cyclosporine (Neoral, Sandimmune, Gengraf)
Classes: Immunosuppressants; DMARDs, Immunomodulators; Calcineurin Inhibitors
Dosing and uses of Neoral, Sandimmune (cyclosporine)
Adult dosage forms and strengths
capsule
- 25mg (Gengraf, Neoral, Sandimmune)
- 50mg (Gengraf, Sandimmune)
- 100mg (Gengraf, Neoral, Sandimmune)
oral solution
- 100mg/mL (Gengraf, Neoral, Sandimmune)
injectable solution
- 50mg/mL (Sandimmune)
Solid Organ Transplantation
Prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants; has been used in combination with azathioprine and corticosteroids
Adjust dosage according to trough levels, general dosage guidelines listed below
OraL
- 4-12 hr pre-transplant: 15 mg/kg PO for 1 dose
- 1-2 wk post-transplant: 15 mg/kg/day PO divided BID
- Reduce 5% per wk until: 5-10 mg/kg/day PO divided BID
IV
- 4-12 hr pre-transplant IV: 5-6 mg/kg IV for 1 dose over 2-6 hours
- Post-transplant, until can tolerate oral therapy: 5-6 mg/kg IV qDay
Rheumatoid Arthritis
Indicated for severe active, rheumatoid arthritis where the disease has not adequately responded to methotrexate; may be used in combination with methotrexate
Gengraf or Neoral: 1.25 mg/kg PO BID; may increase by 0.5-0.75 mg/kg/day after 8 weeks and again after 12 wk if needed, not to exceed 4 mg/kg/day
Discontinue if no improvement observed by 16 wk
Decrease dose by 25-50% at any time to control adverse effects (eg, hypertension, elevations in serum creatine >30% pretreatment leveL
Psoriasis
Indicated for treatment of adult, nonimmunocompromised patients with severe, recalcitrant, plaque psoriasis who have failed to respond to at least 1 systemic therapy (eg, PUVA, retinoids, or methotrexate) or in patients for whom other systemic therapies are contraindicated, or cannot be tolerated
Gengraf or Neoral: 1.25 mg/kg PO BID; may increase by 0.5 mg/kg/day after 4 wk and q2wk if needed, not to exceed 4 mg/kg/day
Discontinue if no improvement observed at 6 weeks on maximum daily dose of 4 mg/kg/day
Decrease dose by 25-50% at any time to control adverse effects (eg, hypertension, elevations in serum creatine >30% pretreatment leveL
Orphan Designations
ALs
- Treatment of amyotropohic lateral sclerosis and its variants
- Orphan sponsor: Maas Biolab,LLC; Tecnology Ventures, Corporation Technopolis 1155 University Blvd., SE; Albuquerque, NM 87106
Traumatic Brain Injury
- Treatment of moderate-to-severe traumatic brain injury
- Orphan sponsor: NeuroVive Pharmaceutical AB, Biomedical Center SE-221 84; Lund, Sweden
Lung Transplant
- Prophylaxis of organ rejection in patients receiving allogeneic lung transplant
- Treatment of acute rejection in recipients of allogeneic lung transplants
- Orphan sponsor: APT Pharmaceuticals, Inc; 700 Airport Blvd, Suite 350; Burlingame, CA 94010
GVHd
- Prophylaxis and treatment of graft versus host disease
- Orphan sponsor: Sigmoid Pharma LTD; Dublin City University; Ireland
Lung Allograft Rejection
- Liposomal: For aerosolized administration in the prevention and treatment of lung allograft rejection
- Orphan sponsor: Vernon Knight, M.D.; Baylor College of Medicine, Dept. of Molecular Phy, One Baylor Plaza; Houston, TX 77030
Pulmonary Rejection With BMt
- Liposomal: For aerosolized administration in the prevention and treatment of pulmonary rejection events associated with bone marrow transplant (BMT)
- Orphan sponsor: Vernon Knight, M.D.; Baylor College of Medicine, Dept. of Molecular Phy, One Baylor Plaza; Houston, TX 77030
Bronchioitis Obliterans (Orphan)
- Liposomal cyclosporine for inhalation
- Orphan sponsor: PARI Pharma GmbH; Moosstrasse 3; Germany
Pediatric dosage forms and strengths
capsule
- 25mg (Gengraf, Neoral, Sandimmune)
- 50mg (Gengraf, Sandimmune)
- 100mg (Gengraf, Neoral, Sandimmune)
oral solution
- 100mg/mL (Gengraf, Neoral, Sandimmune)
injectable solution
- 50mg/mL (Sandimmune)
Solid Organ Transplantation (Off-Label)
Prophylaxis of organ rejection in kidney, liver, and heart allogeneic transplants; has been used in combination with azathioprine and corticosteroids
Children as young as 6 months have received cyclosporine to prevent solid organ transplant rejection
Dosage is same as adults, although children may require higher mg/kg dose than adults
Adjust dosage according to trough levels, general dosage guidelines listed below
OraL
- 4-12 hr pretransplant: 15 mg/kg PO for 1 dose
- 1-2 wk post-transplant: 15 mg/kg/day PO divided BID
- Reduce 5% per wk until: 5-10 mg/kg/day PO divided BID
IV
- 4-12 hr pre-transplant IV: 5-6 mg/kg IV for 1 dose over 2-6 hr
- Posttransplant, until can tolerate oral therapy: 5-6 mg/kg IV qDay
Neoral, Sandimmune (cyclosporine) adverse (side) effects
>10%
Tremor (12-55%)
Nephrotoxicity (32%)
Hypertension (26%)
Infection (3-25%)
Headache (2-25%)
Nausea (23%)
Hirsutism (21%)
Hypertrichosis (5-19%)
Female reproductive disorder (5-19%)
Gum hyperplasia (2-16%)
Triglycerides increased (15%)
Abdominal discomfort (1-15%)
URI (1-14%)
Diarrhea (3-13%)
Dyspepsia (2-12%)
Leg cramps (2-12%)
Parathesia (1-11%)
1-10%
Acne
Convulsions
Pruitus
Hyperkalemia, hypomagnesemia
Pancreatitis
Hepatotoxicity
Flu-like syndrome
Frequency not defined
Leukopenia
Thrombocytopenia
Anaphylaxis
Glomerular capillary thrombosis
Hypomagnesemia
Migraine
Hyponatremia
Postmarketing Reports
Pain in lower extremities
Warnings
Black box warnings
Should be prescribed only by physicians who have experience with immunosuppression in solid organ transplant recipients and can provide necessary follow-up and appropriate monitoring
Coadministration with other immunosuppressants in kidney, liver, and heart transplant recipients, but risk of infection and neoplasia may be increased
Increased risk for development of lymphomas and other malignancies, particularly those of the skin; avoid excess UV light exposure
Increased risk appears related to the intensity and duration of immunosuppression rather than to the use of specific agents; oversuppression of the immune system may result in infection or malignancy; caution with regimens containing multiple immunosuppressants
Sandimmune and Neoral are not bioequivalent and should not be interchanged without physician approval; Neoral (capsules and oral solution) has increased bioavailability compared with Sandimmune (capsules and oral solution)
For a given trough concentration, cyclosporine exposure will be greater with Neoral than with Sandimmune
Sandimmune has decreased bioavailability compared with Neoral and erratic absorption; requires careful monitoring of blood levels and subsequent dosage adjustments
Patients with psoriasis who have been treated with PUVA, methotrexate or immunosuppressants, UVB, coal tar, or radiation are at increased risk for skin malignancies, hypertension, and renal dysfunction
Contraindications
Hypersensitivity
Breastfeeding
(RA/Psoriasis use): Abnormal renal function, uncontrolled HTN, malignancies
(Psoriasis use) Concomitant PUVA, UVB radiation, coal tar, methotrexate, other immunosuppressants
Cautions
Injection: monitor closely for at least 30 min
Risk of hepatotoxicity and nephrotoxicity
Myelosuppression may be severe and prolonged; monitor complete blood and platelet counts
Potential increase risk for optic disk edema and infusion-related anaphylactic reactions
Some malignancies caused by cyclosporine immunosuppression may be fatal (eg, lymphoma)
Serious and fatal cerebral, gastrointestinal and pulmonary hemorrhage; monitor platelets and coagulation parameters and treat accordingly
Anticipate and monitor for signs and symptoms of tumor lysis syndrome occur; treat promptly
Monitor for and discontinue promptly if systemic inflammatory response or capillary leak syndrome suspected
Monitor for signs and symptoms of infection; severe and fatal sepsis as a result of bone marrow suppression; discontinue therapy promptly if infection occur
Monitor for and discontinue if venous occlusive disease of the liver suspected
Monitor liver enzymes and discontinue therapy at first signs of severe hepatotoxicity; fatal hepatotoxicity may occur
Monitor renal function and interrupt or discontinue if creatinine levels increase or acute renal failure occur
Increased risk for serious infection with fatal outcome because of immunosuppression, including activation of latent viruses, eg, BK virus-induced nephropathy
Patients with psoriasis who received coal tar, PUVA, methotrexate, or other immunosuppressants have higher risk of skin cancer with NeoraL
Discontinue therapy if exfoliative or bullous rash suspected or if Stevens-Johnson syndrome or toxic epidermal necrolysis suspected
Monitor for signs and symptoms of enterocolitis and treat promptly
Extensively metabolized by CYP3A isoenzymes, in particular CYP3A4, and is a substrate of the multidrug efflux transporter P-glycoprotein (P-gp); various agents are known to either increase or decrease plasma or whole blood of cyclosporine levels usually by inhibition or induction of CYP3A4 or P-gp or both
Occasionally, patients develop a syndrome of thrombocytopenia and thrombotic microangiopathic hemolytic anemia may result in graft failure
Significant hyperkalemia and hyperuricemia may occur
Neurotoxicity may occur, particularly with high dose methylprednisolone; caution with other drugs that may cause neurotoxicity
Mild or moderate hypertension and rarely severe hypertension may occur; incidence decreases over time; antihypertensive therapy may be required in recipients of kidney, liver, and heart allografts treated with cyclosporine; potassium-sparing diuretics should not be used to treat cyclosporine associated hypertension as cyclosporine may cause hyperkalemia; calcium antagonists can be effective but can interfere with cyclosporine metabolism
Gingival hyperplasia may occur; avoid concomitant nifedipine administration in patients who develop gingival hyperplasia
Seizures may occur when used in combination with high-dose corticosteroids
Pregnancy and lactation
Pregnancy category: C; take into consideration alcohol content of various cyclosporine formulations
Lactation: excreted in breast milk, do not nurse
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Neoral, Sandimmune (cyclosporine)
Mechanism of action
Calcineurin inhibitor
Suppresses cellular and humoral immunity (mainly T cells)
Absorption
Bioavailability: Neoral >Sandimmune
Peak plasma time: Neoral 1.5-2 hr; Sandimmune 3.5 hr
Onset: unknown
Duration: unknown
Distribution
Protein Bound: 90%
Vd: 13 L/kg
Metabolism
Via hepatic CYP3A4
Metabolites: AM1, AM9, AM4n
Enzymes inhibited: CYP3A4 and P-gp
Elimination
Half-Life: 8.4-27 hr
Clearance: 5-7 mL/min/kg
Excretion: Mainly bile and feces; 6% urine
Pharmacogenomics
Substrate of CYP3A4 and CYP3A5
Genetic variant in CYP3A4 containing an A- to G- mutation (called CYP3A4-V or CYP3A4*1B) is associated with impaired enzyme activity
Frequency of this mutation is 4% in the white population, but 67% in the black population
This may be important in the early postsurgical phase when trying to establish adequate therapeutic serum levels
Administration
IV Incompatibilities
Additive: MgSO4
Y-site: amphotericin B cholesteryl sulfate
IV Compatibilities
Solution: NS, D5W
Additive: ciprofloxacin
Y-site: gatifloxacin, linezolid, propofol, sargramostim
IV Preparation
Dilute 1 mL (50 mg) of concentrated inj soln in 20-100 mL of D5W or Ns
Stability of injection of parenteral admixture at room temp (25°C) is 6 hr in PVC; 24 hr in Excel, PAB containers, or glass
Polyoxyethylated castor oil surfactant in cyclosporine injection may leach phthalate from PVC containers such as bags and tubing
Actual amount of DEHP plasticizer leached from PVC containers and administration sets may vary in clinical situations, depending on surfactant concentration, bag size, & contact time
IV Administration
Following dilution, infuse over 2-6 hr
Continuously monitor for at least the first 30 min of the infusion, and then frequently thereafter
Anaphylaxis possible with IV use; reserve only for patients unable to take oral form
Maintain airway; other supportive measures & agents for treating anaphylaxis should be present
Oral Administration
Neoral and Sandimmune are NOT bioequivalent, exercise caution if switching between brands/generics
Storage
Store ampules at controlled room temp; do not refrigerate
Protect ampules from light