in children than in adults (Gimnig et al., 2006). Continuous use of SP is known to cause hematological disorders.

In rare cases, SP causes severe cutaneous reactions (SCR), namely Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Although SJS and TEN have similar clinical characteristics, these reactions differ in their pattern of distribution and the extent of macule formation and epidermal detachment (Emberger et al., 2003; García-Doval et al., 2000). The clinical manifestations of SJS include an erythematous rash with macules of irregular shape and size (Auquier-Dunant et al., 2002; Emberger et al., 2003) and, occasionally, vesicles and bullae that may coalesce and erode, in addition to lesions in the oral mucous membranes, anogenital regions, and conjunctivae (Emberger et al., 2003; Segal et al., 2007). In TEN, cutaneous eruption is generally preceded by 1 to 3 days of fever, sore throat, cough, and burning eyes (García-Doval et al., 2000). Rates of SCR of 10–40 per 100,000 were associated with the use of SP by travelers when SP was being used for malaria prophylaxis (Miller et al., 1986). Note that these rates of SCR were observed in people who received repetitive doses of SP as chemoprophylaxis. Treatment of malaria with SP has been associated with SCR at a rate of 0.3 per 100,000 in children younger than 15 years of age in Malawi and at a rate of 1.7 per 100,000 in adults. The rates of all adverse cutaneous reactions are higher in HIV-infected persons (Gimnig et al., 2006).

The evidence presented from the IPTi trial for safety monitoring was based primarily on passive reports in the six efficacy trials and in the additional trial in Kisumu, but the surveillance methods varied as noted in Table 19 (and Box 1).

TABLE 19 Safety Monitoring for IPTi Surveillance Methods of the Six IPTi-SP Studies and the Kisumu Trial

Trial Site

Surveillance Method(s)

Ifakara

Passive system reports; no cases SCR (trial protocol)

Kumasi

Treatment visit, questions, and monthly home visits

Lambaréné

Day 7 and day 28 visits, monthly home visits; sickness during clinic visits monitored

Manhiça

Home visit 1 week post-dose

Navrongo

20% sample visited <4 weeks post-dose

Tamale

Passive reports and monthly home visits

Kisumu

Passive case detection

SOURCE: Compiled from literature and data presented by the IPTi Consortium, 2008.

The approximately 4,000 children in the six IPTi-SP Consortium studies received an average of 2.8 doses of SP. The incidence of hospitalizations from all causes was reduced in the treatment arm in three of the trials during IPTi. There was no reported evidence of an increased rate of other severe adverse events in SP recipients compared with placebo recipients. Two SP recipients were reported to have developed SJS after the third dose in the Kumasi, Ghana, trial: Both of these children were seen at home by a general physician who noted bullous skin lesions, but did not recommend hospitalization. The children were examined approximately 2 weeks later and were found to be well. As SJS is a severe disorder requiring intensive care and is associated with a high case-fatality rate, the committee questions the validity of the diagnosis of SJS in these two children. Moreover, whatever type of skin reactions these were, they occurred in toddlers who received a dose of SP at 15 months of age. This dosing age, as used in the Kumasi, Ghana, study, is not one that would be part of IPTi-SP implementation through the EPI as



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