iron-dextran complex 200 MG/ML Injectable Solution

INDICATIONS AND USAGE INFeD is indicated for treatment of adult and pediatric patients of age 4 months and older with documented iron deficiency who have intolerance to oral iron or have had an unsatisfactory response to oral iron. INFeD, an iron replacement product, is indicated for treatment of adult and pediatric patients of age 4 months and older with documented iron deficiency who have intolerance to oral iron or an unsatisfactory response to oral iron. ( 1 )

DOSAGE & ADMINISTRATION Oral iron should be discontinued prior to administration of INFeD. Dosage: I. Iron Deficiency Anemia: Periodic hematologic determination (hemoglobin and hematocrit) is a simple and accurate technique for monitoring hematological response, and should be used as a guide in therapy. It should be recognized that iron storage may lag behind the appearance of normal blood morphology. Serum iron, total iron binding capacity (TIBC) and percent saturation of transferrin are other important tests for detecting and monitoring the iron deficient state. After administration of iron dextran complex, evidence of a therapeutic response can be seen in a few days as an increase in the reticulocyte count. Although serum ferritin is usually a good guide to body iron stores, the correlation of body iron stores and serum ferritin may not be valid in patients on chronic renal dialysis who are also receiving iron dextran complex. Although there are significant variations in body build and weight distribution among males and females, the accompanying table and formula represent a convenient means for estimating the total iron required. This total iron requirement reflects the amount of iron needed to restore hemoglobin concentration to normal or near normal levels plus an additional allowance to provide adequate replenishment of iron stores in most individuals with moderately or severely reduced levels of hemoglobin. It should be remembered that iron deficiency anemia will not appear until essentially all iron stores have been depleted. Therapy, thus, should aim at not only replenishment of hemoglobin iron but iron stores as well. Factors contributing to the formula are shown below. a…Blood volume . . . . . . . . . . . . . . . .65 mL/kg of body weight b. Normal hemoglobin (males and females) over 15 kg (33 lbs) . . . . . . . . . . .14.8 g/dL 15 kg (33 lbs) or less . . . . . . . . .12.0 g/dL c. Iron content of hemoglobin . . . . . 0.34% d. Hemoglobin deficit e. Weight Based on the above factors, individuals with normal hemoglobin levels will have approximately 33 mg of blood iron per kilogram of body weight (15 mg/lb). Note: The table and accompanying formula are applicable for dosage determinations only in patients with iron deficiency anemia; they are not to be used for dosage determinations in patients requiring iron replacement for blood loss. TOTAL INFeD REQUIREMENT FOR HEMOGLOBIN RESTORATION AND IRON STORES REPLACEMENT* *Table values were calculated based on a normal adult hemoglobin of 14.8 g/dL for weights greater than 15 kg (33 lbs) and a hemoglobin of 12.0 g/dL for weights less than or equal to 15 kg (33 lbs). The total amount of INFeD in mL required to treat the anemia and replenish iron stores may be approximated as follows: Adults and Children over 15 kg (33 lbs): See Dosage Table. Alternatively, the total dose may be calculated: Dose (mL) = 0.0442 (Desired Hb - Observed Hb) x LBW + (0.26 x LBW) Based on: Desired Hb = the target Hb in g/dL. Observed Hb = the patient’s current hemoglobin in g/dL. LBW = Lean body weight in kg. A patient’s lean body weight (or actual body weight if less than lean body weight) should be utilized when determining dosage. For males: LBW = 50 kg + 2.3 kg for each inch of patient’s height over 5 feet For females: LBW = 45.5 kg + 2.3 kg for each inch of patient’s height over 5 feet To calculate a patient's weight in kg when lbs are known: INFeD should not normally be given in the first four months of life. (See PRECAUTIONS : Pediatric Use). Alternatively, the total dose may be calculated: Dose (mL) = 0.0442 (Desired Hb - Observed Hb) x W + (0.26 x W) Based on: Desired Hb = the target Hb in g/dL. (Normal Hb for Children 15 kg or less is 12 g/dL) W = Weight in kg. To calculate a patient's weight in kg when lbs are known: II. Iron Replacement for Blood Loss: Some individuals sustain blood losses on an intermittent or repetitive basis. Such blood losses may occur periodically in patients with hemorrhagic diatheses (familial telangiectasia; hemophilia; gastrointestinal bleeding) and on a repetitive basis from procedures such as renal hemodialysis. Iron therapy in these patients should be directed toward replacement of the equivalent amount of iron represented in the blood loss. The table and formula described under I. Iron Deficiency Anemia are not applicable for simple iron replacement values. Quantitative estimates of the individual’s periodic blood loss and hematocrit during the bleeding episode provide a convenient method for the calculation of the required iron dose. The formula shown below is based on the approximation that 1 mL of normocytic, normochromic red cells contains 1 mg of elemental iron: Replacement iron (in mg) = Blood loss (in mL) x hematocrit Example: Blood loss of 500 mL with 20% hematocrit Replacement Iron = 500 x 0.20 = 100 mg Administration: The total amount of INFeD required for the treatment of iron deficiency anemia or iron replacement for blood loss is determined from the table or appropriate formula. (See Dosage ). 1. Intravenous Injection - PRIOR TO THE FIRST INTRAVENOUS INFeD THERAPEUTIC DOSE, ADMINISTER AN INTRAVENOUS TEST DOSE OF 0.5 ML. ADMINISTER THE TEST DOSE AT A GRADUAL RATE OVER AT LEAST 30 SECONDS. Although anaphylactic reactions known to occur following INFeD administration are usually evident within a few minutes, or sooner, it is recommended that a period of an hour or longer elapse before the remainder of the initial therapeutic dose is given. Individual doses of 2 mL or less may be given on a daily basis until the calculated total amount required has been reached. INFeD is given undiluted at a slow gradual rate not to exceed 50 mg (1 mL) per minute. 2. Intramuscular Injection - PRIOR TO THE FIRST INTRAMUSCULAR INFeD THERAPEUTIC DOSE, ADMINISTER AN INTRAMUSCULAR TEST DOSE OF 0.5 ML. (See BOXED WARNING and PRECAUTIONS .) The test dose should be administered in the buttock using the same technique as described in the last paragraph of this section. Although anaphylactic reactions known to occur following INFeD administration are usually evident within a few minutes or sooner, it is recommended that at least an hour or longer elapse before the remainder of the initial therapeutic dose is given. If no adverse reactions are observed, INFeD can be given according to the following schedule until the calculated total amount required has been reached. Each day’s dose should ordinarily not exceed 0.5 mL (25 mg of iron) for infants under 5 kg (11 lbs); 1.0 mL (50 mg of iron) for children under 10 kg (22 lbs); and 2.0 mL (100 mg of iron) for other patients. INFeD should be injected only into the muscle mass of the upper outer quadrant of the buttock - never into the arm or other exposed areas - and should be injected deeply, with a 2-inch or 3-inch 19 or 20 gauge needle. If the patient is standing, he/she should be bearing his/her weight on the leg opposite the injection site, or if in bed, he/she should be in the lateral position with injection site uppermost. To avoid injection or leakage into the subcutaneous tissue, a Z-track technique (displacement of the skin laterally prior to injection) is recommended. NOTE: Do not mix INFeD with other medications or add to parenteral nutrition solutions for intravenous infusion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit. DOSAGE I 1 DOSAGE DOSAGE I 2 DOSAGE 13 DOSAGE I 4

WARNINGS AND PRECAUTIONS Delayed Reactions: May occur with large intravenous doses. ( 5.2 ) Increased Risk of Toxicity in Patients with Underlying Conditions: Monitor for toxicity in these patients. ( 5.3 ) Iron Overload: Excessive therapy can lead to iatrogenic hemosiderosis. Do not administer to patients with iron overload. Periodically monitor hematologic and iron parameters. ( 5.4 ) 5.1 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported following the parenteral administration of iron dextran products, including INFeD. Such reactions have been generally characterized by sudden onset of respiratory difficulty and/or cardiovascular collapse. Fatal reactions have been reported following the test dose of iron dextran and have also occurred in situations where the test dose was tolerated. Administer only in a setting where resuscitation equipment and medications are available. Administer a test dose of INFeD prior to the first therapeutic dose [see Dosage and Administration ( 2.4 ) ]. Observe patients for at least one hour after the test dose before administering the remainder of the initial therapeutic dose. During all INFeD administrations, observe patients for signs or symptoms of anaphylactic-type reactions. Use INFeD only in patients in whom clinical and laboratory investigations have established an iron deficient state not amenable to oral iron therapy. The factors that affect the risk for anaphylactic-type reactions to iron dextran products are not fully known but limited clinical data suggest the risk may be increased among patients with a history of drug allergy or multiple drug allergies. Additionally, concomitant use of angiotensin-converting enzyme inhibitor drugs may increase the risk for reactions to an iron dextran product. The extent of risk for anaphylactic-type reactions following exposure to any specific iron dextran product is unknown and may vary among the products. If hypersensitivity reactions occur during administration, stop INFeD immediately and manage reaction medically. 5.2 Delayed Reactions Large intravenous doses, such as used with total dose infusions (TDI), have been associated with an increased incidence of adverse reactions. The adverse reactions are frequently delayed (1 to 2 days) reactions typified by one or more of the following symptoms: arthralgia, backache, chills, dizziness, moderate to high fever, headache, malaise, myalgia, nausea, and vomiting. The onset is usually 24 to 48 hours after administration and symptoms generally subside within 3 to 4 days. The etiology of these reactions is not known. Do not exceed a total daily dose of 2 mL undiluted INFeD. 5. 3 Increased Risk of Toxicity in Patients with Underlying Conditions Monitor for iron toxicity when INFeD is used in patients with serious impairment of liver function. It should not be used during the acute phase of infectious kidney disease. Adverse reactions experienced following administration of INFeD may exacerbate cardiovascular complications in patients with pre-existing cardiovascular disease. Patients with rheumatoid arthritis may have an acute exacerbation of joint pain and swelling following the administration of INFeD. Patients with a history of significant allergies and/or asthma may have an increased risk of hypersensitivity reactions [see Dosage and Administration ( 5.1 )]. 5. 4 Iron Overload Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. All adult and pediatric patients receiving INFeD require periodic monitoring of hematologic and iron parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer INFeD to patients with evidence of iron overload.

CONTRAINDICATIONS INFeD is contraindicated in patients who have demonstrated a previous hypersensitivity to iron dextran [see Warnings and Precautions ( 5.1 ) ] . Known hypersensitivity to INFeD ( 4 )

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The circulating iron released from iron dextran, which is subject to physiological control, replenishes hemoglobin and depleted iron stores. 12.2 Pharmacodynamics Changes in serum ferritin levels represent the changes in calculated cellular non-heme iron levels. After administration of iron dextran, evidence of a therapeutic response can be seen as an increase in the reticulocyte count. 12.3 Pharmacokinetics Following intramuscular injection, INFeD is absorbed within 72 hours with any remaining iron absorbed over the ensuing 3 to 4 weeks. Various studies involving intravenously administered 59 Fe iron dextran to iron deficient subjects, some of whom had coexisting disease, have yielded half-life values ranging from 5 hours to more than 20 hours. The 5 hour value was determined for 59 Fe iron dextran from a study that used laboratory methods to separate the circulating 59 Fe iron dextran from the transferrin bound 59 Fe. The 20 hour value reflects a half-life determined by measuring total 59 Fe, both circulating and bound. It should be understood that these half-life values do not represent clearance of iron from the body. Serum ferritin peaks approximately 7 to 9 days after an intravenous dose of INFeD and returns to baseline after about 3 weeks. Absorption Following intramuscular administration, INFeD is absorbed from the injection site into the capillaries and the lymphatic system. Distribution The circulating iron is bound to the available protein moieties to form hemosiderin or ferritin, or to a lesser extent to transferrin. Elimination The half-life of free iron in the plasma circulation is approximately 5 hours. The half-life of total iron, including both circulating and bound, is approximately 20 hours. These half-life values do not represent clearance of iron from the body. Metabolism Following administration of INFeD, circulating iron dextran is split by the cells of the reticuloendothelial system into its components of iron and dextran. Excretion Negligible amounts of iron are lost via the urinary or alimentary pathways after administration of iron dextran. Dextran, a polyglucose, is either metabolized or excreted. Specific Populations Patients with Renal Impairment In vitro studies have shown that removal of iron dextran by dialysis is negligible. Six different dialyzer membranes were investigated (polysulfone, cuprophane, cellulose acetate, cellulose triacetate, polymethylmethacrylate and polyacrylonitrile), including those considered high efficiency and high flux.