CIDRC

Immune Globulin Intravenous (Human) - ifas 10% Liquid Preparation

REPRINT E N C L O SE D

The First and Only IVIg Therapy With 2 FDA-approved Maintenance Dosing Options for CIDP in Adults

Cornblath DR, van Doorn PA, Hartung H-P, et al, and the ProCID Investigators.

Brain. 2022 Jan 17:awab422. doi: 10.1093/brain/awab422. Epub ahead of print. PMID: 35038723.

“In summary, the ProCID study demonstrated that 1.0 g/kg IVIg is efficacious and well tolerated as maintenance treatment Panzyga Dosing and Rate of Administration for Patients With CIDP2

following a 2.0 g/kg induction dose in patients with

2 g/kg (20 mL/kg) divided into 2 daily doses (1 g/kg [10 mL/kg] on 2 consecutive days)

INITIAL INFUSION RATE

INTRODUCTION • Treatments for chronic inflammatory demyelinating polyneuropathy (CIDP) include intravenous immunoglobulin (IVIg), corticosteroids, and plasma exchange. Where available, IVIg is most frequently used as first-line treatment, usually starting with an induction dose of 2.0 g/kg over 2 to 5 days followed by maintenance dosing of 1.0 g/kg every 3 weeks. No dose-ranging studies with IVIg maintenance therapy have been published • Progress in Chronic Inflammatory Demyelinating polyneuropathy (ProCID) was the largest randomized trial to assess the safety and efficacy of IVIg maintenance therapy in adults with CIDP—and was the first and only IVIg trial to evaluate different (lower and higher) maintenance dosing options for CIPD

active CIDP...”1 LOADING DOSE

Randomized Trial of Three Intravenous Immunoglobulin Doses for Treating Chronic Inflammatory Demyelinating Polyneuropathy

MAINTENANCE DOSE 1 g/kg or 2 g/kg (10-20 mL/kg)

METHODS

every 3 weeks divided in 2 doses given over 2 consecutive days

• Prospective, double-blind, randomized, multicenter, phase 3 study conducted in 142 adults with CIDP

• Treatment: Panzyga (2.0 g/kg induction dose) followed by standard maintenance dose of 1.0 g/kg given every 3 weeks, and two other doses, 0.5 g/kg and 2.0 g/kg over 6 months (24 weeks)

• Primary endpoint: Response rate in the 1.0 g/kg group at week 24, defined

MAXIMUM INFUSION RATE

(first 30 minutes)

(as tolerated)

1 mg/kg/min (0.01 mL/kg/min)

12 mg/kg/min (0.12 mL/kg/min)

as ≥1 point improvement in adjusted INCAT (Inflammatory Neuropathy Cause and Treatment) score at Week 6 vs baseline and maintained at Week 24

• Secondary endpoints: INCAT responses in 0.5 g/kg and 2.0 g/kg arms vs the 1.0 g/kg arm; time to INCAT response; Inflammatory Rasch-built Overall Disability Scale (I-RODS) score; grip strength; Medical Research Council (MRC) score; Pain Intensity Numeric Rating Scale; sum of distal evoked amplitude of 8 motor nerves; safety/tolerability

Contact Octapharma: • In the ProCID study, a loading dose of 2 g/kg of Panzyga was given followed by 7 maintenance infusions every 3 weeks over a period of 6 months

• The initial infusion rate should be maintained for 30 minutes, and if tolerated, the infusion rate may be gradually increased every 15-30 minutes to a maximum of 12 mg/kg/min (0.12 mL/kg/min) as tolerated2

Octapharma USA, Inc. 117 W. Century Road Paramus, NJ 07652 Tel: 201-604-1130

Reimbursement Assistance usreimbursement@octapharma.com Tel: 800-554-4440

Medical Affairs usmedicalaffairs@octapharma.com

For all inquiries relating to drug safety, or to report adverse events, please contact our local Drug Safety Officer: Tel: 201-604-1137 | Cell: 201-772-4546 | Fax: 201-604-1141 or contact the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

www.octapharmausa.com

All patients enrolled in the ProCID study received IVIg induction and maintenance therapy with Panzyga® (Immune Globulin Intravenous [Human] – ifas)

References: 1. Cornblath DR, van Doorn PA, Hartung H-P, et al, and the ProCID Investigators. Brain. 2022 Jan 17:awab422. doi: 10.1093/ brain/awab422. Epub ahead of print. PMID: 35038723. 2. Panzyga full Prescribing Information. Paramus, NJ: Octapharma USA Inc.; 2021.

For additional Important Safety Information, please see full Prescribing Information and Boxed Warning for Panzyga.

©2022. Octapharma USA, Inc. All rights reserved.

Date of preparation: 1/2022. PANZ-0290-PRC

The ProCID study was the first to examine systematically a higher (2.0 g/kg) maintenance dose of IVIg in CIDP and compare efficacy and safety with standard dosing of 1.0 g/kg.1

• All 142 patients were assessed for safety and 139 for efficacy; 121 patients were previously on corticosteroids INDICATION AND USAGE Panzyga (Immune Globulin Intravenous [Human] - ifas) is indicated for the treatment of primary humoral immunodeficiency (PI) in patients 2 years of age and older; this includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies; chronic immune thrombocytopenia (cITP) in adults to raise platelet counts to control or prevent bleeding; and chronic inflammatory demyelinating polyneuropathy (CIDP) in adults to improve neuromuscular disability and impairment.

WARNING: THROMBOSIS, RENAL DYSFUNCTION, AND ACUTE RENAL FAILURE • Thrombosis may occur with immune globulin intravenous (IGIV) products, including Panzyga. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.

• Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in predisposed patients who receive IGIV products, including Panzyga. Patients predisposed to renal dysfunction include those with a degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. Panzyga does not contain sucrose.

• For patients at risk of thrombosis, renal dysfunction, or acute renal failure, administer Panzyga at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. [see Full Prescribing Information, Warnings and Precautions (5.2, 5.4)]

Please see accompanying full Prescribing Information, including Boxed Warning.

Immune Globulin Intravenous (Human) - ifas 10% Liquid Preparation

REPRINT E N C L O SE D

The First and Only IVIg Therapy With 2 FDA-approved Maintenance Dosing Options for CIDP in Adults

Cornblath DR, van Doorn PA, Hartung H-P, et al, and the ProCID Investigators.

Brain. 2022 Jan 17:awab422. doi: 10.1093/brain/awab422. Epub ahead of print. PMID: 35038723.

“In summary, the ProCID study demonstrated that 1.0 g/kg IVIg is efficacious and well tolerated as maintenance treatment Panzyga Dosing and Rate of Administration for Patients With CIDP2

following a 2.0 g/kg induction dose in patients with

2 g/kg (20 mL/kg) divided into 2 daily doses (1 g/kg [10 mL/kg] on 2 consecutive days)

INITIAL INFUSION RATE

INTRODUCTION • Treatments for chronic inflammatory demyelinating polyneuropathy (CIDP) include intravenous immunoglobulin (IVIg), corticosteroids, and plasma exchange. Where available, IVIg is most frequently used as first-line treatment, usually starting with an induction dose of 2.0 g/kg over 2 to 5 days followed by maintenance dosing of 1.0 g/kg every 3 weeks. No dose-ranging studies with IVIg maintenance therapy have been published • Progress in Chronic Inflammatory Demyelinating polyneuropathy (ProCID) was the largest randomized trial to assess the safety and efficacy of IVIg maintenance therapy in adults with CIDP—and was the first and only IVIg trial to evaluate different (lower and higher) maintenance dosing options for CIPD

active CIDP...”1 LOADING DOSE

Randomized Trial of Three Intravenous Immunoglobulin Doses for Treating Chronic Inflammatory Demyelinating Polyneuropathy

MAINTENANCE DOSE 1 g/kg or 2 g/kg (10-20 mL/kg)

METHODS

every 3 weeks divided in 2 doses given over 2 consecutive days

• Prospective, double-blind, randomized, multicenter, phase 3 study conducted in 142 adults with CIDP

• Treatment: Panzyga (2.0 g/kg induction dose) followed by standard maintenance dose of 1.0 g/kg given every 3 weeks, and two other doses, 0.5 g/kg and 2.0 g/kg over 6 months (24 weeks)

• Primary endpoint: Response rate in the 1.0 g/kg group at week 24, defined

MAXIMUM INFUSION RATE

(first 30 minutes)

(as tolerated)

1 mg/kg/min (0.01 mL/kg/min)

12 mg/kg/min (0.12 mL/kg/min)

as ≥1 point improvement in adjusted INCAT (Inflammatory Neuropathy Cause and Treatment) score at Week 6 vs baseline and maintained at Week 24

• Secondary endpoints: INCAT responses in 0.5 g/kg and 2.0 g/kg arms vs the 1.0 g/kg arm; time to INCAT response; Inflammatory Rasch-built Overall Disability Scale (I-RODS) score; grip strength; Medical Research Council (MRC) score; Pain Intensity Numeric Rating Scale; sum of distal evoked amplitude of 8 motor nerves; safety/tolerability

Contact Octapharma: • In the ProCID study, a loading dose of 2 g/kg of Panzyga was given followed by 7 maintenance infusions every 3 weeks over a period of 6 months

• The initial infusion rate should be maintained for 30 minutes, and if tolerated, the infusion rate may be gradually increased every 15-30 minutes to a maximum of 12 mg/kg/min (0.12 mL/kg/min) as tolerated2

Octapharma USA, Inc. 117 W. Century Road Paramus, NJ 07652 Tel: 201-604-1130

Reimbursement Assistance usreimbursement@octapharma.com Tel: 800-554-4440

Medical Affairs usmedicalaffairs@octapharma.com

For all inquiries relating to drug safety, or to report adverse events, please contact our local Drug Safety Officer: Tel: 201-604-1137 | Cell: 201-772-4546 | Fax: 201-604-1141 or contact the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

www.octapharmausa.com

All patients enrolled in the ProCID study received IVIg induction and maintenance therapy with Panzyga® (Immune Globulin Intravenous [Human] – ifas)

References: 1. Cornblath DR, van Doorn PA, Hartung H-P, et al, and the ProCID Investigators. Brain. 2022 Jan 17:awab422. doi: 10.1093/ brain/awab422. Epub ahead of print. PMID: 35038723. 2. Panzyga full Prescribing Information. Paramus, NJ: Octapharma USA Inc.; 2021.

For additional Important Safety Information, please see full Prescribing Information and Boxed Warning for Panzyga.

©2022. Octapharma USA, Inc. All rights reserved.

Date of preparation: 1/2022. PANZ-0290-PRC

The ProCID study was the first to examine systematically a higher (2.0 g/kg) maintenance dose of IVIg in CIDP and compare efficacy and safety with standard dosing of 1.0 g/kg.1

• All 142 patients were assessed for safety and 139 for efficacy; 121 patients were previously on corticosteroids INDICATION AND USAGE Panzyga (Immune Globulin Intravenous [Human] - ifas) is indicated for the treatment of primary humoral immunodeficiency (PI) in patients 2 years of age and older; this includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies; chronic immune thrombocytopenia (cITP) in adults to raise platelet counts to control or prevent bleeding; and chronic inflammatory demyelinating polyneuropathy (CIDP) in adults to improve neuromuscular disability and impairment.

WARNING: THROMBOSIS, RENAL DYSFUNCTION, AND ACUTE RENAL FAILURE • Thrombosis may occur with immune globulin intravenous (IGIV) products, including Panzyga. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.

• Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in predisposed patients who receive IGIV products, including Panzyga. Patients predisposed to renal dysfunction include those with a degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. Panzyga does not contain sucrose.

• For patients at risk of thrombosis, renal dysfunction, or acute renal failure, administer Panzyga at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. [see Full Prescribing Information, Warnings and Precautions (5.2, 5.4)]

Please see accompanying full Prescribing Information, including Boxed Warning.

ProCID STUDY RESULTS Immune Globulin Intravenous (Human) - ifas 10% Liquid Preparation

PRIMARY ENDPOINT: 80% of Patients Receiving a Standard 1 g/kg Maintenance Panzyga Dose Achieved an INCAT Response at 6 Months

Similar Incremental Improvements in Response Rates Were Observed for Secondary Efficacy Variables

INCAT Responder Rates

Incidence of Related Treatment Emergent Adverse Events (TEAEs) Was Similar Across Treatment Arms (Except for Headaches, Which Was Dose Related)

Responder Rates By Panzyga Maintenance Dosing*

1.0 g/kg

2.0 g/kg

32 (46%)

20 (53%)

TEAEs, n

80

56

Infusions, n

482

270

0.5 g/kg

(n=69)

2 g/kg (n=38)

PANZYGA MAINTENANCE DOSE

1 g/kg

PRIMARY ENDPOINT

80%

10

20

30

40

50

60

70

80

90

I-RODS

(n=69)

Patients, n (%)

55%

2 g/kg

72%

(n=38)

92% 0

1 g/kg

100

RESPONDER RATE (% OF PATIENTS)

PANZYGA MAINTENANCE DOSE

(n=35)

Grip Strength

65%

MRC Sum Score

83%

72%

• Median time to INCAT improvement: 1 g/kg arm, 26 days; 2 g/kg arm, 23 days • In patients previously on corticosteroids or Ig therapy, overall response rate was 82% and 61%, respectively • INCAT responder rates increased as the maintenance dose increased, although the effect was driven by a significant difference between the 0.5 and 2.0 g/kg groups (P=0.04) • Odds ratio analysis of the effect of treatement group on response showed overlapping confidence intervals

0

10

20

30

40

50

60

70

NOTE: These were secondary study endpoints only and not included in final approved labeling.

80

86% 90

100

RESPONDER RATE (% OF PATIENTS)

*Responders defined as: I-RODS=Scores using minimum clinically important difference related to the varying standard errors (MCID-SE).

Grip Strength=Minimum clinically important difference (MCID) cut-off of 8 kPa. MRC Sum Scores=Increase of at least 4 points compared with baseline.

• Pain Intensity Numeric Rating Scale score increased during the wash-out phase, then tended to decrease through Week 24.

Mean changes from baseline were -2.2 and -2.2 in the 1.0 and 2.0 g/kg groups, respectively

0.5 g/kg versus 1.0 g/kg

2.0 g/kg versus 0.5 g/kg

2.0 g/kg versus 1.0 g/kg

Adjusted INCAT Score

0.5 (0.2–1.2)

5.8 (1.4–23.6)

2.7 (0.7–10.2)

• There were no clear trends over time in the nerve conduction studies

Grip Strength

0.6 (0.3–1.4)

4.2 (1.4–13.3)

2.5 (0.9–7.0)

• Of the 29 non-responders in the study:

I-RODS

0.5 (0.2–1.3)

3.9 (1.4–10.8)

2.1 (0.8–5.0)

– 22 were on prior corticosteroids

– 11 remained on corticosteroids during the study

MRC Sum Score

0.6 (0.2–1.4)

4.1 (1.2–13.2)

2.3 (0.8–6.7)

– 13 received rescue treatment

– 16 withdrew from the study

– 7 were in the 1.0 g/kg group

– Only 3 were in the 2.0 g/kg group

• Of the 16 non-responders who withdrew, 7 were in the 1.0 g/kg group, and 3 in the 2.0 g/kg group. At the time of early termination, a 51-point improvement in adjusted INCAT scores had been achieved by 5/7 patients in the 1.0 g/kg group, and none of the 3 patients in the 2.0 g/kg group

On Average, Headache Was Reported in 15% of Patients Across All Panzyga Dosing Arms Most commonly

15%

8%

9%

5%

5%

Headache

Fever

Dermatitis

Blood Pressure Increase

Increased Body Temperature

reported related TEAEs across all treatment arms

• Headache was most prevalent in the 1.0 and 2.0 g/kg arms (15% and 24%) • The only TEAE where a dose effect was apparent was headache: 3% in the 0.5 g/kg arm, 14.5% in the 1.0 g/kg arm, and 24% in the 2.0 g/kg group • There were no treatment-related deaths. Two serious adverse reactions (headache and vomiting) were reported in 1 patient but did not lead to discontinuation

“Treatment was well tolerated even in IgG-naïve patients and in those regularly treated with high dose IVIg.”1

Contraindications Panzyga is contraindicated in patients who have a history of severe systemic hypersensitivity reactions, such as anaphylaxis, to human immunoglobulin and in IgA-deficient patients with antibodies against IgA and history of hypersensitivity.

Warnings and Precautions Monitor renal function, including blood urea nitrogen and serum creatinine, and urine output in patients at risk of developing acute renal failure.

Hyperproteinemia, increased serum osmolarity, and hyponatremia may occur in patients receiving Panzyga.

Aseptic meningitis syndrome may occur in patients receiving Panzyga, especially with high doses or rapid infusion.

Warnings and Precautions Carefully consider the relative risks and benefits before prescribing the high dose regimen (for cITP) in patients at increased risk of volume overload.

Panzyga is made from human plasma and may contain infectious agents, e.g. viruses and theoretically, the Creutzfeldt-Jakob disease agent.

Adverse Reactions PI—most common adverse reactions (≥5% study subjects): headache, nausea, fever, fatigue, abdominal pain. cITP in adults—most common adverse reactions (≥5% study subjects): headache, fever, nausea, vomiting, dizziness, anemia.

CIDP in adults—The most common adverse reactions reported in greater than 5% of subjects were: headache, fever, dermatitis, and blood pressure increased.

Please see accompanying full Prescribing Information, including Boxed Warning.

Please see accompanying full Prescribing Information, including Boxed Warning.

Please see accompanying full Prescribing Information, including Boxed Warning.

ProCID STUDY RESULTS Immune Globulin Intravenous (Human) - ifas 10% Liquid Preparation

PRIMARY ENDPOINT: 80% of Patients Receiving a Standard 1 g/kg Maintenance Panzyga Dose Achieved an INCAT Response at 6 Months

Similar Incremental Improvements in Response Rates Were Observed for Secondary Efficacy Variables

INCAT Responder Rates

Incidence of Related Treatment Emergent Adverse Events (TEAEs) Was Similar Across Treatment Arms (Except for Headaches, Which Was Dose Related)

Responder Rates By Panzyga Maintenance Dosing*

1.0 g/kg

2.0 g/kg

32 (46%)

20 (53%)

TEAEs, n

80

56

Infusions, n

482

270

0.5 g/kg

(n=69)

2 g/kg (n=38)

PANZYGA MAINTENANCE DOSE

1 g/kg

PRIMARY ENDPOINT

80%

10

20

30

40

50

60

70

80

90

I-RODS

(n=69)

Patients, n (%)

55%

2 g/kg

72%

(n=38)

92% 0

1 g/kg

100

RESPONDER RATE (% OF PATIENTS)

PANZYGA MAINTENANCE DOSE

(n=35)

Grip Strength

65%

MRC Sum Score

83%

72%

• Median time to INCAT improvement: 1 g/kg arm, 26 days; 2 g/kg arm, 23 days • In patients previously on corticosteroids or Ig therapy, overall response rate was 82% and 61%, respectively • INCAT responder rates increased as the maintenance dose increased, although the effect was driven by a significant difference between the 0.5 and 2.0 g/kg groups (P=0.04) • Odds ratio analysis of the effect of treatement group on response showed overlapping confidence intervals

0

10

20

30

40

50

60

70

NOTE: These were secondary study endpoints only and not included in final approved labeling.

80

86% 90

100

RESPONDER RATE (% OF PATIENTS)

*Responders defined as: I-RODS=Scores using minimum clinically important difference related to the varying standard errors (MCID-SE).

Grip Strength=Minimum clinically important difference (MCID) cut-off of 8 kPa. MRC Sum Scores=Increase of at least 4 points compared with baseline.

• Pain Intensity Numeric Rating Scale score increased during the wash-out phase, then tended to decrease through Week 24.

Mean changes from baseline were -2.2 and -2.2 in the 1.0 and 2.0 g/kg groups, respectively

0.5 g/kg versus 1.0 g/kg

2.0 g/kg versus 0.5 g/kg

2.0 g/kg versus 1.0 g/kg

Adjusted INCAT Score

0.5 (0.2–1.2)

5.8 (1.4–23.6)

2.7 (0.7–10.2)

• There were no clear trends over time in the nerve conduction studies

Grip Strength

0.6 (0.3–1.4)

4.2 (1.4–13.3)

2.5 (0.9–7.0)

• Of the 29 non-responders in the study:

I-RODS

0.5 (0.2–1.3)

3.9 (1.4–10.8)

2.1 (0.8–5.0)

– 22 were on prior corticosteroids

– 11 remained on corticosteroids during the study

MRC Sum Score

0.6 (0.2–1.4)

4.1 (1.2–13.2)

2.3 (0.8–6.7)

– 13 received rescue treatment

– 16 withdrew from the study

– 7 were in the 1.0 g/kg group

– Only 3 were in the 2.0 g/kg group

• Of the 16 non-responders who withdrew, 7 were in the 1.0 g/kg group, and 3 in the 2.0 g/kg group. At the time of early termination, a 51-point improvement in adjusted INCAT scores had been achieved by 5/7 patients in the 1.0 g/kg group, and none of the 3 patients in the 2.0 g/kg group

On Average, Headache Was Reported in 15% of Patients Across All Panzyga Dosing Arms Most commonly

15%

8%

9%

5%

5%

Headache

Fever

Dermatitis

Blood Pressure Increase

Increased Body Temperature

reported related TEAEs across all treatment arms

• Headache was most prevalent in the 1.0 and 2.0 g/kg arms (15% and 24%) • The only TEAE where a dose effect was apparent was headache: 3% in the 0.5 g/kg arm, 14.5% in the 1.0 g/kg arm, and 24% in the 2.0 g/kg group • There were no treatment-related deaths. Two serious adverse reactions (headache and vomiting) were reported in 1 patient but did not lead to discontinuation

“Treatment was well tolerated even in IgG-naïve patients and in those regularly treated with high dose IVIg.”1

Contraindications Panzyga is contraindicated in patients who have a history of severe systemic hypersensitivity reactions, such as anaphylaxis, to human immunoglobulin and in IgA-deficient patients with antibodies against IgA and history of hypersensitivity.

Warnings and Precautions Monitor renal function, including blood urea nitrogen and serum creatinine, and urine output in patients at risk of developing acute renal failure.

Hyperproteinemia, increased serum osmolarity, and hyponatremia may occur in patients receiving Panzyga.

Aseptic meningitis syndrome may occur in patients receiving Panzyga, especially with high doses or rapid infusion.

Warnings and Precautions Carefully consider the relative risks and benefits before prescribing the high dose regimen (for cITP) in patients at increased risk of volume overload.

Panzyga is made from human plasma and may contain infectious agents, e.g. viruses and theoretically, the Creutzfeldt-Jakob disease agent.

Adverse Reactions PI—most common adverse reactions (≥5% study subjects): headache, nausea, fever, fatigue, abdominal pain. cITP in adults—most common adverse reactions (≥5% study subjects): headache, fever, nausea, vomiting, dizziness, anemia.

CIDP in adults—The most common adverse reactions reported in greater than 5% of subjects were: headache, fever, dermatitis, and blood pressure increased.

Please see accompanying full Prescribing Information, including Boxed Warning.

Please see accompanying full Prescribing Information, including Boxed Warning.

Please see accompanying full Prescribing Information, including Boxed Warning.

ProCID STUDY RESULTS Immune Globulin Intravenous (Human) - ifas 10% Liquid Preparation

PRIMARY ENDPOINT: 80% of Patients Receiving a Standard 1 g/kg Maintenance Panzyga Dose Achieved an INCAT Response at 6 Months

Similar Incremental Improvements in Response Rates Were Observed for Secondary Efficacy Variables

INCAT Responder Rates

Incidence of Related Treatment Emergent Adverse Events (TEAEs) Was Similar Across Treatment Arms (Except for Headaches, Which Was Dose Related)

Responder Rates By Panzyga Maintenance Dosing*

1.0 g/kg

2.0 g/kg

32 (46%)

20 (53%)

TEAEs, n

80

56

Infusions, n

482

270

0.5 g/kg

(n=69)

2 g/kg (n=38)

PANZYGA MAINTENANCE DOSE

1 g/kg

PRIMARY ENDPOINT

80%

10

20

30

40

50

60

70

80

90

I-RODS

(n=69)

Patients, n (%)

55%

2 g/kg

72%

(n=38)

92% 0

1 g/kg

100

RESPONDER RATE (% OF PATIENTS)

PANZYGA MAINTENANCE DOSE

(n=35)

Grip Strength

65%

MRC Sum Score

83%

72%

• Median time to INCAT improvement: 1 g/kg arm, 26 days; 2 g/kg arm, 23 days • In patients previously on corticosteroids or Ig therapy, overall response rate was 82% and 61%, respectively • INCAT responder rates increased as the maintenance dose increased, although the effect was driven by a significant difference between the 0.5 and 2.0 g/kg groups (P=0.04) • Odds ratio analysis of the effect of treatement group on response showed overlapping confidence intervals

0

10

20

30

40

50

60

70

NOTE: These were secondary study endpoints only and not included in final approved labeling.

80

86% 90

100

RESPONDER RATE (% OF PATIENTS)

*Responders defined as: I-RODS=Scores using minimum clinically important difference related to the varying standard errors (MCID-SE).

Grip Strength=Minimum clinically important difference (MCID) cut-off of 8 kPa. MRC Sum Scores=Increase of at least 4 points compared with baseline.

• Pain Intensity Numeric Rating Scale score increased during the wash-out phase, then tended to decrease through Week 24.

Mean changes from baseline were -2.2 and -2.2 in the 1.0 and 2.0 g/kg groups, respectively

0.5 g/kg versus 1.0 g/kg

2.0 g/kg versus 0.5 g/kg

2.0 g/kg versus 1.0 g/kg

Adjusted INCAT Score

0.5 (0.2–1.2)

5.8 (1.4–23.6)

2.7 (0.7–10.2)

• There were no clear trends over time in the nerve conduction studies

Grip Strength

0.6 (0.3–1.4)

4.2 (1.4–13.3)

2.5 (0.9–7.0)

• Of the 29 non-responders in the study:

I-RODS

0.5 (0.2–1.3)

3.9 (1.4–10.8)

2.1 (0.8–5.0)

– 22 were on prior corticosteroids

– 11 remained on corticosteroids during the study

MRC Sum Score

0.6 (0.2–1.4)

4.1 (1.2–13.2)

2.3 (0.8–6.7)

– 13 received rescue treatment

– 16 withdrew from the study

– 7 were in the 1.0 g/kg group

– Only 3 were in the 2.0 g/kg group

• Of the 16 non-responders who withdrew, 7 were in the 1.0 g/kg group, and 3 in the 2.0 g/kg group. At the time of early termination, a 51-point improvement in adjusted INCAT scores had been achieved by 5/7 patients in the 1.0 g/kg group, and none of the 3 patients in the 2.0 g/kg group

On Average, Headache Was Reported in 15% of Patients Across All Panzyga Dosing Arms Most commonly

15%

8%

9%

5%

5%

Headache

Fever

Dermatitis

Blood Pressure Increase

Increased Body Temperature

reported related TEAEs across all treatment arms

• Headache was most prevalent in the 1.0 and 2.0 g/kg arms (15% and 24%) • The only TEAE where a dose effect was apparent was headache: 3% in the 0.5 g/kg arm, 14.5% in the 1.0 g/kg arm, and 24% in the 2.0 g/kg group • There were no treatment-related deaths. Two serious adverse reactions (headache and vomiting) were reported in 1 patient but did not lead to discontinuation

“Treatment was well tolerated even in IgG-naïve patients and in those regularly treated with high dose IVIg.”1

Contraindications Panzyga is contraindicated in patients who have a history of severe systemic hypersensitivity reactions, such as anaphylaxis, to human immunoglobulin and in IgA-deficient patients with antibodies against IgA and history of hypersensitivity.

Warnings and Precautions Monitor renal function, including blood urea nitrogen and serum creatinine, and urine output in patients at risk of developing acute renal failure.

Hyperproteinemia, increased serum osmolarity, and hyponatremia may occur in patients receiving Panzyga.

Aseptic meningitis syndrome may occur in patients receiving Panzyga, especially with high doses or rapid infusion.

Warnings and Precautions Carefully consider the relative risks and benefits before prescribing the high dose regimen (for cITP) in patients at increased risk of volume overload.

Panzyga is made from human plasma and may contain infectious agents, e.g. viruses and theoretically, the Creutzfeldt-Jakob disease agent.

Adverse Reactions PI—most common adverse reactions (≥5% study subjects): headache, nausea, fever, fatigue, abdominal pain. cITP in adults—most common adverse reactions (≥5% study subjects): headache, fever, nausea, vomiting, dizziness, anemia.

CIDP in adults—The most common adverse reactions reported in greater than 5% of subjects were: headache, fever, dermatitis, and blood pressure increased.

Please see accompanying full Prescribing Information, including Boxed Warning.

Please see accompanying full Prescribing Information, including Boxed Warning.

Please see accompanying full Prescribing Information, including Boxed Warning.

Immune Globulin Intravenous (Human) - ifas 10% Liquid Preparation

REPRINT E N C L O SE D

The First and Only IVIg Therapy With 2 FDA-approved Maintenance Dosing Options for CIDP in Adults

Cornblath DR, van Doorn PA, Hartung H-P, et al, and the ProCID Investigators.

Brain. 2022 Jan 17:awab422. doi: 10.1093/brain/awab422. Epub ahead of print. PMID: 35038723.

“In summary, the ProCID study demonstrated that 1.0 g/kg IVIg is efficacious and well tolerated as maintenance treatment Panzyga Dosing and Rate of Administration for Patients With CIDP2

following a 2.0 g/kg induction dose in patients with

2 g/kg (20 mL/kg) divided into 2 daily doses (1 g/kg [10 mL/kg] on 2 consecutive days)

INITIAL INFUSION RATE

INTRODUCTION • Treatments for chronic inflammatory demyelinating polyneuropathy (CIDP) include intravenous immunoglobulin (IVIg), corticosteroids, and plasma exchange. Where available, IVIg is most frequently used as first-line treatment, usually starting with an induction dose of 2.0 g/kg over 2 to 5 days followed by maintenance dosing of 1.0 g/kg every 3 weeks. No dose-ranging studies with IVIg maintenance therapy have been published • Progress in Chronic Inflammatory Demyelinating polyneuropathy (ProCID) was the largest randomized trial to assess the safety and efficacy of IVIg maintenance therapy in adults with CIDP—and was the first and only IVIg trial to evaluate different (lower and higher) maintenance dosing options for CIPD

active CIDP...”1 LOADING DOSE

Randomized Trial of Three Intravenous Immunoglobulin Doses for Treating Chronic Inflammatory Demyelinating Polyneuropathy

MAINTENANCE DOSE 1 g/kg or 2 g/kg (10-20 mL/kg)

METHODS

every 3 weeks divided in 2 doses given over 2 consecutive days

• Prospective, double-blind, randomized, multicenter, phase 3 study conducted in 142 adults with CIDP

• Treatment: Panzyga (2.0 g/kg induction dose) followed by standard maintenance dose of 1.0 g/kg given every 3 weeks, and two other doses, 0.5 g/kg and 2.0 g/kg over 6 months (24 weeks)

• Primary endpoint: Response rate in the 1.0 g/kg group at week 24, defined

MAXIMUM INFUSION RATE

(first 30 minutes)

(as tolerated)

1 mg/kg/min (0.01 mL/kg/min)

12 mg/kg/min (0.12 mL/kg/min)

as ≥1 point improvement in adjusted INCAT (Inflammatory Neuropathy Cause and Treatment) score at Week 6 vs baseline and maintained at Week 24

• Secondary endpoints: INCAT responses in 0.5 g/kg and 2.0 g/kg arms vs the 1.0 g/kg arm; time to INCAT response; Inflammatory Rasch-built Overall Disability Scale (I-RODS) score; grip strength; Medical Research Council (MRC) score; Pain Intensity Numeric Rating Scale; sum of distal evoked amplitude of 8 motor nerves; safety/tolerability

Contact Octapharma: • In the ProCID study, a loading dose of 2 g/kg of Panzyga was given followed by 7 maintenance infusions every 3 weeks over a period of 6 months

• The initial infusion rate should be maintained for 30 minutes, and if tolerated, the infusion rate may be gradually increased every 15-30 minutes to a maximum of 12 mg/kg/min (0.12 mL/kg/min) as tolerated2

Octapharma USA, Inc. 117 W. Century Road Paramus, NJ 07652 Tel: 201-604-1130

Reimbursement Assistance usreimbursement@octapharma.com Tel: 800-554-4440

Medical Affairs usmedicalaffairs@octapharma.com

For all inquiries relating to drug safety, or to report adverse events, please contact our local Drug Safety Officer: Tel: 201-604-1137 | Cell: 201-772-4546 | Fax: 201-604-1141 or contact the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

www.octapharmausa.com

All patients enrolled in the ProCID study received IVIg induction and maintenance therapy with Panzyga® (Immune Globulin Intravenous [Human] – ifas)

References: 1. Cornblath DR, van Doorn PA, Hartung H-P, et al, and the ProCID Investigators. Brain. 2022 Jan 17:awab422. doi: 10.1093/ brain/awab422. Epub ahead of print. PMID: 35038723. 2. Panzyga full Prescribing Information. Paramus, NJ: Octapharma USA Inc.; 2021.

For additional Important Safety Information, please see full Prescribing Information and Boxed Warning for Panzyga.

©2022. Octapharma USA, Inc. All rights reserved.

Date of preparation: 1/2022. PANZ-0290-PRC

The ProCID study was the first to examine systematically a higher (2.0 g/kg) maintenance dose of IVIg in CIDP and compare efficacy and safety with standard dosing of 1.0 g/kg.1

• All 142 patients were assessed for safety and 139 for efficacy; 121 patients were previously on corticosteroids INDICATION AND USAGE Panzyga (Immune Globulin Intravenous [Human] - ifas) is indicated for the treatment of primary humoral immunodeficiency (PI) in patients 2 years of age and older; this includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies; chronic immune thrombocytopenia (cITP) in adults to raise platelet counts to control or prevent bleeding; and chronic inflammatory demyelinating polyneuropathy (CIDP) in adults to improve neuromuscular disability and impairment.

WARNING: THROMBOSIS, RENAL DYSFUNCTION, AND ACUTE RENAL FAILURE • Thrombosis may occur with immune globulin intravenous (IGIV) products, including Panzyga. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.

• Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in predisposed patients who receive IGIV products, including Panzyga. Patients predisposed to renal dysfunction include those with a degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. Panzyga does not contain sucrose.

• For patients at risk of thrombosis, renal dysfunction, or acute renal failure, administer Panzyga at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. [see Full Prescribing Information, Warnings and Precautions (5.2, 5.4)]

Please see accompanying full Prescribing Information, including Boxed Warning.

https://doi.org/10.1093/brain/awab422

BRAIN 2022: Page 1 of 10

| 1

David R. Cornblath,1 Pieter A. van Doorn,2 Hans-Peter Hartung,3,4,5,6 Ingemar S. J. Merkies,7,8 Hans D. Katzberg,9 Doris Hinterberger,10 Elisabeth Clodi10 and the ProCID Investigators

Intravenous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy usually starts with a 2.0 g/kg induction dose followed by 1.0 g/kg maintenance doses every 3 weeks. No dose-ranging studies with intravenous immunoglobulin maintenance therapy have been published.

The Progress in Chronic Inflammatory Demyelinating polyneuropathy (ProCID) study was a prospective, doubleblind, randomized, parallel-group, multicentre, phase III study investigating the efficacy and safety of 10% liquid intravenous immunoglobulin (PanzygaV) in patients with active chronic inflammatory demyelinating polyneuropathy. Patients were randomized 1:2:1 to receive the standard intravenous immunoglobulin induction dose and then either 0.5, 1.0 or 2.0 g/kg maintenance doses every 3 weeks. The primary end point was the response rate in the 1.0 g/kg group, defined as an improvement 51 point in adjusted Inflammatory Neuropathy Cause and Treatment score at Week 6 versus baseline and maintained at Week 24. Secondary end points included dose response and safety. This trial was registered with EudraCT (Number 2015–005443-14) and clinicaltrials.gov (NCT02638207).

Between August 2017 and September 2019, the study enrolled 142 patients. All 142 were included in the safety analyses. As no post-infusion data were available for three patients, 139 were included in the efficacy analyses, of whom 121 were previously on corticosteroids. The response rate was 80% (55/69 patients) [95% confidence interval (CI): 69–88%] in the 1.0 g/kg group, 65% (22/34; CI: 48–79%) in the 0.5 g/kg group, and 92% (33/36; CI: 78–97%) in the 2.0 g/kg group. While the proportion of responders was higher with higher maintenance doses, logistic regression analysis showed that the effect on response rate was driven by a significant difference between the 0.5 and 2.0 g/ kg groups, whereas the response rates in the 0.5 and 2.0 g/kg groups did not differ significantly from the 1.0 g/kg group. Fifty-six per cent of all patients had an adjusted Inflammatory Neuropathy Cause and Treatment score improvement 3 weeks after the induction dose alone. Treatment-related adverse events were reported in 16 (45.7%), 32 (46.4%) and 20 (52.6%) patients in the 0.5, 1.0 and 2.0 g/kg dose groups, respectively. The most common adverse reaction was headache. There were no treatment-related deaths.

Intravenous immunoglobulin (1.0 g/kg) was efficacious and well tolerated as maintenance treatment for patients with chronic inflammatory demyelinating polyneuropathy. Further studies of different maintenance doses of intravenous immunoglobulin in chronic inflammatory demyelinating polyneuropathy are warranted.

R

1 2 3 4 5

Department of Neurology, Johns Hopkins University, Baltimore, MD 21287, USA Department of Neurology, Erasmus University Medical Center, Rotterdam 3015CE, The Netherlands Department of Neurology, Heinrich Heine University, Düsseldorf 40225, Germany Brain and Mind Center, University of Sydney, Sydney, NSW 2050, Australia Department of Neurology, Medical University of Vienna, Vienna 1090, Austria

Received August 16, 2021. Revised October 15, 2021. Accepted November 09, 2021. Advance access publication January 17, 2022 C The Author(s) (2022). Published by Oxford University Press on behalf of the Guarantors of Brain.

V

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/ by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

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Randomized trial of three IVIg doses for treating chronic inflammatory demyelinating polyneuropathy

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| BRAIN 2022: Page 2 of 10

D. R. Cornblath et al.

6 Department of Neurology, Palacky University, Olomouc 771 47, Czech Republic 7 Department of Neurology, Maastricht University Medical Center, Maastricht 6229 HX, The Netherlands 8 Curaçao Medical Center, Willemstad, Curaçao 9 Department of Neurology, University of Toronto, Toronto M5G 2C4, Canada 10 Clinical R&D, Octapharma PPG, Vienna 1100, Austria

Keywords: chronic inflammatory demyelinating polyneuropathy; intravenous immunoglobulin; ProCID study; R

panzygaV; randomized controlled trial

Abbreviations: CIDP = chronic inflammatory demyelinating polyneuropathy; I-RODS = Inflammatory Rasch-built Overall Disability Scale; INCAT = Inflammatory Neuropathy Cause and Treatment; IVIg = intravenous immunoglobulin; MRC = Medical Research Council; ProCID = progress in chronic inflammatory demyelinating polyneuropathy; TEAE = treatment-emergent adverse events

Introduction Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, auto-immune mediated polyneuropathy and can be diagnosed using guidelines from the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS).1,2 However, the diagnosis of CIDP is not straightforward,3 and a number of disorders can be mistaken for CIDP.4 Three treatments have been proven effective for CIDP: intravenous immunoglobulin (IVIg), corticosteroids, and plasma exchange.5 Where available, IVIg is the most frequently used first-line treatment due to its safety and efficacy. Based on several clinical studies, treatment with IVIg in CIDP usually starts with an induction dose of 2.0 g/kg over 2 to 5 days followed by maintenance dosing of 1.0 g/kg every 3 weeks.6–8 The optimal maintenance dose may vary between patients, and the EFNS/PNS guidelines recommend that the maintenance dose may need to be adjusted to suit an individual patient’s needs.2 Whilst tailored dosing has been long advocated and is supported by retrospective and real-life data,9–12 there have been no randomized, prospective trials evaluating different IVIg maintenance dose regimens in patients with CIDP. Only one small open, randomized study has evaluated different induction doses of IVIg for CIDP and multifocal motor neuropathy, and the results showed a potential dose-related effect 5 weeks after induction treatment.13 The PATH study evaluated two doses of subcutaneous immunoglobulin (SCIg), 0.2 and 0.4 g/kg every week, in patients with CIDP and showed no significant differences in outcomes between those two SCIg doses during a study period of 24 weeks.14 The Progress in Chronic Inflammatory Demyelinating polyneuropathy (ProCID) study investigated the efficacy and safety of IVIg after a 2.0 g/kg induction dose followed by a standard maintenance dose of 1.0 g/kg given every 3 weeks, and two other doses, 0.5 g/kg and 2.0 g/kg, on outcomes in patients with CIDP during a study period of 24 weeks.

Materials and methods Study drug R

IVIg (PanzygaV, Octapharma) is a glycine-stabilized 10% liquid human IVIg15,16 with proven efficacy and safety as replacement

therapy in primary immunodeficiency17 and for immunomodulation in patients with immune thrombocytopenic purpura.18 This IVIg product is licensed for different indications (including CIDP) in the USA,19 Canada20 and the EU.21

Study design and participants The ProCID study (EudraCT Number 2015–005443-14 and clinical trials.gov identifier NCT02638207) was designed in 2016/2017 and initiated in 2017.22 The trial protocol and statistical analysis plan were published previously.22 Patients were eligible if they were at least 18 years old and had been diagnosed with definite or probable CIDP according to published criteria1 and if they were dependent on treatment with immunoglobulins or corticosteroids. The main exclusion criteria included previous failure of immunoglobulin treatment, treatment with other immunomodulatory/suppressive agents in the prior 6 months, treatment with immuno-chemotherapeutic regimens, and clinical evidence of peripheral neuropathy from another cause. Full inclusion and exclusion criteria were published previously.22 All patients gave written informed consent prior to any study-related procedures. The ethics committees of all participating centres approved the study protocol.

Procedures The study consisted of screening, wash-out, and dose-evaluation phases (Fig. 1). Patients were screened, and, if eligible, entered the wash-out phase, during which their current medication was reduced in a predefined standard manner, to determine whether they had active CIDP. For those previously on IVIg, the dose was reduced by 25% at each sequential infusion until deterioration. For those previously on corticosteroids, the dose was reduced at the discretion of the investigator at a rate to expect study entry within 6–12 weeks and to a dose of prednisolone 420 mg/day or equivalent when deterioration occurred. Low doses of corticosteroids at deterioration could be continued during the study. The wash-out phase had a maximum of 12 weeks, and only patients who deteriorated in this time frame were enrolled and randomized into the dose-evaluation phase. Patients who did not deteriorate in the wash-out phase were considered not to have active CIDP and were excluded from the study. Deterioration was determined by

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Correspondence to: David R. Cornblath, MD Department of Neurology, Johns Hopkins University, Meyer 6-181a 600 North Wolfe St., Baltimore, MD 21287, USA E-mail: dcornbl@jhmi.edu

Efficacy of different IVIg doses in CIDP

BRAIN 2022: Page 3 of 10

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worsening of their overall status according to the Patients’ Global Impression of Change Scale and either an increase in adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) score by 51 point, or a decrease of 58 kPa on grip strength in one hand, or reached the Inflammatory Rasch-built Overall Disability Scale (I-RODS) minimum clinically important difference related to the varying standard errors cut-off of –1.96 or less.23 All patients who deteriorated were randomly assigned 1:2:1 to maintenance doses of 0.5, 1.0 or 2.0 g/kg IVIg in the 24-week doseevaluation phase. They then received an induction dose of IVIg 2.0 g/kg, followed by seven maintenance IVIg doses of 0.5, 1.0 or 2.0 g/kg every 3 weeks (± 4 days). The masked assignment of the correct dose and treatment for each study visit was managed using an interactive web response system. The treatment group assignment was only reported to the hospital pharmacist or designee by a dedicated email to which no other study personnel had access.

The patient was masked to the medication by the use of an opaque (non-transparent) infusion line and overpouches. The evaluating investigator was not involved with administering medication to the patient. Dosing was based on actual body weight and administered over two consecutive days without pre-medication.

Corticosteroids (prednisolone or equivalent) 420 mg/day as concomitant CIDP medication were permitted during the dose-evaluation phase for patients with prior corticosteroid therapy. For all patients in the 0.5 and 1.0 g/kg dose groups who were stable (unimproved) at Week 6 or deteriorated between Weeks 3 and 18, there was the option to administer rescue treatment with two consecutive infusions of IVIg 2.0 g/kg at 3-week intervals (± 4 days).

Following the two IVIg rescue treatments, patients attended an end of study visit. Patients deteriorating after Week 18 or 21 dropped out and had their end of study visit at Week 21 or 24, respectively. Patients in the 2.0 g/kg arm were discontinued from the study if they were stable (unimproved) at Week 6 or deteriorated after Week 3 and before Week 21.

Outcomes The primary outcome was the proportion of responders in the 1.0 g/kg arm at Week 24.8,24 A responder was defined as a subject

who showed an improvement (decrease) 5 1 point in adjusted INCAT score at Week 6 compared with baseline (first visit of the dose-evaluation phase), completed the 24-week study, and maintained the response at Week 24. A non-responder was defined as a subject who did not achieve an improvement of 51 point in adjusted INCAT score by Week 6, or who deteriorated between Week 3 and Week 21, or who discontinued before Week 24, irrespective of adjusted INCAT score at termination.

The main secondary outcomes were the proportion of responders in the 0.5 g/kg and 2.0 g/kg arms at Week 24 relative to baseline compared with the 1.0 g/kg arm based on the adjusted INCAT score, grip strength, I-RODS score, and Medical Research Council (MRC) score, and time to first confirmed worsening on the adjusted INCAT score by 51 point from the value at baseline. Other secondary outcomes were the Pain Intensity Numeric Rating Scale and the sum of the distal evoked amplitude of eight motor nerves. To assess safety and tolerability, treatment-emergent adverse events (TEAEs) per infusion and the number of patients with TEAEs were recorded. An adverse event was defined as a TEAE if first onset or worsening occurred after the start of the first IVIg administration in the study. The full list of outcomes variables has previously been published.22

Statistical analysis The sample size calculation was based on the expected proportion of responders based on the adjusted INCAT score in the 1.0 g/kg dose group. At the time this study was designed, experiences with this dosing regimen were available from the ICE6 and PRIMA7 studies. In the PRIMA study,7 the lower limit of the 95% Wilson-Score confidence interval (CI) for the proportion of responders (R) was 42%, and thus 42% was selected as the threshold for evaluation of the primary endpoint: null hypothesis (H0) R 5 0.42; alternative hypothesis (H1) R 5 0.42. This was tested by comparing the lower limit of the 95% Wilson-Score CI for the observed proportion of responders with a pre-defined threshold of 0.42. We estimated the true percentage of responders in CIDP patients treated with IVIg as 60%. In comparison, 60.7% of patients were responders in the PRIMA study and 54.2% in the ICE study.6,7 We applied these

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Figure 1 Trial design.

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D. R. Cornblath et al.

R

parameters to a computer simulation using SASV statistical analysis software and calculated that a minimum of 62 evaluable patients in the 1.0 g/kg dose group was needed to achieve a power of at least 80%. To account for possible dropouts, it was planned to enrol 70 patients into this group. To allow for the comparison between dose groups, it was planned to enrol half the number of evaluable patients into the 0.5 and 2.0 g/kg groups, resulting in a total of 124 evaluable patients and an enrolment target of 140 patients. The primary evaluation of efficacy end points was based on the full analysis set in an intention-to-treat analysis.

The response rates in the alternative dose groups were compared descriptively and by an odds ratio analysis. All other end points were analysed by means of descriptive statistics. Safety was analysed in all patients who received any amount of IVIg in the study.

In addition, an exploratory logistic regression analysis was performed that included the pretreatment as well as the dose group as predictor variables for response based on adjusted INCAT score.

The same model was applied to treatment responses based on grip strength, I-RODS scores and MRC sum score.

Data availability Individual participant data collected during the trial will not be shared. The study protocol and main results are available at https://clinicaltrials.gov/ct2/show/study/NCT02638207 (Accessed 24 February 2022).

Results Patient disposition Patients were enrolled from 25 centres worldwide between 9 August 2017 and 5 September 2019. A total of 171 patients were screened, and 150 entered the wash-out phase. Eight patients were not eligible for inclusion into the dose-evaluation phase due to their disease not being treatment dependent (n = 4) or withdrawal of consent (n = 4). A total of 142 patients experienced deterioration during the wash-out phase and were randomized:

35 (24.6%) to IVIg 0.5 g/kg, 69 (48.6%) to IVIg 1.0 g/kg, and 38 (26.8%) to IVIg 2.0 g/kg. All 142 randomized patients received at least one infusion of IVIg and were included in the safety analysis set. The intention-to-treat population consisted of 139 patients because no post-infusion data were collected in three patients. The per-protocol set comprised 129 patients: five patients were excluded due to dosing errors, four patients withdrew from study, and one patient was lost to follow-up. In total, 123 patients (86.6%) completed the study (Fig. 2). Of the 19 patients (13.4%) who terminated early and were thus counted as non-responders, the most common reasons were patient’s decision (n = 7, 4.9%) and TEAEs (n = 6, 4.2%). The highest incidence of early terminations was seen in the 0.5 g/kg group (20.0%), compared with 11.6% in the 1.0 g/kg group and 10.5% in the 2.0 g/kg group.

Demographic and baseline characteristics Demographic characteristics in the intention-to-treat population (Table 1) were similar across randomization strata and in the safety analysis set. In total, 91.4% of patients had a history of typical CIDP. Twelve (8.6%) patients had atypical CIDP: nine distal acquired demyelinating symmetric neuropathy and three multifocal acquired demyelinating sensory and motor neuropathy. One hundred and twenty-one patients (87.1%) had been treated previously with corticosteroids for their CIDP, and 18 patients (12.9%) with immunoglobulins. The percentage of patients previously treated for CIDP with immunoglobulins or with corticosteroids was distributed equally across the three dose groups. After deterioration and at the start of the dose-evaluation phase, 44/121 patients (36%) previously on corticosteroids entering this phase were still on corticosteroids, and this was balanced evenly across dose groups (Table 1). The corticosteroid dose was reduced to 420 mg/day in all except two of these 44 patients, one in the 0.5 g/ kg group and one in the 1.0 g/kg group, who were on a dose of 25 mg/day prednisolone equivalent due to a miscalculation in the conversion of methylprednisolone to prednisolone. Neither of these patients were excluded from the analyses. Twelve of the 18 patients (67%) previously on IVIg were still on IVIg at the start of the dose-evaluation phase.

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Figure 2 Trial profile.

Efficacy of different IVIg doses in CIDP

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Table 1 Baseline characteristics Characteristic

Treatment group (intention-to-treat) 1.0 g/kg (n = 69)

2.0 g/kg (n = 36)

13 (38) 57 (40–64) 83 (72–97) 27 (25–31)

31 (45) 59 (51–67) 80 (71–93) 27 (24–30)

13 (36) 61 (49–66) 77 (66–89) 25 (23–29)

34 (100) 0

68 (99) 1 (1)

36 (100) 0

33 (97) 1 (3)

62 (90) 7 (10)

32 (89) 4 (11)

29 (85) 5 (15) 11 (38)

60 (87) 9 (13) 20 (33)

32 (89) 4 (11) 13 (41)

20 (2.5–25) 14.8 ± 7.7 2 (40)

18 (2.5–25) 14.9 ± 7.1 6 (67)

20 (2.5–20) 14.8 ± 7.1 4 (100)

0.9 (0.3–1.4) 0.9 ± 0.8

0.4 (0.3–0.8) 0.5 ± 0.2

0.4 (0.2–0.7) 0.4 ± 0.2

4 (4–5) 27 (20–32)

4 (4–5) 25 (21–31)

4 (4–5) 29 (21–32)

51 (32–68) 52 (28–70) 46 (42–50)

53 (39–78) 54 (38–76) 46 (42–52)

52 (41–64) 54 (38–67) 47 (43–53)

All values are the median (interquartile range) unless otherwise stated (intention-to-treat).

Efficacy For the primary end point, the response rate in the 1.0 g/kg group was 80% (55/69 patients; 95% CI: 69–88%) (Table 2). The lower CI limit of 69% exceeded the predefined threshold of 42%, thus the primary end point was met.

The adjusted INCAT score response rates in the 0.5 and 2.0 g/kg maintenance dose groups were 65% (22/34 patients; 95% CI: 48–79%) and 92% (33/36 patients; 95% CI: 78–97%) at Week 24, respectively. In patients previously on corticosteroids, the response rate across all three dose groups was 82% (99/121 patients; 95% CI: 74–88%) and 66%, 83% and 94% in the 0.5, 1.0 and 2.0 g/kg groups, respectively. In patients previously on immunoglobulin therapy, the response rate across all three dose groups was 61% (11/18 patients; 95% CI: 39–80%) and 60%, 56% and 75% in the 0.5, 1.0 and 2.0 g/kg groups, respectively.

Responder rates in the 1.0 g/kg dose group for grip strength, I-RODS and MRC sum score were 65%, 55% and 72%, respectively (Table 2). Response rates were 56%, 38% and 59% for the 0.5 g/kg cohort and 83%, 72% and 86% for the 2.0 g/kg cohort, respectively (Table 2).

Using logistic regression analysis, the dose group had an effect on the treatment outcomes of adjusted INCAT score (P = 0.040), grip strength (P = 0.047), and I-RODS (P = 0.038), but not MRC sum score (P = 0.066). Odds ratio analyses comparing the 0.5 and 2.0 g/ kg groups to the 1.0 g/kg group showed overlapping CIs (Table 3).

Further analyses showed that the statistical differences were not driven in a stepwise fashion by dose, but due to the differences between the 0.5 g/kg and 2.0 g/kg dose groups (Table 3), with an odds ratio of 5.8 (95% CI: 1.4–23.6) for adjusted INCAT score.

An improvement in least square means change from baseline to end of study was achieved in all dose groups for adjusted INCAT score, grip strength, I-RODS, and MRC sum score (data not shown).

Of the 29 non-responders across the dose groups, 22 were on corticosteroids prior to study enrolment and 11 were still on corticosteroids during the study. Of the 29 non-responders, 13 received rescue treatment; six in the 0.5 g/kg group and seven in the 1.0 g/kg group (Supplementary Table 1). The three remaining non-responders were in the 2.0 g/kg group and therefore not eligible for rescue treatment. Three out of six (50%) patients in the 0.5 g/kg group and 4 of 7 (57%) patients in the 1.0 g/kg group had an improved adjusted INCAT score following rescue treatment (Supplementary Table 1). In the 0.5 g/kg group, one of these patients received rescue treatment despite the adjusted INCAT score not returning to baseline. In the 1.0 g/kg group, another patient received rescue therapy in error. The other 16 non-responders dropped out of the study for various reasons and were considered study non-responders, irrespective of whether their adjusted INCAT score had improved at the time they dropped out: six in the 0.5 g/kg group, seven in the 1.0 g/kg group, and three in the 2.0 g/kg group. At the time of early termination, an improvement of 51 point in adjusted INCAT score had been achieved by all six patients in the 0.5 g/kg group, five of the seven patients in the 1.0 g/kg group, and none of the three patients in the 2.0 g/kg group.

One responder in each dose group did not receive rescue medication (0.5 g/kg and 1.0 g/kg group) or was not discontinued (2.0 g/ kg group) according to protocol despite being stable at Week 6 and subsequently had a response at Week 9 (0.5 and 1.0 g/kg patients) or Week 12 (2.0 g/kg patient) that was maintained at Week 24. In the per protocol set, which excluded 10 intention-to-treat patients

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Female, n (%) Age, years Body weight, kg Body mass index, kg/m2 EFNS/PNS criteria, n (%) Definite CIDP Probable CIDP Type of CIDP, n (%) Typical Atypical Prior treatment, n (%) Corticosteroids Immunoglobulins Patients still on corticosteroids at start of dose-evaluation phase, n (%) Prednisolone equivalent/day (mg) Median (range) Mean ± SD Patients still on IVIg at start of dose-evaluation phase, n (%) IVIg (g/kg) Median (range) Mean ± SD Efficacy scores at screening Adjusted INCAT score (range 0–10) I-RODS (range 0–48) Maximum grip strength (kPa; range 0–160) Dominant hand Non-dominant hand MRC sum score (total range 0–80)

0.5 g/kg (n = 34)

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| BRAIN 2022: Page 6 of 10

D. R. Cornblath et al.

Table 2 Proportion of responders at the end of study Parameter

Adjusted INCAT score Grip strength I-RODS MRC sum score

Treatment group (intention-to-treat)

Overall P-value

0.5 g/kg (n = 34)

1.0 g/kg (n = 69)

2.0 g/kg (n = 36)

65 (48–79) 56 (40–71) 38 (24–55) 59 (42–74)

80 (69–88) 65 (53–75) 55 (43–66) 72 (61–82)

92 (78–97) 83 (68–92) 72 (56–84) 86 (71–94)

0.040 0.047 0.038 0.066

All values are % of patients (95% Cl). The primary end point (adjusted INCAT score response in patients treated with 1.0 g/kg IVIg) is indicated in italics. The overall P-value is

Table 3 Odds ratio analysis of the effect of treatment group on response Parameter

Adjusted INCAT score Grip strength I-RODS MRC sum score

Odds ratio (95% CI) (intention-to-treat) 0.5 g/kg versus 1.0 g/kg

2.0 g/kg versus 0.5 g/kg

2.0 g/kg versus 1.0 g/kg

0.5 (0.2–1.2) 0.6 (0.3–1.4) 0.5 (0.2–1.3) 0.6 (0.2–1.4)

5.8 (1.4–23.6) 4.2 (1.4–13.3) 3.9 (1.4–10.8) 4.1 (1.2–13.2)

2.7 (0.7–10.2) 2.5 (0.9–7.0) 2.1 (0.8–5.0) 2.3 (0.8–6.7)

Figure 3 Time to improvement of 51 point in adjusted INCAT score. Data by maintenance dose group in patients who achieved such an improvement at any time during the study (safety analysis set).

including those three responders, the response rate was 72% (21/ 29 patients; 95% CI: 54–85%) in the 0.5 g/kg group, 83% (54/65 patients; 95% CI: 72–90%) in 1.0 g/kg group, and 91% (32/35 patients; 95% CI: 78–97%) in the 2.0 g/kg group (Supplementary Table 2).

More than half of all patients (n = 78; 56.1%) showed an improvement of 51 adjusted INCAT score point after the induction dose of 2.0 g/kg: 23 of 34 (67.6%) in the 0.5 g/kg group, 35 of 69 (50.7%) in the 1.0 g/kg group and 20 of 36 (55.6%) in the 2.0 g/kg group. By Week 6, 121 of 139 (87.0%) patients had an improvement of 51 adjusted INCAT score point: 30 of 34 (88.2%) in the 0.5 g/kg group, 59 of 69 (85.5%) in the 1.0 g/kg group and 32 of 36 (88.9%) in the 2.0 g/kg group.

Median time to an improvement of 51 adjusted INCAT score point from baseline was 22, 26 and 23 days in the 0.5, 1.0 and

2.0 g/kg groups, respectively (Fig. 3). Overall, 91.2% of patients in the 0.5 g/kg group, 88.4% of patients in the 1.0 g/kg group and 91.7% of patients in the 2.0 g/kg group had an improvement of 51 adjusted INCAT score point at some point in the study. These values are higher than in the primary analysis because patients could show an improvement in the score during the study, but subsequently declined or dropped out and were then considered nonresponders. Median time to response in I-RODS was 63, 64, and 43.5 days in the 0.5, 1.0, and 2.0 g/kg groups, respectively.

The time to first confirmed worsening in adjusted INCAT score by at least 1 point from the value at baseline (Week 0) revealed that only a single patient in the 1.0 g/kg dose group met this criterion, and therefore this analysis was not possible. This was also the case for the time to first confirmed worsening in I-RODS scores as

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calculated using a type 3 logistic regression analysis of effects modelling response from treatment, randomization stratum, CIDP variant, and baseline score without interactions.

Efficacy of different IVIg doses in CIDP

BRAIN 2022: Page 7 of 10

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Table 4 Summary of related TEAEs observed in 55% of patients TEAE

Treatment group (safety analysis set) 0.5 g/kg (n = 35)

2.0 g/kg (n = 38)

Patients, (% of patients)

Events, (% of infusions)

Patients, (% of patients)

Events, (% of infusions)

Patients, (% of patients)

Events, (% of infusions)

16 (45.7) 1 (2.9) 2 (5.7) 4 (11.4) 3 (8.6) 0 3 (8.6) 3 (8.6) 2 (5.7) 2 (5.7) 0 1 (2.9)

37 (16.1) 1 (0.4) 3 (1.3) 4 (1.7) 4 (1.7) 0 4 (1.7) 4 (1.7) 3 (1.3) 2 (0.9) 0 1 (0.4)

32 (46.4) 10 (14.5) 0 5 (7.2) 0 0 6 (8.7) 2 (2.9) 5 (7.2) 2 (2.9) 5 (7.2) 1 (1.4)

80 (16.6) 12 (2.5) 0 10 (2.1) 0 0 6 (1.2) 2 (0.4) 6 (1.2) 5 (1.0) 5 (1.0) 2 (0.4)

20 (52.6) 9 (23.7) 1 (2.6) 4 (10.5) 0 2 (5.3) 2 (5.3) 1 (2.6) 0 3 (7.9) 0 3 (7.9)

56 (20.8) 14 (5.2) 1 (0.4) 5 (1.9) 0 3 (1.1) 3 (1.1) 1 (0.4) 0 3 (1.1) 0 5 (1.9)

this occurred in only three patients: one in the 0.5 g/kg group and two in the 1.0 g/kg group.

The proportion of patients deteriorating during the dose-evaluation phase of the study was low, one each in the 0.5 g/kg and 1.0 g/kg groups, as was the number of patients who were stable at Week 6: 13 (9.4%) patients in total, with five in the 0.5 g/kg group, six in the 1.0 g/kg group, and two in the 2.0 g/kg group (Supplementary Table 1).

Mean pain intensity according to Pain Intensity Numeric Rating Scale score increased during the wash-out phase, then tended to decrease through Week 24. Mean ± standard deviation (SD) changes from baseline were –2.3 ± 3.0, –2.2 ± 2.9 and –2.2 ± 3.3 in the 0.5, 1.0 and 2.0 g/kg groups, respectively.

There were no clear trends over time in the nerve conduction studies.

Safety Median doses of IVIg administered per patient per infusion, including the induction dose, were 70 g (0.7 g/kg) in the 0.5 g/kg group, 101 g (1.1 g/kg) in the 1.0 g/kg group, and 155 g (2.0 g/kg) in the 2.0 g/ kg group. Dosing was based on actual body weight, and there was no maximum daily dose.

In the 0.5 g/kg group, 16 (45.7%) patients experienced 37 related TEAEs over 230 infusions (Table 4). In the 1.0 g/kg group, 32 (46.4%) patients experienced 80 related TEAEs over 482 infusions, and in the 2.0 g/kg group 20 (52.6%) patients experienced 56 related TEAEs over 270 infusions. Overall, the most commonly reported related TEAEs were headache in 20 patients (14.1%), allergic dermatitis in 13 patients (9.2%), pyrexia in 11 patients (7.7%), increased blood pressure in seven patients (4.9%), and increased body temperature in seven patients (4.9%). Headache was the most prevalent related TEAE in the 1.0 and 2.0 g/kg groups (14.5% and 23.7%, respectively), while the most common related TEAE in the 0.5 g/kg group was allergic dermatitis (11.4% of patients). Generally, the incidence of related TEAEs was similar across the treatment groups. The only TEAE where a dose effect was apparent was headache, with an incidence of 2.9% in the 0.5 g/kg group, 14.5% in the 1.0 g/kg group, and 23.7% in the 2.0 g/kg group.

Five patients (3.5%) experienced TEAEs that led to discontinuation of the study drug, one of which, allergic dermatitis in a patient receiving 1.0 g/kg IVIg, was considered related.

Eleven serious TEAEs were reported in six patients (4.2%). Two of these (headache and vomiting) were reported in one patient in

the 1.0 g/kg group and considered related to IVIg treatment, but did not lead to study discontinuation.

Two patients (1.4%) had TEAEs leading to death, but neither event was considered related to the study drug. One patient aspirated leading to respiratory arrest, and one developed meningoencephalitis.

During the study, no haemolysis or thromboembolic events were reported. Laboratory analyses of haematology, clinical chemistry, urinalysis and viral markers did not indicate any safety concerns. There were no findings of note on physical examination or in the vital signs data.

Discussion The ProCID study is the largest randomized study to show that IVIg is effective as maintenance therapy in patients with CIDP and the first to examine systematically a lower and higher IVIg maintenance dose. The primary objective was to assess the efficacy of IVIg administered as a 2.0 g/kg induction dose followed by seven maintenance doses of 1.0 g/kg every 3 weeks. The response rate on this regimen was 80%, and the lower 95% CI limit of 69% exceeded the predefined threshold of 42%, indicating that the primary end point had been met. This threshold was also exceeded in the 0.5 and 2.0 g/kg maintenance groups. Similar responses were seen in other outcome measures.

Published guidelines recommend that the maintenance dose of IVIg may need to be adjusted individually.2 The ProCID study was the first to examine systematically a lower (0.5 g/kg) and a higher (2.0 g/kg) maintenance dose of IVIg in CIDP and compare efficacy with standard dosing of 1.0 g/kg. The adjusted INCAT score response rates were 65, 80 and 92% in the 0.5, 1.0 and 2.0 g/kg maintenance dose groups, respectively. Similar incremental improvements in response rates were observed for secondary efficacy variables. Despite the study not being powered to show a statistically significant dose response, a statistically significant effect of dose on response was observed across all dose groups using logistic regression analysis. However, statistically significant differences between any two of the individual dose groups were only seen between the 0.5 and 2.0 g/kg maintenance groups. Our data therefore suggest that a lower maintenance dose of 0.5 g/kg is sufficient to achieve and maintain a response in 65% of patients but that a higher dose may be beneficial to improve those not responding to low or standard dosing.

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Any related TEAE Headache Somnolence Allergic dermatitis Urticaria Pruritus Pyrexia Chills Blood pressure increased Body temperature increased Blood lactate dehydrogenase increased Nausea

1.0 g/kg (n = 69)

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| BRAIN 2022: Page 8 of 10

induction dose alone, i.e. by Week 3. In comparison, the percentage of responders who had an improved adjusted INCAT score after the induction dose was 44% in the ICE study,27 50% in the PRIMA study7 and 22% in the PRISM study.8 This has important implications for clinical practice. Our study and the ICE trial27 show that nearly all patients who will respond to IVIg do so within 6–8 weeks, that is, a single induction dose and two maintenance doses. Given the issues above with actual patient inclusion, the translation of this to the treatment-naı̈ve patient is less clear.

When to decide that a patient is not responding to IVIg remains a clinical decision, but these data suggest that treating longer than 3 months while waiting for a significant response is not useful.2 A limitation of the study as detailed above, in common with other studies evaluating IVIg in patients with CIDP, is that it evaluates rescue treatment mainly of previously successfully treated CIDP patients whose condition has been allowed to deteriorate prior to treatment, and not newly diagnosed and untreated CIDP patients. Given that the study period was 24 weeks, the longerterm efficacy, safety and relapse rate with the different maintenance doses were not assessed in this study. However, the study demonstrated a low rate of deterioration (1.4%) after Week 6 across all dose groups. Other limitations of the study were that it was not placebo controlled and was not statistically powered to detect a dose response between the three dosing regimens.

In summary, the ProCID study demonstrated that 1.0 g/kg IVIg is efficacious and well tolerated as maintenance treatment following a 2.0 g/kg induction dose in patients with active CIDP, even in those patients having been successfully treated with corticosteroids previously. A lower or higher maintenance dose may be beneficial in some patients, although further studies are needed to confirm this finding.

Acknowledgements This study was sponsored by Octapharma Pharmazeutika Produktionsges.m.b.H. (Vienna, Austria) who thank investigators, trial personnel and patients for their participation. Medical writing assistance was provided by nspm ltd, Meggen, Switzerland, and funded by Octapharma.

Funding This study was funded by Octapharma Produktionsges.m.b.H. (Vienna, Austria).

Pharmazeutika

Competing interests D.R.C. reports consulting for Amgen, Annexon Biosciences, argenx SE, Biotest Pharmaceuticals, Cigna Health Management, CSL Behring, Grifols, Johnson & Johnson, Momenta Pharma, New Enterprise Associates, Octapharma, Pfizer, Pharnext, Polyneuron Pharmaceuticals, Seattle Genetics, and UCB. D.R.C. is on the Data Safety Monitoring Board for the following: Alnylam Pharmaceuticals, Anavex, PledPharma, Hansa Medical, and Mitsubishi Tanabe Pharma Corporation. D.R.C. was involved with technology licensing for AstraZeneca Pharmaceuticals, LP Pharmaceuticals (Xiamen), Genentech, Levicept, Seattle Genetics, Merrimack Pharmaceuticals, and Disarm Therapeutics, outside the submitted work. P.A.v.D. reports grants from Sanquin Blood Supply and Prinses Beatrix Spierfonds, during the conduct of the study; and grants from Grifols, Takeda, Annexion, Argenx, Commonwealth Serum Laboratories, Octapharma, and Hansa, outside the submitted work. H.P.H. reports consulting CSL Behring, Sanofi Genzyme, and UCB. H.P.H. received payments or honoraria from CSL Behring and Octapharma. H.D.K. is on Steering

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The PATH study examined two different doses of SCIg maintenance therapy, 0.2 and 0.4 g/kg every week, the equivalent of 0.6 and 1.2 g/kg IVIg every 3 weeks, in patients with CIDP.14 The study evaluated a 2-fold dose difference and found no differences in either safety or efficacy between these two doses with a study period of 24 weeks.14 In the PATH extension study, the overall relapse rates were 10% in the 0.4 g/kg/week and 48% in the 0.2 g/kg/week group.24 After dose reduction from 0.4 to 0.2 g/kg/week, 51% (27/53) of patients relapsed, of whom 92% (24 of 26) improved after re-initiation of the 0.4 g/kg/week dose.24 In our study, a 2-fold dose difference, low versus standard, or standard versus high dosing, also did not result in a significant difference in response rate. Only the 4-fold dose difference between low (0.5 g/kg) and high (2.0 g/kg) maintenance dosing did, with an odds ratio of 5.8 (95% CI: 1.4–23.6) for adjusted INCAT score. Thus, we postulate that a 2-fold dose difference might be too small to detect significant differences in response rate. Therefore, a larger study, statistically powered to compare different dose ratios, e.g. 2-fold versus 3-fold versus 4-fold, would be needed to confirm a clear dose relationship and to identify potential patient characteristics that might help to predict the required maintenance dose for an individual patient.

The adjusted INCAT score overall response rate of 80% with a 1.0 g/kg maintenance dose in our study was higher than reported in other IVIg studies: ICE 54%, PRIMA 61% and PRISM 76%.6–8 It is of interest to compare groups of patients in the different studies that have been treated previously with corticosteroids or IVIg. Selection of patients who had previously responded to IVIg may impact the IVIg response rate in a trial.14 Our study is the first IVIg study to include a high percentage of patients who were previously treated with corticosteroids and not with IVIg. The higher proportion of patients having been treated with corticosteroids might be due to lower availability of IVIg in some of the countries. The PATH study preselected patients based on IVIg response.14 Corticosteroids are a first-line treatment option for CIDP.2 Corticosteroids are widely available and inexpensive, but long-term use has potentially serious side effects.5,25,26 Unlike the ProCID study, patients previously on corticosteroids (410 mg/day prednisolone or equivalent) were excluded from the ICE study,6 patients previously on ‘high-dose’ corticosteroids were excluded from the PRISM study8 and, although corticosteroid use was not specifically excluded, no information on prior corticosteroid use was provided in the PRIMA study.7 Furthermore, the percentage of patients classified as IVIgnaı̈ve, but potentially on prior corticosteroids, was 23%,6 54%7 and 55%8 in the ICE, PRIMA and PRISM studies, respectively, compared with 87% who were IVIg-naı̈ve and on prior corticosteroids in our study. These differences in prior treatment, along with other differences in patient and study characteristics, might have influenced response rates across studies and make comparisons between the studies difficult. Nevertheless, since the ProCID study clearly differentiated between patients previously successfully treated with IVIg and those previously treated with corticosteroids, with most subjects being in the latter stratum, the study provided a unique opportunity to assess the effects of switching from corticosteroids to IVIg. The high response rates in the corticosteroids stratum, 66%, 83% and 94% in the 0.5 g/kg, 1.0 g/kg and 2.0 g/kg arms, respectively, clearly show that subjects previously on corticosteroids can successfully and safely be transitioned to IVIg. The incidence of treatment-related TEAEs, except for headache, was similar across the dose groups. Treatment was well tolerated even in IgG-naı̈ve patients and in those regularly treated with high dose IVIg. These data show that patients can switch from corticosteroids to IVIg with confidence to potentially avoid the side effects associated with corticosteroid use.

In this study, 56% of all patients and 62% of responders showed an improvement of 51 adjusted INCAT score point after the

D. R. Cornblath et al.

Efficacy of different IVIg doses in CIDP

Supplementary material Supplementary material is available at Brain online.

Appendix I ProCID study investigators Full details are provided in the Supplementary material.

S. Kastrev, V. Rizova, R. Massie, R. Talab, M. Bednar, P. Ridzon, J. csei, K. Rejdak, M. Schmidt, J. Zschüntzsch, C. Rózsa, L. Ve Koszewicz, S. Budrewicz, A. Dulamea, M. Marian, A. Kadar, L. Zecheru-Lapusneanu, V. Mikhailov, D. Zakharov, N. Suponeva, M. Piradov, N. Smolko, D Smolko.

8. Nobile-Orazio E, Pujol S, Kasiborski F, et al. An international multicenter efficacy and safety study of IqYmune in initial and maintenance treatment of patients with chronic inflammatory demyelinating polyradiculoneuropathy: PRISM study. J Peripher Nerv Syst. 2020;25(4):356–365.

9. Rajabally YA, Seow H, Wilson P. Dose of intravenous immunoglobulins in chronic inflammatory demyelinating polyneuropathy. J Peripher Nerv Syst. 2006;11(4):325–329.

10. Rajabally YA, Afzal S. Clinical and economic comparison of an individualised immunoglobulin protocol vs. standard dosing for chronic inflammatory demyelinating polyneuropathy. J Neurol. 2019;266(2):461–467.

11. Kuitwaard K, Fokkink W-JR, Brusse E, et al. Maintenance IV immunoglobulin treatment in chronic inflammatory demyelinating polyradiculoneuropathy. J Peripher Nerv Syst. 2017;22(4): 425–432.

12. Lunn MP, Ellis L, Hadden RD, Rajabally YA, Winer JB, Reilly MM. A proposed dosing algorithm for the individualized dosing of human immunoglobulin in chronic inflammatory neuropathies. J Peripher Nerv Syst. 2016;21(1):33–37.

13. Kubori T, Mezaki T, Kaji R, et al. The clinical usefulness of highdose intravenous immunoglobulin therapy for chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. No to Shinkei. 1999;51(2):127–135.

14. van Schaik IN, Bril V, van Geloven N, et al.; PATH study group.

Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): A randomised, double-blind, placebo-controlled, phase 3 trial.

Lancet Neurol. 2018;17(1):35–46.

15. Mersich C, Ahrer K, Buchacher A, et al. Biochemical characterization and stability of immune globulin intravenous 10% liquid (PanzygaV). Biologicals. 2017;45:33–38.

16. Radomski KU, Lattner G, Schmidt T, Römisch J. Pathogen safety of a new intravenous immune globulin 10% liquid. BioDrugs.

2017;31(2):125–134.

17. Borte M, Melamed IR, Pulka G, et al. Efficacy and safety of human intravenous immunoglobulin 10% (PanzygaV) in patients with primary immunodeficiency diseases: A twostage, multicenter, prospective, open-label study. J Clin Immunol. 2017;37(6):603–612.

18. Arbach O, Taumberger AB, Wietek S, Cervinek L, Salama A. Efficacy and safety of a new intravenous immunoglobulin (PanzygaV) in chronic immune thrombocytopenia. Transfus Med. 2019;29(1):48–54.

17. panzygaV USPI. 2021. https://www.fda.gov/media/115397/down load. Accessed 16 July 2021.

20. panzygaV Canadian Product Monograph. 2017. https://pdf.hres. ca/dpd_pm/00041520.PDF. Accessed 16 July 2021.

21. panzygaV SmPC. 2019. https://www.medicines.org.uk/emc/prod uct/7317/smpc#gref. Accessed 16 July 2021.

22. Cornblath DR, Hartung H-P, Katzberg HD, Merkies ISJ, van Doorn PA. A randomised, multi-centre phase III study of 3 different doses of intravenous immunoglobulin 10% in patients with chronic inflammatory demyelinating polyradiculoneuropathy (ProCID trial): Study design and protocol. J Peripher Nerv Syst. 2018;23(2):108–114.

23. Draak THP, Vanhoutte EK, van Nes SI, et al.; PeriNomS Study Group. Changing outcome in inflammatory neuropathies: Rasch-comparative responsiveness. Neurology. 2014;83(23): 2124–2132.

24. van Schaik IN, Mielke O, Bril V, et al.; PATH study group. Longterm safety and efficacy of subcutaneous immunoglobulin IgPro20 in CIDP: PATH extension study. Neurol Neuroimmunol Neuroinflamm. 2019;6(5):e590.

R

References 1. van den Bergh PYK, Hadden RDM, Bouche P, et al.; Peripheral Nerve Society. European Federation of Neurological Societies/ Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society - first revision. Eur J Neurol. 2010;17(3):356–363.

2. van den Bergh PYK, van Doorn PA, Hadden RDM, et al. European Academy of Neurology/Peripheral Nerve Society Guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force - second revision. J Peripher Nerv Syst. 2021;26(3):242–268.

3. Allen JA, Lewis RA. CIDP diagnostic pitfalls and perception of treatment benefit. Neurology. 2015;85(6):498–504.

4. Neligan A, Reilly MM, Lunn MP. CIDP: Mimics and chameleons.

Pract Neurol. 2014;14(6):399–408.

5. Oaklander AL, Lunn MP, Hughes RA, van Schaik IN, Frost C, Chalk CH. Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): An overview of systematic reviews. Cochrane Database Syst Rev. 2017;1:CD010369.

6. Hughes RAC, Donofrio P, Bril V, et al.; ICE Study Group.

Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): A randomised placebo-controlled trial. Lancet Neurol. 2008;7(2):136–144. ger J-M, Bleecker JL, de Sommer C, et al.; PRIMA study investi7. Le gators. Efficacy and safety of PrivigenV in patients with chronic inflammatory demyelinating polyneuropathy: Results of a prospective, single-arm, open-label Phase III study (the PRIMA study). J Peripher Nerv Syst. 2013;18(2):130–140.

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Committees for Octapharma and Sanofi Genzyme. I.S.J.M. reports grants from Talecris Talents program, GBS/CIDP Foundation International and FP7 EU program, outside the submitted work; Furthermore, a research foundation at the University of Maastricht received honoraria on behalf of him for participation in steering committees of the Talecris Immune Globulin Intravenous For Chronic Inflammatory Demyelinating Polyneuropathy Study, Commonwealth Serum Laboratories, Behring, Octapharma, LFB, Novartis, Union Chimique Belge, outside the submitted work.

H.D.K. reports travel support and consulting fees from Octapharma in relation to a study design advisory board. H.D.K. reports consulting for UCB, Terumo, Akcea, Alnylam, and CSL Behring. H.D.K. is on Data Safety Monitoring Boards or Advisory Boards for UCB and Octapharma. H.D.K. received a grant from Takeda for investigator-initiated research. D.H. and E.C. are employees of Octapharma PPG, Vienna, Austria.

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25. Bunschoten C, Jacobs BC, van den Bergh PYK, Cornblath DR, van Doorn PA. Progress in diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy. Lancet Neurol. 2019;18(8):784–794.

26. Hughes RA, Mehndiratta MM, Rajabally YA. Corticosteroids for chronic inflammatory demyelinating polyradiculoneuropathy.

Cochrane Database Syst Rev. 2017;11:CD002062.

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27. Latov N, Deng C, Dalakas MC, et al.; IGIV-C CIDP Efficacy (ICE) Study Group. Timing and course of clinical response to intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy. Arch Neurol. 2010;67(7): 802–807.

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Mat-No./CAN/DataMatrix: 2013186-03 / Version: 04 / 2021-04-20 / Product code: 821 / Panzyga / USA / 520 × 270 mm / Black / Satzstudio Borngräber / font size 6.3pt 2013186-03

2013186-03

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PANZYGA safely and effectively. See full prescribing information for PANZYGA. PANZYGA, (immune globulin intravenous, human - ifas) 10% Liquid Preparation Initial U.S. Approval: 2018 WARNING: THROMBOSIS, RENAL DYSFUNCTION, and ACUTE RENAL FAILURE See full prescribing information for complete boxed warning – Thrombosis may occur with immune globulin intravenous (IGIV) products, including PANZYGA. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling vascular catheters, hyperviscosity, and cardiovascular risk factors.

– Renal dysfunction, acute renal failure, osmotic nephropathy, and death may occur with the administration of IGIV products in predisposed patients. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. PANZYGA does not contain sucrose.

– For patients at risk of thrombosis, renal dysfunction, or renal failure, administer PANZYGA at the minimum infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.

- - - - - - - - - - - - - - - - - - - -RECENT MAJOR CHANGES - - - - - - - - - - - - - - - - - - - Indications and Usage (1) 01/2021 Dosage and Administration, Dose (2.1) 01/2021 - - - - - - - - - - - - - - - - - - - -INDICATIONS AND USAGE - - - - - - - - - - - - - - - - - - - PANZYGA is an immune globulin intravenous (human) – ifas 10% liquid preparation indicated for the treatment of: – Primary humoral immunodeficiency (PI) in patients 2 years of age and older (1.1).

– Chronic immune thrombocytopenia (ITP) in adults (1.2).

– Chronic inflammatory demyelinating polyneuropathy (CIDP) in adults (1.3)

- - - - - - - - - - - - - - - - - DOSAGE AND ADMINISTRATION - - - - - - - - - - - - - - - - For intravenous use only (2).

Indication

PI

Chronic ITP in adults

CIDP in adults

Dose

Initial Infusion Rate

Maximum Infusion Rate (as tolerated)

300-600 mg/kg (3-6 mL/kg) every 3-4 weeks

1 mg/kg/min (0.01 mL/kg/ min)

14 mg/kg/min (0.14 mL/kg/ min)

2 g/kg (20 mL/kg), divided into 2 daily doses of 1 g/kg (10 mL/kg) given on 2 consecutive days

1 mg/kg/min (0.01 mL/kg/ min)

8 mg/kg/min (0.08 mL/kg/ min)

Loading dose: 2 g/kg (20 mL/kg), divided into 2 daily doses of 1 g/kg (10 mL/kg) given on 2 consecutive days Maintenance dose: 1-2 g/kg (10-20 mL/kg) every 3 weeks divided in 2 doses given over 2 consecutive days

1 mg/kg/min (0.01 mL/kg/ min)

12 mg/kg/min (0.12 mL/kg/ min)

– Ensure that patients with pre-existing renal insufficiency are not volume depleted; discontinue PANZYGA if renal function deteriorates (2, 5.2).

– For patients at risk of renal dysfunction or thrombotic events, administer PANZYGA at the minimum dose and infusion rate practicable (5.2, 5.4).

- - - - - - - - - - - - - - - - -DOSAGE FORMS AND STRENGTHS - - - - - - - - - - - - - - - - Solution containing 10% IgG (100 mg/mL) (3, 16) - - - - - - - - - - - - - - - - - - - - - CONTRAINDICATIONS - - - - - - - - - - - - - - - - - - - - - – History of anaphylactic or severe systemic reactions to human immune globulin (4) – IgA-deficient patients with antibodies against IgA and a history of hypersensitivity (4) - - - - - - - - - - - - - - - - - -WARNINGS AND PRECAUTIONS - - - - - - - - - - - - - - - - - – IgA-deficient patients with antibodies against IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions to PANZYGA. Epinephrine should be available immediately to treat any severe acute hypersensitivity reactions (5.1).

– Monitor renal function, including blood urea nitrogen and serum creatinine, and urine output in patients at risk of developing acute renal failure (5.2).

– Hyperproteinemia, increased serum osmolarity and hyponatremia may occur in patients receiving PANZYGA (5.3).

1

– Hemolysis that is either intravascular or due to enhanced red blood cell sequestration can develop subsequent to PANZYGA treatments. Risk factors for hemolysis include high doses and non-O-blood group. Closely monitor patients for hemolysis and hemolytic anemia (5.6).

– Aseptic Meningitis Syndrome may occur in patients receiving PANZYGA, especially with high doses or rapid infusion (5.5).

– Monitor patients for pulmonary adverse reactions [transfusion-related acute lung injury (TRALI)] (5.7).

– PANZYGA is made from human plasma and may contain infectious agents, e.g., viruses, variant Creutzfeldt-Jakob disease [vCJD] agent and, theoretically, the Creutzfeldt-Jakob disease agent (5.10).

- - - - - - - - - - - - - - - - - - - - - ADVERSE REACTIONS - - - - - - - - - - - - - - - - - - - - - – PI – The most common adverse reactions reported in greater than 5% of subjects during a clinical trial were: headache, nausea, fever, fatigue, and abdominal pain (6).

– Chronic ITP in adults – The most common adverse reactions reported in greater than 5% of subjects during a clinical trial were: headache, fever, nausea, vomiting, dizziness, and anemia (6).

– CIDP in adults – The most common adverse reactions reported in greater than 5% of subjects during a clinical trial were: headache, fever, dermatitis, blood pressure increased (6).

To report SUSPECTED ADVERSE REACTIONS, contact Octapharma at 1-866-7664860 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

- - - - - - - - - - - - - - - - - - - - - DRUG INTERACTIONS - - - - - - - - - - - - - - - - - - - - - – The passive transfer of antibodies may confound the results of serological testing (7).

– The passive transfer of antibodies may interfere with the immune response to live viral vaccines, such as measles, mumps, and rubella (7).

- - - - - - - - - - - - - - - - - - USE IN SPECIFIC POPULATIONS - - - - - - - - - - - - - - - - - Geriatric Use: In patients over age 65 years and in any patient at risk of developing renal insufficiency, infuse PANZYGA at the minimum infusion rate practicable and do not exceed the recommended dose PANZYGA (8.5).

See 17 for PATIENT COUNSELING INFORMATION. Revised: [03/2021] FULL PRESCRIBING INFORMATION: CONTENTS* BOXED WARNING: THROMBOSIS, RENAL DYSFUNCTION AND ACUTE RENAL FAILURE 1 INDICATIONS AND USAGE 1.1 Primary Humoral Immunodeficiency Diseases (PI) 1.2 Chronic Immune Thrombocytopenia (ITP) 1.3 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) 2 DOSAGE AND ADMINISTRATION 2.1 Dose 2.2 Administration 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity 5.2 Renal Failure 5.3 Hyperproteinemia, Increased Serum Viscosity and Hyponatremia 5.4 Thrombotic Events 5.5 Aseptic Meningitis Syndrome 5.6 Hemolysis 5.7 Transfusion-Related Acute Lung Injury (TRALI) 5.8 Hypertension 5.9 Volume Overload 5.10 Transmission of Infectious Agents 5.11 Monitoring Laboratory Tests 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Treatment of Primary Humoral Immunodeficiency (PI) 14.2 Treatment of Chronic Immune Thrombocytopenia (ITP) in Adults 14.3 Treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in Adults 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed.

2013186-03

FULL PRESCRIBING INFORMATION PANZYGA, Immune Globulin Intravenous (Human) – ifas 10% Liquid Preparation WARNING: THROMBOSIS, RENAL DYSFUNCTION, and ACUTE RENAL FAILURE Thrombosis may occur with immune globulin intravenous (IGIV) products, including PANZYGA. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors. (See WARNING and PRECAUTIONS [5.4], PATIENT COUNSELING INFORMATION [17]) Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in predisposed patients who receive IGIV products, including PANZYGA. Patients predisposed to renal dysfunction include those with a degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV product containing sucrose.

PANZYGA does not contain sucrose.

For patients at risk of thrombosis, renal dysfunction or acute renal failure, administer PANZYGA at the minimum dose and infusion rate practicable.

Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. (See DOSAGE and ADMINISTRATION [2.3], WARNINGS and PRECAUTIONS [5.2, 5.4]) 1 INDICATIONS AND USAGE 1.1 Primary Humoral Immunodeficiency Diseases (PI) PANZYGA is indicated for treatment of primary humoral immunodeficiency (PI) in patients 2 years of age and older. This includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

1.2 Chronic Immune Thrombocytopenia (ITP) PANZYGA is indicated for the treatment of adult patients with ITP to raise platelet counts to control or prevent bleeding.

1.3 Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) PANZYGA is indicated for the treatment of adults with chronic inflammatory demyelinating polyneuropathy (CIDP) to improve neuromuscular disability and impairment.

2 DOSAGE AND ADMINISTRATION For intravenous use only 2.1

Dose

Indication

Dose

Initial Infusion Rate (first 30 min)

Maximum Infusion Rate (as tolerated)

Treatment of Primary Humoral Immunodeficiency (PI)*

300 to 600 mg/kg body weight (3-6 mL/kg) administered every 3 to 4 weeks

1 mg/kg/ min (0.01 mL/ kg/min)

14 mg/kg/ min (0.14 mL/ kg/min)

Treatment of Chronic Immune Thrombocytopenia (ITP)

2 g/kg (20 mL/kg), divided into 2 daily doses of 1 g/kg (10 mL/kg) given on 2 consecutive days

1 mg/kg/ min (0.01 mL/ kg/min)

8 mg/kg/ min (0.08 mL/ kg/min)

Treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

Loading Dose: 2 g/kg (20 mL/ kg), divided into 2 daily doses of 1 g/kg (10 mL/kg) given on 2 consecutive days Maintenance dose: 1-2 g/kg (10-20 mL/kg) every 3 weeks divided in 2 daily doses given over 2 consecutive days

1 mg/kg/ min (0.01 mL/ kg/min)

12 mg/kg/ min (0.12 mL/ kg/min)

*Significant differences in the half-life of IgG among patients with PI may necessitate the dose and frequency of immunoglobulin therapy to vary from patient to patient. Determine the proper dose and frequency by monitoring the clinical response. Adjust dose over time to achieve the desired trough levels of IgG and clinical responses.

The initial infusion rate should be maintained for 30 min. Following the initial infusion, and if tolerated, the infusion rate may be gradually increased every 15-30 minutes, as tolerated, to the maximum infusion rate shown in the table above for each indication.

Measles Exposure.

If a patient with primary humoral immunodeficiency has been exposed to measles, it may be prudent to administer an extra dose of IGIV as soon as possible and within 6 days of exposure. A dose of 400 mg/kg should provide a serum level > 240 mIU/mL of measles antibodies for at least two weeks.

If a patient with primary humoral immunodeficiency is at risk of future measles exposure and receives a dose of less than 530 mg/kg every 3-4 weeks, the dose should be increased to at least 530 mg/kg. This should provide a serum level of 240 mIU/mL of measles antibodies for at least 22 days after infusion.

2.2 Administration – Inspect parenteral products visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Do not use PANZYGA if it is turbid and/or if discoloration is observed.

Using a needle, no larger than a 16-gauge needle, insert the needle only

2

3

– – – – – –

once within the stopper area (delineated by the raised ring for penetration).

Penetrate the stopper perpendicularly to its plane and within the ring.

PANZYGA bottles may be pooled under aseptic conditions into sterile infusion bags. Infuse within 8 hours after pooling.

Administer at room or body temperature only by the intravenous route.

PANZYGA is not supplied with an infusion set. If a filtered infusion set is used (not mandatory), choose a filter size of 0.2-200 microns.

Do not administer PANZYGA simultaneously with another intravenous preparation in the same infusion set, including immune globulin products from another manufacturer.

After administration, the infusion line may be flushed with either normal saline or 5% dextrose in water.

Monitor the patient carefully throughout the infusion. Certain adverse drug reactions are related to the rate of infusion, and will disappear promptly after slowing or stopping the infusion. In such cases, after symptoms subside, resume the infusion at a lower rate.

Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients at risk of renal dysfunction or thromboembolic events, administer PANZYGA at the minimum infusion rate practicable [see Warnings and Precautions (5.2, 5.4)]. Do not exceed 3.3 mg/kg/min (0.033 mL/kg/min). Discontinue if renal function deteriorates.

3 DOSAGE FORMS AND STRENGTHS Solution containing 10% IgG (100 mg/mL) (See How Supplied/Storage and Handling (16)).

4 CONTRAINDICATIONS – PANZYGA is contraindicated in patients who have a history of severe systemic hypersensitivity reactions, such as anaphylaxis, to human immunoglobulin.

– PANZYGA is contraindicated in IgA-deficient patients with antibodies against IgA and history of hypersensitivity.

5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Severe hypersensitivity reactions may occur (See Contraindications (4)).[1] In case of hypersensitivity, discontinue PANZYGA infusion immediately and institute appropriate treatment. Have epinephrine available for immediate treatment of severe acute hypersensitivity reactions.

PANZYGA contains trace amounts of IgA (average 100 µg/mL in a 10% solution). IgA-deficient patients with antibodies against IgA are at greater risk of developing severe hypersensitivity and anaphylactoid reactions when administered PANZYGA (See Contraindications (4)).

5.2 Renal Failure Renal dysfunction, acute renal failure, osmotic nephropathy, and death may occur upon use of PANZYGA in predisposed patients.

Ensure that patients are not volume depleted prior to the initiation of the infusion of PANZYGA. For patients at risk of renal dysfunction because of pre-existing renal insufficiency or predisposition to acute renal failure (such as individuals with diabetes mellitus, age greater than 65 years, volume depletion, sepsis, paraproteinemia, or those receiving known nephrotoxic drugs), administer PANZYGA at the minimum infusion rate practicable (See Boxed Warning, and Dosage and Administration (2)).

Periodic monitoring of renal function tests and urine output is particularly important in patients judged to be at risk of developing acute renal failure.

Assess renal function, including a measurement of blood urea nitrogen (BUN)/serum creatinine, prior to the initial infusion of PANZYGA and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of the product.

5.3 Hyperproteinemia, Increased Serum Viscosity and Hyponatremia Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving PANZYGA therapy. It is clinically critical to distinguish true hyponatremia from pseudohyponatremia related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap, because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity and a higher risk of thromboembolic events.[2] 5.4 Thrombotic Events Thrombosis may occur following treatment with immune globulin products, including PANZYGA. Risk factors include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.

Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia / markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients at risk of thrombotic events, administer PANZYGA at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity.[3-5] (See BOXED WARNING, DOSAGE and ADMINSTRATION [2], PATIENT COUNSELING INFORMATION [17]) 5.5 Aseptic Meningitis Syndrome Aseptic meningitis syndrome (AMS) may occur with PANZYGA treatment.

Discontinuation of treatment has resulted in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to two days following infusion with PANZYGA. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting. Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dl, but negative culture results. Conduct a thorough neurological examination in patients exhibiting such symptoms and signs, including CSF studies, to rule out other causes of meningitis. Patients with a history of migraine may be more susceptible. [6] AMS may occur more frequently following high doses (≥ 2 g/kg) and/or rapid infusion of IGIV.

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5.6 Hemolysis PANZYGA may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin test (DAT) (Coombs’ test) result and hemolysis.

Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration and acute hemolysis, consistent with intravascular hemolysis, has been reported. Cases of severe hemolysis-related renal dysfunction/failure or disseminated intravascular coagulation have occurred following infusion of IGIV. The following risk factors may be associated with the development of hemolysis following IGIV administration: high doses (e.g., 2 g/kg or more), given either as a single administration or divided over several days, and non-O blood group.

[7] Other individual patient factors, such as an underlying inflammatory state (as may be reflected by, for example, elevated C-reactive protein or erythrocyte sedimentation rate), have been hypothesized to increase the risk of hemolysis following administration of IGIV [8], but their role is uncertain. Hemolysis has been reported following administration of IGIV for a variety of indications, including ITP. Closely monitor patients for clinical signs and symptoms of hemolysis, particularly patients with risk factors noted above. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit prior to infusion and within approximately 36 to 96 hours post-infusion.

If clinical signs and symptoms of hemolysis or a significant drop in hemoglobin or hematocrit have been observed, perform confirmatory laboratory testing, including direct antiglobulin test. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis.

5.7 Transfusion-Related Acute Lung Injury (TRALI) Noncardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] may occur in patients administered IGIV.[9] TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Signs and symptoms typically appear within 1 to 6 hours after transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support.

Monitor recipients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-HLA and anti-neutrophil antibodies in both the product and patient’s serum.

5.8 Hypertension Elevations of systolic blood pressure to 180 mm Hg or more and/or of diastolic blood pressure to more than 120 mm Hg (hypertensive urgency) can be observed during and/or shortly following infusion of IGIV. Such elevations are reported more often among patients with a history of hypertension. Check patients for a history of hypertension and current antihypertensive medication use. Monitor blood pressure prior to, during, and following PANZYGA infusion.

5.9 Volume Overload Carefully consider the relative risks and benefits before prescribing the high dose regimen (for chronic ITP) in patients at increased risk of volume overload.

5.10 Transmission of Infectious Agents Because PANZYGA is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses and theoretically, the variant Creutzfeldt-Jakob disease and Creutzfeldt-Jakob disease (CJD) agent. The risk of infectious agent transmission has been reduced by screening plasma donors and by including virus inactivation/removal steps in the manufacturing process of PANZYGA. Report all infections thought by a physician or other healthcare provider to have been possibly transmitted by this product to Octapharma at 1-866-7664860. Discuss the risks and benefits of PANZYGA with the patient before prescribing or administering this product.

5.11 Monitoring Laboratory Tests – After infusion of immunoglobulin, the transitory rise of the passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation.

– Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test. Clinically assess patients with known renal dysfunction, diabetes mellitus, age greater than 65 years, volume depletion, sepsis, paraproteinemia, or those receiving nephrotic agents, and monitor as appropriate (BUN; serum creatinine, urine output) during therapy with PANZYGA. – Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with polycythemia, cryoglobulins, fasting chylomicronemia/markedly high triglycerides, or monoclonal gammopathies.

– Consider measuring hemoglobin or hematocrit at baseline and approximately 36 to 96 hours post-infusion in patients at higher risk of hemolysis.

If signs and/or symptoms of hemolysis are present after an infusion of PANZYGA, perform appropriate laboratory testing for confirmation.

– If TRALI is suspected, perform appropriate tests for the presence of antineutrophil antibodies in both the product and patient’s serum.

6 ADVERSE REACTIONS PI: The most common adverse reactions observed at a rate of more than 5% in subjects in clinical trials were: headache, abdominal pain, fever, nausea, and fatigue.

Chronic ITP in adults: The most common adverse reactions observed at a rate of more than 5% in subjects in clinical trials were: headache, fever, nausea, vomiting, dizziness, and anemia.

CIDP in adults: The most common adverse reactions observed at a rate of more than 5% in subjects in clinical trials were: headache, fever, dermatitis, and blood pressure increased.

The most serious adverse reaction observed with PANZYGA treatment during clinical trials was aseptic meningitis in one subject.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a product cannot be directly compared to rates in the clinical trials of another product and may not reflect the rates observed in clinical practice.

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Treatment of Primary Humoral Immunodeficiency (PI) In a prospective, open-label, single-arm, multicenter study in 51 children and adults with PI, subjects received PANZYGA at a dose between 200 to 800 mg/kg body weight every 3 or 4 weeks. Subjects participated in the study for a mean of 360 days. Infusions were initiated at a rate of 1 mg/kg/minute for the first 30 minutes, and, if tolerated, could be advanced to a maximum tolerated rate not exceeding 8 mg/kg/minute. The mean age of subjects was 26.8 years (range: 2 to 65 years).

This study was followed by an extension study that evaluated the safety of PANZYGA administered at higher infusion rates in 21 subjects that successfully had completed the first study. Nineteen of the 21 enrolled patients received PANZYGA up to the maximum allowed infusion rate of 14 mg/kg/minute. In the extension study, medication-related adverse events were reported in 4 of 21 subjects (19%). Adverse reactions occurring in more than 5% of subjects were nausea (9.5%) and headache (9.5%).

In the study in PI, infusion-related adverse events (during or within 72 hours after the end of infusion) were reported in 16 patients (76%) enrolled in the 3-weeks treatment schedule and in 22 patients (73%) in the 4-weeks treatment schedule. Overall, 38 infusions (5%) had at least one adverse event considered related to study medication: 5 infusions (3%) in children, 4 infusions in adolescents (2%), and 29 infusions (8%) in adults. Study medication-related (possible or probable) infusion-related adverse reactions were associated with 35 infusions (5%) (overall); study medication-related headache was noted in 21 infusions (3%).

Table 1: Adverse Reactions* Occurring in more than 5% of Subjects with PI Adverse Reaction

No. of Subjects with Adverse Reaction (percentage of subjects)

Headache

11 (22%)

Abdominal pain (upper)

7 (14%)

Fever

7 (14%)

Nausea

5 (10%)

Sinusitis

4 (8%)

Fatigue

3 (6%)

Bronchitis

3 (6%)

* Any infusional and any study medication related adverse events.

Treatment of Chronic Immune Thrombocytopenia (ITP) in Adults In a prospective, open-label, single-arm, multicenter study, 40 adult subjects with chronic ITP received PANZYGA at a dose of 2 g/kg, administered daily as 1 g/kg intravenous infusions on 2 consecutive days. 3/40 subjects did not receive a second infusion of PANZYGA due to infusion reactions, including chills, headache, fever and nausea. All subjects except 1 received at least 1 infusion with the highest rate of 8 mg/kg/minute. Pre-medication to alleviate potential adverse drug reactions was not allowed in the study.

There were 67 treatment emergent adverse events (TEAEs) reported in 24 (60%) subjects that were related to administration of PANZYGA. 55 of these adverse events (82%) were infusional adverse events that occurred within 72 hours after start of the infusion. Seven of these adverse events in 2 subjects were severe. These included headache, nausea, vomiting and chills.

When analyzed by infusion, infusion-related adverse events were reported in 33 of the 77 infusions (43%).

Table 2: Adverse Reactions* Occurring in more than 5% of Subjects with Chronic ITP in Adults Adverse Reaction

No. of Subjects with Adverse Reaction (percentage of subjects)

Headache

20 (50%)

Fever

9 (23%)

Nausea

7 (18%)

Vomiting

4 (10%)

Dizziness

4 (10%)

Anemia

4 (10%)

* Any infusional and any study medication related adverse events.

One out of 40 subjects with ITP treated with PANZYGA developed aseptic meningitis on Day 2 of the infusion. This subject was managed with antibiotics and supportive care with recovery.

Baseline direct Coomb’s test was performed in 39/40 subjects that were treated with PANZYGA. 10/39 (26%) subjects subsequently developed positive Coomb’s test. One subject was not tested at baseline but had positive results on all 3 subsequent visits. Four of these subjects (10%) developed hemolytic anemia after receiving PANZYGA. These resolved spontaneously without any intervention.

Treatment of Chronic Inflammatory Demyelinating Polyneuropathy in Adults In a prospective, double-blind, randomized, multicenter study, 142 adult subjects with CIDP aged between 18 and 83 years were enrolled and randomized 1:2:1 to receive first a loading dose of 2 g/kg and then 0.5 g/kg, 1.0 g/kg or 2.0 g/kg PANZYGA for 7 maintenance infusions at 3-week intervals during the 24-week Dose-evaluation Phase (mean doses administered – including loading and rescue doses – were 0.91, 1.24 and 1.97 g/kg for 0.5, 1 and 2g/kg group, respectively).

All 142 subjects in this study received at least 1 dose of PANZYGA. The median maximum infusion rate was 0.12 mL/kg/min throughout the study in all dose groups. Seventy-three out of the 142 subjects experienced a total of 209 adverse reactions (AR). Table 3 summarizes the most frequent ARs that occurred in more than 5% of subjects. Generally, the incidence of ARs was similar across the dose groups; the only AR where a dose effect was evident was headache, with an incidence of 2.9% in the 0.5 g/kg group, 14.5% in the 1.0 g/kg group and 23.7% in the 2.0 g/kg group. Pre-medication for AEs was only allowed in subjects who had adverse events during 2 consecutive infusions. During the study 11 subjects (7.75%) received premedication.

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Table 3: Adverse Reactions* Occurring in more than 5% of Adult Subjects with CIDP Adverse Reaction

No. of Subjects with Adverse Reaction (percentage of subjects)

Headache

21 (14.8%)

Fever

20 (14.1%)

Dermatitis

14 (9.9%)

Blood Pressure Increased

11 (7.7%)

* Any infusional and any study medication related adverse events.

Two serious adverse reactions (headache and vomiting) were reported in one subject but did not lead to discontinuation of PANZYGA. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of PANZYGA. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders Leucopenia, hemolysis, pancytopenia Immune system disorders Hypersensitivity (e.g., anaphylaxis), anaphylactic shock, anaphylactic reaction, anaphylactoid reaction, allergic reaction, angioedema, face edema Metabolic and nutritional disorders Fluid overload, (pseudo)hyponatremia Psychiatric disorders Agitation, confusional state, anxiety, nervousness Nervous system disorders Coma, loss of consciousness, seizures, (acute) encephalopathy, cerebrovascular accident, stroke, aseptic meningitis, migraine, speech disorder, paraesthesia, hypoesthesia, photophobia, tremor Cardiac disorders Myocardial infarction, cardiac arrest, angina pectoris, tachycardia, bradycardia, palpitations, cyanosis Vascular disorders Hypotension, (deep vein) thrombosis, peripheral circulatory failure/collapse, hypertension, phlebitis, pallor Respiratory, thoracic and mediastinal disorders Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, respiratory failure, pulmonary embolism, pulmonary edema, bronchospasm, dyspnea, hypoxia, wheezing, cough Gastrointestinal disorders Diarrhea, hepatic dysfunction, abdominal discomfort Skin and subcutaneous tissue disorders Eczema, urticaria, rash (erythematous), pruritus, alopecia, Stevens-Johnson syndrome, epidermolysis, skin exfoliation, erythema (multiforme), dermatitis (e.g., bullous dermatitis) Musculoskeletal and connective tissue disorders Back pain, arthralgia, myalgia, musculoskeletal pain, muscle stiffness, pain in extremity, neck pain, muscle spasm Renal and urinary disorders Acute renal failure, osmotic nephropathy, renal pain General disorders and administration site conditions Injection site reaction, chills, chest pain or discomfort, hot flush, flushing, flu-like illness, feeling cold or hot, edema, hyperhidrosis, malaise, asthenia, lethargy, burning sensation Investigations Hepatic enzymes increased, oxygen saturation decreased, falsely elevated erythrocyte sedimentation rate, positive direct antiglobulin (Coombs’) test 7 DRUG INTERACTIONS Clinical studies have not evaluated mixtures of PANZYGA with other drugs and intravenous solutions. It is recommended that PANZYGA is administered separately from other drugs or medications which the patient may be receiving.

Do not mix the product.

Do not mix PANZYGA with IGIVs from other manufacturers.

Passively transferred antibodies in immunoglobulin preparations can confound the results of serological testing, e.g. false positive Treponema pallidum testing might occur.

Antibodies in PANZYGA may interfere with the response to live viral vaccines, such as measles, mumps, and rubella. Inform physicians of recent therapy with PANZYGA, so that administration of live viral vaccines, if indicated, can be appropriately delayed for 3 or more months from the time of PANZYGA administration.

8

USE IN SPECIFIC POPULATIONS

8.1 Pregnancy Risk Summary No human data are available to indicate the presence or absence of drugassociated risk. Animal reproduction studies have not been conducted with PANZYGA. It is also not known whether PANZYGA can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.

Immune globulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

8.2 Lactation Risk summary No human data are available to indicate the presence or absence of drugassociated risk. The developmental and health benefits of breastfeeding should

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be considered along with the mother’s clinical need for PANZYGA and any potential adverse effects on the breastfed infant from PANZYGA or from the underlying maternal condition.

8.4 Pediatric Use Treatment of Primary Humoral Immunodeficiency (PI) PANZYGA was evaluated in 25 pediatric subjects (age range: 2-15 years). Twentyfive percent of PI subjects exposed to PANZYGA were children (between 2 and 12 years of age). Pharmacokinetics, efficacy and safety were similar to those in adults. No specific dose requirements were necessary to achieve the targeted serum IgG levels in the pediatric subjects.

Treatment of Immune Thrombocytopenia (ITP) in children The safety and effectiveness of PANZYGA have not been established in pediatric patients with ITP. Treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in children The safety and effectiveness of PANZYGA have not been established in pediatric patients with CIDP. 8.5 Geriatric Use Clinical studies of PANZYGA in PID and ITP did not include sufficient numbers of subjects older than 65 years to determine whether they respond differently from younger subjects.

In the clinical study the safety and effectiveness of PANZYGA in subjects with CIDP older than 65 years was similar to those 65 years of age and younger. A total of 36 subjects older than 65 years were included in the clinical trial.

Patients older than 65 years of age may be at increased risk for developing adverse reactions such as thromboembolic events and acute renal failure (See Boxed Warnings and Thrombotic Events (5.4) and Renal Failure (5.2). Do not exceed recommended doses in this population, and apply the minimum practicable infusion rate.

10 OVERDOSAGE With intravenous administration, overdose may lead to fluid overload and hyperviscosity. Patients at risk of complications of fluid overload and hyperviscosity include elderly patients and those with cardiac or renal impairment.

11 DESCRIPTION Immune Globulin Intravenous (Human), PANZYGA, is a solvent/detergent (S/D)treated, sterile preparation of highly purified immunoglobulin G (IgG) derived from large pools of human plasma. PANZYGA is a solution for infusion to be administered intravenously.

This preparation contains approximately 100 mg of protein per mL (10%), of which not less than 96% is normal human immunoglobulin G. PANZYGA contains not more than 3% aggregates, not less than 90% monomers and dimers, and not more than 3% fragments. On average, the product contains 100 µg/mL of IgA, and lower amounts of IgM. PANZYGA contains only trace amounts of sodium, and the pH is between 4.5 and 5.0. The osmolality is in the range of 240-310 mosmol/kg.

The manufacturing process for PANZYGA isolates IgG without additional chemical or enzymatic modification, and the Fc portion is maintained intact.

PANZYGA contains the IgG antibody activities present in the donor population.

IgG subclasses are fully represented with the following approximate percents of total IgG: IgG1 is 65%, IgG2 is 28%, IgG3 is 3% and IgG4 is 4%.

PANZYGA contains a broad spectrum of IgG antibodies against bacterial and viral agents that are capable of opsonization and neutralization of microbes and toxins. PANZYGA contains glycine (15.0-19.5 mg/mL), but no preservatives or sucrose.

All units of human plasma used in the manufacture of PANZYGA are provided

by FDA-approved blood and plasma establishments, and are tested by FDAlicensed serological tests for HBsAg, antibodies to HCV and HIV and Nucleic Acid Test (NAT) for HCV and HIV-1 and found to be non-reactive (negative).

The product is manufactured by the cold ethanol fractionation process followed by purification methodologies, as well as S/D treatment and nanofiltration (20 nm). The S/D mixture used is composed of tri-n-butyl phosphate (TNBP, solvent) and Triton X-100 (Octoxynol, detergent). The PANZYGA manufacturing process shows significant viral reduction and inactivation, demonstrated by in vitro infectivity studies (Table 4). The virus safety of PANZYGA is achieved through a combination of various process steps, including S/D treatment, ionexchange chromatography, and nanofiltration (20 nm).

Table 4 shows the virus clearance during the manufacturing process for PANZYGA, expressed as the mean log10 reduction factor (LRF).

Table 4: Virus Reduction by PANZYGA Manufacturing Process Virus Reduction Factor [log10] Production Step

S/D treatment Ion-exchange chromatography

Non-Enveloped Viruses

Enveloped Viruses HIV-1

PRV

BVDV

MEV

PPV

≥ 4.67

≥ 6.59

≥ 4.47

n.a.

n.a.

n.d.

n.d.

n.d.

5.88

5.83

Nanofiltration (20 nm)

≥ 4.70

≥ 6.57

≥ 3.69

≥ 5.78

5.78

Global reduction factor

≥ 9.37

≥ 13.16

≥ 8.16

≥ 11.66

11.61

HIV-1: Human Immunodeficiency Virus – 1, a model for HIV-1 and HIV-2; PRV: Pseudorabies Virus, a model for large enveloped DNA viruses (e.g., herpes virus); BVDV: Bovine Viral Diarrhea Virus, a model for e.g., Hepatitis C virus (HCV) and West-Nile virus (WNV); MEV: Mouse Encephalomyelitis virus, a model for Hepatitis A virus (HAV); PPV: Porcine Parvovirus, a model for Human Parvovirus B19; n.a.: not applicable; n.d: not done.

8

Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents. [10] Several of the individual production steps in the PANZYGA manufacturing process were shown to decrease TSE infectivity of that experimental model agent.

TSE reduction steps include ion-exchange chromatography and nanofiltration, which together give a total of at least 10.4 log10 decrease of infectivity. These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed.

Table 6: Mean IgG trough levels in subjects with CIDP

12

CLINICAL PHARMACOLOGY

12.1 Mechanism of Action Treatment of Primary Humoral Immunodeficiency (PI) PANZYGA supplies a broad spectrum of opsonic and neutralizing IgG antibodies against bacteria or their toxins. The mechanism of action in PI has not been fully elucidated.

Treatment of Chronic Immune Thrombocytopenia (ITP) in Adults The mechanism of action of immunoglobulins in the treatment of chronic ITP in adults has not been fully elucidated.

Treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in Adults The mechanism of action of immunoglobulins in the treatment of CIDP in adults has not been fully elucidated.

12.2 Pharmacodynamics PANZYGA contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against various infectious agents reflecting the IgG activity found in the donor population. PANZYGA which is prepared from pooled material from not less than 1000 donors, has an IgG subclass distribution similar to that of native human plasma. Adequate doses of IGIV can restore abnormally low IgG level to the normal range. Standard pharmacodynamic studies were not performed.

12.3 Pharmacokinetics Treatment of Primary Humoral Immunodeficiency (PI) In the PI study, 50 pediatric and adult subjects underwent pharmacokinetic assessments. Subjects received infusions of PANZYGA (200 to 800 mg/kg body weight) every 3 or 4 weeks for 12 months. Blood samples for PK study were collected between the 7th and 9th PANZYGA infusion, depending on the individual treatment schedule.

Table 5a and 5b summarize the pharmacokinetic parameters of PANZYGA, based on serum concentrations of total IgG, in subjects receiving infusions every 3, or 4 weeks, respectively.

Table 5: PI Study- Pharmacokinetic Parameters of PANZYGA in Subjects a) PK Parameters: IgG Arm: 3-weeks Parameter N Cmax (mg/mL) AUC (0-tau) (mg*hr/ mL) CL (mL/hr per kg) Vss (mL/ kg) Half-life (days)

Mean SD Mean SD

Mean SD Mean SD Mean SD

Baseline Uncorrected Baseline Corrected 0-<6 6-<12 12-<16 16-75 0-<6 6-<12 12-<16 16-75 Years Years Years Years Years Years Years Years 1 4 8 8 1 4 8 8 18.5 20.0 21.2 23.7 8.8 9.2 9.0 10.9 (3.6) (7.0) (5.9) (1.1) (4.1) (3.9) 6027 7278 7331 8176 1138 1797 1177 1718 (1808) (2168) (1831) (602) (515) (622)

0.1 101 36.1

0.08 (0.02) 99 (5) 32.1 (3.4)

0.06 (0.01) 85 (14) 42.6 (15.9)

0.06 (0.01) 66 (20) 32.4 (12.4)

0.4 67 4.8

0.32 (0.11) 78 (25) 5.9 (1.1)

0.42 (0.08) 59 (25) 4.3 (1.7)

0.30 (0.07) 54 (21) 5.1 (2.2)

b) PK Parameters: IgG Arm: 4-weeks Parameter N Cmax (mg/mL) AUC (0-tau) (mg*hr/ mL) CL (mL/hr per kg) Vss (mL/ kg) Half-life (days)

Mean SD Mean SD

Baseline Uncorrected 0-<6 6-<12 12-<16 16-75 Years Years Years Years 2 5 4 18 15.0 18.7 17.8 17.3 (1.6) (2.0) (3.8) (3.7) 6585 8088 7067 7660 (156) (1385) (1505) (2013)

Mean 0.08 SD (0.00) Mean 94 SD (20) Mean 36.1 SD (11.8)

0.06 (0.01) 131 (71) 71.8 (41.7)

0.07 (0.02) 61 (23) 27.5 (6.6)

0.06 (0.02) 79 (24) 45.1 (20.8)

Baseline Corrected 0-<6 6-<12 12-<16 16-75 Years Years Years Years 2 5 4 18 7.3 9.2 9.6 8.1 (2.2) (2.4) (3.8) (2.1) 1377 1672 1645 1539 (272) (1135) (1058) (648)

0.37 (0.06) 73 (30) 6.2 (1.2)

0.36 (0.19) 111 (85) 8.7 (7.2)

0.96 0.31 (1.49) (0.13) 584 82 (1056) (47) 7.3 7.7 (2.1) (4.5)

Treatment of Chronic Immune Thrombocytopenia (ITP) in Adults Pharmacokinetic studies with PANZYGA have not been performed in adults with chronic ITP. Treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in Adults Pharmacokinetic studies with PANZYGA have not been performed in adult patients with CIDP. The IgG trough levels were evaluated at each visit (Table 6) before the PANZYGA infusion. There was the option of rescue treatment with two consecutive infusions of 2.0 g/kg Panzyga at 3-week intervals (±4 days) for all subjects in the 0.5 and 1.0 g/kg Panzyga arms who were either stable at Week 6 or deteriorated after Week 3 and before Week 18. The actual administered dose for the three dose arms was: 0.91 ± 0.4 (n=35), 1.24 ± 0.2 (n=69) and 1.97 ± 0.2 (n=38) g/kg for 0.5, 1 and 2g/kg, respectively. There were no major differences among the three dose arms in demographic characteristics and baseline IgG levels. The percentage of increase in mean IgG from baseline to the end of study assessment was 46% in the 0.5 g/kg arm, 57% in the 1.0 g/kg arm and 91% in the 2.0 g/kg arm (Table 6).

9

IgG troughs (g/L) Visit / Time point

PANZYGA 0.5 g/kg

PANYZGA 1.0 g/kg

PANZYGA 2.0 g/kg

(N=35)

(N=69)

(N=38)

Visit 2 - Week 0

Mean (SD)

10.6 (3.1)

10.5 (2.5)

10.2 (3.0)

Visit 3 - Week 3

Mean (SD)

17.9 (3.5)

17.1 (3.1)

16.5 (3.3)

Visit 4 - Week 6

Mean (SD)

15.5 (3.0)

16.5 (3.3)

18.5 (4.0)

Visit 5 - Week 9

Mean (SD)

15.6 (3.3)

16.5 (3.0)

19.2 (4.4)

Visit 6 - Week 12

Mean (SD)

14.2 (2.6)

16.8 (3.8)

19.6 (4.3)

Visit 7 - Week 15

Mean (SD)

14.1 (2.7)

16.2 (3.4)

19.7 (4.4)

Visit 8 - Week 18

Mean (SD)

14.1 (2.3)

15.9 (3.1)

19.6 (5.2)

Visit 9 - Week 21

Mean (SD)

14.3 (2.3)

16.0 (3.0)

18.9 (3.5)

End of Study Week 24

Mean (SD)

15.5 (3.6)

16.5 (3.3)

19.5 (4.6)

13

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No animal studies were conducted on carcinogenesis, mutagenesis, or impairment of fertility with PANZYGA. 13.2 Animal Toxicology and/or Pharmacology Several standard nonclinical proof-of-concept and safety studies were performed with PANZYGA in animals. These included acute toxicity, pharmacokinetic, local tolerance, and safety pharmacology studies. PANZYGA. There were no adverse effects attributed to PANZYGA in the animal studies.

TNBP and Octoxynol-9 may be found in PANZYGA in trace amounts. In singleand repeated-dose toxicity studies in animals, these impurities caused no adverse effects when administered (alone or in combination) at doses multiple times higher than the equivalent human dose. A mixture of these compounds did not show teratogenic effects when administered to pregnant rabbits and rats during organogenesis.

14

14.2 Treatment of Chronic Immune Thrombocytopenia (ITP) in Adults A prospective, open-label, single-arm, multicenter study assessed the efficacy, safety, and tolerability of PANZYGA in 40 subjects with chronic ITP and a platelet count of 20 × 109/L or less. Subjects ranged in age from 18 to 72 years (median: 32 years); 43% were female and 57% were male. Ninety percent of the subjects were Caucasian and 10% were Asian.

Subjects received a 2 g/kg dose of PANZYGA administered as two daily 1 g/kg intravenous doses, given on 2 consecutive days. All but one patient received the maximum infusion rate of 8 mg/kg/minute, starting at 1 mg/kg/minute. Platelet counts were measured on Days 1 to 8, 15, and 22.

The study was designed to determine the response rate, defined as the percentage of subjects with an increase in platelet count to at least 50 × 109/L within 7 days after the first infusion (responders). Additionally, maximum platelet count, the time to reach a platelet count of at least 50 × 109/L within the first 7 days, the duration of that response (i.e., the number of days the platelet count remained in excess of 50 × 109/L), and the regression of hemorrhages in subjects who had bleeding at baseline were observed.

Of the 36 subjects in the full analysis set, 29 (81%: 95% CI: 64%-92%). responded to PANZYGA with a rise in platelet count to at least 50 × 109/L within 7 days after the first infusion. The lower bound of the overall 95% confidence interval for the response rate in all 36 subjects (64%) is above the predefined response rate of 60%.

Table 8 shows the median and mean of the maximum platelet count.

Table 8: Maximum Platelet Count (×109/L) ITP subjects (n=36) Median and range

196 (8 to 1067)

Mean ± standard deviation

237 ± 205

Table 7: Study 1 – Summary of Efficacy Results for subjects with PI Category

Result

Unit

Number of subjects

51

Subjects

Total number of subject days

18,349

Days

Annual rate of confirmed serious bacterial infections (SBIs)*

0.080

SBIs/person-year **

Annual rate of other infections

3.682

Inf./person-year

Number of subjects (%) with use of antibiotics

42 (82.4%)

Subjects (%)

Annual rate of use of antibiotics

87

Days/personyear

Absences from work or school due to Infection, number of days (%)

183 (1.0%)

Days (%)

3.6

Days/personyear

Annual rate of absences from work or school due to infection Hospitalization due to infection, number of days

4

Days

Annual rate of hospitalizations due to infection

0.1

Day/person-year

* Defined as bacteremia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia and visceral abscess ** Upper 1-sided 99% confidence interval: 0.503 Throughout the entire study, the serum IgG trough levels were nearly constant for both treatment schedules and were above the required trough levels of about 5-6 g/L. The calculated pharmacokinetic parameters showed that the minimum concentration of IgG was at least 6.8 g/L for both treatment intervals.

16 HOW SUPPLIED/STORAGE AND HANDLING PANZYGA is supplied in 1 g, 2.5 g, 5 g, 10 g, 20 g, and 30 g single-use bottles.

The table below shows the details of available presentations of PANZYGA.

Table 9 shows the median and mean of the time to and duration of platelet response.

Table 9: Time to and Duration of Platelet Response (Responders Only).

Time to Platelet Response (at least 50x109/L) (Days)

Duration of Platelet Response (Days)

ITP Subjects Responders (n=29)

ITP Subjects Responders (n=29)

Median and range

2 (1 to 4)

14 (1 to 20)

Mean ± standard deviation

1.8 ± 0.8

12.4 ± 5.8

CLINICAL STUDIES

14.1 Treatment of Primary Humoral Immunodeficiency (PI) Study 1: In a prospective, open-label, single-arm, multicenter study in 51 children and adults with PI, subjects received PANZYGA at a dose between 200 to 800 mg/kg body weight every 3 or 4 weeks. Subjects participated in the study for a mean of 360 days. Infusions were initiated at a rate of 1 mg/kg/min for the first 30 minutes, and, if tolerated, could be advanced to a maximum tolerated rate not exceeding 8 mg/kg/min. The mean age of subjects was 26.8 years (range: 2 to 65 years).

The primary efficacy endpoint was the number of episodes of serious bacterial infections per patient per year. Serious infection included pneumonia, bacteremia or sepsis, osteomyelitis/septic arthritis, visceral abscesses, or bacterial meningitis. Secondary efficacy variables included: occurrence of any infection of any kind or seriousness; time to resolution of infections; use of antibiotics; the number of days of work/school missed; the number and days of hospitalizations; and the number of episodes of fever.

For the primary endpoint, the observed rate was 0.08 serious bacterial infections per patient per year (4 infections over 50.2 patient-years).

Only 1 adult patient was hospitalized due to an infection for 4 days (overall rate of days in hospital per person-year: 0.080). Episodes of fever were observed for less than 25% of all patients. The mean resolution time was 14 days for serious bacterial infections and 18 days for other infections. Approximately 50% of all patients missed at least 1 day of work or school due to infections, with an annual rate of less than 4 days/person-year.

Table 7 summarizes the efficacy results for all 51 subjects.

Of the 36 subjects, 23 (64%) subjects had bleeding at baseline. Bleeding was minor in 14 subjects (39%), mild in 2 subjects (6%) and moderate in 7 subjects (19%). On Day 7, only 14% of subjects were bleeding (5/36). Persistent bleeding was mild in 1 and minor in 2 subjects. Information regarding bleeding resolution was missing in 2 subjects with moderate bleeding.

14.3 Treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in Adults The efficacy of PANZYGA in adults with CIDP was evaluated in a prospective, double-blind, randomized, multicenter study that enrolled 142 adult subjects (between 18 and 83 years of age) with CIDP who deteriorated in the Wash-out Phase, during which the current medication (immunoglobulins or corticosteroids) was reduced gradually. Subjects were randomized 1:2:1 to receive first a loading dose of 2 g/kg, and then 0.5 g/kg, 1.0 g/kg or 2.0 g/kg PANZYGA according to their respective dose arm for 7 maintenance infusions at 3-week intervals during the 24-week Dose-evaluation Phase. Subjects in the 0.5 g/kg and 1.0 g/kg arms had the option of rescue treatment with two consecutive infusions of 2.0 g/kg Panzyga at 3-week intervals if criteria were met [CLINICAL PHARMACOLOGY (12.3)].

Efficacy was based on the proportion of responders in the 1.0 g/kg PANZYGA arm at Week 24 relative to Baseline (Week 0). A responder was defined as a subject with a decrease of at least 1 point in the adjusted 10-point Inflammatory Neuropathy Cause and Treatment (INCAT) disability score at Week 24 relative to Baseline. The proportion of responders in the 1.0 g/kg arm was 79.71% (95% CI: 68.8, 87.5), with 55 out of 69 subjects classified as responders. Efficacy was supported by the proportion of responders in the 2.0 g/kg dose arm in the adjusted INCAT disability score, and the proportion of responders in the 1.0 g/kg and 2.0 g/kg dose arms in the grip strength, inflammatory Rasch-built Overall Disability Scale (I-RODS) and Medical Research Council (MRC) sum scores (Table 10).

Table 10: Responder rates for different efficacy scores and dose arms 1.0 g/kg N=69

2.0 g/kg N=36

Number (%) of responders

55 (79.7%)

33 (91.7%)

95% CI

68.8; 87.5

78.2; 97.1

Number (%) of responders

38 (55.1%)

26 (72.2%)

95% CI

43.4; 66.2

56; 84.2

Number (%) of responders

45 (65.2%)

30 (83.3%)

95% CI

53.4; 75.4

68.1; 92.1

Number (%) of responders

50 (72.5%)

31 (86.1%)

95% CI

61; 81.6

71.3; 93.9

Adjusted INCAT Disability Score

I-RODS

Grip Strength

MRC Sum Score

15 REFERENCES 1. Duhem C, Dicato MA, Ries F: Side-effects of intravenous immune globulins.

Clin.Exp.Immunol. 1994;97 Suppl 1:79-83.

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11

2. Steinberger BA, Ford SM, Coleman TA: Intravenous immunoglobulin therapy results in post-infusional hyperproteinemia, increased serum viscosity, and pseudohyponatremia. Am.J Hematol. 2003;73:97-100.

3. Dalakas MC: High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994;44:223-226.

4. Go RS, Call TG: Deep venous thrombosis of the arm after intravenous immunoglobulin infusion: case report and literature review of intravenous immunoglobulin-related thrombotic complications. Mayo Clin Proc 2000;75:83-85.

5. Wolberg AS, Kon RH, Monroe DM, et al: Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am.J.Hematol.

2000;65:30-34.

6. Sekul EA, Cupler EJ, Dalakas MC: Aseptic meningitis associated with highdose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern.Med 1994;121:259-262.

7. Kahwaji J, Barker E, Pepkowitz S, et al: Acute Hemolysis After High-Dose Intravenous Immunoglobulin Therapy in Highly HLA Sensitized Patients.

Clin J Am Soc Nephrol 2009;4:1993-1997.

8. Daw Z, Padmore R, Neurath D, et al: Hemolytic transfusion reactions after administration of intravenous immune (gamma) globulin: A case series analysis. Transfusion 2008;48:1598-1601.

9. Rizk A, Gorson KC, Kenney L, et al: Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001;41:264-268.

10. Radomski KU, Lattner G, Schmidt T, Römisch J: Pathogen Safety of a New Intravenous Immune Globulin 10% Liquid. BioDrugs 2017(2): 125-134

Carton NDC Number

Container NDC Number

Size

Grams Protein

68982 – 822 - 01

68982 – 822 - 81

10 mL

1.0

68982 – 822 - 02

68982 – 822 - 82

25 mL

2.5

68982 – 822 - 03

68982 – 822 - 83

50 mL

5.0

68982 – 822 - 04

68982 – 822 - 84

100 mL

10.0

68982 – 822 - 05

68982 – 822 - 85

200 mL

20.0

68982 – 822 - 06

68982 – 822 - 86

300 mL

30.0

PANZYGA is not supplied with an infusion set. If a filtered infusion set is used (not mandatory), choose a filter size of 0.2-200 microns.

Components used in the packaging of PANZYGA are not made with natural rubber latex.

Store PANZYGA for 36 months at +2°C to +8°C (36°F to 46°F) from the date of manufacture. Within its shelf-life, the product may be stored at ≤ +25°C (77°F) for up to 12 months. After storage at ≤ +25°C (77°F), either use immediately or discard the product.

Do not use after expiration date.

Do not freeze. Do not use frozen product.

PANZYGA contains no preservatives. The PANZYGA bottle is for single use only.

Use promptly any bottle that has been entered or opened, and discard partially used bottles.

Dispose of any unused product or waste material in accordance with local requirements.

17 PATIENT COUNSELING INFORMATION Inform patients of the signs and symptoms of hypersensitivity reactions including urticaria, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis, and to contact their physicians immediately if allergic symptoms occur.

Inform patients to immediately report the signs and symptoms of the following conditions to their physician: – Decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath, which may suggest kidney problems (see Renal Failure (5.2)).

– Symptoms of thrombosis which may include: pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body (see Thrombosis (5.4)) – Severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea and vomiting (see Aseptic Meningitis Syndrome (5.5)) – Increased heart rate, fatigue, yellowing of skin or eyes and dark-colored urine (see Hemolysis (5.6)) – Trouble breathing, chest pain, blue lips or extremities, fever (see TRALI (5.7)) Inform patients that PANZYGA is made from human plasma and may contain infectious agents that can cause disease (e.g., viruses, and theoretically, the CJD agent), and that the risk of infectious agent transmission has been reduced by (a) screening plasma donors for prior exposure to viruses, (b) testing the donated plasma for viral infections and (c) inactivating and/or removing viruses during manufacture.

Inform patients that administration of PANZYGA may interfere with the response to live viral vaccines such as measles, mumps and rubella, and to notify their immunizing physician of their therapy with PANZYGA. Manufactured by: Octapharma Pharmazeutika Produktionsges.m.b.H. Oberlaaer Strasse 235 1100 Vienna, Austria Distributed by: Octapharma USA, Inc. Paramus, NJ 07652

12