An Efficacy, Safety and Tolerability Study of Ferrous Ascorbate and Folic Acid (Phosfomin-XT) in Iron Deficiency Anemia BB Adsul*, Qayum Mukaddam**, Prashant Khandeparkar**, Manoj Naik** Abstract Aim: This study was aimed to assess efficacy, safety and tolerability of combination of ferrous ascorbate and folic acid (Phosfomin-XT) in patients with iron deficiency anemia (IDA). Settings and design: A total of 56 patients, who were between 18-55 years of age, with hemoglobin (Hb) 6-9 g/dl and serum ferritin <15 mg/l also complying with the inclusion and exclusion criteria in the protocol were enrolled in the study after obtaining necessary approvals and informed consent. All were dispensed with Phosfomin-XT fixed-dose combination (FDC) of ferrous ascorbate (equivalent to elemental iron 100 mg) + folic acid 1.5 mg tablet once-daily after food for eight weeks. Patients were assessed at baseline and Weeks 2, 4, 6 and 8 for change in Hb level, clinical evaluation and target Hb achievement. Results: Baseline mean Hb was 08.39 ± 0.75 g/dl, which significantly increased to 9.76 ± 0.70 g/dl (16.3%) at Week 2 and further increased to 10.70 ± 0.70 g/dl (27.53%) at Week 4. At Week 6, it increased to 11.55 ± 0.67 g/dl (37.7%) and at Week 8, it increased to 12.53 ± 1.09 g/dl. Conclusions: The present study concludes that Phosfomin-XT (ferrous ascorbate, equivalent to elemental iron 100 mg + folic acid 1.5 mg) tablet should be preferred as first choice of oral iron salts to treat IDA due to positive effect on Hb value and superior tolerability. Keywords: Iron deficiency anemia, ferrous ascorbate, folic acid Iron deficiency is the most common single cause of anemia worldwide, accounting for about half of all anemia cases. Estimates of iron deficiency worldwide range very widely, but the number almost certainly exceeds one billion globally. 1 The principal cause of iron deficiency anemia (IDA) in developing countries is blood lost during menstruation in premenopausal women and not compensated by intake from food and supplements. India continues to be one of the countries with very high prevalence. The National Family Health Survey (NFHS-3) reveals the prevalence of anemia to be 70-80% in children, 70% in pregnant women and 24% in adult men. Prevalence of anemia in India is high because of low dietary intake, poor availability of iron and chronic blood loss due to hookworm infestation and malaria. 2-4 IDA is one result of an advanced stage iron deficiency, which is even more *Associate Professor Dept. of Community Medicine, LTMMC and LTMG Hospital, Sion, Mumbai **Medical Services Division, Abbott Healthcare Pvt. Ltd., Mumbai Address for correspondence Dr BB Adsul Associate Professor Dept. of Community Medicine, LTMMC and LTMG Hospital Sion, Mumbai - 400 022 common. Iron deficiency ranges from iron depletion, which yields little physiological damage, to IDA, which can affect the function of numerous organ systems. Iron depletion causes the amount of stored iron to be reduced, but has no effect on the functional iron. However, a person with no stored iron has no reserves to use if the body enters a state in which it requires more iron than is being absorbed from the diet. Folic acid, after absorption from the gastrointestinal tract, is converted to tetrahydrofolic acid by the liver, which is a cofactor in the biosynthesis of purines and thymidylates of nucleic acids. An exogenous source of folic acid is necessary for the maintenance of normal erythropoiesis. A study suggests that there is 2-fold relation in IDA and folic acid deficiency, where it is likely that in both IDA and megaloblastic anemia, iron deficiency plays an important part in converting subclinical folic acid deficiency by producing additional stress of folate metabolism. 3 Aim To establish the efficacy, safety and tolerability of the combination of ferrous ascorbate and folic acid in treatment of IDA. Indian Journal of Clinical Practice, Vol. 22, No. 11, April 2012 565
Methods Design This was an open prospective noncomparative post marketing clinical trial conducted at the OPD of LTMMC and LTMG Hospital, Sion, Mumbai. The study was conducted in keeping with the principles described in the Declaration of Helsinki and Indian Good Clinical Practices (GCP) guidelines. The clinical trial protocol was approved by the Institutional Ethics Committee. Inclusion Criteria A total of 56 patients of both genders, who were between 18-55 years of age, visiting the OPD were enrolled in the study after obtaining written informed consent from each. The inclusion criteria were: Patient not on any iron supplement for three months prior to enrolment to the study and presence of IDA: Low hemoglobin (Hb 6-9 g/dl) + low serum ferritin (<15 µg/l) showing no occult blood in stool. Exclusion Criteria Patients who were pregnant (confirmed with dipstick method), planning to conceive within next three months including patients who were receiving treatment to facilitate conception, lactating women, were excluded from the study. Also, patients suspected of hypersensitivity to iron or any of the components or ferrous ascorbate were also excluded from the study. Procedures All the patients enrolled in the study were dispensed with fixed-dose combination (FDC) of ferrous ascorbate (equivalent to elemental iron 100 mg) + folic acid 1.5 mg (Phosfomin-XT) once-daily after food for eight weeks. Patients were assessed at baseline and Weeks 2, 4, 6 and 8 (end of the study) for change in mean Hb level from baseline to each visit. Evaluation of clinical signs and symptoms of anemia were also assessed at each visit. Percentage of patients achieving target Hb level of 12 g/dl were assessed at the end of the study. Global assessment of efficacy by patient and investigator was assessed at the end of the study on a 4-point rating scale. Safety was assessed by percentage incidence of gastrointestinal side effects during eight weeks of treatment with study drug and other adverse events of treatment. Global assessment of tolerability was also assessed at end of the study. Results Fifty patients were included for final efficacy analysis, six patients were lost to follow-up. Demographic data had mean age of 32.18 ± 10.4 (years), mean weight of 48.15 ± 8.44 (kg) and mean height of 152.28 ± 6.44 (cm) showing normality of the cases (Table 1). Baseline mean pulse rate was 84.64 ± 5.80, mean 98.33 ± 0.41, mean respiratory rate was 19.04 ± 7.68, mean systolic blood pressure was 117.5 ± 7.73 and mean diastolic blood pressure was 73.00 ± 6.42, which also indicates the normality. Baseline mean Hb was 08.39 ± 0.75 g/dl, which significantly increased to 9.76 ± 0.70 g/dl (16.3%) at Week 2 and further increased to 10.70 ± 0.70 g/dl (27.53%) at Week 4. At Week 6, it increased to 11.55 ± 0.67 g/dl(37.7%) and at Week 8, it increased to 12.53 ± 1.09 g/dl. At all visits the surge was significant (p < 0.05) (Fig. 1). Percentage of patients achieving target Hb level of 12 mg/dl was significant (p < 0.05) at Week 6 (44.00%) and at Week 8 (76.00%) (Fig. 2 and Table 2). Baseline percentage of patients having moderate-tosevere fatigue was 74.00%, which significantly reduced to 24.00% after two weeks and 2.00% after six weeks. None of the patients had fatigue at the end of the study Table 1. Demographic Data (n = 56) Criteria No. Patients enrolled 56 Patients dropout 06 Cases analyzed for efficacy 50 Parameter Mean SD Range Age (years) 32.18 10.04 19-53 Weight (kg) 48.15 8.44 32-77 Height (cm) 152.28 6.44 135-169 Mean hemoglobin level 20 18 16 14 12 10 8 6 4 2 0 Changes in mean hemoglobin level after the treatment 8.39 9.76 10.70 Baseline 2 4 6 8 Duration in weeks Figure 1. Mean hemoglobin changes. 11.55 12.53 566 Indian Journal of Clinical Practice, Vol. 22, No. 11, April 2012
Proportion of cases 100 90 80 70 60 50 40 30 20 10 0 Changes in proportion of cases with achieved targets of 12 hemoglobin level Baseline 2 4 6 8 Duration in weeks Figure 2. Percentage of patients achieving target hemoglobin. Table 2. Changes in Mean Hemoglobin Level after the Treatment Duration in weeks Mean Hb (g/dl) (X ± SD) Baseline 08.39 ± 0.75 Hb levels (g/dl) from baseline 2 *09.76 ± 0.70 1.36 4 *10.70 ± 0.70 2.31 6 *11.55 ± 0.67 3.16 8 *12.53 ± 1.09 4.14 By student t test, *p < 0.05 significant. 12 12 (p < 0.05). Moderate-to-severe pallor was observed in 88.00% patients at baseline, which reduced to 26% at Week 2 and 10.00% at Week 4. In none of the patients moderate-to-severe pallor was observed at Week 6 and Week 8 (p < 0.05). Breathlessness due to anemia was observed in 4.00% cases at baseline which significantly reduced to 2% at Week 2 and 0.00% at Weeks 4, 6 and 8 (p < 0.05) (Table 3). Global Assessment Global assessment for efficacy by patients and investigator towards the therapy showed that 98.00% patients observed good-to-excellent efficacy (Fig. 3). Global assessment for tolerability by investigator and patient showed that 99.00% patients tolerated the medication well (Fig. 4). Adverse Events Only four out of 56 patients had adverse events, which were mild in intensity and did not persist beyond two weeks. Adverse events included nausea (1 patient), constipation (2 patients), vomiting (1 patient) (Table 4). Discussion Iron deficiency anemia is the commonest occurring anemia in Indian population. Estimates suggest that over one-third of the world s population suffers from Table 3. Efficacy Parameters (Signs and Symptoms) Parameters Duration None Mild Moderate Severe No % No % No % No % Fatigue Baseline 11 022.0 02 04.0 26 52.0 11 22.0 2 weeks 12 024.0 26 52.0 *11 22.0 *01 02.0 4 weeks 32 064.0 15 30.0 *03 06.0 - - 6 weeks 46 092.0 03 06.0 *01 02.0 - - 8 weeks *50 100.0 - - - - - - Pallor Baseline - - 06 12.0 34 68.0 10 20.0 2 weeks 05 010.0 32 64.0 *12 24.0 *01 02.0 4 weeks 32 064.0 13 26.0 *05 10.0 - - 6 weeks *45 090.0 05 10.0 - - - - 8 weeks *50 100.0 - - - - - - Breathlessness Baseline 48 096.0 02 04.0 - - - - 2 weeks 49 098.0 01 02.0 - - - - 4 weeks 50 100.0 - - - - - - 6 weeks 50 100.0 - - - - - - 8 weeks 50 100.0 - - - - - - *By Chi-square test, p < 0.05 significant. Indian Journal of Clinical Practice, Vol. 22, No. 11, April 2012 567
48.0% 2.0% 2.0% 50.0% Excellent Good Fair Poor Figure 3. Overall global assessment of efficacy at the end of study by investigator. 30-60 mg is used as prophylaxis for IDA in pregnancy, and also for treatment of IDA in children. Folic acid being a very essential vitamin in process of erythropoiesis has significant role in keeping the cell morphology intact. It is observed that low serum folate levels are associated with the iron deficiency and thus are related to the vicious cycle of deficiencies of iron and folate. 5 Combination of ferrous ascorbate and folic acid covers both the aspects of IDA, where ferrous ascorbate covers fastest rise in iron levels and folic acid covers serum folate levels. There are no published studies on efficacy of FDC of ferrous ascorbate and folic acid in the treatment of IDA. In the present study, a significant improvement was seen in Hb levels, signs and symptoms of IDA like fatigue, pallor, breathlessness with FDC of ferrous ascorbate and folic acid. This FDC of ferrous ascorbate and folic acid also showed excellent gastrointestinal tolerability. Conclusion 44.0% 54.0% Excellent Good Fair Poor Figure 4. Overall global assessment of tolerability at the end of study by investigator. Table 4. Adverse Events Events No of cases Percentage (%) (n = 56) Nausea 01 01.8 Constipation 02 03.6 Vomiting 01 01.8 Total 04 06.0 anemia, mostly IDA. For nearly four decades, studies on iron preparations have been benchmarked against ferrous ascorbate. Properties of ferrous ascorbate are thus considered the gold standard in iron therapy. Ferrous ascorbate is a synthetic molecule of ascorbic acid and iron. Ascorbic acid enhances absorption of iron. Ascorbic acid reduces ferric iron to ferrous iron, which remains soluble even at neutral ph. Ferrous form is absorbed thrice as much as ferric form of iron, the discrepancy becomes even more, when treated with higher dosage of ferric salts. 4 Elemental iron 100 mg is used for the treatment of IDA in pregnancy and This study was an effort to assess the efficacy and tolerability of the FDC of ferrous ascorbate and folic acid and seems to show very promising outcomes although further studies on bigger sample size can be more conclusive. Phosfomin-XT (ferrous ascorbate, equivalent to elemental iron 100 mg + folic acid 1.5 mg) tablet should be preferred as first choice of oral iron salts to treat IDA due to its effect on improvement in Hb levels and excellent gastrointestinal tolerability. Acknowledgment This study was supported by Abbott Healthcare Pvt. Ltd. References 1. Brady PG. Iron deficiency anemia: a call for progressive diagnostic evaluation. South Med J 2007;100(10):966-7. 2. Government of India National Family Health Survey-3 (2005-2006). Vol. 11, Chapter-8, Maternal Health International Institute for Population Sciences 2007:p191-22. 3. Chanarin I, Rothman D, Berry V. Iron deficiency and its relation to folic-acid status in pregnancy: results of a clinical trial. Br Med J 1965;1(5433):480-5. 4. Johnson G, Jacobs P. Bioavailability and the mechanisms of intestinal absorption of iron from ferrous ascorbate and ferric polymaltose in experimental animals. Exp Hematol 2009;18(10):1064-9. 5. Morris MS, Jacques PF, Rosenberg IH, Selhub J. Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr 2007;85(1):193-200. 568 Indian Journal of Clinical Practice, Vol. 22, No. 11, April 2012
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