Replacement therapy in adults, and children and adolescents (0-18 years) in:

·         Primary immunodeficiency (PID) syndromes with impaired antibody production (see section 4.4).

·         Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed.

·         Hypogammaglobulinaemia and recurrent bacterial infections in plateau phase multiple myeloma patients who have failed to respond to pneumococcal immunisation.

·         Hypogammaglobulinaemia in patients after allogeneic haematopoietic stem cell transplantation (HSCT).

·         Congenital AIDS with recurrent bacterial infections.

Immunomodulation in adults, and children and adolescents (0-18 years) in:

·         Primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count.

·         Guillain Barré syndrome.

·         Kawasaki disease.

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

Posology

The dose and dose regimen is dependent on the indication.

In replacement therapy the dose may need to be individualised for each patient dependent on the pharmacokinetic and clinical response. The following dose regimens are given as a guideline.

Replacement therapy in primary immunodeficiency (PID) syndromes

The dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least 5-6 g/l. Three to six months are required after the initiation of therapy for equilibration to occur. The recommended starting dose is 0.4–0.8 g/kg given once, followed by at least 0.2 g/kg given every three to four weeks.

The dose required to achieve a trough level of 5–6 g/l is of the order of 0.2‑0.8 g/kg/month. The dosage interval when steady state has been reached varies from 3 ‑ 4 weeks.

Trough levels should be measured and assessed in conjunction with the incidence of infection. To reduce the rate of infection, it may be necessary to increase the dosage and aim for higher trough levels.

Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed; hypogammaglobulinaemia and recurrent bacterial infections in plateau phase multiple myeloma patients who have failed to respond to pneumococcal immunisation; congenital AIDS with recurrent bacterial infections

The recommended dose is 0.2–0.4 g/kg every three to four weeks.

Hypogammaglobulinaemia in patients after allogeneic haematopoietic stem cell transplantation

The recommended dose is 0.2–0.4 g/kg every three to four weeks. The trough levels should be maintained above 5 g/l.

Primary immune thrombocytopenia (ITP)

There are two alternative treatment schedules:

·         0.8–1g/kg given on day one; this dose may be repeated once within 3 days

·         0.4 g/kg given daily for two to five days.

The treatment can be repeated if relapse occurs.

Guillain Barré syndrome

0.4 g/kg/day over 5 days.

Kawasaki Disease

1.6–2.0 g/kg should be administered in divided doses over two to five days or 2.0 g/kg as a single dose. Patients should receive concomitant treatment with acetylsalicylic acid.

The dosage recommendations are summarised in the following table:

Paediatric population

The posology in children and adolescents (0–18 years) is not different to that of adults as the posology for each indication is given by body weight and adjusted to the clinical outcome of the above mentioned conditions.

Method of administration

For intravenous use.

Human normal immunoglobulin should be infused intravenously at an initial rate of 0.6 ml/kg/hr for 30 min. If well tolerated (see section 4.4), the rate of administration may gradually be increased to a maximum of 4.8 ml/kg/hr.

In PID patients who have tolerated the infusion rate of 4.8 ml/kg/hr well, the rate may be further increased gradually to a maximum of 8.4 ml/kg/hr.

Certain severe adverse drug reactions may be related to the rate of infusion. The recommended infusion rate given under section 4.2 must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period.

Certain adverse reactions may occur more frequently:

·         in case of high rate of infusion

·         in patients who receive human normal immunoglobulin for the first time or, in rare cases, when the human normal immunoglobulin product is switched or when there has been a long interval since the previous infusion.

Potential complications can often be avoided by ensuring that patients:

·         are not sensitive to human normal immunoglobulin by initially injecting the product slowly (0.6-1.2 ml/kg/hr).

·         are carefully monitored for any symptoms throughout the infusion period. In particular, patients naive to human normal immunoglobulin, patients switched from an alternative IVIg product or when there has been a long interval since the previous infusion should be monitored during the first infusion and for the first hour after the first infusion, in order to detect potential adverse signs. All other patients should be observed for at least 20 minutes after administration.

In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped. The treatment required depends on the nature and severity of the adverse reaction.

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

In all patients, IVIg administration requires:

·         adequate hydration prior to the initiation of the infusion of IVIg

·         monitoring of urine output

·         monitoring of serum creatinine levels

·         avoidance of concomitant use of loop diuretics.

Hypersensitivity

True hypersensitivity reactions are rare. They can occur in patients with anti-IgA antibodies.

IVIg is not indicated in patients with selective IgA deficiency where the IgA deficiency is the only abnormality of concern.

Rarely, human normal immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin.

Thromboembolism

There is clinical evidence of an association between IVIg administration and thromboembolic events such as myocardial infarction, cerebral vascular accident (including stroke), pulmonary embolism and deep vein thromboses which is assumed to be related to a relative increase in blood viscosity through the high influx of immunoglobulin in at-risk patients. Caution should be exercised in 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 and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilisation, severely hypovolaemic patients, patients with diseases which increase blood viscosity).

In patients at risk for thromboembolic adverse reactions, IVIg products should be administered at the minimum rate of infusion and dose practicable.

Acute renal failure

Cases of acute renal failure have been reported in patients receiving IVIg therapy. In most cases, risk factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolemia, overweight, concomitant nephrotoxic medicinal products or age over 65.

In case of renal impairment, IVIg discontinuation should be considered. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IVIg products containing various excipients such as sucrose, glucose and maltose, those containing sucrose as a stabiliser accounted for a disproportionate share of the total number. In patients at risk, the use of IVIg products that do not contain these excipients may be considered. Panzyga does not contain sucrose, maltose or glucose.

In patients at risk for acute renal failure, IVIg products should be administered at the minimum rate of infusion and dose practicable.

Aseptic meningitis syndrome (AMS)

Aseptic meningitis syndrome has been reported to occur in association with IVIg treatment. Discontinuation of IVIg treatment has resulted in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to 2 days following IVIg treatment. Cerebrospinal fluid studies are frequently positive with pleocytosis up to several thousand cells per mm³, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dl.

AMS may occur more frequently in association with high-dose (2 g/kg) IVIg treatment.

Haemolytic anaemia

IVIg products can contain blood group antibodies which may act as haemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction (Coombs’ test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg therapy due to enhanced red blood cells (RBC) sequestration. IVIg recipients should be monitored for clinical signs and symptoms of haemolysis (see section 4.8).

Interference with serological testing

After injection of immunoglobulin the transitory rise of various passively transferred antibodies in the patient's blood may result in misleading positive results in serological testing.

Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D may interfere with some serological tests for red cell antibodies for example the direct antiglobulin test (DAT, direct Coombs' test).

Transmissible agents

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV and for the non-enveloped viruses HAV and parvovirus B19.

There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to the viral safety.

It is strongly recommended that every time that Panzyga is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Sodium content

This medicinal product contains not more than 0.03 mmol (or 0.69 mg) sodium per ml. To be taken into consideration by patients on a controlled sodium diet.

Paediatric population

The listed warnings and precautions apply both to adults and children.

Live attenuated virus vaccines

Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of this medicinal product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. Therefore, patients receiving measles vaccine should have their antibody status checked.

Paediatric population

The listed interactions apply both to adults and children.

Pregnancy

The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials and therefore should only be given with caution to pregnant women and breast-feeding mothers. IVIg products have been shown to cross the placenta, increasingly during the third trimester. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected.

Breast-feeding

Immunoglobulins are excreted into the milk and may contribute to protecting the neonate from pathogens which have a mucosal portal of entry.

Fertility

Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be expected.

The ability to drive and operate machines may be impaired by some adverse reactions associated with Panzyga. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.

Summary of the safety profile

Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally.

Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration.

Cases of reversible aseptic meningitis and rare cases of transient cutaneous reactions have been observed with human normal immunoglobulin. Reversible haemolytic reactions have been observed in patients, especially those with blood groups A, B, and AB. Rarely, haemolytic anaemia requiring transfusion may develop after high dose IVIg treatment (see also Section 4.4).

Increase in serum creatinine level and/or acute renal failure have been observed.

Very rarely: thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thromboses.

For safety information with respect to transmissible agents, see section 4.4.

Tabulated list of adverse reactions

The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level).

Frequencies have been evaluated according to the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data).

Within each Organ Class, adverse reactions are presented in order of decreasing seriousness.

Frequency of adverse drug reactions in clinical studies with Panzyga:

† subclinical case

The following reactions have been reported to occur with IVIg treatment and can also occur after Panzyga administration:

Description of selected adverse reactions

For description of selected adverse events, such as hypersensitivity reactions, thromboembolism, acute renal failure, aseptic meningitis syndrome, and haemolytic anaemia, see section 4.4.

Paediatric population

Frequency, type and severity of adverse reactions in children were the same as in adults.

To report any side effect(s):

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Health care professionals are asked to report any suspected adverse reactions.

·         Kingdom of Saudi Arabia:

·         Other GCC states:

Overdose may lead to fluid overload and hyperviscosity, particularly in patients at risk, including elderly patients or patients with cardiac or renal impairment.

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration, ATC-Code: J06B A02.

Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents.

Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1000 donations. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma. Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range.

The mechanism of action in indications other than replacement therapy is not fully elucidated, but includes immunomodulatory effects.

Clinical Studies

A prospective, open-label, non-controlled study was done in 51 patients with primary immunodeficiency syndromes. The patients were recruited into 3 age strata (³2 years and <12 years of age, ³12 years and <16 years of age, and ³16 years and £75 years). The primary endpoint of the study was the rate of serious bacterial infections (SBI) per person-year on treatment. Patients received a total of 17 or 13 infusions of Panzyga over the course of this study, depending on whether their regular treatment intervals were every 3 or 4 weeks, respectively. The dose was 0.2-0.8 g/kg to be infused at increasing infusion rates up to a maximum of 0.08 ml/kg/min. Two patients experienced 4 SBIs. With altogether 49.2 patient exposure years, the result of this primary endpoint was 0.08 SBIs/patient exposure year with an upper 99% confidence interval limit of 0.5. Also the other efficacy parameters calculated by patient exposure year, such as other infections and days with use of antibiotics, absence from school or work, and hospitalised due to infection, were in line with what has been published for other IVIGs previously developed.

This study was followed by an extension study which was carried out in order to assess the tolerability of Panzyga when administered at higher infusion rates (from 0.08 ml/kg/min up to 0.14 ml/kg/min). In total, 21 patients were enrolled. The product was well tolerated and all patients completed the study as planned. Study medication related AEs were reported in 2 children and 2 adults; the most commonly reported reactions were nausea and headache.

A further prospective, open-label, non-controlled study was done in 40 patients with immune thrombocytopenic purpura of at least 12 months duration. Patients received a daily dose of 1 g/kg for 2 consecutive days. Alternative response (AR) according to the EMA Guideline was defined as an increase in platelet count to ≥30x10⁹/L and to at least double the baseline platelet count, confirmed on at least 2 separate occasions at least 7 days apart, and absence of bleeding. An AR was observed in 24 patients (66.7%).

Complete response (CR) according to the EMA Guideline was defined as the achievement of platelet counts ≥100x10⁹/L, to be fulfilled on at least 2 separate visits at least 7 days apart without new bleedings. CR was observed in 18 patients (50.0%).

Loss of AR/CR was applied if the criteria for AR/CR were fulfilled but deteriorated afterwards as a decrease in platelet count to <30x10⁹/L (AR) or <100x10⁹/L (CR) or a decrease in platelet count to less than double the baseline count or as occurrence of bleeding. Regarding loss of AR, 11 of 24 patients (45.8%) who fulfilled the AR criteria had a loss of response. Loss of CR was seen for 14 of 18 patients (77.8%) who fulfilled the CR criteria.

For safety information derived from clinical studies please see Section 4.8.

Paediatric Population

There were no major differences in the proportion of children or adolescent patients with AEs compared with adults. AEs related to the system organ class "infections and infestations" were the most commonly AEs met in all age groups; however, they were reported in a higher percentage of children and adolescent patients. The same difference was noted for gastrointestinal disorders AEs. It was also noticed a higher percentage of patients in children age group having AEs from the system organ class "skin and subcutaneous tissue disorders".

Human normal immunoglobulin is immediately and completely bioavailable in the recipient’s circulation after intravenous administration. It is distributed relatively rapidly between plasma and extravascular fluid, after approximately 3–5 days equilibrium is reached between the intra- and extravascular compartments.

Panzyga has an average half-life of about 26–39 days. This half-life may vary from patient to patient, in particular in primary immunodeficiency.

IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.

Paediatric Population

The results of the pharmacokinetic studies in the different paediatric age groups are summarized in the following table, with a comparison to adults.

Overview on Pharmacokinetic Characteristics of Total IgG for Panzyga Divided by Different Age Groups (median values)

Immunoglobulins are normal constituents of the human body.

The safety of Panzyga has been demonstrated in several non-clinical safety pharmacology (cardiovascular, respiratory, and bronchospastic effects, thrombogenic potential) and toxicology studies (acute toxicity, local tolerance). The non-clinical data reveal no special risk for humans based on these conventional safety pharmacology and toxicity studies. Studies of repeated dose toxicity, genotoxicity, and toxicity to reproduction in animals are impracticable due to induction of and interference by developing antibodies to heterologous proteins. Since clinical experience provides no evidence for carcinogenic potential of immunoglobulins, no experimental genotoxicity/carcinogenicity studies in heterogeneous species were performed.

Glycine                        17.3 mg/ml

Water for injections    ad 1 ml

In the absence of incompatibility studies, this medicinal product must not be mixed with other medicinal products.

Store in a refrigerator (2°C–8°C). Do not freeze. Keep the container in the outer carton in order to protect from light.

The product may be stored at temperatures above +8°C and below +25°C for up to 6 months, without being refrigerated again during this period, and it must be discarded if not used after this.

Pack sizes:

1 g              in                10 ml             in a 20 ml vial

2.5 g           in                25 ml             in a 30 ml vial

5 g              in                50 ml             in a 70 ml bottle

10 g            in                100 ml           in a 100 ml bottle

20 g            in                200 ml           in a 250 ml bottle

30 g            in                300 ml           in a 300 ml bottle

Not all pack sizes may be marketed.

The vials/bottles are made of type II glass closed with bromobutyl rubber stoppers and sealed with aluminium flip-off caps.

The product should be brought to room or body temperature before use.

The solution should be clear or slightly opalescent and colourless or pale yellow.

Solutions that are cloudy or have deposits should be not used.

Any unused product or waste material should be disposed of in accordance with local requirements.

Due to the possibility of bacterial contamination, any remaining contents must be discarded.