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/mLSandimmune I.V. (Canada)Sandoz Cyclosporine (Canada)
Suppresses cell-mediated immune reactions and some humoral immunity, but exact mechanism is not known.
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 .
Vd is 3 to 5 L/kg at steady state (IV). Cyclosporine is 90% protein bound (primarily lipoprotein) and is excreted in human milk.
Extensively metabolized by CYP3A in the liver and to a lesser degree in the GI tract and kidney.
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).
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.
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.
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).
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
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.
None well documented.
Hypertension (53%); arrhythmia, chest pain (at least 3%); abnormal heart sounds, cardiac failure, MI, peripheral ischemia (3% or less).
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).
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%).
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%).
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%).
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).
Leukopenia, lymphoma (6% or less); anemia, epistaxis, lymphadenopathy (3% or less); thrombocytopenia (2% or less); clotting disorders, bleeding, RBC disorders (at least 1%).
Hepatotoxicity (7%); hyperbilirubinemia (at least 1%).
Increased creatinine (at least 3%)
Hyperglycemia, hyperkalemia, hyperuricemia, diabetes mellitus, hypoglycemia, increased or decreased weight (3% or less).
Rigors (at least 2%); muscle pain (2% or less); arthralgia, bone fracture, bursitis, joint dislocation, myalgia, stiffness, synovial cyst, tendon disorder (3% or less).
Sinusitis (7%); bronchitis, coughing, dyspnea, respiratory tract infection, pneumonia (at least 3%); abnormal chest sounds, tonsillitis, bronchospasm (3% or less).
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%).
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.
MonitorBaseline 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.
Category C .
Excreted in breast milk.
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.
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.
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 during long-term use is erratic. Patients with malabsorption may have difficulty achieving therapeutic concentrations with oral use.
Occur rarely with IV use. Have epinephrine 1:1,000 and oxygen readily available.
Have occurred, particularly in combination with high-dose methylprednisolone.
Implement infection control measures if WBC drops; implement bleeding precautions if platelet count drops.
Common adverse reaction; may respond to decreased dose.
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