14.03.2021 İmmünoglobülin İçeren İntravenöz Ürünler Hk, 14.03.2021,ENG

RESTRICTED

MINISTRY OF HEALTH

OF THE REPUBLIC OF TURKEY

Medicines and Medical Devices Agency of Turkey

Number : E-62820468-000-369381 Subject : Intravenous Preparations Containing Immunoglobulin

NORMAL

14.03.2021

DOSSIER

Ref: Our association announcement dated 27.04.2018, with No. E.79754.

Our association decision dated 27.04.2018, with No. E.79754, regarding intravenous products containing immunoglobulin has been updated. The relevant sections of the Summary of Product Characteristics and Package Leaflet of intravenous products containing Immunoglobulin shall be amended as follows.

Therapeutic indications:

1. It is administered for replacement therapy in case of immunodeficiency:

a) In primary (Congenital) immunodeficiencies with disrupted antibody production,

b) In subjects diagnosed with Chronic Lymphocytic Leukemia, with hypogammaglobulinemia, in whom prophylactic antibiotics fall short and who develop recurrent bacterial infections, c) In subjects diagnosed with Multiple Myeloma, who have hypogammaglobulinemia, in whom pneumococcal immunization is insufficient, and who develop recurrent bacterial infections, d) In children and adolescents with congenital AIDS and recurring infections, e) In subjects in whom hypogammaglobulinemia develops following allogeneic hematopoietic stem cell transplantation, f) In case of severe and recurring infections where antimicrobial treatment falls short in the pediatric age group of 0-18 years with a serum IgG level of ˂400 mg/dl in secondary immunodeficiency with disrupted antibody production.

2) For achieving an immunomodulatory effect:

a) In immune thrombocytopenia (ITP) subjects with high hemorrhagic risk or in whom the platelet count needs to be increased before surgical intervention, b) In autoimmune hematolytic anemia cases not responding to/dependent on steroids or for whom steroid utilization is contraindicated, c) In Guillain-Barré syndrome, d) In Kawasaki disease, e) In multifocal motor neuropathy disease, f) In the acute treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), g) In the treatment of Myasthenia Gravis with bulbar involvement.

Posology and mode of administration: The replacement therapy should be initiated and monitored under the supervision of a physician experienced in immunodeficiencies.

Posology/frequency and duration of administration: The posology and frequency of administration vary depending on the indication.

In replacement therapy, it may be necessary to adjust the dose individually depending on the pharmacokinetic and clinical response of the patient. The following dosing schemes are provided for guidance.

Replacement therapy in primary immunodeficiencies The dose should be adjusted to enable the serum IgG level measured before the next infusion to be consistently maintained at the level of minimum 500-600 mg/dL. This is required for 3-6 months as of the onset of treatment in order to achieve this balance. The recommended initial dose is minimum 0.2 g/kg administered once every 3-4 weeks following the infusion of 0.4-0.8 g/kg applied once. The average dose required for fixing the serum immunoglobulin level at 500-600 mg/dL is 0.2-0.8 g/kg. The dose interval changes in 3-4 weeks after achieving a steady serum level. The steady serum levels should be measured and evaluated together with the clinical response of the patient. Dose and/dose interval adjustment may be considered for achieving a higher steady serum level in relation to the clinical response (e.g., frequency of infections).

The recommended dose for the following cases is 0.2-0.4 g/kg administered once every 3-4 weeks:

In subjects diagnosed with Chronic Lymphocytic Leukemia, with hypogammaglobulinemia, in whom prophylactic antibiotics fall short and who develop recurrent bacterial infections,

In subjects diagnosed with Multiple Myeloma, who have hypogammaglobulinemia (IgG<500 mg/dL), in whom pneumococcal immunization is insufficient and who develop recurrent bacterial infections,

In children and adolescents with congenital AIDS and recurring infections.

The recommended dose for the following cases is 0.2-0.4 g/kg administered once every 3-4 weeks. The steady serum levels should be kept above 500 mg/dL:

Patients with bacteremia following allogeneic stem cell transplantation and recurring sinopulmonary infections, with an IgG level of <400 mg/dL.

Replacement therapy in secondary immunodeficiencies The recommended dose for secondary immunodeficiency is 0.2-0.4 g/kg administered once every 3-4 weeks. The steady serum levels should be kept above 500 mg/dL:

Primary immune thrombocytopenia and autoimmune hemolytic anemia There are two alternative dosing schemes:

• On the first day, a dose of 0.8-1 g/kg should be used; the dose may be repeated once within 3 days.

• A dose of 0.4 g/kg/day should be used for a period of 2-5 days. The treatment may be repeated in case of relapse.

Guillain Barré Syndrome A dose of 0.4 g/kg/day should be administered for a period of 5 days.

Kawasaki Disease A single dose of 2 g/kg should be administered for 8-12 hours in combination with acetylsalicylic acid.

Multifocal Motor Neuropathy (MMN) disease Initial dose: a total of 2 g/kg in divided doses for a period of 2-5 days Maintenance dose: 1-2 g/kg once every 2-6 weeks

Chronic inflammatory demyelinating polyneuropathy (CIDP) The recommended initial dose should be a total dose of 2 g/kg in divided doses to be administered in 2-5 consequent days. In case of no response, a total dose of 1 g/kg should be administered for 1-2 days once every 3 weeks and the treatment should be discontinued in case no response is obtained at the end of 2 months. Maintenance dose: It should be administered at a total dose of 0.4-1 g/kg for 1-2 days once every 3 weeks if a response is obtained in the initial treatment. The dose providing the maximum benefit is recommended and the dose should be determined by the physician. The dose should be reduced until the lowest effective maintenance dose is identified, and the frequency of administration should be adjusted.

Myasthenia Gravis A dose of 0.4 g/kg/day for a period of 5 days in the critical phase where no response is obtained to other special treatments.

Pediatric population The posology for each indication in children and adolescents (0-18 years) does not differ from that of adults and should be adjusted according to the clinical endpoints in cases described above.

Mode of Administration: It should be administered intravenously.

Human normal immunoglobulin should be administered intravenously at a rate of 0.3 mL/kg/hour within the first 30 minutes. If this is tolerated well by the patient, the administration speed may be gradually increased up to a maximum rate of 4.8 mL/kg (see Section 4.4). The clinical data obtained on a limited number of patients demonstrated that primary immunodeficiency (PID) patients who could tolerate well the infusion speed of 4.8 mL/kg/hour in adults, could tolerate an infusion speed of 7.2 mL/kg/hour. See Section 4.4 for detailed information on use.

In case of need for dilution before infusion, IVIG may be diluted with a 5% glucose solution until reaching the final concentration (5% immunoglobulin) of 50 mg/mL. See Section 6.6 for detailed information on dilution. In case of the occurrence of side effects associated with infusion, the infusion speed should be reduced or stopped.

Additional Information on Special Populations Renal/Liver impairment: Acute renal impairment cases were reported in patients who received IVIG treatment. IVIG preparations should be administered in the lowest applicable infusion speed and dose in patients with risk of renal impairment (see Section 4.4). No additional information is provided in patients with liver impairment.

Pediatric population: As the posology is administered according to body weight and clinical response in each case mentioned above, the posology will not change in children and adolescents (0-18 years).

Geriatric population: Acute renal impairment cases were reported in patients who received IVIG treatment. It was reported there were certain risk factors in most of these cases including the fact that the patients were above the age of 65. Furthermore, there is clinical evidence demonstrating the connection between the administration of IVIG and thromboembolic events in highly risky patients. Therefore, attention should be paid when prescribing IVIG and administering the infusion in patients with risk factors for thrombotic events including advanced age and the lowest applicable infusion speed and dose should be used (see Section 4.4).

I hereby submit for your information and kindly request that any views, proposals, and remarks on the decision adopted are submitted to the Clinical Evaluation Unit within 1 month effective as of the date of publication of this association decision and that no application is made to the Pharmacological Evaluation Unit on “intravenous products containing immunoglobulin” during the referred process.

Spec. Pharm. Oğuzhan KOYUNCU on behalf of the President of the Agency Head of Department

Distribution: Association of Research-Based Pharmaceutical Companies Pharmaceutical Manufacturers Association of Turkey Turkish Pharmaceutical Industry Association Association of Innovator Pharmaceutical Companies Self-Care Products Association Turkish Foundation on Pharmaceuticals, Pharmacy, Health Sciences and Technologies