Gammaplex

Gammaplex 10%

100 mg/ml solution for infusion

Human normal immunoglobulin (IVIg).

One ml contains 100 mg human normal immunoglobulin (purity of at least 98% IgG).

Each vial of 50 ml contains 5 g of human normal immunoglobulin.

Each vial of 100 ml contains 10 g of human normal immunoglobulin.

Each vial of 200 ml contains 20 g of human normal immunoglobulin.

Distribution of the IgG subclasses (approx. values):

IgG1 ……… 63%

IgG2 ……… 31%

IgG3 ……… 5%

IgG4 ……… 1%

The maximum IgA content is <20 micrograms/ml.

Produced from the plasma of human donors.

For the full list of excipients, see section 6.1.

Solution for infusion.

The solution is clear or slightly opalescent and colourless or pale yellow (see section 6.6).

The pH of the solution is 4.9 – 5.2, the osmolality is not less than 240 mOsmol/kg and typically 280 mOsmol/kg.

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

• Primary immunodeficiency 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, 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 syndromes

The dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least 5 to 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

There are two alternative treatment schedules:

• 0.8-1 g/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.

Indication

Dose

Frequency of injections

Replacement therapy in primary immunodeficiency

Replacement therapy in secondary immunodeficiency

Congenital AIDS

Hypogammaglobulinaemia (< 4 g/l) in patients after allogeneic haematopoietic stem cell transplantation

- starting dose:

0.4 - 0.8 g/kg

- thereafter:

0.2 - 0.8 g/kg

0.2 - 0.4 g/kg

0.2 - 0.4 g/kg

0.2 - 0.4 g/kg

every 3 - 4 weeks to obtain IgG trough level of at least 5 – 6 g/l

every 3 - 4 weeks to obtain IgG trough level of at least 5 – 6 g/l

every 3 - 4 weeks

every 3 - 4 weeks to obtain IgG trough level above 5 g/l.

Immunomodulation:

Primary immune thrombocytopenia

Guillain Barré syndrome

Kawasaki disease

0.8 – 1 g/kg

or

0.4 g/kg/d

0.4 g/kg/d

1.6 – 2 g/kg

or

2 g/kg

on day 1, possibly repeated once within 3 days

for 2 - 5 days

for 5 days

in divided doses over 2 - 5 days in association with acetylsalicylic acid

in one dose in association with acetylsalicylic acid

Elderly

Do not exceed recommended doses, and administer Gammaplex 10% at the minimum infusion rate practicable.

Renal impairment

In patients judged to be at increased risk of developing renal impairment, Gammaplex 10% should be infused at the minimum rate practicable. Renal function should be assessed before the initial infusion of Gammaplex 10% and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing Gammaplex 10% (see section 4.4).

Hepatic impairment

No dose adjustment is necessary for those with hepatic impairment.

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 0.3 ml/kg/hr for 15 minutes. If well tolerated (see section 4.4), the rate of administration may gradually be increased (every 15 minutes as follows: 0.6, 1.2, 2.4, 3.6 ml/kg/hr) to a maximum of 4.8 ml/kg/hr; subsequent infusions can start at 0.6 ml/kg/hr and increased as above.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see also section 4.4).

Hypersensitivity to human immunoglobulins especially in patients with antibodies against IgA.

Certain severe adverse 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 (0.3 ml/kg/hr).

• are carefully monitored for any symptoms throughout the infusion period. In particular, patients naïve 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 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 infaction, 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-exisiting 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 thromophilic disorders, patients with prolonged periods of immobilisation, severely hypovolaemic 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-exisiting renal insufficiency, diabetes mellitus, hypovolaemia, overweight, concomitant nephrotoxic medicinal products or aged 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. Gammaplex 10% does not contain sucrose, glucose or maltose.

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

Transfusion-related acute lung injury (TRALI)

There have been reports of TRALI i.e. noncardiogenic pulmonary oedema, in patients administered IVIg products.

Aseptic meningitis syndrome (AMS)

Aseptic meningitis syndrome has been reported to occur in association with IVIg treatment.

Disontinuation 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 the 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 Coomb's 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 human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), and for the non-enveloped hepatitis A and parvovirus B19 viruses.

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 Gammaplex 10% 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.

Hepatic impairment

There are no special warnings or precautions specific for patients with hepatic impairment.

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 vaccination should have their antibody status checked.

Paediatric population

Interaction studies have not been performed. The reported interactions for adults apply to 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 Gammaplex 10%. 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 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 frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Frequency of Adverse Reactions (ADRs) in clinical studies with Gammaplex.

MedDRA System Organ Class

Adverse reaction

Frequency

Metabolism and nutrition disorders

Fluid retention, dehydration

Common

Decreased appetite, iron deficiency

Uncommon

Psychiatric disorders

Insomnia

Uncommon

Nervous system disorders

Headache

Very common

Dizziness

Common

Migraine, hypoesthesia, paraesthesia, lethargy

Uncommon

Ear and labyrinth disorders

Vertigo

Common

Tinnitus

Uncommon

Cardiac disorders

Palpitations, tachycardia

Common

Vascular disorders

Hypertension, hypotension

Common

Thrombosis, hot flush

Uncommon

Respiratory, thoracic and mediastinal disorders

Nasal congestion

Common

Bronchospasm, epistaxis, pharyngolaryngeal pain

Uncommon

Gastrointestinal disorders

Vomiting, nausea, diarrhoea, abdominal pain

Common

Abdominal distension, constipation, stomatitis

Uncommon

Skin and subcutaneous tissue disorders

Erythema multiforme, urticaria, pruritus

Uncommon

Musculoskeletal, connective tissue disorders

Arthralgia, myalgia, muscle spasms, back pain, neck pain

Common

Musculoskeletal stiffness, pain in extremity

Uncommon

General disorders and administration site conditions

Pyrexia

Very common

Chills, chest discomfort /pain, fatigue, asthenia, infusion site reaction, pain

Common

Investigations

Coombs' direct test positive, anaemia/ haemoglobin decreased

Common

Anti-erythrocyte antibody positive, white blood cell count increased, urinary hemosiderin positive, gastric pH decreased

Uncommon

Description of selected adverse reactions

None of the reported adverse reactions to Gammaplex warrant separate description.

Paediatric population

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults. No clinical trials have been conducted with Gammaplex in children aged 0 - < 2 years.

Reporting of suspected adverse reactions

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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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: J06BA02

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.

GMX01

A phase III, multicentre, non-randomised, open-label study in 50 predominantly adult subjects with primary immunodeficiency diseases (PID), where Gammaplex 5% was infused at a dose of 300 to 800 mg/kg every 21 or 28 days, concluded that Gammaplex 5% was well tolerated and efficacious and therefore suitable for the management of subjects with PID. There were no serious acute bacterial infections during the 12 months of treatment, and the most commonly reported adverse reactions were headache (18 patients), nausea (6 patients), pyrexia (6 patients) and fatigue (6 patients).

GMX02

A later phase III, open-label, multicentre clinical study investigating the safety and efficacy of Gammaplex 5% infused at a dose of 1 g/kg/day for two consecutive days in 35 subjects with chronic immune thrombocytopenic purpura (ITP) showed Gammaplex 5% to be an effective treatment, and hence its efficacy in immunomodulation. The most commonly reported adverse reactions were headache (10 patients), vomiting (6 patients) and pyrexia (5 patients).

GMX07

A multicentre Phase III study in PID in two populations: adults and children. The design for the adult cohort (>16 years), a randomised two-period cross-over design, was different from that for children (single arm non-comparative). All subjects had at least five infusions of Gammaplex 10% and all patients aged >16 years had at least five infusions of Gammaplex 5% in addition. Subjects were dosed at either 21- or 28-day intervals; doses at the PK infusions ranged from 254 to 794 mg/kg for Gammaplex 10% and from 269 to 786 mg/kg for Gammaplex 5%. Overall, the proportion of patients with adverse reactions was similar between the two formulations; the most commonly reported adverse reactions for Gammaplex 10% were headache (14.9% of patients), migraine and pyrexia (6.4% of patients for each).

Paediatric population

Study GMX01 above, comprised predominantly of adult subjects with PID and included seven patients aged less than 18 years (9 – 17 years inclusive). There were no reports of serious adverse reactions in any of the paediatric subjects.

Study GMX02 above in ITP included three subjects aged less than 18 years (6 – 17 years inclusive). One of the paediatric subjects (aged six years) experienced a serious adverse reaction (headache, with vomiting and dehydration).

GMX04

A phase III, multicentre, non-randomised, open-label paediatric study in 25 children and adolescent subjects (aged 3-16 years inclusive) with primary immunodeficiency diseases (PID), where Gammaplex 5% was infused at a dose of 300 to 800 mg/kg every 21 or 28 days, concluded that Gammaplex 5% was well tolerated and efficacious in children with PID. There were two serious acute bacterial infections reported during the 12 months of treatment, and the most commonly reported adverse reactions were headache (8 patients), hypotension (4 patients), pyrexia (3 patients) and tachycardia (3 patients).

GMX07

In the analysis, children were categorised as those patients aged <18 years. The proportion of children with adverse reactions for Gammaplex 10% (7/17, 41.2%) was slightly higher than for adults (9/30, 30.0%) but the most commonly reported was headache for both age groups. Pyrexia was reported in 2 children (11.8%). All other adverse reactions in children were not reported by more than one patient.

Pharmacokinetic/pharmacodynamic relationship(s)

Human normal immunoglobulin is immediately and completely bioavailable in the recipient's circulation after intravenous administration. It is distributed realtively rapidly between plasma and extravascular fluid, after approximately 3-5 days equilibrium is reached between the intra- and extravascular compartments. Human normal immunoglobulin has a half-life of about 31.4 days (range 19.7 to 53.8 days) in adults (>18 years). 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

Gammaplex 10% has a half-life in children (aged <18 years) of about 31.0 days (range 17.0 to 50.4 days), similar to that in adults (see above).

Immunoglobulins are normal constituents of human plasma and therefore toxicity testing in heterologous species is of no relevance. Gammaplex contains highly purified immunoglobulins and has been tested in non-clinical haemodynamic monitoring studies. There is no evidence of effects on blood pressure or heart rate at infusion rates similar to those used clinically. At higher infusion rates or approximately 2- to 7-fold those used clinically, a hypertensive effect was found. No other preclinical studies have been carried out.

Glycine

Polysorbate 80

Water for Injections

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

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

3 years.

Gammaplex 10% should be used immediately after opening.

Do not store above 25°C.

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

50 ml, 100 ml or 200 ml of solution in a Type II glass vial with a halobutyl stopper.

Pack sizes

1 vial (50 ml or 100 ml or 200 ml)

Not all pack sizes may be marketed.

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

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

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

Bio Products Laboratory Ltd

Elstree

WD6 3BX

United Kingdom

PL08801/0045

Date of first authorisation: August 2018