Pharmacokinetics in children

After intravenous administration, human normal immunoglobulin is immediately and completely available with relatively rapid distribution to plasma and extravascular fluid. Within approximately 3 to 5 days, a balance is achieved between the intra- and extravascular compartments. IgG and IgG complexes are degraded in the cells of the reticuloendothelial system and are subsequently taken up by the body and incorporated into other proteins or catabolized. Therefore, IgGs are not metabolized by hepatic enzymes or excreted by the kidneys or liver.

No differences in pharmacokinetic properties are expected in pediatric patients. Current evidence shows that the pharmacokinetic profile of pediatric patients (>3 years) is quite similar to that of adults. Data on pharmacokinetics in younger children are lacking

 A summary of the pharmacokinetic (PK) parameters listed in the SmPCs of the licensed products

Age	3-18 years
t½ (days) mean*	33,9
Cmax (g/l) mean	14,2
Vd (l) mean	4,57
Total Cl (l/dag), mean	0,088

* The half-life may vary from patient to patient, especially in primary immunodeficiency.

dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

CAUTION:
Intravenous 0 years up to 18 years Before administration, ensure adequate hydration and urine production. The infusion rates variers per product and therefore the specific product information of each product should be consulted. Start a low infusion rate and increase the rate gradually based on side effects.

Toxic shock syndrome (TSS) and necrotizing fasciitis (NF)

Intravenous Term neonate 2 g/kg/dose as a single dose. If necessary, consider a second dose of max 2 g/kg on the next day. Alternative treatment: 1 g/kg, day 1, 0.5 g/kg, day 2 and 3  There is only limited and inconclusive evidence on the efficacy of IVIG for this indication. 1 month up to 18 years 2 g/kg/dose as a single dose. If necessary, consider a second dose of max 2 g/kg on the next day. Alternative treatment: 1 g/kg, day 1, 0.5 g/kg, day 2 and 3  There is only limited and inconclusive evidence on the efficacy of IVIG for this indication. Term neonate [24] [26] [31] [32] [33] [34] [37] [38] 2 g/kg/dose as a single dose. If necessary, consider a second dose of max 2 g/kg on the next day. Alternative treatment: 1 g/kg, day 1, 0.5 g/kg, day 2 and 3  There is only limited and inconclusive evidence on the efficacy of IVIG for this indication. 1 month up to 18 years [24] [31] [32] [33] [34] [37] [38] 2 g/kg/dose as a single dose. If necessary, consider a second dose of max 2 g/kg on the next day. Alternative treatment: 1 g/kg, day 1, 0.5 g/kg, day 2 and 3  There is only limited and inconclusive evidence on the efficacy of IVIG for this indication.

Secondary immune deficiency, hypogammaglobulinaemia after allogenic bone marrow transplant
Intravenous Term neonate [7] 0.2 - 0.4 g/kg/dose every 3-4 weeks. Aim for normal serum IgG values (> 5-6 g/l), this may need to be adjusted depending on the clinical picture.   1 month up to 18 years [7] [21] 0.2 - 0.4 g/kg/dose every 3-4 weeks. Aim for normal serum IgG values (> 5-6 g/l), this may need to be adjusted depending on the clinical picture.

Guillain-Barré syndrome, agammaglobulinaemia, hypogammaglobulinaemia and other dysimmunoglobulinaemias, autoimmune encephalitis.
Intravenous Term neonate [1] [6] [9] [17] [18] 0.4 g/kg/day in 1 dose Duration of treatment: 5 days 1 month up to 18 years [1] [6] [9] [17] [18] 0.4 g/kg/day in 1 dose Duration of treatment: 5 days

Immune thrombocytopenia
Intravenous Term neonate [7] 0.8 - 1 g/kg/dose, once only. Dose may possibly be repeated after 3 days. Alternative: 0.4 g/kg for 2-5 days. Dose in consultation with a haematologist. 1 month up to 18 years [7] [21] 0.8 - 1 g/kg/dose, once only. Dose may possibly be repeated after 3 days. Alternative: 0.4 g/kg for 2-5 days. Dose in consultation with a haematologist.

Kawasaki disease
Intravenous Term neonate [2] 2 g/kg/dose, once only. In combination with acetylsalicylic acid. Consider a second dose if necessary.   1 month up to 18 years [2] [21] 2 g/kg/dose, once only. In combination with acetylsalicylic acid Consider a second dose if necessary.

Kawasaki disease with congestive heart failure
Intravenous Term neonate [2] 1 g/kg/day, continuous infusion. Duration of treatment: For 2 days. 1 month up to 18 years [2] 1 g/kg/day, continuous infusion. Duration of treatment: For 2 days.

Hyperbilirubinaemia caused by blood group antagonism
Intravenous Neonates Gestational age ≥ 35 weeks 0.5 - 1 g/kg/dose, as required repeat after 12 hours. According to the guidelines in the Netherlands and Belgium, IVIG is no longer recommended for this indication.

Multifocal motor neuropathy (MMN), chronic inflammatory demyelinizing polyneuropathy (CIDP)
Intravenous Term neonate [6] [9] Initial dose: 2 g/kg split across 2-5 days Maintenance dose: 1 g/kg every 2-4 weeks OR 2 g/kg every 4-8 weeks 1 month up to 18 years [6] [9] [21] Initial dose: 2 g/kg split across 2-5 days Maintenance dose: 1 g/kg every 2-4 weeks OR 2 g/kg every 4-8 weeks

Juvenile dermatomyositis (JDM)

Intravenous Term neonate [8] [10] 1 g/kg/dose in 12-18 hours on two successive days every month. Alternative: 0.4 g/kg/day on five successive days every month. Duration of treatment: For at least 3 months 1 month up to 18 years [8] [10] 1 g/kg/dose in 12-18 hours on two successive days every month. Alternative: 0.4 g/kg/day on five successive days every month. Duration of treatment: For at least 3 months

Congenital AIDS
Intravenous Term neonate [6] [9] 0.2 - 0.4 g/kg/dose every 3-4 weeks. 1 month up to 18 years [6] [9] [21] 0.2 - 0.4 g/kg/dose every 3-4 weeks.

Vasculitis
Intravenous Term neonate [11] [12] [13] [14] 1 - 2 g/kg/day, once only in 1-5 doses. 1 month up to 18 years [11] [12] [13] [14] 1 - 2 g/kg/day, once only in 1-5 doses.

Rejection after kidney transplant

Intravenous Term neonate [15] Little literature is available on the use of immunoglobulins in rejection after kidney transplants. Various dosage schemes are around in the Netherlands, including:  1-2 g/kg one-time only, spread over several days if needed. In the study by Billing, 1 g/kg/week was given for 4 weeks (m=20, combined with 1 dose of rituximab). 1 month up to 18 years [15] Little literature is available on the use of immunoglobulins in rejection after kidney transplants. Various dosage schemes are around in the Netherlands, including:  1-2 g/kg one-time only, spread over several days if needed. In the study by Billing, 1 g/kg/week was given for 4 weeks (m=20, combined with 1 dose of rituximab).

ABO-incompatible kidney transplant
Intravenous Term neonate [16] 0.5 g/kg/dose, once only. 1 month up to 18 years [16] 0.5 g/kg/dose, once only.

Myasthenia gravis (auto-immune)
Intravenous Term neonate [22] 2 g/kg divided over 2-5 days.  To be repeated based on clinical condition 1 month up to 18 years [22] 2 g/kg divided over 2-5 days To be repeated based on clinical condition

Measles pre- exposure prophylaxis

Intravenous 2 years up to 18 years In PID/SID patient receiving a maintenance dose < 0.53 g/kg every 3-4 weeks: increase dose once to 0.53 g/kg. This should yield a serum level > 240 mIE/ml measles antibodies for at least 22 days. 2 years up to 18 years [25] In PID/SID patient receiving a maintenance dose < 0.53 g/kg every 3-4 weeks: increase dose once to 0.53 g/kg. This should yield a serum level > 240 mIE/ml measles antibodies for at least 22 days.

Renal impaiment in children > 3 months

Cases of acute renal insufficiency have been reported in patients who are on IVIg therapy. In cases of reduced renal function, discontinuing the administration of IVIg should be considered.

In children with a risk of renal impairment, the infusion rate must not be higher than 4.8 ml/kg/hour.

The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects in children

Side effects rarely occur when intravenous immunoglobulins are administered. Fever, problems with joints, nausea, vomiting, infusion reaction and exanthema have been reported. Anaphylactic responses are rare and occur above all in patients with IgA deficiency or antibodies against IgA.

In infants and young children with fructose intolerance (that has not yet been diagnosed), the excipient sorbitol can cause a reaction that can sometimes be fatal. Some types of blood glucose meters incorrectly interpret the excipient maltose as glucose.

The most common side effect in children and adolescents is headache [SmPC Octagam]. After applying maltose containig IVIg glycosuria ocurred in children and adolescents. Maltose is hydrolysed to glucose in renal tubules and gets reabsorbed. Capacity of reabsorbtion is age dependent [SmPC Ig Vena]. Indications for high IVIG doses in children (especially children with Kawasaki disease) are associated with a higher reporting rate of hemolytic reactions [SmPC Privigen].

 

The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications

No information available on specific contra indications in children.

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Side effects can largely be prevented by running the infusion in more slowly. An immunologist should be consulted if there are IgA antibodies.

Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

• ANTIINFECTIVES FOR SYSTEMIC USE
• IMMUNE SERA AND IMMUNOGLOBULINS

IMMUNOGLOBULINS

This pages provides a list of drugs from the same ATC class for comparison. This does not necessarily mean that these drugs are interchangeable.

Immunoglobulins, normal human
	Immunoglobulin, normal SUBCUTANEOUS use Related Medicines Menu">	J06BA01

Specific immunoglobulins
	Antirhesus (D) immunoglobulin Related Medicines Menu">	J06BB01
	Hepatitis B immunoglobulin Related Medicines Menu">	J06BB04
	Tetanus immunoglobulin Related Medicines Menu">	J06BB02
	Varicella zoster immunoglobulin Related Medicines Menu">	J06BB03

Antibacterial monoclonal antibodies
	Bezlotoxumab Related Medicines Menu">	J06BC03

IMMUNOGLOBULINS, NORMAL HUMAN
	Immunoglobulin, normal SUBCUTANEOUS use Related Medicines Menu">	J06BA01

Antiviral monoclonal antibodies
	Casirivimab + imdevimab Related Medicines Menu">	J06BD07
	Nirsevimab Related Medicines Menu">	J06BD08
	Palivizumab Related Medicines Menu">	J06BD01

References

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2. Franssen MJAM et al, Werkboek Kinderreumatologie, VU Uitgeverij, 2008, 2e druk
3. Berg van den, HB et al, Werkboek Kinderhematologie, VU Uitgeverij, 2001, 2e druk
4. EMA, Guideline on core SmPC for human normal immunoglobulin for IV administration (IVIg), EMA/CHMP/BPWP/94038/2007 rev 3
5. NVK, Richtlijn preventie, diagnostiek en behandeling van hyperbilirubinemie bijde pasgeborene, geboren na een zwangerschapsduur van meer dan 35 weken, www.nvk.nl, 2008, http://www.nvk.nl/Kwaliteit/Richtlijnenenindicatoren/Richtlijnen.aspx
6. Takeda Manufacturing Austria AG, SmPC Kiovig (EU/1/05/329/001-006) Rev 26, 27-06-2022, www.ema.europa.eu
7. Baxalta Innovations GmbH., SmPC Gammagard S/D 5/10 g, poeder en oplosmiddel voor oplossing voor infusie (RVG 17033/17034). 27-01-2023, www.geneesmiddeleninformatiebank.nl
8. CBO., Richtlijn dermatomyositis, polymyositis en sporadische ‘inclusion body’-myositis., www.diliguide.nl, 2004
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12. Finkel TH et al., Chronic parvovirus B19 infection and systemic necrotising vasculitis: opportunistic infection or aetiological agent., Lancet., 1994, May 21;343(8908):, 1255-8
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21. Octapharma, SmPC Octagam 5% Inf.lsg. (2-38569), https://www.univadis.at/, 12/2018
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23. Prothya Biosolutions Netherlands B.V, SmPC Nanogam 50 mg/ml oplossing voor infusie (RVG 31627) 19-10-2021, www.geneesmiddeleninformatiebank.nl
24. Bustos BR, et al. , [Necrotizing fasciitis of the eyelids and toxic shock syndrome due to Streptococcus pyogenes]. , Rev Chilena Infectol., 2009, 26(2), 152-5
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31. Chen KY, et al., Toxic shock syndrome in Australian children., Arch Dis Child, 2016, 101(8), 736-40
32. Gottlieb M, et al, The Evaluation and Management of Toxic Shock Syndrome in the Emergency Department: A Review of the Literature., J Emerg Med, 2018, 54(6), 807-14
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34. Huang YC, et al., A family cluster of streptococcal toxic shock syndrome in children: clinical implication and epidemiological investigation., Pediatrics, 2001, 107(5), 1181-3
35. Kedrion S.P.A., Ig Vena 50 g/l solution for infusion. Last updated 2-2010., http://www.biogenetech.co.th/wp-content/uploads/2011/10/IgVena_PI0605_E1002_rev.01.pdf
36. Figueras-Aloy J, et al., Intravenous immunoglobulin and necrotizing enterocolitis in newborns with hemolytic disease. , Pediatrics, 2010, 125(1), 139-44
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Overdose