Maxifer

Maxifer

iron sucrose

Manufacturer:

Multicare

Distributor:

Zuellig
Full Prescribing Info
Contents
Iron sucrose.
Description
Each mL of solution for IV injection contains complex ferric hydroxide with sucrose equivalent to elemental iron 20 mg and water for injection.
Maxifer is a brown, sterile, aqueous, complex of polynuclear iron (III)-hydroxide in sucrose for IV use. Iron sucrose injection has a molecular weight of approximately 34,000-60,000 daltons and a structural formula of [Na2Fe5O8(OH)·3(H2O)]n·m(C12H22O11) where n is the degree of iron polymerization and m is the number of sucrose molecules associated with the iron (III)-hydroxide.
Maxifer contains approximately sucrose 30% w/v (300 mg/mL) and has a pH of 10.5-11.1. It contains no preservatives. The osmolarity of the injection is approximately 1250 mOsmol/L.
Action
Hematinic.
Pharmacology: Pharmacodynamics: Following IV administration of Maxifer, iron sucrose is dissociated by the reticuloendothelial system into iron and sucrose. In 22 hemodialysis patients on erythropoietin (recombinant human erythropoietin) therapy treated with iron sucrose containing iron 100 mg 3 times weekly for 3 weeks, significant increases in serum iron and serum ferritin and significant decreases in total iron-binding capacity occurred 4 weeks from the initiation of iron sucrose treatment.
Pharmacokinetics: In healthy adults treated with IV doses of Maxifer, its iron component exhibits first-order kinetics with an elimination t½ of 6 hrs, total clearance of 1.2 L/hr, nonsteady state apparent volume of distribution of 10 L and steady state apparent volume of distribution of 7.9 L. Since iron disappearance from serum depends on the need for iron in the iron stores and iron utilizing tissues of the body, serum clearance of iron is expected to be more rapid in iron-deficient patients treated with Maxifer as compared to healthy individuals. The effects of age and gender on the pharmacokinetics of Maxifer have not been studied. Maxifer is not dialyzable through CA210 (Baxter) High Efficiency or Fresenius F80A High Flux dialysis membranes. In in vitro studies, the amount of iron sucrose in the dialysate fluid was below the levels of detection of the assay (<2 parts/million).
Distribution: In healthy adults receiving IV doses of Maxifer, its iron component appears to distribute mainly in blood and to some extent in extravascular fluid. A study evaluating Maxifer containing iron 100 mg labeled with 52pe/59pe in patients with iron deficiency shows that a significant amount of the administered iron distributes in the liver, spleen and bone marrow and that the bone marrow is an iron trapping compartment and not a reversible volume of distribution.
Metabolism and Elimination: Following IV administration of Maxifer, iron sucrose is dissociated into iron and sucrose by the reticuloendothelial system. The sucrose component is eliminated mainly by urinary excretion. In a study evaluating a single IV dose of Maxifer containing sucrose 1,510 mg and iron 100 mg in 12 healthy adults (9 female, 3 male; age range 32-52 years), 68.3% of the sucrose was eliminated in urine in 4 hrs and 75.4% in 24 hrs. Some iron is also eliminated in the urine. Neither transferrin nor transferrin receptor levels changed immediately after the dose administration. In this study and another study evaluating a single IV dose of iron sucrose containing iron 500-700 mg in 26 anemic patients on erythropoietin therapy (23 female, 3 male; age range 16-60 years), approximately 5% of the iron was eliminated in urine in 24 hrs at each dose level.
Drug-Drug Interactions: Drug-drug interactions involving Maxifer have not been studied. However, like other parenteral iron preparations, Maxifer may be expected to reduce the absorption of concomitantly administered oral iron preparations.
Clinical Trials: Maxifer is used to replenish body iron stores in patients with iron deficiency on chronic hemodialysis and receiving erythropoietin. In these patients, iron deficiency is caused by blood loss during dialysis procedure, increased erythropoiesis and insufficient absorption of iron from the gastrointestinal tract. Iron is essential to the synthesis of hemoglobin to maintain oxygen transport and to the function and formation of other physiologically important heme and nonheme compounds. Most hemodialysis patients require iron IV to maintain sufficient iron stores to achieve and maintain hemoglobin of 11-12 g/dL. Three clinical trials were conducted to assess the safety and efficacy of Maxifer. Two studies were conducted in United States (100 patients) and 1 was conducted in South Africa (131 patients).
Study A: Study A was a multicenter, open-label, historically controlled study in 101 hemodialysis patients (77 patients with Maxifer treatment and 24 in the historical control group) with iron deficiency anemia. Eligibility for Maxifer treatment included patients undergoing chronic hemodialysis 3 times weekly, receiving erythropoietin, hemoglobin concentration >8 and <11 g/dL for at least 2 consecutive weeks, transferrin saturation <20% and serum ferritin <300 ng/mL. The mean age of the patients in the treatment group was 65 years with the age range being 31-85 years. The erythropoietin dose was to be held constant throughout the study. The protocol did not require administration of a test dose; however, some patients received a test dose at the physician's discretion. Exclusion criteria included significant underlying disease, asthma, active inflammatory disease, or serious bacterial or viral infection. Maxifer 5 mL (1 ampoule) containing elemental iron 100 mg was administered through the dialysis line at each dialysis session either as slow injection or a saline diluted slow infusion for a total of 10 dialysis sessions with a cumulative dose elemental iron 1,000 mg. A maximum of 3 vials of Maxifer was administered per week. No additional iron preparations were allowed until after the day 57 evaluation. The mean change in hemoglobin from baseline to day 24 (end of treatment), day 36 and day 57 was assessed. The historical control population consisted of 24 patients with similar ferritin levels as patients treated with Maxifer, who were off iron IV for at least 2 weeks and who had received erythropoietin therapy with hematocrit averaging 31-36 for at least 2 months prior to study entry. The mean age of patients in the historical control group was 56 years, with an age range of 29-80 years. Patient age and serum ferritin levels were similar between treatment and historical control patients. Of the 77 patients in the treatment group, 44 (57%) were male and 33 (43%) were female. The mean baseline hemoglobin, hematocrit, were higher and erythropoietin dose was lower in the historical control population than the Maxifer-treated population. Patients in the Maxifer-treated population showed a statistically significantly greater increase in hemoglobin and hematocrit than did patients in the historical control population. (See table.)

Click on icon to see table/diagram/image

Serum ferritin increased significantly (p=0.0001) at endpoint of study from baseline in the Maxifer-treated population (165.3±24.2 ng/mL) compared to the historical control population (-27.6±9.5 ng/mL). Transferrin saturation also increased significantly (p=0.0016) at endpoint of study from baseline in the Maxifer-treated population (8.8±1.6%) compared to this historical population (-5.1±4.3%).
Study B: Study B was a multicenter, open-label study of Maxifer in 23 iron-deficient hemodialysis patients who had been discontinued from iron dextran due to intolerance. Eligibility criteria and Maxifer administration were otherwise identical to Study A. The mean age of the patients in this study was 53 years, with ages ranging from 21-79 years. Of the 23 patients enrolled in the study, 10 (44%) were male and 13 (56%) were female. The ethnicity breakdown of patients enrolled in this study was as follows: 8 Caucasians (35%); 8 Blacks (35%); 1 Asian (4%); 6 Hispanics (26%). The mean change from baseline to the end of treatment (day 24) in hemoglobin, hematocrit and serum iron parameters was assessed.
All 23 enrolled patients were evaluated for efficacy. Statistically significant increases in mean hemoglobin (1.1±0.2 g/dL), hematocrit (3.6±0.6%), serum ferritin (266.3±30.3 ng/mL) and transferrin saturation (8.7±2%) were observed from baseline to end of treatment.
Study C: Study C was a multicenter, open-label, 2-period (treatment followed by observation period) study in iron deficient hemodialysis patients. Eligibility for this study included chronic hemodialysis patients with a hemoglobin ≤10 g/dL, a serum transferrin saturation ≤20% and a serum ferritin ≤200 ng/mL, who were undergoing maintenance hemodialysis 2-3 times weekly. The mean age of the patients enrolled in this study was 41 years, with ages ranging from 16-70 years. Of 130 patients evaluated for efficacy in this study, 68 (52%) were male and 62 (48%) were female. The ethnicity breakdown of patients enrolled in this study was as follows: 30 Caucasians (23%); 30 Blacks (23%); 6 Asians (5%); 64 others or mixed ethnicity (49%). Forty-eight percent of the patients had previously been treated with oral iron. Exclusion criteria were similar to those in studies A and B. Maxifer, was administered in doses of 100 mg during sequential dialysis sessions until a predetermined (calculated) total dose of iron was administered. Patients received Maxifer at each dialysis session, 2-3 times weekly. One hr after the start of each session, 5 mL iron sucrose (iron 100 mg) in 100 mL NaCl 0.9% was administered into the hemodialysis line. A 50-mg dose (2.5 mL) was given to patients within 2 weeks of study entry. Patients were treated until they reached an individually calculated total iron dose based on baseline hemoglobin level and body weight. Twenty-seven patients (20%) were receiving erythropoietin treatment at study entry and they continued to receive the same erythropoietin dose for the duration of the study. Changes from baseline to observation week 2 and 4 (end of study) were analyzed. The modified intention-to-treat population consisted of 131 patients. Significant (p<0.0001) increases from baseline in mean hemoglobin (1.7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained significantly increased (p<0.0001) at week 4 of the observation period.
Toxicology: Preclinical Safety Data: Single IV doses of Maxifer at iron 150 mg/kg in mice (about 3 times the recommended maximum human dose on a body surface area basis) and iron 100 mg/kg in rats (about 8 times the recommended maximum human dose on a body surface area basis) were lethal. The symptoms of acute toxicity were sedation, hypoactivity, pale eyes and bleeding in the gastrointestinal tract and lungs.
Indications/Uses
Treatment of iron deficiency anemia in patients undergoing chronic hemodialysis who are receiving supplemental erythropoietin therapy.
Dosage/Direction for Use
The dosage of Maxifer is expressed in terms of mg of elemental iron. Each mL contains elemental iron 20 mg.
Adults: Recommended Dose: 100 mg 1-3 times/week up to a total dose of 1,000 mg in 10 doses, may be repeated when needed. Frequency of dosing should be no more than 3 times/week. Patients may continue to require therapy with iron IV at the lowest dose necessary to maintain levels of hemoglobin, hematocrit and laboratory parameters of iron storage within acceptable limits.
Repletion Treatment of Iron Deficiency in Hemodialysis Patients: Recommended Dose: 100 mg by slow IV injection over 5 min or IV infusion over at least 15 min during the dialysis session. Most patients will require a minimum cumulative dose of elemental iron 1,000 mg, administered over 10 sequential dialysis sessions, to achieve a favorable hemoglobin or hematocrit response. Patients may continue to require therapy with Maxifer or other IV iron preparations at the lowest dose necessary to maintain target levels of hemoglobin, hematocrit and laboratory parameters of iron storage within acceptable limits.
Administration: Maxifer must only be administered IV either by slow injection or by infusion. In clinical trials, Maxifer was administered IV directly into the dialysis line.
Slow IV Injection: In chronic renal failure patients, Maxifer may be administered undiluted by slow IV injection into the dialysis line at a rate of 1 mL (iron 20 mg) solution per minute [ie, 5 min/ampoule not exceeding Maxifer (iron 100 mg) 1 ampoule/injection]. Discard any unused portion.
Infusion: Maxifer may also be administered by infusion (into the dialysis line for hemodialysis patients). The content of each vial must be diluted exclusively in a maximum of 100 mL of NaCl 0.9%, immediately prior to infusion. The solution should be infused at a rate of iron 100 mg over a period of at least 15 min. Unused diluted solution should be discarded.
Overdosage
Dosages of in excess of iron needs may lead to accumulation of iron in storage sites leading to hemosiderosis. Periodic monitoring of iron parameters eg, serum ferritin and transferrin saturation may assist in recognizing iron accumulation. Maxifer should not be administered to patients with iron overload and should be discontinued when serum ferritin levels equal or exceed established guidelines. Particular caution should be exercised to avoid iron overload where anemia unresponsive to treatment has been incorrectly diagnosed as iron deficiency anemia.
Symptoms: Symptoms associated with overdosage or infusing Maxifer too rapidly included hypotension, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema and cardiovascular collapse.
Treatment: Most symptoms have been successfully treated with IV fluids, hydrocortisone and/or antihistamines. Infusing the solution as recommended or at a slower rate may also alleviate symptoms.
Contraindications
Known hypersensitivity to iron sucrose injection or any of the inactive components of Maxifer. Patients with evidence of iron overload and in patients with anemia not caused by iron deficiency.
Warnings
Hypersensitivity reactions have been reported with injectable iron products. (See Precautions and Adverse Reactions.)
Special Precautions
General: Because body iron excretion is limited and excess tissue iron can be hazardous, caution should be exercised to withhold iron administration in the presence of evidence of tissue iron overload. Patients receiving Maxifer require periodic monitoring of hematologic and hemanitic parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Iron therapy should be withheld in patients with evidence of iron overload. Transferrin saturation values increase rapidly after IV administration of iron sucrose; thus serum iron values may be reliably obtained 48 hrs after IV dosing. (See Dosage & Administration and Overdosage.)
Hypersensitivity Reactions: Serious hypersensitivity reactions have been rarely reported in patients receiving Maxifer. No life-threatening hypersensitivity reactions were observed in studies A, B, C and 2 post-marketing safety studies. Several cases of mild or moderate reports worldwide were observed between 1992 and 2002 based on estimated use in >2 million patients. (See Adverse Reactions.)
Hypotension: Hypotension has been reported frequently in hemodialysis patients receiving iron IV. Hypotension following administration of Maxifer may be related to rate of administration and total dose administered. Caution should be taken to administer Maxifer according to recommended guidelines. (See Dosage & Administration.)
Carcinogenicity, Mutagenicity & Impairment of Fertility: No long-term studies in animals have been performed to evaluate the carcinogenic potential of Maxifer. It was not genotoxic in the Ames test, the mouse lymphoma cell (L5178YfTK+/-) forward mutation test, the human lymphocyte chromosome aberration test or the mouse micronucleus test. Maxifer at IV doses up to iron 15 mg/kg/day (about 1.2 times the recommended maximum human dose on a body surface area basis) was found to have no effect on fertility and reproductive performance of male and female rats.
Use in pregnancy: Pregnancy Category B: Teratology studies have been performed in rats at IV doses up to iron 13 mg/kg/day (about 0.5 times the recommended maximum human dose on a body surface area basis) and rabbits at IV doses up to iron 13 mg/kg/day (about 1 times the recommended maximum human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to Maxifer. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Maxifer should be used during pregnancy only if clearly needed.
Use in lactation: Maxifer is excreted in milk of rats. It is not known whether Maxifer is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Maxifer is administered to a nursing woman.
Use in children: Safety and effectiveness of Maxifer in pediatric patients have not been established. In a country where Maxifer is available for use in children, at a single site, 5 premature infants (<1,250 g weight) developed necrotizing enterocolitis and 2 of the 5 expired during or following a period when they received Maxifer, several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low-birth weight infants. No causal relationship to Maxifer or any other drugs could be established.
Use in the elderly: Studies A, B and C did not include sufficient numbers of subjects ≥65 years to determine whether they respond differently from younger subjects. Of the 1,051 patients in 2 post-marketing safety studies of Maxifer, 40% were ≥65 years. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Use In Pregnancy & Lactation
Use in pregnancy: Pregnancy Category B: Teratology studies have been performed in rats at IV doses up to iron 13 mg/kg/day (about 0.5 times the recommended maximum human dose on a body surface area basis) and rabbits at IV doses up to iron 13 mg/kg/day (about 1 times the recommended maximum human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to Maxifer. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Maxifer should be used during pregnancy only if clearly needed.
Use in lactation: Maxifer is excreted in milk of rats. It is not known whether Maxifer is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Maxifer is administered to a nursing woman.
Adverse Reactions
Exposure to Maxifer has been documented in 231 patients undergoing chronic hemodialysis in the previously mentioned clinical trials and in 1,051 patients undergoing hemodialysis in 2 post-marketing safety studies. About 1,600 hemodialysis patients treated with Maxifer have been reported in the medical literature.
The safety of Maxifer has been documented in 3 efficacy studies (A, B and C previously described) and 2 post-marketing studies involving a total of 1,282 patients. In the first post-marketing safety study, 665 chronic hemodialysis patients were treated with Maxifer doses of 100 mg at each dialysis session for up to 10 consecutive dialysis sessions for their iron deficiency or on a weekly basis for 10 weeks for maintenance of iron stores. Serious adverse events and drug-related nonserious adverse events were collected. In the second post-marketing safety study, 386 hemodialysis patients were exposed to a single dose of Maxifer (100 mg IV by slow injection over 2 min or 200 mg IV by slow injection over 5 min). The mean age of patients enrolled in the 2 post-marketing safety studies was 59 years, with a range of 20-93 years. Males made up 60% of the population. The ethnicity of the patients enrolled in the 2 studies included Blacks (44%), Caucasians (41%), Asians (3%), Hispanics (11%) and others (1%).
Adverse Events Observed in Studies A, B and C: Adverse reactions, whether or not related to Maxifer administration, reported by >5% of treated patients from a total of 231 patients in the 3 studies are as follows: Hypotension (36%), cramps/leg cramps (23%), nausea, headache, vomiting and diarrhea.
Adverse events, whether or not related to Maxifer administration, reported by >1% of treated patients from a total of 231 patients in the 3 studies are categorized as follows by body system either by investigator term or by COSTART terminology and ranked in order of decreasing frequency within each body system. Some of these symptoms may be seen in patients with chronic renal failure or on hemodialysis not receiving iron IV.
Body as a Whole: Headache, fever, pain, asthenia, feeling unwell, malaise and accidental injury.
General and Cardiovascular Disorders: Hypotension, chest pain, hypertension, hypervolemia.
Gastrointestinal System Disorders: Nausea, vomiting, abdominal pain, elevated liver enzymes, diarrhea.
Central and Peripheral Nervous System: Dizziness.
Musculoskeletal System: Cramps/leg cramps, musculoskeletal pain.
Respiratory System: Dyspnea, pneumonia, cough.
Skin and Appendages: Pruritus, application site reaction.
Adverse Events Observed in Two Post-Marketing Safety Studies: In the 2 post-marketing safety studies, 665 patients received multiple doses of Maxifer and 386 patients received a single dose of Maxifer. In the multiple dose study, 72% of the patients received up to 10 doses, 27% received between 11-30 doses and 1% received 40-50 doses of Maxifer; only serious adverse events and nonserious adverse events considered by the investigators to be drug-related were collected.
Adverse events reported by >1% of 1,051 treated patients are as follows: Congestive heart failure, sepsis and taste perversion.
Hypersensitivity Reactions: See Warnings and Precautions.
In studies A, B and C and 2 post-marketing safety studies, several patients experienced mild or moderate hypersensitivity reactions presenting with wheezing, dyspnea, hypotension, rashes or pruritus.
No serious or life-threatening hypersensitivity reactions associated with Maxifer administration were observed in these studies. From the post-marketing spontaneous reporting system, there were 83 reports of anaphylactoid reactions including patients who experienced serious or life-threatening reactions (anaphylactic shock, loss of consciousness or collapse, bronchospasm with dyspnea or convulsion) associated with Maxifer administration between 1992 and 2002 based on estimated use in >2 million patients.
One hundred thirty (11%) of the 1151 patients evaluated in the 4 US trials had prior other iron IV therapy and were reported to be intolerant (defined as precluding further use of that iron product). When these patients were treated with Maxifer, there were no occurrences of adverse events that precluded further use of Maxifer.
Drug Interactions
Maxifer should not be administered concomitantly with oral iron preparations since the absorption of oral iron is reduced.
Caution For Usage
Do not mix Maxifer with other medications or add to parenteral nutrition solutions for IV infusion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.
Storage
Store at temperatures not exceeding 30°C. Do not freeze. During shipment of Maxifer it is permitted to be stored at 15-30°C (59-86°F).
Shelf-Life: 3 years.
MIMS Class
Vitamins & Minerals (Pre & Post Natal) / Antianemics
ATC Classification
B03AC - Iron, parenteral preparations ; Used in the treatment of anemia
Presentation/Packing
Inj 20 mg/mL (sterile, single-dose amp) x 5 mL x 5's.
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