Clinical Pharmacology

"Adverse Drug Event of the month"

Case details:

A 32 year old female with Acute Myeloid Leukemia with normal WBC and platelet counts pretreatment developed febrile neutropenia post allogenic stem transplantation with an absolute neutrophil count of 68.8% and platelets 60,000/cumm. She was treated using Inj Piperacillin / Tazobactum 500mg, Amikacin 500mg, Vancomycin 500 mg, Fluconazole 200mg, tab Aztreonam 500mg, Linezolid 500mg and GSF 300ug IM (Granulocyte colony stimulating factor). In the view of no response to primary antibiotics after 72 hours the patient was empirically infused with an Indian liposomal Amphotericin B (Fungisome TM 1mg/kg/day over 2 hours) for suspected fungal infection without premedication. Five minutes later she developed chills, giddiness, chest discomfort and fall in blood pressure (BP 80/60mm of Hg, HR 140/min). A diagnosis of hypersensitivity reaction was made and therapy was terminated. The symptoms resolved with termination of infusion and treatment with pheniramine maleate 20mg, hydrocortisone succinate 100mg and paracetamol 500 mg. A causality analysis using the Naranjo's algorithm was done and the adverse event was scored at 7 out of a possible total of 13 (1) (score for a probable adverse event being 5-8). She was advised to discontinue liposomal Amphotericin B and start treatment with Itraconazole 100 mg orally for two weeks. Follow up blood culture was negative and the patientwas afebrile during discharge.

Discussion:

Although liposomal Amphotericin B formulations of Amphotericin B are designed to maintain therapeutic efficacy of Amphotericin B deoxycholate while reducing its associated toxicities (2) it should be noted that hypersensitivity reactions can occur in rare instances ( 0.05 - 1 %). Several cases of hypersensitivity reactions to other lipid formulations of Amphotericin B with fatal outcome have been reported (3-5). In contrast, this patient recovered immediately after terminating the infusion and treatment with pheniramine maleate and steroids. Although the pathophysiology of these hypersensitivity reactions remains unclear and it is postulated that not only Amphotericin B but also lipid component may also contribute to hypersensitivity reaction (5,6,8). However the role of premedication in the prevention of these hypersensitivity reactions is still unclear. Laing and colleagues suggest similar reactions following Ambisome treatment with no subsequent hypersensitivity reaction to Amphotericin B (7) administered after premedication. Hence if treatment with Amphotericin B is to be continued it is recommended to use premedication and a test dose under close medical supervision. All physicians prescribing this drug should be aware of this potential severe complication. This procedure might help to prevent immediate severe hypersensitivity reaction (but cannot exclude allergic reaction during therapy).

References:

1. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ A method for estimating the probability of Adverse drug reaction Clin. Pharmacol Ther 1981; 8: 239 - 244.
2. Gokhale PC, Barapatre RJ, Advani SH, Kshirsagar NA, Pandya SK . Pharmacokinetics and tolerance of liposomal Amphotericin B in patients J of Antimicrob Chemo 1993; 32 :133-39
3. Bates CM, Carey P, Hind CRK Anaphylaxis due to liposomal Amphotericin (Ambisome) Genitourinary Med 1995 ; 71: 413-14
4. Bishara J , Weinberger M, Lin AY, Pitlik S Amphotericin B - not so terrible in Ann Pharmacother 2001 ; 35 : 308-10
5. Prentice HG, Hann IM, Herbbrecht R et al A randomized comparision of liposomal Amphotericin b versus conventional Amphotericin B for treatment of treatment of pyrexia of unknown origin in neutropenic patients. Br J of Hematol 1997 ; 98: 711-718
6. Schneider P, Klein RM, Dietze L, Sohngen D, Hey ll Anaphylaxis due to liposomal Amphotericin ( Ambisome ) Br J of Hematol 1998; 102: 1107-1113
7. Laing RBS , Milne LJR, Leen CLS, Malcolm GP, Steers AJW. Anaphylactic reactions to liposomal Amphotericin B. Lancet 1994; 344:682
8. Ringden O, Andstrom E, Remberger M, Svahn BM, Tollemar J Allergic reactions and other rare side effects to liposomal Amphotericin B. Lancet 1994; 344:1156-57

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