ACCRUFER

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Increased Risk of Inflammatory Bowel Disease Flare [see Warnings and Precautions ( 5.1 )] Iron Overload [see Warnings and Precautions ( 5.2 )] Most common adverse reactions (incidence > 1%) are flatulence, diarrhea, constipation, feces discolored, abdominal pain, nausea, vomiting and abdominal discomfort/distension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Shield Therapeutics Inc at 1-888-963-6267 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience 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 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. 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).

4 CONTRAINDICATIONS ACCRUFER is contraindicated in patients with a history of: Hypersensitivity to the active substance or to any of the excipients [see Description ( 11 )] . Reactions could include shock, clinically significant hypotension, loss of consciousness, and/or collapse. Hemochromatosis and other iron overload syndromes [see Warnings and Precautions ( 5.1 )] . Use may result in iron overdose [see Overdosage ( 10 )]. Receiving repeated blood transfusions. Use may result in iron overload [see Warnings and Precautions ( 5.2 ) and Overdosage ( 10 )]. Hypersensitivity to the active substance or any excipient ( 4 ) Hemochromatosis and other iron overload syndromes ( 4 ) Patients receiving repeated blood transfusions ( 4 )

11 DESCRIPTION ACCRUFER (ferric maltol) capsules, an iron replacement product for oral administration, contain 30 mg iron and 201.5 mg maltol. Ferric maltol contains iron in a stable ferric state as a complex with a trimaltol ligand. Ferric maltol is 3-hydroxy-2-methyl-4H-pyrane-4-one iron (III) complex (3:1) and has the molecular formula (C 6 H 5 O 3 ) 3 Fe and a molecular mass of 431.2. Each red capsule, printed with “30”, contains colloidal anhydrous silica, crospovidone (Type A), lactose monohydrate, magnesium stearate and sodium lauryl sulfate as inactive ingredients. In addition, the capsule shell contains FD&C Blue No. 1, FD&C Red No. 40, FD&C Yellow No.6, hypromellose and titanium dioxide. The ink used for printing the marking contains ammonium hydroxide, ethanol, iron oxide black and propylene glycol. Image 1

2 DOSAGE AND ADMINISTRATION 30 mg twice daily on an empty stomach ( 2.1 ) Continue as long as necessary to replenish body iron stores ( 2.1 ) 2.1 Recommended Dosage The recommended dosage of ACCRUFER is 30 mg twice daily, taken 1 hour before or 2 hours after a meal. Do not open, break, or chew ACCRUFER 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.

1 INDICATIONS AND USAGE ACCRUFER is indicated for the treatment of iron deficiency in adults. ACCRUFER is an iron replacement product indicated for the treatment of iron deficiency in adults. ( 1 )

10 OVERDOSAGE No data are available regarding overdose of ACCRUFER in patients. Acute iron ingestion of 20 mg/kg elemental iron is potentially toxic and 200- 250 mg/kg is potentially fatal. Early signs and symptoms of iron overdose may include nausea, vomiting, abdominal pain and diarrhea. In more serious cases there may be evidence of hypoperfusion, metabolic acidosis and systemic toxicity. Dosages of ACCRUFER in excess of iron needs may lead to accumulation of iron in storage sites leading to hemosiderosis. Periodic monitoring of iron parameters such as serum ferritin and transferrin saturation may assist in recognizing iron accumulation. Do not administer ACCRUFER to patients with iron overload [ see Contraindications ( 4 ) ] .

7 DRUG INTERACTIONS Dimercaprol : Avoid concomitant use. ( 7.2 ) Oral Medications : Separate administration of ACCRUFER from certain oral medications. Monitor clinical responses as appropriate. ( 7.1 , 7.2 ) 7.1 Effect of Other Drugs on ACCRUFER 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. 7.2 Effect of ACCRUFER on Other Drugs 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action ACCRUFER delivers iron for uptake across the intestinal wall and transfer to transferrin and ferritin. 12.2 Pharmacodynamics ACCRUFER has been shown to increase serum iron parameters, including ferritin and transferrin saturation (TSAT). 12.3 Pharmacokinetics 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. Absorption ACCRUFER dissociates upon uptake from the gastrointestinal tract allowing iron and maltol to be absorbed separately. 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. Effect of 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 ).

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3 DOSAGE FORMS AND STRENGTHS Capsules: ACCRUFER contains 30 mg iron, as ferric maltol, in red capsules printed with “30”. Capsules: 30 mg ( 3 )

ACCRUFER Ferric Maltol LACTOSE MONOHYDRATE SODIUM LAURYL SULFATE MAGNESIUM STEARATE SILICON DIOXIDE CROSPOVIDONE HYPROMELLOSES FD&C BLUE NO. 1 TITANIUM DIOXIDE FD&C RED NO. 40 FD&C YELLOW NO. 6 FERRIC MALTOL FERRIC CATION 30

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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 times the human daily dose). Maltol was not carcinogenic in a 2-year study in rats at doses up to 400 mg/kg (approximately 10 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 10 times the human daily dose).

NDA212320

ACCRUFER

Ferric Maltol

73059-001

HUMAN PRESCRIPTION DRUG

ORAL

PRINCIPAL DISPLAY PANEL - 60 Capsules Carton Label - ACCRUFER ® (ferric maltol) capsules 30 mg (60 Capsules) NDC 73059-001-60 ACCRUFeR ® (ferric maltol*) capsules 30 mg For oral administration only 60 capsules Distributed by Shield Therapeutics Inc SHIELD THERAPEUTICS Rx only Bottle Label - ACCRUFER ® (ferric maltol) capsules 30 mg NDC 73059-001-60 ACCRUFeR ® (ferric maltol*) capsules 30 mg For oral administration only 60 capsules SHIELD THERAPEUTICS Rx only *Each capsule contains 30 mg iron (as ferric maltol) WARNING: 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. 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). Usual Dosage: 1 capsule twice daily on an empty stomach. See prescribing information. Distributed by Shield Therapeutics Inc. Carton Label Bottle Label

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Dosing Recommendations Inform patients to take ACCRUFER as directed on an empty stomach, at least 1 hour before or 2 hours after meals. Instruct patients on concomitant medications that should be dosed apart from ACCRUFER [see Dosage and Administration ( 2.1 ) and Drug Interactions ( 7.2 )] . Adverse Reactions Advise patients that ACCRUFER may cause, flatulence, diarrhea, constipation, discolored feces, abdominal pain, nausea, vomiting or abdominal bloating or discomfort. Advise patients to report severe or persistent gastrointestinal symptoms or any allergic reactions to their physician [see Adverse Reactions ( 6.1 )]. Increased Risk of IBD Flare Advise patients that they should not use ACCRUFER if they are experiencing an IBD flare. Iron Overload and Risk of Accidental Overdose in Children Inform patients to keep this product out of reach of children as accidental over 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

14 CLINICAL STUDIES 14.1 Patients with Inflammatory Bowel Disease (IBD) 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. 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). 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.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 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. 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. 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. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied ACCRUFER (ferric maltol) 30 mg iron capsules are supplied as 60 capsules in HDPE bottles with a child-proof polypropylene push-lock. 1 Bottle of 60-count 30 mg ferric iron capsules (NDC 73059-001-60). 16.2 Storage and Handling 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].