CYCLOSPORINE
INTRODUCTION
- Cyclosporine is a large lipophilic cyclic polypeptide (immunosuppressant agent).
-Used for the prevention of graft rejection in solid organ transplant patients, and for the treatment of psoriasis, rheumatoid arthritis and a variety of other autoimmune diseases.
Dosage Forms
- Capsule, Microemulsion (Neoral®): 25 mg; 100 mg.
- Capsule, soft gelatin (Sandimmune®): 25 mg; 50 mg; 100 mg.
- Injection: 50 mg/mL (5 mL).
- Solution, oral (Sandimmune®): 100 mg/mL (50 mL).
-Solution, oral, microemulsion (Neoral®): 100 mg/mL (50 mL)
Usual Dosage.
1- Children and Adults (oral dosage is ~3 times the I.V. dosage); dosage should be based on ideal body weight.
2- I.V.
- 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.
- Maintenance: 2-10 mg/kg/day in divided doses every 8-12 hours; dose should be adjusted to
maintain whole blood FPIA trough conc. in the reference range.
3-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.
- Autoimmune diseases: 1-3 mg/kg/day.
- Capsule, soft gelatin (Sandimmune®): 25 mg; 50 mg; 100 mg.
- Injection: 50 mg/mL (5 mL).
- Solution, oral (Sandimmune®): 100 mg/mL (50 mL).
-Solution, oral, microemulsion (Neoral®): 100 mg/mL (50 mL)
Usual Dosage.
1- Children and Adults (oral dosage is ~3 times the I.V. dosage); dosage should be based on ideal body weight.
2- I.V.
- 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.
- Maintenance: 2-10 mg/kg/day in divided doses every 8-12 hours; dose should be adjusted to
maintain whole blood FPIA trough conc. in the reference range.
3-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.
- Autoimmune diseases: 1-3 mg/kg/day.
Adverse Reactions.
1->10%:
- Cardiovascular: Hypertension.
- Dermatologic: Hirsutism.
-Gastrointestinal: Gingival hypertrophy.
-Neuromuscular & skeletal: Tremor.
-Renal: Nephrotoxicity.
2- 1% to 10%:
- Central nervous system: Seizure, headache.
- Dermatologic: Acne.
- Gastrointestinal: Abdominal discomfort, nausea, vomiting.
-Neuromuscular & skeletal: Leg cramps.
3- <1%:
- tachycardia, warmth, flushing, hyperkalemia, hypomagnesemia, hyperuricemia, pancreatitis, hepatotoxicity, myositis, paresthesias, respiratory distress, sinusitis, anaphylaxis and increased susceptibility to infection.
- Cardiovascular: Hypertension.
- Dermatologic: Hirsutism.
-Gastrointestinal: Gingival hypertrophy.
-Neuromuscular & skeletal: Tremor.
-Renal: Nephrotoxicity.
2- 1% to 10%:
- Central nervous system: Seizure, headache.
- Dermatologic: Acne.
- Gastrointestinal: Abdominal discomfort, nausea, vomiting.
-Neuromuscular & skeletal: Leg cramps.
3- <1%:
- tachycardia, warmth, flushing, hyperkalemia, hypomagnesemia, hyperuricemia, pancreatitis, hepatotoxicity, myositis, paresthesias, respiratory distress, sinusitis, anaphylaxis and increased susceptibility to infection.
Overdosage/Toxicology
-Symptoms of overdose include: hepatotoxicity, nephrotoxicity, nausea, vomiting, tremor.
PHARMACOKINETICS
ONSET/DURATION.
1- INITIAL RESPONSE:
- Psoriasis, oral: 4 weeks.
- Rheumatoid arthritis, oral: 4 to 8 weeks.
2- DURATION: Multiple Dose.
-Psoriasis, oral: 8 to 16 weeks.
- Rheumatoid arthritis, oral: 4 weeks.
1- INITIAL RESPONSE:
- Psoriasis, oral: 4 weeks.
- Rheumatoid arthritis, oral: 4 to 8 weeks.
2- DURATION: Multiple Dose.
-Psoriasis, oral: 8 to 16 weeks.
- Rheumatoid arthritis, oral: 4 weeks.
THERAPEUTIC DRUG CONCENTRATION
-High-performance liquid chromatography (HPLC), 150 to 400 ng/mL in whole blood.
- Trough conc. generally provided the most useful information, and were used for
routine therapeutic monitoring.
-Newer monoclonal fluorescence polarization (monoclonal TDx assay) and radioimmuno assay (various) are now available that are relatively specific for cyclosporine and produce results similar to the HPLC assay.
- Monoclonal radioimmunoassay, 150 to 400 ng/mL in whole blood.
-General: 100-500 mcg/L .
- Transplantation.
- Kidney:100-350 mcg/L .
- Liver : 200-500 mcg/L .
- Bone marrow: 250-500 mcg/L .
- Serum cyclosporine.
- level should be assessed 3-5 days after dosage adjustment, initiation of therapy or discontinuation known CYP450-3A4 inducers or inhibitors.
- During the early post-transplant period and for the first weeks to months, cyclosporine concentrations should be monitored 2 to 3 times weekly.
- Less frequent monitoring should be possible later unless the patient has clinical problems (ie, diarrhea, hepatic dysfunction, rejection episode).
- Trough conc. generally provided the most useful information, and were used for
routine therapeutic monitoring.
-Newer monoclonal fluorescence polarization (monoclonal TDx assay) and radioimmuno assay (various) are now available that are relatively specific for cyclosporine and produce results similar to the HPLC assay.
- Monoclonal radioimmunoassay, 150 to 400 ng/mL in whole blood.
-General: 100-500 mcg/L .
- Transplantation.
- Kidney:100-350 mcg/L .
- Liver : 200-500 mcg/L .
- Bone marrow: 250-500 mcg/L .
- Serum cyclosporine.
- level should be assessed 3-5 days after dosage adjustment, initiation of therapy or discontinuation known CYP450-3A4 inducers or inhibitors.
- During the early post-transplant period and for the first weeks to months, cyclosporine concentrations should be monitored 2 to 3 times weekly.
- Less frequent monitoring should be possible later unless the patient has clinical problems (ie, diarrhea, hepatic dysfunction, rejection episode).
SAMPLING TIME.
-Peak.
- Oral, microemulsion Neoral® 1.5 to 2 hours.
- Sandimmune®:Neoral® 3.1(8-18):1.5 hours.
-520:698 ng/mL.
- Trough.
- Oral: 12-18 hours after dose (chronic usage).
- I.V.: 12 hours after dose or immediately prior to next dose.
- Oral, microemulsion Neoral® 1.5 to 2 hours.
- Sandimmune®:Neoral® 3.1(8-18):1.5 hours.
-520:698 ng/mL.
- Trough.
- Oral: 12-18 hours after dose (chronic usage).
- I.V.: 12 hours after dose or immediately prior to next dose.