Maltofer®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MALTIFER® (MALTOFER®)

Composition:

Active substance:
1 tablet contains 357 mg of iron (III) hydroxide polymaltose complex, equivalent to 100 mg of iron;

Excipients:
microcrystalline cellulose, cocoa powder, sodium cyclamate, polyethylene glycol 6000, talc, vanillin, dextrates, chocolate flavor.

Pharmaceutical form.
Chewable tablets.

Main physicochemical properties:
brown tablets with white specks and a score line.

Pharmacotherapeutic group.
Antianemic agents. Oral iron (III) preparations. ATC code B03AB05.

Pharmacological Properties.

Pharmacodynamics.

The surface of the iron (III) hydroxide core in the polymaltose complex is surrounded by non-covalently bound polymaltose molecules, resulting in an average total molecular weight of approximately 50 kDa. The structure of the iron (III) hydroxide core within the iron-polymaltose complex resembles that of ferritin—the physiological protein storage form of iron. The iron polymaltose complex is stable and does not release large amounts of free iron under normal physiological conditions. Due to its size, diffusion of the iron polymaltose complex across the mucosa 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 utilized for hemoglobin synthesis in the bone marrow or stored primarily in the liver in the form bound to ferritin.

Clinical Efficacy.

The efficacy of Maltofer® in normalizing hemoglobin levels and replenishing 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 iron polymaltose complex were used in these studies. The primary goal of oral iron replacement therapy is to maintain the body's endogenous iron stores within normal limits (to prevent iron deficiency, for example, in conditions of increased demand), to replenish iron stores, or to correct existing iron deficiency anemia.

Clinical Studies in Adults.

A total of 11 controlled clinical trials evaluated monotherapy with the iron (III) hydroxide polymaltose complex compared to placebo and/or oral iron (II) preparations.

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

The efficacy of the iron polymaltose complex in treating adult patients with iron deficiency anemia was compared to 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 iron polymaltose complex and 238 received iron (II) sulfate. The mean baseline hemoglobin level was 10.35 ± 0.92 g/dL (in the iron polymaltose complex group) and 10.20 ± 0.93 g/dL (in the iron (II) 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 iron polymaltose complex group) and 11.94 ± 1.84 g/dL (in the iron (II) sulfate group), p = 0.93. The increase in hemoglobin level was 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) has been investigated in numerous clinical studies 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 iron (III) hydroxide polymaltose 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 higher the absorption). It has been established that, unlike iron (II) salts, food does not negatively affect the bioavailability of iron from Maltofer®: a clinical study demonstrated a significant increase in iron bioavailability when administered with food, while three other studies showed only a positive trend without statistically significant clinical effect.

Elimination.

Iron not absorbed is excreted in the 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 to any component of the medicinal product;
• excessive iron content in the body (e.g., hemochromatosis, hemosiderosis);
• disorders of iron excretion mechanisms (lead anemia, sideroachrestic anemia, thalassemia);
• anemias not caused by iron deficiency (e.g., hemolytic anemia, megaloblastic anemia due to vitamin B12 deficiency).

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 combined with vitamin D3, bromazepam, magnesium aspartate, D-penicillamine, methyldopa, paracetamol, and auranofin showed no interaction with iron(III) hydroxide polymaltose complex.

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

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

Concomitant use of parenteral iron preparations and Maltofer® is not recommended, as such use would inhibit absorption of orally administered iron preparations. Parenteral iron preparations may be used only when treatment with oral iron preparations is inappropriate.

The use of the medicinal product does not affect the results of tests for occult blood (hemoglobin-sensitive tests); therefore, there is no need to discontinue treatment with the medicinal product.

Special precautions for use

Treatment of anemia should always be carried out 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 after starting treatment), the treatment regimen should be reassessed.

Caution should be exercised in patients receiving repeated blood transfusions, as red blood cells already contain iron stores, and administration of the drug may lead to iron overload. Infections and tumors may cause the development of anemia. Iron-containing preparations for oral use may be administered after the underlying disease has been treated, taking into account the benefit-risk ratio.

When prescribing the drug to patients with diabetes mellitus, it should be considered that 1 chewable tablet contains 0.03 bread units.

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

Administration of the iron polymaltose complex may result in dark-colored stools; however, this is not of clinical significance.

Clinical data on the use of Maltifer® in patients with hepatic or renal insufficiency are limited. A careful benefit-risk assessment should be performed before prescribing Maltifer® to these patients.

One chewable tablet of Maltifer® contains 10 mg of sodium. This amount corresponds to 0.5% of the WHO recommended maximum daily sodium intake for adults, which is 2 g.

Use during pregnancy or breastfeeding

Data on use during the first trimester of pregnancy do not indicate adverse effects on pregnancy or on fetal or neonatal health. Epidemiological data are lacking. Animal studies have not revealed direct or indirect harmful effects on pregnancy, embryonal or fetal development. However, the drug should be used with caution during pregnancy.

Human breast milk contains iron bound to lactoferrin. It is unknown how much iron from the iron (III) hydroxide polymaltose complex passes into breast milk.

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

Ability to affect reaction speed when driving or operating machinery

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

Dosage and Administration.

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

Treatment of iron deficiency without anaemia.
The recommended dose for adolescents aged 12 years and older and adults is 50–100 mg of iron. One tablet of Maltofer® contains 100 mg of iron. A 50 mg dose of iron can be achieved by using other dosage forms of Maltofer®.

Treatment of iron-deficiency anaemia.
The recommended dose for adolescents aged 12 years and older and adults is 1–3 tablets of Maltofer® (100–300 mg of iron).

The daily dose may be taken once daily or divided into several doses. Maltofer® chewable tablets should be taken during or immediately after a meal; they may be chewed or swallowed whole.

The duration of treatment for iron-deficiency anaemia until normalization of haemoglobin levels is on average 3–5 months. After this, administration of the medicinal product should be continued at the appropriate dosage for treatment of iron deficiency without anaemia to replenish iron stores. The duration of treatment for latent iron deficiency without anaemia is 1–2 months.

Children.
The medicinal product is indicated for use in children aged 12 years and older. For children under 12 years of age, Maltofer® syrup or Maltofer® oral drops are recommended.

Overdose.

In case of overdose, iron intoxication or accumulation is unlikely due to the low toxicity of iron(III) hydroxide polymaltose complex (in mice and rats, the dose causing death in 50% of animals (LD50) is > 2000 mg iron/kg body weight); iron absorption is expected to become saturated.
No cases of accidental overdose with fatal outcomes have been reported.

Adverse Reactions

Undesirable effects are classified according to their frequency of occurrence into the following categories: very common (> 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (< 1/1,000).

The safety and tolerability of Maltifer® were evaluated based on a meta-analysis of data from 24 publications and clinical trial reports involving 1,473 patients who received the drug. The most significant adverse drug reactions reported in these trials involved four organ system classes (see below).

Change in stool color is a well-known adverse reaction associated with oral iron preparations; however, this phenomenon is not clinically significant and is often not reported. Other common adverse events included gastrointestinal disorders (nausea, constipation, diarrhea, and abdominal pain).

Gastrointestinal disorders

Very common: change in stool color*.

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

Uncommon: vomiting (including vomiting, belching), change in tooth enamel color, 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 observed in the meta-analysis 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 reaction.

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

Shelf life.
5 years.

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

Packaging.
10 tablets in a blister; 3 blisters per cardboard box.

Prescription status.
Prescription only.

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

Manufacturer's name and address of the place of business.
Rechenstrasse 37, 9014 St. Gallen, Switzerland / Rechenstrasse 37, 9014 St. Gallen, Switzerland.