Ferric Carboxymaltose

WARNING: SYMPTOMATIC HYPOPHOSPHATEMIA • Ferric carboxymaltose injection can cause severe, prolonged hypophosphatemia associated with serious outcomes, including hospitalization, osteomalacia and fractures requiring clinical intervention [see Warnings and Precautions (5.1) ] . • Hypophosphatemia has occurred in patients with normal baseline phosphate levels and without apparent risk factors for hypophosphatemia [see Warnings and Precautions (5.1) ] . • Check serum phosphate levels prior to a repeat course of treatment in patients at risk for low serum phosphate and in any patient who receives a repeat course of therapy within three months [see Dosage and Administration (2.1 , 2.3) ] . Correct pre-existing hypophosphatemia prior to administering ferric carboxymaltose injection [see Warnings and Precautions (5.1) ] . • Advise patients receiving ferric carboxymaltose injection about the risk of hypophosphatemia and to report any signs and symptoms of hypophosphatemia (e.g., fatigue, muscle weakness or pain, bone and joint pain, bone fractures) [see Warnings and Precautions (5.1) ] . WARNING: SYMPTOMATIC HYPOPHOSPHATEMIA See full prescribing information for complete boxed warning. • Ferric carboxymaltose injection can cause severe, prolonged hypophosphatemia associated with serious outcomes, including hospitalization, osteomalacia and fractures requiring clinical intervention ( 5.1 ). • Hypophosphatemia has occurred in patients with normal baseline phosphate levels and without apparent risk factors for hypophosphatemia ( 5.1 ). • Check serum phosphate levels prior to a repeat course of treatment in patients at risk for low serum phosphate and in any patient who receives a repeat course of therapy within three months. Correct pre-existing hypophosphatemia prior to administering ferric carboxymaltose injection ( 2.1 , 2.3 , 5.1 ). • Advise patients receiving ferric carboxymaltose injection about the risk of hypophosphatemia and to report any signs and symptoms of hypophosphatemia (e.g., fatigue, muscle weakness or pain, bone and joint pain, bone fractures) ( 5.1 ).

5 WARNINGS AND PRECAUTIONS • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after ferric carboxymaltose administration for at least 30 minutes and until clinically stable following completion of each administration. ( 5.2 ) • Hypertension: Monitor patients closely for signs and symptoms of hypertension following each ferric carboxymaltose administration. ( 5.3 ) 5.1 Symptomatic Hypophosphatemia Symptomatic hypophosphatemia, including severe cases, with serious outcomes such as osteomalacia and fractures requiring clinical intervention have occurred in patients treated with ferric carboxymaltose in the post-marketing setting. These cases have occurred after single and multiple doses of ferric carboxymaltose. Risk factors for hypophosphatemia include a history of gastrointestinal disorders associated with malabsorption of fat-soluble vitamins or phosphate, inflammatory bowel disease, concurrent or prior use of medications that affect proximal renal tubular function, hyperparathyroidism, vitamin D deficiency, malnutrition, and hereditary hemorrhagic telangiectasia (HHT or Osler-Weber-Rendu syndrome). However, individuals without apparent risk factors have experienced symptomatic hypophosphatemia. In most cases, hypophosphatemia resolved within three months. Check serum phosphate levels prior to a repeat course of treatment if the patient is at risk for low serum phosphate or if the patient will receive a repeat course of therapy within three months of the prior course [see Dosage and Administration (2.1 , 2.3) ] . Correct pre-existing hypophosphatemia prior to administering ferric carboxymaltose. Monitor serum phosphate levels in patients at risk for chronic low serum phosphate. Treat hypophosphatemia as medically indicated. Consider permanent discontinuation of ferric carboxymaltose for severe symptomatic hypophosphatemia or persistent hypophosphatemia . 5.2 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving ferric carboxymaltose. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. Monitor patients for signs and symptoms of hypersensitivity during and after ferric carboxymaltose administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer ferric carboxymaltose when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions [see Adverse Reactions (6.1 , 6.2) ] . In clinical trials, serious anaphylactic/anaphylactoid reactions were reported in 0.1% (2/1,775) of subjects receiving ferric carboxymaltose. Other serious or severe adverse reactions potentially associated with hypersensitivity which included, but not limited to, pruritus, rash, urticaria, wheezing, or hypotension were reported in 1.5% (26/1,775) of these subjects. 5.3 Hypertension In clinical studies, hypertension was reported in 4% (67/1,775) of subjects in clinical trials 1 and 2. Transient elevations in systolic blood pressure, sometimes occurring with facial flushing, dizziness, or nausea were observed in 6% (106/1,775) of subjects in these two clinical trials. These elevations generally occurred immediately after dosing and resolved within 30 minutes. Monitor patients for signs and symptoms of hypertension following each ferric carboxymaltose administration [see Dosage and Administration (2) ] . 5.4 Laboratory Test Alterations In the 24 hours following administration of ferric carboxymaltose, laboratory assays may overestimate serum iron and transferrin bound iron by also measuring the iron in ferric carboxymaltose.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Symptomatic Hypophosphatemia [see Warnings and Precautions (5.1) ] • Hypersensitivity Reactions [see Warnings and Precautions (5.2) ] • Hypertension [see Warnings and Precautions (5.3) ] • Laboratory Test Alterations [see Warnings and Precautions (5.4) ] • The most common adverse reactions in adult patients (> 2%) are nausea, hypertension, flushing, injection site reactions, erythema, hypophosphatemia, and dizziness. ( 6.1 ) • The most common adverse reactions in pediatric patients (≥ 4%) are hypophosphatemia, injection site reactions, rash, headache, and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) 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, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. Adults In two randomized clinical studies [Studies 1 and 2, see Clinical Studies (14) ], a total of 1,775 patients were exposed to ferric carboxymaltose 15 mg/kg body weight up to a maximum single dose of 750 mg of iron on two occasions separated by at least 7 days up to a cumulative dose of 1,500 mg of iron. Adverse reactions reported by ≥ 1% of treated patients are shown in the following table. Table 2. Adverse reactions reported in ≥ 1% of Study Patients in Clinical Trials 1 and 2 Ferric Carboxymaltose (N = 1,775) % Pooled Comparators Includes oral iron and all formulations of IV iron other than ferric carboxymaltose. (N = 1,783) % Oral iron (N = 253) % Nausea 7.2 2 1.2 Hypertension Injection site discoloration was also included in the injection site local administration reactions grouped term. Headache includes headache and migraine. Hepatic enzyme increased includes alanine aminotransferase increased and aspartate aminotransferase increased. Dysgeusia includes dysgeusia and ageusia. Rash includes rash, urticaria, skin exfoliation, blister, erythema multiforme, injection site rash, rash maculo-papular, and rash pruritic. 4 2 0.4 Flushing Grouped Terms: Hypertension includes hypertension, blood pressure increased, and hypertensive crisis. Flushing includes flushing and hot flush. Injection site reactions include injection site extravasation, injection site discoloration, injection site pain, injection site irritation, injection site bruising, injection site reaction, injection site discomfort, injection site erythema, injection site hematoma, injection site hemorrhage, injection site pruritus, injection site rash, and injection site swelling. Erythema includes erythema and injection site erythema. Dizziness includes dizziness, balance disorder, and vertigo. 4 0.2 0 Injection site reactions 3 3.2 0 Erythema 3 0.6 0 Hypophosphatemia 2.1 0.1 0 Dizziness 2.1 1.3 0.4 Vomiting 2 1 0.4 Injection Site Discoloration 1.4 0.3 0 Headache 1.3 1.2 0.4 Hepatic enzyme increased 1.2 0.2 0 Dysgeusia 1.2 2.1 0 Hypotension 1 2 0 Rash 1 0.3 0 Constipation 0.5 0.9 3.2 Other adverse reactions reported by ≥ 0.5% of treated patients include abdominal pain, diarrhea, gamma glutamyl transferase increased, paresthesia, and sneezing. Transient decreases in laboratory blood phosphorus levels (< 2 mg/dL) have been observed in 27% (440/1,638) of patients in clinical trials. Pooled data from two Phase 3 studies 1VIT09030 (NCT00981045) and 1VIT09031 (NCT00982007) with a dosing regimen of ferric carboxymaltose 15 mg/kg up to a maximum of 750 mg x 2 doses to a cumulative dose of 1,500 mg of iron were analyzed to compare rates of adverse reactions in two Phase 3 parallel group studies 1VIT07017 (NCT00548860) and 1VIT07018 (NCT00548691) with a dosing regimen of ferric carboxymaltose 15 mg/kg up to a maximum of 1,000 mg single dose (Table 3). Table 3. Adverse Reactions (≥ 1% in any Treatment Group) In Patients Receiving Two Doses of 15 mg/kg to a Maximum of 750 mg to a Cumulative Dose of 1,500 mg or a Single Dose of Ferric Carboxymaltose 15 mg/kg to a Maximum of 1,000 mg Ferric Carboxymaltose 15 mg/kg to a maximum of 750 mg x 2 doses to a cumulative dose of 1,500 mg Ferric Carboxymaltose 15 mg/kg to a maximum of 1,000 mg single dose IVIT09030 and IVIT09031 Included studies 1VIT07017, 1VIT07018, 1VIT09030 and 1VIT09031 (N = 1,775) % IVIT07017 and IVIT07018 (N = 1,200) % Any Adverse Reaction 24 12 Injection site reactions Grouped Terms 3 4 Injection site extravasation Injection site extravasation and injection site discoloration were also included in the injection site reactions grouped term. 0.2 2 Hepatic enzyme increased 1.2 1.2 Rash 1 1.2 Headache 1.3 1 Dizziness 2.1 1 Dysgeusia 1.2 1 Nausea 7.2 1 Hypertension 4 1 Hypophosphatemia 2.1 1 Erythema 3 0.3 Flushing 4 0.3 Vomiting 2 0.2 Injection site discoloration 1.4 < 0.1 Hypotension 1 < 0.1 Pediatric Patients The safety of ferric carboxymaltose in pediatric patients was evaluated in study 1VIT17044 (NCT03523117; Study 3). Study 1VIT17044 was a randomized, active-controlled study in which 40 patients (1 to 12 years of age: 10 patients, 12 to 17 years of age: 30 patients) received ferric carboxymaltose 15 mg/kg to a maximum single dose of 750 mg (whichever was smaller) on Days 0 and 7 for a maximum total dose of 1,500 mg; 38 patients evaluable for safety in the control arm received an age-dependent formulation of oral ferrous sulfate for 28 days. The median age of patients who received ferric carboxymaltose was 14.5 years (range, 1-17); 83% were female; 88% White and 13% Black. The most common adverse reactions (≥ 4%) were hypophosphatemia, injection site reactions, rash, headache, and vomiting. Table 4 summarizes the adverse reactions in Study 3. Table 4. Adverse Reactions of any Grade in Pediatric Patients Receiving Ferric Carboxymaltose in Study 3 Ferric Carboxymaltose (N = 40) % Oral Ferrous Sulfate (N = 38) % Any Adverse Reactions 35 26 Hypophosphatemia Grouped Terms Injection site reactions include infusion site hematoma, infusion site hypoesthesia and injection site pain. Hypophosphatemia includes hypophosphatemia and blood phosphorus decreased. Rash includes rash, exanthema and urticaria. 13 0 Injection site reactions 8 0 Rash 8 0 Headache 5 3 Vomiting 5 3 Nasopharyngitis 3 5 Flushing 3 0 Gastrointestinal infections 3 0 Liver function test increased 3 0 Platelet count decreased 3 0 White blood cell count decreased 3 0 Patients with Iron Deficiency and Heart Failure The safety of ferric carboxymaltose was evaluated in adult patients with iron deficiency and heart failure in randomized controlled trials FAIR-HF (NCT00520780), CONFIRM-HF (NCT01453608) and AFFIRM-AHF (NCT02937454) in which 1,016 patients received ferric carboxymaltose versus 857 received placebo. The overall safety profile of ferric carboxymaltose was consistent across the studied indications. 6.2 Post-marketing Experience The following adverse reactions have been identified during post approval use of ferric carboxymaltose. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been reported from the post-marketing spontaneous reports with ferric carboxymaltose: • Cardiac disorders: Tachycardia • General disorders and administration site conditions: Chest discomfort, chills, pyrexia • Metabolism and nutrition disorders: Hypophosphatemia • Musculoskeletal and connective tissue disorders: Arthralgia, back pain, hypophosphatemic osteomalacia • Nervous system disorders: Syncope • Respiratory, thoracic and mediastinal disorders: Dyspnea • Skin and subcutaneous tissue disorders: Angioedema, erythema, pruritus, urticaria • Pregnancy: Fetal bradycardia

<table styleCode="Noautorules" width="100%"><caption>Table 2. Adverse reactions reported in &#x2265; 1% of Study Patients in Clinical Trials 1 and 2</caption><col width="31%"/><col width="23%"/><col width="23%"/><col width="23%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Ferric Carboxymaltose (N = 1,775) %</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Pooled Comparators</content><footnote ID="_Ref152733286">Includes oral iron and all formulations of IV iron other than ferric carboxymaltose.</footnote> <content styleCode="bold">(N = 1,783) %</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Oral iron (N = 253) %</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypertension<footnote ID="_Ref152733313">Injection site discoloration was also included in the injection site local administration reactions grouped term. Headache includes headache and migraine. Hepatic enzyme increased includes alanine aminotransferase increased and aspartate aminotransferase increased. Dysgeusia includes dysgeusia and ageusia. Rash includes rash, urticaria, skin exfoliation, blister, erythema multiforme, injection site rash, rash maculo-papular, and rash pruritic.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Flushing<footnote ID="_Ref152733333">Grouped Terms: Hypertension includes hypertension, blood pressure increased, and hypertensive crisis. Flushing includes flushing and hot flush. Injection site reactions include injection site extravasation, injection site discoloration, injection site pain, injection site irritation, injection site bruising, injection site reaction, injection site discomfort, injection site erythema, injection site hematoma, injection site hemorrhage, injection site pruritus, injection site rash, and injection site swelling. Erythema includes erythema and injection site erythema. Dizziness includes dizziness, balance disorder, and vertigo. </footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site reactions<footnoteRef IDREF="_Ref152733333"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Erythema<footnoteRef IDREF="_Ref152733333"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypophosphatemia </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dizziness<footnoteRef IDREF="_Ref152733333"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vomiting </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection Site Discoloration<footnoteRef IDREF="_Ref152733313"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache<footnoteRef IDREF="_Ref152733333"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hepatic enzyme increased<footnoteRef IDREF="_Ref152733333"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dysgeusia<footnoteRef IDREF="_Ref152733333"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypotension </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Rash<footnoteRef IDREF="_Ref152733333"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Constipation </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.5</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.9</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>3.2</paragraph></td></tr></tbody></table>

<table styleCode="Noautorules" width="100%"><caption>Table 3. Adverse Reactions (&#x2265; 1% in any Treatment Group) In Patients Receiving Two Doses of 15 mg/kg to a Maximum of 750 mg to a Cumulative Dose of 1,500 mg or a Single Dose of Ferric Carboxymaltose 15 mg/kg to a Maximum of 1,000 mg</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Ferric Carboxymaltose 15 mg/kg to a maximum of 750 mg x 2 doses to a cumulative dose of 1,500 mg</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Ferric Carboxymaltose 15 mg/kg to a maximum of 1,000 mg single dose</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">IVIT09030 and IVIT09031</content><footnote ID="_Ref152733453">Included studies 1VIT07017, 1VIT07018, 1VIT09030 and 1VIT09031 </footnote><content styleCode="bold"> (N = 1,775) %</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">IVIT07017 and IVIT07018</content><footnoteRef IDREF="_Ref152733453"/><content styleCode="bold"> (N = 1,200) %</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Any Adverse Reaction </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>24</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site reactions<footnote ID="_Ref152733476">Grouped Terms </footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site extravasation<footnote ID="_Ref152733485">Injection site extravasation and injection site discoloration were also included in the injection site reactions grouped term.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hepatic enzyme increased<footnoteRef IDREF="_Ref152733476"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Rash<footnoteRef IDREF="_Ref152733476"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache<footnoteRef IDREF="_Ref152733476"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dizziness<footnoteRef IDREF="_Ref152733476"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dysgeusia<footnoteRef IDREF="_Ref152733476"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypertension<footnoteRef IDREF="_Ref152733476"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypophosphatemia </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Erythema<footnoteRef IDREF="_Ref152733476"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Flushing<footnoteRef IDREF="_Ref152733333"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4 </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.3 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vomiting </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2 </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.2 </paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site discoloration<footnoteRef IDREF="_Ref152733485"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>&lt; 0.1</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Hypotension </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>&lt; 0.1</paragraph></td></tr></tbody></table>

<table styleCode="Noautorules" width="100%"><caption>Table 4. Adverse Reactions of any Grade in Pediatric Patients Receiving Ferric Carboxymaltose in Study 3</caption><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Ferric Carboxymaltose (N = 40) %</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Oral Ferrous Sulfate (N = 38) %</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Any Adverse Reactions </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>35</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>26</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypophosphatemia<footnote ID="_Ref152733749">Grouped Terms Injection site reactions include infusion site hematoma, infusion site hypoesthesia and injection site pain. Hypophosphatemia includes hypophosphatemia and blood phosphorus decreased. Rash includes rash, exanthema and urticaria.</footnote></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Injection site reactions<footnoteRef IDREF="_Ref152733749"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Rash<footnoteRef IDREF="_Ref152733749"/></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vomiting </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nasopharyngitis </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Flushing </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Gastrointestinal infections </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Liver function test increased </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Platelet count decreased </paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>White blood cell count decreased </paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0</paragraph></td></tr></tbody></table>