Venofer - instructions for use, dose, side effects, contraindications

Active substance:
iron (III)	20 mg
in the form of iron (III) hydroxide of the sucrose complex	510-570 mg
Excipients:
sodium hydroxide	0-5 mg
in the form of 10% sodium hydroxide solution	q.s. until the pH is adjusted to 10.5-11.0
water for injections	580-640 mg

Description:Aqueous solution of brown color.

Pharmacotherapeutic group:An antianemic agent, an iron preparation for parenteral administration

ATX: & nbsp

B.03.A.C.02 Iron oxide saccharate

Pharmacodynamics:

Mechanism of action

The active component of the drug Venofer^® - iron-sucrose complex - consists of the nucleus of multinucleated iron hydroxide (III), surrounded by a large number of non-covalently bound sucrose molecules. The average molecular weight of this complex is approximately 43 kDa. 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 multinuclear iron-containing core of this complex is captured mainly by the reticuloendothelial system of the liver, spleen, and bone marrow. In the next step, iron is used to synthesize hemoglobin, myoglobin and other iron-containing enzymes, or is stored primarily in the liver in the form of ferritin.

Pharmacokinetics:

Distribution

Ferrokinetics of iron-sucrose complex labeled ⁵²Fe and ⁵⁹Fe, was evaluated in patients with anemia and chronic renal failure. During the first 6-8 hours ⁵²Fe was captured by the liver, spleen and bone marrow.It is believed that the capture of the radioactive label by the spleen, rich in macrophages, is typical for the capture of iron by the reticuloendothelial system.

After intravenous administration of a single dose of the Venofer® preparation containing 100 mg of iron to healthy volunteers, the maximum total serum iron concentrations were achieved 10 minutes after the injection, with an average concentration of 538 μmol / L. The volume distribution of the central chamber fully corresponded to the volume of the plasma (about 3 liters).

Biotransformation

After injection, sucrose is mostly disintegrated, and the multinuclear iron-containing nucleus is mainly captured by the reticuloendothelial system of the liver, spleen, and bone marrow. After 4 weeks of administration, the iron utilization by erythrocytes is from 59 to 97%.

Excretion

The average molecular weight of the iron-sucrose complex is approximately 43 kDa, which is quite a lot to prevent excretion through the kidneys.

Excretion of iron by the kidneys in the first 4 hours after the injection of a dose of the preparation of Venofer® containing 100 mg of iron was less than 5% of the administered dose.After 24 hours, the total serum iron concentration was reduced to the level before administration. The excretion of saccharose by the kidneys was about 75% of the administered dose.

Indications:

Venofer® is used to treat iron deficiency conditions in the following cases:

- with a clinical need for rapid replacement of iron stores;

- 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 preparation Venofer® is contraindicated in the following cases:

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

- anemia not caused by iron deficiency;

- presence of signs of iron overload or inborn violations of its utilization processes;

- I trimester of pregnancy.

Carefully:

Patients with bronchial asthma, eczema, polyvalent allergies, allergic reactions to other parenteral iron preparations and to persons who have low iron binding capacity of the serum and / or deficiency of folic acid Venofer^®should be administered with caution.

Also, caution is required when administering iron preparations to patients with hepatic insufficiency, with acute or chronic infectious diseases, and individuals who have increased serum ferritin levels because parenterally administered iron can have adverse effects in the presence of a bacterial or viral infection.

Pregnancy and lactation:

A moderate amount of data on the use of Venofer® by pregnant women in II and III trimesters of pregnancy did not reveal any threats to the mother or newborn.

However, Venofer® should be used during II and III trimester of pregnancy only when the potential benefit to the mother exceeds the potential risk to the fetus.

The use of the drug in the first trimester of pregnancy is contraindicated.

The results of animal studies did not reveal any direct or indirect adverse effects on the course of pregnancy, embryo / fetal development, childbirth, or postnatal development.

The amount of data on the release of iron with human breast milk after intravenous iron-sucrose complex is limited.In a small clinical study, healthy, breast-feeding mothers with iron deficiency received 100 mg of iron in the form of an iron-sucrose complex. Four days after the treatment, the content of iron in breast milk did not increase, and the difference in comparison with the control group (n= 5) was not observed. It can not be ruled out that the iron from the drug Venofer^® may be given to a newborn / infant with mother's milk, therefore an assessment of the risk-benefit ratio should be made.

Dosing and Administration:

Application

The drug Venofer^® is administered only intravenously: by drip infusion, or by slow injection, or directly into the venous portion of the dialysis system.

Before use, the ampoule / vials should be inspected for sediment or damage. Use only ampoules / bottles with a homogeneous, non-precipitating brown solution.

Each ampoule / vial of the preparation Venofer® is intended exclusively for single use. Any residues of unused medicinal product or its waste should be disposed of in accordance with local requirements.

Introduction of the drug Venofer^® should be carried out under the supervision of medical personnel who have experience in the diagnosis and treatment of anaphylactic reactions, in the conditions of a specialized department. It should be possible to carry out anti-shock therapy, which includes a 0.1% solution of epinephrine (adrenaline), antihistamines and / or corticosteroids.

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 administration of the preparation of Venofer® in a therapeutic dose for the absence of undesirable phenomena.

Intravenous drip infusion

Venofer® is diluted only with a 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:

The dose of the drug Venofer^®(mg of iron)	The dose of the preparation Venofer® (ml of the preparation Venofer®)	The maximum dilution volume is 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 lower concentrations of iron is unacceptable for reasons related to the stability of the solution.

Intravenous injection

Venofer® 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

Venofer® can be administered during the hemodialysis session directly to the venous site of the dialysis system, subject to the same conditions as for intravenous injection.

Doses

For each patient, the cumulative dose of the Venofer® preparation should be calculated individually, which can not be exceeded.

Calculation of dose

The total cumulative dose of the preparation Venofer®, equivalent to the total iron deficiency (mg), is determined based on the hemoglobin (Hb) and body weight (MT). The dose of the drug Venofer^® should be individually calculated for each patient according to the total iron deficiency calculated according to the following Hanzoni 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] to [mg])

The total amount of the preparation Venofer® to be injected (in ml) = Total iron deficiency [mg] / 20 mg iron / ml

The total amount of the drug Venofer^® (ml), which should be entered, depending on the body weight, the actual hemoglobin content and the target hemoglobin content *:

Weight body weight [kg]	The total amount of the drug Venofer^®(20 mg of iron per ml), which should be introduced
	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	1140	57	1000	50	880	44
40	1360	68	1220	61	1080	54	940	47
45	1480	74	1320	66	1140	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 Venofer®, needed to compensate for iron deficiency, can be calculated by the following formulas:

If the amount of blood lost is known: the administration of 200 mg of iron (10 ml of the preparation of Venofer®) should lead to approximately the same increase in hemoglobin concentration as the transfusion of 1 portion of blood (400 ml with hemoglobin concentration = 150 g / l).

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

The necessary volume of the drug Venofer^® [ml] = number of portions of lost blood x 10 ml

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

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

Example:

With a body weight of 60 kg and a decrease in hemoglobin content of 10 g / L

=> = 150 mg of iron must be replenished

=> 7.5 ml of the preparation Venofer®

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 the preparation Venofer^® (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 of use, do not exceed the dose of 0.15 ml of the drug Venofer^® (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 Venofer® (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 with a body weight of more than 70 kg: 500 mg of iron (25 ml of the preparation Venofer®), 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) recorded in the clinical trials of the preparation Venofer® 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 the drug Venofer® were hypersensitivity reactions that were observed in clinical trials with a frequency of 0.25 events per 100 subjects.

The table below shows the undesirable drug reactions, registered after the use of the drug Venofer® in clinical trials, as well as in the post-marketing period.

System-Organ Class	Frequent (≥1/100, <1/10)	Infrequent (≥1/1000, <1/100)	Rare (≥1/10 000, <1/1000)	Frequency unknown¹⁾
Infringements from immune system		Hypersensitivity		Anaphylactoid reactions, angioedema
Disturbances from the nervous system	Disturbance of taste sensations	Headache, dizziness, paresthesia, hypoesthesia	Fainting, drowsy	Reduced consciousness, confusion, loss of consciousness, anxiety, tremor
Heart Disease			Heart palpitations	Bradycardia, tachycardia
Vascular disorders	Reduction of 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		Itching, 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-glutamyl transferase, 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 frequent: pain at the injection / infusion site, extravasation in place injections / infusions, irritation at the injection / infusion site, reaction at the injection / infusion site, changing skin coloration at the injection / infusion site, bruising at the injection / infusion site, itching in place injection / infusion.

Overdose:

Overdose can cause an overload with iron, which can manifest itself with symptoms of hemosiderosis.Overdose should be treated with a chelating agent for binding iron or in accordance with standards of medical practice.

Interaction:

As with all parenteral iron preparations, the preparation Venofer^® it is not recommended to be used concomitantly with oral iron preparations, since absorption of oral iron can decrease, so oral iron therapy should be started no earlier than 5 days after the last injection.

The Venofer^® can be mixed only with a sterile 0.9% (w / v) solution of sodium chloride.

When mixed with other solutions or medicines, there is a risk of precipitation and / or interaction.

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

Special instructions:

Parenterally administered iron preparations can cause allergic or anaphylactoid reactions that can potentially be lethal, so there should be antiallergic drugs, as well as equipment for cardiopulmonary resuscitation and appropriate procedures. After previous uncomplicated injections of parenteral iron complexes, hypersensitivity reactions were also observed. After each injection of Venofer®, all patients should be monitored for undesirable events for at least 30 minutes.

Patients with a history of bronchial asthma, eczema, other atopic allergies or allergic reactions to other parenteral iron preparations should be treated with caution because such patients in particular may have a risk of developing an allergic reaction.

In patients with impaired liver function, parenteral iron should be used only after a thorough assessment of the risk-benefit ratio. Patients with impaired liver function, when iron overload is a provoking factor, parenteral iron should not be used. In order to avoid overloading with iron, it is recommended to carefully monitor the level of iron in the body.

Parenteral iron should be used with caution in the presence of acute or chronic infection.

Patients with bacteraemia are advised to stop using the product Venofer®

In patients with chronic infection, an assessment should be made of the relationship between risk and benefit.

Avoid penetration of the drug into the peri-venous space, as this can lead to the appearance of pain, the development of inflammation and the dyeing of the skin in brown. 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.

Venofer® should be used only when the indications for use are confirmed by the results of the relevant studies (for example, serum ferritin level, transferrin saturation level, hemoglobin content (Hb), erythrocyte indices - MCV, SIT, ICSU).

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 0.9% sodium chloride solution (NaCl)

The chemical and physical stability after dilution at room temperature (15-25 ° C) is 12 hours. However, from a microbiological point of view, the drug should be used immediately after dilution.If the product has not been used immediately after dilution, the person who uses this solution is responsible for the conditions and storage time after dilution, which in any case should not exceed 3 hours at room temperature, unless dilution was performed in controlled and proper aseptic conditions.

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

Data on the impact on the ability to drive vehicles or work with other mechanisms is not available. However, some unwanted reactions (such as dizziness, confusion, and others (listed in the "Side effect" section)) can have a negative effect on the ability to drive vehicles or work with other mechanisms. Patients who report these adverse reactions are advised not to drive vehicles or work with other mechanisms until these symptoms disappear completely.

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 Heb.F.), having a notch on the neck of the ampoule and technical color marks in the form of one or two rims and a point.

To 5 ml of the preparation in colorless, transparent glass bottles (type I according to Hebrew F), closed with an elastic stopper and an aluminum cap with a tear-off element.

5 ampoules or bottles in a polyvinyl chloride outline pack together with the instruction for use are packed in a cardboard box.

Storage conditions:

In the original packaging, at a temperature of no higher than 25 ° C.

The drug is not subject to freezing.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:П N014041 / 01

Date of registration:14.08.2008 / 19.05.2016

Expiration Date:Unlimited

The owner of the registration certificate:Vifor (International) Inc.Vifor (International) Inc. Switzerland

Manufacturer: & nbsp

VIFOR (International), Inc. Switzerland

BIPSO, GmbH Germany

IDT BIOLOGIKA, GmbH Germany

Representation: & nbspTakeda Pharmaceuticals Ltd.Takeda Pharmaceuticals Ltd.

Information update date: & nbsp02.02.2017

Illustrated instructions

Instructions

Venofer® (Venofer®)