Clinical Pharmacology

"Adverse Drug Event of the month"

Flu -like syndrome in a patient after an over ingestion of Levamisole ( a spontaneous report from a private practitioner)

Case report:
A 18 year old female patient presented to a private practitioner in a Mumbai suburb with complaints of recurrent aphthous stomatitis since two months. Although the patient was treated with oral supplements of Vitamin B complex; zinc and ZyteeTM (local application containing 9% choline salicylate and 0.02%Benzalkonium chloride), there was no symptom relief. Subsequently the patient was advised Tablet Levamisole 150 mg as a single dose. However, the patient took the tablet daily for six consecutive days. She then presented with complaints of headache, bodyache, myalgia and fatigue. At the time of examination her vital parameters were stable and blood investigations done subsequently were normal (Table1). She was treated with antipyretics and analgesics. The patient's symptoms subsided and she recovered gradually over two days. She is well at the time of writing this report.

Discussion
Levamisole hydrochloride is the (S)- enantiomer of teramizole (1). The drug is rapidly and extensively absorbed after oral administration with a plasma half-life of 4 to 6 hours. It is metabolized in the liver and excreted mainly in urine as a metabolite and a small proportion in faeces.

Levamisole causes spastic paralysis of intestinal nematodes and hence is used as an anthelmintic. It also enhances function of cytokines and T cells and is thus used as an immunomodulator in the treatment of Dukes' stage C colon cancer along with 5 - fluorouracil. It is also used in the treatment of aphthous ulcers and rheumatic disorders as an immunomodulator (1, 2). As an anthelmintic the drug is given in a single dose (150 mg for adults and 3 mg/kg/day for children). For the treatment of carcinoma colon levamisole is given orally as an adjuvant to fluorouracil in the dose of 50 mg every 8 hours for three days starting 7 to 30 days after surgery and repeated every 14 days (3).

When given in a single dose Levamisole is generally well tolerated and adverse effects are usually limited to nausea, vomiting, abdominal pain, dizziness and headache. When given over a longer period adverse effects are more frequent and include hypersensitivity reactions such as influenza (flu) - like syndrome, fever, arthralgia, skin rashes, and cutaneous vasculitis. Central nervous system symptoms include headache, dizziness, and convulsions. Hematological abnormalities like agranulocytosis, leucopenia, thrombocytopenia and gastro- intestinal disturbances, including dysguesia (abnormal taste in the mouth) are also observed (3).

Elevated concentration of enzyme aspartate aminotransferase, SIADH and inflammatory leucoencephalopathy were the rare adverse events observed during treatment with levamisole. Two fatalities caused by septic shock have been described associated with long-term use of Levamisole as an adjuvant for cancer therapy (4).

Treatment of levamisole toxicity is essentially supportive and symptomatic. No antidote is available. In case of acute over dosage gastric lavage may be helpful. (5) Use of levamisole should be avoided in patients with pre-existing blood disorders. Alcohol consumption should also be avoided, as it is known to produce a disulfiram - like reaction. Good patient physician communication will avoid such overingestion. Patient should be vigilant and should take the medication strictly as per the physician's instruction to avoid such adverse events from happening.

References
1. Dollery C, Boobis A, Rawlins M, Thomas S, Wilkins M, editors. In: Therapeutic Drugs. 2nd ed. UK: Churchill Livingston Company, 1986. p. L 26-9.

2. Krensky AM, Strom TB, Bluestone JA. Immunomodulators: immunosuppressive agents, tolerogens, and immunostimulants. In: Hardman JG, Limbird LE, Gilman AG, editors. Goodman and Gillman's The pharmacological basis of therapeutics. 10th ed. NY: McGraw- Hill, Medical Publishing Division; 2001.p 1463-84.

3. Anthelmintics. In: Reynolds JE, editor. Martindale The extra pharmacopoeia. 31st edition. London: Royal Pharmaceutical Society of Great Britain. 1996. p. 116.

4. Amery WK, Butterworth BS. The dosage regimen of levamisole in cancer: is it related to efficacy and safety? Int Jr of Immunopharmac 1983; 5:1-9

5. Available from http://www.mosbeysdrugconsult.com/ accessed on 9th November 2004.

Department Of Clinical Pharmacology
Seth GS Medical College and KEM Hospital,
Parel,
Mumbai 400 012

Private Practitioner at Sundaram clinic,
Tilak Nagar, Chembur,
Mumbai 400 089
E- mail: lvasudevan@vsnl.net