance treatment, the dose should be slowly reduced to the lowest effective level, which, during the remission phases, should not exceed 5 mg/kg per day.
Nephrotic syndrome: For inducing remission, the recommended daily dose, given in 2 divided oral doses, is 5 mg/kg for adults and 6 mg/kg for children if, except for proteinuria, renal function is normal. In patients with impaired renal function, the initial dose should not exceed 2.5 mg/kg per day. The combination of Cipol-N with low doses of oral corticosteroids is recommended if the effect of Cipol-N alone is not satisfactory, especially in steroid-resistant patients. If no improvement has been observed after 3 months' treatment, Cipol-N therapy should be discontinued. The doses need to be adjusted individually according to efficacy (proteinuria) and safety (primarily serum creatinine), but should not exceed 5 mg/kg per day in adults and 6 mg/kg per day in children.
For maintenance treatment, the dose should be slowly reduced to the lowest effective level.
Rheumatoid arthritis: For the first 6 weeks of treatment the recommended dose is 3 mg/kg per day orally given in two divided doses. If the effect is insufficient, the daily dose may then be increased gradually as tolerability permits, but should not exceed 5 mg/kg. To achieve full effectiveness, up to 12 weeks of this drug may be required.
For maintenance treatment the dose has to be titrated individually to the lowest effective level according to tolerability. This drug can be given in combination with low-dose corticosteroids and/or non-steroidal anti-inflammatory drugs. This drug can also be combined with low-dose weekly methotrexate in patients who have insufficient response to methotrexate alone, by using initially 2.5 mg/kg in two divided doses per day, with the option to increase the dose as tolerability permits.
Psoriasis: Due to the variability of this condition, treatment must be individualized.
For inducing remission, the recommended initial dose is 2.5 mg/kg per day orally given in two divided doses. If there is no improvement after 1 month, the daily dose may be gradually increased, but should not exceed 5 mg/kg. Treatment should be discontinued in patients in whom sufficient response of psoriatic lesions cannot be achieved within 6 weeks on 5 mg/kg per day, or in whom the effective dose is not compatible with the established safety guidelines.
Initial doses of 5 mg/kg per day are justified in patients whose condition requires rapid improvement. Once satisfactory response is achieved, this drug may be discontinued and subsequent relapse managed with re-introduction of this drug at the previous effective dose. In some patients, continuous maintenance therapy may be necessary.
For maintenance treatment, doses have to be titrated individually to the lowest effective level, and should not exceed 5 mg/kg per day.
Atopic dermatitis: Due to the variablility of this condition, treatment must be individualized. The recommended dose range is 2.5 to 5 mg/kg per day given in 2 divided oral doses. If a starting dose of 2.5 mg/kg per day does not achieve a satisfactory response within two weeks of therapy, the daily dose may be rapidly increased to a maximum of 5 mg/kg. In very severe cases, rapid and adequate control of the disease is more likely to occur with a starting dose of 5 mg/kg per day. Once satisfactory response is achieved, the dose should be reduced gradually and, if possible, Cipol-N should be discontinued. Subsequent relapse may be managed with a further course of Cipol-N.
Although a course of 8 weeks' therapy may be sufficient to achieve clearing, up to 1 year's therapy has been shown to be effective and well tolerated, provided the monitoring guidelines are followed.
Special population: Renal impairment all indications: Cyclosporine undergoes minimal renal elimination and its pharmacokinetics is not affected by renal impairment. However, due to its nephrotoxic potential, a careful monitoring of the renal function is recommended.
Non-transplant indications: Patients with impaired renal function, except nephrotic syndrome patients, should not receive cyclosporine. In nephrotic syndrome patients with impaired renal function, the initial dose should not exceed 2.5 mg/kg per day.
Hepatic impairment: Dose reduction may be necessary in patients with severe liver impairment to maintain blood levels within the recommended target range.
Pediatrics: Experience with cyclosporine in children is still limited. Clinical studies have included children from 1 year of age using standard cyclosporine dosage with no particular problems. In several studies, pediatric patients required and tolerated higher doses of cyclosporine per kg body weight than those used in adults.
This drug use in children for non-transplant indications other than nephrotic syndrome cannot be recommended.
Geriatrics (65 years old and above): Experience with cyclosporine in the elderly is limited, but no particular problems have been reported following the use of the drug at the recommended dose.
Mode of Administration: This drug should always be given in two divided doses. Capsules should be swallowed whole.

The oral LD₅₀ of cyclosporine is about 2.3, 1.5 or greater than 1 g/kg in mice, rats, and rabbits, respectively.
The IV LD₅₀ is 148, 104, or 46 mg/kg in mice, rats, and rabbits, respectively.
Symptom: Overdosage of cyclosporine is likely to produce symptoms that are mainly extensions of common adverse reactions. Transient hepatotoxicity and nephrotoxicity may occur but should resolve following elimination or discontinuance of the drug.
Treatment: In acute oral cyclosporine overdose, the stomach should be emptied by inducing emesis. Induction of emesis is probably useful up to 2 hours after ingestion. If the patient is comatose, having seizures, or lacks the gag reflex, gastric lavage may be performed if an endotracheal tube with cuff inflated is in place to prevent aspiration of gastric contents. Supportive and symptomatic treatment should be initiated. Hemodialysis and charcoal hemoperfusion reportedly are not useful for enhancing the elimination of cyclosporine following overdosage. When overdosage occurs in patients prescribed cyclosporine therapy, the drug may be withheld for a few days or alternate-day therapy may be initiated until the patient is stabilized.

Hypersensitivity to cyclosporine, or any component of the products.
Rheumatoid arthritis or psoriasis patients with abnormal renal function, uncontrolled hypertension, or malignancies.
The risk of developing malignancies of the skin and lymphoproliferative disorders is increased in patients receiving cyclosporine concurrently with PUVA or UVB, methotrexate or other immunosuppressive agents, coal tar or radiation therapy in psoriasis patients.

Cyclosporine should be used for therapeutic applications other than transplantation only by clinicians experienced in such use of immunosuppressive therapy.
Immunosuppression with cyclosporine may result in increased susceptibility to infection, including serious infections with fatal outcomes, and the possible development of lymphoma.
Immunosuppressed patients are at an increased risk for opportunistic infections, including reactivation of latent viral infections.
Because of the increased risk for skin cancer, patients should be advised to limit ultraviolet light exposure.
When necessary, (e.g., because of changes in oral absorption of the drug), dosage adjustment should be made to avoid toxicity resulting from high blood or plasma concentrations of the drug or to prevent possible organ rejection resulting from low concentrations.
Cyclosporine should be monitored routinely in allograft recipients and periodically in patients with rheumatoid arthritis.
Patients receiving cyclosporine should be informed of the necessity of routine laboratory testing (e.g., BUN and serum creatinine, bilirubin, and liver enzyme concentrations) for the assessment of renal and hepatic function.
Patients should be given careful dosage instructions, advised of the potential risks during pregnancy, and informed of the increased risk of neoplasia during cyclosporine therapy.
At high dosages, cyclosporine may cause nephrotoxicity and/or hepatotoxicity.

Although there are no adequate and well-controlled studies using cyclosporine in pregnant women, the drug has been shown to be embryotoxic and fetotoxic in rats and rabbits when administered orally at maternally toxic doses.
In women who received cyclosporine therapy throughout pregnancy, premature birth (gestational age of 28-36 weeks) and reduced neonatal weight occurred consistently. Most of the pregnancies also were complicated by growth retardation (which may be severe), fetal loss, preeclampsia, eclampsia, premature labor, abruptio placentae, oligohydramnios, Rh incompatibility, and fetoplacental dysfunction.
Cyclosporine should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. In patients with psoriasis, the risks and benefits of therapy with cyclosporine during pregnancy should be evaluated carefully, with discontinuance of therapy considered seriously because of possible disruption of the interaction between the mother and fetus.
Since cyclosporine is distributed into milk, nursing should be avoided in women receiving the drug.

Frequency >10%: Cardiovascular: Hypertension (8% to 53%), edema (5% to 14%).
Central nervous system: Headache (2% to 25%), paresthesia (1% to 11%).
Dermatologic: Hypertrichosis (5% to 19%).
Endocrine & metabolic: Hirsutism (21% to 45%), increased serum triglycerides (15%), female genital tract disease (9% to 11%).
Gastrointestinal: Nausea (2% to 23%), diarrhea (3% to 13%), gingival hyperplasia (2% to 16%), abdominal distress (<1% to 15%), dyspepsia (2% to 12%).
Genitourinary: Urinary tract infection (kidney transplant: 21%).
Infection: Increased susceptibility to infection (3% to 25%), viral infection (kidney transplant: 16%).
Neuromuscular & skeletal: Tremor (7% to 55%), leg cramps (2% to 12%).
Renal: Increased serum creatinine (16% to ≥50%), renal insufficiency (10% to 38%).
Respiratory: Upper respiratory infection (1% to 14%).
Kidney, liver, and heart transplant only: Cardiovascular: Chest pain (≤4%), flushing (<1% to 4%), glomerular capillary thrombosis, myocardial infarction.
Central nervous system: Convulsion (1% to 5%), anxiety, confusion, lethargy, tingling sensation.
Dermatologic: Skin infection (7%), acne vulgaris (1% to 6%), nail disease (brittle fingernails), hair breakage, night sweats, pruritus.
Endocrine & metabolic: Gynecomastia (<1% to 4%), hyperglycemia, hypomagnesemia, weight loss.
Gastrointestinal: Vomiting (2% to 10%), anorexia, aphthous stomatitis, constipation, dysphagia, gastritis, hiccups, pancreatitis.
Genitourinary: Hematuria.
Hematologic & oncologic: Leukopenia (<1% to 6%), lymphoma (<1% to 6%), anemia, thrombocytopenia, upper gastrointestinal hemorrhage.
Hepatic: Hepatotoxicity (<1% to 7%).
Infection: Localized fungal infection (8%), cytomegalovirus disease (5%), septicemia (5%), abscess (4%), fungal infection (systemic: 2%).
Neuromuscular & skeletal: Arthralgia, myalgia, weakness.
Ophthalmic: Conjunctivitis, visual disturbance.
Otic: Hearing loss, tinnitus.
Respiratory: Sinusitis (<1% to 7%), pneumonia (6%).
Miscellaneous: Fever.
Rheumatoid arthritis only: Cardiovascular: Chest pain (4%), cardiac arrhythmia (2%), abnormal heart sounds, cardiac failure, myocardial infarction, peripheral ischemia.
Central nervous system: Dizziness (8%), pain (6%), insomnia (4%), depression (3%), migraine (2% to 3%), anxiety, drowsiness, emotional lability, hypoesthesia, lack of concentration, malaise, neuropathy, nervousness, paranoia, vertigo.
Dermatologic: Cellulitis, dermatological reaction, dermatitis, diaphoresis, dyschromia, eczema, enanthema, folliculitis, nail disease, pruritus, urticaria, xeroderma.
Endocrine & metabolic: Menstrual disease (3%), decreased libido, diabetes mellitus, goiter, hot flash, hyperkalemia, hyperuricemia, hypoglycemia, increased libido, weight gain, weight loss.
Gastrointestinal: Vomiting (9%), flatulence (5%), gingivitis (4%), constipation, dysgeusia, dysphagia, enlargement of salivary glands, eructation, esophagitis, gastric ulcer, gastritis, gastroenteritis, gingival hemorrhage, glossitis, peptic ulcer, tongue disease, xerostomia.
Genitourinary: Leukorrhea (1%), breast fibroadenosis, hematuria, mastalgia, nocturia, urine abnormality, urinary incontinence, urinary urgency, uterine hemorrhage.
Hematologic & oncologic: Purpura (3% to 4%), anemia, carcinoma, leucopenia, lymphadenopathy.
Hepatic: Hyperbilirubinemia.
Infection: Abscess (including renal), bacterial infection, candidiasis, fungal infection, herpes simplex infection, herpes zoster, viral infection.
Neuromuscular & skeletal: Arthralgia, bone fracture, dislocation, myalgia, stiffness, synovial cyst, tendon disease, weakness.
Ophthalmic: Cataract, conjunctivitis, eye pain, visual disturbance.
Otic: Tinnitus, deafness, vestibular disturbance.
Renal: Abscess (renal), increased blood urea nitrogen, polyuria, pyelonephritis.
Respiratory: Cough (5%), dyspnea (5%), sinusitis (4%), abnormal breath sounds, bronchospasm, epitaxis, tonsilitis.
Psoriasis only: Cardiovascular: Chest pain, flushing.
Central nervous system: Psychiatric disturbance (4% to 5%), pain (3% to 4%), dizziness, insomnia, nervousness, vertigo.
Dermatologic: Acne vulgaris, folliculitis, hyperkeratosis, pruritus, skin rash, xeroderma.
Endocrine & metabolic: Hot flash.
Gastrointestinal: Abdominal distention, constipation, gingival hemorrhage, increased appetite.
Genitourinary: Urinary frequency.
Hematologic & oncologic: Abnormal erythrocytes, altered platelet function, blood coagulation disorder, carcinoma, hemorrhagic diathesis.
Hepatic: Hyperbillirubinemia.
Neuromuscular & skeletal: Arthralgia (1% to 6%).
Ophthalmic: Visual disturbance.
Respiratory: Flu-like symptoms (8% to 10%), bronchospasm (5%), cough (5%), dyspnea (5%), rhinitis (5%), respiratory tract infection.
Miscellaneous: Fever.

Nephrotoxic drugs: Interaction that may potentiate renal dysfunction are well substantiated between cyclosporine and various drugs, including aminoglycosides, vancomycin, co-trimoxazole, ciprofloxacin, melphalan, amphotericin B, ketoconazole, certain nonsteroidal anti-inflammatory agents (NSAIAs) (e.g., azapropazone, diclofenac, naproxen, sulindac), cimetidine, ranitidine, fibric acid derivatives (e.g., fenofibrate, bezafibrate), methotrexate, colchicine, and tacrolimus.
Concomitant administration of cyclosporine and colchicine may increase concentrations of cyclosporine, resulting in additive nephrotoxic effects. Cyclosporine also may reduce clearance of colchicine increasing the potential for enhanced colchicine toxicity (myopathy, neuropathy), particularly in patients with renal impairment. Patients should be monitored closely for colchicine toxicity during concurrent administration with cyclosporine; colchicine should be discontinued or dosage of the drug reduced if toxicity occurs.
Immunosuppressive and Antineoplastic agents: The modified formulations of cyclosporine may be administered with other immunosuppressives, although the degree of immunosuppression produced may result in an increased risk of lymphoma and other neoplasms and in susceptibility to infection.
Concomitant administration of cyclosporine and sirolimus substantially increases blood sirolimus concentrations. Sirolimus should be given 4 hours following cyclosporine administration to minimize the effect on sirolimus concentrations; concomitant administration of cyclosporine and methotrexate resulted in elevation of the AUC of methotrexate in patients with rheumatoid arthritis.
Potassium-sparing Drugs: Because cyclosporine may cause hyperkalemia, the drug should not be used concomitantly with potassium-sparing diuretics. Caution is advised and control of potassium concentrations recommended when cyclosporine is administered concomitantly with potassium-sparing drugs (e.g., angiotensin converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists) or potassium-containing drugs or in patients receiving a potassium-rich diet.
Drugs and Foods Affecting Hepatic Microsomal Enzymes: Because cyclosporine is extensively metabolized, the concentration of drug in biologic fluid (e.g., plasma, blood) may be altered by drugs or foods that effect hepatic microsomal enzymes, especially cytochrome P-450 isoenzyme subfamily CYP3A.
Drugs that decrease the metabolism and increase concentration of cyclosporine: diltiazem, nicardipine, verapamil, mibefradil, fluconazole, itraconazole, ketoconazole, voriconazole, clarithromycin, erythromycin, quinupristin/dalfopristin, methylprednisolone, allopurinol, amiodarone, bromocriptine, colchicine, imatinib, danazol, oral contraceptives, or metoclopramide.
Drugs that increase the metabolism and decrease concentration of cyclosporine: nafcillin, rifampin, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, octreotide, sulfinpyrazone, terbinafine, or ticlopidine.
Concomitant administration of cyclosporine with drugs that affect its metabolism requires monitoring of the concentration of cyclosporine in biologic fluid with appropriate adjustment of cyclosporine dosage.
Concomitant administration of prednisolone with cyclosporine may result in decreased plasma clearance of prednisolone, and plasma concentrations of cyclosporine may be increased during concomitant therapy with cyclosporine and methylprednisolone.
Concomitant oral administration of grapefruit juice with cyclosporine has been reported to increase bioavailability of cyclosporine.
The possibility that the immune response to vaccination may be diminished in patients receiving cyclosporine should be considered. In addition, because of the immunosuppressive effects of cyclosporine, the manufacturers recommend that live vaccines be avoided during therapy with the drug.
Concomitant administration of cyclosporine and metoclopramide has resulted in increased area under the blood concentration-time curve of cyclosporine. It has been suggested that absorption of cyclosporine increased through acceleration of gastric emptying of the drug stimulated by metoclopramide.
Concomitant use of cyclosporine and orlistat should be avoided because of the potential for decreased cyclosporine absorption.
Concomitant use of bosentan and cyclosporine has resulted in decreased plasma cyclosporine concentrations by approximately 50% and increased steady state plasma bosentan concentrations by about 3- to 4- fold.
Concomitant administration of cyclosporine and digoxin has resulted in decrease in apparent volume of distribution and serum clearance of digoxin. Cardiac glycoside toxicity (e.g., bidirectional ventricular tachycardia, anorexia, nausea, vomiting, diarrhea) occurred and serum digoxin concentrations were increased within a few days after patients already receiving digoxin began receiving cyclosporine.

Store below 30°C.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs) / Immunosuppressants

L04AD01 - ciclosporin ; Belongs to the class of calcineurin inhibitors. Used as immunosuppressants.

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