TIPHER

Composition

active substance: 1 ml of solution contains 20 mg of iron (in the form of iron (III) hydroxide sucrose complex);
excipients: sodium hydroxide, water for injection.

Dosage form

Solution for injection or concentrate for solution for infusion.
Main physical and chemical properties: dark brown colloidal solution.

Pharmacotherapeutic group

Anti-anaemic agents. Iron preparations. ATC code B03A C.

Pharmacological properties

Pharmacodynamics.
The active ingredient of the medicinal product Tipher, iron sucrose, consists of multinuclear centers of iron (III) hydroxide surrounded by a large number of non-covalently bound sucrose molecules. The average molecular weight of the complex is approximately 43 kDa. The multinuclear iron center has a structure similar to that of ferritin, which is a physiological iron-containing protein. The complex is designed in such a way that the absorbed iron is delivered in a controlled manner to proteins that ensure its transportation and storage in the body (transferrin and ferritin, respectively).
After intravenous administration, the multinuclear iron center from the complex is taken up mainly by the reticulo-endothelial system of the liver, spleen and bone marrow. At the second stage, iron is used for the synthesis of hemoglobin, myoglobin, and other iron-containing enzymes or is stored in the liver as ferritin.
Pharmacokinetics.
Distribution. The sucrose ferrokinetics of iron labeled with ⁵²Fe and ⁵⁹Fe was evaluated in 6 patients with anemia and chronic renal failure. During the first 6-8 hours, ⁵²Fe is taken up by the liver, spleen, and bone marrow. Radioactive iron uptake occurs in macrophages of the reticulo-endothelial system of the spleen.
After intravenous administration of a single dose of iron (III) hydroxide sucrose complex containing 100 mg of iron to healthy volunteers, the maximum iron concentration was observed 10 minutes after administration and reached an average value of 538 mmol/L. The volume of distribution in the central chamber corresponded to the volume in the blood plasma (approximately 3 liters).
Metabolism. After injection, sucrose almost completely breaks down, and the multinuclear iron center is taken up mainly by the reticulo-endothelial system of the liver, spleen, and bone marrow.
Within 4 weeks after injection, iron absorption by red blood cells ranges from 68% to 97%.
Pharmacokinetics in certain patient groups. It is not yet known whether renal and hepatic insufficiency affects the pharmacological properties of iron (III) hydroxide sucrose complex (see section “Features of application”).

Therapeutic indications

The use of the medicinal product Tipher is indicated for patients with iron deficiency in the following indications:

• in case of intolerance to oral iron preparations;
• in the presence of diseases of the gastrointestinal tract (ulcerative colitis), when oral iron preparations may provoke an exacerbation of the disease
• in iron deficiency conditions that are resistant to therapy, when control of these conditions with oral iron preparations is insufficient.

Tipher should be used only when the indications are based on appropriate studies. Relevant laboratory tests include determination of the level of such indicators as hemoglobin, serum ferritin, transferrin saturation.

Contraindications

• Known hypersensitivity to the active substance or to other components of the medicine.
• Anemia not related to iron deficiency (e.g., hemolytic anemia, megaloblastic anemia due to vitamin В₁₂ deficiency, erythropoiesis disorders, bone marrow hypoplasia, anemia caused by lead poisoning).
• Iron overload (hemochromatosis, hemosiderosis) or hereditary disorders of iron absorption (sideroacrestic anemia, thalassemia, porphyria cutis).
• I trimester of pregnancy.

Interaction with other medicinal products and other types of interactions

Tipher is indicated for patients who cannot be prescribed oral iron preparations due to their intolerance, ineffectiveness, or the presence of gastrointestinal diseases. Tipher should not be used concomitantly with iron-containing oral medications, as the absorption of orally administered iron is reduced.

Special warnings and precautions for use

The intravenous administration of parenteral iron products can cause immediate-type acute hypersensitivity reactions (anaphylactoid/anaphylactic reactions), which may be fatal. Such reactions have been reported even where previous administrations of parenteral iron products have been tolerated without complications. In the case of patients who have had hypersensitivity reactions to iron dextran, Tipher may only be administered in compelling situations and under strict precautionary measures.
Treatment with Tipher should be prescribed by the attendant physician only after carefully determining the indication.
Tipher should only be used if healthcare professionals who can assess and treat anaphylactic reactions are immediately available as well as only in an institution in which all facilities for resuscitation are available. Before each administration of Tipher, patients should be actively questioned about previous undesirable effects from intravenous iron products.
Typical symptoms of acute hypersensitivity reactions are: fall in blood pressure, tachycardia (and even anaphylactic shock), respiratory symptoms (including bronchospasm, laryngeal and pharyngeal oedema), abdominal symptoms (including abdominal cramps, vomiting) or skin symptoms (including urticaria, erythema, pruritus). Patients should be carefully monitored for any signs and symptoms of a hypersensitivity reaction during and for at least 30 minutes after the administration of parenteral iron products. Should allergic reactions or signs of intolerance occur during administration, the treatment must be stopped immediately.
Adrenaline, e.g. in doses of 0.3 mg intramuscularly, is recommended in the first instance for the emergency drug treatment of acute anaphylactic/anaphylactoid reactions, and only after this antihistamines and/or corticosteroids (later onset of action).
The risk of hypersensitivity reactions is increased in patients with known allergies including drug intolerance, a history of severe asthma, eczema and other forms of atopy, and also in patients withimmunological or inflammatory disorders. (e.g. systemic lupus erythematosus, rheumatoid arthritis). In patients with liver dysfunction, parenteral iron should only be administered after careful risk/benefit assessment. Parenteral iron administration should be avoided in patients with hepatic dysfunction where iron overload is a precipitating factor. Careful monitoring of iron status is recommended to avoid iron overload.
In patients with elevated ferritin level parenteral iron may have an unfavorable effect on the courseof a bacterial or viral infection. Parenteral iron must be used with caution in case of acute or chronic infection. In patients with chronic infection a risk/benefit evaluation has to be performed. It is recommended that the administration of Tipher is stopped in patients with ongoing bacteraemia.
Paravenous leakage must be avoided because leakage of Tipher at the injection site can lead to pain, inflammation, tissue necrosis and brown discoloration of the skin. In the case of paravenous leakage, iron administration must be stopped immediately.
A drop in blood pressure is commonly observed in association with the intravenous administrationof iron. Therefore, the infusion should be administered with caution.
Recommendations on the flow rate of the intravenous administration of iron should be strictly followed to prevent the development of arterial hypotension. A higher frequency of adverse reactions (especially of arterial hypotension) is associated with an increase in the dose or flow rate of administration of this medicinal product.
Particular caution with the administration of Tipher is needed in patients with hepatic impairment, decompensated cirrhosis of the liver, epidemic hepatitis, Osler-Rendu-Weber syndrome, infectious kidney disorders in the acute phase, uncontrolled hyperparathyroidism.
Tipher contains up to 7 mg sodium per mL.

Pregnancy and lactation
Pregnancy.
There is some data from the use of iron sucrose complex in pregnant women in the first trimester. Data from the use of iron sucrose complex in pregnant women in the second and third trimester showed no safety concerns for the mother or newborn.
It is so far unknown whether the iron (lIl) hydroxide sucrose complex, which is present in Tipher, crosses the placenta. Transferrin-bound iron does cross the placental barrier. Lactoferrin-bound iron passes into breast milk.
There are no investigations on the influence on iron levels in newborns.
Tipher is contraindicated during the first trimester of pregnancy (see Section «Contraindications») and may only be used during the 2nd and 3rd trimester if strictly indicated.
A careful risk/benefit assessment is necessary before administration during pregnancy since hypersensitivity reactions may result in a particular risk to the mother and child (see Section «Special warnings and precautions for use»).
Body weight before the onset of pregnancy should be used to calculate the required quantity of iron, to avoid a potential overdose. Foetal bradycardia may occur following administration of parenteral irons. It is usually transient and a consequence of a hypersensitivity reaction in the mother. The unborn baby should be carefully monitored during intravenous administration of parenteral irons to pregnant women.
Breast-feeding.
There is limited information on the excretion of iron in human milk following administration of intravenous iron sucrose, therefore the risk/benefit should be assessed.
In one clinical study, 10 healthy breast-feeding mothers with iron deficiency received 100 mg iron in the form of iron sucrose. Four days after treatment, the iron content of the breast milk had not increased and there was no difference from the control group (n=5). It cannot be excluded that newborns/infants may be exposed to iron derived from Tapher via the mother’s milk, therefore the risk/benefit should be assessed.

Effects on ability to drive and use machines.
No corresponding studies have been carried out. Tipher is unlikely to influence the ability to drive or use machines. However, if symptoms such as dizziness, confusion or light-headedness occur following the administration of Tipher, affected patients should not drive a car or use machines until the symptoms have abated.

Posology and method of administration

Tipher may only be administered slowly via the intravenous route. Tipher must NOT be administered subcutaneously or intramuscularly.
Tipher should only be administered where the indication is confirmed by appropriate investigations. Suitable laboratory analyses are haemoglobin. serum ferritinб transferrin saturation.
Patients should be carefully monitored for any signs and symptoms of a hypersensitivity reaction during and after the administration of iron products. The immediate assistance must be given, if necessary (see Section «Special warnings and precautions for use»).
The cumulative dose of Tipher must be calculated for each patient individually and must not beexceeded. The dose is calculated on the basis of body weight and Hb (hemoglobin) value.
If the required total dose exceeds the maximum permissible single dose of 200 mg (injection) or 500 mg (infusion), then the administration of the total dose must be divided.

Calculating the dose
The total cumulative dose of Tipher, equivalent to the total iron deficit (mg), is determined by the haemoglobin level (Hb) and body weight (BW). The dose of Tipher must be individually calculated for each patient according to the total iron deficit calculated with the following Ganzoni formula:

Total iron deficit (mg) = BW (kg) x (target Hb (g/l) – actual Hb (g/l)) x 0.24* + storage iron (mg).
Less than 35 kg BW: target Hb – 130 g/l and storage iron – 15 mg/kg BW.
35 kg BW and above: target Hb – 150 g/l and storage iron – 500 mg.
* Factor 0.24 = 0.0034 х 0.07 х 1000 (iron content of Hb = 0.34%, blood volume = 7% of BW, factor 1000 = conversion of “g” to “mg”).

Table 1

The total cumulative dose of Tipher (ml) to be administered, taking into account the patient’s body weight and Hb level

Table 2

The required Hb level depending on the patient’s BW

To convert Hb (mM) to Hb (g/dl), multiply the first value by 1.6.
If the total dose required exceeds the maximum permissible single dose of 200 mg (injection) or 500 mg (infusion), the administration should be carried out in several doses.

Normal posology
Adults
5-10 ml of Tipher (100-200 mg of iron) 1-3 times a week. See below for application time and dilution ratio.
Children above 3 years of age
There are only limited data on the use of the preparation in children. In case of clinical need, it is recommended to administer no more than 0.15 ml of the drug (3 mg of elemental iron) per 1 kg of body weight 1-3 times a week. See below for dosing time and dilution ratio.
Maximum tolerated single or weekly dose
Adults
For injections, the maximum tolerated dose administered no more than 3 times per week is 10 ml of the medicine (200 mg of iron), with an administration duration of at least 10 minutes.
For infusion, the maximum tolerated dose administered no more than once a week in patients with a body weight of more than 70 kg is 500 mg of iron (25 ml of the medicine) for at least 3.5 hours;
in patients with a body weight of 70 kg or less – 7 mg of iron per 1 kg of body weight for at least 3.5 hours.
The infusion time should be strictly adhered to, even if the patient does not receive the maximum tolerated single dose.
If there is no improvement in haematological parameters (increase in haemoglobin level by approximately 1 g/l blood per day or by approximately 1.0-2.0 g/dl 1-2 weeks after treatment initiation), the initial diagnosis of the patient should be reviewed and the presence of persistent blood loss should be excluded.
Administration
Tipher must only be administered intravenously by drip infusion, by slow injection or directly into the venous line of the dialysis machine.
Tipher must not be administered intramuscularly or subcutaneously.
If the total dose required exceeds the maximum permissible single dose, the total dose should be divided into several doses.
Intravenous drip infusion
Tipher must only be diluted immediately before administration in sterile 0.9% sodium chloride solution according to the procedure specified in Table 3.

Table 3

Intravenous injection
The medicine Tipher may be administered by intravenously by slow infusion at a rate of 1 ml undiluted solution per minute, but the maximum volume of the solution should not exceed 10 ml (200 mg of iron) per injection.
Paravenous leakage must be avoided, as the leakage of Tipher at the injection site may lead to pain, inflammation, tissue necrosis and potentially prolonged brown discoloration of the skin (see section «Special warnings and precautions for use»).
Injection into the venous area of the dialysis system
Tipher can be injected directly into the venous portion of the dialysis system during a hemodialysis session, strictly following the rules for intravenous injection.

Children.
Due to insufficient data, it is not recommended to use Tipher for the treatment of children under 3 years of age.

Overdose

An overdose may lead to acute iron overload, which may manifest as haemosiderosis. In case of an overdose, symptomatic therapy and, if necessary, iron binding agents (chelates) are recommended.

Undesirable effects

The most common adverse reactions observed during clinical trials of iron (III) hydroxide sucrose complex included dysgeusia, which occurred with a frequency of 4.5 events per 100 people. Other common adverse reactions include nausea, arterial hypotension, arterial hypertension, and infusion site pain, which occurred with a frequency of 1 to 2 events per 100 people.
The most important serious adverse reactions associated with the use of iron (III) hydroxide sucrose complex include hypersensitivity reactions, which occurred with a frequency of 0.25 events per 100 people during clinical trials. Immediate hypersensitivity reactions (anaphylactoid/anaphylactic reactions) were rare. In general, anaphylactoid/anaphylactic reactions are very serious adverse reactions that can be fatal (see section «Special warnings and precautions for use»). Symptoms include circulatory collapse, arterial hypotension, tachycardia, respiratory symptoms (bronchospasm, laryngeal edema, pharyngeal edema), gastrointestinal symptoms (abdominal pain, vomiting), skin symptoms (urticaria, erythema, pruritus).
Adverse reactions are classified according to the frequency of occurrence into the following categories: common (˂ 1/10 to ≥ 1/100), rare (˂ 1/100 to ≥ 1/1000) and very rare (˂ 1/1000 to ≥ 1/10000), frequency unknown (available data do not allow estimating the frequency, as such events have been reported only in post-marketing studies).
Immune system
Rare: hypersensitivity reactions.
Metabolism and nutritional disorders
Rare: iron overload.
Nervous system
Common: dysgeusia, dizziness.
Rare: headache, paresthesia, hypoesthesia.
Very rare: loss of consciousness, drowsiness.
Cardiac system
Rare: arterial hypotension and collapse, tachycardia.
Very rare: bradycardia.
Vascular system
Common: arterial hypotension, arterial hypertension.
Rare: thrombophlebitis, phlebitis.
Respiratory system, chest and mediastinal organs
Rare: dyspnoea.
Renal and urinary system
Very rare: chromaturia.
Digestive tract
Common: nausea.
Rare: vomiting, abdominal pain, diarrhoea, constipation.
Liver and gallbladder
Rare: increased levels of alanine aminotransferase, increased levels of aspartate aminotransferase, increased levels of gamma-glutamyltransferase.
Very rare: increased levels of lactate dehydrogenase in the blood.
Skin and subcutaneous tissues
Rare: itching, rash.
Musculoskeletal system and connective tissue
Rare: muscle cramps, myalgia, arthralgia, limb pain, back pain.
Common disorders and reactions at the injection site
Common: injection site reactions¹.
Rare: chest pain, chills, asthenia, fatigue, peripheral edema, pain.
Very rare: increased sweating, fever.
¹ The most commonly observed adverse reactions are pain, extravasation, irritation, injection site reactions, skin discolouration, haematoma and itching at the injection/infusion site.
The following adverse reactions have been reported in voluntary post-marketing studies:
Frequency unknown: confusion, bradycardia, thrombophlebitis.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals and the patients or their legal guardians/carers are asked to report any suspected adverse reactions via the State Expert Center of the Ministry of Health of Ukraine at the link: https://aisf.dec.gov.ua

Shelf life

3 years.
Do not use the product after the expiry date indicated on the package.
After opening the ampoule from a microbiological point of view, the medicine must be used immediately.
After dilution with 0.9% sodium chloride solution from a microbiological point of view, the medicine must be used immediately.

Storage conditions

Store in the original packaging at a temperature not exceeding 25°C. Do not freeze.
Keep out of the reach of children.

Incompatibilities

Tipher must only be mixed with sterile 0.9% sodium chloride solution. No other intravenous solutions or therapeutic agents should be added, as there is a risk of precipitation and/or other pharmaceutical interactions. Compatibility with polyethylene and polyvinyl chloride containers has not been studied.

Packaging

5 ml in ampoules. 5 ampoules in a cardboard box.

Prescription status

Available on prescription.

Manufacturer

RAFARM SA

Manufacturer’s location and address of the place of operation
Thesi Pousi-Xatzi Agiou Louka, Paiania Attiki, TK 19002, Tϴ 37, Greece.