**11. Late-onset side effects of IVIG**

102 Immunodeficiency

infectious complications.

**Duration Months** 

**Patients Treated** 

6 42 200-800

12 51 300–600

12 46 300–600

12 61 300–600

9 73 100–600

15 51 34–352

postinfusion, b) 0-430 min postinfusion, c) 0-72 h postinfusion

Octagam 5% 12 46 300–600

Privigen 10% 12 80 200–888

**Dose Acute**

mg/Kg/21– 28 d

mg/Kg/21– 28 d

mg/Kg/21– 28 d

mg/Kg/21– 28 d

mg/Kg/21– 28 d

mg/Kg/21– 28d.

mg/Kg/21– 28 d

mg/Kg/ wk

**Table 6.** Clinical trials in patients with primary immunodeficiency disorders [22]

AE:Adverse event, infect/subj/y: infections per subject per year, NF:nanofiltration, SAE:serios adverse event a) 0-48 h

**Serious Bacterial Infect/subj/y** **Other Bacterial Infect/subj/y**

0 3.65 21.7% a 0

0 061. NR 8.2% c 2

0.021 1. 96 11.8% c 0

0.07 0.18 5.7% a 0

0.1 0 5.5% b 0

0.04 4.4 Local, 49%;

0 0.07 31.2% c 2 (1 patient)

0.08 3.55 18.5% b 5 (1 subject)

Systemic 5.4%

0

**Related, Temporally Associated AEs (%of Infusions** 

**Drug-Related SAEs** 

**Product Study**

CarimuneNF Liquid (12%)

Flebogamma

Flebogamma 5% DIF

Gammagard liquid 10%

Gamunex 10%

Vivaglobin 16%

5%

likely. Most IVIG reactions are mild, however anaphylaxis may occur occasionally. Adverse reactions are characterized by chills, headache, low grade fever, back or abdominal pain, nausea, vomiting, myalgias, rhinitis, asthma, flushing on face, vertigo, anxiety, conjunctival congestion, occasional rash and drop of arterial pressure. Varying rates of adverse events have been reported (Table 6) [53-56]. Thus, close monitoring of a patient during infusion is essential to identify and manage reactions [8,24,53]. Recently, manufacturing processes of immunoglobulins have been improved and new IVIG products have been developed. Several trials with these products demonstrated that the infusion related adverse reactions were reduced [24,53]. IVIG infusions have to be done at hospital or home by professionally educated staff if possible. Local anesthetic cream (EMLA Cream) could be applied on skin prior infusion to reduce pain in small children. Administration IVIG via indewelling venous catheter is not encouraged because of additional adverse events such as thrombotic and

A variety of side effects due to IVIG therapy have been reported in different tissues [7-11,21- 25,27,28,57]:

Central nervous system: rarely aseptic menengitis

Hematologic: hemolytic anemia, leukopenia, neutropenia, monocytopenia, disseminated intravascular coagulation and changes in blood rheology

Cardiovascular system: rarely heart attack, most commonly, drop in arterial blood pressure

Urogenital system: During the period between June 1985 and November 1998, 88 cases of kidney injuries had been reported to FDA. Acute renal failure occured with IVIG preparations stabilized with sucrose, where as those stabilized with D-sorbitol did not cause such an effect. Patients whose urinary output decreases, who suddenly gain weight with edeme on feet and ankles and those who experience dyspnea should be monitored very closely.

Liver Disease: The risk of Hepatitis C, Hepatitis B, HIV infection, prion disease disappeared after the initiation of viral inactivation (solvent-detergent or pasteurization) methods and PCR studies which took place after CDC's confirmation of 88 infections among 137 suspected hepatitis C cases (occuring after IVIG) in 1994. Therefore they are reliable preparations.

Skin: severe cutaneus vasculitis, dermatitis (egzema) and hair loss

Other: Life threatening parvovirus B19 has occured due to IVIG, hyperproteinemia, increased serum viscosity, pseudo-hyponatremia during infusions, transient serum sickness.

#### **12. How to manage adverse reactions?**

An expert monitoring is necessary for prompt diagnosis and treatment of adverse reactions. Most side effects resolve by themselves and are usually due to the speed of infusion. Infusion should temporarily be stopped 15 to 30 minutes if the symptoms appear or should be continued with slower rate once the symptoms disappear. Since the side effects are usually non-IgE dependent, the use of antihistamines is controversial, but diphenhydramine, acetaminophen or ibuprofen may be helpful. More severe reactions can be treated with 50 to 100 mg of hydrocortisone in adults and intravenous hydration is helpful.

Those who are reactive to IVIG should receive premedication. Thirty minutes prior to IVIG administration, oral nonsteroid anti-inflamatory agent (acetaminophen 15 mg/kg), antihistaminic agent (Benadryl 1mg/kg) or one hour prior to infusion intravenous hydrocortisone (6 mg/kg) should be administered [8,24].

#### **13. Subcutaneos immunoglobulin**

As an alternative to intravenous immunoglobulin treatment, immunoglobulins can be administered subcutaneously to patients with primary immunodeficiencies, Subcutaneous infusion of IgG was introduced more than 20 years ago but has gained ground in recent years [29,30,58-64]. Three ready-to-use liquid preparations of human IgG specifically formulated for subcutaneous infusions have been lisenced in US (Table 7). It can be stored at a temperature up to 25°C.

Immunoglobulin Treatment of Immunodeficient Patients 105

switching from IVIG to SCIG. Berger M et al reported that the doses that will yield desired serum levels for IVIG and SCIG may be estimated with the help of pharmacokinetic studies [8]. Area under the curve (AUC) of serum IgG versus time and trough level ratios (TLRs) on SCIG/IVIG were evaluated as guides for adjusting the dose. The mean dose adjustments required for non-inferior AUCs with 2 different SCIG preparations were 137% (± 12%) and 153% (± 16%). However, there were wide variations between adjustments required by different subjects, and in the resulting TLRs. Recent studies allow estimation of the ratio of IgG levels with different dose adjustments, and of the steady state serum levels with different SCIG doses [8]. When switching a patient from IVIG to SCIG, practising immunologist can tailor the dosage based on measured serum IgG levels and the clinical response Skoda-Smith S et al recommended a sample calculation process for converting from IVIG to subcutaneous IG, thus weekly dose for subcutaneous Ig should calculate as

Safety and therapeutic efficacy of subcutaneous immunoglobulin products has been demonstrated in children and pregnant women. Therapeutic efficacy of intravenous or subcutaneous immunoglobulin treatment in reducing infections was equal [5,28,57,65,66]. In an international study performed by Chapel et al. the efficacy of immunoglobulin replacement therapy given via intravenously or subcutaneously in patients with PAD was compared [60]. Forty patients received subcutaneous or intravenous immunoglobulin for the first year and switched to the alternative treatment in the second year, and the study showed that there was no difference in efficacy and adverse reactions between both routes. In another study, Fasth A et al. used a 16%, ready-to-use human normal immunoglobulin solution subcutaneously in children with PID previously receiving regular IVIG treatment, and the study showed that mild injection reactions were the adverse effects of the treatment, and the rate of bacterial infections was not different between both IVIG treatments. In the at home treatment there were fewer missed school

The cost effectiveness of the use of subcutaneous IG compared to IVIG therapy had been investigated in several studies [67,68]. The mean cost of both immunoglobulins was evaluated in the study performed by Beaute J et al. and they showed that monthly doses were equal for both routes of administration. In addition SCIG and IVIG (hospital-based) costs were also similar, but the costs may differ from one country to another [52]. Although this theoretical model showed little difference between the costs, SCIG seems to be expensive compared to IVIG due to the doses of immunoglobulin, but further studies are needed. Overall costs may be higher in CVID, because these patients need higher doses of

The SCIG home therapy was reported to give better health and improved school/social functioning for the children, reduced emotional distress and limitations on personal time for the parents and fewer limitations on family activities [58-64]. Pharmacokinetic studies reveal a more physiologic profile, in peak and trough levels of serum IgG [62,66]. Local tissue

1.37 X IVIg dose [65].

days, low healthcare expenses [62].

immunoglobulin [21,52].


**Table 7.** Commercial subcutaneous IG Products(Immune deficiency Foundation, October 2011)

The infusion can be applied through fine butterfly needles under the skin into the abdomen or thighs. Infusion pumps are used to administer the infusions and usually take 45 to 90 minutes. The amount of fluid given weekly to babies and children is 10 mls per site and 30 mls per site for older children. Subcutaneous infusion of 10-20% immunoglobulin, with the rate of 0.05-0.20 ml/kg/hour is advised. The recommended maintenance dose is 100 mg/kg/week. Immunoglobulin trough levels should be >5 g/L for patients with agammaglobulinaemia and 3 g/L greater than the initial IgG level for patients with CVID; however, the clinical response should be consider in choosing the dose and trough level [24]. Parents and patients can be educated on how to infuse the preparation at home. These infusions are better tolerated compared to IVIG and time sparing (home administration). Subcutaneous infusions are recommended to patients who are small children or reactive to IVIG or have poor veins.

Bioavailability and pharmacokinetics properties of subcutaneous IgG (SCIG) differs from intravenous IgG (IVIG). There are still debates about how the dose should be adjusted when switching from IVIG to SCIG. Berger M et al reported that the doses that will yield desired serum levels for IVIG and SCIG may be estimated with the help of pharmacokinetic studies [8]. Area under the curve (AUC) of serum IgG versus time and trough level ratios (TLRs) on SCIG/IVIG were evaluated as guides for adjusting the dose. The mean dose adjustments required for non-inferior AUCs with 2 different SCIG preparations were 137% (± 12%) and 153% (± 16%). However, there were wide variations between adjustments required by different subjects, and in the resulting TLRs. Recent studies allow estimation of the ratio of IgG levels with different dose adjustments, and of the steady state serum levels with different SCIG doses [8]. When switching a patient from IVIG to SCIG, practising immunologist can tailor the dosage based on measured serum IgG levels and the clinical response Skoda-Smith S et al recommended a sample calculation process for converting from IVIG to subcutaneous IG, thus weekly dose for subcutaneous Ig should calculate as 1.37 X IVIg dose [65].

104 Immunodeficiency

Gammagard S/D10%

Hizentra

a temperature up to 25°C.

**Product Manufacturer Dosage** 

Baxter Corporation

BayerC CSL Behring CSL Behring

Vivaglobulin CSL Behring 16%

IVIG or have poor veins.

**form** 

10% liquid <40 kg:20 mL/hr/site >40 kg:30 mL/hr/site

20% Liquid

liquid

years [29,30,58-64]. Three ready-to-use liquid preparations of human IgG specifically formulated for subcutaneous infusions have been lisenced in US (Table 7). It can be stored at

> **Stabilizin g agent /PH**

PH 4.85

pH4.6-5.2

**Antimicrobial processes** 

Cohn-Oncley fractionation, Ion exchange chromotography, 35 nmNanofiltration, Solvent-detergen, pH 4, elevated temperature

incubation

filtration Nanofiltration, pH4.0incubation TSE reduction steps include; Octonic acid fractionation, Depth filtration and virus

filtration

precipitation, pasteurization, Diafiltered and ultrafiltered

3mg/mL none Cold alcohol fractionation,

Cold alcohol fractionation, Octonic acid fractionation Anion exchange chromatography,Depth

Ethanol-fatty alcohol/pH

**IgA µg/mL** 

<50 380

<1700 μg/mL 445

 37 **Osmolarity mOsm/kg** 

240-300

**Sodium Content** 

Trace <10mmol/L

none glycine

**Table 7.** Commercial subcutaneous IG Products(Immune deficiency Foundation, October 2011)

The infusion can be applied through fine butterfly needles under the skin into the abdomen or thighs. Infusion pumps are used to administer the infusions and usually take 45 to 90 minutes. The amount of fluid given weekly to babies and children is 10 mls per site and 30 mls per site for older children. Subcutaneous infusion of 10-20% immunoglobulin, with the rate of 0.05-0.20 ml/kg/hour is advised. The recommended maintenance dose is 100 mg/kg/week. Immunoglobulin trough levels should be >5 g/L for patients with agammaglobulinaemia and 3 g/L greater than the initial IgG level for patients with CVID; however, the clinical response should be consider in choosing the dose and trough level [24]. Parents and patients can be educated on how to infuse the preparation at home. These infusions are better tolerated compared to IVIG and time sparing (home administration). Subcutaneous infusions are recommended to patients who are small children or reactive to

Bioavailability and pharmacokinetics properties of subcutaneous IgG (SCIG) differs from intravenous IgG (IVIG). There are still debates about how the dose should be adjusted when Safety and therapeutic efficacy of subcutaneous immunoglobulin products has been demonstrated in children and pregnant women. Therapeutic efficacy of intravenous or subcutaneous immunoglobulin treatment in reducing infections was equal [5,28,57,65,66]. In an international study performed by Chapel et al. the efficacy of immunoglobulin replacement therapy given via intravenously or subcutaneously in patients with PAD was compared [60]. Forty patients received subcutaneous or intravenous immunoglobulin for the first year and switched to the alternative treatment in the second year, and the study showed that there was no difference in efficacy and adverse reactions between both routes. In another study, Fasth A et al. used a 16%, ready-to-use human normal immunoglobulin solution subcutaneously in children with PID previously receiving regular IVIG treatment, and the study showed that mild injection reactions were the adverse effects of the treatment, and the rate of bacterial infections was not different between both IVIG treatments. In the at home treatment there were fewer missed school days, low healthcare expenses [62].

The cost effectiveness of the use of subcutaneous IG compared to IVIG therapy had been investigated in several studies [67,68]. The mean cost of both immunoglobulins was evaluated in the study performed by Beaute J et al. and they showed that monthly doses were equal for both routes of administration. In addition SCIG and IVIG (hospital-based) costs were also similar, but the costs may differ from one country to another [52]. Although this theoretical model showed little difference between the costs, SCIG seems to be expensive compared to IVIG due to the doses of immunoglobulin, but further studies are needed. Overall costs may be higher in CVID, because these patients need higher doses of immunoglobulin [21,52].

The SCIG home therapy was reported to give better health and improved school/social functioning for the children, reduced emotional distress and limitations on personal time for the parents and fewer limitations on family activities [58-64]. Pharmacokinetic studies reveal a more physiologic profile, in peak and trough levels of serum IgG [62,66]. Local tissue reactions are more frequent but the systemic side effect profile is low. Local tissue reactions are often mild and tend to improve over time. Adults switching therapy reported improved vitality, mental health, and social functioning. Treatment satisfaction (TS) scores and healthrelated quality of life (HRQOL) was improved in adults and children with immunodeficiency [69].

Immunoglobulin Treatment of Immunodeficient Patients 107

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According to ESID registry (http://www.esid.org), 4462 of 10,039 patients with PID receive IgG replacement (74% intravenous, 26% subcutaneous, <0.5% intramuscular). There is a wide variety of frequency of subcutaneous IgG replacement therapy in European countries. Sweden was the first country to deliver IgG via the SC route, therefore more than 80% of all patients with antibody deficiencies receive SCIg [3].
