What's Happening in IV Gamma Globulin: Clinical Use and Costs

1. What's Happening in IV Gamma Globulin: Clinical Use and Costs Stacy M. Borans, MD Chief Medical Officer Advanced Medical Strategies stacy.borans@mdstrat.com

2. Learning ObjectivesFor Gamma Globulin • Understand the diseases for which IVIG therapy is appropriate • Identify when IVIG therapy is inappropriate • Understand the mechanism of action of IVIG therapy • Identify IVIG therapy dosage and duration for indicated diseases • Estimate the costs associated with IVIG therapy

3. What is Gamma Globulin? • A major class of immunoglobulins found in the blood, including many of the most common antibodies circulating in the blood. • Also called immunoglobulin G (IgG). • And immunoglobulins are????

4. What is Gamma Globulin? • Monomeric immunoglobulin which isbuilt of two heavy chains (γ) and two light chains • Each molecule has two antigen binding sites • Most abundant immunoglobulin • only immunoglobulin that can pass through the placenta

5. What is Gamma Globulin?

6. How does Gamma Globulin Work? • Binds to pathogens: • Viruses • Bacteria • Fungi • Protects the body from them in 3 ways: • Complement Activation • Opsonization for Phagocytosis • Toxin Neutralization

7. How does Gamma Globulin Work? • Complement Activation: • System of serum proteins interact in a cascade • Classical Pathway: activated by antibody-antigen complexes • Trigger for the classical pathway is either IgG or IgM antibody bound to antigen • Major part of human immune response

8. How does Gamma Globulin Work? • Phagocytosis: • Large particles are enveloped by larger particles’ cell membranes • Specialized cells perform phagocytosis to reduce inflammation • Involved in immune tolerance-prevents inflammation against normal body components • IGG coats the surface of foreign bodies making them more attractive to phagocytic cells

9. When should Gamma Globulin be given? • Primary Immunodeficiency Disorders: • congenital agammaglobulinemia • hypogammaglobulinemia • common variable immunodeficiency • severe combined immunodeficiency (SCID) • X-linked immunodeficiency with hyperimmunoglobulin M • Wiskott-Aldrich syndrome

10. When should Gamma Globulin be given? • Idiopathic thrombocytopenic purpura • Secondary immunodeficiency in chronic lymphocytic leukemia (CLL) • Pediatric HIV infection • Kawasaki syndrome • Prevention of graft versus host disease (GVHD) and infection in adult transplant recipient

11. Primary Immunodeficiency Disorders • Many different types of this • Genetic disorders: defective or mutative genes • Children with these disorders develop frequent, severe or unusual infections • Pneumonia • Thrush • Infections of the skin and mucous membranes in the eyes, mouth, and genital area

12. Primary Immunodeficiency Disorders • Diagnosis usually made with blood tests • Circulating IgG levels typically low in pertinent disorders • Treatment is usually multi-focused: • Antibiotics to target specific infections: May be used for preventative treatment • Gamma Globulin to increase antibody response • Cytokine Therapy: boost the immune system

13. Primary Immunodeficiency Disorders • Treatments do not cure the underlying disorder • Gamma Globulin administration: • 200-400 mg/kg administered monthly • Can be given more frequently • Minimum IgG level not established • Only curative treatment for these patients is bone marrow transplantation

14. When should Gamma Globulin be given? • CLL: B-cell type, prevention of recurrent bacterial infections • Pediatric HIV/ARC: prevention of serious bacterial infections • Allogenic Transplant Patients: • 20 years of age or older and • administered in the first 100 days after BMT and • manifested by interstitial pneumonia or infections

15. Gamma Globulin Dosage • B-cell Chronic Lymphocytic Leukemia: • 400 mg/kg every 3 to 4 weeks is recommended • Allogenic Transplant: • 500 mg/kg body weight on days -7 and -2 pretransplant • weekly through day 90 post-transplant • Pediatric HIV: • 400 mg/kg (8 mL/kg) body weight every 28 days

16. Idiopathic Thrombocytopenic Purpura • Low platelet count (thrombocytopenia) of no known cause (idiopathic). • Occurs most often in women over 40 years of age • Symptoms include bruising, nosebleeds, and bleeding gums • Acute and Chronic Forms: • lasting for 6 months or less or • Lasting for over 1 year

17. Idiopathic Thrombocytopenic Purpura • Mild ITP does not require treatment • Treat when: • platelets are under 10,000 or • Platelets under 50,000 and hemorrhage • Steroids are first line • Gamma Globulin reserved for life threatening cases

18. Idiopathic Thrombocytopenic Purpura • Gamma Globulin effect only temporary • Given in order to prevent splenectomy or • To help make the splenectomy procedure more safe • Usual Gamma Globulin Dosage: • Adults: 1-2 g/kg IV administered over 1-5 d • Peds: 1 g/kg once

19. Kawasaki Disease • Febrile Illness of childhood • Fever lasts for longer than 5 days and usually is quite high • Involves the skin, mouth, and lymph nodes • Untreated, the disorder can lead to cardiac complications-aneurysms

20. Kawasaki Disease • Has 3 phases: • Acute febrile phase (days 1-11) • Subacute phase (days 11-21) • Convalescent phase (days 21-60): • Some do add a 4th phase: chronic • Cardiac aneurysms are the only clinically significant manifestation of 4th phase • Treatment should begin within first 10 days

21. Kawasaki Disease • Gamma Globulin and Aspirin are mainstays of therapy • Patients also placed on anticoagulation • Gamma Globulin appears to be effective in improving the inflammation in the disease • Dosage/Duration • 400 mg/kg/d IV in a single daily infusion for 4 d or • single dose of 2 g/kg IV infused over 12 h

22. “Off-Label” Gamma Globulin Use • Several disorders have generally accepted use: • Guillain-Barré Syndrome • Lambert-Eaton Myasthenic Syndrome • Multifocal Motor Neuropathy • Multiple Sclerosis-Relapsing/Remitting • Chronic Inflammatory Demyelinating Polyneuropathies • Dermatomyositis/Polymyositis

23. Guillain-Barré Syndrome(Acute Inflammatory Demyelinating Polyneuropathy) • immune-mediated process generally characterized by motor, sensory, and autonomic dysfunction • Symptoms: • progressive symmetric ascending muscle weakness • Paralysis • Hyporeflexia (diminished reflexes) • Severe cases progress to respiratory failure • Patients may have prior infection

24. Guillain-Barré Syndrome(Acute Inflammatory Demyelinating Polyneuropathy) • Other causes are linked to GBS • Muscle weakness ascends from distal to proximal • Pain is most pronounced in shoulder, back, buttocks and thighs • Autonomic dysfunction is usually present: • Tachycardia/bradycardia • Blood pressure fluctuations • Urinary retention/constipation

25. Guillain-Barré Syndrome(Acute Inflammatory Demyelinating Polyneuropathy) • Diagnosis is usually made on clinical signs/symptoms • Lumbar Puncture and nerve conduction studies can be very helpful • Treatment is generally supportive and most patients make a complete recover within 6-12 months • Maximal recovery is seen 18 months after onset

26. Guillain-Barré Syndrome(Acute Inflammatory Demyelinating Polyneuropathy) • Treatment: • Steroids alone are ineffective • Plasma Exchange • Gamma Globulin: 400 mg/kg/d IV for 5 d • Both Plasma Exchange and Gamma Globulin are equally effective • Goal is to shorten recovery time by 50% • Mechanism of Action is unclear

27. Multifocal Motor Neuropathy • Acquired immune-mediated polyneuropathy • Progressive weakness, fasciculations and cramping • No sensory involvement • May resemble amyotrophic lateral sclerosis • No muscle atrophy • Slower progression

28. Multifocal Motor Neuropathy • Weakness is asymmetric and distal • Progresses over long time period • Duration of disease prior to diagnosis ranges from several months to more than 15 years. • Patients can remain productive and employed even with symptoms • Events leading to motor nerve dysfunction not completely understood

29. Multifocal Motor Neuropathy • 50% of cases have elevated titers of anti-GM1 antibodies • Electrodiagnostic testing documents conduction blocks • Upper Motor Neuron symptoms absent • Creatinine Kinase is usually elevated although less than 3 times normal

30. Multifocal Motor Neuropathy • Treatment: • Gamma Globulin and Cyclophosphamide are most effective • Plasmapheresis and steroids alone are ineffective • Gamma Globulin Dosage: • Initial dose: 2 g/kg IV over 2-5 days • Maintenance Dose: 1-2 g/kg IV q4-8wk

31. Toxic Shock Syndrome • Symptoms include fever, rash, hypotension and multi-organ involvement • Typically associated with tampon use in women • Organisms responsible are Staph Aureus and Strep Pyogenes • Patients are usually critically ill, often requiring respiratory and ventilatory support

32. Toxic Shock Syndrome • Staphylococcus TSS: • Fever, hypotension, and rash • Involvement of 3 or more organ systems • Absence of other diseases • Streptococcus TSS: • Isolation of group A strep from a site • Hypotension • Involvement of 2 or more organ systems

33. Toxic Shock Syndrome • An absence of immunity is considered to be a major risk factor • Gamma Globulin has been reported to be effective in toxin neutralization in TSS • Requires further studies to evaluate its use • Dosage: • 400 mg/kg IV as single dose infused over several hours • Patients require aggressive support and antibiotic therapy

34. Chronic Fatigue Syndrome Amyotrophic lateral sclerosis Autoimmune neutropenia Stevens Johnson Syndrome Recurrent Spontaneous Miscarriage Epilepsy Hemolytic Uremic Syndrome Rheumatoid Arthritis Alzheimer’s Disease Parkinson’s Disease Huntington’s Chorea Asthma Myocarditis Polymyositis Other Diseases

35. More Common: Gammagard Gamimune Gammar-P Sandoglobulin Gamunex Less Common: Flebogamma Iveegam Octagam Polygam Venoglobulin-S Gamma Globulin Preparations

36. Gamma Globulin Costs • Average Wholesale Price for 5 gram vial: • $600 • UCR (200% AWP): $1,200 • Average Wholesale Price for 10 gram vial: • $1,100 • UCR (200% AWP): $2,200

37. Gamma Globulin Costs • Average Reasonable Charges (75 kg patient): • 400mg/kg = 30,000 mg = 30 grams • AWP for three 10 gram vials = $3,300 • UCR Charges: $6,600/dose • Dose of 2g/kg = 150 grams • AWP for fifteen 10 gram vials = $16,500 • UCR Charges: $33,000/dose

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