Plitagamma

Patient Information Leaflet: Information for the User

Plitagamma 50 mg/ml infusion solution

Normal human immunoglobulin for intravenous use (IVIg)
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.
• This medicine has been prescribed for you only. Do not give it to others, even if they have the same symptoms as you, because it could be harmful.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor, pharmacist, or nurse. See section 4.

Contents of this leaflet:

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

1. What Plitagamma is and what it is used for

What Plitagamma is
Plitagamma is a normal human immunoglobulin solution for intravenous use. This
medicinal product belongs to a group of medicines called intravenous immunoglobulins.
Immunoglobulins are human antibodies that are also present in blood.

What Plitagamma is used for
They are used in the treatment of conditions in which the immune system does not function properly.
Specifically, it is used for:

Treatment of adults, children and adolescents (2–18 years) who do not have sufficient levels of
antibodies (replacement therapy) in the following cases:

• Patients with congenital deficiency in antibody production (Primary Immunodeficiency Syndrome – PID)
• Patients with acquired deficiency in antibody production (Secondary Immunodeficiencies, SID) with severe or recurrent infections, ineffective antibiotic treatment, and demonstrated inability to produce specific antibodies (PSAF)* or IgG blood levels < 4 g/l
  *PSAF = inability to achieve at least a 2-fold increase in IgG antibody titres against pneumococcal vaccines containing polysaccharide and polypeptide antigens.

Treatment of adults, children and adolescents (2–18 years) with autoimmune disorders due to certain
inflammatory diseases (immunomodulation), in the following conditions:

• Patients with insufficient platelet counts (Primary Immune Thrombocytopenia, ITP), who are at high risk of bleeding or prior to surgical procedures to correct platelet count.
• 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.
• Patients with Kawasaki disease (in combination with acetylsalicylic acid). This is an acute disease occurring mainly in childhood, characterized by inflammation of blood vessels (arteries) throughout the body.
• Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP), a rare and progressive disease causing limb weakness, numbness, pain and fatigue.
• Multifocal Motor Neuropathy (MMN), a rare disease causing slowly progressive, asymmetric weakening of the limbs, without loss of sensation.

2. What you need to know before using Plitagamma

Do not use Plitagamma

• If you are allergic (hypersensitive) to normal human immunoglobulins or to any of the other ingredients of this medicine (listed in section 6).
• If you have immunoglobulin A (IgA) deficiency or have developed antibodies against IgA.
• If you have hereditary fructose intolerance, a rare genetic disease in which the enzyme that metabolizes fructose is absent. In newborns and young children (0–2 years), hereditary fructose intolerance (HFI) may not yet have been diagnosed, and in this population, administration of Plitagamma may cause death. Therefore, newborns and young children must not receive this medicine (see special warnings regarding excipients at the end of this section).

Warnings and precautions
Talk to your doctor or nurse before using Plitagamma.
Your doctor or another healthcare professional will closely monitor and observe you carefully throughout the entire infusion period with Plitagamma and for up to one hour after the infusion has ended, to ensure that no adverse reactions occur.
Some side effects may occur more frequently:

• if the infusion rate is too high;
• if you have a condition with low levels of antibodies in the blood (hypo- or agammaglobulinemia, with or without IgA deficiency);
• if you are receiving normal human immunoglobulins for the first time, or if you have been switched to a different medicine containing normal human immunoglobulins, or if a long time has passed since your previous intravenous infusion (e.g., several weeks).
• Allergic reactions are rare. However, you may still be allergic (hypersensitive) to immunoglobulins (antibodies) without knowing it.

This may occur even if you have previously received human immunoglobulins and tolerated prior administrations. This possibility is particularly relevant if you do not have sufficient immunoglobulin A (IgA) in your blood (IgA deficiency with anti-IgA antibodies).
Patients with pre-existing risk factors
Inform your doctor if you have any other illness or condition, as immunoglobulins may increase the risk of thromboembolic events, including heart attack, stroke, pulmonary embolism, or deep vein thrombosis, due to increased blood viscosity.
In particular, inform your doctor if:

• you have diabetes,
• you have high blood pressure (hypertension),
• you have a history of blood vessel diseases (vascular diseases) or thrombotic episodes,
• you are overweight,
• you have reduced blood volume (hypovolemia),
• you have diseases causing increased blood viscosity,
• you are over 65 years of age.

Patients with kidney problems
If you have kidney disease, your doctor should consider whether to discontinue treatment, as cases of acute renal failure have been reported in patients receiving IVIg, usually in the presence of other risk factors.
Effects on blood tests
After receiving Plitagamma, the results of certain blood tests may be altered for a period of time corresponding to the duration of the medicine’s effect. If you are due to have a blood test after receiving Plitagamma, inform the laboratory staff or your doctor that you have taken this medicine.
In case of an adverse reaction, your doctor will decide whether to reduce the rate of administration or to 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, your doctor should administer standard shock treatment. Inform your doctor if you suffer from any of the conditions described above; your doctor will exercise particular caution when prescribing and administering Plitagamma to you.
Viral safety
When medicines are produced from human plasma or blood, precautionary measures are taken to prevent infections that could be transmitted to patients. These measures include:

• careful selection of plasma and blood donors to ensure that those at risk of infection are excluded,
• testing of each donation and plasma pool for viruses or infections,
• inclusion of viral inactivation or removal methods during the manufacturing process of human plasma or blood.

Despite these measures, when medicines derived from human plasma or blood are administered, the possibility of transmitting an infection cannot be completely ruled out. This applies to all viruses of unknown origin, emerging viruses, or other types of infections.
The measures taken are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B, and hepatitis C, as well as against non-enveloped viruses such as hepatitis A and parvovirus B19.
Immunoglobulins have not been associated with hepatitis A or parvovirus B19 infections, probably because the antibodies against these infections contained in the product have a protective effect.
It is strongly recommended that, whenever Plitagamma is administered, the name and batch number of the medicine be recorded to maintain traceability of the batches used.
Children and adolescents
During the infusion of Plitagamma, vital signs (body temperature, blood pressure, heart rate, and respiratory rate) must be monitored.
Newborns and young children (0–2 years) may have hereditary fructose intolerance (HFI), a disease that may not yet have been diagnosed by your doctor. Administration of this medicine may cause death; therefore, newborns and young children must not receive this medicine.
Other medicines and Plitagamma

Inform your doctor or pharmacist 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.
• Effects on vaccines: Plitagamma may reduce the effectiveness of certain types of vaccines (live attenuated virus vaccines). For rubella, mumps, and varicella, a period of up to 3 months should elapse after administration of this product before receiving these vaccines. For measles, this interval should be extended to 1 year. Administration of immunoglobulin may affect the efficacy of live attenuated virus vaccines such as those for measles, rubella, mumps, and varicella for up to 3 months; therefore, a 3-month interval should be observed before vaccination with live attenuated virus vaccines (rubella, mumps, and varicella). In the case of measles, this weakening of the immune response may last up to one year. Therefore, antibody levels should be checked in patients receiving the measles vaccine.
• During treatment with Plitagamma, concomitant use of medicines that increase urine production (loop diuretics) should be avoided.

Pregnancy, breastfeeding, and fertility
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor or pharmacist before using this medicine.
This medicine has not been studied in pregnancy; therefore, it should be administered with caution to pregnant women and breastfeeding mothers. It has been shown that intravenously administered immunoglobulins cross the placenta and may affect the fetus, particularly after the third trimester. Use of this medicine in pregnant women has not indicated harmful effects on the course of pregnancy, the fetus, or the newborn.
After administration of this medicine to breastfeeding mothers, the active substance (immunoglobulins) has been detected in breast milk, which may protect the newborn from external agents entering through mucous membranes.
Use of this medicine in women has not indicated harmful effects on fertility.
Driving and using machines
During treatment, reactions (e.g., dizziness or nausea) may occur that could affect your ability to drive or operate machinery. Patients experiencing adverse reactions during treatment should wait until these reactions have resolved before driving or operating machinery.
Plitagamma contains sorbitol
This medicine contains 50 mg of sorbitol per ml.
Sorbitol is a source of fructose. If your doctor has diagnosed you (or the child) with hereditary fructose intolerance, a rare genetic disease, you (or the child) must not take this medicine.
Patients with hereditary fructose intolerance are unable to metabolize fructose, and its accumulation may cause serious side effects.
Before taking this medicine, inform your doctor if you (or the child) suffer from hereditary fructose intolerance or if the child feels unwell, vomits, or experiences unpleasant reactions such as bloating, stomach cramps, or diarrhea after consuming sweet foods or drinks.
Plitagamma contains sodium
This medicine contains less than 7.4 mg of sodium (the main component of table salt) per 100 ml. This corresponds to 0.37% of the maximum daily recommended dietary intake for an adult.

3. How to use Plitagamma

Plitagamma can only be administered by physicians or healthcare professionals through intravenous infusion.
The dose to be administered depends on your medical condition and body weight and will be determined by your doctor according to your individual needs (see the instructions for healthcare professionals section at the end of this leaflet).
At the beginning of the infusion, you will receive Plitagamma at a low infusion rate (0.01–0.02 ml/kg/min). If you tolerate it well, your doctor may gradually increase the infusion rate (up to 0.1 ml/kg/min).

Use in children and adolescents
The dose in children and adolescents (2–18 years of age) is not different from that in adults, as it is determined based on the child's medical condition and body weight.

If you use more Plitagamma than you should
If you are given more Plitagamma than required, fluid overload may occur and your blood may become too thick (hyperviscous). This is particularly possible if you are a high-risk patient, an elderly patient, or a patient with cardiac or renal problems. Inform your doctor immediately.
Immunoglobulins may increase blood viscosity and increase the risk of myocardial infarction, stroke, pulmonary embolism, or deep vein thrombosis.

If you forget to use Plitagamma
Inform your doctor immediately and follow his or her instructions.
Do not take a double dose to make up for a missed dose.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody experiences them.
Rarely, the following side effects have been reported with immunoglobulin-based medicines:

• chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, hypotension, and mild back pain;
• a sudden drop in blood pressure and, in isolated cases, anaphylactic shock, even if you have not shown hypersensitivity during previous administrations;
• cases of non-infectious inflammation of the tissues covering the Central Nervous System (aseptic meningitis syndrome);
• cases of temporary reduction in red blood cells (reversible haemolytic anaemia/haemolysis);
• cases of transient skin reactions;
• increase in blood creatinine levels (a parameter measuring kidney function) and/or acute kidney injury;
• thromboembolic reactions (blood clot formation), such as: myocardial infarction, pulmonary embolism, deep vein thrombosis, stroke.
• cases of acute lung injury associated with transfusion (TRALI) causing hypoxia (lack of oxygen), dyspnoea (difficulty breathing), tachypnoea (rapid breathing), cyanosis (lack of oxygen in the blood), fever, and hypotension.

Other side effects
Common (may affect up to 1 in 10 infusions):

• headache (cephalalgia)
• fever
• tachycardia (increased heart rate)
• reduction in blood pressure (hypotension)
• reduction in diastolic blood pressure (diastolic hypotension)

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

• positive Coombs test
• dizziness (motion sickness)
• hypertension (increased blood pressure)
• systolic hypertension (increased systolic blood pressure)
• diastolic hypertension (increased diastolic blood pressure)
• increased systolic blood pressure readings
• decreased systolic blood pressure readings
• increased body temperature readings
• bronchitis
• nasopharyngitis
• productive cough
• wheezing
• abdominal pain (including upper abdominal pain)
• diarrhoea
• vomiting
• nausea
• urticaria
• pruritus
• pruritic rash
• back pain
• myalgia (muscle pain)
• arthralgia (joint pain)
• febrile chills (feeling cold with shivering in presence of fever)
• pain
• infusion site reaction
• pain at infusion site
• swelling at infusion site
• infusion-related reaction

Rare (may affect up to 1 in 1,000 infusions):

• abnormal behaviour
• migraine
• blood pressure fluctuations
• hot flushes (flushing)
• cough
• asthma
• epistaxis (nosebleed)
• nasal discomfort
• laryngeal pain
• contact dermatitis
• hyperhidrosis (excessive sweating)
• skin rash
• muscle spasms
• neck pain
• limb pain
• urinary retention
• chills
• asthenia (weakness)
• erythema at infusion site
• extravasation at infusion site
• inflammation at infusion site
• pruritus at infusion site
• peripheral oedema
• increased alanine aminotransferase (liver transaminase)

Additional side effects in children and adolescents
Compared to adults, a higher incidence of headache, fever, increased heart rate, and low blood pressure has been observed in children.
Assessment of vital signs such as body temperature, heart rate, respiratory rate, and blood pressure in paediatric studies has not revealed significant changes in this population.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report side effects directly via the national reporting system for adverse reactions.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Plitagamma

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 the carton after "Exp.".
Do not store above 30 °C. Do not freeze.
The solution should be clear or slightly opalescent. Do not use this medicine if you notice that the solution is cloudy or contains a deposit.
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. Package contents and other information

What Plitagamma contains

• The active substance is normal human immunoglobulin (IVIg). One ml contains 50 mg of normal human immunoglobulins, of which at least 97% consists of IgG.

A 10 ml vial contains: 0.5 g of normal human immunoglobulin
A 50 ml vial contains: 2.5 g of normal human immunoglobulin
A 100 ml vial contains: 5 g of normal human immunoglobulin
A 200 ml vial contains: 10 g of normal human immunoglobulin
A 400 ml vial contains: 20 g of normal human immunoglobulin

Percentage distribution of IgG subclasses (approximate values):
IgG 66.6%
IgG 28.5%
IgG 2.7%
IgG 2.2%
The IgA content is less than 50 micrograms/ml.
Product derived from human donor plasma.

• The other components are D-sorbitol and water for injections (see section 2 for further information on the components).

Description of the appearance of Plitagamma and contents of the pack
Plitagamma is a clear or slightly opalescent, colorless or pale yellow infusion solution.
Plitagamma is supplied in:

• Type II glass vial with a stopper (chlorobutyl or chlorobutyl-isoprene rubber) containing 10 ml of solution
• Type II glass vials with a stopper (chlorobutyl or chlorobutyl-isoprene rubber) containing 50 ml, 100 ml, 200 ml, or 400 ml of solution

Pack: 1 vial.
Not all pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
08150 Barcelona - SPAIN

The following information is intended exclusively for healthcare professionals (for further
information see section 3):
Dosage and method of administration
The dose and dosing regimen depend on the indication.
The dose should be adjusted according to the specific needs of each patient, as determined by clinical response. Body-weight-based dosing may require adjustment in underweight or overweight patients.
The recommended dosages are summarized in the following table:

Plitagamma must be administered intravenously at an initial rate of
0.01–0.02 ml/kg/min for the first thirty minutes. If well tolerated, the infusion rate may be
gradually increased up to a maximum of 0.1 ml/kg/min.
Paediatric population
Plitagamma is contraindicated in children from 0 to 2 years of age.
Since the dosage for each indication is calculated based on body weight and must be adjusted according to the clinical response to the above-mentioned conditions, the dosage in children and adolescents (2–18 years) is not considered different from that in adults.
Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Plitagamma must not be mixed with other drugs or intravenous fluids and must be administered through a separate intravenous line.
Special warnings
Sorbitol
One ml of this medicinal product contains 50 mg of sorbitol.
This medicinal product must not be administered to patients with hereditary fructose intolerance, as medicinal products containing sorbitol/fructose administered intravenously may be life-threatening in these patients.
A thorough clinical history, with particular attention to symptoms of hereditary fructose intolerance, must be obtained before administering this medicinal product.
In children under 2 years of age, hereditary fructose intolerance may not yet have been diagnosed. Plitagamma is contraindicated in children under 2 years of age.
In case of accidental administration and suspected fructose intolerance, administration must be immediately discontinued, normal blood glucose levels must be restored, and organ function must be stabilised through intensive therapy.
Interference with blood glucose measurement is not expected.
Sodium
This medicinal product contains less than 7.4 mg of sodium per 100 ml, equivalent to 0.37% of the maximum daily intake recommended by the WHO, which corresponds to 2 g of sodium for an adult.
It is strongly recommended that, whenever Plitagamma is administered, the name and batch number of the product be recorded to ensure traceability between the patient and the batch used.
Instructions for handling and disposal
The product must be brought to room temperature (not exceeding 30 °C) before use.
The solution should be clear or slightly opalescent. Do not use Plitagamma if the solution appears cloudy or contains precipitates.
Unused medicinal product and waste material derived from this medicinal product must be disposed of in accordance with local regulations.