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INFUFER®
Sabex
Iron Dextran
Hematinic - Iron Supplement
 
Action And Clinical Pharmacology: After i.m. injection, iron dextran is absorbed from the injection site into the capillaries and the lymphatic system. Circulating iron dextran is dissociated by the reticuloendothelial system. The ferric iron is transported by transferrin and incorporated into hemoglobin and storage sites. Only traces of unmetabolized iron dextran are excreted in urine, bile or feces. The drug is negligibly removed by hemodialysis. Most of the i.m. injection of iron dextran is absorbed within 72 hours, with the remainder absorbed over 3 to 4 weeks.

The half-life of i.v. administered [9e] iron dextran to iron deficient subjects has ranged from 5 hours to more than 20 hours; however, these values do not represent loss of iron from the body, and accumulation of iron to potentially toxic levels should be avoided.

Iron status following iron dextran administration by i.v. infusion was assessed in 8 chronic hemodialysis patients (3 female, 5 male; mean age 54±9.9 years) not receiving parenteral iron or r-HuEPO (recombinant human erythropoietin) therapy within the previous 8 weeks. Iron dextran was administered in doses of 100 mg diluted in 100 mL of NaCl 0.9%, during the last hour of successive dialysis sessions (usually 2 to 3 sessions per week) until the total dose was attained (mean total dose of 950±220 mg). An initial test dose of 25 mg was administered over 5 minutes, the patient observed for 15 minutes for anaphylaxis, and the remaining 75 mg dose administered over 1 hour. Iron dextran increased the iron status in these chronic hemodialysis patients. Plasma ferritin and transferrin saturation values increased significantly at the first time point assessed. Plasma ferritin values remained elevated for at least 4 weeks post-completion of dosing, while transferrin saturation values remained elevated only during the iron dextran administration period. Hemoglobin (Hb) and hematocrit tended to increase, with levels 4 weeks post-completion of dosing significantly higher than the time at which half the iron dextran dose had been administered. The greater increase in Hb was observed in patients with a baseline ferritin of <100 µg/L compared to ferritin values of >100 µg/L. Therefore, the presence of both a transferrin saturation <20% and plasma ferritin <100 µg/L may improve the identification of hemodialysis patients who will often respond to parenteral iron with an increase in Hb.

Iron status following iron dextran administration by i.v. infusion was assessed in 14 r-HuEPO (recombinant human erythropoietin)-treated hemodialysis patients who completed the study (3 female, 11 male; mean age 59±5.2 years; mean r-HuEPO dose per week 11 429±2 142 units) not receiving parenteral iron therapy within the previous 12 months. Iron dextran was administered in doses of 100 mg diluted in 100 mL NaCl 0.9%, during the last half-hour of hemodialysis. Doses were given once a week for 10 consecutive weeks, for a total dose of 1 000 mg. An initial test dose of 25 mg was administered and the patient observed for 1 hour for anaphylaxis. Iron dextran had a significant impact on the ferritin levels, which is reflective of the patient's iron stores. Significant increases in serum iron and transferrin saturation were observed, with a peak at 8 weeks following initiation of iron dextran therapy. These changes did not translate into an increase in hemoglobin levels. For patients concurrently taking r-HuEPO, 20% of those enrolled (5/25) experienced an adverse reaction to iron dextran. Hypertension was observed in 2 patients (one 3 hours following the test dose, the other during the second dose at week 2). In addition, 1 patient had an anaphylactic response to the test dose. Finally, in the 5 patients who experienced adverse reactions, the following were observed: dizziness, headache, faintness, unconsciousness, distress, palpitations, increased heart rate and blood flow, hypotension, chest pain, flushing, cyanosis, diarrhea, limb cramps, shortness of breath, urticaria and itching.

Indications And Clinical Uses: For treatment of patients with documented iron deficiency in whom oral administration is unsatisfactory or impossible. It may be administered by i.m. injection or by i.v. infusion. I.V. infusion must be confined to the hospital treatment of patients for whom the i.m. route or other forms of therapy are inappropriate or are not available.

Contra-Indications: Hypersensitivity to the product. All anemias not associated with iron deficiency.

Iron dextran is not to be used during the acute phase of infectious kidney disease, not to be given i.v. to patients with a history of asthma and not to be administered concomitantly with oral iron preparations.

Manufacturers' Warnings In Clinical States: The parenteral use of complexes of iron and carbohydrates has resulted in anaphylactic-type reactions. Deaths associated with such administration have been reported. Therefore, iron dextran should be used only in those patients in whom the indications have been clearly established and laboratory investigations confirm an iron deficient state not amenable to oral iron therapy.

Large i.v. doses, such as those used with total dose infusions (TDIs) have been associated with an increased incidence of adverse effects. The adverse effects frequently are delayed (1 to 2 days) and include 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. Similar symptoms reported following i.m. injection usually subside within 3 to 7 days. The estimate of risk/benefit should take into consideration the potential for a delayed reaction.

Iron dextran injection should be used with extreme care in patients with serious impairment of liver function.

Iron dextran injection should not be used during the acute phase of infectious kidney disease.

Adverse reactions experienced following administration of iron dextran injection may exacerbate cardiovascular complications in patients with pre-existing cardiovascular disease.

Animal studies have shown a risk of carcinogenesis associated with the i.m. injection of iron-carbohydrate complexes. Sarcomas were produced when large doses were given to rodents or when small doses were injected repeatedly into the same site in rodents and rabbits.

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 i.m. injections of iron dextran.

Precautions: Unwarranted therapy with parenteral iron will cause excess storage of iron with the consequent possibility of exogenous hemosiderosis. Such iron overload is particularly apt to occur in patients with hemoglobinopathies and other refractory anemias that might be erroneously diagnosed as iron deficiency anemias.

Iron dextran injection should be used with caution in individuals with histories of significant allergies and/or asthma.

Anaphylaxis and other hypersensitivity reactions have been reported after uneventful test doses as well as therapeutic doses of iron dextran injection. Therefore, administration of subsequent test doses during therapy should be considered (see Dosage).

Epinephrine should be immediately available in the event of acute hypersensitivity reactions. The usual dose of epinephrine is 0.5 mL of a 1:1 000 solution, by s.c. or i.m. injection. Note: Patients using beta-blocking agents may not respond adequately to epinephrine, and they may require isoproterenol or similar beta-agonist agents.

Patients with rheumatoid arthritis may have an acute exacerbation of joint pain and swelling following the administration of iron dextran injection.

There have been published reports, from New Zealand, associating the use of i.m. iron dextran in neonates with an increased incidence of gram-negative sepsis, primarily due to E. coli.

Information for the Patient: Patients should be advised of the potential adverse reactions associated with the use of iron dextran injection (see Adverse Effects).

Drug/Laboratory Test Interactions : Large doses of iron dextran (5 mL or more) have been reported to give a brown color to serum from a blood sample drawn 4 hours after administration. Iron dextran injection may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium.

Serum iron determinations by colorimetric assays may not be meaningful for 3 weeks following the administration of iron dextran.

Serum ferritin peaks approximately 7 to 9 days after an i.v. dose and slowly returns to baseline after about 3 weeks.

Examination of the bone marrow for iron stores may not be meaningful for prolonged periods following therapy with iron dextran injection because residual iron dextran may remain in the reticuloendothelial cells.

Bone scans involving 99m Tc-diphosphonate have been reported to show a dense, crescentic area of activity in the buttocks, following the contour of the iliac crest, 1 to 6 days after i.m. injections of iron dextran.

Bone scans with 99m Tc-labeled bone seeking agents, in the presence of high serum ferritin levels or following iron dextran infusions, have been reported to show reduction of bony uptake, marked renal activity and increased blood pool and soft tissue accumulation.

Pregnancy: Iron dextran has been shown to be teratogenic and embryocidal in nonanemic mice, rats, rabbits, dogs and monkeys when given in doses of about 3 times the maximum human dose. 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 have been reported in monkeys at a total i.v. dose of 90 mg iron/kg over a 14-day period. Similar effects were observed in mice and rats after administration of a single dose of 125 mg iron/kg. Fetal abnormalities in rats and dogs were observed at doses of 250 mg iron/kg and higher. The animals used in these tests were not iron deficient. There are no adequate and well-controlled studies in pregnant women. Iron dextran injection should be used in pregnant women only if the potential benefit justifies the potential risk to the fetus.

Placental Transfer: Various animal studies have demonstrated placental transfer of iron dextran complex, and studies in pregnant humans have demonstrated inconclusive results.

It appears that some iron does reach the fetus, but the form in which it crosses the placenta is not clear.

Lactation: Caution should be exercised when iron dextran is administered to a nursing woman. Traces of unmetabolized iron dextran are excreted in human milk.

Children: Not recommended for use in infants under 4 months of age (see Dosage).

Adverse Reactions: Severe/Fatal: Anaphylactic reactions to iron dextran injection, including fatal anaphylaxis, have been reported. Such reactions which occur most often within the first several minutes of administration are generally characterized by the sudden onset of respiratory difficulty and/or cardiovascular collapse.

The incidence of these acute hypersensitivity reactions has been estimated between 0.1 to 0.6% (see Warnings). (See Precautions pertaining to immediate availability of epinephrine.) Administration must be stopped immediately when signs of an anaphylactoid reaction are seen.

Mild/moderate: Delayed reactions may occur (see Warnings). In a surveillance program of 1 260 patients treated with total dose infusion of iron dextran injection, the overall reaction rate was 29.8%, with 14.3% immediate reactions occurring on the day of infusion and 17.7% delayed reactions occurring on later days; 2.1% of patients experienced both immediate and delayed reactions. (Severe reactions were recorded in 5.3% of patients.)

Cardiovascular: chest pain, chest tightness, shock, hypotension, hypertension, tachycardia, flushing, arrhythmias. (Flushing and hypotension may occur from too rapid i.v. administration.)

Dermatologic: urticaria, pruritus, purpura, rash.

Gastrointestinal: abdominal pain, nausea, vomiting, diarrhea.

Hematologic/Lymphatic: leukocytosis, lymphadenopathy.

Musculoskeletal/Soft Tissue: arthralgia, arthritis (may represent reactivation in patients with quiescent rheumatoid arthritis, see Precautions), myalgia; backache; sterile abscess, atrophy/fibrosis (i.m. injection site); brown skin and/or underlying tissue discoloration (staining), soreness or pain at or near i.m. injection sites; cellulitis; swelling; inflammation; local phlebitis at or near i.v. injection site.

Neurologic: convulsions, seizures, syncope, headache, weakness, unresponsiveness, paresthesia, febrile episodes, chills, dizziness, disorientation, numbness.

Respiratory: respiratory arrest, dyspnea, bronchospasm.

Urologic: hematuria.

Delayed Reactions: arthralgia, backache, chills, dizziness, fever, headache, malaise, myalgia, nausea, vomiting (see Warnings).

Miscellaneous: febrile episodes, sweating, shivering, chills, malaise, altered taste.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdosage with iron dextran injection is unlikely to produce acute adverse reactions. Excessive doses beyond 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 adverse accumulation of iron in concurrent medical conditions such as chronic renal failure, Hodgkin's disease and rheumatoid arthritis.

Dosage And Administration: Oral iron should be discontinued prior to administration of iron dextran.

Dosage is calculated specifically for each patient dependent upon body weight, age, sex and degree of anemia, using a dosage table or some suitable formula. It is preferred that iron dextran be given by the i.m. route, unless there are valid reasons for i.v. administration. The i.v. infusion of iron dextran should be restricted to hospital usage only.

Dosage Determinations in Patients with Iron Deficiency Anemia: Periodic hematologic determination of hemoglobin and hematocrit should be used as a guide for monitoring hematological response. As iron storage may lag behind the appearance of normal blood morphology, other tests, such as serum iron, total iron binding capacity, serum ferritin and percent saturation of transferrin, may be needed for detecting and monitoring the iron deficient state of the patient.

Reticulocyte count should increase within a few days of iron dextran administration.

Serum ferritin levels may not correlate with body iron stores 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, Table I and the accompanying 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. Thus, therapy should aim at not only the restoration of hemoglobin but also the replenishment of iron stores.

Factors contributing to the formula include:

mg blood iron = mL blood X g hemoglobin X mg iro lb body weight lb body weight mL blood g hemoglobin

a) Blood volume 65 mL/kg of body weight. b) Normal hemoglobin (males and females), over 15 kg (33 lbs) 14.8 g/100 mL, 15 kg (33 lbs) or less 12 g/100 mL. 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/kg (15 mg/lb).

Note: The formula and accompanying table 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.

The total amount of iron dextran in mL required to treat the anemia and replenish iron stores may be approximated as follows: For Adults and Children over 15 kg (33 lbs): See Table I.

Alternatively, the total dose may be calculated as follows:

Dose (mL)=0.0442 (Desired Hb-Observed Hb)´LBW+ (0.26´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. To convert the patient's weight from pounds to kg: patient's weight in pounds/2.2=weight in kg. 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.

Children 5 to 15 kg (11 to 33 lbs): See Table I. Iron dextran should not normally be given in the first 4 months of life (see Precautions, Children).

Alternatively, the total dose may be calculated as follows:

Dose (mL)=0.0442 (Desired Hb-Observed Hb)´W+ (0.26´W).

Based on: Desired Hb=the target Hb in g/dL. (Normal Hb for children 15 kg or less is 12 g/dL.) Observed Hb=the patient's current Hb in g/dL. W=Weight in kg. To convert the patient's weight from pounds to kg: Patient's weight in pounds/2.2=weight in kg.

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 lost blood. The table and formulae presented under 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)´hematocrit.

Example: Blood loss of 500 mL with 20% hematocrit.

Replacement iron=500´0.20=100 mg.

Replacement iron=500{times}0.20=100 mg..

Infufer dose = 100 mg = 2 mL. 50 mg/mL

Administration: The total amount of iron dextran required for the treatment of iron deficiency anemia or iron replacement for blood loss is determined from the table or appropriate formula (see Dosage).

I.M. Injection: Prior to receiving their first therapeutic dose, all patients should be given an i.m. test dose of 0.5 mL gradually. The test dose should be administered in the same recommended test site and by the same technique as described in the last paragraph of this section. Although anaphylactic reactions known to occur following iron dextran 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, iron dextran 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 iron) for children under 10 kg (22 lbs); and 2 mL (100 mg of iron) for other patients. It is recommended that these be given as a graded series of injections starting with a test dose of 0.5 mL (25 mg elemental iron), 1 mL, then 2 mL, while the patient is observed carefully for adverse reactions. The injections should be administered gradually. If the patient is moderately active, injections may be given daily into alternate buttocks. In inactive or bedridden patients, the frequency of injections should be reduced to once or twice weekly.

Deep i.m. injection in the upper outer quadrant of the buttock, using a Z-track technique (with displacement of the skin laterally prior to injection) insures absorption and will help to avoid staining of the skin. A 5 cm needle is recommended for the adult of average size.

The i.m. route of administration is to be used unless there are valid reasons for i.v. administration.

I.V. Infusion: Prior to receiving their first therapeutic dose, all patients should be given a test dose of 0.5 mL (equivalent to 25 mg elemental iron) by i.v. infusion administered slowly over at least 5 minutes at a rate of not more than 5 drops/minute. If the test dose is well tolerated, the rate of infusion may be increased progressively to 45 to 60 drops/minute (3 to 4 mL/minute).

Anaphylactoid reactions are usually evident within a few minutes. If at any time during the i.v. administration, any signs of a hypersensitivity reaction or intolerance are detected, administration must be stopped immediately. Resuscitative equipment should be available, and the reactions treated with 0.5 mL of aqueous epinephrine 1:1 000 given s.c. with general supportive measures, followed by either oral or parenteral antihistamines and/or corticosteroids (see Precautions).

Iron dextran may be administered in large volumes via the Total Dose Infusion technique for the hospital treatment of patients for whom the i.m. route or other forms of therapy are inappropriate or are not available.

The i.v. route should not be used for patients with a history of asthma. If the i.v. route is judged necessary for patients with a history of allergy, effective antihistamine cover should be given before administration of the iron dextran.

Total Dose Infusion (TDI) Technique: The total amount of calculated iron dextran required is added aseptically immediately before use to the required volume, usually 500 mL of sterile NaCl 0.9% or Dextrose 5% solution. The use of Dextrose 5% solution has been associated with a higher incidence of local pain and phlebitis.

A test dose of 25 mg of elemental iron should be administered slowly over 5 minutes at an infusion rate not exceeding 5 drops/minute. If no hypersensitivity reaction occurs following an observation period of at least 1 hour, the remainder of the dose may be infused over 1 to 3 hours, or as much as 6 to 8 hours at an infusion rate of 3 to 4 mL/minute. The vein should then be flushed with about 10 mL of saline. Patients should be observed closely during the infusion and for at least 1 hour after it is completed.

The i.m. route of administration is to be used unless there are valid reasons for i.v. administration.

Preparation of Infusion Solutions: For i.v. infusion with dilution, iron dextran may be diluted in NaCl 0.9% or Dextrose 5%. The diluted preparations are chemically stable for 24 hours at room temperature. Discard unused portion.

Solutions of iron dextran in Dextrose 5% solution must not be autoclaved, because precipitation may occur. Other agents should not be added to iron dextran infusions, nor should iron dextran be added to blood for transfusion.

Iron dextran has been reported to be incompatible with oxytetracycline and with sulfadiazine sodium in i.v. infusion.

Note: Do not mix iron dextran with other medications or add to parenteral nutrition solutions for i.v. infusion.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit.

Infusion Following Hemodialysis Procedure: Chronic hemodialysis patients who develop anemia may be administered iron dextran in 100 mg doses diluted in 100 mL of NaCl 0.9% during the last hour of successive dialysis sessions until the total dose is attained. A test dose of 25 mg of elemental iron should be administered slowly over 5 minutes, and the patient monitored for adverse reactions over a 1-hour period before continuing with the initial infusion, as described previously.

Availability And Storage: Each mL of injection contains: elemental iron 50 mg as an iron dextran complex and sodium chloride 0.9% in water for injection. Sodium hydroxide or hydrochloric acid may be used to adjust pH. Preservative-free. Single use, clear glass vials of 2 mL, boxes of 10. Single use, clear glass vials of 5 mL, boxes of 5. Store between 15 and 25°C. Do not freeze.