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Drugs reference index «Cyclosporine (Cyclosporin A)»

Cyclosporine

( Cyclosporin A ) Pronunciation: (SIGH-kloe-spore-EEN)Class: Immunosuppressive, Ophthalmic emulsion

Trade Names:Gengraf- Capsules 25 mg- Capsules 100 mg- Oral solution 100 mg/mL

Trade Names:Neoral- Capsules, soft gelatin, for microemulsion 25 mg- Capsules, soft gelatin, for microemulsion 50 mg- Oral solution for microemulsion 100 mg/mL

Trade Names:Restasis- Ophthalmic emulsion 0.05%

Trade Names:Sandimmune- Capsules, soft gelatin 25 mg- Capsules, soft gelatin 50 mg- Capsules, soft gelatin 100 mg- Oral solution 100 mg/mL- IV solution 50 mg/mL

Sandimmune I.V. (Canada)Sandoz Cyclosporine (Canada)

Pharmacology

Suppresses cell-mediated immune reactions and some humoral immunity, but exact mechanism is not known.

Pharmacokinetics

Absorption

Oral

Absorption is incomplete and variable. Bioavailability is less than 10% in liver transplant patients ( Sandimmune ), up to 89% in renal transplant patients ( Sandimmune ), and about 30% for the oral solution. T max is 1.5 to 2 h ( Gengraf and Neoral ) and 3.5 h ( Sandimmune ). Food decreases the AUC and C max .

Distribution

Vd is 3 to 5 L/kg at steady state (IV). Cyclosporine is 90% protein bound (primarily lipoprotein) and is excreted in human milk.

Metabolism

Extensively metabolized by CYP3A in the liver and to a lesser degree in the GI tract and kidney.

Elimination

Eliminated primarily in the bile; 6% is excreted unchanged in the urine (0.1% as unchanged drug). The t ½ is about 8.4 h ( Gengraf and Neoral ) and about 19 h ( Sandimmune ). Blood Cl is about 5 to 7 mL/min/kg (IV).

Indications and Usage

Prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants in conjunction with adrenal corticosteroid therapy; treatment of chronic rejection in patients previously treated with other immunosuppressive agents; increase tear production in patients whose tear production is presumed to be suppressed because of ocular inflammation associated with keratoconjunctivitis sicca (ophthalmic emulsion).

Gengraf , Neoral

Treatment of severe active, rheumatoid arthritis (RA) where disease is not adequately responsive to methotrexate; treatment of adult, nonimmunocompromised patients with severe, recalcitrant, plaque psoriasis who have failed to respond to a least one systemic therapy or in patients for whom other systemic therapies are contraindicated, or cannot be tolerated.

Contraindications

Hypersensitivity to polyoxyethylated castor oil, which is present in concentrate for injection; active ocular infections (ophthalmic emulsion).

Gengraf , Neoral

RA and psoriasis patients with abnormal renal function, uncontrolled hypertension or malignancies; psoriasis patients receiving Gengraf or Neoral should not receive concomitant PUVA or UVB therapy, methotrexate, or other immunosuppressive agents, coal tar, or radiation therapy.

Dosage and Administration

TransplantsAdults and Children

Sandimmune PO 15 mg/kg/day (range, 14 to 18 mg/kg/day) beginning 4 to 12 h before transplantation. Continue for 1 to 2 wk postoperatively, then taper dose 5% per wk to maintenance level of 5 to 10 mg/kg/day. Lower doses may be used on basis of patient response, rejection rate, and cyclosporine plasma concentrations. IV 5 to 6 mg/kg/day as single IV dose starting 4 to 12 h before transplantation. Switch to oral form as soon as patient can tolerate. Gengraf , Neoral : PO Give initial dose 4 to 12 h prior to transplantation or postoperatively. For renal transplant patients, the mean initial dose was approximately 9 mg/kg/day, 8 mg/kg/day for liver transplant patients, and 7 mg/kg/day for heart transplant patients, divided into 2 equal doses. Subsequent doses were adjusted to achieve a predefined cyclosporine blood concentration.

Tear ProductionAdults and Children 16 yr of age and older Restasis

Ophthalmic Instill 1 drop twice daily in each eye approximately 12 h apart.

RAGengraf , Neoral

PO Start with 1.25 mg/kg twice daily. Onset of effect generally occurs between weeks 4 to 8. If sufficient clinical benefit is seen and well tolerated, the dose may be increased by 0.5 to 0.75 mg/kg/day after 8 wk and again after 12 wk (max, 4 mg/kg/day). Discontinue if no benefit by week 16 of therapy.

PsoriasisGengraf , Neoral

PO Start with 1.25 mg/kg twice daily for at least 4 wk, barring adverse reactions. Increase dosage at 2-wk intervals if significant clinical improvement has not occurred. Based on patient response, increase the dose by about 0.5 mg/kg/day at 2-wk intervals (max, 4 mg/kg/day).

General Advice

  • Injection
  • Injection should be used for patient unable to take oral therapy. Patient should be switched to oral therapy as soon as able to take oral medications.
  • Dilute IV concentrate immediately before use. Dilute each mL (50 mg) of concentrate with 20 to 100 mL of sodium chloride 0.9% injection or dextrose 5% injection in a glass container.
  • Administer diluted infusion solution by slow IV infusion over 2 to 6 h.
  • Do not administer if particulate matter, cloudiness, or discoloration noted.
  • Discard any unused diluted infusion solution after 24 h.
  • Ophthalmic emulsion
  • For topical use in the eyes only.
  • May be used concomitantly with artificial tears, but separate instillation of each product by at least 15 min.
  • Before administering, invert unit dose vial a few times to obtain a uniform, white, opaque emulsion.
  • Ensure that patient is not wearing contact lenses at time of administration of emulsion. Contact lenses must be removed before instilling emulsion and can be reinserted 15 min following instillation of emulsion.
  • Open vial immediately before administration and instill 1 drop in affected eye(s). Compress lacrimal sac for 2 to 3 min following instillation to reduce systemic absorption.
  • Discard vial immediately after each use. Do not save vial for future use.
  • Do not allow tip of vial to touch eye, eyelid, fingers, or any other surface.
  • Oral
  • Administer capsules and oral solution on a consistent schedule with respect to time of day and meals.
  • Sandimmune oral solution may be diluted with milk, chocolate milk, or orange juice, preferably at room temperature, to make solution more palatable. Gengraf and Neoral oral solution may be diluted with room temperature orange or apple juice to make solution more palatable. To dilute cyclosporine oral solution, withdraw prescribed dose of oral solution using supplied dosage syringe and transfer the solution to a glass container containing the diluent. Do not use plastic utensils because cyclosporine binds to plastic. Stir mixture well and administer immediately after mixing. Do not allow mixture to stand before administering. Rinse container with more diluent to ensure that total dose has been taken. Replace dosage syringe in protective cover after use.
  • Do not rinse dosage syringe with water or other cleaning agents either before or after use. If dosing syringe needs to be cleaned, ensure that it is completely dry before resuming use to prevent variation in cyclosporine dose.

Storage/Stability

Injection

Store ampules and vials at controlled room temperature (below 86°F). Protect from light.

Ophthalmic emulsion

Store vials of ophthalmic emulsion at controlled room temperature (59° to 77°F).

Oral
  • Store Sandimmune and Gengraf capsules and oral solution at controlled room temperature (59° to 86°F). Store oral solution in original container. Do not store oral solution in refrigerator. Protect from freezing. Discard any unused oral solution 2 mo after opening.
  • Store Neoral capsules in original unit-dose container at controlled room temperature (68° to 77°F). Do not store oral solution in refrigerator. Discard any unused oral solution 2 mo after opening. At temperatures below 68°F, the solution may gel or light flocculation or sediment formation may occur. Allow to warm to room temperature to reverse these changes, which do not impact medication effectiveness.

Drug Interactions

Allopurinol, amiodarone, beta-blockers (eg, carvedilol), bromocriptine, colchicine, danazol, diltiazem, fluconazole, grapefruit and grapefruit juice, imipenem-cilastatin, itraconazole, ketoconazole, macrolide antibiotics (eg, erythromycin), metoclopramide, nefazodone, nicardipine, protease inhibitors (eg, indinavir, nelfinavir, ritonavir, saquinavir), quinupristin/dalfopristin, serotonin reuptake inhibitors (eg, fluoxetine, sertraline), verapamil

May increase cyclosporine concentrations.

Aminoglycosides, amphotericin B, cimetidine, colchicine, NSAIDs, ranitidine, tacrolimus, trimethoprim-sulfamethoxazole, melphalan, quinolones

Additive nephrotoxicity possible.

Azathioprine, corticosteroids, cyclophosphamide, verapamil

May cause additive immunosuppression, increasing risk of infection and malignancy.

Carbamazepine, hydantoins, nafcillin, octreotide, orlistat, phenobarbital, rifampin, rifabutin, St. John's wort, terbinafine, ticlopidine

May decrease cyclosporine effects.

Digoxin, methotrexate, sirolimus

Plasma levels of these agents may be elevated by cyclosporine.

Etoposide

May increase etoposide concentrations.

Live vaccines

Vaccination may be less effective.

Metoclopramide

Increases absorption of cyclosporine.

Potassium-sparing diuretics

Causes hyperkalemic effects; avoid concomitant use.

Statins (eg, lovastatin)

May cause severe myopathy or rhabdomyolysis; avoid concurrent use.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypertension (53%); arrhythmia, chest pain (at least 3%); abnormal heart sounds, cardiac failure, MI, peripheral ischemia (3% or less).

CNS

Tremor (55%); headache (15%); convulsions (5%); confusion, depression, dizziness, insomnia, migraine, paresthesia (at least 3%); anxiety, decreased or increased libido, nervousness, emotional lability, hypoesthesia, vertigo, impaired concentration, neuropathy, paranoia, somnolence, asthenia (3% or less); encephalopathy (postmarketing).

Dermatologic

Hirsutism (45%); flushing (4% or less); alopecia, bullous eruptions, hypertrichosis, rash, skin ulcer (at least 3%); hyperpigmentation, angioedema, dermatitis, dry skin, urticaria, sweating (3% or less); acne, brittle fingernails (2% or less); folliculitis, keratosis, pruritus, skin malignancies (at least 1%).

EENT

Pharyngitis, rhinitis (at least 3%); abnormal vision, cataract, conjunctivitis, deafness, eye pain, taste perversion, tinnitus, vestibular disorder (3% or less); hearing loss (2% or less).

Ophthalmic emulsion

Ocular burning (17%); conjunctival hyperemia, discharge, epiphora, eye pain, foreign body sensation, pruritus, stinging, visual disturbances (1% to 5%).

GI

Gum hyperplasia (16%); nausea, vomiting (10%); diarrhea (8%); abdominal discomfort (7% or less); anorexia, dyspepsia, flatulence, gingivitis, rectal hemorrhage, stomatitis (at least 3%); dysphagia, enanthema, eructation, esophagitis, gastric ulcer, gastroenteritis, glossitis, gastritis, peptic ulcer, salivary gland enlargement, tongue disorder, tooth disorder (3% or less); hiccoughs (2% or less); constipation, gingival bleeding (at least 1%).

Genitourinary

Renal function impairment (38%), gynecomastia (4% or less); dysuria, leucorrhea, menstrual disorder, micturition frequency (at least 3%); abnormal urine, breast pain, breast fibroadenosis, hematuria, increased BUN, nocturia, polyuria, pyelonephritis, urinary incontinence, uterine hemorrhage, renal abscess (3% or less).

Hematologic-Lymphatic

Leukopenia, lymphoma (6% or less); anemia, epistaxis, lymphadenopathy (3% or less); thrombocytopenia (2% or less); clotting disorders, bleeding, RBC disorders (at least 1%).

Hepatic

Hepatotoxicity (7%); hyperbilirubinemia (at least 1%).

Lab Tests

Increased creatinine (at least 3%)

Metabolic-Nutritional

Hyperglycemia, hyperkalemia, hyperuricemia, diabetes mellitus, hypoglycemia, increased or decreased weight (3% or less).

Musculoskeletal

Rigors (at least 2%); muscle pain (2% or less); arthralgia, bone fracture, bursitis, joint dislocation, myalgia, stiffness, synovial cyst, tendon disorder (3% or less).

Respiratory

Sinusitis (7%); bronchitis, coughing, dyspnea, respiratory tract infection, pneumonia (at least 3%); abnormal chest sounds, tonsillitis, bronchospasm (3% or less).

Miscellaneous

Cramps (4%); accidental trauma, fever, flu-like symptoms, pain, purpura (at least 3%); abscess, bacterial infection, cellulitis, fungal infection, herpes simplex, herpes zoster, moniliasis, viral infection, tumor, malaise (3% or less); allergic reaction, edema, fever (2% or less); increased appetite (at least 1%).

Precautions

Warnings

Only physicians experienced in immunosuppressive therapy and managing organ transplant patients should prescribe cyclosporine. Manage patients in facilities equipped and staffed with adequate lab and supportive medical resources.

Cyclosporine may increase susceptibility to infection and development of neoplasia.

Administer Sandimmune with adrenal corticosteroids but not with other immunosuppressants. Cyclosporine for microemulsion ( Neoral , Gengraf ) may be given with other immunosuppressants.

Sandimmune capsules and oral solution have decreased bioavailability compared with Neoral and Gengraf . Oral absorption during chronic Sandimmune use is erratic. Monitor cyclosporine blood levels during oral therapy at repeated intervals and make dose adjustments to avoid toxicity or possible organ rejection. For a given trough concentration, cyclosporine exposure will be greater with Neoral and Gengraf than with Sandimmune . If a patient who is receiving exceptionally high doses of Sandimmune is converted to Neoral or Gengraf , use particular caution. Neoral and Gengraf are not bioequivalent to Sandimmune and cannot be used interchangeably.

Psoriasis patients have an increased risk of developing skin malignancies if previously treated with PUVA, methotrexate, other immunosuppressants, UVB, coal tar, or radiation therapy.

Cyclosporine can cause systemic hypertension and nephrotoxicity.

Renal function impairment, including structural kidney damage, is a potential consequence of therapy. Monitor renal function during therapy.

Monitor

Baseline evaluations in psoriasis patients

Before initiating therapy in psoriasis patient, ensure that a dermatologic and physical exam, at least 2 BP measurements and 2 Scr levels, and BUN, CBC, uric acid, lipids, and serum magnesium and potassium to establish baseline have been performed. Evaluate BP, Scr, BUN, CBC, uric acid, lipids and serum magnesium every 2 wk during initial 3 mo of therapy and then monthly thereafter if patient is stable or more frequently when dosage adjustments are made. Notify health care provider of significant changes. Be prepared to reduce cyclosporine dose if patient develops sustained hypertension or elevations in Scr.

Baseline evaluations in RA patients

Before initiating therapy in RA patient, ensure that a physical exam, and at least 2 BP measurements and 2 Scr levels to establish baseline have been performed. Evaluate BP and Scr every 2 wk during initial 3 mo of therapy and then monthly thereafter if patient is stable. Monitor BP and Scr after a NSAID dose increase or initiation of a new NSAID during treatment. If patient also receives methotrexate, evaluate CBC and liver function before starting therapy and monthly during treatment.

Blood levels

Ensure that cyclosporine blood levels are regularly monitored in transplant patient and periodically monitored in RA patient. Be prepared to adjust cyclosporine dose.

Infection

Monitor patient for signs and symptoms of bacterial, viral, or fungal infection. Report to health care provider immediately if noted or suspected.

Organ rejection

Monitor patient for signs or symptoms of organ rejection. Inform health care provider immediately is suspected.

Response to therapy (ophthalmic emulsion)

Monitor patient's response to therapy. Notify health care provider if symptoms do not improve or worsen, or if patient experiences bothersome ocular adverse reactions (eg, burning, pain, discharge).

Serum levels

Because of decreased bioavailability of Sandimmune as compared to Gengraf and Neoral , ensure that cyclosporine serum levels are closely monitored (eg, every 4 to 7 days until preconversion blood trough level is attained) in patient being converted from Sandimmune to Gengraf or Neoral or vice versa.

Pregnancy

Category C .

Lactation

Excreted in breast milk.

Children

Sandimmune

Although safety and efficacy have not been established, patients as young as 6 mo of age have received the drug.

Gengraf , Neoral

Although safety and efficacy have not been established, transplant patients as young as 1 yr of age have received the drugs. Safety and efficacy not established for treatment of psoriasis or rheumatoid arthritis in children younger than 18 yr of age.

Restasis

Safety and efficacy not established in children younger than 16 yr of age.

Elderly

Use with caution because of greater frequency of decreased hepatic, renal, or cardiac function, and concomitant diseases or other drug therapy. Elderly patients more likely to develop systolic hypertension and more likely to show serum creatinine increases of 50% or more above baseline after 3 to 4 mo of therapy.

Renal Function

Requires close monitoring and possible dosage adjustment. Ensure that renal function (BUN, Scr) is evaluated before starting and periodically thereafter during treatment. Notify health care provider if increases in BUN or Scr are noted. Be prepared to monitor cyclosporine levels more frequently and adjust the dose as indicated.

Absorption

Absorption during long-term use is erratic. Patients with malabsorption may have difficulty achieving therapeutic concentrations with oral use.

Anaphylactic reactions

Occur rarely with IV use. Have epinephrine 1:1,000 and oxygen readily available.

Convulsions

Have occurred, particularly in combination with high-dose methylprednisolone.

Infection control measures

Implement infection control measures if WBC drops; implement bleeding precautions if platelet count drops.

Nephrotoxicity

Common adverse reaction; may respond to decreased dose.

Overdosage

Symptoms

Hepatotoxicity, nephrotoxicity.

Patient Information

  • Explain name, dose, action, and potential adverse reactions of drug, including increased risk of lymphoproliferative disorders and other malignancies.
  • Advise patient, family, or caregiver that medication will be used in combination with other agents to achieve max benefit.
  • Caution patient not to change brands or switch to another doseform of cyclosporine without contacting health care provider. Advise patient that health care provider supervision is required to change brands or doseforms safely.
  • Instruct patient to take capsules and oral solution on a consistent schedule with regard to food and at the same time each day.
  • Advise patient that an odor may be noted when opening the medication container, but that it will disappear shortly after opening and does not mean that there is anything wrong with the medication.
  • Advise patient using Sandimmune oral solution that it may be diluted with milk, chocolate milk, or orange juice, preferably at room temperature, to make solution more palatable. Advise patient using Gengraf or Neoral oral solution that they may be diluted with room temperature orange or apple juice to make solution more palatable. Advise patient to withdraw prescribed dose of oral solution using supplied dosage syringe and transfer the solution to a glass container containing the diluent, stir well to mix, swallow immediately after mixing, and then rinse container with more diluent to ensure that total dose has been taken. Instruct patient to replace dosage syringe in protective cover after use. Caution patient not to use plastic utensils because cyclosporine binds to plastic, not to prepare mixture ahead of time, and not to change diluents frequently.
  • Caution patient using oral solution not to clean the dosage syringe with water or other cleaning agents either before or after use because moisture can cause variations in dose. Advise patient that if dosing syringe needs to be cleaned, to be sure that it is completely dry before resuming use.
  • Advise patient that if a dose is missed to take it as soon as remembered unless it is almost time for the next dose. If it is almost time for the next dose, advise patient to skip the missed dose and take the next dose at the regularly scheduled time. Caution patient not to double the dose to catch up.
  • Caution patient not to change the dose or stop taking unless advised by health care provider.
  • Instruct patient to continue to take other medications prescribed for preventing organ transplant rejection or treating RA or psoriasis.
  • Caution patient not to eat grapefruit or drink grapefruit juice while taking cyclosporine.
  • Instruct patient to notify health care provider immediately if any of the following occur: fever, chills, sore throat or other signs of infection; bleeding or unusual bruising; flu-like symptoms, persistent nausea, fatigue, right upper quadrant abdominal pain, yellowing of skin or eyes, dark urine.
  • Advise patient to contact health care provider if experiencing bothersome adverse reactions or any unusual problems.
  • Instruct diabetic patient to monitor blood glucose more frequently when drug is started or dose is changed, and to inform health care provider of significant changes in readings.
  • Instruct patient in BP and pulse measurement skills.
  • Advise patient to monitor and record BP and pulse at home and to inform health care provider if abnormal measurements are noted. Also advise patient to take record of BP and pulse to each follow-up visit.
  • Advise patient that medication may increase skin cancer risk and to avoid unnecessary exposure to UV light (eg, sunlight, tanning booths) and to use sunscreens and wear protective clothing when exposed to UV light.
  • Caution patient that drug may cause dizziness and to use caution while driving or performing other tasks requiring mental alertness or coordination until tolerance is determined.
  • Ensure that women of childbearing potential use nonhormonal contraception (eg, diaphragm, condom) while taking cyclosporine.
  • Instruct patient not to take any prescription or OTC medications, potassium-containing salt substitutes, potassium supplements, herbal preparations, or dietary supplements (eg, St. John's wort) unless advised by health care provider.
  • Ophthalmic Emulsion
  • Remind patient or caregiver that ophthalmic emulsion is for use in the eye(s) only.
  • Caution patient wearing contact lenses that lenses should not be used in conditions with decreased tear production. If patient insists on wearing contact lenses, instruct patient to remove lenses before instilling ophthalmic emulsion and wait at least 15 min after instillation before reinserting lenses.
  • Review dosing schedule with patient or caregiver.
  • Teach patient or caregiver proper technique for instilling ophthalmic emulsion: wash hands; invert unit dose vial a few times to obtain a uniform, white, opaque emulsion; open vial immediately before administration; do not allow tip of dropper bottle to touch eye, eyelid, fingers, or any other surface; tilt head back, look up; pull lower eyelid down to form pocket; instill 1 drop in the pocket; look downward before closing eye; compress lacrimal sac for 2 to 3 min. Caution patient not to rub eye(s).
  • Instruct patient to discard vial immediately after each use and not to save the vial or contents for future use.
  • Advise patient that artificial tears can be used in combination with cyclosporine ophthalmic emulsion, but to separate administration of each product by 15 min.
  • Advise patient or caregiver to contact health care provider if ophthalmic emulsion causes intolerable stinging, burning, or other effects, if eye or eyelid inflammation is noted, or if eye symptoms (dry eyes) do not improve or worsen.
  • Injection
  • Advise patient or caregiver that medication will be prepared and administered by a health care provider until patient can take oral mycophenolate.

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