Pentaglobin

PACKAGE LEAFLET: INFORMATION FOR THE USER

Pentaglobin 50 mg/ml solution for infusion

Human immunoglobulin
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, pharmacist, or nurse.
• If you experience any side effects, including those not listed in this leaflet, tell your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

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

1. What Pentaglobin is and what it is used for

Pentaglobin is a medicine derived from human blood, containing antibodies (antibodies are components of the human body's immune defenses). This medicine is available as a solution for infusion, which is administered intravenously by drip infusion.

Pentaglobin is used

• as supportive therapy for severe bacterial infections in combination with antibiotic therapy.
• as replacement therapy for missing antibodies (immunoglobulins) in patients with severe acquired immunodeficiency.

2. What you should know before using Pentaglobin

Do not use Pentaglobin

• if you are allergic to human immunoglobulins or to any of the other ingredients of this medicine (listed in section 6).
• if you have immunoglobulin A (IgA) deficiency, particularly if you have antibodies against IgA in your blood, as this may cause anaphylaxis.

Warnings and precautions
Talk to your doctor or nurse before Pentaglobin is administered to you:

• if you are receiving human immunoglobulins for the first time, after a long period without treatment, or if your immunoglobulin preparation has been changed. In these cases, your doctor will closely monitor you.
• if you have an active infection or underlying chronic inflammation;
• if you are significantly overweight or elderly;
• if you suffer from high blood pressure (hypertension), diabetes, or vascular diseases;
• if you have a high predisposition to form blood clots;
• if you have been bedridden for a long time;
• if you have low blood volume (hypovolemia) or your blood tends to thicken;
• if you have pre-existing kidney disease or are taking medicines that may have harmful effects on your kidney function. In such cases, there is an increased risk of developing adverse effects. Your doctor may decide to discontinue treatment with Pentaglobin or take other precautionary measures (for example, by using a particularly slow infusion rate).

You may be allergic to immunoglobulins without knowing it, even if you previously tolerated immunoglobulin treatment well. However, true hypersensitivity reactions are rare. Some adverse reactions (e.g. headache, flushing, chills, myalgia, wheezing, tachycardia, lower back pain, nausea, and hypotension) may be related to the infusion rate. If you experience such reactions during Pentaglobin administration, inform your doctor immediately. The doctor will decide whether to reduce the infusion rate, stop the infusion, and initiate appropriate medical measures to treat the reaction.

Information on safety regarding infections
When medicines are manufactured from human blood or plasma (the liquid part of blood), all possible precautions are taken to prevent transmission of infectious agents to patients.
These include:

• careful selection of blood and plasma donors to exclude those at risk of carrying infections;
• testing of each individual donation and plasma pools for signs of viral infections;
• inclusion of steps in the manufacturing process of blood or plasma that can inactivate or remove viruses.

Despite these measures, the risk of transmitting infections through medicines derived from human blood or plasma cannot be completely ruled out. This applies also to unknown or emerging viruses or other types of infection.

The measures taken are considered effective against enveloped viruses, such as:

• human immunodeficiency virus (HIV),
• hepatitis B virus (HBV),
• hepatitis C virus (HCV).

The measures taken may have limited effectiveness against non-enveloped viruses, such as:

• hepatitis A virus (HAV),
• parvovirus B19.

To date, no cases of transmission of hepatitis A or parvovirus B19 have been associated with immunoglobulins, probably because the antibodies contained in the product provide protective activity against these infections.

It is strongly recommended that each time Pentaglobin is administered to you, your doctor records the name and batch number of the medicine, to keep track of the batch used. The batch number allows identification of the specific plasma used as the starting material for the administered medicine. If necessary, a link can be established between you and the source material.

Other medicines and Pentaglobin
Inform your doctor or pharmacist if you are currently using, have recently used, or might use any other medicines.
Pentaglobin may reduce the effectiveness of certain vaccines, such as vaccines against:

• measles
• rubella
• mumps
• varicella.

After receiving Pentaglobin, you should wait three months before being vaccinated; for the measles vaccine, the waiting period may extend up to one year.
Loop diuretics
Avoid concomitant use of loop diuretics (a group of medicines that increase urine production).

Pregnancy and breastfeeding
If you are pregnant, think you may be pregnant, planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before using this medicine.
Your doctor will decide whether you can receive Pentaglobin treatment during pregnancy or breastfeeding.

Driving and using machines
Pentaglobin has minor effects on the ability to drive and use machines. If you experience adverse effects during treatment, you should wait until they resolve before driving or operating machinery.

Pentaglobin contains glucose and sodium
1 ml of infusion solution contains 25 mg of glucose. This medicine contains 8.75 g of glucose per 350 ml dose for an adult (body weight 70 kg). This should be taken into account in patients with diabetes mellitus.
Pentaglobin contains 0.078 mmol/ml (1.79 mg/ml) of sodium (the main component of table salt). This medicine contains 627.6 mg of sodium (the main component of table salt) per daily dose of approximately 350 ml for an adult (body weight 70 kg). This corresponds to about 31% of the maximum recommended daily dietary intake for an adult.

3. How to use Pentaglobin

Pentaglobin will be administered to you by your doctor. The dosage depends on your immune status and the severity of the disease.
The recommended dose is:
Newborns and infants
5 ml (0.25 g) per kg of body weight per day for 3 consecutive days. Further administrations depend on the clinical condition.
Children and adults
For treatment of severe bacterial infections: 5 ml (0.25 g) per kg of body weight per day for 3 consecutive days. Further administrations depend on the clinical condition.
As replacement therapy for missing antibodies (immunoglobulins) in patients with acquired immunodeficiency or immunosuppression due to medications or radiation: 3–5 ml (0.15–0.25 g) per kg of body weight. If necessary, repeat administration at weekly intervals.
It is infused into a vein (intravenous administration) at the following infusion rates:
Newborns and infants:
1.7 ml per kg of body weight per hour using an infusion pump.
Children and adults:
0.4 ml per kg of body weight per hour,
alternatively: for the first 100 ml at 0.4 ml per kg of body weight per hour, then continuously at 0.2 ml per kg of body weight per hour until reaching 15.0 ml per kg of body weight within 72 hours.
Examples:

Hepatic impairment
There is no evidence to require dose adjustment.
Renal impairment
No dose adjustment unless clinically justified; see section “Warnings and precautions”.
Elderly
No dose adjustment unless clinically justified.
Method of administration
Pentaglobin is intended for intravenous administration (intravenous infusion).
The medicinal product should be warmed to room temperature or body temperature before use.
If you receive more Pentaglobin than you should
An excessive amount of Pentaglobin may cause fluid overload and increased blood viscosity (hyperviscosity), particularly in patients at risk, including children, elderly patients, or those with impaired cardiac or renal function. If you think that you or your child have received too much Pentaglobin, speak to your doctor immediately.
If you have any doubts about how to use this medicinal product, consult your doctor, pharmacist, or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.
The following side effects have been reported in clinical studies with Pentaglobin:
Common (may affect up to 1 in 10 people):

• low blood pressure
• nausea, vomiting
• increased sweating (hyperhidrosis)

Uncommon (may affect up to 1 in 100 people):

• allergic reactions
• skin reactions/allergic dermatitis
• back pain

The following side effects have been reported after Pentaglobin has been marketed:
Not known (frequency cannot be estimated from the available data)

• inflammation of the membranes covering the brain and spinal cord (aseptic meningitis)
• reduced red blood cell count (haemolytic anaemia)/breakdown of red blood cells (haemolysis)
• anaphylactic shock, anaphylactoid reaction, hypersensitivity
• headache, dizziness
• rapid heartbeat (tachycardia)
• skin redness (flushing)
• shortness of breath (dyspnoea)
• itching (pruritus)
• acute renal failure and/or blood test results indicating impaired kidney function (increased serum creatinine levels)
• chills, fever

Children and adolescents
Although the nature and frequency of adverse reactions in neonates and young children are generally comparable to those observed in other age groups (e.g. infusion reactions, anaphylactic reactions, hypersensitivity), their clinical presentation in terms of reported signs and symptoms may vary and may also include, for example, changes in heart rate (increased or decreased heart rate), increased respiratory rate, reduced oxygen saturation, skin colour changes including pallor and/or cyanotic appearance, reduced muscle tone.
In general, human immunoglobulin preparations may cause the following side effects:

• chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, joint pain, low blood pressure, and moderate back pain
• reduced number of red blood cells due to their destruction within blood vessels (reversible haemolytic reactions) and (rarely) haemolytic anaemia requiring transfusion
• (rarely) a sudden drop in blood pressure and, in isolated cases, anaphylactic shock
• (rarely) transient skin reactions (including cutaneous lupus erythematosus – frequency not known)
• (very rarely) thromboembolic reactions such as heart attack (myocardial infarction), stroke, blood clots in the lung vessels (pulmonary embolism), blood clots in a vein (deep vein thrombosis)
• cases of temporary acute inflammation of the protective membranes covering the brain and spinal cord (reversible aseptic meningitis)
• cases of blood test results indicating impaired kidney function and/or acute renal failure
• cases of acute transfusion-related lung injury (TRALI). This leads to accumulation of fluid in the air spaces of the lungs of non-cardiac origin (non-cardiogenic pulmonary oedema). Symptoms include severe breathing difficulty (respiratory distress), increased respiratory rate (tachypnoea), abnormally low levels of oxygen in the blood (hypoxia), and increased body temperature (fever).

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, please inform 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 Pentaglobin

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 carton after
Exp.
Store in a refrigerator (2°C–8°C). Do not freeze. Keep in the original packaging to
protect the medicine from light.
Before using the medicine, visually inspect the solution to ensure it is clear or slightly to moderately milky (opalescent). Pentaglobin must not be used if the solution is cloudy or contains deposits.
After opening the container, the infusion solution must be administered immediately. Discard any unused solution due to the risk of bacterial contamination.
Do not dispose of medicines 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 Pentaglobin contains

• The active substance is human immunoglobulin with high IgM content. 1 ml of solution contains 50 mg of human plasma proteins, of which ≥ 95% are immunoglobulins: IgM 6 mg, IgA 6 mg, IgG 38 mg.
• The other components are monohydrate glucose, sodium chloride, water for injections.

Description of the appearance of Pentaglobin and contents of the pack
Pentaglobin is a solution that is slightly to moderately opalescent and colourless to slightly yellowish, supplied in clear glass vials.
Pentaglobin is available in the following pack sizes:
Each pack contains 1 vial with 10 ml (0.5 g), 50 ml (2.5 g), or 100 ml (5.0 g) of solution.

Marketing Authorisation Holder and Manufacturer
Biotest Pharma GmbH
Landsteinerstraße 5
63303 Dreieich
Tel.: (06103) 801-0
Fax: (06103) 801-150
Email: [email protected]

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

Warnings and precautions

Possible complications can often be avoided by ensuring that patients:

• Are not sensitive to normal human immunoglobulins; to this end, initially administer the product at a low infusion rate (0.4 ml/kg body weight/hour).
• Are closely monitored throughout the entire infusion period for any symptoms. In particular, patients receiving normal human immunoglobulins for the first time, those previously treated with a different immunoglobulin preparation, or those in whom a long time has passed since the last infusion should be monitored in hospital or in a controlled healthcare setting throughout the first infusion and for one hour after the infusion, to detect any adverse reactions and to ensure immediate availability of emergency treatment if required. All other patients should be monitored for at least 20 minutes after administration.

In all patients, intravenous immunoglobulin (IVIg) therapy requires:

• Adequate hydration prior to the start of IVIg infusion,
• Monitoring of urine output,
• Monitoring of serum creatinine levels,
• Avoidance of concomitant administration of loop diuretics.

If an adverse reaction occurs, the infusion rate should be reduced or the infusion stopped. The required therapy should be appropriate to the type and severity of the adverse reaction.

Infusion-related reactions
Certain adverse reactions (e.g. headache, flushing, chills, myalgia, dyspnea, tachycardia, back pain, nausea, and hypotension) may be related to the infusion rate. The recommended infusion rates described in the section "How to use Pentaglobin" must be strictly observed, and patients must be closely monitored throughout the infusion for any symptoms.

Certain adverse effects may occur more frequently:

• In patients receiving normal human immunoglobulins for the first time, or, rarely, when switching from another normal human immunoglobulin product, or when a long time has passed since the previous infusion.
• In patients with an active infection or underlying chronic inflammation.

Hypersensitivity
Hypersensitivity reactions are rare. Anaphylaxis may develop in patients:

• With undetectable IgA levels who have anti-IgA antibodies,
• Who have previously tolerated treatment with normal human immunoglobulins.

In case of shock, standard medical measures for shock treatment must be applied.

Thromboembolism
Clinical evidence indicates an association between intravenous administration of immunoglobulins (intravenous immunoglobulin, IVIg) and thromboembolic events such as myocardial infarction, cerebrovascular accident (including stroke), pulmonary embolism, and deep vein thrombosis. These events are believed to be related to a relative increase in blood viscosity due to high-dose immunoglobulin administration in at-risk patients. Caution is required when prescribing and infusing intravenous immunoglobulins in obese patients and in patients with pre-existing risk factors for thrombotic events (e.g. advanced age, hypertension, diabetes mellitus, history of vascular disease or thrombotic episodes, patients with acquired or hereditary thrombophilic disorders, patients with prolonged immobilisation, patients with severe hypovolemia, patients with diseases increasing blood viscosity).

In patients at risk of thromboembolic adverse effects, IVIg should be administered at the lowest feasible infusion rate and dose.

Acute renal failure
Cases of acute renal failure have been reported in patients treated with IVIg. In most cases, risk factors were identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolemia, obesity, concomitant use of nephrotoxic drugs, or age over 65 years.

Renal function parameters should be assessed before IVIg infusion, particularly in patients at potentially increased risk of developing acute renal failure, and subsequently 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 impairment occurs, discontinuation of IVIg should be considered.

Cases of renal dysfunction and acute renal failure have been associated with the use of various authorised IVIg preparations containing different excipients such as sucrose, glucose, and maltose. However, preparations with the highest number of reported cases have contained sucrose as a stabiliser. In at-risk patients, the use of IVIg products not containing these excipients may be considered. Pentaglobin does not contain sucrose or maltose but contains glucose (see also section “Pentaglobin contains glucose”).

Aseptic Meningitis Syndrome (AMS)
AMS has been reported in association with IVIg treatment. The syndrome typically manifests within a few hours to 2 days after IVIg administration. Cerebrospinal fluid (CSF) analyses are frequently positive, showing pleocytosis up to several thousand cells/mm³, predominantly granulocytic, and elevated protein levels up to several hundred mg/dl. AMS may occur more frequently with high-dose IVIg treatment (2 g/kg).

Patients presenting with these signs and symptoms should undergo careful neurological evaluation, including CSF analysis, to exclude other causes of meningitis.

Discontinuation of IVIg treatment has resulted in resolution of AMS within a few days, without sequelae.

Hemolytic anemia
Intravenously administered immunoglobulins (IVIg preparations) may contain antibodies against blood groups, which can act as hemolysins and induce in vivo coating of erythrocytes (RBCs) with immunoglobulins, resulting in a positive direct antiglobulin test (direct Coombs test), and rarely, hemolysis. Hemolytic anemia may develop following IVIg therapy due to enhanced sequestration of RBCs. Patients treated with intravenous immunoglobulins should be monitored for signs and symptoms of hemolysis.

Neutropenia/Leukopenia
Transient decreases in neutrophil count and/or episodes of neutropenia, sometimes severe, have been reported after IVIg treatment. This typically occurs within 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 treated with IVIg. TRALI is characterised by severe hypoxia, dyspnea, tachypnea, cyanosis, fever, and hypotension. Symptoms associated with TRALI generally develop during or within 6 hours after transfusion, often within 1–2 hours. Therefore, patients receiving IVIg should be monitored, and IVIg infusion must be stopped immediately in case of adverse pulmonary reactions. TRALI is a potentially life-threatening condition requiring immediate admission to intensive care.

Interference with serological testing
After administration of immunoglobulins, the temporary increase in various passively transferred antibodies in the patient's blood may lead to false-positive results in serological tests. Passive transfer of antibodies against erythrocyte antigens, such as A, B, D, may interfere with certain serological tests for anti-erythrocyte antibodies, for example the direct antiglobulin test (direct antiglobulin test, DAT, direct Coombs test).

Special precautions for handling
Pentaglobin may only be mixed with 0.9% NaCl physiological solution.