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Cyclosporine

Pronunciation
( Cyclosporin A )

Pronunciation: SYE-kloe-SPOR-een
Class: Immunosuppressive, Ophthalmic emulsion

Trade Names

Cyclosporine modified
- Capsules, soft gelatin 50 mg

Gengraf
- Capsules 25 mg (as cyclosporine modified)
- Capsules 100 mg (as cyclosporine modified)
- Solution, oral 100 mg/mL (as cyclosporine modified)

Neoral
- Capsules, soft gelatin 25 mg (as cyclosporine modified)
- Capsules, soft gelatin 100 mg (as cyclosporine modified)
- Solution, oral 100 mg/mL (as cyclosporine modified)

Restasis
- Emulsion, ophthalmic 0.05%

Sandimmune
- Capsules, soft gelatin 25 mg
- Capsules, soft gelatin 100 mg
- Solution, oral 100 mg/mL
- Injection, solution, concentrate 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.

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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 approximately 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 ( Gengraf and Neoral ).

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 CYP3A4 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 half-life is approximately 8.4 h ( Gengraf and Neoral ) and approximately 19 h ( Sandimmune ). Blood Cl is approximately 5 to 7 mL/min/kg (IV).

Special Populations

Elderly

No significant difference in the pharmacokinetic parameters was seen in elderly patients with rheumatoid arthritis (RA) compared with younger patients.

Indications and Usage

Prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants in conjunction with adrenal corticosteroid therapy; Sandimmune may be used in the 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 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 cyclosporine or any component of the product, including polyoxyethylated castor oil (injection only); 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

Psoriasis
Gengraf , 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 approximately 0.5 mg/kg/day at 2-wk intervals (max, 4 mg/kg/day). Discontinue if satisfactory response cannot be achieved by wk 6 of therapy at 4 mg/kg/day or the patient's max tolerated dose.

Rheumatoid Arthritis
Gengraf , Neoral

PO Start with 1.25 mg/kg twice daily. Onset of effect generally occurs between weeks 4 and 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.

Tear Production
Adults and Children 16 y of age and older Restasis

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

Transplants
Adults 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 dose of 5 to 10 mg/kg/day; some centers have successfully tapered the maintenance dose to as low as 3 mg/kg/day in selected renal transplant patients without an apparent rise in rejection rate. 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. Total daily doses were divided into 2 equal doses. Subsequent doses were adjusted to achieve a predefined cyclosporine blood concentration.

General Advice

  • Injection
  • Injection should be used for patients unable to take oral therapy. Patients should be switched to oral therapy as soon as they are 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.
  • 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 juice 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.
  • Sandimmune is not bioequivalent to Neoral or Gengraf . Conversion using a 1:1 ratio may result in lower blood concentrations. Increased cyclosporine blood concentration monitoring is needed to avoid potential underdosing.

Storage/Stability

Injection

Store ampules and vials below 86°F. Protect from light. Discard any unused diluted infusion solution after 24 h.

Ophthalmic emulsion

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

Oral
  • Store Sandimmune capsules and oral solution between 59° and 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 Gengraf and Neoral capsules and oral solution in original container between 68° and 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; these changes do not impact medication's effectiveness. Allow to warm to room temperature to reverse these changes.

Drug Interactions

ACE inhibitors (eg, captopril)

The risk of hyperkalemia may be increased. Use with caution and closely monitor potassium concentrations. In addition, acute renal failure has been reported with coadministration of ACE inhibitors and cyclosporine. If an interaction is suspected, discontinue the ACE inhibitor. Dose reduction or discontinuation of cyclosporine may also be necessary.

Aliskiren, caspofungin

Pharmacologic effects and plasma concentrations of these agents may be increased by cyclosporine. Coadministration is not recommended.

Allopurinol, amiodarone, azole antifungal agents (eg, fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole), beta-blockers (eg, carvedilol), bromocriptine, chloramphenicol, chloroquine, clonidine, danazol, diltiazem, grapefruit and grapefruit juice, hormonal contraceptives, imatinib, macrolide antibiotics (eg, clarithromycin, erythromycin, telithromycin), methoxsalen, methyltestosterone, metoclopramide, metronidazole, mibefradil, micafungin, nefazodone, nicardipine, propafenone, quinupristin/dalfopristin, serotonin reuptake inhibitors (eg, fluoxetine, fluvoxamine, sertraline), sulfonylureas (eg, glipizide, glyburide), tigecycline, verapamil, vitamin E

May increase cyclosporine concentrations, increasing the risk of toxicity (eg, nephrotoxicity). Closely monitor cyclosporine concentrations and the clinical response of the patient when one of these agents is started or stopped. If an interaction is suspected, adjust the cyclosporine dose as needed.

Aluminum salts

Aluminum salts may decrease plasma concentrations and pharmacologic effects of oral cyclosporine. Do not coadminister.

Aminoglycosides (eg, gentamicin, tobramycin, vancomycin), amphotericin B, cimetidine, fenofibrate, fluoroquinolones (eg, ciprofloxacin), ketoconazole, melphalan, methotrexate, NSAIDs (eg, diclofenac, naproxen, sulindac), ranitidine, tacrolimus, trimethoprim/sulfamethoxazole

The risk of renal dysfunction may be increased. Monitor cyclosporine concentrations and renal function. Adjust the cyclosporine dose as needed.

Barbiturates (eg, phenobarbital), carbamazepine, clindamycin, efavirenz, gemfibrozil, griseofulvin, hydantoins (eg, phenytoin), nafcillin, octreotide, orlistat, oxcarbazine, rifabutin, rifampin, St. John's wort, terbinafine, ticlopidine, troglitazone

Cyclosporine levels may be decreased, resulting in a reduction in the pharmacologic effects (eg, graft loss, transplanted organ rejection). Monitor cyclosporine concentrations and observe the patient for signs of rejection or toxicity when one of these agents is started or stopped . Adjust the cyclosporine dose as needed.

Berberine, chamomile, quercetin

Elevated cyclosporine concentrations with a risk of toxicity (eg, nephrotoxicity) may occur. Advise patients receiving cyclosporine to avoid berberine, chamomile, or quercetin, and caution them not to use herbal products without consulting their health care provider.

Bortezomib

Neurotoxicity of bortezomib and cyclosporine may be increased. Closely monitor the patient and adjust treatment as needed.

Bosentan

Trough concentrations of bosentan may be elevated, increasing the risk of adverse effects, while cyclosporine plasma levels may be decreased. Coadministration is contraindicated.

Colchicine

Severe adverse clinical symptoms, including GI, hepatic, renal, and neuromuscular toxicity, may occur during coadministration. Coadministration of cyclosporine and colchicine is contraindicated in patients with hepatic or renal impairment. In patients with healthy hepatic or renal function, use with caution at a maximum dosage of colchicine 0.3 mg twice daily. Cyclosporine may increase the risk of colchicine toxicity (eg, myopathy, neuropathy), especially in patients with renal dysfunction. Closely monitor the clinical response of the patient and for adverse reactions. Adjust therapy as needed.

Digoxin

Digoxin plasma levels may be elevated by cyclosporine. Severe digitalis toxicity has been seen within days of starting cyclosporine. Closely monitor the clinical response of the patient and discontinue or adjust the digoxin dose as needed.

Doxorubicin, etoposide

Serum concentration of these agents may be elevated, resulting in increased toxicity. Monitor the clinical response of the patient (including CBC) and adjust the dose of these agents as needed.

Everolimus

Everolimus serum concentration may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Monitor the clinical response of the patient (including renal function and hematologic parameters) when the cyclosporine dose is started, stopped, or changed. Adjust the everolimus dose as needed.

Ezetimibe

Cyclosporine and ezetimibe concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Monitor cyclosporine concentrations when ezetimibe is coadministered. Adjust the cyclosporine dose as needed. In addition, monitor patients for cyclosporine or ezetimibe adverse reactions.

Foscarnet

The risk of renal failure may be increased because of additive or synergistic nephrotoxicity. Closely monitor renal function. If nephrotoxicity occurs, it may be necessary to discontinue foscarnet.

HMG-CoA reductase inhibitor (eg, lovastatin simvastatin)

May cause severe myopathy or rhabdomyolysis; avoid concurrent use. If coadministration cannot be avoided, the dose of the HMG-CoA reductase inhibitor should be reduced according to the label recommendations. In patients with signs and symptoms of myopathy or those at risk of severe renal injury secondary to rhabdomyolysis, temporarily withhold or discontinue the HMG-CoA reductase inhibitor.

Imipenem/Cilastatin

Neurotoxicity of imipenem/cilastatin and cyclosporine may be increased. Closely monitor the patient and adjust treatment as needed.

Immunosuppressive agents (eg, corticosteroids), radiation therapy (eg, PUVA, UV-light treatment)

Concurrent treatment should be avoided because of the possibility of excessive immunosuppression.

Live vaccines

Vaccination may be less effective and the use of live attenuated vaccines should be avoided. Defer live vaccination until immune function improves.

Meglitinides (eg, nateglinide, repaglinide)

Meglitinide plasma concentrations may be elevated, increasing the pharmacologic effect and risk of hypoglycemia. Closely monitor blood glucose and adjust the meglitinide dose as needed.

Methotrexate

The AUC of methotrexate and its metabolite may be increased and decreased, respectively, by coadministration of cyclosporine. Monitor the clinical response of the patient when cyclosporine is started or stopped. Adjust the methotrexate dose as needed.

Mycophenolate

Plasma concentrations and pharmacologic effects of mycophenolate may be decreased by cyclosporine. Larger mycophenolate doses may be needed after starting cyclosporine. Monitor mycophenolic acid concentrations and the clinical response of the patient when starting or stopping cyclosporine. Adjust the mycophenolate dose as needed.

Nondepolarizing muscle relaxants (eg, vecuronium)

Cyclosporine may prolong the neuromuscular blocking effects of nondepolarizing muscle relaxants. Closely monitor the extent and duration of neuromuscular blockade. Be prepared to decrease the dosage of the nondepolarizing agent and provide mechanical respiratory support as needed.

Omeprazole

Cyclosporine levels may be increased, decreased, or unchanged. Monitor cyclosporine concentrations and observe the clinical response of the patient when starting or stopping omeprazole. Adjust the cyclosporine dose as needed.

Potassium-containing drugs (eg, potassium penicillin)

The risk of hyperkalemia may be increased. Use with caution. Closely monitor potassium concentrations.

Potassium-sparing diuretics

Coadministration may cause hyperkalemia. Avoid concomitant use.

Protease inhibitors (eg, indinavir, nelfinavir, ritonavir, saquinavir)

Plasma concentrations and pharmacologic effects of both protease inhibitors and cyclosporine may occur. Adjust treatment as needed.

Red yeast rice

Red yeast rice contains HMG-CoA reductase inhibitor–like components. The risk of HMG-CoA reductase inhibitor–like adverse reactions (eg, rhabdomyolysis) may be increased with coadministration of cyclosporine. Patients receiving cyclosporine should be advised to avoid red yeast rice and cautioned not to use herbal products without consulting their health care provider.

Sirolimus

Sirolimus plasma concentrations may be elevated, resulting in increased toxicity. Administer sirolimus 4 h after cyclosporine to prevent variations in sirolimus concentrations.

Trimethoprim

Both a decrease in the immunosuppressive action of cyclosporine and an increase in the risk of nephrotoxicity have been reported during coadministration of trimethoprim. Close clinical and laboratory monitoring of cyclosporine is indicated. If an interaction is suspected, consider substituting another antimicrobial agent for trimethoprim.

Vinca alkaloids (eg, vinblastine, vincristine)

The pharmacologic and toxic effects of vinca alkaloids may be increased by cyclosporine. Use with caution. Monitor the clinical response of the patient and adjust the vinca alkaloid dose as needed.

Drug/food interactions

Administration of food decreases the AUC and C max of cyclosporine. Potassium-rich diets may increase the risk of hypokalemia. Closely monitor potassium concentrations. Grapefruit or grapefruit juice may increase cyclosporine concentrations. Unless patients have been instructed by a health care provider to take cyclosporine with grapefruit juice, grapefruit juice should be avoided while taking cyclosporine. Pomelo juice may elevate cyclosporine concentrations, increasing the risk of toxicity (eg, nephrotoxicity). Patients should be advised to avoid pomelo juice while taking cyclosporine. Red wine may decrease cyclosporine concentrations, decreasing pharmacologic effects. Advise patients to avoid red wine while taking cyclosporine.

Adverse Reactions

Cardiovascular

Hypertension (53%); chest pain (6%); arrhythmia (5%); abnormal heart sounds, cardiac failure, MI, peripheral ischemia (1% to less than 3%).

CNS

Tremor (55%); headache (25%); paresthesia (11%); dizziness (8%); depression, fatigue (6%); convulsions (5%); insomnia (4%); migraine (3%); anxiety, asthenia, confusion, decreased or increased libido, emotional lability, hypoesthesia, impaired concentration, malaise, nervousness, neuropathy, paranoia, somnolence, vertigo (1% to less than 3%); encephalopathy (postmarketing).

Dermatologic

Hirsutism (45%); hypertrichosis (19%); rash (12%); acne (6%); flushing (5%); alopecia, purpura (4%); abnormal pigmentation, angioedema, dermatitis, dry skin, eczema, folliculitis, increased sweating, keratosis, nail disorder, pruritus, skin disorder, skin malignancies, urticaria (1% to less than 3%); brittle fingernails (2% or less); bullous eruptions, skin ulcer (1%).

EENT

Ear disorder (5%); pharyngitis (4%); rhinitis (3%); abnormal vision, cataract, conjunctivitis, deafness, eye pain, taste perversion, tinnitus, vestibular disorder (1% to less than 3%); 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

Nausea (23%); gum hyperplasia (16%); abdominal pain (15%); diarrhea (13%); dyspepsia (12%); nausea/vomiting (10%); vomiting (9%); abdominal discomfort, stomatitis (7%); flatulence (5%); GI disorder, gingivitis (4%); anorexia, rectal hemorrhage (3%); abdominal distension, constipation, dry mouth, dysphagia, enanthema, eructation, esophagitis, gastric ulcer, gastroenteritis, gingival bleeding, glossitis, peptic ulcer, salivary gland enlargement, tongue disorder, tooth disorder (1% to at least 3%); hiccups (2% or less).

Genitourinary

Renal dysfunction (38%); UTI (21%); nonprotein nitrogen increased (19%); gynecomastia, micturition frequency (4%); menstrual disorder (3%); abnormal urine, breast pain, breast fibroadenosis, hematuria, increased BUN, micturition urgency, nocturia, polyuria, pyelonephritis, renal abscess, urinary incontinence, uterine hemorrhage (1% to less than 3%); dysuria, leukorrhea (1%); glomerular capillary thrombosis; BK virus–associated nephropathy (postmarketing).

Hematologic-Lymphatic

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

Hepatic

Hepatotoxicity (7%); hyperbilirubinemia (1% to less than 3%).

Lab Tests

Increased creatinine (48%); elevated triglycerides (15%); elevated cholesterol (less than 3%).

Metabolic-Nutritional

Hypomagnesemia (6%); diabetes mellitus, hyperkalemia, hyperuricemia, hypoglycemia, increased or decreased weight (1% to less than 3%).

Musculoskeletal

Leg cramps/involuntary muscle contractions (12%); arthralgia (6%); arthropathy (5%); rigors (3%); bone fracture, bursitis, joint dislocation, myalgia, stiffness, synovial cyst, tendon disorder (1% to less than 3%); muscle pain (2% or less).

Respiratory

Upper respiratory tract infection (14%); respiratory infection (9%); sinusitis (7%); pneumonia (6%); bronchospasm, coughing, dyspnea (5%); bronchitis (3%); abnormal chest sounds, tonsillitis (1% to less than 3%).

Miscellaneous

Viral infection (16%); edema (14%); pain (13%); flu-like symptoms (10%); local fungal infection (8%); wound and skin infections (7%); cytomegalovirus infection, septicemia (5%); abscess, cramps (4%); fever (3%); bacterial infection, carcinoma, cellulitis, fungal infection, goiter, herpes simplex, herpes zoster, hot flushes, increased appetite, moniliasis, tumor, viral infection (1% to less than 3%); allergic reaction (2% or less).

Precautions

Warnings

Only health care providers 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 modified ( Neoral , Gengraf ) may be given with other immunosuppressants.

Sandimmune capsules and oral solution have decreased bioavailability compared with Neoral and Gengraf . Oral absorption during long-term 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 or other immunosuppressants, UVB, coal tar, or radiation therapy.

Cyclosporine can cause systemic hypertension and nephrotoxicity.

Renal 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 patients, ensure that a dermatologic and physical exam, at least 2 BP measurements and 2 serum creatinine levels, and BUN, CBC, uric acid, lipids, and serum magnesium and potassium to establish baseline have been performed. Evaluate BP, serum creatinine, 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. Be prepared to reduce cyclosporine dose if patient develops sustained hypertension or elevations in serum creatinine.

Baseline evaluations in RA patients

Before initiating therapy in RA patients, ensure that a physical exam, and at least 2 BP measurements and 2 serum creatinine levels to establish baseline have been performed. Evaluate BP and serum creatinine every 2 wk during initial 3 mo of therapy and then monthly thereafter if patient is stable. Monitor BP and serum creatinine 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 patients and periodically monitored in RA patients. Be prepared to adjust cyclosporine dose.

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

Infection

Monitor patients for signs and symptoms of bacterial, viral, or fungal infection.

Organ rejection

Monitor patient for signs or symptoms of organ rejection.

Response to therapy (ophthalmic emulsion)

Monitor patient's response to therapy.


Pregnancy

Category C .

Lactation

Excreted in breast milk.

Children

Gengraf , Neoral

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

Sandimmune

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

Restasis

Safety and efficacy not established in children younger than 16 y 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, serum creatinine) is evaluated before starting and periodically thereafter during treatment. 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 1:1000 and oxygen readily available.

Convulsions

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

Hematologic effects

Syndrome of thrombocytopenia and microangiopathic hemolytic anemia has developed occasionally and may result in graft failure.

Hepatotoxicity

May occur, especially when cyclosporine is used in high doses. May respond to decreased dose.

Hypertension

Common adverse reaction; may require antihypertensive therapy.

Metabolic effects

Significant hyperkalemia, sometimes associated with hyperchloremic metabolic acidosis, and hyperuricemia have been seen occasionally.

Nephrotoxicity

May occur, especially when cyclosporine is used in high doses. May respond to decreased dose.

Overdosage

Symptoms

Drowsiness, headache, hepatotoxicity, nephrotoxicity, tachycardia, vomiting.

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 their health care provider. Advise patient that a 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.

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