DEXFERRUM®
`
`
`(IRON DEXTRAN INJECTION, USP)
`Rx Only
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`NDA 40-024/S-022
`Page 3
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`WARNING: RISK FOR ANAPHYLACTIC-TYPE REACTIONS
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`Anaphylactic-type reactions, including fatalities, have followed the parenteral
`administration of iron dextran injection.
`• Have resuscitation equipment and personnel trained in the detection and
`
`
`treatment of anaphylactic-type reactions readily available during Dexferrum
`administration.
`• Administer a test Dexferrum dose prior to the first therapeutic dose. If no
`
`
`signs or symptoms of anaphylactic-type reactions follow the test dose,
`administer the full therapeutic Dexferrum dose.
`• During all Dexferrum administrations, observe for signs or symptoms of
`
`anaphylactic-type reactions. Fatal reactions have followed the test dose of
`iron dextran injection. Fatal reactions have also occurred in situations where
`
`the test dose was tolerated.
`• Use Dexferrum only
`
`in patients
`laboratory
`in whom clinical and
`
`
`investigations have established an iron deficient state not amenable to oral
`
`
`iron therapy.
`• Patients with a history of drug allergy or multiple drug allergies may be at
`
`
`increased risk of anaphylactic-type reactions to Dexferrum.
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` DESCRIPTION: DEXFERRUM® (IRON DEXTRAN INJECTION, USP) is a dark brown, slightly
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`viscous sterile liquid complex of ferric oxyhydroxide for intravenous use. Each mL contains: 50 mg
`
`
` elemental iron as an iron dextran complex. Sodium chloride may have been added for tonicity. Water
`for injection q.s. pH (range 4.5-7.0) adjusted with hydrochloric acid and, if necessary, sodium
`hydroxide. Sterile, nonpyrogenic.
`
` Therapeutic Class: Hematinic
`
` CLINICAL PHARMACOLOGY: General: Circulating iron dextran is removed from the plasma by
`
`cells of the reticuloendothelial system, which split the complex into its components of iron and
`
`dextran. The iron is immediately bound to the available protein moieties to form hemosiderin or
`ferritin, the physiological forms of iron, or to a lesser extent to transferrin. This iron which is subject to
`physiological control replenishes hemoglobin and depleted iron stores.
`
` Dextran, a polyglucose, is either metabolized or excreted. Negligible amounts of iron are lost via the
`urinary or alimentary pathways after administration of iron dextran.
`
`Studies involving intravenously administered iron dextran to iron deficient subjects who had coexisting
`end-stage renal disease and other clinical problems, have yielded individual half-life values ranging
`from 9.4 to 87.4 hours. The average half-life value equaled 58.9 hours. These studies measured the
`total serum iron directly as well as the transferrin-bound iron, non-radio-isotopically. It should be
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`
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`understood that these half-life values do not represent clearance of iron from the body. Iron is not
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`Pharmacosmos, Exh. 1014, p. 1
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`NDA 40-024/S-022
`Page 4
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`easily eliminated from the body and accumulation of iron can be toxic.
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`
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`In vitro studies have shown that removal of iron dextran by dialysis is negligible1,2. Six different
`dialyzer membranes were investigated (polysulphone, cuprophane, cellulose acetate, cellulose
`
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`triacetate, polymethylmethacrilate and polyacrylonitrile), including those considered high efficiency
`
`and high flux.
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`INDICATIONS AND USAGE: Dexferrum is indicated for treatment of patients with documented
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`iron deficiency in whom oral administration is unsatisfactory or impossible.
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`
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`CONTRAINDICATIONS: Hypersensitivity to the product. All anemias not associated with iron
`deficiency.
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`WARNINGS:
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`
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`Risk for Anaphylactic-type Reactions: Anaphylactic-type reactions, including fatalities, have
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`
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`followed the parenteral administration of iron dextran. Always have resuscitation equipment and
`personnel trained in the detection and treatment of anaphylactic-type reactions readily available during
`Dexferrum adminisration. Prior to the first therapeutic dose, administer a test Dexferrum dose of 0.5
`mL intravenously at a gradual rate over at least five minutes. Although reactions are usually evident
`
`within a few minutes, observe patients for at least one hour before administering the therapeutic dose.
`
`During all Dexferrum administrations, observe patients for signs or symptoms of anaphylactic-type
`reactions. Fatal reactions have followed the test dose of iron dextran and have also occurred in
`situations where the test dose was tolerated. Use Dexferrum only in patients in whom clinical and
`
`laboratory investigations have established an iron deficient state not amenable to oral iron therapy.
`
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`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
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`anaphylactic-type reactions following exposure to any specific iron dextran product is unknown and
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`may vary among the products. Iron dextran products differ in chemical characteristics and may differ
`
`in clinical effects. Iron dextran products are not clinically interchangeable.
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`Delayed Reactions: Large intravenous doses, such as used with total dose infusions (TDI), have been
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`associated with an increased incidence of adverse effects. The adverse effects frequently are delayed
`(1-2 days) reactions typified by one or more of the following symptoms: arthralgia, backache, chills,
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`dizziness, moderate to high fever, headache, malaise, myalgia, nausea, and vomiting. The onset is
`usually 24-48 hours after administration and symptoms generally subside within 3-4 days. The etiology
`of these reactions is not known. The potential for a delayed reaction must be considered when
`estimating the risk/benefit of treatment.
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`
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`The maximum daily dose should not exceed 2 mL undiluted iron dextran.
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`Risks in Patients with Underlying Conditions: Dexferrum should be used with extreme care in
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`patients with serious impairment of liver function. It should not be used during the acute phase of
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`infectious kidney disease.
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`Pharmacosmos, Exh. 1014, p. 2
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`NDA 40-024/S-022
`Page 5
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`Adverse reactions experienced following administration of Dexferrum may exacerbate cardiovascular
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`complications in patients with pre-existing cardiovascular disease.
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`Carcinogenesis: A risk of carcinogenesis may attend the intramuscular injection of iron-carbohydrate
`complexes. Such complexes have been found under experimental conditions to produce sarcoma when
`large doses or small doses injected repeatedly at the same site were given to rats, mice, and rabbits, and
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`possibly in hamsters.
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`The long latent period between the injection of a potential carcinogen and the appearance of a tumor
`makes it impossible to measure accurately the risk in man. There have, however, been several reports
`in the literature describing tumors at the injection site in humans who had previously received
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`
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`intramuscular injections of iron-carbohydrate complexes.
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`PRECAUTIONS: General: Unwarranted therapy with parenteral iron will cause excess storage of
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`iron with the consequent possibility of exogenous hemosiderosis. Such iron overload is particularly apt
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`to occur in patients with hemoglobinopathies and other refractory anemias that might be erroneously
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`diagnosed as iron deficiency anemias.
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`Dexferrum should be used with caution in individuals with histories of significant allergies and/or
`asthma.
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`Anaphylaxis and other hypersensitivity reactions have been reported after uneventful test doses as well
`
`as therapeutic doses of iron dextran injection. Therefore, administer a test dose prior to the first
`
`
`and DOSAGE AND
`(See BOXED WARNING
`
`of Dexferrum.
`administration
`
`ADMINISTRATION).
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`Epinephrine should be immediately available in the event of acute hypersensitivity reactions. (Usual
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`adult dose: 0.5 mL of a 1:1000 solution, by subcutaneous or intramuscular injection.) Note: Patients
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`using beta-blocking agents may not respond adequately to epinephrine. Isoproterenol or similar beta-
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`agonist agents may be required in these patients.
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`Patients with rheumatoid arthritis may have an acute exacerbation of joint pain and swelling following
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`the administration of Dexferrum.
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`Information For Patients: Patients should be advised of the potential adverse reactions associated
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`with the use of Dexferrum.
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`Drug/Laboratory Test Interactions: Large doses of iron dextran (5 mL or more) have been reported
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`to give a brown color to serum from a blood sample drawn 4 hours after administration.
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`The drug may cause falsely elevated values of serum bilirubin and falsely decreased values of serum
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`calcium.
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`Serum iron determinations (especially by colorimetric assays) may not be meaningful for 3 weeks
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`following the administration of iron dextran.
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`Serum ferritin peaks approximately 7 to 9 days after an intravenous dose of Dexferrum and slowly
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`returns to baseline after about 3 weeks.
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`Pharmacosmos, Exh. 1014, p. 3
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`NDA 40-024/S-022
`Page 6
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`Examination of the bone marrow for iron stores may not be meaningful for prolonged periods
`following iron dextran therapy because residual iron dextran may remain in the reticuloendothelial
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`
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`cells.
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`Bone scans with 99m Tc-labeled bone seeking agents, in the presence of high serum ferritin levels or
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`following iron dextran infusions, have been reported to show reduction of bony uptake, marked renal
`activity, and excessive blood pool and soft tissue accumulation.
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`Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS.
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` Pregnancy: Teratogenic Effects, Pregnancy Category C: Iron dextran has been shown to be
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`teratogenic and embryocidal in mice, rats, rabbits, dogs, and monkeys when given in doses of about 3
`times the maximum human dose.
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`No consistent adverse fetal effects were observed in mice, rats, rabbits, dogs and monkeys at doses of
`50 mg iron/kg or less. Fetal and maternal toxicity has been reported in monkeys at a total intravenous
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`dose of 90 mg iron/kg over a 14 day period. Similar effects were observed in mice and rats on
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`administration of a single dose of 125 mg iron/kg. Fetal abnormalities in rats and dogs were observed
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`at doses of 250 mg iron/kg and higher. The animals used in these tests were not iron deficient. There
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`are no adequate and well-controlled studies in pregnant women. Dexferrum should be used during
`pregnancy only if the potential benefit justifies the potential risk to the fetus.
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`Placental Transfer: Various animal studies and studies in pregnant humans have demonstrated
`inconclusive results with respect to the placental transfer of iron dextran as iron dextran. It appears that
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`some iron does reach the fetus, but the form in which it crosses the placenta is not clear.
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`Nursing Mothers: Caution should be exercised when Dexferrum is administered to a nursing woman.
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`Traces of unmetabolized iron dextran are excreted in human milk.
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`Pediatric Use: Not recommended for use in infants under 4 months of age (See DOSAGE AND
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`ADMINISTRATION).
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`ADVERSE REACTIONS: Severe/Fatal: Anaphylactic reactions have been reported with the use of
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`iron dextran injection; on occasions these reactions have been fatal. Such reactions, which occur most
`often within the first several minutes of administration, have been generally characterized by sudden
`
`onset of respiratory difficulty and/or cardiovascular collapse. Because fatal anaphylactic reactions have
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`
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`been reported after administration of iron dextran injection, the drug should be given only when
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`resuscitation techniques and treatment of anaphylactic and anaphylactoid shock are readily available.
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`(See BOXED WARNING and PRECAUTIONS: General, pertaining to immediate availability of
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`
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`epinephrine.)
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`Cardiovascular: Chest pain, chest tightness, shock, cardiac arrest, hypotension, hypertension,
`tachycardia, bradycardia, flushing, arrhythmias. (Flushing and hypotension may occur from too rapid
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`injections by the intravenous route.)
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`Dermatologic: Urticaria, pruritus, purpura, rash, cyanosis.
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`Gastrointestinal: Abdominal pain, nausea, vomiting, diarrhea.
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`Pharmacosmos, Exh. 1014, p. 4
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`NDA 40-024/S-022
`Page 7
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`Hematologic/lymphatic: Leucocytosis, lymphadenopathy.
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`Musculoskeletal/soft tissue: Arthralgia, arthritis (may represent reactivation in patients with quiescent
`
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`rheumatoid arthritis -See PRECAUTIONS: General), myalgia; backache; sterile abscess; brown skin
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`and/or underlying tissue discoloration (staining); cellulitis; swelling; inflammation; local phlebitis at or
`near intravenous injection site.
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`Neurologic: Convulsions, seizures, syncope, headache, weakness, unresponsiveness, paresthesia,
`febrile episodes, chills, dizziness, disorientation, numbness, unconsciousness.
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`Respiratory: Respiratory arrest, dyspnea, bronchospasm, wheezing.
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`Urologic: Hematuria.
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`Delayed reactions: Arthralgia, backache, chills, dizziness, fever, headache, malaise, myalgia, nausea,
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`vomiting (See WARNINGS).
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`Miscellaneous: Febrile episodes, sweating, shivering, chills, malaise, altered taste.
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`OVERDOSAGE: Overdosage with iron dextran is unlikely to be associated with any acute
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`manifestations. Dosages of iron dextran in excess of the requirements for restoration of hemoglobin
`
`and replenishment of iron stores may lead to hemosiderosis. Periodic monitoring of serum ferritin
`levels may be helpful in recognizing a deleterious progressive accumulation of iron resulting from
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`impaired uptake of iron from the reticuloendothelial system in concurrent medical conditions such as
`chronic renal failure, Hodgkins disease, and rheumatoid arthritis. The LD50 of iron dextran is not less
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`than 500 mg/kg in the mouse.
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`DOSAGE AND ADMINISTRATION: Oral iron should be discontinued prior to administration of
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`Dexferrum.
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`Dosage:
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`I. Iron Deficiency Anemia: Periodic hematologic determination (hemoglobin and hematocrit) is a
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`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
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`morphology. Serum iron, total iron binding capacity (TIBC) and percent saturation of transferrin are
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`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.
`
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`Although serum ferritin is usually a good guide to body iron stores, the correlation of body iron stores
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`and serum ferritin may not be valid in patients on chronic renal dialysis who are also receiving iron
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`dextran complex.
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`Although there are significant variations in body build and weight distribution among males and
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`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
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`Pharmacosmos, Exh. 1014, p. 5
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`

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`NDA 40-024/S-022
`Page 8
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`replenishment of iron stores in most individuals with moderately or severely reduced levels of
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`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.
`
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`Factors contributing to the formula are shown below.
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`
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`mg blood iron = mL blood
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`
`lb body weight
`lb body weight
`
`
`a)
`b)
`
` x
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`
`
`g hemoglobin x mg iron
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`
`g hemoglobin
`mL blood
`
`Blood volume………………………………..65 mL/kg of body weight
`Normal hemoglobin (males and females)
`over 15 kg (33 lbs)…………………………..14.8 g/dl
`15 kg (33 lbs) or less………………………...12 g/dl
`Iron content of hemoglobin………………….0.34%
`Hemoglobin deficit
`
`Weight
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`
`
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`c)
`d)
`e)
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`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).
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`
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`Note: The table and accompanying formula are applicable for dosage determinations only in patients
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`
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`with iron deficiency anemia; they are not to be used for dosage determinations in patients requiring
`iron replacement for blood loss.
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`TOTAL DEXFERRUM® REQUIREMENT FOR HEMOGLOBIN
`
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`RESTORATION AND IRON STORES REPLACEMENT*
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`
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`Milliliter Requirement of Dexferrum Based On Observed
`
`Hemoglobin of
`7
`6
`
`
`(g/dl)
`(g/dl)
`3
`2
`5
`5
`8
`7
`13
`12
`16
`15
`19
`18
`23
`21
`26
`24
`29
`27
`32
`30
`36
`33
`39
`36
`42
`39
`45
`42
`49
`45
`52
`48
`55
`51
`58
`54
`62
`57
`65
`60
`
`PATIENT
`LEAN BODY
`
`WEIGHT
`lb
`kg
`
`5
`10
`15
`20
`25
`30
`35
`40
`45
`50
`55
`60
`65
`70
`75
`80
`85
`90
`95
`100
`
`11
`22
`33
`44
`55
`66
`77
`88
`99
`110
`121
`132
`143
`154
`165
`176
`187
`198
`209
`220
`
`3
`
`(g/dl)
`3
`7
`10
`16
`20
`23
`27
`31
`35
`39
`43
`47
`51
`55
`59
`63
`66
`70
`74
`78
`
`4
`
`(g/dl)
`3
`6
`9
`15
`18
`22
`26
`29
`33
`37
`41
`44
`48
`52
`55
`59
`63
`66
`70
`74
`
`5
`
`(g/dl)
`3
`6
`9
`14
`17
`21
`24
`28
`31
`35
`38
`42
`45
`49
`52
`55
`59
`62
`66
`69
`
`8
`
`(g/dl)
`2
`4
`7
`11
`14
`17
`20
`22
`25
`28
`31
`34
`36
`39
`42
`45
`48
`50
`53
`56
`
`9
`
`(g/dl)
`2
`4
`6
`10
`13
`15
`18
`21
`23
`26
`28
`31
`34
`36
`39
`41
`44
`46
`49
`52
`
`10
`
`(g/dl)
`2
`3
`5
`9
`12
`14
`17
`19
`21
`24
`26
`28
`31
`33
`35
`38
`40
`42
`45
`47
`
`Pharmacosmos, Exh. 1014, p. 6
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`

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`NDA 40-024/S-022
`Page 9
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`105
`110
`115
`120
`
`231
`242
`253
`264
`
`82
`86
`90
`94
`
`77
`81
`85
`88
`
`73
`76
`80
`83
`
`68
`71
`75
`78
`
`63
`67
`70
`73
`
`59
`62
`64
`67
`
`54
`57
`59
`62
`
`50
`52
`54
`57
`
`
` *Table values were calculated based on a normal adult hemoglobin of 14.8 g/dl for weights greater
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` than 15 kg (33 lbs) and a hemoglobin of 12.0 g/dl for weights less than or equal to 15 kg (33 lbs).
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`The total amount of Dexferrum in mL required to treat the anemia and replenish iron stores may be
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` approximated as follows:
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`Adults and Children over 15 kg (33 lbs): See Dosage Table. Alternatively the total dose may be
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`
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`calculated:
`
`
`
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`Dose (mL) = 0.0442 (Desired Hb - Observed Hb) x LBW + (0.26 x LBW)
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`
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`Based on: Desired Hb = the target Hb in g/dl.
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`Observed Hb = the patient’s current hemoglobin in g/dl.
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`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.
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`
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`For males: LBW = 50 kg + 2.3 kg for each inch of patient’s height over 5 feet
`
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`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:
`patient’s weight in pounds = weight in kilograms
`
`
`2.2
`
`Children 5 -15 kg (11 -33 lbs): See Dosage Table.
`
`
`
`
`
`
` Dexferrum should not normally be given
`PRECAUTIONS: Pediatric Use)
`
`
`Alternatively the total dose may be calculated:
`
`
`in
`
`the first four months of
`
`life. (See
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`
`
`
`
` Dose (mL) = 0.0442 (Desired Hb - Observed Hb) x W + (0.26 x W)
`
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`
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`W = Weight in kg.
`
`Based on: Desired Hb = the target Hb in g/dl. (Normal Hb for Children 15 kg or less is 12 g/dl)
`
`
`
`To calculate a patient’s weight in kg when lbs are known:
`patient’s weight in pounds = weight in kilograms
`2.2
`
`
`
`Pharmacosmos, Exh. 1014, p. 7
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`

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`NDA 40-024/S-022
`Page 10
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` II. Iron Replacement for Blood Loss: Some individuals sustain blood losses on an intermittent
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`or repetitive basis. Such blood losses may occur periodically in patients with hemorrhagic
`diatheses (familial telangiectasia; hemophilia; gastrointestinal bleeding) and on a repetitive
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`basis from procedures such as renal hemodialysis.
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`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.
`
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`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
`
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`
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`Replacement Iron = 500 x 0.20 = 100 mg
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`
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`Dexferrum dose = 100 mg = 2 mL
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`
`
`50
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`
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`Administration: The total amount of Dexferrum required for the treatment of iron deficiency
`anemia or iron replacement for blood loss is determined from the table or appropriate formula
`(See Dosage).
`
`Dexferrum is administered by intravenous injection. PRIOR TO THE FIRST DEXFERRUM
`
`THERAPEUTIC DOSE, ADMINISTER A TEST DOSE OF 0.5 ML INTRAVENOUSLY
`
`(See BOXED WARNING and PRECAUTIONS). ADMINISTER THE TEST DOSE AT A
`GRADUAL RATE OVER AT LEAST FIVE MINUTES. Although anaphylactic reactions
`known to occur following Dexferrum 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. Dexferrum is given undiluted at a slow gradual rate not to exceed
`50 mg (1 mL) per minute.
`
`
`If no adverse reactions are observed, Dexferrum 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 mL (50 mg of
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`
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`iron) for children under 10 kg (22 lbs); and 2 mL (100 mg of iron) for other patients.
`
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`NOTE: Do not mix Dexferrum with other medications or add to parenteral nutrition solutions
`
`for intravenous infusion.
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`
`
`
`
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`Parenteral drug products should be inspected visually for particulate matter and discoloration
`prior to administration, whenever the solution and container permit.
`
`Pharmacosmos, Exh. 1014, p. 8
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`

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`NDA 40-024/S-022
`Page 11
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`HOW SUPPLIED: Dexferrum® (Iron Dextran Injection, USP) containing 50 mg of elemental
`
`iron per mL.
`
`NDC 0517-0234-10 2 mL Single Dose Vial
`
`
`NDC 0517-0134-10 1 mL Single Dose Vial
`
`
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`Packaged in boxes of 10
`
`Packaged in boxes of 10
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`Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) (See USP
`Controlled Room Temperature).
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`
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`REFERENCES:
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`1. Hatton RC, Portales IT, Finley A, Ross EA. Removal of Iron Dextran by Hemodialysis:
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`An In Vitro Study. Am. J Kid Dis. 1995; 26(2):327-330.
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`2. Manuel MA, Stewart WK, St. Clair Neill GD, Hutchinson F. Loss of Iron-Dextran
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`through Cuprophane Membrane of a Disposable Coil Dialyser. Nephron. 1972; 9:94-98.
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`U.S. Patent 5,624,668
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`
`
`IN0234
`
`Rev. 8/08
`MG #7721
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`Dexferrum® is manufactured under license from Vifor (International) Inc., Switzerland.
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`AMERICAN REGENT, INC.
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`SHIRLEY, NY 11967
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`Pharmacosmos, Exh. 1014, p. 9