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Special Alerts
Immunosuppressant Drugs: Risk of Opportunistic Infections - July 2009
The U.S. Food and Drug Administration (FDA) is alerting healthcare professionals of updated labeling requirements to emphasize an increased risk for opportunistic infections (eg, activation of latent viral infections, including BK virus-associated nephropathy) in patients treated with certain immunosuppressant agents. The labeling changes will be required for cyclosporine (Neoral®, Sandimmune®), mycophenolate (Cellcept®, Myfortic®), and sirolimus (Rapamune®). This risk has been previously reported and reflected in the prescribing information for tacrolimus (Prograf®). Analyses of the FDA's Adverse Event Reporting System (AERS) has shown an association between BK virus-associated nephropathy and immunosuppressant drug use (primarily in renal transplant patients) which can lead to renal allograft loss. Patients should be monitored for this risk and early intervention is essential. Immunosuppressant therapy adjustments should be considered in patients who develop BK virus-associated nephropathy.
For additional information, refer to the following FDA website: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm171828.htm
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
CycloSPORINE may be confused with cyclophosphamide, Cyklokapron®, cycloSERINE
CycloSPORINE modified (Neoral®, Gengraf®) may be confused with cycloSPORINE non-modified (Sandimmne®)
Gengraf® may be confused with Prograf®
Neoral® may be confused with Neurontin®, Nizoral®
Sandimmune® may be confused with Sandostatin®
Pronunciation
(SYE kloe spor een)
U.S. Brand Names
Index Terms
Generic Available
Yes: Excludes ophthalmic emulsion
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Prophylaxis of organ rejection in kidney, liver, and heart transplants, has been used with azathioprine and/or corticosteroids; severe, active rheumatoid arthritis (RA) not responsive to methotrexate alone; severe, recalcitrant plaque psoriasis in nonimmunocompromised adults unresponsive to or unable to tolerate other systemic therapy
Ophthalmic emulsion (Restasis®): Increase tear production when suppressed tear production is presumed to be due to keratoconjunctivitis sicca-associated ocular inflammation (in patients not already using topical anti-inflammatory drugs or punctal plugs)
Use: Dental
Used as an immunosuppressive agent
Use: Unlabeled/Investigational
Short-term, high-dose cyclosporine as a modulator of multidrug resistance in cancer treatment; allogenic bone marrow transplants for prevention and treatment of graft-versus-host disease; also used in some cases of severe autoimmune disease (eg, SLE, myasthenia gravis, inflammatory bowel disease) that are resistant to corticosteroids and other therapy; focal segmental glomerulosclerosis
Pregnancy Risk Factor
C
Pregnancy Considerations
Reproductive toxicity has been observed in animal studies; mutagenic and teratogenic effects were not observed in the standard test systems following oral administration. In humans, cyclosporine crosses the placenta. Based on clinical use, premature births and low birth weight were consistently observed. Use only if the benefit to the mother outweighs the possible risks to the fetus.A pregnancy registry has been established for pregnant women taking immunosuppressants following any solid organ transplant (National Transplantation Pregnancy Registry, Temple University, 877-955-6877).
Lactation
Enters breast milk/not recommended
Breast-Feeding Considerations
The AAP does not recommend breast-feeding during therapy due to possible immune suppression in the infant as well as the unknown effects on growth or association with carcinogenesis.
Contraindications
Hypersensitivity to cyclosporine or any component of the formulation. Rheumatoid arthritis and psoriasis: Abnormal renal function, uncontrolled hypertension, malignancies. Concomitant treatment with PUVA or UVB therapy, methotrexate, other immunosuppressive agents, coal tar, or radiation therapy are also contraindications for use in patients with psoriasis. Ophthalmic emulsion is contraindicated in patients with active ocular infections.
Warnings/Precautions
Boxed warnings:
• Experienced physician: See “Other warnings/precautions” below.
• Hypertension: See “Concerns related to adverse effects” below.
• Infection: See “Concerns related to adverse effects” below.
• Malignancy: See “Concerns related to adverse effects” below.
• Nephrotoxicity: “Concerns related to adverse effects” below.
• Non-interchangeability of modified/non-modified forms: See “Dosage form specific issues” below.
• Skin cancer: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Hepatotoxicity: Increased hepatic enzymes and bilirubin have occurred (when used at high doses); improvement usually seen with dosage reduction.
• Hypertension: [U.S. Boxed Warning]: May cause hypertension.
• Infection: [U.S. Boxed Warning]: Increased risk of infection with use; fatal infections have been reported.
• Malignancy: [U.S. Boxed Warning]: Increased risk of lymphomas and other malignancies with use, particulary those of the skin; risk is related to intensity/duration of therapy and the use of more than one immunosuppressive agent; all patients should avoid excessive sun/UV light exposure.
• Nephrotoxicity: [U.S. Boxed Warning]: Renal impairment, including structural kidney damage has occurred (when used at high doses); monitor renal function closely. Use caution with other potentially nephrotoxic drugs (eg, acyclovir, aminoglycoside antibiotics, amphotericin B, ciprofloxacin).
• Skin cancer: [U.S. Boxed Warning]: Risk of skin cancer may be increased in psoriasis patients with a history of PUVA and possibly methotrexate or other immunosuppressants, UVB, coal tar, or radiation; increased risk of skin cancer has also been established in transplant patients; risk is related to intensity/duration of therapy and the use of more than one immunosuppressive agent; all patients should avoid excessive sun/UV light exposure.
Disease-related concerns:
• Rheumatoid arthritis: Appropriate use: If receiving other immunosuppressive agents, radiation or UV therapy, concurrent use of cyclosporine is not recommended.
Special populations:
• Pediatrics: Safety and efficacy for use in psoriasis have not been established in children. Safety and efficacy of the ophthalmic emulsion have not been established in children <16 years of age. Safety and efficacy for use in juvenile rheumatoid arthritis have not been established.
• Transplant patients: To be used initially with corticosteroids. May cause significant hyperkalemia and hyperuricemia. May cause seizures, particularly if used with high-dose corticosteroids. Encephalopathy has been reported, predisposing factors include hypertension, hypomagnesemia, hypocholesterolemia, high-dose corticosteroids, high cyclosporine serum concentration, and graft-versus-host disease; may be more common in patients with liver transplant. Make dose adjustments based on cyclosporine blood concentrations. Anaphylaxis has been reported with I.V. use; reserve for patients who cannot take oral form.
Dosage form specific issues:
• Corn oil: Product may contain corn oil.
• Ethanol: Products may contain ethanol.
• Injection: Contains Cremophor® EL (polyoxyethylated castor oil), which has been associated with rare anaphylactic reactions.
• Non-interchangeability of modified/non-modified forms: Use caution when changing dosage forms; products are not equally interchangeable. Cyclosporine (modified) refers to the capsule dosage formulation of cyclosporine in an aqueous dispersion (previously referred to as “microemulsion”). [U.S. Boxed Warning]: Cyclosporine (modified) has increased bioavailability as compared to cyclosporine (non-modified) and cannot be used interchangeably without close monitoring.
• Propylene glycol: Products may contain propylene glycol.
Other warnings/precautions:
• Experienced physician: [U.S. Boxed Warning]: Adjustment of dose should only be made under the direct supervision of an experienced physician.
• Monitoring of concentrations: Monitor cyclosporine concentrations closely following the addition, modification, or deletion of other medications.
• Vaccines: Live, attenuated vaccines may be less effective; use should be avoided.
Adverse Reactions
Adverse reactions reported with systemic use, including rheumatoid arthritis, psoriasis, and transplantation (kidney, liver, and heart). Percentages noted include the highest frequency regardless of indication/dosage. Frequencies may vary for specific conditions or formulation.
>10%:
Cardiovascular: Hypertension (8% to 53%), edema (5% to 14%)
Central nervous system: Headache (2% to 25%)
Dermatologic: Hirsutism (21% to 45%), hypertrichosis (5% to 19%)
Endocrine & metabolic: Triglycerides increased (15%), female reproductive disorder (9% to 11%)
Gastrointestinal: Nausea (23%), diarrhea (3% to 13%), gum hyperplasia (2% to 16%), abdominal discomfort (<1% to 15%), dyspepsia (2% to 12%)
Neuromuscular & skeletal: Tremor (7% to 55%), paresthesia (1% to 11%), leg cramps/muscle contractions (2% to 12%)
Renal: Renal dysfunction/nephropathy (10% to 38%), creatinine increased (16% to ?50%)
Respiratory: Upper respiratory infection (1% to 14%)
Miscellaneous: Infection (3% to 25%)
Kidney, liver, and heart transplant only (?2% unless otherwise noted):
Cardiovascular: Flushes (<1% to 4%), MI
Central nervous system: Convulsions (1% to 5%), anxiety, confusion, fever, lethargy
Dermatologic: Acne (1% to 6%), brittle fingernails, hair breaking, pruritus
Endocrine & metabolic: Gynecomastia (<1% to 4%), hyperglycemia
Gastrointestinal: Nausea (2% to 10%), vomiting (2% to 10%), diarrhea (3% to 8%), abdominal discomfort (<1% to 7%), cramps (0% to 4%), anorexia, constipation, gastritis, mouth sores, pancreatitis, swallowing difficulty, upper GI bleed, weight loss
Hematologic: Leukopenia (<1% to 6%), anemia, thrombocytopenia
Hepatic: Hepatotoxicity (<1% to 7%)
Neuromuscular & skeletal: Paresthesia (1% to 3%), joint pain, muscle pain, tingling, weakness
Ocular: Conjunctivitis, visual disturbance
Otic: Hearing loss, tinnitus
Renal: Hematuria
Respiratory: Sinusitis (<1% to 7%)
Miscellaneous: Lymphoma (<1% to 6%), allergic reactions, hiccups, night sweats
Rheumatoid arthritis only (1% to <3% unless otherwise noted):
Cardiovascular: Hypertension (8%), edema (5%), chest pain (4%), arrhythmia (2%), abnormal heart sounds, cardiac failure, MI, peripheral ischemia
Central nervous system: Dizziness (8%), pain (6%), insomnia (4%), depression (3%), migraine (2%), anxiety, hypoesthesia, emotional lability, impaired concentration, malaise, nervousness, paranoia, somnolence, vertigo
Dermatologic: Purpura (3%), abnormal pigmentation, angioedema, cellulitis, dermatitis, dry skin, eczema, folliculitis, nail disorder, pruritus, skin disorder, urticaria
Endocrine & metabolic: Menstrual disorder (3%), breast fibroadenosis, breast pain, diabetes mellitus, goiter, hot flashes, hyperkalemia, hyperuricemia, hypoglycemia, libido increased/decreased
Gastrointestinal: Vomiting (9%), flatulence (5%), gingivitis (4%), gum hyperplasia (2%), constipation, dry mouth, dysphagia, enanthema, eructation, esophagitis, gastric ulcer, gastritis, gastroenteritis, gingival bleeding, glossitis, peptic ulcer, salivary gland enlargement, taste perversion, tongue disorder, tooth disorder, weight loss/gain
Genitourinary: Leukorrhea (1%), abnormal urine, micturition urgency, nocturia, polyuria, pyelonephritis, urinary incontinence, uterine hemorrhage
Hematologic: Anemia, leukopenia
Hepatic: Bilirubinemia
Neuromuscular & skeletal: Paresthesia (8%), tremor (8%), leg cramps/muscle contractions (2%), arthralgia, bone fracture, joint dislocation, myalgia, neuropathy, stiffness, synovial cyst, tendon disorder, weakness
Ocular: Abnormal vision, cataract, conjunctivitis, eye pain
Otic: Tinnitus, deafness, vestibular disorder
Renal: BUN increased, hematuria, renal abscess
Respiratory: Cough (5%), dyspnea (5%), sinusitis (4%), abnormal chest sounds, bronchospasm, epistaxis
Miscellaneous: Infection (9%), abscess, allergy, bacterial infection, carcinoma, fungal infection, herpes simplex, herpes zoster, lymphadenopathy, moniliasis, diaphoresis increased, tonsillitis, viral infection
Psoriasis only (1% to <3% unless otherwise noted):
Cardiovascular: Chest pain, flushes
Central nervous system: Psychiatric events (4% to 5%), pain (3% to 4%), dizziness, fever, insomnia, nervousness, vertigo
Dermatologic: Hypertrichosis (5% to 7%), acne, dry skin, folliculitis, keratosis, pruritus, rash, skin malignancies
Endocrine & metabolic: Hot flashes
Gastrointestinal: Nausea (5% to 6%), diarrhea (5% to 6%), gum hyperplasia (4% to 6%), abdominal discomfort (3% to 6%), dyspepsia (2% to 3%), abdominal distention, appetite increased, constipation, gingival bleeding
Genitourinary: Micturition increased
Hematologic: Bleeding disorder, clotting disorder, platelet disorder, red blood cell disorder
Hepatic: Hyperbilirubinemia
Neuromuscular & skeletal: Paresthesia (5% to 7%), arthralgia (1% to 6%)
Ocular: Abnormal vision
Respiratory: Bronchospasm (5%), cough (5%), dyspnea (5%), rhinitis (5%), respiratory infection
Miscellaneous: Flu-like syndrome (8% to 10%)
Postmarketing and/or case reports (any indication): Anaphylaxis/anaphylactoid reaction (possibly associated with Cremophor® EL vehicle in injection formulation), benign intracranial hypertension, cholesterol increased, death (due to renal deterioration), encephalopathy, gout, hyperbilirubinemia, hyperkalemia, hypomagnesemia (mild), impaired consciousness, neurotoxicity, papilloedema, pulmonary edema (noncardiogenic), uric acid increased
Ophthalmic emulsion (Restasis®):
>10%: Ocular: Burning (17%)
1% to 10%: Ocular: Hyperemia (conjunctival 5%), eye pain, pruritus, stinging
Metabolism/Transport Effects
Substrate of CYP3A4 (major); Inhibits CYP2C9 (weak), 3A4 (moderate)
Drug Interactions
ACE Inhibitors: May enhance the nephrotoxic effect of CycloSPORINE. Risk D: Consider therapy modification
Aliskiren: CycloSPORINE may increase the serum concentration of Aliskiren. Risk X: Avoid combination
Ambrisentan: CycloSPORINE may increase the serum concentration of Ambrisentan. Risk C: Monitor therapy
Aminoglycosides: May enhance the nephrotoxic effect of CycloSPORINE. Risk C: Monitor therapy
Amiodarone: May decrease the metabolism of CycloSPORINE. Risk D: Consider therapy modification
Amphotericin B: May enhance the nephrotoxic effect of CycloSPORINE. Risk C: Monitor therapy
Androgens: May enhance the hepatotoxic effect of CycloSPORINE. Androgens may increase the serum concentration of CycloSPORINE. Risk D: Consider therapy modification
Antacids: May decrease the serum concentration of CycloSPORINE. Specifically when cyclosporine is administered orally. Risk C: Monitor therapy
Antifungal Agents (Azole Derivatives, Systemic): May decrease the metabolism of CycloSPORINE. Risk D: Consider therapy modification
Barbiturates: May increase the metabolism of CycloSPORINE. Risk D: Consider therapy modification
Bosentan: CycloSPORINE may increase the serum concentration of Bosentan. Bosentan may decrease the serum concentration of CycloSPORINE. Risk X: Avoid combination
Bromocriptine: May increase the serum concentration of CycloSPORINE. Risk C: Monitor therapy
Calcium Channel Blockers (Dihydropyridine): CycloSPORINE may decrease the metabolism of Calcium Channel Blockers (Dihydropyridine). Nicardipine may likewise inhibit the metabolism of cyclosporine. Cyclosporine dosage adjustments might be needed. Exceptions: Clevidipine. Risk C: Monitor therapy
Calcium Channel Blockers (Nondihydropyridine): May decrease the metabolism of CycloSPORINE. CycloSPORINE may decrease the metabolism of Calcium Channel Blockers (Nondihydropyridine). Risk D: Consider therapy modification
CarBAMazepine: May decrease the serum concentration of CycloSPORINE. Risk D: Consider therapy modification
Cardiac Glycosides: CycloSPORINE may decrease the metabolism of Cardiac Glycosides. Risk D: Consider therapy modification
Carvedilol: May increase the serum concentration of CycloSPORINE. Risk D: Consider therapy modification
Caspofungin: CycloSPORINE may enhance the adverse/toxic effect of Caspofungin. Significant increases in alanine transaminase have been reported. Risk D: Consider therapy modification
Colchicine: P-Glycoprotein Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Risk D: Consider therapy modification
Colchicine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Colchicine. Management: Reduce colchicine (adult) dose as directed when using with a moderate CYP3A4 inhibitor, and increase monitoring for colchicine-related toxicity. Use extra caution in patients with impaired renal and/or hepatic function. Risk D: Consider therapy modification
Corticosteroids (Systemic): May increase the serum concentration of CycloSPORINE. CycloSPORINE may increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
CYP3A4 Substrates: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
Dabigatran Etexilate: P-Glycoprotein Inhibitors may increase the serum concentration of Dabigatran Etexilate. Risk X: Avoid combination
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
DOXOrubicin: CycloSPORINE may decrease the metabolism of DOXOrubicin. Risk D: Consider therapy modification
Dronedarone: CycloSPORINE may increase the serum concentration of Dronedarone. Risk X: Avoid combination
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Eplerenone: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Eplerenone. Management: A lower starting dose of eplerenone (25 mg once daily for adults) is recommended in patients with hypertension who are also taking drugs that are moderate inhibitors of CYP3A4. Risk D: Consider therapy modification
Etoposide: CycloSPORINE may decrease the metabolism of Etoposide. Risk D: Consider therapy modification
Etoposide Phosphate: CycloSPORINE may increase the serum concentration of Etoposide Phosphate. CycloSPORINE may decrease the metabolism, via CYP isoenzymes, and decrease the p-glycoprotein-mediated elimination of Etoposide Phosphate. Risk D: Consider therapy modification
Everolimus: CycloSPORINE may increase the serum concentration of Everolimus. Risk X: Avoid combination
Ezetimibe: CycloSPORINE may increase the serum concentration of Ezetimibe. Ezetimibe may increase the serum concentration of CycloSPORINE. Risk D: Consider therapy modification
FentaNYL: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of FentaNYL. Risk D: Consider therapy modification
Fibric Acid Derivatives: CycloSPORINE may enhance the nephrotoxic effect of Fibric Acid Derivatives. Fibric Acid Derivatives may decrease the serum concentration of CycloSPORINE. Management: Careful consideration of the risks and benefits should be undertaken prior to use of this combination; extra monitoring of renal function and cyclosporine concentrations will likely be required. Adjustment of cyclosporine dose may be necessary. Risk D: Consider therapy modification
Fluconazole: May decrease the metabolism of CycloSPORINE. Risk D: Consider therapy modification
Grapefruit Juice: May decrease the metabolism of CycloSPORINE. Risk D: Consider therapy modification
Griseofulvin: May increase the metabolism of CycloSPORINE. Risk D: Consider therapy modification
Halofantrine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Halofantrine. Risk D: Consider therapy modification
HMG-CoA Reductase Inhibitors: CycloSPORINE may increase the serum concentration of HMG-CoA Reductase Inhibitors. Management: Use of cyclosporine with pitavastatin is contraindicated. Limit rosuvastatin to 5 mg/day and simvastatin to 10 mg/day (adult doses). Caution and close monitoring should be used with any cyclosporine-statin combination. Exceptions: Fluvastatin; Pitavastatin. Risk D: Consider therapy modification
Imatinib: May increase the serum concentration of CycloSPORINE. Risk C: Monitor therapy
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Macrolide Antibiotics: May decrease the metabolism of CycloSPORINE. Exceptions: Dirithromycin [Off Market]; Spiramycin. Risk C: Monitor therapy
Melphalan: May enhance the nephrotoxic effect of CycloSPORINE. Risk C: Monitor therapy
Methotrexate: May increase the serum concentration of CycloSPORINE. This may result in nephrotoxicity. CycloSPORINE may increase the serum concentration of Methotrexate. This may result in nausea, vomiting, oral ulcers, hepatotoxicity and/or nephrotoxicity. Risk D: Consider therapy modification
Metoclopramide: May increase the absorption of CycloSPORINE. Risk C: Monitor therapy
MetroNIDAZOLE: May decrease the metabolism of Calcineurin Inhibitors. Risk C: Monitor therapy
Minoxidil: CycloSPORINE may enhance the adverse/toxic effect of Minoxidil. Severe hypertrichosis has been reported. Risk C: Monitor therapy
Mycophenolate: CycloSPORINE may decrease the serum concentration of Mycophenolate. Specifically, cyclosporine may decrease concentrations of the active metabolite mycophenolic acid. Risk D: Consider therapy modification
Nafcillin: May increase the metabolism of CycloSPORINE. Risk C: Monitor therapy
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Nonsteroidal Anti-Inflammatory Agents: May enhance the nephrotoxic effect of CycloSPORINE. Nonsteroidal Anti-Inflammatory Agents may increase the serum concentration of CycloSPORINE. Risk D: Consider therapy modification
Norfloxacin: May decrease the metabolism of CycloSPORINE. Risk C: Monitor therapy
Omeprazole: May increase the serum concentration of CycloSPORINE. Risk C: Monitor therapy
P-Glycoprotein Inducers: May decrease the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Inhibitors: May increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
P-Glycoprotein Substrates: P-Glycoprotein Inhibitors may increase the serum concentration of P-Glycoprotein Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Risk C: Monitor therapy
Phenytoin: May increase the metabolism of CycloSPORINE. Risk D: Consider therapy modification
Pimecrolimus: CYP3A4 Inhibitors (Moderate) may decrease the metabolism of Pimecrolimus. Risk C: Monitor therapy
Pitavastatin: CycloSPORINE may increase the serum concentration of Pitavastatin. Risk X: Avoid combination
Probucol: May decrease the serum concentration of CycloSPORINE. Risk C: Monitor therapy
Protease Inhibitors: May increase the serum concentration of CycloSPORINE. CycloSPORINE may increase the serum concentration of Protease Inhibitors. Risk D: Consider therapy modification
Pyrazinamide: May decrease the serum concentration of CycloSPORINE. Risk C: Monitor therapy
Quinupristin: May decrease the metabolism of CycloSPORINE. Risk D: Consider therapy modification
Ranolazine: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Ranolazine. Management: Limit the ranolazine adult dose to a maximum of 500 mg twice daily in patients concurrently receiving moderate CYP3A4 inhibitors (e.g., diltiazem, verapamil, erythromycin, etc.). Risk D: Consider therapy modification
Repaglinide: CycloSPORINE may increase the serum concentration of Repaglinide. Risk C: Monitor therapy
Rifamycin Derivatives: May increase the metabolism of CycloSPORINE. Risk D: Consider therapy modification
Rivaroxaban: P-Glycoprotein Inhibitors may increase the serum concentration of Rivaroxaban. Risk C: Monitor therapy
Salmeterol: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Salmeterol. Risk C: Monitor therapy
Saxagliptin: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Saxagliptin. Risk C: Monitor therapy
Silodosin: P-Glycoprotein Inhibitors may increase the serum concentration of Silodosin. Risk X: Avoid combination
Sirolimus: May enhance the adverse/toxic effect of CycloSPORINE. An increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) has been described. CycloSPORINE may increase the serum concentration of Sirolimus. This is of specific concern with cyclosporine [MODIFIED]. Risk D: Consider therapy modification
Sitaxsentan: CycloSPORINE may increase the serum concentration of Sitaxsentan. Risk X: Avoid combination
Somatostatin Analogs: May decrease the serum concentration of CycloSPORINE. Risk D: Consider therapy modification
St Johns Wort: May increase the metabolism of CycloSPORINE. Risk D: Consider therapy modification
Sulfinpyrazone [Off Market]: May decrease the serum concentration of CycloSPORINE. Risk C: Monitor therapy
Sulfonamide Derivatives: May enhance the nephrotoxic effect of CycloSPORINE. Sulfonamide Derivatives may decrease the serum concentration of CycloSPORINE. Exceptions: Sulfacetamide. Risk C: Monitor therapy
Sulfonylureas: May increase the serum concentration of CycloSPORINE. Risk C: Monitor therapy
Tacrolimus: May enhance the nephrotoxic effect of CycloSPORINE. CycloSPORINE may enhance the nephrotoxic effect of Tacrolimus. CycloSPORINE may increase the serum concentration of Tacrolimus. Tacrolimus may increase the serum concentration of CycloSPORINE. Risk X: Avoid combination
Temsirolimus: May enhance the adverse/toxic effect of CycloSPORINE. An increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) has been described with concomitant sirolimus use. Risk D: Consider therapy modification
Terbinafine: May decrease the serum concentration of CycloSPORINE. Risk C: Monitor therapy
Tolvaptan: CYP3A4 Inhibitors (Moderate) may increase the serum concentration of Tolvaptan. Risk X: Avoid combination
Topotecan: P-Glycoprotein Inhibitors may increase the serum concentration of Topotecan. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live virus vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Food: Grapefruit juice increases cyclosporine serum concentrations.
Herb/Nutraceutical: Avoid St John's wort; as an enzyme inducer, it may increase the metabolism of and decrease plasma levels of cyclosporine; organ rejection and graft loss have been reported. Avoid cat's claw, echinacea (have immunostimulant properties).
Storage
Capsule: Store at controlled room temperature.
Injection: Store at controlled room temperature; do not refrigerate. Ampuls should be protected from light. Stability of injection of parenteral admixture at room temperature (25°C) is 6 hours in PVC; 24 hours in Excel®, PAB® containers, or glass.
Ophthalmic emulsion: Store at 15°C to 25°C (59°F to 77°F). Vials are single-use; discard immediately following administration.
Oral solution: Store at controlled room temperature; do not refrigerate. Use within 2 months after opening; should be mixed in glass containers.
Reconstitution
Sandimmune® injection: Injection should be further diluted [1 mL (50 mg) of concentrate in 20-100 mL of D5W or NS] for administration by intravenous infusion.
Compatibility
Stable in D5W, fat emulsion 10%, fat emulsion 20%, NS.
Y-site administration: Compatible: Alatrofloxacin, gatifloxacin, linezolid, propofol, sargramostim. Incompatible: Amphotericin B cholesteryl sulfate complex.
Compatibility when admixed: Compatible: Ciprofloxacin. Incompatible: Magnesium sulfate.
Mechanism of Action
Inhibition of production and release of interleukin II and inhibits interleukin II-induced activation of resting T-lymphocytes.
Pharmacodynamics/Kinetics
Absorption:
Ophthalmic emulsion: Serum concentrations not detectable.
Oral:
Cyclosporine (non-modified): Erratic and incomplete; dependent on presence of food, bile acids, and GI motility; larger oral doses are needed in pediatrics due to shorter bowel length and limited intestinal absorption
Cyclosporine (modified): Erratic and incomplete; increased absorption, up to 30% when compared to cyclosporine (non-modified); less dependent on food, bile acids, or GI motility when compared to cyclosporine (non-modified)
Distribution: Widely in tissues and body fluids including the liver, pancreas, and lungs; crosses placenta; enters breast milk
Vdss: 4-6 L/kg in renal, liver, and marrow transplant recipients (slightly lower values in cardiac transplant patients; children <10 years have higher values)
Protein binding: 90% to 98% to lipoproteins
Metabolism: Extensively hepatic via CYP3A4; forms at least 25 metabolites; extensive first-pass effect following oral administration
Bioavailability: Oral:
Cyclosporine (non-modified): Dependent on patient population and transplant type (<10% in adult liver transplant patients and as high as 89% in renal transplant patients); bioavailability of Sandimmune® capsules and oral solution are equivalent; bioavailability of oral solution is ?30% of the I.V. solution
Children: 28% (range: 17% to 42%); gut dysfunction common in BMT patients and oral bioavailability is further reduced
Cyclosporine (modified): Bioavailability of Neoral® capsules and oral solution are equivalent:
Children: 43% (range: 30% to 68%)
Adults: 23% greater than with cyclosporine (non-modified) in renal transplant patients; 50% greater in liver transplant patients
Half-life elimination: Oral: May be prolonged in patients with hepatic impairment and shorter in pediatric patients due to the higher metabolism rate
Cyclosporine (non-modified): Biphasic: Alpha: 1.4 hours; Terminal: 19 hours (range: 10-27 hours)
Cyclosporine (modified): Biphasic: Terminal: 8.4 hours (range: 5-18 hours)
Time to peak, serum: Oral:
Cyclosporine (non-modified): 2-6 hours; some patients have a second peak at 5-6 hours
Cyclosporine (modified): Renal transplant: 1.5-2 hours
Excretion: Primarily feces; urine (6%, 0.1% as unchanged drug and metabolites)
Dosage
Neoral®/Genraf® and Sandimmune® are not bioequivalent and cannot be used interchangeably.
Children: Refer to adult dosing; children may require, and are able to tolerate, larger doses than adults.
Adults:
Newly-transplanted patients: Adjunct therapy with corticosteroids is recommended. Initial dose should be given 4-12 hours prior to transplant or may be given postoperatively; adjust initial dose to achieve desired plasma concentration
Oral: Dose is dependent upon type of transplant and formulation:
Cyclosporine (modified):
Renal: 9 ± 3 mg/kg/day, divided twice daily
Liver: 8 ± 4 mg/kg/day, divided twice daily
Heart: 7 ± 3 mg/kg/day, divided twice daily
Cyclosporine (non-modified): Initial dose: 15 mg/kg/day as a single dose (range 14-18 mg/kg); lower doses of 10-14 mg/kg/day have been used for renal transplants. Continue initial dose daily for 1-2 weeks; taper by 5% per week to a maintenance dose of 5-10 mg/kg/day; some renal transplant patients may be dosed as low as 3 mg/kg/day
Note: When using the non-modified formulation, cyclosporine levels may increase in liver transplant patients when the T-tube is closed; dose may need decreased
I.V.: Cyclosporine (non-modified): Manufacturer's labeling: Initial dose: 5-6 mg/kg/day as a single dose (1/3 the oral dose), infused over 2-6 hours; use should be limited to patients unable to take capsules or oral solution; patients should be switched to an oral dosage form as soon as possible
Note: Many transplant centers administer cyclosporine as "divided dose" infusions (in 2-3 doses/day) or as a continuous (24-hour) infusion; dosages range from 3-7.5 mg/kg/day. Specific institutional protocols should be consulted.
Conversion to cyclosporine (modified) from cyclosporine (non-modified): Start with daily dose previously used and adjust to obtain preconversion cyclosporine trough concentration. Plasma concentrations should be monitored every 4-7 days and dose adjusted as necessary, until desired trough level is obtained. When transferring patients with previously poor absorption of cyclosporine (non-modified), monitor trough levels at least twice weekly (especially if initial dose exceeds 10 mg/kg/day); high plasma levels are likely to occur.
Rheumatoid arthritis: Oral: Cyclosporine (modified): Initial dose: 2.5 mg/kg/day, divided twice daily; salicylates, NSAIDs, and oral glucocorticoids may be continued (refer to Drug Interactions); dose may be increased by 0.5-0.75 mg/kg/day if insufficient response is seen after 8 weeks of treatment; additional dosage increases may be made again at 12 weeks (maximum dose: 4 mg/kg/day). Discontinue if no benefit is seen by 16 weeks of therapy.
Note: Increase the frequency of blood pressure monitoring after each alteration in dosage of cyclosporine. Cyclosporine dosage should be decreased by 25% to 50% in patients with no history of hypertension who develop sustained hypertension during therapy and, if hypertension persists, treatment with cyclosporine should be discontinued.
Psoriasis: Oral: Cyclosporine (modified): Initial dose: 2.5 mg/kg/day, divided twice daily; dose may be increased by 0.5 mg/kg/day if insufficient response is seen after 4 weeks of treatment. Additional dosage increases may be made every 2 weeks if needed (maximum dose: 4 mg/kg/day). Discontinue if no benefit is seen by 6 weeks of therapy. Once patients are adequately controlled, the dose should be decreased to the lowest effective dose. Doses lower than 2.5 mg/kg/day may be effective. Treatment longer than 1 year is not recommended.
Note: Increase the frequency of blood pressure monitoring after each alteration in dosage of cyclosporine. Cyclosporine dosage should be decreased by 25% to 50% in patients with no history of hypertension who develop sustained hypertension during therapy and, if hypertension persists, treatment with cyclosporine should be discontinued.
Focal segmental glomerulosclerosis (unlabeled use): Initial: 3 mg/kg/day divided every 12 hours
Autoimmune diseases (unlabeled use): 1-3 mg/kg/day
Keratoconjunctivitis sicca: Ophthalmic (Restasis®): Children ?16 years and Adults: Instill 1 drop in each eye every 12 hours
Dosage adjustment in renal impairment: For severe psoriasis:
Serum creatinine levels ?25% above pretreatment levels: Take another sample within 2 weeks; if the level remains ?25% above pretreatment levels, decrease dosage of cyclosporine (modified) by 25% to 50%. If two dosage adjustments do not reverse the increase in serum creatinine levels, treatment should be discontinued.
Serum creatinine levels ?50% above pretreatment levels: Decrease cyclosporine dosage by 25% to 50%. If two dosage adjustments do not reverse the increase in serum creatinine levels, treatment should be discontinued.
Hemodialysis: Supplemental dose is not necessary.
Peritoneal dialysis: Supplemental dose is not necessary.
Dosage adjustment in hepatic impairment: Probably necessary; monitor levels closely
Dental Usual Dosing
Note: Neoral®/Genraf® and Sandimmune® are not bioequivalent and cannot be used interchangeably.
Autoimmune diseases: Adults: 1-3 mg/kg/day
Administration: Oral
Oral solution: Do not administer liquid from plastic or styrofoam cup. May dilute Neoral® oral solution with orange juice or apple juice. May dilute Sandimmune® oral solution with milk, chocolate milk, or orange juice. Avoid changing diluents frequently. Mix thoroughly and drink at once. Use syringe provided to measure dose. Mix in a glass container and rinse container with more diluent to ensure total dose is taken. Do not rinse syringe before or after use (may cause dose variation).
Administration: I.V.
The manufacturer recommends that following dilution, intravenous admixture be administered over 2-6 hours. However, many transplant centers administer as divided doses (2-3 doses/day) or as a 24-hour continuous infusion. Patients should be under continuous observation for at least the first 30 minutes of the infusion, and should be monitored frequently thereafter.
Administration: Other
Ophthalmic emulsion: Prior to use, invert vial several times to obtain a uniform emulsion. Remove contact lenses prior to instillation of drops; may be reinserted 15 minutes after administration. May be used with artificial tears; allow 15 minute interval between products.
Administration: I.V. Detail
Anaphylaxis has been reported with I.V. use; reserve for patients who cannot take oral form. Patients should be under continuous observation for at least the first 30 minutes of the infusion, and should be monitored frequently thereafter. Maintain patent airway; other supportive measures and agents for treating anaphylaxis should be present when I.V. drug is given. Discard solution after 24 hours.
Monitoring Parameters
Monitor blood pressure and serum creatinine after any cyclosporine dosage changes or addition, modification, or deletion of other medications. Monitor plasma concentrations periodically.
Transplant patients: Cyclosporine trough levels, serum electrolytes, renal function, hepatic function, blood pressure, lipid profile
Psoriasis therapy: Baseline blood pressure, serum creatinine (2 levels each), BUN, CBC, serum magnesium, potassium, uric acid, lipid profile. Biweekly monitoring of blood pressure, complete blood count, and levels of BUN, uric acid, potassium, lipids, and magnesium during the first 3 months of treatment for psoriasis. Monthly monitoring is recommended after this initial period. Also evaluate any atypical skin lesions prior to therapy. Increase the frequency of blood pressure monitoring after each alteration in dosage of cyclosporine. Cyclosporine dosage should be decreased by 25% to 50% in patients with no history of hypertension who develop sustained hypertension during therapy and, if hypertension persists, treatment with cyclosporine should be discontinued.
Rheumatoid arthritis: Baseline blood pressure, and serum creatinine (2 levels each); serum creatinine every 2 weeks for first 3 months, then monthly if patient is stable. Increase the frequency of blood pressure monitoring after each alteration in dosage of cyclosporine. Cyclosporine dosage should be decreased by 25% to 50% in patients with no history of hypertension who develop sustained hypertension during therapy and, if hypertension persists, treatment with cyclosporine should be discontinued.
Reference Range
Reference ranges are method dependent and specimen dependent; use the same analytical method consistently
Method-dependent and specimen-dependent: Trough levels should be obtained:
Oral: 12-18 hours after dose (chronic usage)
I.V.: 12 hours after dose or immediately prior to next dose
Therapeutic range: Not absolutely defined, dependent on organ transplanted, time after transplant, organ function and CsA toxicity:
General range of 100-400 ng/mL
Toxic level: Not well defined, nephrotoxicity may occur at any level
Test Interactions
Specific whole blood, HPLC assay for cyclosporine may be falsely elevated if sample is drawn from the same line through which dose was administered (even if flush has been administered and/or dose was given hours before).
Dietary Considerations
Administer this medication consistently with relation to time of day and meals. Avoid grapefruit juice with oral cyclosporine use.
Patient Education
Oral: Take dose at the same time each day. You will be susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations without consulting prescriber). Avoid excessive exposure to sun. Practice good oral hygiene to reduce gum inflammation; see a dentist regularly during treatment. Report severe headache; unusual hair growth or deepening of voice; mouth sores or swollen gums; signs of infection; persistent nausea, vomiting, or abdominal pain; muscle pain or cramping; tremors; unusual swelling of extremities, weight gain, or change in urination; difficulty breathing; or chest pain or rapid heartbeat. Increase in blood pressure or damage to the kidney is possible. Your prescriber will need to monitor you closely. Do not change one brand of cyclosporine for another; any changes must be done by your prescriber. If you are taking this medication for psoriasis, your risk of cancer may be increased when taking additional medications. Oral solution: Diluting oral solution improves flavor. Dilute Neoral® with orange juice or apple juice. Dilute Sandimmune® with milk, chocolate milk, or orange juice. Avoid changing what you mix with your cyclosporine. Mix thoroughly and drink at once. Use syringe provided to measure dose. Mix in a glass container (do not use plastic or styrofoam) and rinse container with more juice/milk to ensure total dose is taken. Do not rinse syringe before or after use (may cause dose variation). Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.
Geriatric Considerations
Cyclosporine has not been specifically studied in the elderly. Cyclosporine is being used in combination therapy for the treatment of severe rheumatoid arthritis.
Additional Information
Cyclosporine (modified): Refers to the capsule dosage formulation of cyclosporine in an aqueous dispersion (previously referred to as “microemulsion”). Cyclosporine (modified) has increased bioavailability as compared to cyclosporine (non-modified) and cannot be used interchangeably without close monitoring.
Cardiovascular Considerations
Cyclosporine is widely used in the cardiovascular setting, particularly in patients with cardiac transplantation. In these patients, an important consequence of cyclosporine use is hypertension. Because of widespread drug interactions, the concomitant use of other drugs and the addition of new drugs should be carefully evaluated to ensure that these do not influence the concentrations of cyclosporine.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Mouth sores, swallowing difficulty, gingivitis, gum hyperplasia, xerostomia (normal salivary flow resumes upon discontinuation), abnormal taste, tongue disorder, tooth disorder, and gingival bleeding.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
None reported
Mental Health: Effects on Psychiatric Treatment
Carbamazepine and phenobarbital may increase the clearance of cyclosporine resulting in decreased levels; nefazodone may inhibit the clearance of cyclosporine resulting in increased levels of cyclosporine. There have been reports of serious drug interactions between cyclosporine and St John's wort. This interaction produces a reduction in serum cyclosporine levels resulting in subtherapeutic levels, rejection of transplanted organs, and graft loss.
Nursing: Physical Assessment/Monitoring
Assess effectiveness and interactions of other medications patient may be taking. Monitor kidney and hepatic function closely. Monitor blood pressure and assess for signs of fluid retention periodically. Assess results of laboratory tests, therapeutic effectiveness, and adverse reactions at beginning of therapy and periodically throughout therapy. Teach patient appropriate administration, possible side effects, and symptoms to report. I.V.: Monitor closely for first 30 minutes of infusion and frequently thereafter to assess for adverse reactions.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule [modified]:
Gengraf®: 25 mg [contains alcohol 12.8%]; 100 mg [contains alcohol 12.8%]
Capsule [non-modified]: 25 mg, 100 mg
Capsule, soft gel [modified]: 25 mg, 50 mg, 100 mg
Neoral®: 25 mg [contains alcohol 11.9% and corn oil]; 100 mg [contains alcohol 11.9% and corn oil]
Capsule, soft gel [non-modified]:
Sandimmune®: 25 mg [contains alcohol 12.7% and corn oil]; 100 mg [contains alcohol 12.7% and corn oil]
Emulsion, ophthalmic [preservative free]:
Restasis®: 0.05% (0.4 mL) [contains 30 single-use vials/box]
Injection, solution [non-modified]: 50 mg/mL (5 mL)
Sandimmune®: 50 mg/mL (5 mL) [contains Cremophor® EL (polyoxyethylated castor oil) and alcohol 32.9%]
Solution, oral [modified]: 100 mg/mL (50 mL)
Gengraf®: 100 mg/mL (50 mL) [contains propylene glycol]
Neoral®: 100 mg/mL (50 mL) [contains alcohol 11.9%, corn oil, and propylene glycol]
Solution, oral [non-modified]: 100 mg/mL (50 mL)
Sandimmune®: 100 mg/mL (50 mL) [contains alcohol 12.5%]
Pricing: U.S. (www.drugstore.com)
Capsules (CycloSPORINE)
25 mg (60): $84.99
100 mg (60): $299.98
Capsules (CycloSPORINE Modified)
25 mg (30): $33.99
100 mg (30): $140.96
Capsules (Gengraf)
25 mg (60): $85.99
100 mg (60): $319.87
Capsules (Neoral)
25 mg (60): $85.99
100 mg (30): $160.99
Capsules (SandIMMUNE)
25 mg (60): $133.52
100 mg (60): $498.13
Emulsion (Restasis)
0.05% (30): $120.73
Solution (CycloSPORINE Modified)
100 mg/mL (50): $230.00
Solution (Neoral)
100 mg/mL (50): $301.71
Solution (SandIMMUNE)
50 mg/mL (5): $42.94
100 mg/mL (50): $423.97
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International Brand Names
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Last full review/revision October 2009
Content last modified October 2009
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