No

Immunosuppressant Agent

Immunosuppressant which may be used with azathioprine and/or corticosteroids to prolong organ and patient survival in kidney, liver, and heart transplants; used in allogeneic bone marrow transplants for prevention and treatment of graft-versus-host disease; also used in some cases of severe autoimmune disease that are resistant to corticosteroids and other therapy.

C

Clinical effects on the fetus: Based on small numbers of patients, the use of cyclosporine during pregnancy apparently does not pose a major risk to the fetus

Hypersensitivity to cyclosporine, Cremophor® EL (I.V. solution), or any other I.V. component (ie, polyoxyl 35 castor oil is an ingredient of the parenteral formulation, and polyoxyl 40 hydrogenated castor oil is an ingredient of cyclosporine capsules and solution for microemulsion)

Infection and possible development of lymphoma may result. Make dose adjustments to avoid toxicity or possible organ rejection using cyclosporine blood levels because absorption is erratic and elimination is highly variable. Administer with adrenal corticosteroids but not with other immunosuppressive agents. Adjustment of dose should only be made under the direct supervision of an experienced physician. Reserve I.V. use for patients who cannot take oral form. Maintain patent airway; other supportive measures and agents for treating anaphylaxis should be present when I.V. drug is given. Nephrotoxic: If possible avoid concomitant use of other potentially nephrotoxic drugs (eg, acyclovir, aminoglycoside antibiotics, amphotericin B, ciprofloxacin). Injectable form contains ethanol.

>10%:

Cardiovascular: Hypertension

Dermatologic: Hirsutism

Endocrine & metabolic: Hypomagnesemia, hyperkalemia

Gastrointestinal: Gingival hyperplasia

Neuromuscular & skeletal: Tremor

Renal: Nephrotoxicity

1% to 10%:

Central nervous system: Seizure, headache

Dermatologic: Acne

Gastrointestinal: Abdominal discomfort, nausea, vomiting

Hepatic: Hepatotoxicity

Neuromuscular & skeletal: Leg cramps

Miscellaneous: Increased susceptibility to infection

<1% (Limited to important or life-threatening symptoms): Hypotension, tachycardia, warmth, flushing, hyperkalemia, hypomagnesemia, hyperuricemia, renal toxicity, respiratory distress

Symptoms of overdose include hepatotoxicity, nephrotoxicity, nausea, vomiting, tremor. CNS secondary to direct action of the drug may not be reflected in serum concentrations, may be more predictable by renal magnesium loss.

CYP3A3/4 enzyme substrate

Increased toxicity:

Drugs that increase cyclosporine concentrations: Azithromycin, clarithromycin, diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, nicardipine, verapamil, grapefruit juice

Drugs that enhance nephrotoxicity of cyclosporine: Aminoglycosides, amphotericin B, acyclovir

Lovastatin - myositis, myalgias, rhabdomyolysis, acute renal failure

Nifedipine - increases risk of gingival hyperplasia

Cyclosporine injection is a clear, faintly brown-yellow solution which should be stored at <30°C and protected from light

Cyclosporine concentrate for injection should be further diluted [1 mL (50 mg) of concentrate in 20-100 mL of D₅W or or NS] for administration by intravenous infusion. Light protection is not required for intravenous admixtures of cyclosporine.

Stability of injection of parenteral admixture at room temperature (25°C): 6 hours in PVC; 24 hours in Excel, PAB containers, or glass

Polyoxyethylated castor oil (Cremophor EL®) surfactant in cyclosporin injection may leach phthalate from PVC containers such as bags and tubing. The actual amount of diethylhexyl phthalate (DEHP) plasticizer leached from PVC containers and administration sets may vary in clinical situations, depending on surfactant concentration, bag size, and contact time.

Doses <250 mg should be prepared in 100 mL of D₅W or NS

Doses >250 mg should be prepared in 250 mL of D₅W or NS

Minimum volume: 100 mL D₅W or NS

Do not refrigerate oral or I.V. solution

Oral solution: Use the contents of the oral solution within two months after opening; should be mixed in glass containers

Cyclosporine injection is a clear, faintly brown-yellow solution which should be stored at <30°C and protected from light

Cyclosporine concentrate for injection should be further diluted [1 mL (50 mg) of concentrate in 20-100 mL of D₅W or or NS] for administration by intravenous infusion. Light protection is not required for intravenous admixtures of cyclosporine.

Stability of injection of parenteral admixture at room temperature (25°C): 6 hours in PVC; 24 hours in Excel, PAB containers, or glass

Polyoxyethylated castor oil (Cremophor EL®) surfactant in cyclosporin injection may leach phthalate from PVC containers such as bags and tubing. The actual amount of diethylhexyl phthalate (DEHP) plasticizer leached from PVC containers and administration sets may vary in clinical situations, depending on surfactant concentration, bag size, and contact time.

Doses <250 mg should be prepared in 100 mL of D₅W or NS

Doses >250 mg should be prepared in 250 mL of D₅W or NS

Minimum volume: 100 mL D₅W or NS

Do not refrigerate oral or I.V. solution

Oral solution: Use the contents of the oral solution within two months after opening; should be mixed in glass containers

Inhibition of production and release of interleukin II and inhibits interleukin II-induced activation of resting T-lymphocytes

Absorption: Oral:

Solution or soft gelatin capsule (Sandimmune®): Erratically and incompletely absorbed; dependent on the presence of food, bile acids, and GI motility; larger oral doses of cyclosporine are needed in pediatric patients versus adults due to a shorter bowel length resulting in limited intestinal absorption

Solution in microemulsion or soft gelatin capsule in a microemulsion are bioequivalent (Neoral®): Erratically and incompletely absorbed; increased absorption, up to 30% when compared to Sandimmune®; absorption is less dependent on food intake, bile, or GI motility when compared to Sandimmune®

Distribution: Widely distributed in tissues and body fluids including the liver, pancreas, and lungs; crosses the placenta; excreted into breast milk

V_dss: 4-6 L/kg in renal, liver, and marrow transplant recipients (slightly lower values in cardiac transplant patients; children <10 years of age have higher values)

Protein binding: 90% to 98% of cyclosporine in the blood is bound to lipoproteins

Metabolism: Undergoes extensive first-pass metabolism following oral administration; extensively metabolized by the cytochrome P-450 system in the liver

Bioavailability:

Solution or soft gelatin capsule (Sandimmune®): Dependent on patient population and transplant type (<10% in adult liver transplant patients and as high as 89% in renal patients)

Children: 28% (range: 17% to 42%); with gut dysfunction commonly seen in BMT patients, oral bioavailability is further reduced

Solution or soft gelatin capsule in a microemulsion (Neoral®):

Children: 43% (range: 30% to 68%)

Adults: 23% greater than with Sandimmune® in renal transplant patients. 50% greater in liver transplant patients

Half-life:

Solution or soft gelatin capsule (Sandimmune®): Biphasic, alpha phase: 1.4 hours and terminal phase 6-24 hours (prolonged in patients with hepatic dysfunction)

Solution or soft gelatin capsule in a microemulsion (Neoral®): 8.4 hours, lower in pediatric patients versus adults due to the higher metabolism rate

Time to peak serum concentration:

Oral solution or capsule (Sandimmune®): 2-6 hours; some patients have a second peak at 5-6 hours

Oral solution or capsule in a microemulsion (Neoral®): 1.5-2 hours (in renal transplant patients)

Elimination: Primarily in the bile; clearance is more rapid in pediatric patients than in adults; clearance is decreased in patients with liver disease; 6% of dose excreted in the urine as unchanged drug (0.1%) and metabolites

Children and Adults (oral dosage is ~3 times the I.V. dosage); dosage should be based on ideal body weight:

Initial: 5-6 mg/kg/day beginning 4-12 hours prior to organ transplantation. Patients should be switched to oral cyclosporine as soon as possible; dose should be infused over 2-24 hours.

Maintenance: 2-10 mg/kg/day in divided doses every 8-12 hours; dose should be adjusted to maintain whole blood FPIA trough concentrations in the reference range

Oral: Solution or soft gelatin capsule (Sandimmune®):

Initial: 14-18 mg/kg/day, beginning 4-12 hours prior to organ transplantation

Maintenance: 5-15 mg/kg/day divided every 12-24 hours; maintenance dose is usually tapered to 3-10 mg/kg/day.

Focal segmental glomerulosclerosis: Initial: 3 mg/kg/day divided every 12 hours

Autoimmune diseases: 1-3 mg/kg/day

Dosing considerations of cyclosporine:

Switch from I.V. to oral therapy:

Threefold increase in dose

T-tube clamping:

Decrease dose; increased availability of bile facilitates absorption of CsA

Pediatric patients:

About 2-3 times higher dose compared to adults

Liver dysfunction:

Decrease I.V. dose; increase oral dose

Renal dysfunction:

Decrease dose to decrease levels if renal dysfunction is related to the drug.

Dialysis:

Not removed

Inhibitors of hepatic metabolism:

Decrease dose

Inducers of hepatic metabolism:

Monitor drug level; may need to increase dose

Oral: Solution or soft gelatin capsule in a microemulsion (Neoral®): Based on the organ transplant population:

Initial: Same as the initial dose for solution or soft gelatin capsule (listed above) or

Renal: 9 mg/kg/day (range: 6-12 mg/kg/day)

Liver: 8 mg/kg/day (range: 4-12 mg/kg/day)

Heart: 7 mg/kg/day (range: 4-10 mg/kg/day)

Note: A 1:1 ratio conversion from Sandimmune® to Neoral® has been recommended initially; however, lower doses of Neoral® may be required after conversion to prevent overdose. Total daily doses should be adjusted based on the cyclosporine trough blood concentration and clinical assessment of organ rejection. CsA blood trough levels should be determined prior to conversion. After conversion to Neoral®, CsA trough levels should be monitored every 4-7 days. Neoral® and Sandimmune® are not bioequivalent and cannot be used interchangeably.

Hemodialysis: Supplemental dose is not necessary.

Peritoneal dialysis: Supplemental dose is not necessary.

Dosing adjustment in hepatic impairment: Probably necessary, monitor levels closely.

Dosing adjustment recommendations for renal impairment during cyclosporine therapy for severe psoriasis:

Serum creatinine levels greater than or equal to 25% above pretreatment levels: Take another sample within 2 weeks. If the level remains greater than or equal to 25% above pretreatment levels, decrease dosage of cyclosporine microemulsion by 25% to 50%. If 2 dosage adjustments do not reverse the increase in serum creatinine levels, treatment should be discontinued.

Serum creatinine greater than or equal to 50% above pretreatment levels: Decrease cyclosporine dosage by 25% to 50%. If 2 dosage adjustments do not reverse the increase in serum creatinine levels, treatment should be discontinued.

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.

Grapefruit juice will increase absorption; mix at room temperature, may use milk, chocolate milk, or orange juice

Cyclosporine trough levels, serum electrolytes, renal function, hepatic function, blood pressure, serum cholesterol

Psoriasis therapy: Biweekly monitoring of blood pressure, complete blood count, and levels of BUN, uric acid, potassium, lipids and magnesium during the first three months of treatment for psoriasis. Monthly monitoring is recommended after this initial period.

Reference ranges are method dependent and specimen dependent; use the same analytical method consistently; trough levels should be obtained immediately prior to next dose

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

Cyclosporine adsorbs to silicone; specific whole blood 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)

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.

None reported

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

No information available to require special precautions

Gingival hypertrophy

Use glass container for liquid solution (do not use plastic or styrofoam cup). Mixing with milk, chocolate milk, or orange juice at room temperature improves flavor. Mix thoroughly and drink at once. Take dose at the same time each day. You will be susceptible to infection; avoid crowds and exposure to any infectious diseases. Do not have any vaccinations without consulting prescriber. Practice good oral hygiene to reduce gum inflammation; see dentist regularly during treatment. Report acute headache; unusual hair growth or deepening of voice; mouth sores or swollen gums; persistent nausea, vomiting, or abdominal pain; muscle pain or cramping; unusual swelling of extremities, weight gain, or change in urination; or chest pain or rapid heartbeat. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to be pregnant. Do not breast-feed.

Do not administer liquid from plastic or styrofoam cup; mixing with milk, chocolate milk, or orange juice preferably at room temperature, improves palatability; stir well; do not allow to stand before drinking; rinse with more diluent to ensure that the total dose is taken; after use, dry outside of pipette; do not rinse with water or other cleaning agents; may cause inflamed gums

Capsule (Sandimmune®): 25 mg, 100 mg

Capsule, soft gel: 25 mg, 100 mg

Capsule, soft gel (Sandimmune®): 50 mg

Capsule, soft gel for microemulsion (Neoral®): 25 mg, 100 mg

Injection (Sandimmune®): 50 mg/mL (5 mL)

Solution, oral (Sandimmune®): 100 mg/mL (50 mL)

Solution, oral for microemulsion (Neoral®): 100 mg/mL (50 mL)

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