Tot’hema^® (Solution) Instructions for Use

Marketing Authorization Holder

Laboratoire Innotech International (France)

Manufactured By

Innothera Chouzy (France)

Contact Information

INNOTEK LLC (Russia)

ATC Code

B03AE10 (Iron preparations in combination with other drugs)

Dosage Form

Tot’hema®

Oral solution: 10 ml amp. 20 pcs.

Dosage Form, Packaging, and Composition

Oral solution dark brown, with a characteristic odor; a small amount of sediment may be present.

Excipients: glycerol, liquid dextrose (glucose), sucrose, anhydrous citric acid, sodium citrate dihydrate, sodium benzoate, polysorbate 80, caramel color (E150c)*, “Tutti-frutti” flavor**, purified water.

* Composition of caramel color (E150c): dextrose (glucose), ammonium hydroxide.
** Composition of “Tutti-frutti” flavor: isoamyl acetate, isoamyl butyrate, benzaldehyde, ethylmethylphenylglycidate, gamma-undecalactone, ethyl vanillin, ethanol, water.

10 ml – double-ended ampoules made of yellow type III glass (10) – cardboard trays (2) – cardboard packs.

Clinical-Pharmacological Group

Antianemic drug

Pharmacotherapeutic Group

Antianemic drugs; iron preparations; other combined iron preparations

Pharmacological Action

Tot’hema^® is a combined antianemic preparation containing ferrous iron in the form of the organic salt iron gluconate hydrate, as well as Manganese gluconate and Copper gluconate.

Pharmacodynamics

Iron, being a part of numerous cellular structures and participating in the activity of many enzymatic systems (cytochromes, catalases), plays a very important role in oxygen transport and oxidative metabolic processes, and is also an essential element for the human body, which is particularly necessary for ATP production, DNA synthesis, and electron transfer. Iron is the central atom of heme groups embedded in hemoglobin and is therefore necessary for hemoglobin formation.

Iron preparations help eliminate iron deficiency in the body and prevent its occurrence if there is an increased need for iron or its insufficient reserves.

Pharmacokinetics

Absorption

Iron is actively absorbed primarily in the duodenum and jejunum. Maximum absorption is observed when iron is taken on an empty stomach. Absorption varies and depends on the body’s iron stores and physiological needs. In iron deficiency states, its absorption is enhanced. The absorption of iron can be affected by the simultaneous intake of certain foods, beverages, or certain medicines. Copper may positively influence iron transport in enterocytes.

Distribution

After absorption, the main part of iron binds to transferrin and is transported to the bone marrow, where it is captured by erythroid cells of the bone marrow for hemoglobin synthesis; the remainder is contained in the blood and deposited in organs in the form of ferritin, hemosiderin, and myoglobin.

Metabolism

Iron, copper, and manganese are metal ions that are not metabolized in the liver.

Excretion

The main routes of excretion are the gastrointestinal tract (desquamation of erythrocytes, heme breakdown during erythrocyte extravasation), the genitourinary tract, and the skin.

The main route of excretion for manganese and copper is with bile.

Indications

• Treatment of iron deficiency anemia (IDA) in adults and children from 3 months of age;
• Prevention of iron deficiency in risk groups:
  • During pregnancy;
  • In children born to mothers with iron deficiency;
  • In cases of insufficient dietary iron intake;
  • In blood donors.

ICD codes

Dosage Regimen

Orally.

Shake the ampoule before opening.

The contents of the ampoule are dissolved in plain or sweetened water.

Tear off a piece of cardboard along the dotted line from the pack and fold it in half to safely break off the tips of the ampoule. Break off the tips of the ampoule from both sides, as shown in the picture, and pour the contents of the ampoule into a glass.

The preparation is preferably taken before meals, but the time of administration, and sometimes the dose, may be adjusted depending on tolerance from the digestive system.

The daily dose can be divided into several doses or taken at one time.

One ampoule contains 50 mg of elemental iron.

Treatment of iron deficiency anemia

Infants from 3 months and children 3 mg of elemental iron per 1 kg of body weight per day, not exceeding 60 mg.

Adults from 100 to 150 mg of elemental iron per day, i.e., from 2 to 3 ampoules per day, once or in several doses.

Prevention of iron deficiency

Children from 3 months to 5 years 2 mg of elemental iron per 1 kg of body weight per day, but not more than 30 mg.

Children from 6 years and older, adults, including blood donors 50 mg of elemental iron per day, i.e., 1 ampoule per day.

Pregnant women 50 mg of elemental iron per day, i.e., 1 ampoule per day during the last 2 trimesters of pregnancy (or from the 4th month).

Special patient groups

Patients with renal insufficiency dose adjustment is generally not required.

Patients with hepatic insufficiency dose adjustment is generally not required.

Duration of use

Treatment should last long enough to eliminate anemia (normalization of hemoglobin, mean corpuscular volume) and/or restore iron stores (serum ferritin, transferrin saturation coefficient).

Anemia caused by iron deficiency hemoglobin should be checked 4 weeks after starting treatment. The timing of further laboratory tests will depend on the degree of anemia. The duration of use in children and adults is determined individually. The duration of treatment is usually from 3 to 6 months depending on the depletion of iron stores; treatment may be extended over time if the cause of anemia is not eliminated. Treatment must be continued for another 3 months after hemoglobin normalization.

Adverse Reactions

Adverse reactions are listed according to the system organ class and frequency of occurrence. The frequency of adverse reactions is presented as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data).

The following adverse reactions may occur with the use of Tot’hema^®

* According to published data, the gastrointestinal mucosa of patients receiving treatment with iron preparations may become pigmented, which may create difficulties during gastrointestinal surgical interventions.

** Brown or black spots on teeth, reversible after discontinuation of treatment.

Contraindications

• Hypersensitivity to the active substances or to any of the excipients;
• Iron overload due to increased intestinal absorption or altered iron metabolism (e.g., hemochromatosis, thalassemia, refractory anemia, aplastic anemia, sideroblastic anemia) or due to excessive parenteral administration (e.g., repeated or chronic blood transfusions);
• Anemias not associated with iron deficiency (e.g., hemolytic anemia, megaloblastic anemia, anemia of inflammation);
• Lead intoxication; copper or manganese intoxication, Wilson’s disease;
• Sucrase/isomaltase deficiency, fructose intolerance, glucose-galactose malabsorption;
• Children under 3 months of age.

With caution

Diabetes mellitus, impaired liver function (including alcoholic liver disease, non-alcoholic fatty liver disease, and viral hepatitis), chronic inflammatory bowel diseases, diverticula, gastritis, gastrointestinal disorders and intestinal ulcers, gastric and duodenal ulcer in the acute phase.

Use in Pregnancy and Lactation

Pregnancy

There are limited data on the use of iron in the first trimester of pregnancy to assess the risk of malformations.

Clinical study data do not show any effect of iron preparation intake during pregnancy on infant birth weight, prematurity, and neonatal mortality.

Animal studies have not shown any reproductive toxicity.

For each active substance, preclinical data did not reveal any particular danger to humans at the proposed doses, based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, and reproductive and developmental toxicity.

Thus, Tot’hema^® can be used during pregnancy if necessary.

Breastfeeding

Iron is present in breast milk in small amounts. Its concentration does not depend on the mother’s intake of iron preparations during breastfeeding. Thus, no effects on breastfed newborns/infants are expected.

The preparation can be taken during breastfeeding.

Fertility

No effect on male or female fertility was observed in animal studies.

Pediatric Use

Contraindication: children under 3 months of age.

Special Precautions

This medicinal product must not be administered parenterally.

Accidental overdose may lead to intoxication, which can be fatal, especially in children (see section “Overdose”).

Accidental aspiration during the intake of the oral iron solution may cause granulomas, damage or necrosis of the bronchial mucosa, which can lead to coughing, hemoptysis and/or bronchostenosis (even if aspiration occurred several days or months before the onset of these symptoms). Elderly patients and patients experiencing swallowing difficulties are particularly at risk of aspiration. Patients should seek medical attention if aspiration is suspected.

Not recommended for the treatment of hyposideremia (decreased serum iron concentration) in inflammatory syndrome.

Whenever possible, the causes that caused the iron deficiency should be eliminated simultaneously with the intake of iron preparations.

1 ampoule of the preparation contains 1/4 bread unit.

To avoid darkening of tooth enamel, the solution should be swallowed immediately and not held in the mouth.

Patients with renal insufficiency may have an increased need for iron and require iron preparations to treat its deficiency or anemia. In non-dialysis patients, especially with renal insufficiency stages 2-3, oral intake of iron preparations is possible if they are well tolerated. In dialysis patients with chronic renal failure (stage 5D) and, potentially, in patients at stages 3-5, iron preparations should be administered intravenously. Tot’hema^® must not be administered intravenously.

Caution is required when using Tot’hema^® in patients with impaired liver function, including alcoholic liver disease, non-alcoholic fatty liver disease, and viral hepatitis, as well as in patients with gastrointestinal diseases such as chronic inflammatory bowel diseases, intestinal stenoses, diverticula, gastritis, gastrointestinal disorders, and intestinal ulcers.

Simultaneous consumption of large amounts of tea or coffee inhibits iron absorption.

Prevention of iron deficiency in children is based on the early introduction of a varied diet.

According to data published in the literature, the gastric and gastrointestinal mucosa in patients receiving iron preparations may be pigmented, which may create difficulties during gastrointestinal surgical interventions.

Excipients

Patients with fructose intolerance, glucose malabsorption, or sucrase-isomaltase deficiency (rare hereditary diseases) should not take this preparation.

The glucose and sucrose contained in the preparation may be harmful to tooth enamel with prolonged use (e.g., at least 2 weeks).

This medicinal product contains 108 mg of alcohol (ethanol) in one 10 ml ampoule. The amount of ethanol in 10 ml of this medicine is equivalent to less than 3 ml of beer or 2 ml of wine. The small amount of alcohol in this medicine will not have any noticeable effects.

This preparation contains less than 1 mmol sodium (23 mg) in one 10 ml ampoule, i.e., it is essentially “sodium-free”.

This preparation contains 20 mg of sodium benzoate in one 10 ml ampoule. Sodium benzoate may enhance jaundice (yellowing of the skin and eyes) in newborn children (under 4 weeks of age).

Effect on ability to drive and use machines

There are no data on the negative effect of the preparation on the ability to drive vehicles and other mechanisms.

Overdose

Iron salt overdose

Overdose of iron salts is possible both with accidental intake of large doses of the preparation and with regular use at approved doses, and is especially dangerous in children. Oral doses of iron of 20 mg/kg and above are considered toxic. A serum iron concentration of 5 µg/ml and above indicates severe iron salt poisoning.

An iron dose of about 60 mg/kg is considered extremely dangerous for children. In children, intoxication with iron salts, if medical assistance is not provided in a timely manner, can lead to a fatal outcome. In this regard, iron preparations must be stored out of the reach of children.

If an overdose of iron salts is suspected, a doctor should be consulted immediately.

Emergency measures before medical assistance is provided: gastric lavage with plain water (it is necessary to drink several glasses of water and induce vomiting).

Acute overdose

Acute overdose of iron salts can proceed in several stages.

1. Intoxication phase (first 6 hours after overdose): nausea, vomiting, bloody diarrhea, abdominal pain, weakness, pale skin, cold clammy sweat, acidosis, weak pulse, decreased blood pressure, palpitations, central nervous system depression of varying severity up to coma, convulsions.

2. Intoxication phase (6-24 hours after overdose): temporary stabilization of the condition.

3. Intoxication phase (24-48 hours after overdose): renal and hepatic failure, jaundice, metabolic acidosis, collapse, fever, pulmonary edema, shock up to coma.

4. Intoxication phase (several weeks after overdose): liver damage, intestinal obstruction.

Treatment

If an overdose of iron salts is suspected, treatment should be started immediately.

Children

1. In the first hours after overdose, vomiting should be induced.
2. Gastric lavage should be performed. Laxatives should not be used for young children due to the risk of diarrhea. The patient requires constant monitoring: in case of possible aspiration of vomit, suction and oxygen may be needed. In case of more severe intoxication in children and the development of subsequent stages of poisoning, therapeutic measures should be carried out by a doctor.
3. The plasma iron concentration should be constantly monitored.
4. In case of serious poisoning, in the event of shock or coma with high plasma iron levels, assistance must be provided immediately and administration of the specific iron antidote solution – deferoxamine – should be started, according to the instructions for use of the preparation. Shock, dehydration, and acid-base disturbances must be eliminated by an appropriate therapeutic method.

Adults

1. In the first hours after overdose, vomiting should be induced.
2. Gastric lavage should be performed. The patient requires constant monitoring; in case of possible aspiration of vomit, suction and oxygen may be needed. For faster bowel emptying, an aqueous solution of mannitol and sorbitol may be used.
3. The plasma iron concentration should be constantly monitored.
4. In case of serious poisoning, in the event of shock or coma with high plasma iron levels, assistance must be provided immediately and administration of the specific iron antidote solution – deferoxamine – should be started, according to the instructions for use of the preparation. Shock, dehydration, and acid-base disturbances must be eliminated by an appropriate therapeutic method.

Manganese salt overdose

Symptoms: nausea, vomiting, diarrhea, decreased activity, muscle pain, lethargy, fatigue, drowsiness, headache, hallucinations, memory impairment, depression, impaired muscle tone, paresthesia, muscle atrophy, symptoms of parkinsonism.

Treatment: symptomatic therapy.

Copper salt overdose

Symptoms: nausea, vomiting, diarrhea, abdominal pain, chest pain, metallic taste in the mouth, muscle pain, increased irritability, depressive state.

Treatment: gastric lavage, enterosorbents, intake of diuretics and laxatives, symptomatic therapy.

Drug Interactions

Combinations not recommended

Parenteral iron preparations

Lipothymia (fainting) or even shock due to the rapid release of iron from its complex form and saturation of transferrin.

Combinations requiring precautions

Tetracyclines (oral)

Reduced absorption of tetracyclines and iron in the gastrointestinal tract.

Intake of iron salts with tetracyclines should be separated (by more than 2 hours if possible).

Fluoroquinolones

Reduced absorption of fluoroquinolones in the gastrointestinal tract.

Intake of iron salts with fluoroquinolones should be separated (by more than 2 hours if possible).

Antacids and adsorbents

Reduced absorption of iron in the gastrointestinal tract.

As a precaution, the intake of antacids and adsorbents should be separated from the intake of any other medicines (by more than 2 hours if possible).

Bisphosphonates (oral)

Reduced absorption of bisphosphonates in the gastrointestinal tract.

Intake of iron salts should be separated from the intake of bisphosphonates (by at least 30 minutes to more than 2 hours if possible, depending on the bisphosphonate).

Calcium

Reduced absorption of iron salts in the gastrointestinal tract.

Iron salts should be taken between meals, not together with calcium.

Cholestyramine

Reduced absorption of iron salts in the gastrointestinal tract.

Iron salts should be taken 1-2 hours before or 4 hours after taking cholestyramine.

Entacapone

Reduced absorption of entacapone and iron in the gastrointestinal tract due to chelation of iron by entacapone.

Intake of iron salts with entacapone should be separated (by more than 2 hours if possible).

HIV integrase inhibitors

Reduced absorption of integrase inhibitors in the gastrointestinal tract.

Intake of iron salts with integrase inhibitors should be separated (by more than 2 hours if possible).

Bictegravir

Reduced absorption of bictegravir in the gastrointestinal tract by almost two-thirds when taken concomitantly orally or on an empty stomach.

Take bictegravir at least 2 hours before taking iron salts or at the same time with food.

Trientine

Reduced serum iron concentration.

Intake of iron salts with trientine should be separated (with an interval of more than 2 hours if possible).

Carbidopa, levodopa

Reduced absorption of carbidopa and levodopa in the gastrointestinal tract.

Intake of iron salts with carbidopa and levodopa should be separated (by more than 2 hours if possible).

Methyldopa

Reduced absorption of methyldopa in the gastrointestinal tract (complex formation).

Intake of iron salts with methyldopa should be separated (by more than 2 hours if possible).

Penicillamine

Reduced absorption of penicillamine in the gastrointestinal tract.

Intake of iron salts with penicillamine should be separated (by more than 2 hours if possible).

Thyroid hormones

Reduced gastrointestinal absorption of thyroid hormones.

Intake of iron salts with thyroid hormones should be separated (by more than 2 hours if possible).

Strontium

Reduced absorption of strontium in the gastrointestinal tract.

Intake of iron salts with strontium should be separated (by more than 2 hours if possible).

Zinc

Reduced absorption of zinc in the gastrointestinal tract.

Intake of iron salts with zinc should be separated (by more than 2 hours if possible).

Food

Phytic acids (whole grains), vegetables, polyphenols (tea, coffee, red wine), calcium (milk, dairy products), and some proteins (eggs) significantly impair iron absorption.

Intake of iron salts with these types of food should be separated (by more than 2 hours if possible).

Combination to be considered

Acetohydroxamic acid

Reduced absorption of both medicines in the gastrointestinal tract due to iron chelation.

Storage Conditions

The medicine should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The medicine is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.