Tardiferon

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

Composition:

Active ingredient: 1 tablet contains 247.25 mg of dried ferrous sulfate, equivalent to 80 mg of iron (II);

Excipients: maltodextrin, microcrystalline cellulose, ammonio-methacrylate copolymer dispersion (type B), ammonio-methacrylate copolymer dispersion (type A), talc, glycerol dibehenate, triethyl citrate, yellow iron oxide (E 172), red iron oxide (E 172), titanium dioxide (E 171); Sepifilm LP010 (hypromellose, microcrystalline cellulose, stearic acid).

Pharmaceutical form. Prolonged-release tablets with coating.

Main physico-chemical properties: Round, orange-pink coated tablets.

Pharmacotherapeutic group.

Antianemic agents. Iron preparations. Divalent iron preparations for oral use. Ferrous sulfate.

ATC code B03A A07.

Pharmacological Properties.

Pharmacodynamics.

Tardiferon belongs to prolonged-action complex iron preparations. It contains ferrous iron ions, the use of which replenishes iron deficiency in the body and stimulates hematopoiesis. The drug restores iron levels necessary for hemoglobin synthesis.

Iron plays a key physiological role in many functions, such as oxygen transport, ATP production, DNA synthesis, and electron transfer.

Pharmacokinetics.

Absorption occurs in the duodenum and proximal segment of the small intestine.

The combination of ferrous sulfate with excipients ensures continuous and gradual release of iron. Iron absorption increases when body iron stores are depleted and decreases when iron stores are elevated.

Iron salts are generally poorly absorbed (10–20% of the administered dose). Gradual iron release promotes improved absorption over a prolonged period.

Iron absorption may be altered by concomitant intake of certain foods or beverages, as well as by co-administration with certain medicinal products (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction").

There is no active mechanism for iron excretion.

The average daily iron excretion in healthy subjects is 0.8–1 mg/day.

The main excretion pathways are the gastrointestinal tract (enterocyte desquamation, heme degradation due to extravasation of erythrocytes), the urogenital tract, and the skin. Excess absorbed iron is excreted in the feces.

Preclinical safety data.

Preclinical data obtained from standard pharmacological safety studies, repeated-dose toxicity, genotoxicity, carcinogenicity, as well as reproductive and developmental toxicity studies, revealed no special hazard to humans when used at recommended doses.

Clinical characteristics.

Indications.

• Iron-deficiency (hypochromic) anemias.
• Prevention of iron-deficiency anemias in pregnant women when adequate dietary iron intake cannot be ensured.

Contraindications.

Excess iron in the body, especially normo- or hypersideremic anemias, such as thalassemia, refractory anemia, anemia due to medullary insufficiency.

Hypersensitivity to the active substance or to any excipient.

Interaction with other medicinal products and other forms of interaction.

Since iron ions inhibit the absorption of oral tetracyclines, concomitant administration of these medicinal products should be avoided.

Combinations not recommended

• Iron salts (for parenteral administration)

Risk of lipotimia or shock due to rapid release of iron from its complex form and saturation of transferrin.

Combinations requiring special precautions

• Bisphosphonates

Reduced gastrointestinal absorption of bisphosphonates due to formation of poorly absorbable complexes.

Do not take iron salts simultaneously with bisphosphonates (if possible, an interval of at least 30 minutes to more than 2 hours should be ensured, depending on the bisphosphonate).

• Tetracyclines (for oral use)

Reduced gastrointestinal absorption of tetracyclines and iron.

Do not take iron salts simultaneously with tetracyclines (if possible, an interval of more than 2 hours should be ensured).

• Fluoroquinolones

Reduced gastrointestinal absorption of fluoroquinolones.

Do not take iron salts simultaneously with fluoroquinolones (if possible, an interval of more than 2 hours should be ensured).

• Penicillamine

Reduced gastrointestinal absorption of penicillamine.

Do not take iron salts simultaneously with penicillamine (if possible, an interval of more than 2 hours should be ensured).

• Zinc, strontium

Do not take iron salts simultaneously with zinc and strontium (if possible, an interval of more than 2 hours should be ensured).

• Thyroid hormones

Reduced gastrointestinal absorption of thyroid hormones.

Do not take thyroid hormones simultaneously with iron (if possible, an interval of more than 2 hours should be ensured).

• Cholestyramine

Reduced gastrointestinal absorption of iron.

Do not take iron salts simultaneously with cholestyramine (they should be administered, for example, 1–2 hours before or 4 hours after cholestyramine).

• Calcium

Reduced gastrointestinal absorption of iron salts due to calcium.

Do not take iron salts during meals containing calcium.

• Methyldopa, levodopa

Reduced gastrointestinal absorption of dopaminergic derivatives.

Do not take iron salts simultaneously with methyldopa and levodopa (if possible, an interval of more than 2 hours should be ensured).

• Salts of magnesium, aluminum, and calcium, oxides and hydroxides (gastrointestinal mineral preparations)

Reduced gastrointestinal absorption of iron salts.

Do not take iron salts simultaneously with gastrointestinal mineral preparations (if possible, an interval of more than 2 hours should be ensured).

• Other forms of interaction

Phytic acid (whole grains), polyphenols (tea, coffee, red wine), calcium (milk, dairy products), and certain proteins (eggs) significantly reduce iron absorption.

Do not take iron salts simultaneously with these food products (if possible, an interval of more than 2 hours should be ensured).

Special precautions for use

It should be noted that iron-deficiency anemias associated with inflammatory syndromes are not amenable to treatment with iron preparations.

In cases of anemia, the underlying etiological causes must be established.

The drug may darken stool color to black, which may interfere with the diagnosis of chronic gastrointestinal bleeding. The fecal occult blood test may sometimes yield false-positive results.

If tablets containing ferrous sulfate accidentally enter the respiratory tract (e.g., if aspirated), necrosis of the bronchial mucosa may occur, potentially leading to cough, hemoptysis, bronchial stenosis, and/or pulmonary infection (even if the aspiration occurred several days or months before symptom onset). Elderly patients and patients with swallowing difficulties should be treated only after careful assessment of the risk of aspiration of ferrous sulfate tablets. Alternative dosage forms should be considered. In case of accidental aspiration of tablets (e.g., choking), medical advice must be sought (see section "Adverse reactions").

According to published data, brown-black pigmentation of the gastrointestinal mucosa (pseudomelanosis/melanosis) rarely occurs in elderly patients receiving iron preparations who also have chronic kidney disease, diabetes mellitus, and/or hypertension. This pigmentation may interfere with gastrointestinal surgery and should be taken into account, especially when surgery is planned. Therefore, surgeons should be informed about iron intake, considering this risk (see section "Adverse reactions").

Due to the risk of oral ulceration and tooth discoloration, tablets should not be sucked, chewed, or held in the mouth; they should be swallowed whole with water.

Do not take together with medicinal products containing iron.

Use 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). Exacerbation may occur in patients with rheumatoid arthritis. To prevent constipation, the drug should be taken with a large amount of fluid.

Approximately every 4 weeks, the following parameters should be monitored to assess the degree of iron deficiency, response to treatment, and need for continued iron supplementation: hemoglobin, erythrocyte count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), reticulocyte count, serum iron, and transferrin.

Monitoring should include both correction of anemia (Hb, MCV) and restoration of iron stores (serum ferritin, serum transferrin receptor, and transferrin saturation coefficient).

Serum ferritin measurement allows assessment of iron accumulation; a serum ferritin level < 15 μg/L indicates absence of body iron stores.

Use during pregnancy or breastfeeding

There are limited data on the use of iron during the first trimester of pregnancy regarding the risk of malformations. Clinical studies indicate that iron supplementation during pregnancy does not affect birth weight, preterm delivery, or neonatal mortality.

Animal studies do not indicate reproductive toxicity.

Therefore, iron salts may be used during pregnancy if clinically indicated.

Iron is excreted in breast milk in small amounts. Its concentration does not depend on maternal intake. Consequently, no adverse effects on neonates/infants are expected.

Tardiferon may be used during breastfeeding.

Fertility

Animal studies have not shown any effect on fertility in males or females.

Ability to affect reaction speed when driving vehicles or operating machinery

Tardiferon has no effect or a negligible effect on the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

For oral use in adults and children aged 7 years and older.

The tablets should not be sucked, chewed, or held in the mouth; they must be swallowed whole with water. The tablets should be taken before or during meals (except for specific products mentioned in the section "Interaction with Other Medicinal Products and Other Forms of Interaction"), depending on gastrointestinal tolerance.

Prophylaxis.

Pregnant women: 1 tablet daily or 1 tablet every other day during the last two trimesters of pregnancy (or from the 4th month).

Treatment of iron-deficiency anemia.

Children aged 7 years: 1 tablet daily (in the morning); children aged 10 years and adults: 1–2 tablets daily (in the morning and evening).

Duration of treatment

Treatment should be continued long enough to correct anemia and replenish iron stores. Treatment of iron-deficiency anemia lasts from 3 to 6 months, depending on the degree of iron depletion, and may be extended after consultation with a physician.

Monitoring of efficacy is useful only after 3 months from the start of treatment and should include correction of anemia (Hb, MCV) and restoration of iron stores (serum ferritin, serum transferrin receptor, and transferrin saturation coefficient).

Children.

Not to be used in children under 7 years of age.

Overdose.

Cases of overdose with iron salts have been reported, particularly in children. The risk of toxicity associated with overdose begins at a dose of elemental iron of 20 mg/kg and increases significantly at 60 mg/kg.

Iron poisoning develops in 5 consecutive symptomatic stages:

• gastrointestinal stage, including signs of irritation of the gastrointestinal mucosa, most commonly abdominal pain, nausea, vomiting, diarrhea, and bleeding (hematemesis, melena), which may progress to necrosis;
• latent clinical stage, with stabilization or regression of gastrointestinal symptoms;
• systemic stage, characterized by metabolic acidosis with an anion gap, coagulopathy, and hemodynamic instability (hypovolemia, hypotension) leading to organ hypoperfusion (acute renal failure, lethargy and coma, often with seizures), potentially resulting in shock;
• hepatotoxic stage, the symptoms of which may range from elevated transaminases to coagulopathy and hepatic encephalopathy.

Even when symptoms of poisoning have subsided, gastrointestinal stricture due to gastrointestinal ulcer healing may still occur. Therefore, monitoring for suggestive signs is recommended.

Diagnosis is primarily based on clinical symptoms and confirmed by elevated serum iron levels. Abdominal X-ray may be performed to confirm the presence of tablets in the gastrointestinal tract. Treatment must be initiated as soon as possible:

• Symptomatic treatment: careful patient monitoring is required. Shock, dehydration, and acid-base disturbances should be managed according to standard practices in specialized units (respiratory support, volume expansion, hydro-electrolyte balance, and maintenance of diuresis).
• Gastrointestinal decontamination: decontamination may be considered under specialized conditions in specific situations but should not be routinely applied. In particular, whole bowel irrigation with polyethylene glycol solution may be considered if a significant number of iron tablets or concretions are visible on abdominal X-ray. It should be continued until clear effluent is obtained.
• Chelation therapy: depending on serum iron concentration, severity, or persistence of symptoms, a chelating agent is recommended in cases of severe poisoning. Deferoxamine is the agent of first choice according to therapeutic protocols. For more detailed information, refer to the medical instructions for deferoxamine.

Adverse Reactions

Adverse reactions are categorized according to frequency as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10000, < 1/1000), very rare (< 1/10000), and not known (available data do not allow estimation of the frequency of these reactions).

Immune system disorders

Not known: Hypersensitivity reactions, urticaria.

Respiratory, thoracic and mediastinal disorders

Uncommon: Laryngeal edema.

Not known: 2pulmonary necrosis, 2pulmonary granuloma, 2bronchial stenosis, 2pharyngeal ulcers.

Gastrointestinal disorders

Common: Constipation, diarrhea, abdominal distension, abdominal pain, change in stool color, nausea.

Uncommon: Abnormal bowel movements, dyspepsia, vomiting, gastritis.

Not known: 1tooth discoloration, 1oral ulceration, gastrointestinal melanosis, 2esophageal lesions, 2esophageal ulcers.

Skin and subcutaneous tissue disorders

Uncommon: Pruritus, erythematous rash.

1 Tooth discoloration and oral ulceration may occur with incorrect use, such as chewing, sucking, or holding the tablets in the mouth.

2 In patients, especially elderly patients and those with swallowing difficulties, esophageal lesions (esophageal ulcers), pharyngeal ulcers, bronchial granulomas and/or bronchial necrosis may occur due to accidental aspiration of tablets containing ferrous sulfate into the respiratory tract (see section "Special Warnings and Precautions for Use").

Other special population groups.

According to published data, brown-black pigmentation of the gastrointestinal mucosa (pseudomelanosis/melanosis) has been rarely observed in elderly patients receiving iron-containing medications who also have chronic kidney disease, diabetes mellitus, and/or hypertension. This pigmentation may interfere with gastrointestinal surgical procedures and should be taken into account (see section "Special Warnings and Precautions for Use").

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.

Shelf life

3 years.

Storage conditions

Keep in the original packaging.

Keep out of the reach of children.

Packaging

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

Prescription status

Prescription only.

Manufacturer

Pierre Fabre Médicament Production.

Pierre Fabre Medicament Production.

Manufacturer's name and address of the place of business

Progipharm production site, Rue du Lycée, 45500 Gien, France.

site Progipharm, Rue du Lycee, 45500 Gien, France.