Get your patient on Accrufer (Ferric Maltol)

Adults and Children Aged 10 Years and Above ​

The recommended dosage of ACCRUFER is 30 mg orally twice daily, on an empty stomach 1 hour before or 2 hours after meals.

Swallow capsules whole. Do not open, break, or chew capsules.

Treatment duration will depend on the severity of iron deficiency but generally at least 12 weeks of treatment is required. The treatment should be continued as long as necessary until ferritin levels are within the normal range.

Risk Summary

ACCRUFER is not absorbed systemically as an intact complex following oral administration, and maternal use is not expected to result in fetal exposure to the drug [see Clinical Pharmacology (12.3 )] .

In animal reproduction studies, oral administration of ferric or ferrous compounds to gravid CD1-mice and Wistar-rats during organogenesis at doses 13 to 32 times the recommended human dose resulted in no adverse developmental outcomes. An overdose of iron in pregnant women may carry a risk for spontaneous abortion, gestational diabetes and fetal malformation (see Data) .

In animal reproduction studies, oral administration of maltol to pregnant Crl: COBS-CD (SD) BR rats during organogenesis at doses 6 times the recommended human dose resulted in no adverse developmental outcomes (see Data) .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, 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.

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.

The safety and effectiveness of ACCRUFER for the treatment of iron deficiency have been established in pediatric patients 10 years and older. Use of ACCRUFER for this indication is supported by evidence from adequate and well-controlled studies of ACCRUFER in adults with additional data from an adequate and well-controlled study conducted in pediatric patients aged 10 years and older [ see Clinical Studies (14.3 )].

Safety and effectiveness of ACCRUFER have not been established in pediatric patients under 10 years.

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.

Avoid use of ACCRUFER in patients with an active inflammatory bowel disease (IBD) flare, as there is potential risk of increased inflammation in the gastrointestinal tract.

Excessive therapy with iron products can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. Do not administer ACCRUFER to patients with evidence of iron overload or patients receiving intravenous iron [see Contraindications (4 )] . Assess iron parameters prior to initiating ACCRUFER and monitor iron parameters while on therapy [see Overdosage (10 ) and Clinical Pharmacology (12.2 )] .

Accidental overdose of iron-containing 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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to ACCRUFER in 175 adult patients in the placebo-controlled phase of three randomized studies 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.

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).

Pediatric Patients with Iron Deficiency Anemia

The safety profile of ACCRUFER in pediatric patients was assessed in 24 patients aged 10 to <18 years of age enrolled to the FORTIS trial and treated with ACCRUFER.

Overall, the safety profile reported in pediatric patients was consistent with the safety profile reported in adult patients with iron deficiency anemia.

Oral Medications

There are no empirical data on avoiding drug interactions between ACCRUFER and concomitant oral medications. Concomitant use of some drugs may reduce the bioavailability of iron after administration of ACCRUFER. Separate the administration of ACCRUFER from these drugs. The duration of separation may depend on the absorption characteristics of the medication concomitantly administered, such as time to peak concentration or whether the drug is an immediate or extended release product. Monitor clinical response to ACCRUFER.

Dimercaprol

Concomitant use of iron products with dimercaprol may increase the risk of nephrotoxicity. Avoid concomitant use of ACCRUFER with dimercaprol.

Oral Medications

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.

ACCRUFER delivers iron for uptake across the intestinal wall and transfer to transferrin and ferritin.

ACCRUFER has been shown to increase serum iron parameters, including ferritin and transferrin saturation (TSAT) in adults and pediatric patients 10 years and older.

Adults

The pharmacokinetic properties of serum iron after administration of ACCRUFER was assessed in subjects with iron deficiency (with or without anemia) following a single dose and at steady state (after 1 week) of ACCRUFER 30 mg, 60 mg, or 90 mg twice daily (1 to 3 times the approved recommended dosage). Total serum iron concentrations increase in a less than dose proportional manner with increasing ACCRUFER doses. Total serum iron peak values were reached 1.5 to 3 hours after administration of ACCRUFER, and were comparable between Day 1 and Day 8.

Pediatric Population

In a pharmacokinetic substudy of the FORTIS trial [see Clinical Studies (14.3 )] in pediatric patients with iron-deficiency anemia, ferric maltol 15 mg or 30 mg was administered orally twice daily, for 7-10 days in children aged 10 to <18 years. After a single dose of 30 mg on Day 1, baseline-corrected serum iron reached peak concentration (C _max = 119 µg/dL) at 2 hours, with a AUC _0-t of 374 h·µg/dL in children aged 12 to <18 years. After a single dose of 15 mg on Day 1, baseline-corrected serum iron reached peak concentration (C _max = 40 µg/dL) at 2.1 hours, with a AUC _0-t of 60.1 h·µg/dL in children aged 10 to 11 years. No accumulation of maltol glucuronide was observed.

Absorption

ACCRUFER dissociates upon uptake from the gastrointestinal tract allowing iron and maltol to be absorbed separately.

Effect of Food

Food has been shown to decrease the bioavailability of iron after administration of ferric maltol capsules.

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.

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 ).

Ferric Maltol

ACCRUFER is not absorbed systemically as an intact complex.

Carcinogenicity studies have not been conducted with ferric maltol.

Ferric maltol was mutagenic in vitro in reverse bacterial mutation (Ames) assays. Ferric maltol increased revertant frequency in the absence and presence of metabolic activation.

Fertility studies have not been conducted with ferric maltol.

Maltol

The carcinogenic potential of maltol has been evaluated in long-term animal toxicity studies in two species: CD-1 mice and Sprague-Dawley rats. Maltol was not carcinogenic in a 18-month study in mice at doses up to 400 mg/kg (approximately 5.6 times the human daily dose). Maltol was not carcinogenic in a 2-year study in rats at doses up to 400 mg/kg (approximately 11.2 times the human daily dose).

Maltol was mutagenic in vitro in reverse bacterial mutation (Ames) assays. Maltol increased revertant frequency in the absence and 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 11.2 times the human daily dose).

The safety and efficacy of ACCRUFER for the treatment of iron deficiency anemia was studied in two randomized, placebo-controlled trials: AEGIS 1 (NCT01252221 ) and AEGIS 2 (NCT01340872 ). These trials enrolled 128 patients (age range 18-76 years; 45 males and 83 females) with quiescent IBD (58 patients with Ulcerative Colitis [UC] and 70 patients with Crohns disease [CD]) and baseline Hb concentrations between 9.5 g/dL and 12 /13 g/dL for females / males and ferritin < 30 mcg/L. All patients had discontinued prior oral ferrous product treatment due to lack of efficacy or inability to tolerate oral iron replacement products. Subjects were randomized 1:1 to receive either 30 mg ACCRUFER twice daily or a matched placebo control for 12 weeks.) and AEGIS 2 (NCT01340872 ). These trials enrolled 128 patients (age range 18-76 years; 45 males and 83 females) with quiescent IBD (58 patients with Ulcerative Colitis [UC] and 70 patients with Crohns disease [CD]) and baseline Hb concentrations between 9.5 g/dL and 12 /13 g/dL for females / males and ferritin < 30 mcg/L. All patients had discontinued prior oral ferrous product treatment due to lack of efficacy or inability to tolerate oral iron replacement products. Subjects were randomized 1:1 to receive either 30 mg ACCRUFER twice daily or a matched placebo control for 12 weeks.

The major efficacy outcome was the mean difference in Hb concentration from baseline to week 12 between ACCRUFER and placebo. The Least Square [LS] mean difference from baseline was 2.18 g/dL (p<0.0001)(see Table 2).

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.

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).

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.

The efficacy of ACCRUFER for the treatment of iron deficiency was evaluated in 24 patients aged 10 to <18 (age range 10-17 years; 4 males and 20 females; 13 White, 8 Black or African American, 2 Asian, 1 Other; 10 Hispanic or Latino, 14 Not Hispanic or Latino) with iron deficiency anemia who received aged-based dosing of ACCRUFER twice daily in the FORTIS study. Patients aged 10-11 years received 15 mg twice daily while patients 12 to <18 years received 30 mg twice daily.

Efficacy was assessed based on mean change from baseline to week 12 in Hb (g/dL) (descriptive statistics). A clinically significant increase in Hb was observed in children 10 years and above receiving ACCRUFER orally twice daily for 12 weeks (see Table 4). The results are presented for the pooled population who received either 15 mg twice daily or 30 mg orally twice daily (based on age). The 15 mg twice daily dose is not approved and not recommended for use. The recommended dosage of ACCRUFER in pediatric patients aged 10 years and over is 30 mg orally twice daily.

^a Subset of patients in the 10 to <18 subgroup
^b Modified-Intent to Treat (mITT) population: all subjects who received at least 1 dose of study drug

The mean change in Hb at week 12 in the subgroup (N=21) who received the recommended dose of ACCRUFER 30 mg orally twice daily was 1.23 g/dL [SD 1.00].

The mean ferritin levels in ACCRUFER subjects aged 10 to <18 years (N=24) at baseline were 11.4 mcg/L [SD 10.06] and the mean ferritin levels at Week 12 were 20 mcg/L [SD 13.51] with a mean overall improvement of 8.6 mcg/L [SD 10.29].

ACCRUFER (ferric maltol) 30 mg iron capsules are supplied as 60 red capsules, printed with “30”, in HDPE bottles with a child-proof polypropylene push-lock.

1 Bottle of 60-count 30 mg ferric iron capsules (NDC 73059-001-60).

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP controlled room temperature].