Venital

PACKAGE LEAFLET: INFORMATION FOR THE USER

VENITAL 50 g/l Solution for infusion

Normal human immunoglobulin (IVIg) for intravenous use
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or nurse.
• If you get any side effects, including those not listed in this leaflet, tell your doctor or nurse. See section 4.

Contents of this leaflet:

1. What VENITAL is and what it is used for
2. What you need to know before using VENITAL
3. How to use VENITAL
4. Possible side effects
5. How to store VENITAL
6. Contents of the pack and other information

1. What VENITAL is and what it is used for

VENITAL is a normal human immunoglobulin solution for intravenous use. Immunoglobulins
are human antibodies also present in blood.
VENITAL is used for:
Treatment of adults, children and adolescents (0-18 years) who do not have sufficient antibodies (replacement
therapy) in the following cases:

1. Patients with congenital deficiency in antibody production (primary immunodeficiency syndromes).
2. Patients with acquired deficiency in antibody production (secondary immunodeficiencies) suffering from severe or recurrent infections due to various medical conditions (for example, oncological or autoimmune diseases or as a consequence of treatment for such diseases). These patients have undergone antibiotic treatment proven ineffective and have not shown a sufficiently positive increase in IgG antibody titres after vaccination (pneumococcal vaccines with polysaccharide and polypeptide antigens) or have an IgG blood level < 4 g/l.

Treatment of adults, children and adolescents (0-18 years) with certain inflammatory diseases
(immunomodulation) in the following situations:

1. Patients with insufficient platelets (Primary Immune Thrombocytopenia, ITP) who are at high risk of bleeding or prior to surgical procedures to correct platelet count.
2. Patients with Guillain-Barré syndrome. This is an acute disease characterized by inflammation of the peripheral nerves, causing severe muscle weakness, particularly in the legs and upper limbs.
3. Patients with Kawasaki disease (in combination with acetylsalicylic acid). This is an acute disease affecting mainly young children, characterized by inflammation of blood vessels throughout the body.
4. Patients with Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP). This chronic disease is a rare disorder of the peripheral nerves characterized by a gradual increase in weakness of the legs and, to a lesser extent, the arms.
5. Patients with Multifocal Motor Neuropathy (MMN). This is a rare condition affecting motor nerves and characterized by slowly progressive, asymmetric limb weakness without loss of sensation.

2. What you should know before using VENITAL

Do not use VENITAL
If you are allergic (hypersensitive) to human immunoglobulins or to any of the other components of
this medicine (listed in section 6).
If you have antibodies in your blood directed against IgA-type immunoglobulins, because administration of
a product containing IgA may cause a severe allergic reaction.

Warnings and precautions
Talk to your doctor or nurse before using VENITAL.
Your doctor or another healthcare professional will closely monitor you and carefully observe you throughout
the entire infusion period with VENITAL to ensure that no reactions occur.
Some adverse reactions may occur more frequently:

• if the infusion rate is too high;

• if you have uncontrolled symptoms of untreated infections (e.g., fever) or symptoms of chronic inflammation;

• if you are receiving normal human immunoglobulins for the first time;

• in rare cases when switching from another type of normal human immunoglobulin medicinal product, or when a long interval has passed since the previous infusion.

• In certain conditions, immunoglobulins may increase the risk of myocardial infarction, stroke, pulmonary embolism, or deep vein thrombosis, because they increase blood viscosity. Therefore, your doctor will exercise particular caution in the following circumstances:

• if you are overweight,

• if you are elderly,

• if you have diabetes,

• if you have high blood pressure (hypertension),

• if your blood volume is too low (hypovolemia),

• if you have or have had blood vessel problems (vascular diseases),

• if you have an increased tendency for blood clotting (inherited or acquired thrombophilic disorders),

• if you suffer from thrombotic episodes,

• if you have diseases that increase blood density (viscosity),

• if you have had a prolonged period of immobility,

• if you have or have had kidney problems or if you are taking medicines that may damage the kidneys (nephrotoxic medicines), as cases of acute renal failure have been reported. In case of kidney damage, your doctor will consider discontinuing treatment.

• You may be allergic (hypersensitive) to immunoglobulins (antibodies) without knowing it. This may occur even if you have previously received normal human immunoglobulins and tolerated prior administrations. This possibility is particularly relevant if you have insufficient levels of IgA-type immunoglobulins (IgA deficiency with anti-IgA antibodies). In these rare cases, allergic (hypersensitivity) reactions such as a drop in blood pressure or shock may occur.

If an adverse reaction occurs, your doctor will decide whether to reduce the rate of administration or to stop
the infusion. Furthermore, your doctor will determine the necessary treatment based on the nature and severity
of the adverse effect.
In case of shock, standard treatment for shock must be administered. Inform your doctor if you suffer from
any of the conditions described above; your doctor will exercise particular caution when prescribing and administering
VENITAL to you.

Viral safety
Medicines prepared from human blood or plasma are subject to a number of safety measures to prevent transmission of infections to patients. These measures include careful selection of blood or plasma donors to ensure potentially infected donors are excluded, and testing of each donation and plasma pool to detect the possible presence of viruses. Manufacturers of these medicines also incorporate steps in the processing of blood or plasma capable of inactivating or removing pathogens. Despite these measures, when administering medicines prepared from human blood or plasma, the possibility of transmitting an infection cannot be completely excluded. This also applies to emerging or unknown viruses or other types of infectious agents.
The measures adopted are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and the non-enveloped hepatitis A virus (HAV). The measures adopted have limited effectiveness against non-enveloped viruses such as parvovirus B19.
Immunoglobulins have not been associated with hepatitis A or parvovirus B19 infections, which may be due to the presence of antibodies against these infections in the product, providing protective capacity.
It is strongly recommended to record the brand name and batch number each time you receive a dose of VENITAL, in order to maintain documentation of the batches used.

Children and adolescents
A mild and transient glucosuria (presence of glucose in urine) without clinical signs has been observed in pediatric patients after administration of Ig VENA, which has the same pharmaceutical form and qualitative and quantitative composition as VENITAL. This event may be related to the maltose contained in Ig VENA, as well as in VENITAL (same pharmaceutical form and qualitative and quantitative composition), since in the renal tubules, maltose is hydrolyzed to glucose, which is reabsorbed and excreted in urine only in small amounts. Glucose reabsorption is an age-dependent mechanism. The transient increase in plasma maltose may exceed the kidney's capacity to reabsorb the sugar, resulting in a positive test for glucose in urine.

Other medicines and VENITAL
Inform your doctor if you are taking, have recently taken, or might take any other medicines.
Normal human immunoglobulins for intravenous use must not be mixed with other medicinal products, nor with other IVIg-containing products.

Live attenuated virus vaccines
Administration of immunoglobulin may impair the efficacy of live attenuated virus vaccines, such as those for measles, rubella, mumps, and varicella, for a period of at least 6 weeks and up to 3 months. After administration of this product, a three-month interval must elapse before vaccination with live attenuated virus vaccines. In the case of measles, this weakening of the immune response may last up to one year. Therefore, antibody levels should be monitored in patients receiving the measles vaccine.

Loop diuretics (a group of medicines that increase urine production)
Avoid concomitant use of loop diuretics.

Blood tests
VENITAL may interfere with certain blood tests due to the temporary increase of various antibodies that are passively transferred into your bloodstream after immunoglobulin infusion; this increase in antibodies may cause certain blood tests to yield results that may not be accurate. Passive transfer of antibodies against erythrocyte antigens, e.g., A, B, D (determining blood group), may interfere with certain serological tests for red blood cell antibodies, for example, the direct antiglobulin test (DAT, direct Coombs test).

Blood glucose testing
Some blood glucose monitoring systems (e.g., those based on glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ) or on the colorimetric glucose oxidoreductase method) falsely recognize the maltose (100 mg/ml) contained in VENITAL as glucose. This may result in falsely elevated blood glucose readings during the infusion and for approximately 15 hours after the infusion ends, potentially leading to inappropriate insulin administration, posing a life-threatening risk or even fatal hypoglycemia. Additionally, cases of true hypoglycemia may remain untreated if the hypoglycemic state is masked by falsely elevated glucose values. Therefore, during administration of VENITAL or other parenteral products containing maltose, blood glucose measurement must be performed using glucose-specific methods. The instructions for use of the glucose monitoring system, including those of the test strips, must be carefully reviewed to determine whether the system is suitable for use in patients treated with parenteral products containing maltose. If in doubt, contact the manufacturer of the glucose monitoring system to determine its suitability for use with parenteral maltose-containing products.

Children and adolescents
Although no specific interaction studies have been conducted in the pediatric population, no differences from adult patients are expected.

Pregnancy, breastfeeding, and fertility

• If you are pregnant, suspect you may be pregnant, planning a pregnancy, or breastfeeding, consult your doctor before taking this medicine. Your doctor will decide whether it is appropriate to use VENITAL during pregnancy and breastfeeding.
• Clinical studies with VENITAL have not been conducted in pregnant women. It has been shown that intravenous human immunoglobulin products cross the placenta increasingly during the third trimester. However, antibody-containing medicines have been used for years in pregnant women, and no harmful effects on the course of pregnancy, the fetus, or the newborn are expected.
• If you are breastfeeding while being treated with VENITAL, the antibodies contained in the product may pass into breast milk. Therefore, your baby may be protected against certain infections.
• Clinical experience with immunoglobulins suggests that no harmful effects on fertility are expected.

Driving and using machines
The ability to drive vehicles or operate machinery may be impaired by certain adverse reactions associated with
VENITAL. Patients who experience adverse reactions during treatment should wait until symptoms resolve before driving or operating machinery.

VENITAL contains maltose and sodium
The product contains 100 mg of maltose per ml.
This medicinal product contains approximately 69 mg of sodium per liter. This should be taken into account for patients on a controlled sodium diet.

3. How to use VENITAL

VENITAL may only be used in hospitals or clinics and healthcare facilities by medical professionals or other healthcare providers.
The dose and treatment schedule depend on the indication; your doctor will determine the appropriate dose and treatment regimen for you.
At the beginning of the infusion, you will receive VENITAL at a low infusion rate. If you tolerate it well, your doctor may gradually increase the infusion rate.

Use in children and adolescents
The dosage in children and adolescents (0–18 years) does not differ from that in adults, as the dosage for each indication is based on body weight and adjusted according to the patient's clinical response.

If you use more VENITAL than you should
If you are given more VENITAL than you should, fluid overload may occur and the blood may become too thick (hyperviscous); this is particularly likely in at-risk patients, especially elderly patients or those with impaired cardiac or renal function.
If you have any doubts about the use of this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
The following side effects may generally occur after treatment with immunoglobulins:

• chills, headache, dizziness, fever, vomiting, nausea, allergic reactions, arthralgia (joint pain), drop in blood pressure, and moderate lower back pain have been reported occasionally;
• isolated cases of temporary reduction in red blood cells (reversible hemolytic anemia/hemolysis);
• a sudden drop in blood pressure has been reported rarely and, in some isolated cases, hypersensitivity reactions (anaphylactic shock) may occur even when the patient has not shown reactions to previous administrations;
• rare cases of transient skin reactions have been observed;
• very rarely, thromboembolic reactions (blood clot formation) have been observed, which may cause myocardial infarction, stroke, blockage of the pulmonary arteries (pulmonary embolism), and deep vein thrombosis;
• cases of transient non-infectious meningitis (reversible aseptic meningitis);
• increased levels of creatinine in the blood and/or cases of sudden renal failure have been reported;
• cases of transfusion-related acute lung injury (TRALI).

The side effects reported during administration of Ig VENA, an immunoglobulin with the same pharmaceutical form and qualitative and quantitative composition as VENITAL, in clinical studies and those reported after the medicine was placed on the market are listed below in order of decreasing frequency.
Common (may affect up to 1 in 10 people)

• Back pain
• Nausea
• Generalized weakness, fatigue, fever
• Muscle pain
• Headache, drowsiness

Frequency not known (cannot be estimated from available data)

• Non-infectious meningitis
• Destruction and consequent deficiency of red blood cells
• Allergic reactions and life-threatening allergic shock
• Confusional state
• Stroke, dizziness, involuntary tremor, numbness and tingling of the skin or a limb
• Heart attack, bluish or purplish skin discoloration, rapid heartbeat, slow heartbeat, irregular heartbeat
• Blood clots in large veins and blood vessels, low blood pressure, high blood pressure, pallor
• Blood clots in a major artery of the lungs, abnormal fluid accumulation in the lungs, difficulty breathing with shortness of breath and cough
• Vomiting, diarrhea, abdominal pain
• Rapid swelling of the skin, hives, redness and inflammation of the skin, rash, itching, eczema, excessive sweating
• Muscle and joint pain, back pain, neck pain, musculoskeletal stiffness
• Sudden renal failure
• Venous inflammation at the injection site, chills, chest pain or discomfort, facial swelling, general feeling of malaise
• Increased level of creatinine in the blood

Additional side effects in children and adolescents
The frequency, type, and severity of adverse reactions in children are expected to be the same as in adults.
A slight and transient glycosuria (presence of glucose in urine) without clinical significance has been observed in children after administration of Ig VENA, which has the same pharmaceutical form and qualitative and quantitative composition as VENITAL.
For information on viral safety, see section 2 “Before using VENITAL”.
Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, consult your doctor or nurse. You may also report side effects directly via the website https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store VENITAL

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label and outer packaging after "Exp.". The expiry date refers to the last day of the month.
Store in a refrigerator (2 °C - 8 °C).
Once the infusion container has been opened, the contents must be used immediately.
Keep the vial in the outer packaging.
Do not freeze.
Do not use this medicine if you notice that the solution is cloudy, contains deposits, or shows any change in colour.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Contents of the pack and other information

What VENITAL contains
The active substance in VENITAL is normal human immunoglobulin.
One ml of solution contains 50 mg of normal human immunoglobulin.
The solution contains human proteins at a concentration of 50 g/l, of which at least 95% consists of
immunoglobulin G (IgG).
The distribution of immunoglobulin G (IgG) subclasses is as follows:
IgG 62.1%
IgG 34.8%
IgG 2.5%
IgG 0.6%
The maximum IgA content is 50 micrograms/ml.
Produced from plasma of human donors.
The other components are maltose and water for injections.

Description of the appearance of VENITAL and contents of the pack
VENITAL is an infusion solution, clear or slightly opalescent, colourless or pale yellow.
VENITAL 1 g/20 ml infusion solution, 20 ml vial.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder:
Kedrion S.p.A. - Loc. Ai Conti, 55051 Castelvecchio Pascoli, Barga (Lucca) - ITALY.
Manufacturer: Kedrion S.p.A., 55027 Bolognana, Gallicano (Lucca) - ITALY.

The following information is intended exclusively for physicians or healthcare professionals:

Instructions for correct use

• Prior to administration, bring the product to room or body temperature.
• Visually inspect the solution before administration for the presence of particles or discoloration. Do not use cloudy solutions or those containing deposits.
• Normal human immunoglobulin (VENITAL) must be administered intravenously at an initial rate of 0.46–0.92 ml/kg/h (10–20 drops per minute) for 20–30 minutes. In case of an adverse reaction, the infusion rate must be reduced or the infusion stopped. If well tolerated, the infusion rate may be gradually increased up to a maximum of 1.85 ml/kg/h (40 drops per minute).
• In patients with PID who tolerate an infusion rate of 0.92 ml/kg/h, the infusion rate may be gradually increased to 2 ml/kg/h, then to 4 ml/kg/h, and up to a maximum of 6 ml/kg/h, every 20–30 minutes, but only if the patient tolerates the infusion well.
• In general, dosage and infusion rate must be individually adjusted according to the patient's needs. Depending on body weight, dosage, and the occurrence of adverse reactions, the patient may not reach the maximum infusion rate. In case of an adverse reaction, the infusion must be immediately stopped and resumed at the most appropriate rate for the patient.

Special populations
In paediatric patients (0–18 years) and elderly patients (>64 years), the initial infusion rate should be 0.46–0.92 ml/kg/h (10–20 drops per minute) for 20–30 minutes. If well tolerated and based on the patient's clinical condition, the infusion rate may be gradually increased up to a maximum of 1.85 ml/kg/h (40 drops per minute).

Particular precautions
Some serious adverse reactions to the product may be due to the infusion rate.
Potential complications can often be avoided by ensuring:

• Patients are not sensitive to normal human immunoglobulin by starting administration slowly (at an infusion rate between 0.46 and 0.92 ml/kg/h);
• Patients are closely monitored for any symptoms during the infusion period. In particular, patients receiving normal human immunoglobulin for the first time, patients switching from another IVIg product, and patients who have had a long interval since their last infusion should be monitored during and for the first hour after the first infusion to detect potential signs of adverse reactions. All other patients should be observed for at least 20 minutes after administration. In all patients, IVIg administration requires:
• Adequate hydration before starting IVIg infusion;
• Monitoring of urine output;
• Monitoring of serum creatinine levels;
• Avoidance of concomitant use of loop diuretics.
  In case of an adverse reaction, the infusion rate must be reduced or the infusion stopped. The necessary treatment depends on the nature and severity of the adverse effect. In case of shock, standard medical treatment for shock must be initiated.

Infusion reactions
Some adverse reactions (e.g., headache, flushing, chills, myalgia, wheezing, tachycardia, back pain, nausea, and hypotension) may be related to the infusion rate. The recommended infusion rate must be strictly followed. Patients must be closely monitored and carefully observed for any symptoms during the infusion period.

Adverse reactions may occur more frequently:

• In patients receiving normal human immunoglobulin for the first time, or, rarely, when switching to a different immunoglobulin-containing medicinal product, or after a long interval since the previous infusion;
• In patients with untreated infection or chronic inflammation.

Children and adolescents
No specific measures or monitoring are required for the paediatric population.
No differences are expected in the paediatric population (0–18 years).

Thromboembolism
Clinical evidence shows an association between IVIg administration and thromboembolic events such as myocardial infarction, cerebrovascular accident (including stroke), pulmonary embolism, and deep vein thrombosis, presumed to be related to a relative increase in blood viscosity due to a high influx of immunoglobulin in at-risk patients. Caution is required when prescribing and administering IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events (such as advanced age, hypertension, diabetes mellitus, history of vascular disease or thrombotic episodes, patients with inherited or acquired thrombophilic disorders, immobilized patients, severely hypovolemic patients, or patients with conditions increasing blood viscosity).
In patients at risk of thromboembolic adverse reactions, IVIg products should be administered at the lowest feasible infusion rate and dose.

Acute renal failure
Cases of acute renal failure have been reported in patients receiving IVIg. In most cases, risk factors were identified, including pre-existing renal insufficiency, diabetes mellitus, hypovolemia, obesity, concomitant administration of nephrotoxic drugs, or age over 65 years.
Renal function parameters should be assessed before IVIg infusion, particularly in patients considered potentially at risk of developing acute renal failure, and again at appropriate intervals. In patients at risk of acute renal failure, IVIg products should be administered at the lowest feasible infusion rate and dose. If renal function changes occur, discontinuation of IVIg treatment should be considered.
Although cases of renal dysfunction and acute renal failure have been associated with the use of many IVIg products containing various excipients such as sucrose, glucose, and maltose, those containing sucrose as a stabilizer represent a very high proportion of the total number of cases. In at-risk patients, the use of IVIg products not containing these excipients may be considered.

Aseptic Meningitis Syndrome (AMS)
Aseptic meningitis syndrome may occur in association with IVIg treatment.
The syndrome typically begins several hours to 2 days after IVIg administration. Cerebrospinal fluid studies often show pleocytosis up to several thousand cells per mm³, predominantly granulocytes, and elevated protein levels up to several hundred mg/dl.
AMS may occur more frequently with high-dose IVIg (2 g/kg).
Patients presenting with such signs and symptoms should undergo a complete neurological evaluation, including cerebrospinal fluid studies, to exclude other causes of meningitis.
Discontinuation of IVIg treatment has led to resolution of AMS within a few days, without sequelae.

Haemolytic anaemia
IVIg products may contain blood group-specific antibodies that can act as haemolysins and induce in vivo coating of red blood cells with immunoglobulins, resulting in a positive direct antiglobulin reaction (Coombs test) and, rarely, haemolysis. Haemolytic anaemia may develop following IVIg therapy due to increased red blood cell sequestration. Patients receiving IVIg should be monitored for clinical signs and symptoms of haemolysis.

Neutropenia/Leucopenia
A transient decrease in neutrophil count and/or episodes of neutropenia, sometimes severe, have been reported after IVIg treatment. This typically occurs within a few hours or days after IVIg administration and resolves spontaneously within 7–14 days.

Transfusion-Related Acute Lung Injury (TRALI)
There have been rare reports of non-cardiogenic acute pulmonary oedema (transfusion-related acute lung injury, TRALI) in patients receiving IVIg. TRALI is characterised by severe hypoxia, dyspnoea, tachypnoea, cyanosis, fever, and hypotension. TRALI-associated symptoms typically occur during or within 6 hours of transfusion, usually within 1–2 hours. Therefore, patients receiving IVIg should be monitored, and infusion must be immediately stopped if pulmonary adverse reactions occur. TRALI is a life-threatening condition requiring immediate admission to intensive care.

This product contains 100 mg/ml of maltose as excipient. Maltose interference with blood glucose tests may lead to overestimation of glucose values and, consequently, inadequate insulin administration, potentially resulting in life-threatening hypoglycaemia and patient death. Additionally, true hypoglycaemia may remain untreated if the hypoglycaemic state is masked by falsely elevated glucose readings. For further details, see the section “Blood glucose testing”.

Dosage recommendations
Replacement therapy must be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency.

Dosage
The dose and dosing schedule depend on the indication. The dose must be individualised for each patient based on clinical response. Weight-based dosing may require adjustment in underweight or overweight patients.
The following dosing regimens may be used as a reference.

Treatment of primary immunodeficiency syndromes
The dosing regimen should aim to achieve a trough IgG level (measured just before the next infusion) of at least 6 g/L or within the normal reference range for the patient's age group.
It takes 3 to 6 months from the start of therapy to reach steady-state IgG levels.
The recommended initial dose is 0.4–0.8 g/kg as a single infusion, followed by at least 0.2 g/kg every 3–4 weeks.
The dose required to achieve a trough level of 6 g/L is approximately 0.2–0.8 g/kg/month. The interval between doses ranges from 3 to 4 weeks once steady state is achieved. Trough IgG levels should be measured and evaluated together with the incidence of infections. Dose increases and higher trough levels may be necessary to reduce the frequency of bacterial infections.

Secondary immunodeficiencies
The recommended dose is 0.2–0.4 g/kg every 3–4 weeks.
Trough IgG levels should be measured and evaluated together with infection incidence. The dose should be adjusted as needed to achieve optimal protection against infections. Dose increases may be necessary in patients with persistent infection; dose reduction may be considered when the patient remains infection-free.

Primary immune thrombocytopenia
Two alternative treatment regimens are available:

• 0.8–1 g/kg on Day 1; this dose may be repeated once within 3 days;
• 0.4 g/kg daily for 2–5 days. Treatment may be repeated in case of relapse.

Guillain-Barré Syndrome
0.4 g/kg/day for 5 days (repetition of the dose may be considered in case of relapse).

Kawasaki disease
2.0 g/kg should be administered as a single dose. Patients must receive concomitant treatment with acetylsalicylic acid.

Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)
Initial dose: 2 g/kg administered over 2–5 consecutive days.
Maintenance doses:
1 g/kg over 1–2 consecutive days every 3 weeks.
The effect of treatment should be evaluated after each cycle; if no treatment effect is observed after 6 months, treatment should be discontinued.
If therapy is effective, long-term administration is at the physician’s discretion based on patient response and maintenance response. Dosage and intervals may need to be adjusted according to the individual course of the disease.

Multifocal Motor Neuropathy (MMN)
Initial dose: 2 g/kg administered over 2–5 consecutive days.
Maintenance doses: 1 g/kg every 2–4 weeks or 2 g/kg every 4–8 weeks.
The effect of treatment should be evaluated after each cycle; if no treatment effect is observed after 6 months, treatment should be discontinued.
If therapy is effective, long-term administration is at the physician’s discretion based on patient response and maintenance response. Dosage and intervals may need to be adjusted according to the individual course of the disease.

The recommended doses are summarised in the following table:

Indication	Dose	Frequency of injections
Replacement therapy
Primary immunodeficiency syndromes	Initial dose: 0.4–0.8 g/kg Maintenance dose: 0.2–0.8 g/kg	every 3–4 weeks
Secondary immunodeficiencies	0.2–0.4 g/kg	every 3–4 weeks
Immunomodulation:
Primary immune thrombocytopenia	0.8–1 g/kg Or 0.4 g/kg/day	Day 1, possibly repeated once within 3 days for 2–5 days
Guillain-Barré syndrome	0.4 g/kg/day	for 5 days
Kawasaki disease	2 g/kg	single dose, in combination with acetylsalicylic acid
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)	Initial dose: 2 g/kg Maintenance dose: 1 g/kg	divided over 2–5 days every 3 weeks; 1–2 days
Multifocal motor neuropathy (MMN)	Initial dose: 2 g/kg Maintenance dose: 1 g/kg Or 2 g/kg	for 2–5 consecutive days every 2–4 weeks Or every 4–8 weeks for 2–5 days

Use in children and adolescents
The dosage in children and adolescents (0-18 years) is not different from that in adults, as the dosage for each indication is based on body weight and adjusted according to the clinical outcome of the respective conditions.

Hepatic impairment
There is no evidence to require dose adjustment.

Renal impairment
No dose adjustment is necessary unless clinically justified.

Elderly
No dose adjustment is necessary unless clinically justified.

CIDP
Due to the rarity of the disease and, consequently, the limited overall number of patients, experience with the use of intravenous immunoglobulins in children with CIDP is limited; therefore, only literature data are available. However, published data consistently show that IVIg treatment is equally effective in children and adults, in line with what is observed for the approved indications of IVIg.

PACKAGE LEAFLET: INFORMATION FOR THE USER

VENITAL 50 g/l Infusion Solution

Normal human immunoglobulin (IVIg) for intravenous use
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or nurse.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor or nurse. See section 4.

Contents of this leaflet:

1. What VENITAL is and what it is used for
2. What you need to know before using VENITAL
3. How to use VENITAL
4. Possible side effects
5. How to store VENITAL
6. Contents of the pack and other information

1. What VENITAL is and what it is used for

VENITAL is a normal human immunoglobulin solution for intravenous use. Immunoglobulins are human antibodies also present in blood.
VENITAL is used for:
Replacement therapy in adults, children and adolescents (0-18 years) who do not have sufficient antibodies in the following conditions:

1. Patients with congenital deficiency in antibody production (primary immunodeficiency syndromes).
2. Patients with acquired deficiency in antibody production (secondary immunodeficiencies) suffering from severe or recurrent infections due to various medical conditions (e.g. oncological or autoimmune diseases or as a consequence of treatment for such diseases). These patients have been treated with antibiotics that proved ineffective and have not shown a sufficiently positive increase in IgG antibody titres after vaccination (pneumococcal vaccines with polysaccharide and polypeptide antigens) or have an IgG level in their blood < 4 g/l.

Treatment of adults, children and adolescents (0-18 years) with certain inflammatory diseases (immunomodulation) in the following situations:

1. Patients with insufficient platelets (Primary Immune Thrombocytopenia, ITP) who are at high risk of bleeding or prior to surgical procedures to correct platelet count.
2. Patients with Guillain-Barré syndrome. This is an acute disease characterized by inflammation of the peripheral nerves, causing severe muscle weakness, particularly in the legs and upper limbs.
3. Patients with Kawasaki disease (in combination with acetylsalicylic acid). This is an acute disease affecting mainly young children, characterized by inflammation of blood vessels throughout the body.
4. Patients with Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP). This chronic disease is a rare disorder of the peripheral nerves characterized by a gradual increase in leg weakness and, to a lesser extent, arm weakness.
5. Patients with Multifocal Motor Neuropathy (MMN). This is a rare condition affecting motor nerves, characterized by slowly progressive, asymmetric limb weakness without loss of sensation.

2. What you should know before using VENITAL

Do not use VENITAL
If you are allergic (hypersensitive) to human immunoglobulins or to any of the other ingredients of
this medicine (listed in section 6).
If you have antibodies in your blood directed against IgA-type immunoglobulins, as administration of
a product containing IgA may cause a severe allergic reaction.

Warnings and precautions
Talk to your doctor or nurse before using VENITAL.
Your doctor or another healthcare professional will closely monitor and carefully observe you throughout
the entire VENITAL infusion period to check for any reactions.
Adverse reactions may occur more frequently:

• if the infusion rate is too high;

• if you have uncontrolled symptoms of untreated infections (e.g. fever) or symptoms of chronic inflammation;

• if you are receiving normal human immunoglobulins for the first time;

• in rare cases when switching from another type of normal human immunoglobulin medicinal product, or after a long interval since the previous infusion.

• In certain conditions, immunoglobulins may increase the risk of myocardial infarction, stroke, pulmonary embolism, or deep vein thrombosis, as they may increase blood viscosity. Therefore, your doctor will exercise particular caution in the following circumstances:

• if you are overweight,

• if you are elderly,

• if you have diabetes,

• if you have high blood pressure (hypertension),

• if your blood volume is too low (hypovolemia),

• if you have or have had blood vessel problems (vascular diseases),

• if you have an increased tendency for blood clotting (inherited or acquired thrombophilic disorders),

• if you suffer from thrombotic episodes,

• if you have diseases that increase blood density (viscosity),

• if you have had a prolonged period of immobility,

• if you have or have had kidney problems or are taking medicines that may damage the kidneys (nephrotoxic medicines), as cases of acute kidney failure have been reported. In case of kidney damage, your doctor will consider discontinuing treatment.

• You may be allergic (hypersensitive) to immunoglobulins (antibodies) without knowing it. This may occur even if you have previously received normal human immunoglobulins and tolerated earlier administrations. This possibility is particularly relevant if you have insufficient IgA-type immunoglobulins (IgA deficiency with anti-IgA antibodies). In these rare cases, allergic (hypersensitivity) reactions such as low blood pressure or shock may occur. In case of an adverse reaction, your doctor will decide whether to reduce the infusion rate or stop the infusion. Additionally, your doctor will determine the necessary treatment based on the nature and severity of the adverse effect.

In case of shock, standard shock treatment must be administered. Inform your doctor if you suffer from
any of the conditions described above; your doctor will use particular caution when prescribing and administering
VENITAL to you.

Viral safety
Medicines prepared from human blood or plasma undergo several safety measures to prevent transmission of infections to patients. These measures include careful selection of blood or plasma donors to exclude potentially infected donors, and testing of each donation and plasma pool to detect possible presence of viruses. Manufacturers of these medicines also incorporate into the manufacturing process certain steps capable of inactivating or removing pathogens. Despite these measures, when administering medicines prepared from human blood or plasma, the possibility of transmitting an infection cannot be completely ruled out. This also applies to emerging or unknown viruses or other types of infectious agents.
The measures adopted are considered effective against lipid-enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and the non-lipid-enveloped hepatitis A virus (HAV). The measures adopted have limited effectiveness against non-lipid-enveloped viruses such as parvovirus B19.
Immunoglobulins have not been associated with hepatitis A or parvovirus B19 infections, which may be due to the presence of protective antibodies against these infections in the product.
It is strongly recommended to record the brand name and batch number each time a dose of VENITAL is administered, in order to maintain documentation of the batches used.

Children and adolescents
A mild and transient glycosuria (presence of glucose in urine) without clinical signs has been observed in pediatric patients after administration of Ig VENA, which has the same pharmaceutical form and qualitative and quantitative composition as VENITAL. This event may be related to the maltose content in Ig VENA, as well as in VENITAL (same pharmaceutical form and qualitative and quantitative composition), since in the renal tubules, maltose is hydrolyzed to glucose, which is reabsorbed and excreted in urine only in small amounts. Glucose reabsorption is an age-dependent mechanism. The transient increase in plasma maltose may exceed the kidney's capacity to reabsorb sugar, resulting in a positive test for glucose in urine.

Other medicines and VENITAL
Inform your doctor if you are taking, have recently taken, or might take any other medicines.
Normal human immunoglobulins for intravenous use must not be mixed with other medicinal products, nor with other IVIg-containing products.

Live attenuated virus vaccines
Administration of immunoglobulin may impair the efficacy of live attenuated virus vaccines such as those for measles, rubella, mumps, and varicella for a period of at least 6 weeks and up to 3 months. After administration of this product, a three-month interval must pass before vaccination with live attenuated virus vaccines. In the case of measles, this weakening of the immune response may last up to one year. Therefore, antibody levels should be monitored in patients receiving the measles vaccine.

Loop diuretics (a group of medicines that increase urine production)
Avoid concomitant use of loop diuretics.

Blood tests
VENITAL may interfere with certain blood tests due to the temporary increase of various antibodies passively transferred into your bloodstream after immunoglobulin infusion; this antibody increase may cause certain blood tests to yield incorrect results. Passive transfer of antibodies against erythrocyte antigens, e.g. A, B, D (determining blood group), may interfere with certain serological tests for red blood cell antibodies, for example the direct antiglobulin test (DAT, direct Coombs test).

Blood glucose testing
Some blood glucose monitoring systems (e.g. those based on glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ) or on the glucose oxidoreductase colorimetric method) falsely recognize the maltose (100 mg/ml) contained in VENITAL as glucose. This may result in falsely elevated blood glucose readings during the infusion and for approximately 15 hours after the end of the infusion, potentially leading to inappropriate insulin administration, posing a life-threatening risk or even fatal hypoglycemia. Additionally, cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated glucose values. Consequently, during administration of VENITAL or other parenteral products containing maltose, blood glucose measurement must be performed using glucose-specific methods. The instructions for use of the glucose monitoring system, including those for test strips, must be carefully reviewed to determine whether the system is suitable for use in patients treated with parenteral products containing maltose. If in doubt, contact the manufacturer of the glucose monitoring system to determine its suitability for use with parenteral products containing maltose.

Children and adolescents
Although no specific interaction studies have been conducted in the pediatric population, no differences from adult patients are expected.

Pregnancy, breastfeeding, and fertility

• If you are pregnant, suspect you may be pregnant, planning pregnancy, or breastfeeding, consult your doctor before taking this medicine. Your doctor will decide whether it is appropriate to use VENITAL during pregnancy and breastfeeding.
• No clinical studies have been conducted with VENITAL in pregnant women. It has been shown that intravenous human immunoglobulin products cross the placenta increasingly during the third trimester. However, antibody-containing medicines have been used for years in pregnant women and have not been associated with harmful effects on the course of pregnancy, the fetus, or the newborn.
• If you are breastfeeding and receiving VENITAL treatment, the antibodies contained in the product may pass into breast milk. Therefore, your baby may be protected from certain infections.
• Clinical experience with immunoglobulins suggests that no harmful effects on fertility are expected.

Driving and using machines
The ability to drive vehicles or operate machinery may be impaired by certain adverse reactions associated with
VENITAL. Patients experiencing adverse reactions during treatment should wait until symptoms resolve before driving or operating machinery.

VENITAL contains maltose and sodium
The product contains 100 mg of maltose per ml.
This medicinal product contains approximately 69 mg of sodium per litre. This should be taken into account for patients on a controlled sodium diet.

3. How to use VENITAL

VENITAL can only be used in hospitals, clinics, or healthcare facilities by medical professionals or other healthcare providers.
The dose and treatment schedule depend on the indication; your doctor will determine the dose and treatment schedule suitable for you.
At the beginning of the infusion, you will receive VENITAL at a low infusion rate. If you tolerate it well, your doctor may gradually increase the infusion rate.

Use in children and adolescents
The dosage in children and adolescents (0–18 years) does not differ from that in adults, as the dosage for each indication is based on body weight and adjusted according to the patient's clinical response.

If you use more VENITAL than you should
If you are given more VENITAL than you should, fluid overload may occur and the blood may become too thick (hyperviscous); this is particularly observed in at-risk patients, especially elderly patients or those with impaired cardiac or renal function.

If you have any doubts about the use of this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
The following side effects may generally occur after treatment with immunoglobulins:

• chills, headache, dizziness, fever, vomiting, nausea, allergic reactions, arthralgia (joint pain), drop in blood pressure, and moderate lower back pain have been reported occasionally;
• isolated cases of temporary reduction in red blood cells (reversible haemolytic anaemia/haemolysis);
• a sudden drop in blood pressure has been reported rarely and, in some isolated cases, hypersensitivity reactions (anaphylactic shock) may occur even when the patient has not shown reactions to previous administrations;
• rare cases of transient skin reactions have been observed;
• very rare cases of thromboembolic reactions (blood clot formation) have been observed, which may lead to myocardial infarction, stroke, blockage of the pulmonary veins (pulmonary embolism), and deep vein thrombosis;
• cases of transient non-infectious meningitis (aseptic reversible meningitis);
• increased levels of creatinine in the blood and/or cases of sudden renal failure have been reported;
• cases of transfusion-related acute lung injury (TRALI).

The side effects reported during administration of Ig VENA, an immunoglobulin with the same pharmaceutical form and qualitative and quantitative composition as VENITAL, in clinical studies and those reported after marketing of the medicine are listed below in order of decreasing frequency.
Common (may affect up to 1 in 10 people)

• Back pain
• Nausea
• Generalised weakness, fatigue, fever
• Muscle pain
• Headache, drowsiness

Frequency not known (cannot be estimated from available data)

• Non-infectious meningitis
• Destruction and consequent deficiency of red blood cells
• Allergic reactions and life-threatening allergic shock
• Confusion
• Stroke, dizziness, involuntary tremor, numbness and tingling of the skin or a limb
• Heart attack, bluish or purplish skin discoloration, rapid heartbeat, slow heartbeat, irregular heartbeat
• Blood clots in major veins and blood vessels, low blood pressure, high blood pressure, pallor
• Blood clots in a major pulmonary artery, abnormal fluid volume in the lungs, difficulty breathing with laboured breathing and cough
• Vomiting, diarrhoea, abdominal pain
• Rapid swelling of the skin, hives, redness and inflammation of the skin, rash, itching, eczema, excessive sweating
• Pain in muscles and joints, back pain, neck pain, musculoskeletal stiffness
• Sudden renal failure
• Venous inflammation at injection site, chills, chest pain or discomfort, facial swelling, general feeling of malaise
• Increased level of creatinine in the blood

Additional side effects in children and adolescents
The frequency, type, and severity of adverse reactions in children are expected to be the same as in adults.
A slight and transient glycosuria (presence of glucose in urine) without clinical significance has been observed in children after administration of Ig VENA, which has the same pharmaceutical form and qualitative and quantitative composition as VENITAL.
For information on viral safety, see section 2 “Before using VENITAL”.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or nurse. You can also report side effects directly via the website https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store VENITAL

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the label and on the outer packaging after "Exp.". The expiry date refers to the last day of the month.
Store in a refrigerator (2 °C - 8 °C).
Before use and within the expiry date, the product may be stored at room temperature, not exceeding 25°C, for a maximum of 6 consecutive months. After this period, the product must be discarded. In any case, once stored at room temperature, the product must not be returned to the refrigerator.
Record the date of starting room temperature storage on the outer carton.
Once the infusion container has been opened, the contents must be used immediately.
Keep the vial in the outer packaging.
Do not freeze.
Do not use this medicine if you notice that the solution is cloudy, contains deposits, or shows any change in colour.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer in use. This will help protect the environment.

6. Package Contents and Other Information

What VENITAL Contains
The active substance in VENITAL is normal human immunoglobulin.
One ml of solution contains 50 mg of normal human immunoglobulin.
The solution contains human proteins at a concentration of 50 g/l, of which at least 95% consists of
immunoglobulin G (IgG).
The subclasses of immunoglobulin G (IgG) have the following distribution:
IgG 62.1%
IgG 34.8%
IgG 2.5%
IgG 0.6%
The maximum IgA content is 50 micrograms/ml.
Produced from plasma of human donors.
The other components are maltose and water for injections.

Description of the Appearance of VENITAL and Contents of the Package
VENITAL is an infusion solution, clear or slightly opalescent, colorless or pale yellow.
VENITAL 2.5 g/50 ml infusion solution, 50 ml vial + extensible hanger
VENITAL 5 g/100 ml infusion solution, 100 ml vial + extensible hanger
VENITAL 10 g/200 ml infusion solution, 200 ml vial + extensible hanger

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder:
Kedrion S.p.A. - Loc. Ai Conti, 55051 Castelvecchio Pascoli, Barga (Lucca) - ITALY.
Manufacturer: Kedrion S.p.A., 55027 Bolognana, Gallicano (Lucca) - ITALY.

The following information is intended exclusively for physicians or healthcare professionals:
Instructions for Correct Use

• Before administration, bring the product to room or body temperature.
• Before administration, visually inspect the solution for particles or discoloration. Do not use cloudy solutions or those containing deposits.
• Normal human immunoglobulin (VENITAL) must be infused intravenously at an initial rate of 0.46–0.92 ml/kg/h (10–20 drops per minute) for 20–30 minutes. In case of adverse reaction, the infusion rate must be reduced or the infusion stopped. If well tolerated, the infusion rate may be gradually increased up to a maximum of 1.85 ml/kg/h (40 drops/minute).
• In patients with PID who tolerate an infusion rate of 0.92 ml/kg/h, the infusion rate may be gradually increased to 2 ml/kg/h, 4 ml/kg/h, up to a maximum of 6 ml/kg/h, every 20–30 minutes, and only if the patient tolerates the infusion well.
• In general, dosage and infusion rate must be individually adjusted according to the patient's needs. Depending on body weight, dosage, and occurrence of adverse reactions, the patient may not reach the maximum infusion rate. In case of adverse reaction, the infusion must be immediately stopped and resumed at the most appropriate rate for the patient.

Special Populations
In pediatric patients (0–18 years) and elderly patients (>64 years), the initial infusion rate
should be 0.46–0.92 ml/kg/h (10–20 drops per minute) for 20–30 minutes. If well tolerated and based on the patient's clinical condition, the infusion rate may be gradually increased
up to a maximum of 1.85 ml/kg/h (40 drops/minute).

Instructions for Use of the Extensible Hanger

1. Initial condition of the vial with the hanger label
2. Invert the vial
3. Rotate the lower edge of the hanger label upward to extend it
4. Hang the vial on the support

Special Precautions
Some serious adverse reactions to the product may be due to the infusion rate.
Potential complications can often be avoided by ensuring:

• that patients are not sensitive to normal human immunoglobulin by administering the product slowly at the beginning (with an infusion rate between 0.46 and 0.92 ml/kg/h);
• that patients are closely monitored for any symptoms during the infusion period. In particular, patients receiving normal human immunoglobulin for the first time, patients who have changed the type of IVIg product, and patients with a long interval since the previous infusion must be monitored during the first infusion and for the first hour after the first infusion to detect potential signs of adverse reactions. All other patients must be observed for at least 20 minutes after administration. In all patients, IVIg administration requires:
• adequate hydration before starting the IVIg infusion;
• monitoring of urinary output;
• monitoring of serum creatinine levels;
• avoidance of concomitant use of loop diuretics. In case of adverse reaction, the infusion rate must be reduced or the infusion stopped. The necessary treatment depends on the nature and severity of the adverse effect. In case of shock, standard medical treatment for shock must be performed.

Infusion Reaction
Some adverse reactions (e.g., headache, flushing, chills, myalgia, wheezing,
tachycardia, back pain, nausea, and hypotension) may be related to the infusion rate. The
recommended infusion rate must be strictly followed. Patients must be closely monitored and carefully observed for any symptoms during the infusion period.
Adverse reactions may occur more frequently

• in patients receiving normal human immunoglobulin for the first time or, in rare cases, when switching to a different normal human immunoglobulin medicinal product, or after a long interval since the previous infusion
• in patients with untreated infection or chronic inflammation

Children and Adolescents
No specific measures or monitoring are required for the pediatric population.
No differences are expected in the pediatric population (0–18 years).

Thromboembolism
Clinical evidence shows a relationship between IVIg administration and thromboembolic events such as myocardial infarction, cerebrovascular accident (including stroke), pulmonary embolism, and deep vein thrombosis, presumed to be related to a relative increase in blood viscosity due to a high influx of immunoglobulin in at-risk patients. Caution is required when prescribing and infusing IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events (such as advanced age, hypertension, diabetes mellitus, history of vascular disease or thrombotic episodes, patients with inherited or acquired thrombophilic disorders, patients immobilized for prolonged periods, severely hypovolemic patients, patients with diseases increasing blood viscosity).
In patients at risk for thromboembolic adverse reactions, IVIg-based products must be administered at the lowest feasible infusion rate and dose.

Acute Renal Failure
Cases of acute renal failure have been reported in patients receiving IVIg. In most
cases, risk factors were identified and included pre-existing renal insufficiency, diabetes
mellitus, hypovolemia, overweight, concomitant administration of nephrotoxic drugs, or age over
65 years.
Renal parameters must be evaluated before IVIg infusion, particularly in patients considered potentially at risk of developing acute renal failure, and again at appropriate intervals. In
patients at risk of acute renal failure, IVIg-based products must be administered at the
lowest feasible infusion rate and dose.
If renal function changes occur, discontinuation of IVIg treatment should be considered. Although cases of renal dysfunction and acute renal failure have been associated with the use of many IVIg-based medicinal products containing various excipients such as sucrose, glucose, and
maltose, those containing sucrose as a stabilizer represent a very high percentage of the total number. In patients at risk, the use of IVIg-based medicinal products not containing these excipients may be considered.

Aseptic Meningitis Syndrome (AMS)
Aseptic meningitis syndrome may occur in association with IVIg treatment.
Generally, the syndrome begins after a period ranging from several hours to 2 days following IVIg treatment. Cerebrospinal fluid studies often show pleocytosis up to several thousand cells per mm³, predominantly granulocytes, and elevated protein levels, up to several hundred mg/dl.
AMS may occur more frequently in association with high doses of IVIg (2 g/kg).
Patients presenting such signs and symptoms should undergo a complete neurological examination, including cerebrospinal fluid studies, to exclude other causes of meningitis.
Discontinuation of IVIg treatment has led to resolution of AMS within a few days, without consequences.

Hemolytic Anemia
IVIg-based products may contain blood group-specific antibodies that can act as hemolysins and induce in vivo coating of red blood cells with immunoglobulins, causing a positive direct antiglobulin reaction (Coombs test) and, rarely, hemolysis. Hemolytic anemia may develop following IVIg therapy due to increased sequestration of red blood cells. Patients receiving IVIg should be monitored for clinical signs and symptoms of hemolysis.

Neutropenia/Leukopenia
A transient decrease in neutrophil count and/or episodes of neutropenia, sometimes severe, have been
reported after IVIg treatment. This usually occurs within a few hours or days after IVIg administration and resolves spontaneously within 7–14 days.

Transfusion-Related Acute Lung Injury (TRALI)
A few cases of non-cardiogenic acute pulmonary edema (transfusion-related acute lung injury, TRALI) have been reported in patients receiving IVIg. TRALI is characterized by severe hypoxia,
dyspnea, tachypnea, cyanosis, fever, and hypotension. Symptoms associated with TRALI typically appear
during or within 6 hours after transfusion, usually within 1–2 hours. Therefore, patients receiving IVIg must be monitored, and IVIg infusion must be immediately stopped if pulmonary adverse reactions occur. TRALI is a condition that may be life-threatening and requires immediate admission to an intensive care unit.

This product contains 100 mg of maltose per ml as excipient. Maltose interference with blood glucose tests may lead to overestimation of glucose values and, consequently, inappropriate insulin administration, which may cause a life-threatening hypoglycemic state and patient death. In addition, real hypoglycemia may not be treated if the hypoglycemic state is masked by falsely elevated glucose values. For further details, see the section “Blood Glucose Testing”.

Dosage Recommendations
Replacement therapy must be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency.

Dosage
The dose and dosing regimen depend on the indication. The dose must be individualized for each patient based on clinical response. Weight-based dosing may require adjustment in underweight or overweight patients.
The following dosing regimens may be used as reference.

Replacement Therapy in Primary Immunodeficiency Syndromes
The dosing regimen should aim to achieve a trough level of IgG (measured before the next infusion) of at least 6 g/L or within the normal reference range for the patient's age group.
From the start of therapy, it takes 3 to 6 months to reach equilibrium (steady-state IgG levels).
The recommended initial dose is 0.4–0.8 g/kg as a single administration, followed by at least 0.2 g/kg administered every 3–4 weeks.
The dose required to achieve a trough level of 6 g/L of IgG is in the range of 0.2–0.8 g/kg/month.
The interval between doses varies from 3 to 4 weeks after reaching steady state. Trough IgG levels should be measured and evaluated together with the incidence of infections. It may be necessary to increase the dose and achieve higher trough levels to reduce the frequency of bacterial infections.

Secondary Immunodeficiencies
The recommended dose is 0.2–0.4 g/kg every 3–4 weeks.
Trough IgG levels should be measured and evaluated together with the incidence of infection. The dose should be adjusted as needed to achieve optimal protection against infections; an increase may be necessary in patients with persistent infection; a dose reduction may be considered when the patient remains infection-free.

Primary Immune Thrombocytopenia
Two alternative treatment regimens exist:

• 0.8–1 g/kg administered on Day 1; this dose may be repeated once within 3 days;
• 0.4 g/kg daily for 2–5 days. Treatment may be repeated in case of relapse.

Guillain-Barré Syndrome
0.4 g/kg/day for 5 days (possible repetition of the dose in case of relapse).

Kawasaki Disease
2.0 g/kg must be administered as a single dose. Patients must receive concomitant treatment with acetylsalicylic acid.

Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP)
Initial dose: 2 g/kg divided over 2–5 consecutive days.
Maintenance dose:
1 g/kg over 1–2 consecutive days every 3 weeks.
The effect of treatment must be evaluated after each cycle; if no treatment effect is observed after 6 months, treatment should be discontinued.
If therapy is effective, long-term administration is at the physician's discretion based on patient response and maintenance response. Dosage and intervals may need to be adjusted based on individual disease course.

Multifocal Motor Neuropathy (MMN)
Initial dose: 2 g/kg administered over 2–5 consecutive days.
Maintenance doses: 1 g/kg every 2–4 weeks or 2 g/kg every 4–8 weeks.
The effect of treatment must be evaluated after each cycle; if no treatment effect is observed after 6 months, treatment should be discontinued.
If therapy is effective, long-term administration is at the physician's discretion based on patient response and maintenance response. Dosage and intervals may need to be adjusted based on individual disease course.

The recommended doses are summarized in the following table:

Indication	Dose	Frequency of injections
Replacement therapy
Primary immunodeficiency syndromes	Initial dose: 0.4 - 0.8 g/kg Maintenance dose: 0.2 - 0.8 g/kg	every 3 – 4 weeks
Secondary immunodeficiencies	0.2 - 0.4 g/kg	every 3 – 4 weeks
Immunomodulation:
Primary immune thrombocytopenia	0.8 - 1 g/kg Or 0.4 g/kg/day	day 1, possibly repeated once within 3 days for 2 – 5 days
Guillain-Barré syndrome	0.4 g/kg/day	for 5 days
Kawasaki disease	2 g/kg	single dose, in combination with acetylsalicylic acid
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)	Initial dose: 2 g/kg Maintenance dose: 1 g/kg	divided over 2 – 5 days every 3 weeks; 1 – 2 days
Multifocal motor neuropathy (MMN)	Initial dose: 2 g/kg Maintenance dose: 1 g/kg Or 2 g/kg	over 2–5 consecutive days every 2–4 weeks Or every 4–8 weeks over 2–5 days

Use in children and adolescents
The dosage in children and adolescents (0–18 years) is not different from that in adults, as the dosage for each indication is based on body weight and adjusted according to the clinical outcome of the aforementioned conditions.

Hepatic impairment
There is no evidence to require dose adjustment.

Renal impairment
No dose adjustment is necessary unless clinically justified.

Elderly
No dose adjustment is necessary unless clinically justified.

CIDP
Due to the rarity of the disease and, consequently, the small overall number of patients, experience with the use of intravenous immunoglobulins in children with CIDP is limited; therefore, only literature data are available. However, published data consistently show that IVIg treatment is equally effective in children and adults, in line with what is observed for the established indications for IVIg.