Maltofer®

Pharmacological properties.

Pharmacodynamics.

The surface of the iron (III) hydroxide core within the polymaltose complex is surrounded by non-covalently bound polymaltose molecules, resulting in an average molecular weight of approximately 50 kDa. The structure of the iron (III) hydroxide core in the iron-polymaltose complex resembles that of ferritin—the physiological protein storage form of iron. The polymaltose complex of iron hydroxide is stable and does not release significant amounts of iron under normal physiological conditions. Due to its size, diffusion of the polymaltose iron complex across the mucous membrane is approximately 40 times lower than that of most water-soluble iron (II) salts, which exist in aqueous solutions as the hexaaqua-iron (II) complex. Iron from the polymaltose complex is absorbed in the intestine via active mechanisms.

Absorbed iron binds to transferrin and is used for hemoglobin synthesis in the bone marrow or stored primarily in the liver in the form of ferritin-bound iron.

Clinical efficacy.

The efficacy of Maltofer® in normalizing hemoglobin levels and restoring iron stores, compared to placebo or similar iron preparations in various dosage forms, has been demonstrated in numerous clinical studies involving infants, children, adolescents, and adults. Both solid and liquid dosage forms of the polymaltose iron complex were used in these studies. The primary goal of oral iron replacement therapy is to maintain the body's iron stores within the normal range (for prevention of iron deficiency, e.g., in cases of increased demand), replenish iron stores, or correct existing iron-deficiency anemia.

Clinical studies in adults.

A total of 11 controlled clinical trials of monotherapy with the polymaltose complex of iron (III) hydroxide were conducted, comparing it with placebo and/or oral iron (II) preparations.

Over 900 patients participated in these studies, approximately 500 of whom received monotherapy with the polymaltose complex of iron (III) hydroxide. At the beginning of treatment, no significant differences in hematological parameters or iron status (hemoglobin (Hb) level, mean corpuscular volume (MCV), serum ferritin) were observed between the study populations. Oral replacement therapy with the polymaltose iron complex at doses of 100–200 mg of iron/day over several weeks, up to six months, resulted in clinically significant increases in iron and hematological parameters at the end of therapy compared to baseline values. Improvement in hematological parameters (Hb, MCV, serum ferritin) after a 12-week course of therapy with the polymaltose iron complex was comparable to that achieved with iron (II) sulfate.

The efficacy of the polymaltose iron complex in treating adult patients with iron-deficiency anemia was compared with that of iron (II) sulfate in a meta-analysis of six prospective randomized clinical trials. The total number of patients included in the meta-analysis was 557; 319 received the polymaltose iron hydroxide complex and 238 received iron (II) sulfate. The mean baseline hemoglobin level was 10.35 ± 0.92 g/dL (in the polymaltose complex group) and 10.20 ± 0.93 g/dL (in the iron sulfate group). After a treatment period of 8–13 weeks with equivalent doses, the mean hemoglobin level was 12.13 ± 1.19 g/dL (in the polymaltose complex group) and 11.94 ± 1.84 g/dL (in the iron sulfate group), p = 0.93. Hemoglobin level increases were greater with longer treatment duration for both agents.

Clinical studies in children and adolescents.

The use of Maltofer® in the treatment of children and adolescents (up to 18 years of age) was investigated in numerous clinical trials involving over 1000 patients. The efficacy of Maltofer® in improving iron parameters has been confirmed compared to placebo or other iron preparations.

Pharmacokinetics.

Absorption and distribution. Studies with radiolabeled polymaltose iron hydroxide complex demonstrated a good correlation between iron absorption and iron accumulation in hemoglobin. There is a correlation between the degree of iron deficiency and the relative amount of iron absorbed (the greater the iron deficiency, the better the absorption). Food does not negatively affect the bioavailability of iron from Maltofer®, unlike iron (II) salts: a clinical study demonstrated that iron bioavailability significantly increases when taken with food, while three other studies showed only a positive trend without a statistically significant clinical effect.

Elimination.

Unabsorbed iron is excreted in feces.

Clinical characteristics.

Indications.

Treatment of iron deficiency without anemia and iron-deficiency anemia.

Iron deficiency and its severity must be confirmed by appropriate laboratory tests.

Contraindications.

• Known hypersensitivity or intolerance to the active substance or any component of the medicinal product;
• excess iron in the body (e.g., hemochromatosis, hemosiderosis);
• impaired iron elimination mechanisms (lead anemia, sideroblastic anemia, thalassemia);
• anemias not caused by iron deficiency (e.g., hemolytic anemia, vitamin B12 deficiency megaloblastic anemia).

Interaction with other medicinal products and other forms of interaction.

Studies in rats using tetracycline, aluminum hydroxide, acetylsalicylic acid, sulfasalazine, calcium carbonate, calcium acetate, calcium phosphate with vitamin D3, bromazepam, magnesium aspartate, D-penicillamine, methyldopa, paracetamol, and auranofin did not reveal any interaction with the polymaltose complex of iron (III) hydroxide.

In vitro studies showed no interaction between the polymaltose complex of iron (III) hydroxide and food components such as phytic acid, oxalic acid, tannins, sodium alginate, choline and choline salts, vitamin A, vitamin D3, vitamin E, soybean oil, and soy flour. These results suggest that the polymaltose complex of iron (III) hydroxide can be taken during or immediately after meals.

Interaction between the polymaltose complex of iron (III) hydroxide and tetracycline or aluminum hydroxide was investigated in three clinical trials (crossover studies involving 22 patients each). No significant reduction in tetracycline absorption was observed. Tetracycline plasma concentrations did not fall below the level required for bacteriostatic action. The use of aluminum hydroxide and tetracycline did not reduce iron absorption from the polymaltose iron hydroxide complex. Therefore, the polymaltose complex of iron (III) hydroxide can be used simultaneously with tetracyclines, other phenolic compounds, and aluminum hydroxide.

Concomitant use of parenteral iron preparations and Maltofer® is not recommended, as this may inhibit the absorption of orally administered iron. Parenteral iron preparations should only be used when oral therapy is unsuitable.

The use of the medicinal product does not affect the results of the fecal occult blood test (hemoglobin-sensitive), so there is no need to discontinue treatment.

Special precautions.

Treatment of anemia should always be conducted under medical supervision. If there is no improvement in hematological parameters (an increase in hemoglobin levels by approximately 20–30 g/L within 3 weeks of starting treatment), the treatment regimen should be re-evaluated.

Caution should be exercised in patients receiving repeated blood transfusions, as red blood cells already contain iron stores, and administration of the medicinal product may lead to iron overload. Infections and tumors may cause anemia. Oral iron preparations may be administered after treatment of the underlying condition, considering the benefit-risk ratio.

Maltofer®, syrup, contains a small amount of ethanol (alcohol), less than 100 mg in 30 mL of solution (maximum daily dose).

When prescribing the medicinal product to patients with diabetes mellitus, it should be noted that 1 mL of syrup contains 0.04 bread units.

The medicinal product should not be administered to patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency, as Maltofer ® , syrup, contains sucrose and sorbitol.

Iron preparations should be used with caution in patients with the following conditions: leukemia, chronic liver and kidney diseases, inflammatory gastrointestinal disorders, peptic ulcer of the stomach and duodenum, intestinal diseases (enteritis, ulcerative colitis, Crohn's disease).

Dark stool color may occur during treatment with the polymaltose iron complex, but this is not clinically significant.

1 mL of Maltofer ® syrup contains 1 mg of sodium. This amount is equivalent to 0.05% of the WHO recommended maximum daily sodium intake for adults (2 g).

1 mL of Maltofer ® syrup contains 0.28 g of sorbitol. Sorbitol may cause gastrointestinal disturbances and mild laxative effects. This medicinal product should not be used by patients with hereditary fructose intolerance.

1 mL of Maltofer ® syrup contains 200 mg of sucrose. This should be considered in patients with diabetes mellitus. Sucrose may be harmful to teeth.

Maltofer ® contains methylparahydroxybenzoate (E 218) and propylparahydroxybenzoate (E 216), which may cause allergic reactions (possibly delayed).

Use during pregnancy or breastfeeding.

Data on use during the first trimester of pregnancy do not indicate adverse effects on pregnancy or fetal or neonatal health. Epidemiological data are lacking. Animal studies have not shown direct or indirect harmful effects on pregnancy, embryonic or fetal development. However, the medicinal product should be used cautiously during pregnancy.

Human breast milk contains iron bound to lactoferrin. It is unknown how much iron from the polymaltose complex of iron (III) hydroxide passes into breast milk. It is unlikely that Maltofer® will have an adverse effect on a breastfed infant.

Use of Maltofer ® during pregnancy or breastfeeding is recommended only after consultation with a physician. A benefit-risk assessment should be performed.

Ability to affect reaction rate when driving or operating machinery.

Appropriate studies have not been conducted. It is unlikely that Maltofer ® affects reaction speed during driving or operating complex machinery.

Method of administration and dosage.

The dose and duration of treatment depend on the degree of iron deficiency.

The daily dose can be taken once or divided into several doses.

Maltofer ® should be taken during or immediately after meals.

The measuring cap provided in the Maltofer ® syrup packaging allows accurate dosing. Maltofer ® syrup can be mixed with fruit or vegetable juices or with infant formula. A slight color change of the mixture does not affect the efficacy or taste of the medicinal product.

The duration of treatment for iron-deficiency anemia until normalization of hemoglobin levels is on average 3–5 months. After this, administration of the medicinal product should continue at an appropriate dose for treating iron deficiency without anemia to restore iron stores. The duration of treatment for iron deficiency without anemia is 1–2 months.

Daily iron dose.

*This dosage can be achieved by using Maltofer® oral drops, 50 mg/mL.

Children. The drug may be used in children from birth. Due to the need for very low doses of the drug in premature infants, Maltofer® oral drops are recommended.

Overdose.

In case of overdose, intoxication or iron accumulation is unlikely due to the low toxicity of the iron (III) hydroxide polymaltose complex (for mice and rats the dose causing death in 50% of animals (LD₅₀) is > 2000 mg iron/kg body weight); saturation of iron absorption is expected . There have been no reports of accidental overdose resulting in death.

Adverse reactions.

Adverse events are classified according to frequency of occurrence into the following categories: very common ( > 1/10), common (< 1/10, ≥ 1/100), uncommon (< 1/100, ≥ 1/1000), rare (< 1/1000).

The safety and tolerability of Maltofer® were evaluated based on a meta-analysis of data from 24 publications and clinical trial reports involving 1473 patients who received the drug. The most significant adverse drug reactions reported in these trials involved four organ system classes (see below).

Discoloration of stool is a well-known adverse reaction associated with oral iron preparations, but this phenomenon is not clinically significant and is often not reported. Other common adverse events included gastrointestinal disturbances (nausea, constipation, diarrhea, and abdominal pain).

Immune system disorders.

Very rare: allergic reactions.

Gastrointestinal disorders.

Very common: change in stool color*.

Common: diarrhea, nausea, abdominal pain (including abdominal pain, dyspepsia, epigastric discomfort, bloating), constipation.

Uncommon: vomiting (including vomiting, belching), discoloration of dental enamel, gastritis.

Skin and subcutaneous tissue disorders.

Uncommon: pruritus, rash (including rash, macular rash, bullous rash**, urticaria**, erythema**).

Nervous system disorders.

Uncommon: headache.

Musculoskeletal and connective tissue disorders.

Rare: muscle spasms (including involuntary muscle contractions, tremor), myalgia.

*The frequency of stool color change based on the meta-analysis results is lower, although this is a well-known adverse event associated with oral iron preparations. Therefore, stool color change has been classified as a very common adverse event.

**Information on these events was obtained from spontaneous post-marketing reports; according to evaluation, the frequency is < 1/491 (upper limit of 95% confidence interval).

Maltofer® syrup contains parahydroxybenzoate as a preservative, which may cause allergic reactions (possibly delayed).

Shelf life. 3 years.

Storage conditions. Store in a place protected from light at a temperature not exceeding 25 °C. Keep out of reach of children!

Packaging. 150 mL in a bottle; 1 bottle with a measuring cap in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Vifor (International) Inc., Switzerland / Vifor (International) Inc., Switzerland.

Manufacturer's address and place of business.

Rechenstrasse 37, 9014 St. Gallen, Switzerland / Rechenstrasse 37, 9014 St. Gallen, Switzerland.