Regulatory Decision Summary for VITAMIN A (100,000 IU ) and VITAMIN E (20 IU ) ORAL LIQUID PREPARATION

The safety and efficacy of high dose Vitamin A supplementation (VAS) for prevention of the sequelae of Vitamin A deficiency (VAD) such as night blindness, Bitots spots, and xerophthalmia in children 6-11 months of age in geographic areas where VAD is prevalent, was demonstrated by literature evidence. There was insufficient evidence of efficacy for overall mortality prevention, as the evidence was conflicting and deemed inconclusive. However, the evidence to support the use of high dose VAS for prevention of the sequelae of VAD in geographic areas where VAD is prevalent was found sufficient based on the submitted published literature, and therefore the proposed indication was revised to reflect this claim.

The systematic review/meta-analysis of VAS reported four trials with a 53% reduction in Bitots spots prevalence (RR = 0.45 (95% CI 0.33-0.61), while one trial reported no effect on Bitots spots incidence (RR = 0.93, 95% CI 0.76-1.14). One trial reported a 47% reduction in night blindness incidence (RR = 0.53, 95% CI 0.28-0.99). Two trials reported a 68% reduction in night blindness prevalence (RR = 0.32, 95% CI 0.21-0.50). Three trials reported no combined effect on xerophthalmia incidence while two trials reported a 69% reduction in xerophthalmia prevalence (RR = 0.31, 95% CI 0.22-0.45). Results of the Deworming and Enhanced Vitamin A Supplementation Project (DEVTA), demonstrated that allocation to VAS halved the prevalence of severe VAD (that is, retinol <0.35 μmol/L(tag = micromoles per litre)) 1-5 months after treatment from 6% to 13%. The prevalence of Bitots spots was also halved in the supplemented group compared to not supplemented group from 1.4% to 3.5%.

There are a few uncertainties of safety and efficacy associated with the use of high dose VAS. There is potential antagonism between vitamin A and vitamin D which was demonstrated in animal studies. High-dose vitamin supplementation may intensify the severity of bone demineralization. There is also potential for vitamin A to aggravate zinc deficiency which might already be present in children concomitantly with VAD. Interactions between VAS and vaccination have been extensively reported in literature; the live measles vaccine and the inactivated diphtheria-tetanus-pertussis (DTP) vaccine should never be administered concomitantly with high dose VAS due to the potential to cause negative adverse events.

The vitamin A absorption can be impaired in the presence of common gastrointestinal and respiratory infections. Recent fever and malaria may also adversely affect absorption and retention of vitamin A. Furthermore, absorption can be incomplete in patients with fat malabsorption, low protein intake, hepatic or pancreatic disease. Vitamin E is included in the formulation given reports that it may increase absorption of Vitamin A; however, the exact role of Vitamin E in the formulation has not been characterized. These uncertainties are outlined in the Product Monograph.

Overall, the benefit of high dose VAS for prevention of the sequelae of vitamin A deficiency such as night blindness, Bitots spots, and xerophthalmia in geographic areas where VAD is prevalent outweighs the risks under the conditions of use recommended in the Product Monograph.