AQUAPHERROL

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AQUAFERROL (AQUAFERROL)

Composition:

Active substance: 1 ml of syrup contains 35.7 mg of iron(III) hydroxide polymaltose complex, equivalent to 10 mg of iron;

Excipients: white crystalline sugar, sorbitol solution, non-crystallizing (E 420), methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), ethanol 96%, caramel flavor, sodium hydroxide, purified water.

Pharmaceutical form. Syrup.

Main physicochemical properties: dark brown syrup.

Pharmacotherapeutic group.

Antianemic agents. Oral iron(III) preparations.

ATC code B03A B05.

Pharmacological Properties

Pharmacodynamics

The surface of the iron (III) hydroxide polynuclear core within the iron-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 polynuclear core in 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, the diffusion of the iron-polymaltose 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 either used for hemoglobin synthesis in the bone marrow or stored primarily in the liver in a form bound to ferritin.

Clinical Efficacy

The efficacy of the medicinal product in normalizing hemoglobin levels and replenishing iron stores, compared to placebo or other 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 the normal range (for prevention of iron deficiency, e.g., 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 studies of monotherapy with iron (III) hydroxide polymaltose complex were conducted, comparing it with placebo and/or oral iron (II) preparations.

More than 900 patients participated in these studies, approximately 500 of whom received monotherapy with iron (III) hydroxide polymaltose complex. At the start of treatment, no significant differences in hematological parameters and iron status markers (hemoglobin [Hb], mean corpuscular volume [MCV], serum ferritin) were observed between the study groups. Oral replacement therapy with the iron-polymaltose complex at doses of 100–200 mg iron/day over several weeks, up to 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 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 iron-polymaltose hydroxide 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 averaging 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. Hemoglobin level increases were greater with longer treatment duration for both agents.

Clinical Studies in Children and Adolescents

The use of the medicinal product 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 the medicinal product in improving iron parameters has been confirmed compared to placebo or other iron preparations.

Pharmacokinetics

Absorption and Distribution. Studies using radiolabeled iron-polymaltose hydroxide complex demonstrated a good correlation between iron absorption and iron accumulation in hemoglobin. A correlation exists between the degree of iron deficiency and the relative amount of iron absorbed (the greater the iron deficiency, the higher the absorption). Food intake, in contrast to iron (II) salts, does not negatively affect the bioavailability of iron from the medicinal product: a clinical study demonstrated a statistically significant increase in iron bioavailability when administered with food, while three other studies showed only a positive trend without a statistically significant clinical effect.

Metabolism and Excretion

Iron that is not absorbed is excreted in feces.

Clinical characteristics.

Indications.

Treatment of iron deficiency without anemia (latent iron deficiency) and iron deficiency anemia (clinically evident iron deficiency).

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;
• Excessive iron content in the body (e.g., hemochromatosis, hemosiderosis);
• Disorders of iron excretion mechanisms (lead poisoning anemia, sideroachrestic anemia, thalassemia);
• Anemia 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, aluminium hydroxide, acetylsalicylic acid, sulfasalazine, calcium carbonate, calcium acetate, calcium phosphate combined with vitamin D3, bromazepam, magnesium aspartate, D-penicillamine, methyldopa, paracetamol, and auranofin did not reveal any interaction with the iron(III) hydroxide polymaltose complex.

In vitro studies showed no interaction between the 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, vitamin E, soybean oil, and soy flour. Study results indicate that the iron(III) hydroxide polymaltose complex can be administered during or immediately after food intake.

Interaction between the iron(III) hydroxide polymaltose complex and tetracycline or aluminium hydroxide was investigated in three clinical studies (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 aluminium hydroxide and tetracycline did not reduce iron absorption from the iron(III) hydroxide polymaltose complex. Therefore, the iron(III) hydroxide polymaltose complex may be used concomitantly with tetracyclines, other phenolic compounds, and aluminium hydroxide.

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

Administration of Aquaferrol does not affect the results of fecal occult blood tests (hemoglobin-sensitive tests); therefore, there is no need to discontinue its use.

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 re-evaluated.

Caution is advised 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. Oral iron preparations may be administered after treatment of the underlying condition, taking into account the benefit-risk ratio.

Aquaferrol Syrup contains a small amount of ethanol – less than 100 mg in 20 mL of solution.

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

The medicinal product Aquaferrol must not be administered to patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency, as the product contains sugar and sorbitol.

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

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

1 mL of Aquaferrol syrup contains 1 mg of sodium. This amount corresponds to 0.05% of the WHO recommended maximum daily intake of sodium for adults, which is 2 g.

1 mL of Aquaferrol syrup contains 400.0 mg 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 Aquaferrol syrup contains 200.0 mg of sugar. This should be taken into account in patients with diabetes mellitus. Sugar may be harmful to teeth.

The medicinal product Aquaferrol contains methylparaben (E 218) and propylparaben (E 216), which may cause allergic reactions (possibly delayed).

Use during pregnancy or breastfeeding.

Data on the use of the drug during the first trimester of pregnancy do not indicate any adverse effects on pregnancy or on the health of the fetus or newborn. Epidemiological data are lacking. Animal studies have not revealed any direct or indirect harmful effects on pregnancy, embryonic or fetal development. Nevertheless, 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.

It is unlikely that administration of Aquaferrol will have any adverse effect on a breastfed infant.

Use of Aquaferrol 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.

No specific studies have been conducted. It is unlikely that Aquaferrol affects reaction speed during driving or operating complex machinery.

Dosage and Administration.

The daily dose of the medication and duration of treatment depend on the degree of iron deficiency (see the daily dosage table).

The daily dose can be taken once or divided into several doses, during or immediately after meals.

The measuring cup provided with Aquaferrol can be used to accurately measure the required dose. Aquaferrol syrup may be mixed with fruit or vegetable juices or with infant formula. A slight change in the color of the mixture does not affect the efficacy or taste of the preparation.

The treatment duration for iron-deficiency anemia is on average 3–5 months until hemoglobin levels normalize. After this, the medication should be continued at the appropriate dosage for treating iron deficiency without anemia, in order to restore iron stores. The treatment duration for iron deficiency without anemia is 1–2 months.

Daily dosage table

Children.

The drug can be used in children from birth. Due to the need for very small doses in premature infants, it is recommended to use similar medicinal products with a lower concentration of the active substance.

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. No cases of accidental overdose with fatal outcome have been reported.

Adverse Reactions.

Adverse reactions are classified according to the frequency of occurrence into the following categories: very common (≥ 1/10), common (< 1/10, ≥ 1/100), uncommon (< 1/100, ≥ 1/1000). The safety and tolerability of the drug Aquaferrol were assessed based on the results of a meta-analysis of data from 24 publications and clinical trial reports involving 1473 patients who received the drug. The most significant adverse 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, but this phenomenon is not clinically significant and is often not reported. Other common adverse events included gastrointestinal disorders (nausea, constipation, diarrhea, and abdominal pain).

Immune system

Very rare: allergic reactions.

Gastrointestinal tract

Very common: change in stool color*.

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

Uncommon: vomiting (including vomiting, belching), change in tooth enamel color, gastritis.

Skin and subcutaneous tissue

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

Nervous system

Uncommon: headache.

Musculoskeletal and connective tissue

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

*The incidence rate of stool color change according to 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 reaction.

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

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

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25°C.

Keep out of reach of children.

Packaging.

125 ml in a bottle; 1 bottle with a measuring cup in a carton.

Prescription status. Prescription only.

Manufacturer.

JSC "Tekhnolog".

Manufacturer's address and location of its business activities.

8 Stara Prorina Street, Uman, Cherkasy region, 20300, Ukraine.