A cluster of cases of severe cardiotoxicity among kala-azar patients treated with a high-osmolarity lot of sodium antimony gluconate.

Abstract

In India, sodium antimony gluconate is the drug of choice for kala-azar. Due to increasing unresponsiveness to this drug in the current epidemic that began in the early 1970s, daily doses of 20 mg/kg/day for 30 days or more is recommended as opposed to the 10 mg/kg/day dose for 6-10 days used in the past. Of the 130-150 patients treated annually at our center with locally made sodium antimony gluconate, serious cardiotoxicity has occurred in less than 10%. During April 1995 at the University Hospital in Varanasi, we encountered life-threatening cardiotoxicity after 3-28 days of therapy in each of the eight patients being treated with a new lot of this drug made by a different manufacturer. Of the eight patients, six each developed congestive heart failure and/or prolongation of the corrected QT interval (QTc), and three died as a direct consequence of drug-induced toxicities. In three instances, the life-threatening complications occurred with a cumulative dose of less than 300 mg/kg. In patients with prolonged QTc, ventricular premature beats and ventricular tachycardia were recorded; in one patient, the ventricular tachycardia progressed to torsade de pointes, culminating in ventricular fibrillation and death. Since switching to different lots of this drug, we have not seen further clustering of dangerous cardiotoxicity. The antimony content of the implicated drug was comparable with that in lots from other manufacturers that did not show overt toxicity, but the osmolarity was approximately 300 mOsm/L higher. The simple technique of measuring of osmolarity may help identify inappropriately manufactured drug.

Treatment options for visceral leishmaniasis: a systematic review of clinical studies done in India, 1980–2004

“…It is difficult to establish with certainty whether substandard products may have had a role in the generation of resistance, but there is some evidence that it has added to toxicity. 71,72 Independent of quality, a combination of economical constraints, inadequate prescribing, inconvenience due to the prolonged schedule, toxicity, and poor efficacy has likely contributed to the use of subtherapeutic doses. Patients have to use their own resources to buy drugs, but can ill afford it and often consult unqualified practitioners.…”

Substandard/Counterfeit Antimicrobial Drugs

“…Substandard anthelmintics such as mebendazole (50,79), albendazole (50), praziquantel (185,208), piperazine (173), rafoxanide (209), and pyrazinamide (7) have been reported (Tables 7 and 8). Other substandard antiparasitic drugs, such as pentavalent antimonials and lindane, have been reported in India (186), Sudan (180), and Lebanon (181). Characteristics of substandard antiparasitic drugs include no active ingredient (50), increased impurities (185) or osmolality (186), altered labeling (50) and formulation characteristics (185), expired and diluted products (180), and reduced efficacy (209).…”

Drug policy for visceral leishmaniasis: a cost‐effectiveness analysis

“…Antimonials are not an ideal drug; they have to be administered parenterally over a period of 28-30 days, generally requiring hospitalization. Antimonials have shown rare but serious side effects, such as cardio, pancreas and liver toxicity (Gasser et al 1994;Sundar et al 1998c;Thakur et al 1998;Rijal et al 2003), whose importance increases if the patient is coinfected with HIV (Delgado et al 1999;Laguna et al 1999). Resistance to antimonials has been reported in up to 65% of patients in some villages of Bihar, India (Sundar 2001).…”