Cyclosporine


Cyclosporine is a potent immunosuppressive agent used to prevent rejection of transplanted organs.
 
Incidence
23 cases of hypersensitivity have been reported (17 in patients, 5 in normal volunteers).
 
Clinical manifestations
General: anaphylactic shock.
 
Respiratory: dyspnea, bronchospasm.
 
E.N.T.: laryngospasm.
 
Cutaneous: erythematous skin rash (generalized or mainly on face and trunk), urticaria, pruritus, periorbital edema. In the 17 patients reported: 5/17 no previous exposure, 12/17 previous exposure to cyclosporine or cremophor EL (15 intravenous route, 2 oral route).
 
Diagnostic methods
Cutaneous testing is seldom performed: 2/17 patients had positive skin-tests.
 
Provocation challenge: oral or intravenous.
 
Mechanisms
The organic solvent (cremophor E.L.) contained in the intravenous solution (not in oral form) has been implicated.
 
IgE-mediated hypersensitivity (positive skin-tests, no specific IgE found).
 
Complement activation.
 
Direct histamine release.
 
Management
Use alternative formulations of cyclosporine:
  • oral solution (cyclosporine 100 mg/ ml): Sandimmune (diluent: polyoxyethylated oleic glycerides).
  • oral soft gelatin capsule: Sandimmune (diluent: polyoxyethylated glycolysed glycerides)
  • oral solution microemulsion: Neoral (diluent: polyoxyl 40 hydrogenated castor oil)
  • oral soft gelatin capsule microemulsion: Neoral (diluent: polyoxyl 40 hydrogenated castor oil).


The soft, corn oil-based gelatin capsule appears to be the safest formulation of cyclosporine.

 

If high-dose intravenous cyclosporine is used:
 
  • cyclosporine solutions are incompatible with polyvinyl chloride (PVC) plastics and must be prepared in non-PVC plastic bags, glass bottles or polypropylene syringes. Tubing used for the infusion must not contain PVC.
  • cyclosporine should be diluted to 0.5 to 2.5 mg/ ml with 5% dextrose or 0.9% sodium chloride. After adding cyclosporine to the carrier fluid, the infusion must be mixed thoroughly by shaking or swirling the bottle. The infusion fluid must appear homogenous.
  • the tubing system must be primed with 0.9% saline or 5% dextrose.
  • high-dose cyclosporine should not be administered to the patient unless the patient has received appropriate corticosteroid and antihistamine premedication.
  • During the first ten minutes of the first and second cyclosporine infusions, supervision by medical personnel with proper resuscitation skills is advisable.

References

  1. Volcheck G.W, Van Delenn R.G, "Anaphylaxis to intravenous cyclosporine and tolerance to oral cyclosporine: case report and review", Ann. Allergy. Asthma. Immunol., 1998; 80 (2): 159-63
  2. Liau-Chu M, Theis J.G.W, Koren G, "Mechanism of anaphylactoid reactions: improper preparation of high-dose intravenous cyclosporine leads to bolus infusion of cremophor EL and cyclosporine", Ann. Pharmacother., 1997; 31: 1287-91
  3. Boehnke-Michaud L, "Methods for preventing reactions secondary to cremophor EL", Ann. Pharmacother., 1997; 31: 1402-4
  4. Theis J.G.W, Liau-Chu M, Chan H.S, Doyle J, Greenberg M.L, Koren G, "Anaphylactoid reactions in children receiving high-dose intravenous cyclosporine for reversal of tumor resistance: the causative role of improper dissolution of cremophor EL", J. Clin. Oncol., 1995; 13 (10): 2508-16

As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.