Chemical formula: C₆₂H₁₁₁N₁₁O₁₂ Molecular mass: 1,202.635 g/mol PubChem compound: 5284373
Ciclosporin interacts in the following cases:
Ciclosporin is an inhibitor of organic anion transporter proteins (OATP). Co-administration of drugs that are substrates of OATP with ciclosporin may increase plasma levels of co-medications that are substrates of this transporter.
Sulfonamides reduce the activity of ciclosporine.
Barbiturates are expected to decrease ciclosporin levels.
All inducers of CYP3A4 are expected to decrease ciclosporin levels.
All inhibitors of CYP3A4 may lead to increased levels of cyclosporine.
Ciclosporin is an inhibitor of CYP3A4. Co-administration of drugs that are substrates of CYP3A4 with ciclosporin may increase plasma levels of co-medications that are substrates of this enzyme.
The concomitant intake of grapefruit and grapefruit juice has been reported to increase the bioavailability of ciclosporin.
All inducers of P-glycoprotein are expected to decrease ciclosporin levels.
All inhibitors of P-glycoprotein may lead to increased levels of cyclosporine.
Ciclosporin is an inhibitor of the multidrug efflux transporter P-glycoprotein (P-gp). Co-administration of drugs that are substrates of P-gp with ciclosporin may increase plasma levels of co-medications that are substrates of this transporter.
Care should be taken when using ciclosporin together with other active substances that exhibit nephrotoxic synergy such as H2-receptor antagonists. During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered medicinal product should be reduced or alternative treatment considered.
Caution is required with concomitant use of potassium-sparing medicinal products (e.g. potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists) or potassium-containing medicinal products since they may lead to significant increases in serum potassium.
Ketoconazole, fluconazole, itraconazole and voriconazole could more than double ciclosporin exposure.
Oral contraceptives may lead to increased levels of cyclosporine.
Erythromycin can increase ciclosporin exposure 4- to 7-fold, sometimes resulting in nephrotoxicity. Clarithromycin has been reported to double the exposure of ciclosporin. Azitromycin increases ciclosporin levels by around 20%.
Care should be taken when using ciclosporin together with other active substances that exhibit nephrotoxic synergy such as aminoglycosides (including gentamycin, tobramycin). During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered medicinal product should be reduced or alternative treatment considered.
Quinolone increases the activity and toxicity of ciclosporin.
Protease inhibitors may lead to increased levels of cyclosporine.
A significantly increased exposure to anthracycline antibiotics (e.g. doxorubicine, mitoxanthrone, daunorubicine) was observed in oncology patients with the intravenous co-administration of anthracycline antibiotics and very high doses of ciclosporin.
Hydantoin analogs reduce the activity of ciclosporin.
Care should be taken when using ciclosporin together with other active substances that exhibit nephrotoxic synergy such as NSAIDs (including diclofenac, naproxen, sulindac). During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered medicinal product should be reduced or alternative treatment considered.
During treatment with ciclosporin, vaccination may be less effective and the use of live attenuated vaccines should be avoided.
Acetazolamide increases the activity and toxicity of ciclosporin.
Following concomitant administration of ciclosporin and aliskiren, a P-gp substrate, the Cmax of aliskiren was increased approximately 2.5-fold and the AUC approximately 5-fold. However, the pharmacokinetic profile of ciclosporin was not significantly altered. Co-administration of ciclosporin and aliskiren is not recommended.
Allopurinol may lead to increased levels of cyclosporine.
Multiple dose administration of ambrisentan and ciclosporin in healthy volunteers resulted in an approximately 2-fold increase in ambrisentan exposure, while the ciclosporin exposure was marginally increased (approximately 10%).
Amiodarone substantially increases the plasma ciclosporin concentration concurrently with an increase in serum creatinine. This interaction can occur for a long time after withdrawal of amiodarone, due to its very long half-life (about 50 days).
Care should be taken when using ciclosporin together with other active substances that exhibit nephrotoxic synergy such as amphotericin B. During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered medicinal product should be reduced or alternative treatment considered.
Atazanavir increases the activity and toxicity of ciclosporin.
Co-administration of atorvastatin with cyclosporine increases the risk of myopathy and rhabdomyolysis.
Care should be taken when using ciclosporin together with other active substances that exhibit nephrotoxic synergy such as bezafibrate. During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered medicinal product should be reduced or alternative treatment considered.
Bosentan is expected to decrease ciclosporin levels.
Co-administration of bosentan and ciclosporin in healthy volunteers increases the bosentan exposure several-fold and there was a 35% decrease in ciclosporin exposure. Co-administration of ciclosporin with bosentan is not recommended.
Carbamazepine is expected to decrease ciclosporin levels.
Carvedilol increases the activity and toxicity of ciclosporin.
Care should be taken when using ciclosporin together with other active substances that exhibit nephrotoxic synergy such as ciprofloxacin. During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered medicinal product should be reduced or alternative treatment considered.
Clindamycin reduces the activity of ciclosporine.
Colchicine may lead to increased levels of cyclosporine.
Concomitant administration of dabigatran extexilate is not recommended due to the P-gp inhibitory activity of ciclosporin.
Danazol has been reported to increase ciclosporin blood concentrations by approximately 50%.
The concomitant use of diclofenac and ciclosporin has been found to result in a significant increase in the bioavailability of diclofenac, with the possible consequence of reversible renal function impairment. The increase in the bioavailability of diclofenac is most probably caused by a reduction of its high first-pass effect. If NSAIDs with a low first-pass effect (e.g. acetylsalicylic acid) are given together with ciclosporin, no increase in their bioavailability is to be expected.
Diltiazem (at doses of 90 mg/day) can increase ciclosporin plasma concentrations by up to 50%.
Efavirenz reduces the levels of cyclosporine.
Elevations in serum creatinine were observed in the studies using everolimus or sirolimus in combination with full-dose ciclosporin for microemulsion. This effect is often reversible with ciclosporin dose reduction. Everolimus and sirolimus had only a minor influence on ciclosporin pharmacokinetics. Co-administration of ciclosporin significantly increases blood levels of everolimus and sirolimus.
Care should be taken when using ciclosporin together with other active substances that exhibit nephrotoxic synergy such as fenofibrate. During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered medicinal product should be reduced or alternative treatment considered.
Griseofulvin reduces the activity of cyclosporine.
Imatinib could increase ciclosporin exposure and Cmax by around 20%.
Imipenem increases the activity and toxicity of ciclosporin.
Caution is recommended when co-administering ciclosporin with lercanidipine.
Care should be taken when using ciclosporin together with other active substances that exhibit nephrotoxic synergy such as methotrexate. During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered medicinal product should be reduced or alternative treatment considered.
Methylprednisolone (high dose) may lead to increased levels of cyclosporine.
Metoclopramide may lead to increased levels of cyclosporine.
Nefazodone may lead to increased levels of cyclosporine.
Nicardipine may lead to increased levels of cyclosporine.
The concurrent administration of nifedipine with ciclosporin may result in an increased rate of gingival hyperplasia compared with that observed when ciclosporin is given alone.
Octreotide decreases oral absorption of ciclosporin and a 50% increase in the ciclosporin dose or a switch to intravenous administration could be necessary.
Omeprazole increases the activity and toxicity of ciclosporin.
Orlistat is expected to decrease ciclosporin levels.
Oxcarbazepine is expected to decrease ciclosporin levels.
Phenytoin is expected to decrease ciclosporin levels.
Probucol is expected to decrease ciclosporin levels.
Propafenone increases the activity and toxicity of ciclosporin.
Pyrazinamide reduces the activity of ciclosporine.
Ciclosporin may increase the plasma concentrations of repaglinide and thereby increase the risk of hypoglycaemia.
Rifampicin induces ciclosporin intestinal and liver metabolism. Ciclosporin doses may need to be increased 3- to 5-fold during co-administration.
Rifamycin reduces the activity of ciclosporine.
Sevelamer reduces the activity of ciclosporine.
Sulfadimidine is expected to decrease ciclosporin levels.
Sulfinpyrazone reduces the activity of ciclosporine.
Sulfinpyrazone is expected to decrease ciclosporin levels.
Sulindac may increase the nephrotoxicity of ciclosporine.
Concomitant use of ciclosporin and tacrolimus should be avoided due to the risk for nephrotoxicity and pharmacokinetic interaction via CYP3A4 and/or P-gp.
Ciclosporin can reduce the metabolism and clearance of tamsulosin.
Co-administration with telaprevir resulted in approximately 4.64-fold increase in ciclosporin dose normalised exposure (AUC).
Terbinafine is expected to decrease ciclosporin levels.
Testosterone can increase the hepatotoxicity of ciclosporine.
Thiopental may increase the metabolism and clearance of ciclosporine.
Tiaprofenic acid may increase the nephrotoxicity of ciclosporine.
Ticlopidine is expected to decrease ciclosporin levels.
Ciclosporin can reduce the metabolism and clearance of tolterodine.
Ciclosporin can increase the toxicity of tramadol by reducing its metabolism and clearance.
Cyclosporin can increase the effectiveness/toxicity of trazodone by reducing its metabolism and clearance.
Care should be taken when using ciclosporin together with other active substances that exhibit nephrotoxic synergy such as trimethoprim. During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered medicinal product should be reduced or alternative treatment considered.
Ursodiol increases blood levels of ciclosporine.
Care should be taken when using ciclosporin together with other active substances that exhibit nephrotoxic synergy such as vancomycin. During the concomitant use of a drug that may exhibit nephrotoxic synergy, close monitoring of renal function should be performed. If a significant impairment of renal function occurs, the dosage of the co-administered medicinal product should be reduced or alternative treatment considered.
Verapamil increases ciclosporin blood concentrations 2- to 3-fold.
Ciclosporin enhances the risk of hyperkalaemia, especially in patients with renal dysfunction. Caution is also required when ciclosporin is co-administered with potassium-sparing drugs (e.g. potassium-sparing diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists) or potassium-containing medicinal products as well as in patients on a potassium rich diet. Control of potassium levels in these situations is advisable.
Ciclosporin enhances the clearance of magnesium. This can lead to symptomatic hypomagnesaemia, especially in the peri-transplant period. Control of serum magnesium levels is therefore recommended in the peri-transplant period, particularly in the presence of neurological symptom/signs. If considered necessary, magnesium supplementation should be given.
Caution is required when treating patients with hyperuricaemia.
Regular monitoring of blood pressure is required during ciclosporin therapy. If hypertension develops, appropriate antihypertensive treatment must be instituted. Preference should be given to an antihypertensive agent that does not interfere with the pharmacokinetics of ciclosporin, e.g. isradipine.
Nafcillin is expected to decrease ciclosporin levels.
Animal studies have shown reproductive toxicity in rats and rabbits. Cyclosporine gave no evidence of mutagenic or teratogenic effects in the standard test systems with oral application (rats up to 17 mg/kg and rabbits up to 30 mg/kg per day orally). Cyclosporine oral solution, USP has been shown to be embryo- and fetotoxic in rats and rabbits when given in doses 2-5 times the human dose. At toxic doses (rats at 30 mg/kg/day and rabbits at 100 mg/kg/day), cyclosporine oral solution, USP was embryo- and fetotoxic as indicated by increased pre- and postnatal mortality and reduced fetal weight together with related skeletal retardations. In the well-tolerated dose range (rats at up to 17 mg/kg/day and rabbits at up to 30 mg/kg/day), cyclosporine oral solution, USP proved to be without any embryolethal or teratogenic effects.
Experience with ciclosporin in pregnant women is limited. Pregnant women receiving immunosuppressive therapies after transplantation, including ciclosporin and ciclosporin-containing regimens, are at risk of premature delivery (<37 weeks).
There are no adequate and well-controlled studies in pregnant women and therefore, cyclosporine should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the fetus.
A limited number of observations in children exposed to ciclosporin in utero are available, up to an age of approximately 7 years. Renal function and blood pressure in these children were normal. However, there are no adequate and well-controlled studies in pregnant women and therefore ciclosporin should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the foetus. The ethanol content of the ciclosporin formulations should also be taken into account in pregnant women.
Following oral administration, ciclosporin is excreted in breast milk. The ethanol content of the ciclosporin formulations should also be taken into account in women who are breast-feeding. Mothers receiving treatment with ciclosporin should not breast-feed because of the potential of ciclosporin to cause serious adverse drug reactions in breast-fed newborns/infants. A decision should be made whether to abstain from breast-feeding or to abstain from using ciclosporin, taking into account the importance of the medicinal product to the mother.
Following oral administration, ciclosporin is excreted in breast milk. There is insufficient information on the effects of ciclosporin in newborns/infants. However, at therapeutic doses of ciclosporin in eye drops, it is unlikely that sufficient amounts would be present in breast milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from ciclosporin eye drops therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
There is limited data on the effect of ciclosporin on human fertility.
No impairment of fertility has been reported in animals receiving intravenous ciclosporin.
Ciclosporin is not recommended in women of childbearing potential not using effective contraception.
No data exist on the effects of ciclosporin on the ability to drive and use machines.
Use of eye drops, emulsion, may induce temporary blurred vision or other visual disturbances which may affect the ability to drive or use machines. Patients should be advised not to drive or use machines until their vision has cleared.
The principal adverse reactions observed in clinical trials and associated with the administration of ciclosporin include renal dysfunction, tremor, hirsutism, hypertension, diarrhoea, anorexia, nausea and vomiting.
Many side effects associated with ciclosporin therapy are dose-dependent and responsive to dose reduction. In the various indications the overall spectrum of side effects is essentially the same; there are, however, differences in incidence and severity. As a consequence of the higher initial doses and longer maintenance therapy required after transplantation, side effects are more frequent and usually more severe in transplant patients than in patients treated for other indications.
Anaphylactoid reactions have been observed following intravenous administration.
Patients receiving immunosuppressive therapies, including ciclosporin and ciclosporin-containing regimens, are at increased risk of infections (viral, bacterial, fungal, parasitic). Both generalised and localised infections can occur. Pre-existing infections may also be aggravated and reactivation of polyomavirus infections may lead to polyomavirus-associated nephropathy (PVAN) or to JC virus associated progressive multifocal leukopathy (PML). Serious and/or fatal outcomes have been reported.
Patients receiving immunosuppressive therapies, including ciclosporin and ciclosporin containing regimens, are at increased risk of developing lymphomas or lymphoproliferative disorders and other malignancies, particularly of the skin. The frequency of malignancies increases with the intensity and duration of therapy. Some malignancies may be fatal.
Adverse drug reactions from clinical trials are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000) very rare (<1/10,000), not known (cannot be estimated from the available data).
Adverse drug reactions from clinical trials:
Common: Leucopenia
Uncommon: Thrombocytopenia, anaemia
Rare: Haemolytic uraemic syndrome, microangiopathic haemolytic anaemia
Not known*: Thrombotic microangiopathy, thrombotic thrombocytopenic purpura
Very common: Hyperlipidaemia
Common: Hyperglycaemia, anorexia, hyperuricaemia, hyperkalaemia, hypomagnesaemia
Very common: Tremor, headache
Common: Convulsions, paraesthesia
Uncommon: Encephalopathy including Posterior Reversible Encephalopathy Syndrome (PRES), signs and symptoms such as convulsions, confusion, disorientation, decreased responsiveness, agitation, insomnia, visual disturbances, cortical blindness, coma, paresis and cerebellar ataxia
Rare: Motor polyneuropathy
Very rare: Optic disc oedema, including papilloedema, with possible visual impairment secondary to benign intracranial hypertension
Not known*: Migraine
Very common: Hypertension
Common: Flushing
Common: Nausea, vomiting, abdominal discomfort/pain, diarrhoea, gingival hyperplasia, peptic ulcer
Rare: Pancreatitis
Common: Hepatic function abnormal
Not known*: Hepatotoxicity and liver injury including cholestasis, jaundice, hepatitis and liver failure with some fatal outcome
Very common: Hirsutism
Common: Acne, hypertrichosis
Uncommon: Allergic rashes
Common: Myalgia, muscle cramps
Rare: Muscle weakness, myopathy
Not known*: Pain of lower extremities
Very common: Renal dysfunction
Rare: Menstrual disturbances, gynaecomastia
Common: Pyrexia, fatigue
Uncommon: Oedema, weight increase
* Adverse events reported from post marketing experience where the ADR frequency is not known due to the lack of a real denominator.
There have been solicited and spontaneous reports of hepatotoxicity and liver injury including cholestasis, jaundice hepatitis and liver failure in patients treated with ciclosporin. Most reports included patients with significant co-morbidities, underlying conditions and other confounding factors including infectious complications and co-medications with hepatotoxic potential. In some cases, mainly in transplant patients, fatal outcomes have been reported.
Patients receiving calcineurin inhibitor (CNI) therapies, including ciclosporin and ciclosporin-containing regimens, are at increased risk of acute or chronic nephrotoxicity. There have been reports from clinical trials and from the post-marketing setting associated with the use of Neoral. Cases of acute nephrotoxicity reported disorders of ion homeostasis, such as hyperkalaemia, hypomagnesaemia, and hyperuricaemia. Cases reporting chronic morphological changes included arteriolar hyalinosis, tubular atrophy and interstitial fibrosis.
Isolated cases of pain of lower extremities have been reported in association with ciclosporin. Pain of lower extremities has also been noted as part of Calcineurin-Inhibitor Induced Pain Syndrome (CIPS).
Clinical studies have included children from 1 year of age using standard ciclosporin dosage with a comparable safety profile to adults.
In five clinical studies including 532 patients who received ciclosporin and 398 as control group, ciclosporin was administered at least once a day in both eyes, for up to one year. The most common adverse reactions were eye pain (19.2%), eye irritation (17.8%), lacrimation (6.4%), ocular hyperaemia (5.5%) and eyelid erythema (1.7%) which were usually transitory and occurred during instillation.
The majority of adverse reactions reported in clinical studies with the use of ciclosporin were ocular and mild to moderate in severity.
The following adverse reactions listed below were observed in clinical studies. They are ranked according to system organ class and classified according to the following convention: very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1,000), very rare (<1/10,000), or not known (cannot be estimated from the available data).
Uncommon: Keratitis bacterial, herpes zoster ophthalmic.
Common: Erythema of eyelid, lacrimation increased, ocular hyperaemia, vision blurred, eyelid oedema, conjunctival hyperaemia, eye irritation, eye pain.
Uncommon: Conjunctival oedema, lacrimal disorder, eye discharge, eye pruritus, conjunctival irritation, conjunctivitis, foreign body sensation in eyes, deposit eye, keratitis, blepharitis, corneal decompensation, chalazion, corneal infiltrates, corneal scar, eyelid pruritus, iridocyclitis.
Very common: Instillation site pain.
Common: Instillation site irritation, instillation site erythema, instillation site lacrimation.
Uncommon: Instillation site reaction, instillation site discomfort, instillation site pruritus, instillation site foreign body sensation.
Instillation site pain was a frequently reported local adverse reaction associated with the use of ciclosporin during clinical trials. It is likely to be attributable to ciclosporin.
One case of severe epithelial erosion of the cornea identified as corneal decompensation by the investigator resolved without sequeleae was reported.
Patients receiving immunosuppressive therapies, including ciclosporin, are at increased risk of infections. Both generalised and localised infections can occur. Pre-existing infections may also be aggravated. Cases of infections have been reported uncommonly in association with the use of ciclosporin.
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