Cyclosporine (Neoral)

1. Health Canada Product Monograph — Cyclosporine

• Cyclosporine is used to prevent rejection following solid organ transplantation, such as kidney, liver, and heart transplants.
• It is used to treat transplant rejection in patients already receiving other immunosuppressive drugs.
• It is used to prevent graft rejection following bone marrow transplantation and to prevent or treat graft-versus-host disease.
• It is used to treat severe psoriasis in patients for whom conventional therapy is ineffective or inappropriate.
• It is used to treat severe active rheumatoid arthritis in patients for whom standard slow-acting antirheumatic drugs are inappropriate or ineffective.
• It is used to treat steroid-dependent or steroid-resistant nephrotic syndrome caused by certain kidney diseases, both to induce and to maintain remission.

• There are no adequate, well-controlled studies of cyclosporine in pregnant women.
• Pregnant women taking immunosuppressive therapy after transplantation, including cyclosporine, are at increased risk of premature delivery.
• Animal studies have shown that cyclosporine can be toxic to the developing embryo or fetus at doses below the maximum recommended human dose.
• Cyclosporine should not be used during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus, and the alcohol content of the oral formulations should also be considered.
• In patients treated for psoriasis, the risk and benefit of continuing cyclosporine during pregnancy should be carefully weighed, with serious consideration given to stopping treatment.

• Cyclosporine passes into breast milk, and mothers receiving treatment should not breastfeed.
• Because of the potential for serious side effects in breastfed infants, a decision must be made whether to stop breastfeeding or stop the medication, taking into account how important the medication is for the mother.

• Experience with cyclosporine in older adults is limited, but no unique problems have been identified at recommended doses.
• Age-related declines in kidney function can require closer monitoring and possible dose adjustment in older adults.
• In rheumatoid arthritis studies, older patients were more likely to develop high blood pressure and larger rises in creatinine during treatment.

• Cyclosporine is not recommended in children for non-transplant uses other than nephrotic syndrome.
• Pediatric patients have a similar range of side effects to adults but may need higher doses per kilogram of body weight to reach the same blood levels.
• Studies in nephrotic syndrome have included children as young as one year of age using standard dosing.

• For solid organ transplantation, treatment may start within 12 hours before surgery at 10 to 15 mg/kg per day in two divided doses, continued for one to two weeks after surgery, then gradually reduced according to blood levels to a maintenance dose of about 2 to 6 mg/kg per day in two divided doses.
• When combined with other immunosuppressants such as corticosteroids, lower starting doses of about 3 to 6 mg/kg per day may be used.
• For patients who cannot take oral cyclosporine before or after surgery, the intravenous concentrate (Sandimmune I.V.) is given at about one-third of the oral dose, starting at 3 to 5 mg/kg per day, and switched to oral therapy as soon as possible.
• For bone marrow transplantation, maintenance treatment is typically about 12.5 mg/kg per day in two divided doses, continued for at least three months before being gradually tapered to zero by one year after transplant.
• For psoriasis, the initial dose is 2.5 mg/kg per day in two divided doses, increased gradually if needed, up to a maximum of 5 mg/kg per day; treatment is stopped if the skin has not adequately improved after six weeks on the maximum dose.
• For rheumatoid arthritis, the initial dose is 2.5 mg/kg per day in two divided doses for the first six weeks, increased gradually as tolerated up to a maximum of 5 mg/kg per day; full effectiveness may take up to twelve weeks.
• For nephrotic syndrome, dosing is individualized and titrated to the lowest effective level, generally not exceeding 5 mg/kg per day in adults except in specific pediatric cases.
• Regular monitoring of cyclosporine blood trough levels, kidney function (serum creatinine), and blood pressure is required throughout treatment, with the dose reduced if creatinine rises more than 30% above the patient's own baseline.
• Cyclosporine dosing must always be individualized and adjusted based on blood levels, clinical response, and tolerability, because absorption varies considerably between patients.

If overdose is suspected, seek emergency medical attention immediately or contact your regional Poison Control Centre without delay.

• Experience with acute cyclosporine overdose is limited; oral doses as high as about 150 mg/kg have been tolerated with relatively minor effects such as vomiting, drowsiness, headache, a fast heartbeat, unusual skin sensations in the hands and feet, facial flushing, and gum soreness or bleeding.
• High cyclosporine levels can cause temporary liver and kidney toxicity, though no permanent damage has been reported after oral overdose.
• More serious symptoms of toxicity have occurred following accidental intravenous overdose in premature newborns.
• There is no specific antidote; management is supportive, with monitoring for signs of toxicity.
• Cyclosporine is not effectively removed by dialysis or charcoal hemoperfusion.

• Tremor may occur.
• Headache may occur.
• Excess hair growth (hirsutism) may occur.
• High blood pressure may occur.
• Nausea, vomiting, or diarrhea may occur.
• Loss of appetite may occur.
• Swollen or overgrown gums (gingival hyperplasia) may occur.
• Flushing may occur.
• Fluid retention (swelling) may occur.
• Acne may occur.
• Muscle cramps or muscle pain may occur.

Serious side effects require immediate discussion with the prescriber or emergency care.

• Cyclosporine can impair kidney function, sometimes leading to persistent structural kidney damage with long-term use.
• Cyclosporine can raise the risk of serious infections, including reactivation of viruses that can cause kidney disease (BK virus) or a rare, serious brain infection called progressive multifocal leukoencephalopathy.
• Cyclosporine increases the risk of lymphoma and other cancers, particularly skin cancer, especially with long-term or high-intensity treatment.
• Serious liver problems, including liver failure, have been reported, sometimes with a fatal outcome, particularly in patients with other risk factors.
• Neurological toxicity can occur, including tremor, seizures, and rarely more complex effects such as vision changes, confusion, or loss of consciousness.
• High potassium, high uric acid, and low magnesium levels can occur, especially early after transplant or in patients with reduced kidney function.
• Rare cases of a serious blood clotting disorder (hemolytic uremic syndrome, with low platelets and red blood cell breakdown) have been reported.
• Anaphylactoid reactions, including facial flushing and breathing difficulty, have occurred with the intravenous form, related to its castor oil-based carrier.
• Seek urgent medical attention for severe headache with vision changes, seizures, signs of a serious infection such as high fever, or sudden swelling and difficulty breathing during an intravenous infusion.

• Use with caution and only under the supervision of a physician experienced in immunosuppressive therapy and transplant management.
• Use with caution in patients with high blood pressure, since cyclosporine can cause or worsen hypertension.
• Use with caution in patients with abnormal kidney function, and monitor kidney function closely throughout treatment.
• Use with caution in patients taking other drugs that can harm the kidneys or that affect cyclosporine blood levels.
• Use with caution in patients with high cholesterol or triglycerides, since cyclosporine can worsen these levels.
• Use with caution in patients with a history of skin cancer or significant sun exposure, and advise patients to avoid excess sun and ultraviolet light exposure.
• Avoid live vaccines during treatment, since immune suppression can make them less safe and less effective.
• Avoid St. John's wort, since it can lower cyclosporine blood levels and reduce its effectiveness.
• Use with caution when driving or operating machinery, since cyclosporine can rarely cause visual disturbances, tremor, or impaired consciousness.

• Contraindicated in patients with known hypersensitivity to cyclosporine or any ingredient in the formulation.
• Contraindicated for treating psoriasis or rheumatoid arthritis in patients with abnormal kidney function, uncontrolled high blood pressure, active malignancy other than certain skin cancers, uncontrolled infection, or a primary or secondary immune deficiency.
• Contraindicated in combination with bosentan.

• Many azole antifungal drugs, such as ketoconazole, fluconazole, and itraconazole, raise cyclosporine blood levels and increase the risk of toxicity.
• Macrolide antibiotics, including erythromycin, clarithromycin, and azithromycin, raise cyclosporine blood levels.
• Calcium channel blockers such as diltiazem and nicardipine can raise cyclosporine blood levels; nifedipine combined with cyclosporine can worsen gum overgrowth.
• Enzyme-inducing drugs, such as rifampicin, phenytoin, phenobarbital, and carbamazepine, lower cyclosporine blood levels and can risk under-immunosuppression and organ rejection.
• Nonsteroidal anti-inflammatory drugs, such as diclofenac and naproxen, combined with cyclosporine can increase the risk of kidney impairment.
• Potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers, and potassium supplements combined with cyclosporine can raise the risk of high potassium levels.
• Tacrolimus should not be combined with cyclosporine because of an increased risk of kidney toxicity.
• Lovastatin and other HMG-CoA reductase inhibitors (statins) combined with cyclosporine increase the risk of muscle toxicity.
• Digoxin, colchicine, and other P-glycoprotein substrates can build up to higher levels when combined with cyclosporine, and this combination requires monitoring.
• Methotrexate combined with cyclosporine, particularly in rheumatoid arthritis, carries an increased risk of kidney toxicity.
• Fibrate cholesterol medications, such as bezafibrate and fenofibrate, can cause reversible kidney function impairment when combined with cyclosporine.
• Mycophenolate combined with cyclosporine can result in lower mycophenolic acid levels than expected.

• Neoral can generally be taken with or without food, since its microemulsion formulation is designed to provide consistent absorption regardless of meals.
• Grapefruit and grapefruit juice should be avoided, since they interfere with cyclosporine's breakdown and can raise blood levels.
• Once a patient is stabilized on Neoral, it should be taken consistently the same way relative to meals each day, and patients should not switch between different cyclosporine products without medical supervision, since absorption differs between formulations.

• Neoral is usually taken twice daily, approximately 12 hours apart, at the same times each day.
• It can be taken with or without food, but should be taken the same way relative to meals every day to keep blood levels consistent.
• Sandimmune I.V. is given as a slow intravenous infusion by a healthcare professional, typically over several hours, and is not self-administered.

• Store Neoral capsules at 15°C to 25°C, in their original blister packaging until ready to use.
• Store Neoral oral solution between 15°C and 30°C, not below 20°C for more than one month, and use within two months of opening; do not refrigerate or freeze.
• Store Sandimmune I.V. concentrate between 15°C and 30°C, protected from light; do not refrigerate or freeze.

• Cyclosporine is a powerful immune-suppressing medicine used to prevent transplant rejection or to treat certain severe autoimmune conditions.
• Regular blood tests are needed to check your cyclosporine level, kidney function, blood pressure, and cholesterol throughout treatment.
• Because cyclosporine weakens your immune system, take precautions against infection and tell your healthcare provider promptly about any fever, chills, or signs of illness.
• Avoid grapefruit and grapefruit juice, and check with your pharmacist before starting any new medication, herbal product, or supplement, since many interact with cyclosporine.
• Protect your skin from the sun and have regular skin checks, since cyclosporine increases the risk of skin cancer over time.