concomitant use of accrufer may decrease the bioavailability of some drugs, including mycophenolate, ethinyl estradiol, ciprofloxacin and doxycycline [see clinical pharmacology ( 12.3 )] . for oral drugs where reductions in bioavailability may cause clinically significant effects on its safety or efficacy, separate the administration of accrufer by at least 4 hours. monitor clinical responses to concomitant drugs as appropriate.

taining products is a leading cause of fatal poisoning in children under 6. keep this product out of reach of children. in case of accidental overdose, call a doctor or poison control center immediately.

tudies conducted in patients with anemia and quiescent inflammatory bowel disease (ibd) (studies aegis 1 & 2) or non-dialysis dependent chronic kidney disease (ckd) (aegis 3). the pooled patient population had a mean age of 58 years, 67.4% were female (n=118), and 81.7% (n=143) were caucasian. table 1 presents all adverse reactions occurring in the placebo-controlled period of the pooled randomized studies [see clinical studies ( 14 )] occurring at a rate of > 1% in the treated group, and for which the rate for accrufer exceeds the rate for placebo. table 1. adverse reactions reported by ≥1% of patients treated with accrufer during placebo-controlled period of pooled studies (studies aegis1/2 and aegis 3) accrufer 30 mg bid (n = 175) placebo (n = 120) body system adverse reaction gastrointestinal flatulence 4.6% 0.0% diarrhea 4.0% 1.7% constipation 4.0% 0.8% feces discolored 4.0% 0.8% abdominal pain 2.9% 2.5% nausea 1.7% 0.8% vomiting 1.7% 0.0% abdominal discomfort 1.1% 0.0% abdominal distension 1.1% 0.0% the proportion of patients who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of studies was 4.6% for patients taking accrufer. the most common adverse reaction leading to discontinuation of accrufer in these studies was abdominal pain (1.7% of patients).

concomitant use of accrufer may decrease the bioavailability of some drugs, including mycophenolate, ethinyl estradiol, ciprofloxacin and doxycycline [see clinical pharmacology ( 12.3 )] . for oral drugs where reductions in bioavailability may cause clinically significant effects on its safety or efficacy, separate the administration of accrufer by at least 4 hours. monitor clinical responses to concomitant drugs as appropriate.

loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk untreated iron deficiency anemia (ida) in pregnancy is associated with adverse maternal outcomes such as post-partum anemia. adverse pregnancy outcomes associated with ida include increased risk for preterm delivery and low birth weight. data animal data in embryofetal development studies in mice and rats, pregnant animals received oral doses of ferric or ferrous compounds (ferrous sulfate or ferric sodium pyrophosphate) of up to 160 mg/kg/day in mice, or up to 200 mg/kg/day in rats, during the period of organogenesis. administration of ferric or ferrous compounds at doses 13 times (in mice) or 32 times (in rats) the recommended human dose resulted in no maternal toxicity and no adverse developmental outcomes. in a multigeneration reproductive and developmental study in rats, pregnant animals received oral doses of maltol of 100, 200, and 400 mg/kg/day, during the period of organogenesis. administration of maltol at doses 6 times the recommended human dose resulted in no maternal toxicity and no adverse developmental outcomes. 8.2 lactation risk summary there are no data on the presence of accrufer in human milk, the effects on the breastfed child, or the effects on milk production. accrufer is not absorbed systemically as an intact complex by the mother following oral administration, and breastfeeding is not expected to result in exposure of the child to accrufer. 8.4 pediatric use safety and effectiveness of accrufer have not been established in pediatric patients. 8.5 geriatric use of the 295 patients in the randomized trials of accrufer, 39% of patients were aged 65 and older, while 23% were aged 75 and older. no overall differences in safety or effectiveness were observed between these patients and younger patients.

food food has been shown to decrease the bioavailability of iron after administration of ferric maltol. drug interaction studies in vitro of the drugs screened for an interaction with ferric maltol in vitro at ph 1.2, 4.5 and 6.8, only mycophenolate and ethinyl estradiol showed any potential for interaction. mycophenolate recovery was reduced by up to 16% at ph 1.2 but there was no interaction at ph 4.5; due to solubility issues data are not available for ph 6.8. ethinyl estradiol recovery was reduced by up to 35% at ph 4.5; due to solubility issues data are not available for ph 1.2 and ph 6.8. these potential oral interactions can be avoided by spacing the administration of those drugs and accrufer [ see drug interactions ( 7.2 )] . lisinopril, metoprolol and warfarin showed no interaction at any of the 3 ph conditions and can be taken with accrufer. no interaction with ferric maltol was observed for atorvastatin (ph 6.8), and norgestimate (ph 1.2) (data were not obtainable at the other ph conditions due to solubility issues). in vivo no clinical studies evaluating the drug interaction potential of accrufer have been conducted. iron-containing preparations may decrease ciprofloxacin absorption into the bloodstream, resulting in lower serum and urine levels and reduced effectiveness. absorption of tetracyclines including doxycycline is reported to be impaired by iron-containing preparations. 12.6 maltol phamacokinetics maltol is metabolized through glucuronidation (ugt1a6) and sulphation in vitro . of the total maltol ingested, a mean of between 39.8% and 60% was excreted in the urine as maltol glucuronide. there was no clinically meaningful change in exposure of maltol or maltol glucuronide in subjects with non-dialysis dependent chronic kidney disease (egfr of > 15 ml/min/1.73m 2 and <60 ml/min/1.73m 2 ).

d presence of metabolic activation. maltol was clastogenic in vivo in a mouse micronucleus assay (increase in polychromatic erythrocytes) at intraperitoneal doses of 774 mg/kg. absorbed maltol is rapidly conjugated with glucuronic acid. it is therefore unlikely that the mutagenic activity of maltol would be expressed under the conditions of oral human intake. in a multi-generation animal reproduction study in male and female rats, there were no effects on mating, fertility, or early embryonic development at doses up to 400 mg/kg/day (approximately 10 times the human daily dose).

s 2.18 g/dl (p<0.0001)(see table 2). table 2. summary of hemoglobin concentration (g/dl) and change from baseline to week 12 aegis 1 & 2 - analysis using multiple imputation - full analysis set population visit (week) statistic accrufer (n = 64) placebo (n =64) baseline mean (sd) 11.0 (1.03) 11.10 (0.85) mean change from baseline to week 12 ls mean (se) 2.25 (0.12) 0.06 (0.13) treatment comparison difference in change from baseline lsm difference (se) accrufer placebo) 1-sided lower 97.5%ci p-value accrufer versus placebo 2.18 (0.19) (1.81) <0.0001 note: multiple imputation was based on treatment, gender, disease [uc or cd], and hb concentration at baseline, week 4, and 8. for each imputed dataset, the change from baseline to week 12 was analyzed using an ancova model with treatment as the factor and gender, disease, baseline hb concentration as covariates. the ls mean difference in change from baseline hb to week 4 and 8 between accrufer and placebo were 1.04 g/dl and 1.73 g/dl, respectively. the mean ferritin (mcg/l) levels in accrufer subjects at baseline were 8.6 mcg/l [sd 6.77]) and the mean ferritin (mcg/l) levels at week 12 were 26.0 mcg/l [sd 30.57] with a mean overall improvement of 17.3 mcg/l. following completion of the 12-week placebo-controlled phase of the studies, eligible patients transitioned to accrufer 30 mg twice daily open-label treatment for an additional 52 weeks. during the open-label phase with accrufer, the mean change in hb concentration from baseline to week 64 was 3.1 g/dl [sd 1.46 g/dl, n = 35] and the ferritin value demonstrated a mean of 68.9 mcg/l [sd 96.24] at 64 weeks, with a mean overall improvement of 60.4 mcg/l. 14.2 patients with chronic kidney disease (ckd) the safety and efficacy of accrufer for the treatment of iron deficiency anemia was studied in aegis 3 (nct02968368), a trial that enrolled 167 patients (mean age 67.4 years, range 30-90 years; 50 males and 117 females) with non-dialysis dependent chronic kidney disease (ckd) and baseline hemoglobin (hb) concentrations between 8g/dl and 11 g/dl and ferritin < 250 mcg/l with a transferrin saturation (tsat) <25% or ferritin < 500 mcg/l with a tsat <15%. accrufer was administered at a dose of 30 mg twice daily. subjects were randomized 2:1 to receive either 30 mg accrufer twice daily or a matched placebo control for 16 weeks. the major efficacy outcome was the mean difference in hb concentration from baseline to week 16 between accrufer and placebo. the ls mean difference was 0.52 g/dl (p= 0.0149) (see table 3). table 3. summary of hemoglobin concentration (g/dl) and change from baseline to week 16 analysis using multiple imputation intent-to-treat population visit (week) statistic accrufer (n = 111) placebo (n = 56) baseline mean (sd) 10.06 (0.77) 10.03 (0.82) mean change from baseline to week 16 ls mean (se) 0.50 (0.12) -0.02 (0.16) treatment comparison difference in change from baseline lsm difference (se) accrufer – placebo 95% ci p-value accrufer versus placebo 0.52 (0.21) (0.10, 0.93) 0.0149 note: multiple imputation was based on treatment, gender, egfr at baseline, and hb concentration at baseline, week 4 and 8. for each imputed dataset, the change from baseline to week 16 was analyzed using an ancova model with treatment as the factor and baseline hb concentration, baseline egfr as covariates. the ls mean difference in change from baseline hb to week 4 and 8 between accrufer and placebo were 0.13 g/dl and 0.46 g/dl, respectively. the mean change in ferritin concentration from baseline to week 16 was 49.3 mcg/l for the accrufer group and 6.3 mcg/l for the placebo group. the mean difference for accrufer versus placebo was 43.0 mcg/l.

r dose of iron products is a leading cause of fatal poisonings in children. in case of accidental overdose, advise them to call a doctor or poison control center immediately [see warnings and precautions ( 5.2 )]. distributed by shield therapeutics inc, 9020 capital of texas highway north, austin, tx, 78759

best way to feed your baby during treatment with accrufer. tell your healthcare provider about all the medicines you take , including prescription and over-the-counter medicines, vitamins, and herbal supplements. taking accrufer with certain other medicines may affect each other causing serious side effects. some medicines may need to be taken at least 4 hours before or 4 hours after you have taken your accrufer dose. ask your healthcare provider for a list of these medicines if you are not sure if you take one of these medicines. especially tell your healthcare provider if you take: dimercaprol other oral iron tablets or health supplements containing iron ask your healthcare provider if you are not sure if you take one of these medicines. know the medicines you take. keep a list of them to show to your healthcare provider and pharmacist when you get a new medicine. how should i take accrufer? take accrufer exactly as your healthcare provider tells you to. take accrufer 2 times a day on an empty stomach 1 hour before or 2 hours after meals. swallow accrufer capsules whole. do not open, break, or chew accrufer capsules. in case of accidental overdose, call your healthcare provider or go to the nearest hospital emergency room right away. what are the possible side effects of accrufer? accrufer may cause serious side effects, including: increased risk of inflammatory bowel disease (ibd) flare. you should avoid taking accrufer if you have inflammatory bowel disease (ibd) and are experiencing a flare. too much iron stored in your body (iron overload). your healthcare provider should check the iron level in your blood before you start and during treatment with accrufer. risk of overdose in children due to accidental swallowing. accidental overdose of iron-containing products is a leading cause of death from poisoning in children under 6. keep accrufer in a safe place and out of the reach of children. the most common side effects of accrufer include: gas diarrhea constipation discolored stools stomach pain nausea or vomiting stomach area discomfort or bloating these are not all the possible side effects of accrufer. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. how should i store accrufer? store accrufer at room temperature between 68°f to 77°f (20°c to 25°c). keep accrufer and all medicines out of reach of children. general information about the safe and effective use of accrufer. medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use accrufer for a condition for which it was not prescribed. do not give accrufer to other people, even if they have the same symptoms that you have. it may harm them. you can ask your healthcare provider or pharmacist for information about accrufer that is written for health professionals. what are the ingredients in accrufer? active ingredient: ferric maltol inactive ingredients: capsule: colloidal anhydrous silica, crospovidone (type a), lactose monohydrate, magnesium stearate, sodium lauryl sulfate capsule shell: fd&c blue no. 1 fd&c red no. 40, fd&c yellow 6, hypromellose, titanium dioxide. ink: ammonium hydroxide, ethanol, iron oxide black, propylene glycol distributed by shield therapeutics inc, 9020 capital of texas highway north, austin, tx, 78759 us patents 7459569, 9248148, 9802973, 10179120 this patient information has been approved by the u.s. food and drug adminstration. issued: february 2022