cyclosporine (Rx)

>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

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 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.

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

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