Iron [III] hydroxide sucrose complex APC - instructions for use, dose, side effects, contraindications

The active component - iron-sucrose complex - consists of the nucleus of multinucleated iron hydroxide [III], surrounded by a large number of non-covalently bound sucrose molecules.The molecular weight (MM) of this complex is approximately equal to 43 kDa, which is sufficient to prevent excretion through the kidneys. The structure of a multinucleated iron-containing nucleus is similar to that of the core of the ferritin protein, the physiological iron depot. This complex is designed to create a controlled source of iron for the proteins responsible for the transport and deposition of iron in the body (respectively, transferrin and ferritin).

After intravenous injection, the iron of this complex is captured mainly by the liver, spleen and bone marrow. In the next step, iron is used for the synthesis of hemoglobin, myoglobin and other iron-containing enzymes, or stored in the liver in the form of ferritin.

Pharmacokinetics:

After a single intravenous injection of a drug containing 100 mg of iron, the maximum iron concentration, on average, 538 mmol / l, is reached 10 minutes after the injection. The volume of distribution of the central chamber corresponds almost completely to the volume of the serum (about 3 liters).

Half-life about 6 hours. The distribution volume in the stable state is approximately 8 l, indicating a low distribution of iron in the liquid media of the body. Due to the low iron stability of the sugar compared with transferrin, there is a competitive exchange of iron in favor of transferrin and as a result, about 31 mg of iron is transferred within 24 hours.

The excretion of iron by the kidneys within the first 4 hours after the injection is less than 5% of the total clearance. After 24 hours, the serum iron level returns to its original (before administration) value, and about 75% sucrose leaves the vascular bed.

Have 6 patients with iron deficiency anemia, renal anemia or functional iron deficiency have studied the iron kinetics in the form of an iron saccharate complex containing a radioactive label ⁵⁹Fe and ⁵²Fe. Clearance ⁵²Fe from the plasma varied in the range of 60-100 minutes. 2-4 weeks after the introduction, the maximum utilization ⁵⁹Fe from erythrocytes varied in the range of 59% -97%.

Indications:

Iron [III] hydroxide sucrose complex APC is used to treat iron deficiency states in the following cases:

- if it is necessary to quickly fill iron;

- in patients who do not tolerate oral iron preparations or do not follow the treatment regimen;

- in the presence of active inflammatory bowel disease, when oral iron preparations are ineffective.

Contraindications:

The use of the drug is contraindicated in the event that:

- Anemia is not associated with iron deficiency (eg, hemolytic anemia, megaloblastic anemia, erythropoiesis disorders, bone marrow hypoplasia);

- There are signs of iron overload (hemosiderosis, hemochromatosis) or disruption of the process of its utilization;

- hypersensitivity to iron-sucrose complex, solution of iron-sucrose complex or to any of the components of the drug;

- I trimester of pregnancy.

Carefully:

Patients with bronchial asthma, eczema, polyvalent allergy, allergic reactions to other parenteral iron preparations and persons with low serum iron binding capacity and / or folic acid deficiency iron [III] hydroxide sucrose complex APC must be used with caution.

Also, care is required when administered iron preparations to patients with liver failure, acute or chronic infectious disease and individuals who have serum ferritin indicators increased due to the factthat parenterally administered iron can have an adverse effect in the presence of a bacterial or viral infection.

Pregnancy and lactation:

Limited experience in the use of the drug in pregnant women showed no adverse effect of iron sugarate on the course of pregnancy and fetal / newborn health. To date, there have not been well-controlled studies in pregnant women. The results of reproduction studies in animals showed no direct or indirect adverse effects on embryo / fetal development, childbirth, or postnatal development. Nevertheless, an assessment of the risk / benefit ratio is required.

The intake of unmetabolized iron saccharate in breast milk is unlikely. However, the risk / benefit ratio should be evaluated before the drug is used during breastfeeding.

Dosing and Administration:

Application

The preparation of Iron [III] hydroxide, the sucrose complex of APC is administered only intravenously: by dropwise infusion, or slow injection, or directly into the venous portion of the dialysis system.

Before using the ampoule, it should be inspected for sediment or damage.Use only ampoules with a homogeneous, non-precipitating brown solution.

Each ampule of the preparation Iron [III] hydroxide sucrose complex APC is intended exclusively for single use. Any residues of unused medicinal product or its waste should be disposed of in accordance with local requirements.

The preparation of iron [III] hydroxide, the sucrose complex of APC should be administered under the supervision of medical personnel who have experience in the diagnosis and treatment of anaphylactic reactions, under the conditions of a specialized department.

It should be possible to carry out anti-shock therapy, including 0,1% epinephrine (adrenaline) solution, antihistamine and / or corticosteroid preparations. The test dose is not a reliable prognostic factor for the development of subsequent hypersensitivity reactions, and therefore its preliminary administration is not recommended.

During the administration of the drug and immediately after the administration, patients should be under the supervision of a physician. When the first signs of anaphylactic reactions appear, the drug should be discontinued immediately.

It is necessary to observe each patient for at least 30 minutes after each injection of Iron [III] hydroxide, the sucrose complex of APC in a therapeutic dose for the absence of undesirable phenomena.

Intravenous drip infusion

Iron [III] hydroxide sucrose complex APC is diluted only by sterile 0.9% (w / v) solution of sodium chloride (NaCl). The diluted solution should be clear, brown in color. Dilution should be performed immediately before infusion, and the resulting solution should be administered as follows:

Dose of the preparation Iron [III] hydroxide sucrose complex APC (mg iron)	Dose of the preparation Iron [III] hydroxide sucrose complex APC (ml of iron preparation [III] hydroxide sucrose complex APC)	The maximum dilution volume of a sterile 0.9% (w / v) solution NaCl	Minimal infusion time
100 mg	5 ml	100 ml	15 minutes
200 mg	10 ml	200 ml	30 minutes
300 mg	15 ml	300 ml	1,5 hour
400 mg	20 ml	400 ml	2,5 hours
500 mg	25 ml	500 ml	3,5 hours

Dilution of the drug to a lower concentration of iron is unacceptable for reasons related to the stability of the solution.

Intravenous injection

Iron [III] hydroxide, the sucrose complex of APC can be administered by slow intravenous injection at a rate of 1 ml of undiluted solution per minute and its dose should not exceed 10 ml (200 mg of iron) per injection.

Injection into the venous site of the dialysis system

Iron [III] hydroxide, the sucrose complex of APC can be administered during the hemodialysis session directly to the venous dialysis site, subject to the same conditions as for intravenous injection.

Doses

For each patient, the cumulative dose of the Iron preparation [III] should be calculated individually, the hydroxide of the APC sucrose complex, which can not be exceeded.

Calculation of dose

The total cumulative dose of Iron [III] hydroxide, the sucrose complex APC equivalent to total iron deficiency (mg) is determined based on the hemoglobin (Hb) and body weight (MT).

The dose of the preparation Iron [III] hydroxide, the sucrose complex of APC should be individually calculated for each patient according to the total iron deficiency calculated according to the following Hansoni formula, for example:

Total iron deficiency [mg] = body weight [kg] x (target hemoglobin content - actual hemoglobin content) [g / l] x 0.24 * + deposited iron [mg]

With a body weight of less than 35 kg: the target hemoglobin content = 130 g / l, and the amount of deposited iron = 15 mg / kg body weight

With a body weight of 35 kg or more: the target hemoglobin content = 150 g / l, and the amount of deposited iron = 500 mg

* Coefficient 0.24 = 0.0034 (iron content in hemoglobin = 0.34%) x 0.07 (blood mass ~ 7% of body weight) x 1000 (translation of [g] into [mg])

Total amount of iron preparation [III] hydroxide sucrose complex APC, which should be administered (in ml) = total iron deficiency [mg] / 20 mg iron / ml

Total amount of the preparation Iron [III] hydroxide is the sucrose complex APC (ml), which should be entered, depending on the body weight, the actual hemoglobin content and the target hemoglobin content.

Weight body weight [kg]	Total amount of iron preparation (III) hydroxide 03 q complex APC (20 mg of iron per ml), which should be introduced
Weight body weight [kg]	hemoglobin 60 g / l		hemoglobin 75 g / l		hemoglobin 90 g / l		hemoglobin 105 g / l
	mg Fe	ml	mg Fe	ml	mg Fe	ml	mg Fe	ml
5	160	8	140	7	120	6	100	5
10	320	16	280	14	240	12	220	11
15	480	24	420	21	380	19	320	16
20	640	32	560	28	500	25	420	21
25	800	40	700	35	620	31	520	26
30	960	48	840	42	740	37	640	32
35	1260	63	1 140	57	1000	50	880	44
40	1360	68	1220	61	1080	54	940	47
45	1480	74	1320	66	1 140	57	980	49
50	1580	79	1400	70	1220	61	1040	52
55	1680	84	1500	75	1300	65	1100	55
60	1800	90	1580	79	1360	68	1140	57
65	1900	95	1680	84	1440	72	1200	60
70	2020	101	1760	88	1500	75	1260	63
75	2120	106	1860	93	1580	79	1320	66
80	2220	111	1940	97	1660	83	1360	68
85	2340	117	2040	102	1720	86	1420	71
90	2440	122	2120	106	1800	90	1480	74

*With a body weight of less than 35 kg: Target hemoglobin content = 130 g / l

With a body weight of 35 kg or more: Target hemoglobin content = 150 g / l

To transfer hemoglobin (mmol) to hemoglobin (g / l), multiply the first value by 16.If the total required dose exceeds the maximum permissible single dose, it should be divided into several administrations.

If after 1-2 weeks there is no response from hematological parameters, the initial diagnosis should be reviewed.

Calculation of the dose for replenishment of iron stores after blood loss or when autologous blood is taken

The dose of iron preparation [III] hydroxide sucrose complex APC, necessary to compensate for iron deficiency, can be calculated by the following formulas:

If the amount of blood lost is known: the introduction of 200 mg of iron (10 ml of the preparation Iron [III] hydroxide sucrose complex APC) should lead to approximately the same increase in hemoglobin concentration as the transfusion 1 portions of blood (400 ml with a hemoglobin concentration = 150 g / l).

The amount of iron that must be replenished [mg] = the number of portions of lost blood x 200 mg

Necessary amount of iron preparation [III] hydroxide sucrose complex APC [ml] = number of portions of lost blood x 10 ml

If the hemoglobin content is below the desired: the formula assumes that it is not necessary to replenish the iron depot.

The amount of iron that must be replenished [mg] = body weight [kg] x 0.24 x (target hemoglobin - actual hemoglobin content) [g / l]

Example:

At a body weight of 60 kg and a decrease in the hemoglobin content of 10 g / L => 150 mg of iron, it is necessary to replenish => 7.5 ml of iron preparation [III] is needed, the hydroxide is the sucrose complex of APC

The maximum tolerable single and weekly doses are indicated below in the sections "Standard doses" and "Maximum tolerable single and weekly doses".

Standard doses

Patients of adult and advanced age

5-10 ml of preparation Iron [III] hydroxide sucrose complex APC (100-200 mg of iron) 1-3 times a week.

The time of administration and the method of dilution are indicated in the section "Application".

Children

There is only a moderate amount of data on the use of the drug in children in the study. In case of clinical need, do not exceed the dose of 0.15 ml of the preparation Iron [III] hydroxide sucrose complex APC (3 mg of iron) per kg of body weight not more than 3 times a week.

The time of administration and the method of dilution are indicated in the section "Application".

Maximum tolerated single and weekly doses

Patients of adult and advanced age

The maximum tolerable dose per day, injected as an injection, is not more than 3 times a week:

10 ml of the preparation Iron [III] hydroxide sucrose complex APC (200 mg of iron), administered for a minimum of 10 minutes.

The maximum tolerated dose per day, administered as an infusion is not more often than 1 time per week:

Patients weighing more than 70 kg: 500 mg of iron (25 ml of Iron [III] hydroxide sucrose complex APC), administered for a minimum of 3.5 hours.
Patients weighing 70 kg or less: 7 mg iron / kg body weight, administered for a minimum of 3.5 hours.

It is necessary to strictly adhere to the infusion time specified in the "Application" section, even if the patient has not received the maximum tolerable single dose.

Side effects:

The most frequent undesirable drug reaction (NLR), registered in the framework of clinical studies of iron [III] hydroxide sucrose complex, was a change in taste sensations, which was observed at a frequency of 4.5 events per 100 subjects. The most important serious undesirable drug reactions associated with the use of iron [III] hydroxide sucrose complex were hypersensitivity reactions that were observed in clinical trials with a frequency of 0.25 phenomena per 100 subjects.

The table below shows the undesirable drug reactions recorded after the use of iron [III] hydroxide sucrose complex in clinical trials, as well as in post-marketing period.

System-Organ Class	Frequent (≥1/100, <1/10)	Infrequent (≥1/1000, <1/100)	Rare (≥1/10 000, <1/1000)	Frequency unknown
Infringements from immune system		Hypersensitivity		Anaphylactoid reactions, angioedema
Disturbances from the nervous system	Violation gustatory sensations	Headache, dizziness, paresthesia, hypoesthesia	Fainting, drowsy	Reduced level of consciousness, confusion, loss of consciousness, anxiety, tremor
Heart Disease			Feeling palpitation	Bradycardia, tachycardia
Vascular disorders	Decrease arterial pressure, arterial hypertension	Hyperemia, phlebitis		Vascular collapse, thrombophlebitis
Disturbances from the respiratory system, chest and mediastinal organs		Dyspnea		Bronchospasm
Disorders from the gastrointestinal tract	Nausea	Vomiting, abdominal pain, diarrhea, constipation
Disturbances from the skin and subcutaneous tissues		Skin itching, skin rash		Hives, erythema
Disturbances from musculoskeletal and connective tissue		Muscle spasms, myalgia, arthralgia, pain in the limbs, back pain
Disorders from the kidneys and urinary tract			Chromaturia
Are common disorders and disorders at the site of administration	Reactions at the injection / infusion site²)	Chills, asthenia, fatigue, peripheral edema, pain	Pain in the chest, hyperhidrosis, pyrexia.	Cold sweat, general malaise, pallor
Laboratory and instrumental data		Increased activity of gamma-glutamyltransferase, increased activity of alanine aminotransferase, increased activity of aspartate aminotransferase, increased ferritin level in blood plasma.	Increased lactate dehydrogenase activity in the blood

¹⁾ Spontaneous messages received in the post-registration period

²⁾ Most common: pain at the injection / infusion site, injection site / infusion extravasation, injection site / infusion irritation, injection / infusion site reaction, skin discoloration at the injection / infusion site, bruising at the injection / infusion site, itching in place injection / infusion.

Overdose:Overdose can cause acute overload with iron, which manifests itself as symptoms of hemosiderosis.In case of overdose, it is recommended to use symptomatic agents and, if necessary, iron binding substances (chelates), for example deferoxamine in / in.

Interaction:

Iron [III] hydroxide, the sucrose complex of APC should not be administered simultaneously with the medicinal forms of iron for oral administration, as it helps to reduce the absorption of iron from the gastrointestinal tract. Treatment with oral iron preparations can begin no earlier than 5 days after the last injection.

Iron [III] hydroxide sucrose complex APC can be mixed in a single syringe only with a sterile sodium chloride solution 0.9% (w / v). No other solutions for intravenous administration and therapeutic agents are added, since there is a risk of precipitation and / or other pharmaceutical interactions.

Compatibility with containers of other materials than glass, polyethylene and polyvinyl chloride, has not been studied.

Special instructions:

Iron [III] hydroxide, the sucrose complex of APC should be administered only to those patients in whom the diagnosis of anemia is confirmed by appropriate laboratory data (for example,serum ferritin or hemoglobin and hematocrit, the number of erythrocytes and their parameters-the mean erythrocyte volume, the mean hemoglobin in erythrocyte, or the mean concentration of hemoglobin in the erythrocyte).

Intravenous iron preparations can cause allergic or anaphylactoid reactions, which can be potentially life threatening. Therefore, it is necessary to be ready for the introduction of antiallergic drugs and the use of conventional methods of cardiopulmonary resuscitation. After previous uncomplicated injections of parenteral iron complexes, hypersensitivity reactions were also observed. Patients should be under constant medical supervision during the administration of the drug and for at least 30 minutes after the injection.

In connection with the high risk of allergic reactions in patients with bronchial asthma, eczema, polyvalent allergy, allergic reactions to other parenteral iron preparations, the drug should be administered with caution.

With special care Iron [III] hydroxide sucrose complex APC should be used in patients with disorders of liver function(decompensated liver cirrhosis, infectious hepatitis, including those caused by elevated levels of ferritin, as well as patients with acute or chronic infection, with Osler-Randu-Weber syndrome, infectious diseases of the kidneys in the acute stage, uncontrolled hyperparathyroidism.

Parenteral administration of iron can adversely affect the course of a bacterial or viral infection.

Also caution is required when administering the drug to individuals with a low serum ability to bind iron and / or a deficiency of folic acid.

It is necessary to strictly adhere to the speed of administration of the drug (with rapid administration of the drug, blood pressure may decrease). A higher incidence of undesirable side effects (in particular, lowering blood pressure), which may also be severe, is associated with an increase in dose. Thus, the time of administration of the drug, given in the section "Methods of administration and dose", should be strictly observed, even if the patient does not receive the drug in the maximum tolerable single dose.

It is necessary to avoid penetration of the drug into the circumveneous area, becausegetting the drug out of the vessel leads to tissue necrosis and brown staining of the skin. In cases of unintentional penetration of the drug into the circumferential space, treatment should be carried out in accordance with the standards of medical practice.

Shelf life after the first opening of the container: From a microbiological point of view, the drug should be used immediately.

Shelf life after dilution with saline solution: Chemical and physical stability after dilution at room temperature is 12 hours. FROM microbiological point of view, the drug should be used immediately.

If the product has not been used immediately after dilution, the user is responsible for the storage conditions and time, which in any case should not exceed 3 hours at room temperature in the event that the dilution was performed under controlled and guaranteed aseptic conditions.

Effect on the ability to drive transp. cf. and fur:

It is unlikely that the drug may have an undesirable effect on the ability to drive a car and work with mechanisms.However, when developing symptoms such as dizziness, confusion, or a fainting condition, patients should not drive vehicles or mechanisms until these symptoms disappear.

Form release / dosage:

Solution for intravenous administration, 20 mg / ml.

Packaging:

By 5 ml of the drug in colorless, clear glass ampoules (type I according to the USA).

For 3 or 5 ampoules in a polyvinyl chloride outline pack together with instructions for use, they are packed in a cardboard box.

Storage conditions:

Store in a dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-004176

Date of registration:03.03.2017

Expiration Date:03.03.2022

The owner of the registration certificate:ARS, LLC ARS, LLC Russia

Manufacturer: & nbsp

ROSLEKS PHARM, LLC Russia

VMG Pharmaceuticals, Private Ltd. India

Information update date: & nbsp04.04.2017

Illustrated instructions

Instructions

Iron [III] hydroxide sucrose complex APC (Ferric (III) hydroxide sacharose complex ARS)