Pentaglobin

PACKAGE LEAFLET: INFORMATION FOR THE USER

Pentaglobin, 50 mg/ml, solution for infusion
Human normal immunoglobulin for intravenous administration
Please read all of 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 further questions, ask your doctor, pharmacist, or nurse.
• If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Leaflet contents:

1. What Pentaglobin is and what it is used for
2. Important information 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 made from human blood and contains antibodies (antibodies are components of the body's immune system). It is available as a solution for infusion given by intravenous drip ("drip infusion").
Pentaglobin is used

• for the treatment of bacterial infections when used together with antibiotics
• for replacement therapy in patients who do not have sufficient levels of their own antibodies (immunoglobulins) and who have severe acquired immunodeficiency disorders

2. Important information before using Pentaglobin

When not to use Pentaglobin

• if the patient is allergic to human immunoglobulin or to any of the other ingredients of this medicine (listed in section 6)
• if the patient has immunoglobulin A deficiency, particularly in the presence of antibodies against immunoglobulin A in the blood, as this may lead to anaphylaxis.

Warnings and precautions
Before starting treatment with Pentaglobin, discuss with your doctor, pharmacist, or nurse:

• if the patient is receiving human immunoglobulin for the first time or after a long break, or if the patient’s immunoglobulin-containing medicine is being changed. In such cases, the doctor will closely monitor the patient
• if the patient has an active infection or a coexisting chronic inflammatory condition
• if the patient is allergic to immunoglobulins (see section "When not to use Pentaglobin")
• if the patient
  • has significant overweight or is elderly,
  • has high blood pressure (hypertension),
  • diabetes or vascular diseases,
  • has increased tendency for blood clotting in blood vessels,
  • has been bedridden for a prolonged period,
  • has low blood volume (hypovolemia) or if the patient’s blood is concentrated,
  • has kidney disease or is taking medicines that may harm kidney function

In such cases, more adverse reactions may occur. If necessary, the doctor may discontinue treatment with Pentaglobin or take other precautions (e.g. reduce the infusion rate).
The patient may be allergic (hypersensitive) to immunoglobulins and not be aware of it. Hypersensitivity reactions may occur even if the patient previously received human immunoglobulins and tolerated them well. However, true hypersensitivity reactions are rare. Some adverse effects (e.g. headache, sudden facial flushing, chills, muscle pain, wheezing, tachycardia, back pain, nausea, and hypotension) may be related to the infusion rate.
If such reactions occur during administration of Pentaglobin, the patient should immediately inform the doctor. The doctor will decide whether to reduce the infusion rate, stop the infusion, and initiate necessary medical measures to treat these reactions.

Information regarding safety with respect to infections
Pentaglobin is manufactured from human plasma (the liquid part of blood). When medicines are made from human blood or plasma, specific precautions are taken to prevent transmission of infectious agents to patients. All blood donors are tested for the presence of viruses and infectious diseases. In addition, steps are taken to inactivate or remove viruses.
Despite these precautions, it cannot be completely excluded that when administering medicines derived from human blood or plasma, transmission of infectious agents may occur.
These measures are considered effective against enveloped viruses such as:

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

The effectiveness of these measures may be limited against non-enveloped viruses such as:

• hepatitis A virus (HAV)
• parvovirus B19

No association has been observed between immunoglobulins and hepatitis A or parvovirus B19 infection, probably because the antibodies against these infections contained in this medicine provide protective effects.
It is strongly recommended that the doctor records the name and batch number of Pentaglobin each time the patient receives a dose. The batch number identifies the starting materials used in the medicine. This allows, if necessary, linking the patient to the specific starting material used.

Children and adolescents
In newborns and infants, symptoms of infusion-related reactions, hypersensitivity, or allergic reactions may differ from those in other age groups; see section "Possible side effects".

Pentaglobin and other medicines
Tell your doctor or pharmacist about any other medicines the patient is currently taking, has recently taken, or plans to take.
Pentaglobin may reduce the effectiveness of certain vaccines, e.g. the effectiveness of vaccines against:

• measles
• rubella
• mumps
• varicella (chickenpox)
  It may be necessary to wait up to 3 months before receiving certain vaccines and up to one year before receiving the measles vaccine.

Concomitant use of loop diuretics (commonly known as water pills) with Pentaglobin should be avoided.

Pregnancy and breastfeeding
If the patient is pregnant or breastfeeding, suspects she may be pregnant, or is planning to become pregnant, she should consult her doctor or pharmacist before using this medicine.
The doctor will decide whether the patient can be treated with Pentaglobin during pregnancy and breastfeeding.

Driving and operating machinery
Pentaglobin has minor influence on the ability to drive and use machines. If the patient experiences adverse effects during treatment, he/she should wait until these effects have subsided before driving or operating machinery.

Pentaglobin contains glucose and sodium
1 ml of infusion solution contains 25 mg glucose (equivalent to approximately 0.0021 bread units).
A daily adult dose of approximately 350 ml (for a 70 kg body weight) contains 8.75 g glucose, equivalent to approximately 0.735 bread units. This should be taken into account in patients on a diabetic diet.
Pentaglobin contains 0.078 mmol/ml (1.79 mg/ml) of sodium (the main component of table salt).
The daily adult dose of approximately 350 ml (for a 70 kg body weight) contains 27.3 mmol (627.6 mg) of sodium. This corresponds to approximately 31% of the maximum daily intake of 2 g sodium for adults recommended by WHO.

3. How to use Pentaglobin

Pentaglobin is administered by a physician. The dosage depends on the patient's immunological status and the severity of the disease.

Recommended dose:

Newborns and infants
5 ml (0.25 g) per kg of body weight per day for 3 consecutive days. Further doses to be repeated according to clinical course.

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 doses to be repeated according to clinical course.

For replacement of missing antibodies (immunoglobulins) in patients with immunosuppression due to drugs or radiation, and in severe acquired immunodeficiency: 3–5 ml (0.15–0.25 g) per kg of body weight.

If necessary, repeating doses at weekly intervals is recommended.

Pentaglobin will be administered intravenously (intravenous infusion) 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, to achieve 15.0 ml per kg of body weight within 72 hours.

Examples:

Hepatic function disorders
There is no evidence to support the need for dose adjustment.
Renal function disorders
Dose adjustment is required only if clinically indicated, see section
"Warnings and precautions".
Elderly patients
Dose adjustment is not required unless clinically indicated.
Method of administration
Pentaglobin is intended for intravenous infusion (intravenous drip).
The medicinal product should be brought to room temperature or body temperature prior to administration.
Administration of a higher than recommended dose of Pentaglobin
An excessive dose of Pentaglobin may lead to fluid overload and increased blood viscosity,
particularly in patients at risk, including children, elderly patients, or
patients with cardiac or renal function disorders. If a patient believes they have received an excessive dose
of Pentaglobin, they should discuss this with their doctor as soon as possible.
If you have any further questions regarding the use of this medicinal product, consult your
doctor, pharmacist, or nurse.

4. Possible adverse reactions

Like all medicines, this medicine can cause adverse reactions, although not everybody will experience them.
The following adverse reactions have been reported in clinical trials with
Pentaglobin:
Common (may occur in up to 1 in 10 patients):

• low blood pressure
• nausea, vomiting
• excessive sweating

Uncommon (may occur in up to 1 in 100 patients):

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

The following adverse reactions have been reported after Pentaglobin was placed on the market:
Frequency unknown (frequency cannot be estimated from the available data):

• meningitis (aseptic meningitis)
• anaemia (haemolytic anaemia)/breakdown of red blood cells (haemolysis)
• anaphylactic shock, pseudoanaphylactic reactions, hypersensitivity reactions
• headache, dizziness
• rapid heartbeat (tachycardia)
• skin redness
• shortness of breath
• itching
• acute kidney failure and (or) blood test results indicating impaired kidney function (increased serum creatinine concentration)
• chills, fever

Children and adolescents:
Although newborns and infants generally experience comparable adverse reactions (e.g. infusion-related reactions, anaphylactic reactions, hypersensitivity) compared to other age groups, their subjective and objective symptoms may differ. Additionally, changes in heart rate (fast or slow heartbeat), rapid breathing, decreased oxygen saturation, skin discoloration including pallor and (or) bluish colour, and reduced muscle tone may occur.
Human immunoglobulin preparations may generally cause the following adverse
reactions:

• chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, joint pain, low arterial blood pressure, and moderate back pain
• reduction in red blood cells due to destruction of these cells within blood vessels ((reversible) haemolytic reactions), and (rarely) haemolytic anaemia requiring transfusion
• (rarely) sudden drop in blood pressure and, in sporadic cases, anaphylactic shock
• (rarely) transient skin reactions (including cutaneous lupus erythematosus – frequency unknown)
• (very rarely) thromboembolic events such as myocardial infarction, stroke, blood clots in the lung vessels (pulmonary embolism), blood clots in veins (deep vein thrombosis)
• cases of transient 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) sudden kidney failure
• cases of acute transfusion-related lung injury (TRALI). This leads to non-cardiac accumulation of fluid in the air spaces of the lungs (non-cardiogenic pulmonary oedema). The patient will experience severe breathing difficulties (respiratory distress syndrome), rapid breathing (tachypnoea), abnormally low levels of oxygen in the blood (hypoxia), and elevated body temperature (fever).

Reporting of adverse reactions
If any adverse reactions occur, including any adverse reactions not listed in this leaflet, tell your doctor, pharmacist, or nurse. Adverse reactions can be reported directly to the Department of Monitoring Adverse Drug Reactions of the Office for Registration of Medicinal Products, Medical Devices and Biocidal Products:
Al. Jerozolimskie 181C
02-222 Warsaw
Tel.: +48 22 49 21 301
Fax: +48 22 49 21 309
Website: https://smz.ezdrowie.gov.pl
Adverse reactions can also be reported to the marketing authorisation holder.
Reporting adverse reactions helps to provide more information on the safety of the medicine.

5. How to store Pentaglobin

Keep the 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 "Expiry date".
Store in a refrigerator (2°C–8°C). Do not freeze. Store in the original packaging to protect from light.
The solution should be inspected before use. The solution must be clear or slightly to moderately opalescent. Do not use Pentaglobin if the solution is cloudy or contains a precipitate.
After opening the packaging, the infusion solution should be used immediately. Due to the risk of bacterial contamination, any unused solution must be discarded.
Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. Such measures will help protect the environment.

6. Contents of the pack and other information

What Pentaglobin contains

• The active substance is: human immunoglobulin
• 1 ml of solution contains 50 mg of human plasma protein, including immunoglobulin  95%: IgM 6 mg, IgA 6 mg, IgG 38 mg.
• Other ingredients are: glucose monohydrate, sodium chloride, water for injections.

What Pentaglobin looks like and contents of the pack
Pentaglobin is a slightly brownish-yellow, clear or slightly opalescent solution in colourless glass vials.
Pentaglobin is available in the following pack sizes:
Pack containing 1 vial of 10 ml (0.5 g), 50 ml (2.5 g), or 100 ml (5.0 g).

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

Information intended exclusively for healthcare professionals:

Warnings and precautions
Potential complications can often be avoided by ensuring that:

• patients are not hypersensitive to normal human immunoglobulin by initially administering the medicinal product slowly (0.4 mL/kg body weight/hour),
• patients are closely monitored throughout the entire infusion period for any symptoms. In particular, patients receiving normal human immunoglobulin for the first time, patients who have previously received another IVIg product, or patients with a long interval since the last infusion should be monitored in a hospital or controlled healthcare facility during the first infusion and for one hour after the first infusion for possible adverse reactions and to ensure immediate access to emergency treatment if problems occur. All other patients should be observed for at least 20 minutes after administration.

In all patients, IVIg administration requires:

• adequate hydration prior to starting IVIg infusion,
• monitoring of diuresis,
• monitoring of serum creatinine concentration,
• avoidance of concomitant use of loop diuretics.

If an adverse reaction occurs, the infusion rate should be reduced or the infusion stopped. Required treatment depends on the type and severity of the adverse reaction.

Infusion-related reaction
Some adverse reactions (e.g., headache, sudden facial flushing, chills, muscle pain, wheezing, tachycardia, lower back pain, nausea, and hypotension) may be related to the infusion rate. The recommended infusion rate specified in section "How to use Pentaglobin" must be strictly followed. Patients must be carefully monitored and closely observed during the infusion for any symptoms.

Adverse reactions may occur more frequently:

• in patients receiving normal human immunoglobulin for the first time, or in rare cases in patients who have switched from a previously administered normal human immunoglobulin-containing medicinal product to another product, or in patients with a long interval since the last infusion,
• in patients with active infection or coexisting chronic inflammatory conditions.

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

• with undetectable IgA who have antibodies against IgA,
• who previously tolerated immunoglobulin therapy well.

In case of shock, standard medical management for shock treatment should be applied.

Thromboembolic complications
There is clinical evidence of an association between intravenous immunoglobulin (IVIg) administration and thromboembolic events such as myocardial infarction, cerebrovascular incident (including stroke), pulmonary embolism, and deep vein thrombosis. It is believed that administering high-dose immunoglobulin to patients at risk leads to a relative increase in blood viscosity. Caution should be exercised when prescribing and infusing immunoglobulins to obese patients, patients with existing risk factors for thrombotic events (such as advanced age, hypertension, diabetes, diagnosed vascular disease or history of thrombotic episodes), patients with acquired or congenital predispositions to thrombosis, patients after prolonged immobilization, patients with severe hypovolemia, and patients with diseases associated with increased blood viscosity.

In patients with existing risk of thromboembolic adverse events, IVIg products should be administered at the lowest possible infusion rate and at the smallest possible dose.

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

Renal parameters should be evaluated before IVIg infusion and subsequently at appropriate intervals, especially in patients with potential increased risk of acute renal failure. In patients with existing risk of acute renal failure, IVIg products should be administered at the lowest possible infusion rate and at the smallest possible dose.

If renal function abnormalities occur, discontinuation of IVIg administration should be considered.

Cases of renal function disorders and acute renal failure have been observed following administration of many registered IVIg products containing various excipients such as sucrose, glucose, and maltose, with sucrose-containing products accounting for the majority of such cases. In patients at risk, use of IVIg products not containing such excipients may be considered. Pentaglobin does not contain sucrose or maltose but contains glucose (see section "Pentaglobin contains glucose").

Aseptic Meningoencephalitis Syndrome (AMS)
AMS has been reported in association with IVIg treatment. The syndrome usually occurs within several hours to 2 days after IVIg therapy. Cerebrospinal fluid (CSF) analysis often reveals pleocytosis of up to several thousand cells/mm³, predominantly granulocytic series, and increased protein levels up to several hundred mg/dL. AMS may occur more frequently with high-dose IVIg treatment (2 g/kg).

Patients exhibiting such objective and subjective symptoms should undergo thorough neurological evaluation, including cerebrospinal fluid examination, to exclude other causes of meningitis.

Discontinuation of IVIg treatment resulted in AMS remission within a few days without sequelae.

Hemolytic anemia
Intravenous immunoglobulins (IVIg medicinal products) may contain blood group antibodies acting as hemolysins, causing in vivo coating of red blood cells (RBCs) with immunoglobulins, resulting in a positive direct antiglobulin reaction (Coombs test), and rarely, hemolysis. Hemolytic anemia may develop after IVIg treatment due to enhanced RBC sequestration. Patients treated with IVIg should be monitored for clinical 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. These usually occur within hours or days after IVIg administration and resolve spontaneously within 7–14 days.

Transfusion-Related Acute Lung Injury (TRALI)
Acute non-cardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] has been reported in patients receiving IVIg. TRALI is characterized by severe hypoxia, dyspnea, tachypnea, cyanosis, fever, and arterial hypotension. TRALI symptoms typically occur during or within 6 hours of transfusion, often within 1–2 hours. Therefore, patients receiving IVIg should be monitored for pulmonary adverse reactions, and infusion should be immediately discontinued if such reactions occur. TRALI is a potentially life-threatening condition requiring immediate treatment in an intensive care unit.

Effect on serological test results
After administration of immunoglobulin, transient increases in various passively transferred antibodies may occur in the patient's blood, potentially causing false-positive serological test results.

Passive transfer of antibodies against erythrocyte antigens, e.g., A, B, D, may interfere with results of certain serological tests for red blood cell antibodies, such as the direct antiglobulin test (DAT, direct Coombs test).

Special precautions for preparation of the medicinal product for administration
Pentaglobin may only be mixed with physiological saline solution.