Download Immune Globulin Replacement Therapy

Medication Policy Manual
Policy No: dru020
Topic: Immune Globulin Replacement Therapy,
(IVIG, SCIG):
Carimune® NF
Bivigam®
®
Flebogamma DIF
Gammagard®
®
Gammagard S/D
Gammaplex®
®
Gamunex-C
Hizentra™
Hyqvia®
Octagam®
Privigen®
Date of Origin: January 1996
Committee Approval Date: April 13, 2015
Next Review Date: April 2016
Effective Date: May 1, 2015
IMPORTANT REMINDER
This Medical Policy has been developed through consideration of medical necessity, generally
accepted standards of medical practice, and review of medical literature and government
approval status.
Benefit determinations should be based in all cases on the applicable contract language. To the
extent there are any conflicts between these guidelines and the contract language, the contract
language will control.
The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to
dictate to providers how to practice medicine. Providers are expected to exercise their medical
judgment in providing the most appropriate care.
Description
Intravenous immune globulin (IVIG) and subcutaneous immune globulin (SCIG; Hizentra® or
Hyqvia®) are preparations containing antibodies purified from human blood. They are used in
the treatment of many different conditions resulting from immune deficiencies or other
immunologic conditions.
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Page 1 of 27
Policy/Criteria
I.
Most contracts require prior authorization approval of immune globulins prior to
coverage. Immune globulins may be considered medically necessary when criteria A
AND B below are met.
A.
Alternative Site of Care - for Washington, Oregon, and Idaho
commercial, fully insured members only (does not apply to Medicare)
Immune globulin replacement therapy is administered in a non-hospital
outpatient setting (also referred to as an “alternative site of care”; such as a
provider’s office, an infusion center, or home infusion), unless both of the
following criteria 1 and 2 below are met:
1.
All non-hospital outpatient settings are greater than 10 miles further
from the member’s home than the hospital outpatient setting.
AND
2.
The member’s home is not eligible for home infusion services (such as
home is not within the service area or is deemed unsuitable for care by
the home infusion provider).
NOTE: Alternative Site of Care criteria will be waived for payment of the first
dose, to allow for adequate transition time to arrange for a non-hospital
outpatient setting for the infusion.
AND
B.
At least one of the following diagnostic criteria 1. through 5. below is
met:
1.
Immunodeficiency (primary or acquired), as defined in criteria a. or
b.:
a.
A diagnosis of one of the following and documented
hypogammaglobulinemia (a low baseline serum IgG level):
i.
Primary humoral immunodeficiency diseases (PID) (as
defined in Appendix I).
ii.
HIV infected children (< 13 years of age) with
hypogammaglobulinemia.
iii.
Hematologic malignancy-related hypogammaglobulinemia:
A. Post-allogeneic bone marrow transplant (BMT)
B. B-cell medicated cancer [e.g., chronic lymphocytic
leukemia (CLL), B-cell lymphoma]
iv.
Hypogammaglobulinemic neonates, with a low birth weight
(less than 1500g) or in a setting with high baseline infection
rate or morbidity.
OR
b.
A diagnosis of dysgammaglobulinemia, primary or due to multiple
myeloma in patients with stable disease, and high risk of recurrent
infections despite prophylactic antibiotic therapy, patients with
poor IgG response to the pneumococcal vaccine, or have low normal
IgG levels during acute sepsis episodes.
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OR
2.
Hematologic disorders (immune-mediated), not responding to
alternative therapies, or at high risk of bleeding:
a.
Acquired Factor VIII inhibitor, when conventional therapy is
ineffective or not tolerated. (e.g., immunosuppressive therapy with
cyclophosphamide, steroids, or azathioprine).
OR
b.
OR
c.
OR
d.
OR
e.
OR
f.
Autoimmune hemolytic anemia (AIHA) not responding to
alternative therapies (e.g., steroids, immunosuppressive agents,
plasmapheresis, rituximab and/or splenectomy).
Fetal (neonatal) alloimmune thrombocytopenia (FAIT) with
documented diagnosis.
Idiopathic thrombocytopenia purpura, also known as “immune
thrombocytopenia,” (acute; ITP), when a rapid increase in platelet
count is necessary, such as in an acute bleeding episode or prior
an invasive procedure (including surgery, epidural anesthesia, or
Cesarean section).
ITP (chronic), when the platelet count is dangerously low, defined
as a platelet count less than 30,000 cells/mm3 in children, less
than 20,000 cells/mm3 in adults, or less than 30,000 cells/mm3
along with signs/symptoms of bleeding in adults.
ITP in pregnancy, when at least one of the following criteria are
met:
i.
Platelet counts less than 10,000/mm3 in the third
trimester, despite an adequate course of corticosteroids,
unless use of steroids are contraindicated, or not tolerated.
OR
ii.
Platelet counts less than 30,000/mm3 associated with
bleeding before vaginal delivery or C-section.
(For IVIG use in preparation for C-section or epidural
anesthesia, see criteria 2d. above)
OR
g.
OR
h.
Post-transfusion purpura (hemolytic transfusion reaction) in
severely affected patients.
Pure red cell aplasia (PRCA, viral) with documented parvovirus
B19 infection and severe anemia.
OR
3.
Neuromuscular disorders, when significant functional impairment is
present:
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a.
Acute inflammatory demyelinating polyneuropathy, including
Guillain-Barré syndrome (GBS), when one of criteria i. through iv.
below are met:
i.
Deteriorating pulmonary function tests.
OR
ii.
OR
iii.
OR
iv.
Rapid deterioration with symptoms for less than 2 weeks.
Rapidly deteriorating ability to ambulate.
Inability to walk independently for 10 meters.
OR
b.
Chronic inflammatory demyelinating polyneuropathy (CIDP)
when all of criteria i., ii., and iii. below are met:
i.
Significant functional disability.
AND
ii.
Documentation of slowing of nerve conduction velocity on
electromyogram (EMG)/ nerve conduction study (NCS).
AND
iii.
Documentation of elevated spinal fluid protein on lumbar
puncture OR a nerve biopsy confirming the diagnosis.
OR
Dermatomyositis (adult), with documented EMG abnormalities
and/or increased CPK levels, with associated severe disability
when steroid therapy is ineffective or not tolerated.
c.
OR
d.
Dermatomyositis (juvenile, JDM), with muscle weakness and
associated severe disability, with at least ONE of the following
documented diagnostic criteria below:
i.
Evidence of myositis, demonstrated by abnormality of
muscle biopsy, MRI, OR EMG.
OR
ii.
OR
e.
Increased muscle enzymes levels (such as CPK, AST, LDH,
and/or aldolase)
OR
iii.
Cutaneous changes, including heliotrope dermatitis (rash
on the upper eyelids) and Gottron's papules (papules over
the knuckles), not responding to oral corticosteroids,
methotrexate, and/or another oral immunosuppressant.
Lambert-Eaton myasthenic syndrome (LEMS) when other
treatment options are ineffective or not tolerated. (e.g.,
pyridostigmine bromide, azathioprine, and/or prednisone).
OR
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f.
OR
g.
Multifocal motor neuropathy (MMN) in patients with conduction
block.
Myasthenia gravis for the treatment of acute crisis (e.g.,
respiratory failure, swallowing difficulties) OR chronic
decompensation, when other treatments are ineffective or not
tolerated (e.g., plasmapheresis, pyridostigmine, azathioprine,
cyclosporine, and cyclophosphamide).
OR
h.
Paraneoplastic opsoclonus ataxia syndrome (Opsoclonusmyoclonus ataxia syndrome, OMS) in pediatric neuroblastoma
patients with significant functional impairment and not
responding to an adequate course of steroids (at least 3 to 7 days).
OR
i.
Pemphigoid, refractory immunobullous disease (e.g., bullous
pemphigoid, pemphigus foliaceus, pemphigus vulgaris) until
conventional treatment takes effect (e.g., immunosuppressive
agents and plasmapheresis).
OR
j.
Polymyositis in patients with severe active illness when other
treatments have been ineffective or not tolerated (e.g.,
corticosteroids, azathioprine, methotrexate, or cyclophosphamide).
OR
k.
Stiff-Person Syndrome when treatment with other agents is
ineffective or not tolerated. (e.g., diazepam, baclofen, clonazepam,
valproic acid, and clonidine).
OR
l.
Systemic lupus erythematosus, for severe active disease when
other interventions are ineffective or not tolerated (e.g.,
corticosteroids and immunosuppressive agents, such as
cyclophosphamide or azathioprine).
OR
4.
Transplant (solid organ), antibody-mediated rejection:
a.
Prevention of antibody (Ab)-mediated rejection: Prior to solid
organ transplant and in the peri-operative period, for patients at
high risk for Ab-mediated rejection, including highly sensitized
patients, and those receiving an ABO-incompatible organ.
OR
b.
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Treatment of antibody-mediated rejection (a.k.a. vascular
rejection, humoral rejection): following solid organ transplant and
confirmed by either biopsy or presence of panel reactive antibodies
(PRAs).
Page 5 of 27
OR
5.
Other Miscellaneous conditions, when criteria are met:
a.
Kawasaki syndrome, during the first ten days of diagnosis.
OR
b.
II.
Pediatric intractable epilepsy in candidates for surgical resection or
when other interventions are ineffective or not tolerated. Examples
of other interventions include, but are not limited to,
anticonvulsant medications, ketogenic diets, and steroids. [85]
Administration, Quantity Limitations, and Authorization Period
A.
OmedaRx does not consider immune globulins to be self-administered
medications.
B.
When prior authorization is approved, immune globulins may be authorized in
quantities as follows:
1.
Initial Authorization: Immune globulins may be authorized for the period
defined in Table 1, based on diagnosis, in a non-hospital outpatient
setting, unless waived per criteria I.A. above.
NOTE: Alternative Site of Care criteria will be waived for payment of the
first dose, to allow for adequate transition time to arrange for a nonhospital outpatient setting for the infusion.
2.
C.
Continued Authorization: If the diagnosis is eligible for re-authorization
(as listed in Table 1), the maximum number of infusions that may be
authorized per year are based on the diagnosis being treated.
Authorization shall be reviewed as follows to confirm that current medical
necessity criteria are met and that the medication is effective.
1. Initial authorization shall be reviewed at the end of the initial authorization
period (as defined in Table 1).
2. Continued authorization (after the initial period) shall be reviewed at least
annually, and clinical documentation indicating that there is disease stability
or improvement must be provided (such as decrease in infections or
improvement of functional impairment from baseline). In addition, for
patients with immunodeficiency (on replacement therapy) documentation of a
current low/normal IgG trough level must be provided at least annually,
except for those patients with dysgammaglobulinemia (such as those with
multiple myeloma).
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Table 1. Initial Authorization
Frequency/Duration
Indication
Reauthorization Criteria/Duration
May be given no more frequently
than:
Replacement Therapy - Immunodeficiency [with documented hypogammaglobulinemia (low IgG levels) or poor immune response
(dysgammaglobulinemia)]
Primary humoral immunodeficiency
disease (PID)
One dose per month x 12 months
Hematologic malignancy-related
hypogammaglobulinemia (e.g., CLL,
post-BMT)
One dose per month x 12 months
HIV+ children with
hypogammaglobulinemia
One dose per month x 12 months
Hypogammaglobulinemic neonates
One dose per month x 6 months
Documented current evidence of clinical improvement, such as
decreased occurrence of infections; x 12 months.
Hematologic disorders (immune-mediated)
Acquired Factor VIII Inhibitor
One dose per month x 6 months
Documented initial response and continued presence of Factor
VIII inhibitor; x 12 months
Autoimmune hemolytic anemia,
(AIHA)
One dose per month x 6 months
Documented initial response and recurrence of clinically
significant, symptomatic anemia; x 12 months
Fetal (neonatal) alloimmune
thrombocytopenia (FAIT)
One dose per week until the estimated
date of delivery.
No reauthorization
ITP (acute)
Up to four doses (authorization is for
up to a 6 month window).
May re-authorize under Chronic ITP; however, use of IVIG
chronically is generally discouraged, given the short duration of
action. On a chronic basis, IVIG may be indicated for ACUTE,
intermittent use in patients with episodes of acutely low platelets.
ITP (chronic)
One dose per month x 6 months. IVIG
treatment only covered until
conventional therapy takes effect.
Authorization x 6 months. Documented initial response to IVIG
and:
-Continued thrombocytopenia, defined as a platelet count of <
20,000 OR less than 30,000 cells/m3 and clinically significant
bleeding. OR
-Patient is scheduled for an invasive procedure with high risk of
bleeding.
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Frequency/Duration
Indication
Reauthorization Criteria/Duration
May be given no more frequently
than:
ITP in pregnancy
One dose per month until the
estimated date of delivery.
May re-authorize under Chronic ITP
Post-transfusion purpura (hemolytic
transfusion reaction)
Up to two doses in 2 weeks (authorization is for up to a 2 week window)
No reauthorization
Pure red cell aplasia (PRCA), viral
One dose per month x 6 months
Documentation of initial response, parvovirus, and recurrence of
significant anemia; x 12 months
Acute inflammatory demyelinating
polyneuropathy (including GBS)
One dose per month x 3 months
May re-authorize under Chronic IDP
Chronic inflammatory demyelinating
polyneuropathy (CIDP)
Dermatomyositis, refractory
One dose per month x 6 months
Documented functional improvement; x 12 months
One dose per month x 3 months.
Documented improvement in muscle strength and/or decreased
CPK levels; x 6 months
Lambert-Eaton myasthenic
syndrome
One dose per month x 6 months
Multifocal motor neuropathy (MMN)
One dose per month x 6 months.
Myasthenia gravis (acute and
chronic)
One dose per month x 6 months.
Paraneoplastic opsoclonus ataxia
syndrome
One dose (authorization is for up to a 2
week window)
Documented functional improvement; x 6 months.
Polymyositis
One dose per month x 3 months.
Documented improvement in muscle strength and/or decreased
CPK levels; x 6 months
Pemphigoid, refractory
No reauthorization
Stiff-Person syndrome
One dose per month x 6 months, until
conventional therapy takes effect.
One dose per month x 3 months.
Systematic lupus erythematosus
One dose per month x 6 months.
Documented improvement in muscle strength and/or decreased
CPK levels; x 6 months
Neuroimmunologic disorders
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Documented improvement in muscle function/strength; x 12
months
Documented functional improvement; x 6 months
Page 8 of 27
Frequency/Duration
Indication
Reauthorization Criteria/Duration
May be given no more frequently
than:
Transplant (solid organ)
Prevention of acute rejection (preand peri-operative)
Up to 4 doses pre-transplant, then 1
dose weekly for 4 weeks posttransplant. (not to exceed 8 doses total;
authorization is for up to a 3 month
window)
Further authorization may be considered under “Treatment of Abmediated rejection”
Treatment of antibody (Ab)-mediated
(humoral) rejection
One dose, once per rejection episode
(authorization is for up to a 2 week
window)
Documented improvement from previous course and confirmation
of another episode of rejection; one dose per rejection episode may
be authorized.
Kawasaki syndrome
Up to two doses given within 10 days of
symptom onset (authorization is up to
a 2 week window)
No reauthorization
Pediatric intractable epilepsy
One dose per month x 6 months.
Documented of significantly reduced frequency and/or duration of
seizures; x 6 months
Other Miscellaneous disorders
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III.
Subcutaneous administration of immune globulin (SCIG) is considered an alternative to
intravenous administration of immune globulin and may be considered medically
necessary when one of the criteria in Section I is met.
IV.
For Washington, Oregon, and Idaho commercial, fully insured members only
(does not apply to Medicare)
Immune globulin replacement therapy is considered not medically necessary when
administered in a hospital outpatient setting when an alternative site of care (nonhospital outpatient setting) is a treatment option (see Section I: Alternative Site of
Care).
V.
IVIG/SCIG is considered investigational when used for all other conditions, including,
but not limited to:
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
Acute disseminated encephalomyelitis (ADEM)
Acute lymphocytic leukemia
Acute renal failure
Adrenoleukodystrophy
Adult HIV infection
Alzheimer's disease
Aplastic anemia
Asthma
Atopic dermatitis
Autism
Behçet's syndrome (Behçet’s disease)
Cardiomyopathy, recent-onset dilated
Chronic fatigue syndrome
Clostridium difficile, recurrent
Cystic fibrosis
Diabetes
Diamond-Blackfan anemia
Endotoxemia
Heart block, congenital
Hemolytic anemia (other than autoimmune)
Hemophagocytic syndrome
Human T-lymphocyte virus-1 myelopathy
Hyper IgE syndrome
Immune mediated neutropenia
Inclusion body myositis
Infectious disease in high risk neonates and adults following surgery or trauma
Lumbosacral plexopathy
Multiple sclerosis
Narcolepsy/cataplexy
Neonatal hemochromatosis
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31.
32.
Neonatal hemolytic disease
Nephropathy, membranous
33.
Nephrotic syndrome
34.
Ophthalmopathy, euthyroid
35.
Paraproteinemic neuropathy
36.
Post-polio syndrome
37.
Recurrent spontaneous abortion
38.
Rheumatoid arthritis
39.
Systemic Sclerosis, diffuse cutaneous (dcSS)
40.
Stevens-Johnson Syndrome
41.
Still's Disease (Systemic Juvenile Immune Arthritis, SJIA)
42.
Surgery or trauma
43.
Thrombocytopenia, nonimmune
45.
Thrombotic Thrombocytopenic Purpura, including Hemolytic Uremic Syndrome
(TTP/HUS), neonatal autoimmune and transfusion refractory.
Tic disorder (Based on DSM Criteria)\
46.
Toxic epidermal necrolysis (TEN)
47.
Urticaria, delayed pressure
48.
Uveitis
44.
49.
50.
Vasculitic syndromes, other systemic (not specified above), such as antineutrophil
cytoplasmic antibody- (ANCA) associated vasculitis [microscopic polyangiitis
(MPA)], and eosinophilic granulomatosis with polyangiitis (EGPA) [Churg-Strauss
Syndrome (CSS)].
Von Willebrand’s syndromeWegener's (granulomatosis with polyangiitis, an
ANCA-associated vasculitis)
Position Statement
Summary
Intravenous immune globulin (IVIG)
-
-
All IVIG preparations are generally considered therapeutically interchangeable. [32-34]
Minor immunoglobulin A (IgA) and immunoglobulin G (IgG) subclass differences exist. [32-34]
IVIG preparations with low IgA content are used to minimize reactions in patients with
hypogammaglobulinemia and concurrent IgA deficiency or when anti-IgA antibodies are
present in a recipient. [32-34]
Differences in formulation may guide product selection (e.g., pre-mixed liquid vs. lyophilized
powder, 5% vs. 10%, low sucrose, low osmolarity).
Subcutaneous immune globulin (SCIG)
-
Hizentra® is an immune globulin product for subcutaneous use, approved for patients with
primary immune deficiency (PID). [81] It is available as a 20 % solution for weekly
subcutaneous infusion.
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-
-
-
-
-
Hyqvia® is also an immune globulin product for subcutaneous use, approved for patients
with PID, and is available as a 10 % solution for every three to four week subcutaneous
infusion. [105]Gammaked®, Gamunex-C®, and Gammagard liquid® are approved for both
intravenous and subcutaneous use for treatment of PID. [89-91] All three are available as a 10
% solution.
SCIG has a lower bioavailability than IVIG, so must be given in higher doses to achieve the
same serum IgG concentrations.
However, subcutaneous delivery may result in higher steady-state IgG levels due to less
variation in IgG levels.
Multiple injection sites (three to four) are necessary for weekly infusion (Hizentra,
Gammaked, Gamunex-C, Gammagard) for an average patient because of the volume that
must be infused, whereas Hyqvia may be infused monthly.
Hyqvia 10% is formulated with hyaluronidase, to allow for larger volume infusion at a single
injection site. Up to 600 mL (60 grams) may be given per injection site (for patients > 40 kg)
at an infusion rate up to 300 mL/hour. The recommended maximum dose per injection site
for Hizentra 20% is 25 mL (5 grams), given over a maximum of 25 mL/hour.
None of these products have been approved for SC administration for any other indications,
other than PID. Because other diagnoses usually require larger doses (based on grams per
kilogram) with a high volume per dose, subcutaneous administration is generally not
feasible.
Injection site swelling, redness, and itching were reported in the majority of patients.
Dosing Considerations and Therapeutic Levels for Replacement Therapy for Treatment of
Immunodeficiency with Hypogammaglobulinemia
-
A plasma IgG level of 200 mg/dL is often a common minimum target for patients being
considered for IVIG replacement therapy. [4]
In patients with mild to moderate IgG deficiency with levels of 300 mg/dL-400mg/dL, the
decisions to treat are based on clinical symptoms and antigenic challenge. [31]
Dosing adjustment in replacement therapy is based on clinical response and IgG levels. [4]
* The trough or steady state IgG level is obtained before scheduled infusions and
frequently guides IVIG dose selection.
* The minimum serum concentration of IgG necessary for protection has not been firmly
established. However, maintenance of serum trough IgG levels above 500 mg/dL has
been considered a sufficient target to prevent most systemic infections. [4, 31] Some
patients may require an IgG level of 400-500 mg/dL above their baseline value for
protection.
* In patients with severe hypogammaglobulinemia, IgG levels (trough) should be checked
every three to six months in growing children and every six to twelve months in adults.
[56]
-
Dosing of IVIG for conditions other than hypogammaglobulinemia do NOT require
monitoring of IgG levels. Efficacy in conditions other than hypogammaglobulinemia is based
on clinical response, including improvement or resolution of disease symptoms.
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-
New technologies and pharmaceuticals allow therapeutic services, such as infusion therapy,
to be administered safely, effectively, and much less costly outside of the hospital outpatient
setting. Alternative sites of care (such as doctor’s offices, infusion centers, and home
infusion) are well-established, accepted by physicians, and reduce the overall cost of care.
Clinical Efficacy
IMMUNODEFICIENCY (Primary or Secondary) - Replacement Therapy for
Hypogammaglobulinemia [1, 4-5, 27, 34, 43]
Primary humoral immunodeficiency diseases
* All available immune globulin replacement products are FDA-approved for use in
primary immunodeficiency (PID). [94]
* X-linked agammaglobulinemia (congenital agammaglobulinemia) occurs in male infants,
usually presenting in the first 3 years of life.
* Common variable immunodeficiency (CVID; acquired hypogammaglobulinemia; adult
onset hypogammaglobulinemia; dysgammaglobulinemia) is characterized by low to
normal IgG levels and inability to produce an antibody response to protein (e.g., tetanus)
or carbohydrate antigens (e.g., Pneumovax). Most patients experience severe recurrent
and/or chronic infections.
* Combined immunodeficiency syndromes, including Wiskott-Aldrich syndrome, are rare,
inherited syndromes.
* Immunoglobulin reference ranges vary depending on the age of the patient and the
particular assay method used. The usual immune globulin maintenance dose is 100800mg/kg/month and therapy is usually life-long.
* Serum trough levels should be maintained at 400 – 600 mg/dl. Documentation of the
rationale should be provided in the event that a trough level greater than 600 mg/dl is
required. [72]
* Hypogammaglobulinemic neonates
o
o
Treatment with IVIG is usually reserved for patients with recurrent severe
infections, not responding to antibiotic prophylaxis.
The usual IVIG dose is 400 – 600 mg/kg/month, administered as a single dose, or up
to several months in duration. [67]
Acquired Deficiencies:
- Hematologic malignancy-related hypogammaglobulinemia (including B-cell cancers,
multiple myeloma, and post-bone marrow transplant (BMT)
* Use of immune globulin replacement in hypogammaglobulinemic patients with B-cell
cancers (including CLL), multiple myeloma and post-allogeneic bone marrow transplant
(BMT) is supported by guidelines. [83, 100]
* IVIG therapy reduces the incidence of bacterial infections in patients with hematologic
malignancies to approximately 50% of the incidence without IVIG administration. [4, 34]
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* Previously, use of IVIG prophylaxis post-BMT was common for prevention of graft
versus host disease (GVHD); however, with improved immunosuppressant regimens, the
use of routine IVIG prophylaxis is no longer supported. [100]
* Monthly IVIG infusions of 400 mg/kg are recommended to maintain the serum IgG level.
-
HIV-infected children < 13 years of age [92]
* Current guidelines recommend IVIG use among HIV-infected children who have
hypogammaglobulinemia (IgG <400 mg/dL), to prevent serious bacterial infections
(SBIs).
* IVIG is no longer recommended for primary prevention of SBIs in children, unless
hypogammaglobulinemia is present. During the pre-HAART (highly-active antiretroviral
therapy) era, IVIG was shown to decrease the frequency of bacterial infections and
hospitalization in children with AIDS, however only in those not receiving daily
Pneumocystis carinii pneumoniae (PCP) prophylaxis.
AUTOIMMUNE (IMMUNE-MEDIATED) DISORDERS
-
-
Pooled immune globulin (IVIG) has been studied and found to be useful in a variety of
autoimmune disorders, including hematologic, neuromuscular and infectious disease-related
diseases. However, given the rarity of many of these disorders, the evidence for safety and
efficacy in some diagnoses is insufficient at this time.
The mechanism of action of IVIG in autoimmune disorders is thought to include acute
neutralization of circulating autoantibodies, toxins, and cytokine modulation, as well as
long-term reduction of antibody production and suppression of T-cell cytokines. [1]
Hematologic (immune-mediated) Disorders: [83]
Acquired Factor VIII inhibitor [21-25]
-
-
A sufficient treatment course is usually 6-12 weeks before attempting a different
immunosuppressive agent. Patients are generally treated until remission (elimination of the
inhibitor) occurs, which may take several months.
Treatment regimens of 1 gm/kg for 2 days or 400 mg/kg for 5 days have been studied. In one
study, only 6 of 19 patients responded to IVIG within 40 days of treatment. [60]
Fetal (neonatal) alloimmune thrombocytopenia (FAIT): [58, 83]
-
-
ACOG guidelines recommend IVIG as first line treatment for documented fetal
thrombocytopenia. [58]
A trial comparing IVIG treatment with and without dexamethasone in siblings showed
that:[2]
--
IVIG treatment was associated with an increase in mean platelet count of
69,000/mm3.
--
There were no instances of intracranial hemorrhages, although hemorrhage had
occurred previously in 10 untreated siblings.
The recommended dose of IVIG is 1 gm/kg/week, increasing to 2 gm/kg/week in refractory
cases. [59]
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Idiopathic thrombocytopenia purpura (ITP) [5,83, 84]
-
-
Normal platelet count range is 115,000/mm3 to 440,000/mm3.
Acute ITP
* In various studies, 64% to 100% of IVIG recipients attained platelet counts greater than
100,000 cells/mm3 within 7 days. [4, 34]
* A maximum of 1 gm/kg/day for three or four doses of IVIG on alternate days is
recommended. Acute ITP is usually seen in children and typically resolves
spontaneously within 2 months.
Chronic ITP [4, 8-10]
* Current evidence does not support that IVIG alters the natural course of chronic ITP,
affects long-term morbidity/mortality, or increases the rate of long-term remission.
* IVIG is not indicated for the maintenance of platelet counts in chronic ITP; however,
IVIG maybe be used episodically in patients with chronic ITP, for acutely low platelet
levels.
* Steroids and/or splenectomy are considered the first-line treatment of choice for chronic
ITP. Although the use of IVIG may be considered as a steroid-sparing adjunctive
therapy for chronic ITP, [5,83,84] other therapies with a more durable response should be
considered, such as splenectomy, rituximab (Rituxan), eltrombopag (Promacta) or
romiplostim (Nplate). [5,84]
* IVIG may be considered in patients with dangerously low platelet counts (less than
10,000 to 20,000 per mm3 in adults or less than 30,000 per mm3 in children) or patients
undergoing an invasive procedure, and therefore may be at an increased risk for
significant bleeding, such as intracranial hemorrhage.
* Choosing Wisely®, an evidence-based initiative to promote wise use of medical
resources, states that patients with ITP should not be treated in the absence of bleeding
or a very low platelet count. Only rarely should patients be treated when platelet counts
are above 30,000, such a preparation of surgery or an invasive procedure. Unnecessary
treatment exposes patients to potential adverse events and raises the overall cost of
care, with unknown clinical benefit. [106]
* The usual dose of IVIG is 1 to 2 gm/kg divided into equal amounts and given over 2 to 5
days.
-
ITP in pregnancy (a.k.a. Pregnancy-Associated ITP) [44,83,84]
* The goal of therapy is to minimize the risk of bleeding complications due to
thrombocytopenia. [44]
* Platelet function is typically normal so it is not necessary to maintain platelet count in
the normal range. [44]
* The first line of treatment is prednisone, usual dose 1-2mg/kg/day. [44]
* IVIG is useful in cases that are resistant to steroids and when a rapid rise in platelets is
necessary. A response typically occurs within 6 – 72 hours of IVIG treatment. [44]
* For patients nearing the end of their pregnancy and preparing for use of epidural
anesthesia, IVIG coverage will be considered under “ITP, acute” criteria, for use prior to
an invasive procedure. Because the evidence is less useful in determining the exact
threshold platelet levels needed for prevention of bleeding, the use of IVIG is generally
© 2015 OmedaRx. All rights reserved.
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Page 15 of 27
at the discretion of the treating anesthesiologist or surgeon, and pregnant patients are
managed like non-pregnant patients. [83,84]
* The American College of Obstetrics and Gynecology (ACOG) recognizes the high cost of
IVIG therapy and suggests consultation from a physician experienced in the treatment
of ITP when considering use of IVIG therapy. [44]
.
Post-transfusion purpura (hemolytic transfusion reaction)
-
Post-transfusion purpura is a rare condition that can occur in patients undergoing blood
transfusions. It typically develops approximately one-week after blood transfusion.
IVIG may be considered first-line therapy in severely affected patients. [1, 83]
The recommended dose of IVIG is 500 mg/kg/day for two consecutive days. Rapid platelet
recovery has been seen within days of treatment.
Pure Red Cell Aplasia (PRCA), Viral [83]
-
-
Parvovirus B19 infects and lyses red cell precursors, which can cause pure red cell aplasia.
IVIG therapy is usually reserved for patients with chronic parvovirus infection and chronic
anemia.
Chronic parvovirus infection with anemia usually occurs in immunocompromised patients.
If the immunodeficiency improves, the parvovirus and anemia may spontaneously resolve.
The usual dose of IVIG is 2-4 grams/kg, divided as 400 mg/kg/day for 5 – 10 days, 1
gm/kg/day for 3 days or 0.5 gm/kg weekly for 4 weeks. Initial treatment courses may be
indicated with recurrence of anemia and increase in parvovirus B19 DNA. [71,83]
Neuromuscular Disorders:
Inflammatory demyelinating polyneuropathy (IDP) [85, 86, 96]
-
-
Acute IDP, including Guillain-Barré syndrome (GBS) [57,97]
* IVIG appears to be effective in adult patients with Guillain-Barré syndrome when
given within 2 weeks of symptom onset.
* The recommended IVIG dose is 400 mg/kg/day for 5 days. If relapse occurs within 1-2
weeks of initial therapy, an additional treatment course of IVIG may be effective.
Further treatment does not improve outcomes and is not recommended.
Chronic IDP (CIDP)
* Treatment options include plasmapheresis, IVIG, and corticosteroids.
* The usual IVIG dose is 400 mg/kg/day for 5 days, repeated every 6 weeks.
Dermatomyositis (DM), adult and pediatric (juvenile)
-
High-dose IVIG is a safe and effective treatment for refractory dermatomyositis
unresponsive to corticosteroid therapy. [5,7,27,33,36, 85,86,95]
For adults, abnormalities on EMG or elevations in CPK are accepted diagnostic criteria.
Juvenile dermatomyositis (JDM) is characterized by a vasculopathy affecting both the
muscle and the skin. For pediatric patients, a number of muscle enzymes, including CPK,
LDH, AST or aldolase, may be used to confirm the diagnosis. Myositis may also be
confirmed by an abnormal muscle biopsy, EMG or MRI. Children can also have specific skin
manifestations associated with the dermatomyositis, including Gottron papules on the
dorsal surface of the knuckles and heliotrope rash over the eyelids. [107-109]
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dru020.22
Page 16 of 27
-
The recommended IVIG dose is 2 gm/kg per month.
Lambert-Eaton myasthenic syndrome (LEMS) [39, 85-87]
-
LEMS is a rare acquired autoimmune disorder characterized by proximal weakness of
extremities, decreased reflexes, and dryness of mouth and eyes.
Patients reported improved limb, respiratory muscle, and bulbar muscle strength with IVIG,
compared to placebo in a small randomized crossover trial (n = 9). [73]
The recommended dose of IVIG is 2 gm/kg administered over 2 – 5 days.
Multifocal motor neuropathy (MMN) [75-79, 85, 86]
-
Small controlled trials demonstrate significant increase in muscle strength associated with
IVIG administration, long-term benefits, and safety. [6,26]
The recommended IVIG dose is 2 gm/kg/month, administered over 2 – 5 days.
Conduction block is the hallmark of this disease. Additionally, patients with anti-GM1
antibodies show an increased chance of response to IVIG However, anti-GM antibodies are
present in only 30-80% of patients with MMN and are not specific to MMN. In addition,
patients who lack anti-GM1 antibodies may have a favorable response to IVIG; therefore the
clinical utility of monitoring anti-GM1 antibodies is uncertain. [75]
Myasthenia gravis (MG) [85, 86]
-
Randomized trials examining short-term treatment of myasthenia gravis with IVIG have
shown no difference between IVIG and plasma exchange or IVIG and methylprednisolone[69]
IVIG may be useful in treating patients with severe myasthenia gravis who fail to respond
to the maximum tolerated doses of corticosteroids and/or immunosuppressants. [70]
There is no evidence to determine whether IVIG improves function or reduces steroid
requirements for moderate to severe myasthenia gravis. [69]
The recommended dose of IVIG is 1 – 2 gm/kg/month administered over 2 – 5 days. [69]
Paraneoplastic opsoclonus ataxia syndrome (Opsoclonus-myoclonus) [85, 101]
-
-
-
Opsoclonus-myoclonus is a rare neurological syndrome characterized by an unsteady gait,
brief shock-like muscle spasms, and irregular rapid eye movements and can be a
paraneoplastic (e.g., with neuroblastoma) or non-paraneoplastic syndrome.
IVIG is a therapeutic option for pediatric neuroblastoma patients with paraneoplastic
opsoclonus ataxia syndrome, along with other immunologic treatments, including
glucocorticoids, cyclophosphamide, mycophenolate and plasma exchange. [85,101]
Evidence supporting the use of IVIG in this condition consists of retrospective chart reviews
and case reports. However, a randomized phase II trial is currently investigating the use of
IVIG in treating children with opsoclonus-myoclonus associated with neuroblastomas.
[73,74,102]
Refractory pemphigoid bullous (e.g., pemphigus foliaceus, pemphigus vulgaris) [27, 38, 88]
-
-
IVIG is typically given in combination with conventional treatments, such as
immunosuppressive agents and plasmapheresis, and is discontinued once conventional
treatment (such as corticosteroids, azathioprine, cyclophosphamide, etc.) takes effect. IVIG
is not considered a maintenance therapy for pemphigus foliaceus, pemphigus vulgaris or
other autoimmune mucocutaneous blistering diseases.
The usual dose of IVIG is 1-2 gm/kg administered over 3 days. This regimen may be
repeated every 3-4 weeks.
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dru020.22
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Polymyositis [85, 86, 95]
-
-
Polymyositis is an inflammatory myopathy with no unique clinical features. It is typically a
diagnosis of exclusion in patients with slowly progressive muscle weakness. Traditional
therapies include immunosuppressive medications or steroids.
IVIG may be considered for patients not responding to first-line immunosuppression.
The recommended dose of IVIG is 2 gm/kg/month administered over 2 – 5 days.
Stiff Person Syndrome [37, 85]
-
-
Sixteen patients were randomized to IVIG or placebo for 3 months, and then crossed over to
the alternate treatment after a 1 month washout period. IVIG patients demonstrated
decreased stiffness scores, decreased frequency of falls, ability to walk more easily without
assistance, and improved ability to perform work-related tasks. Benefits lasted 6 weeks to 1
year without additional treatment.
The usual dose of IVIG is 400 mg/kg/day for 3 – 5 days.
Systemic Lupus Erythematosus
-
Small case series suggest some benefit from treatment with IVIG when compared to
cyclophosphamide.
The usual dose of IVIG is 400 mg/kg/day for 5 days.
Transplant (Solid Organ) –
Antibody-mediated rejection [27, 98]
-
-
-
Acute allograft (organ) rejection may be cellular (T-cell mediated) or humoral (antibodymediated) (AHR, AMR).
Pre-treatment with IVIG (desensitization) may reduce the risk of AMR in highly sensitized
renal transplant patients. [27,98]
A randomized, double-blind trial comparing IVIG to placebo in 101 highly sensitized renal
transplant candidates concluded that IVIG is better than placebo in improving
transplantation rates. [68]
Acute humoral rejection (AHR) is also an AMR and can occur outside of the peri-operative
period, but most commonly within 6 months after transplant. The diagnosis is confirmed by
a renal biopsy. The goal of therapy is early antibody elimination with IVIG, pheresis, or a
combination of modalities.
A variety of protocols have been developed for the use of IVIG in treating AMR after solid
organ transplant. [27,98]
Other Miscellaneous Disorders:
Kawasaki syndrome
-
-
IVIG in conjunction with aspirin given within the first 10 days of illness can reduce the
incidence of coronary artery abnormalities by 65% - 78%, compared with treatment with
aspirin alone. [4, 34-35,99] IVIG is not effective if more than ten days have elapsed from onset of
symptoms.
The usual dose of IVIG is 2 gm/kg as a single dose, but may be repeated if the patient fails
to defervesce. [99]
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dru020.22
Page 18 of 27
INVESTIGATIONAL CONDITIONS [1, 5, 13-15, 17-20, 27, 46-52]
-
The University Hospital Consortium (UHC), an alliance of 68 academic health centers,
performed a critical assessment of off-label IVIG uses.
-
The UHC determined published data to be inadequate to support the use of IVIG in various
conditions. [1]
-
Asthma: Further trials in asthma patients are necessary to delineate patient subsets that
would best benefit from IVIG therapy, and define optimal dosing in this condition. [17-20]
-
HIV (adults): The use of IVIG in HIV-infected adults is not definitive to substantiate a
positive benefit on overall long-term health outcomes. [3]
-
Multiple sclerosis, progressive: There is not substantial evidence to support IVIG in the
treatment of chronic progressive multiple sclerosis. [28-30, 64]
-
Multiple sclerosis; relapsing-remitting type: IVIG may provide some benefit in reducing the
acute exacerbation rate in relapsing-remitting multiple sclerosis. [5, 27, 54]
*
Trials are generally limited to small numbers of patients and have lacked complete
data on clinical outcomes.
*
Current evidence suggests little benefit with regard to slowing disease progression.
*
The American Academy of Neurology does not consider IVIG to be a first-line therapy
in the treatment of relapsing-remitting multiple sclerosis.
-
Post-Polio: Two published trials of post-polio syndrome failed to demonstrate a statistically significant benefit compared to placebo in improvement of muscle strength. [65, 66]
-
Recurrent pregnancy loss, or recurrent spontaneous abortion (due to anti-phospholipid
or anti-cardiolipin antibodies):
*
Recurrent pregnancy loss is defined as three or more pregnancies resulting in
spontaneous abortion prior to 20 weeks of gestational age. These women often have
immunologic abnormalities, particularly antiphospholipid antibodies. [27]
*
IVIG has not been established as a safe or effective therapy to prevent recurrent
spontaneous abortion in women with immunologic abnormalities, such as elevated
natural killer cells, defective cytokines, or defective growth factors. [13-15, 62]
*
One randomized controlled trial comparing IVIG to thyroid replacement therapy for
the prevention of miscarriages found IVIG to be less effective. There was a
statistically significant higher rate of live birth among women treated with thyroid
replacement therapy. [61]
*
A small randomized controlled trial in 85 women with a history of three or more
spontaneous abortions before 10 weeks of gestation compared low molecular heparin
(LMW) plus aspirin with IVIG therapy. The percentage of live births in the LMW plus
aspirin versus the IVIG treatment group was 72.5% and 39.5%, respectively. [80]
*
A randomized controlled trial in 82 women with a history of idiopathic secondary
miscarriage compared live birth rates in those who received intravenous immune
globulin versus placebo infusion (saline). There was no statistical difference between
treatment groups. [82]
*
ACOG recommendations state:
© 2015 OmedaRx. All rights reserved.
dru020.22
Page 19 of 27
-
--
If results are positive for the same antibody on two consecutive tests 6 to
8 weeks apart, initiate heparin and low-dose aspirin with next pregnancy
attempt.
--
IVIG is not effective in preventing recurrent pregnancy loss. [55]
Additional conditions for which published data is determined to be inconclusive or
inadequate to support the use of IVIG include Alzheimer's disease, atopic dermatitis,
recurrent C. difficile, narcolepsy/cataplexy, neonatal hemochromatosis, chronic sinusitis,
tic disorder, delayed pressure urticaria, systemic sclerosis (diffuse cutaneous, dcSS) and
toxic epidermal necrolysis. [27, 46-52, 63,103, 104]
ALTERNATIVE SITE OF CARE:
-
-
-
-
-
Use of an alternative site of care, including non-hospital outpatient infusion centers and
home infusion services, is an accepted standard medical practice. These alternative sites
of care offer high-quality services for patients and reduce the overall cost of care, as
compared to a hospital-based infusion center.
All medications infused outside of a hospital setting (at an alternative site of care) have
undergone an evaluation for safe infusion and development of infusion standards,
including adverse drug reaction (ADR) management and reporting algorithms.
For use of an alternative site of care, every patient undergoes a patient assessment
during the intake process by the infusion provider, which includes evaluation of
individual clinical assessment parameters. These parameters may include, but are not
limited to, previous tolerance of products (such as IVIG), assessment of kidney function,
risk factors for developing thromboembolic events, and venous access.
For use of home infusion services, an assessment is conducted to determination whether
or not the home is a safe, appropriate site of care, with adequate support for infusion in
the home.
Because these “alternative site of care” providers need time to arrange for assessment
and coordinate the first dose of each new medication, the first dose of infused
medications may be covered in a hospital-based infusion center, if needed, to allow
adequate time for a seamless transition of care. This may include arranging for delivery
of medications and/or patient education, such as for self-administration of medications
such as subcutaneous immune globulin (SCIG).
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dru020.22
Page 20 of 27
Cross References
BlueCross BlueShield Association Medical Policy # 8.01.05; Intravenous Immune Globulin
Therapy (6/2013)
Maximum Drug Dosage Policy, Medication Policy Manual, Policy No. dru237
Nplate®, romiplostim, Medication Policy Manual, Policy No. dru162
Promacta®, eltrombopag, Medication Policy Manual, Policy No. dru180
Rituxan®, rituximab, Medication Policy Manual, Policy No. dru214
Codes
CPT
Number
Description
90780-90781 IV infusion for therapy
CPT
90284
Immune globulin (SCIg), human, for SC use
CPT
90283
Immune globulin (IVIG), human, for IV use
HCPCS
J1459
Injection, Immune Globulin (Privigen), IV, non-lyophilized (e.g., liquid)
500 MG
HCPCS
J1557
Injection, Immune Globulin (Gammaplex), IV, non-lyophilized (e.g.,
liquid) 500 MG
HCPCS
J1559
Injection, Immune Globulin (Hizentra), 100 mg
HCPCS
J1561
Injection, Immune Globulin, (Gamunex), IV, non-lyophilized, (e.g.,
liquid), 500 MG
HCPCS
J1566
Injection, Immune Globulin (Carimune), IV, lyophilized, 500 MG
HCPCS
J1568
HCPCS
J1569
HCPCS
J1572
Injection, Immune Globulin (Octagam), IV, non-lyophilized (e.g., liquid)
500 MG
Injection, Immune Globulin, (Gammagard), IV, non-lyophilized, (e.g.,
liquid), 500 MG
Injection, Immune Globulin, (Flebogamma), IV, non-lyophilized, (e.g.,
liquid), 500 MG
HCPCS
Unassigned
Immune Globulin, (BIVIGAM)
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Appendix I: Primary Humoral Immunodeficiencies, as defined by the following
diagnostic criteria:
1. X-linked agammaglobulinemia (congenital agammaglobulinemia) diagnosis accompanied by
marked deficits or absence of all five immunoglobulin classes (IgG, IgM, IgA, IgE, and IgD),
decreased circulating B lymphocytes, and normal numbers of functioning T lymphocytes.
OR
2. Hypogammaglobulinemia (a general term describing serum levels of IgG which are below the
lower limits of normal).
OR
3. Common variable immunodeficiency (CVID; acquired hypogammaglobulinemia; adult onset
hypogammaglobulinemia; dysgammaglobulinemia) documented with low to normal IgG
levels and the inability to produce an antibody response to protein (e.g., tetanus) or
carbohydrate antigens (e.g., Pneumovax).
OR
4. Immunoglobulin subclass deficiency (e.g., X-Linked immunodeficiency with hyper-IgM)
accompanied by very low serum concentrations of IgG, IgA, and IgE, with normal or, more
frequently, greatly elevated polyclonal IgM concentrations.
OR
5. Combined immunodeficiency syndromes, including Wiskott-Aldrich syndrome, accompanied
by marked deficits in IgG, IgA and IgM, low lymphocyte counts, and absent or below normal
levels of both B- and T-lymphocytes.
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