• Hizentra: Thrombosis may occur with immune globulin products, including Hizentra. 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. For patients at risk of thrombosis, administer Hizentra 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.
• Gammagard Liquid: Thrombosis may occur with immune globulin products, including Gammagard. 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 Thrombosis may occur in the absence of known risk factors. For patients at risk of thrombosis, administer GAMMAGARD LIQUID 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 of hyperviscosity
  Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in predisposed patients with immune globulin intravenous (IGIV) products including GAMMAGARD LIQUID. Renal dysfunction and acute failure occur more commonly with IGIV products containing sucrose. GAMMAGARD LIQUID does not contain sucrose
• Gammunex-C: Thrombosis may occur with immune globulin products, including Gammunex-C. 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. For patients at risk of thrombosis, administer GAMUNEX-C 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.
  Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with immune globulin intravenous (IGIV) products in predisposed patients. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. GAMUNEX-C does not contain sucrose. For patients at risk of renal dysfunction or failure, administer GAMUNEX-C at the minimum concentration available and the minimum infusion rate practicable.
• Gammaked: Thrombosis may occur with immune globulin products, including Gammaked. 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. For patients at risk of thrombosis, administer GAMMAKED 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.
  Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with immune globulin intravenous (IGIV) products in predisposed patients. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. GAMMAKED does not contain sucrose. For patients at risk of renal dysfunction or failure, administer GAMMAKED at the minimum concentration available and the minimum infusion rate practicable.
• HyQvia: Thrombosis may occur with immune globulin products, including HyQvia. 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. For patients at risk of thrombosis, administer HYQVIA 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 of hyperviscosity.
• Cuvitru: Thrombosis may occur with immune globulin products, including Cuvitru. 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. For patients at risk of thrombosis, administer CUVITRU 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 of hyperviscosity.
• Cutaquig: Thrombosis may occur with immune globulin products, including Cutaquig. 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. For patients at risk of thrombosis, administer Cutaquig 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 of hyperviscosity
• Xembify: Thrombosis may occur with immune globulin products, including Xembify. 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. Thrombosis may occur in the absence of known risk factors. For patients at risk of thrombosis, administer Xembify 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.]

The requirements of the Horizon BCBSNJ Immune Globulin Subcutaneous Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable).

I. Please refer to a separate policy on Site of Administration for Infusion and Injectable Prescription Medications (Policy #142) under the Drug Section.

II. Immunoglobulin subcutaneous is medically necessary for the FDA-approved indication when all of the following criteria is met:

• The prescriber is a specialist in the area of the patient’s diagnosis (e.g. immunologist) or has consulted with a specialist in the area of the patient’s diagnosis

A. Baseline values for blood urea nitrogen (BUN) and serum creatinine obtained within 30 days of request; AND
B. Primary immunodeficiency (PID) is defined as:
1. member’s IgG level is <200 mg/dl OR both of the following
2. member has a history of multiple hard to treat infections as indicated by at least one of the following:
a. Four or more ear infections within 1 year
b. Two or more serious sinus infections within 1 year
c. Two or more months of antibiotics with little effect
d. Two or more pneumonias within 1 year
e. Recurrent or deep skin abscesses
f. Need for intravenous antibiotics to clear infections
g. Two or more deep-seated infection including septicemia; AND
3. The member has a deficiency in producing antibodies in response to vaccination; AND
a. Baseline titers were drawn before challenging with vaccination; AND
b. Titers were draw between 4 and 8 weeks of vaccination
AND
C. Members who have previous treatment with IVIG:
• Hizentra for members 2 years and older
• Gammagard Liquid for members > 2 years and older
• Gamunex-C for members 2 years and older
• Gammaked for members 2 years and older
• HyQvia for members 18 years and older
• Cuvitru for members 2 years and older
• Cutaquig for members 18 years and older
• Xembify for members 2 years and older

Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) when all of the following criteria has been met:
A. Assess renal function, including blood urea nitrogen and serum creatinine within 30 days of request; AND
[INFORMATIONAL NOTE: Patients with very mild symptoms which do not or only slightly interfere with activities of daily living may be monitored without treatment.]
B. Baseline disease severity has been documented using objective clinical measuring tool (e.g. INCAT, Medical Research Council (MRC) muscle strength,6 MWT, Rankin, Modified Rankin) and renewals will require current results; AND
• Used as initial maintenance therapy for prevention of disease relapses after treatment and stabilization with intravenous immunoglobulin (IVIG); OR
• Used for re-initiation of maintenance therapy after experiencing a relapse and requiring re-induction therapy with IVIG (see Section IV for criteria)
C. Members who have previous treatment with IVIG:
• Hizentra for member is 18 years of age or older

[INFORMATIONAL NOTES:
For Hizentra:
• The safety and efficacy of Hizentra in pediatric patients under the age of 2 years has not been studied.
• The main efficacy trial for Hizentra was an open label, prospective, multicenter, single-arm, phase III trial conducted in 49 patients (aged 5-72 years) who were previously treated with IVIG. These patients received weekly subcutaneous infusions of Hizentra for a duration of 15 months including a 12-week wash-in/out period and a 12-month efficacy period. The dose was calculated from the previous IVIG dose and was adjusted to be have an equivalent area under the curve. Mean serum IgG trough levels in the efficacy period were maintained between 1,210 mg/dL and 1,290 mg/dL and the mean serum IgG concentration was 1,253 mg/dL. All of these levels met the normal range for IgG. In reference to the efficacy endpoints, no serious bacterial infections occurred in the study and non-serious bacterial infections occurred in 81.6% of patients.
• Hizentra is indicated in patients with primary humoral immunodeficiency (PI), which includes, but is not limited to, the humoral immune defect in congenital agammaglobulinemia, common variable immunodeficiency (CVID), X-linked agammaglobulinemia (XLA), Wiskott-Aldrich syndrome, and severe combined immunodeficiencies (SCID).
• Hizentra is contraindicated in individuals with hyperprolinemia and those with a history of anaphylactic or severe systemic response to immune globulin preparations and in individuals with selective immunoglobulin A deficiency (serum IgA <0.05 g/L).

For Gammagard Liquid (for subcutaneous administration):
• The safety and efficacy of Gammagard Liquid in pediatric patients under the age of 2 years have not been studied.
• Gammagard Liquid is contraindicated in patients who have had a history of anaphylactic or severe systemic hypersensitivity reactions to the administration of human immune globulin and in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity.
• Subcutaneous Gammagard Liquid is indicated as replacement therapy for PID, which includes, but is not limited to, CVID, X-linked agammaglobulinemia, congenital agammaglobulinemia with antibodies against IgA and a history of hypersensitivity.

For HyQvia (for subcutaneous administration)
• The safety and efficacy of HyQvia subcutaneous administration has not been established in pediatric patients.
• HyQvia is contraindicated in patients who have a history of anaphylactic or severe systemic hypersensitivity reactions to Immune Globulin (Human) and in IgA deficient patients with antibodies against IgA and a history of hypersensitivity. It is also contraindicated in patients with known systemic hypersensitivity to hyaluronidase or Recombinant Human Hyaluronidase of HyQvia.
• HyQvia is indicated in patients with primary humoral immunodeficiency (PI), which includes, but is not limited to, the humoral immune defect in congenital agammaglobulinemia, common variable immunodeficiency (CVID), X-linked agammaglobulinemia (XLA), Wiskott-Aldrich syndrome, and severe combined immunodeficiencies (SCID).

For Gamunex-C and Gammaked (for subcutaneous administration):
• The safety and efficacy of Gamunex C/Gammaked subcutaneous administration in pediatric patients under the age of 2 years has not been studied.
• Subcutaneous Gamunex-C/Gammaked is indicated in patients with primary humoral immunodeficiency (PI), which includes, but is not limited to, the humoral immune defect in congenital agammaglobulinemia, common variable immunodeficiency (CVID), X-linked agammaglobulinemia (XLA), Wiskott-Aldrich syndrome, and severe combined immunodeficiencies (SCID).
• Gamunex-C/Gammaked is contraindicated in patients who have had a history of anaphylactic or severe systemic reactions to human immunoglobulin and in IgA deficient patients


For Cuvitru (for subcutaneous administration):
· The safety and efficacy of Cuvitru has not been evaluated in neonates or infants <2 years old.
· Cuvitru is indicated as replacement therapy for primary humoral immunodeficiency (PI), which includes, but is not limited to, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiences (SCID).
· Cuvitru is contraindicated in patients who have had an anaphylactic or severe systemic hypersensitivity reaction to the subcutaneous administration of human immune globulin and in IgA-deficient patients with antibodies against IgA and a history of hypersensitivity.

European Federation of Neurological Societies and Peripheral Nerve Society (EFNS/PNS) Criteria
· Clinical inclusion criteria for typical CIDP require both of the following:
o Chronically progressive, stepwise, or recurrent symmetric proximal and distal weakness and sensory dysfunction of all extremities, developing over at least two months; cranial nerves may be affected
o Absent or reduced tendon reflexes in all extremities
· Clinical inclusion criteria for atypical CIDP require one of the following, but otherwise as in typical CIDP (tendon reflexes may be normal in unaffected limbs):
o Predominantly distal (distal acquired demyelinating symmetric neuropathy, DADS) or
o Asymmetric (multifocal acquired demyelinating sensory and motor neuropathy [MADSAM], Lewis-Sumner syndrome) or
o Focal (eg, involvement of the brachial or lumbosacral plexus or of one or more peripheral nerves in one upper or lower limb) or
o Pure motor or
o Pure sensory (including chronic immune sensory polyradiculopathy affecting the central process of the primary sensory neuron)

For Cutaquig (for subcutaneous administration):
• The safety and efficacy of Cutaquig have not been established in patients under 17 years of age. There are only limited data available on the safety and efficacy of Cutaquig administration in pediatric patients. Cutaquig was evaluated in 23 pediatric subjects (15 children, 8 adolescents) with primary humoral immunodeficiency (PI)
• Cutaquig , indicated as replacement therapy for primary humoral immunodeficiency (PI) in adults. This includes, but is not limited to, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.
• Cutaquig is contraindicated In IgA-deficient patients with antibodies against IgA and a history of hypersensitivity to human globulin treatment.
• Cutaquig efficacy was established in a prospective, open-label, non-controlled, single-arm, multicenter study to evaluate the pharmacokinetics (PK), efficacy, tolerability and safety of Cutaquig in subjects with primary Fhumoral immunodeficiency (PI). The study was conducted in 61 subjects (38 adult and 23 pediatric subjects < 16 years of age) who received weekly SC infusions with Cutaquig during a 12-week wash-in/wash-out period followed by a 12-month efficacy period during which efficacy, pharmacokinetics, safety, tolerability, and quality of life (QoL) parameters of Cutaquig were evaluated. At the time of data analysis, 47 subjects (35 adults; 12 pediatric subjects) had completed the study, 8 pediatric subjects were continuing in the study, and 6 subjects (3 adults; 3 pediatric subjects) had discontinued the study prematurely at the time of data analysis. During the efficacy period the mean weekly dose was 175 mg/kg BW, with individual doses ranging from 60 to 390 mg/kg BW. The median duration of infusion per week was 1.5 hours Overall, 33 female subjects and 28 male subjects participated in this study. The youngest subject enrolled in the study was 2 years old and the oldest was 73 years old. The mean age in the adult group (16–75 yrs) was 46.6 years.. The main objective of the study was to assess the efficacy of Cutaquig in preventing serious bacterial infections (SBI defined as bacteraemia/sepsis, bacterial meningitis, osteomyelitis/septic arthritis, bacterial pneumonia and visceral abscess). This endpoint was considered successful if the upper bound of the 99% confidence interval for the rate of SBIs was < 1.0 per subject-year of follow up. This criterion was met, as no SBIs were reported at any time during the study.

For Xembify (for subcutaneous administration):
• The safety and efficacy of Xembify has not been evaluated in neonates or infants <2 years old.
• Xembify 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.
• Xembify is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. As well as, IgA deficient patients with antibodies against IgA and history of hypersensitivity to human immune globulin treatment.
• Safety and efficacy were based on a prospective, open label, single arm, multicenter clinical trial that evaluated the safety and efficacy of Xembify compared with Gamunex-C. The primary outcome was annualized serious bacterial infection rate during the 6 months on Xembify. Results showed the annual rate of serious bacterial infections for Xembify was 0.05 events per subject-year (1 event in 20 subject-years) which was found to be lower than 1.0 serious bacterial infections/subject-year, the threshold specified as effective. Serious bacterial infections included bacteremia/sepsis, bacterial meningitis, bacterial pneumonia, osteomyelitis/septic arthritis, or visceral abscess. Regarding safety, the most common treatment-emergent adverse events were local infusion site reactions (eg, erythema, pain, edema, pruritus) and systemic reactions including cough and diarrhea.]

A. Request is for FDA-recommended dose of:
• Hizentra
  • Primary Immunodeficiency: weekly dose for patients switching from IVIG: Initial dose (given 1 week after last IVIG infusion) is 1.37 x previous IVIG dose (grams)/ number of weeks between IVIG doses; weekly dose for patients switching from immune globulin subcutaneous treatment: Initial dose (given 1 week after the last SCIG dose) is recommended to be the same as the weekly dose of prior immune globulin subcutaneous treatment. For 2 week dose – administer twice the calculated weekly dose. For more frequent dosing, divide the calculated weekly dose by the desired number of times per week (e.g. for 3 times per week, divide weekly dose by 3). Dose will be titrated based on clinical response and serum IgG trough levels.
  · CIDP: weekly subcutaneous dose (given 1 week after the last IVIG infusion) of 0.2 g/kg (1 mL/kg) body weight administered in 1 or 2 sessions over 1 or 2 consecutive days
  [INFORMATIONAL NOTE: As per the FDA labeled package insert dosing and administration section,
  • If CIDP symptoms worsen, consider re-initiating treatment with an IVIG while discontinuing Hizentra.
  • If improvement and stabilization are observed during IVIG treatment, consider reinitiating Hizentra at the dose of 0.4 g/kg body weight per week, administered in 2 sessions per week over 1 or 2 consecutive days, while discontinuing IVIG.
  • If CIDP symptoms worsen on the 0.4 g/kg body weight per week dose, consider re-initiating therapy with an IVIG while discontinuing Hizentra.]
• Gammagard Liquid (for subcutaneous administration) - weekly dose: Initial Dose (given 1 week after the last IVIG infusion) is 1.37 x previous IVIG dose divided by the number of weeks between intravenous doses. Dose will be titrated based on clinical response and serum IgG trough levels.
• Gamunex-C/Gammaked (for subcutaneous administration) - weekly dose: Initial Dose (given 1 week after the last IVIG infusion) is 1.37 x previous IVIG dose divided by the number of weeks between intravenous doses. Dose will be titrated based on clinical response and serum IgG trough levels.
• HyQvia (for subcutaneous subcutaneous administration): Administer the first dose 1 week after the last IVIG or SCIG treatment and iIncrease the dose and frequency from a 1-week dose to a 3- or 4-week dose (see ramp-up schedule in package insert). For patients switching from IVIG: Administer HyQvia at the same dose and frequency as the previous IVIG treatment, after initial ramp up. For patients naïve to or switching from immune globulin subcutaneous treatment: Administer HyQvia at 300 to 600 mg/kg at 3 to 4 week intervals, after initial ramp-up.
• Cuvitru (for subcutaneous administration) – weekly dose for patients switching from IVIG or HyQvia: Initial Dose (given 1 week after the last IVIG or HyQvia infusion) is 1.30 x previous IVIG or HyQvia dose divided by the number of weeks between IVIG or HyQvia doses; weekly dose for patients switching from immune globulin subcutaneous treatment: Initial dose dose (given 1 week after the last SCIG dose) is recommended to be the same as the weekly dose of prior immune globulin subcutaneous treatment. Can be administered from daily up to every two weeks (biweekly). Biweekly dose: twice the weekly dose (using calculation above). Frequent dosing (2-7 times per week): divide the calculated weekly dose by the desired number of times per week. Doses divided over the course of a week, or once weekly, or biweekly, achieve similar exposure when administered regularly at steady-state. Dose will be titrated based on clinical response and serum IgG trough levels.
• Cutaquig (for subcutaneous administration) – weekly dose for patients switching from IVIG: Initial Dose (given 1 week after the last IVIG infusion) is 1.40 x previous IVIG dose (in grams) divided by the number of weeks between IVIG doses; weekly dose for patients switching from immune globulin subcutaneous treatment: Initial dose (given 1 week after the last SCIG infusion) is recommended to be the same as the weekly dose of prior immune globulin subcutaneous treatment. Dose will be titrated based on clinical response and serum IgG trough levels.
  [INFORMATIONAL NOTE:
  • Ensure that patients have received IVIG or SCIG treatment at regular intervals for at least 3 months.
  • To convert the dose (in grams) to milliliters (mL), multiply the calculated dose (in grams) by 6.
  • Provided the total weekly dose is maintained, any dosing interval from daily up to weekly can be used and will result in systemic IgG exposure that is comparable to the previous IVIG treatment]
• Xembify (for subcutaneous administration) - weekly dose for patients switching from IVIG: Initial Dose (given 1 week after the last IVIG infusion) is 1.37 x previous IVIG dose (in grams) divided by the number of weeks between IVIG doses. Weekly dose for patients switching from immune globulin subcutaneous treatment: Initial dose (given 1 week after the last SCIG dose) is recommended to be the same as the weekly dose of prior immune globulin subcutaneous treatment. To convert the dose in grams to mL, multiply the calculated initial SQ dose (in grams) by 5. Provided the total weekly dose is maintained, any dosing interval from daily up to weekly will achieve similar systemic IgG exposure when administered regularly at steady-state.
  AND
B. Dose is calculated by the following: ·
• Actual body weight in members weighing up to 100kg with a BMI <30 kg/m² OR
• Adjusted body weight if one or more of the following criteria are met:
  • If BMI =/ >30 kg/m² OR
  • If the members actual body weight is >20% over the members ideal body.

Use the following dosing formulas to calculate the adjusted body weight (round dose to nearest 5 gram increment in adult members):

Dosing formulas

BMI = 703 x (weight in pounds/height in inches2)

IBW(kg) for males = 50 + [2.3 (height in inches – 60)]

IBW(kg) for females = 45.5 + [2.3 x (height in inches – 60)]

Adjusted body weight = IBW + 0.5 (actual body weight – IBW)

A. Absence of unacceptable toxicity from the drug (e.g.: severe hypersensitivity/anaphylaxis, thrombosis, aseptic meningitis syndrome, hemolytic anemia, hyperproteinemia, acute lung injury, etc); AND
B. BUN and serum creatinine obtained within the last 6 months and the concentration and rate of infusion adjusted accordingly; AND
C. Primary Immunodeficiency
1. Disease response as evidenced by one or more of the following:
a. Decrease in the frequency of infection
b. Decrease in the severity of infection
D. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) [Hizentra ONLY]
1. Renewals will be authorized for patients that have demonstrated a beneficial clinical response to maintenance therapy, without relapses, based on an objective clinical measuring tool (e.g., INCAT, Medical Research Council (MRC) muscle strength, 6-MWT, Rankin, Modified Rankin, etc.); OR
2. Patient is re-initiating maintenance therapy after experiencing a relapse while on Hizentra; AND
a. Patient improved and stabilized on IVIG treatment: AND
b. Patient was NOT receiving maximum dosing of Hizentra prior to relapse
[INFORMATIONAL NOTES:

As per the FDA-approved Hizentra package insert, the dose will be adjusted over time based on clinical response and serum IgG trough levels. The FDA-product labeling recommends the measurement of the serum IgG trough level after 2-3 months treatment with Hizentra. Dose adjustment based on trough levels can be calculated to detect the difference of the patient’s serum IgG trough level from the target IgG trough level (1.3 times the last IGIV trough level). Adjust the dose to achieve a serum IgG trough level that is approximately 290 mg/dL higher than the last trough level during prior IGIV therapy. Start treatment with Hizentra 1week after the patient’s last Immune Globulin Intravenous (Human) (IGIV) infusion, when the patient has received IGIV infusions at regular intervals for at least 3 months

As per the FDA-approved Gammagard Liquid package insert, the dose will be adjusted over time to achieve the desired clinical response and serum IgG levels. To guide dose adjustment, calculate the difference between the patient’s target serum IgG trough level and the IgG trough level during subcutaneous treatment..

As per the FDA-approved Gamunex-C/Gammaked package insert, to determine if a dose adjustment may be considered, measure the patient’s serum IgG trough level on IGIV and as early as 5 weeks after switching from IGIV to subcutaneous. To determine if further dose adjustments are necessary, monitor the patient’s IgG trough level every 2 to 3 months. However, patient’s clinical response should be the primary consideration in dose adjustment To adjust the dose based on trough levels, calculate the difference (in mg/dL) of the patient’s serum IgG trough level from the target IgG trough level, then find the difference in Table 1 of the package insert and the corresponding amount (in mLs) by which to increase or decrease the weekly dose based on the patient’s body weight.

As per the FDA-approved HyQvia package insert, if HyQvia is administered at the same dose and frequency, the serum IgG levels from HyQvia should be comparable to serum IgG levels from intravenous treatment.For dose adjustment: Calculate the difference between the patient’s serum IgG trough level during HyQvia treatment and the IgG trough level during the previous intravenous treatment. Find this difference (in mg/dL) in the columns of Table 2 of the package insert and the corresponding amount (in mL) by which to increase or decrease the dose based on the patient’s body weight and desired change in IgG trough level.

As per the FDA-approved Cuvitru package insert, when switching from IGIV or HyQvia, begin treatment once week after the patient’s last IGIV or HyQvia infusion. For frequent dosing (2-7 times per week), divide the calculated weekly dose by the desired number of times per week. For biweekly dosing, multiply the calculated weekly dose by 2. To guide dose adjustment, calculate the difference between the patient’s target serum IgG trough level and the IgG trough level during subcutaneous treatment. Find this difference (in mg/dL) in Table 1 of the package insert and the corresponding amount (in mL) by which to increase (or decrease) the weekly/biweekly dose based on the patient's body weight.

As per the FDA-approved Xembify package insert, before switching the patient’s serum IgG trough level must be obtained to guide subsequent dose adjustments. When switching from IVIG, the dose must be calculated using a dose adjustment factor of 1.37.For frequent dosing (2-7 times per week), divide the calculated weekly dose by the desired number of times per week. For weekly dosing, convert the monthly IVIG dose into an equivalent weekly dose and increase it using the adjustment factor of 1.37. For dose adjustments, calculate the difference of the patient’s serum IgG trough level from the target IgG trough level. Find this difference (in mg/dL) in Table 1 of the package insert and the corresponding amount (in mL) by which to increase (or decrease) the weekly dose based on the patient’s body weight.]

Medicare Coverage:
Subcutaneous immune globulin (J1559, J1561, J1562, J1569, J1575, J1555 and J7799 (Xembify®)) is covered when LCD Local Coverage Determination (LCD):External Infusion Pumps (L33794) and Article A52507 criteria are met. For additional information and eligibility, refer to Local Coverage Determination (LCD):External Infusion Pumps (L33794) and Local Coverage Article: External Infusion Pumps - Policy Article (A52507.) Available to be accessed at Noridian Healthcare Services, LLC, (DME MAC), Local Coverage Determinations (LCDs) search page: https://www.cms.gov/medicare-coverage-database/indexes/lcd-list.aspx?Cntrctr=389&ContrVer=1&CntrctrSelected=389*1&s=38&DocType=1&bc=AAgAAAAAAAAA&#aFinal.
For the administration of subcutaneous immune globulins with the following HCPCS codes - J1559, J1561, J1562, J1569, and J1555 only an E0779 infusion pump is covered. If a different pump is used, it will be denied as not reasonable and necessary.
For the administration of subcutaneous immune globulin with HCPCS code J1575, only an E0781 infusion pump is covered. If a different pump is used, it will be denied as not reasonable and necessary.

Per Local Coverage Article A53127 Self-Administered Drug Exclusion List, Medicare covers drugs that are furnished “incident to” a physician’s service provided that the drugs are medically reasonable and necessary, approved by the Food and Drug Administration (FDA) and are not usually administered by the patients who take them. Therefore, Medicare Advantage Products will cover Immune Globulin Subcutaneous (Vivaglobin, Hizentra, Gammagard Liquid, Gamunex-C/Gammaked, HyQvia, and Cuvitru for Subcutaneous Administration when the applicable NCD, LCD and LCD Coverage Article are met AND the drug is furnished and administered by a licensed medical provider as part of a physician service. For members with a Medicare drug plan (Part D) Immune Globulin Subcutaneous (Vivaglobin, Hizentra, Gammagard Liquid, Gamunex-C/Gammaked, HyQvia, and Cuvitru may be covered under that plan.

National Coverage Determination (NCD) for Intravenous Immune Globulin for the Treatment of Autoimmune Mucocutaneous Blistering Diseases (250.3). Available to be accessed at CMS National Coverage Determinations (NCDs) Alphabetical Index search page: https://www.cms.gov/medicare-coverage-database/indexes/ncd-alphabetical-index.aspx.

Local Coverage Determination (LCD): Intravenous Immune Globulin (IVIG) (L35093).

Local Coverage Article: Self-Administered Drug Exclusion List (A53127). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/LcdSearch?_afrLoop=90769712476969#!%40%40%3F_afrLoop%3D90769712476969%26centerWidth%3D100%2525%26leftWidth%3D0%2525%26rightWidth%3D0%2525%26showFooter%3Dfalse%26showHeader%3Dfalse%26_adf.ctrl-state%3D63y7eftob_46

**Note: Bullet 1 of the policy section referring to Site of Administration for Infusion and Injectable Prescription Medications (Policy #142) does not apply for Medicare Advantage Products.

Medicaid Coverage
For Horizon NJ Health members, please follow this link for the corresponding HNJH drug policy https://services3.horizon-bcbsnj.com/ddn/NJhealthWeb.nsf

________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Immune Globulin Subcutaneous (Vivaglobin, Hizentra, Gammagard Liquid, Gamunex-C/Gammaked, HyQvia, Cuvitru, Cutaquig, and Xembify for Subcutaneous Administration)
Vivaglobin
Hizentra
Gammagard
Gamunex-C
Gammaked
HyQvia
Cuvitru
Cutaquig
Xembify
Immune Globulin, Subcutaneous
Subcutaneous, Immune Globulin

References:
1. Product Information: Vivaglobin (immune globulin subcutaneous). Behring, Marburg, Germany. April 2010.

2. Gardulf A, Nicolay U, Asensio O, et al. Rapid subcutaneous IgG replacement therapy is effective and safe in children and adults with primary immunodeficiencies – a prospective, multi-national study. J Clin Immunol 2006 March;26(2):177-185.

3. Ochs HD, Gupta S, Kiessling P, et al. Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases. J Clin Immunol. 2006 May;26(3):265-73.

4. Abd-Allah SA, Jansen PW, Ashwal S, et al: Intravenous immunoglobulin as therapy for pediatric Guillain-Barre syndrome.J Child Neurol 1997;12:376-380.

5. Anon J, et al. Plasma Exchange/Sandoglobulin(R) Guillain-Barre Syndrome Trial Group: Randomized trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barre syndrome. Lancet 1997;349:225-230.

6. Van der Meche FGA, Schmitz PIM, et al. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barre syndrome. N Engl J Med 1992;326(17):1123-9.

7. MICROMEDEX® Healthcare Series: DRUGDEX Drug Point. Immune Globin: Non-FDA Labeled Indications: Guillain-Barre Syndrome. May 2009. [Available at: http://www.thomsonhc.com/hcs/librarian/ND_T/HCS/ND_PR/Main/CS/A0BBB4/DUPLICATIONSHIELDSYNC/333A8A/ND_PG/PRIH/ND_B/HCS/SBK/1/ND_P/Main/PFPUI/Gy129to2YY9oMU/PFActionId/hcs.common.RetrieveDocumentCommon/DocId/298670/ContentSetId/100/SearchTerm/vivaglobin/SearchOption/BeginWith#secN10408]. Accessed May 11, 2009.

8. Harbo T, Anderson H, Hess A, et al. Subcutaneous versus intravenous immunoglobulin in multifocal motor neuropathy: a randomized, single-blinded cross-over trial. Eur J Neurol. 2009 May, 16(5): 631-638.

9. Lee DH, Linker R, Paulus W, et al. Subcutaneous immunoglobulin infusion: a new therapeutic option in chronic inflammatory demyelinating polyneuropathy. Muscle & Nerve. 37: 406-409. 2008.

10. ClinicalTrials.gov. Subcutaneous Immunoglobulin Treatment of Patients With Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP). [ Available from: http://clinicaltrials.gov/ct2/show/NCT01017159?term=immunoglobulin&rank=4 ] [ cited 31 Mar 2010]
11. Lin J, Wang K, Kraft S, Roberts R. Resolution of warts in association with subcutaneous immunoglobulin in immune deficiency. Pediatric Dermatology 2009. 26(2): 155-158.

12. Schleinitz N, Estelle J, Benarous L, et al. Subcutaneous immunoglobulin administration : an alternative to intravenous infusion as adjuvant treatment for dermatomyositis. Clin Rheumatol 2008. 27(8):1067-1068.

13. CSL Behring LLC. Hizentra (immune globulin subcutaneous (Human) 20% Liquid . Kankakee, IL. March 2018.

14. Zenker O, Andresen I. Comparative local tolerability of IgPro20, a new 20% immunoglobulin preparation for subcutaneous administration. CSL Behring. Poster. 2010.

15. Hagan J, Fasano M, Spector S, et al. Efficacy and safety of a new 20% immunoglobulin preparation for subcutaneous administration, IgPro20, in patients with primary immunodeficiency. CSL Behring. Poster Presentation at the American Academy of Allergy Asthma and Immunology. February 26-Mar 2, 2010.

16. Berger M. Subcutaneous immunoglobulin replacement in primary immunodeficiencies. Clinical Immunology. 112(2004): 1-7.

17. Waniewski J, Gardulf A, Hammarstrom L. Bioavailability of γ-Globulin After Subcutaneous Infusions in Patients with Common Variable Immunodeficiency. J Clin Immun. 14(2): 90-97. 1994.

18. Borte M, Ritchie B, Plebani A. Improvement in Quality of Life in Newly Diagnosed Patients with Primary Immunodeficiency Initiating Replacement Therapy with Subcutaneous Vivaglobin. Poster presented at: American Academy of Allergy Asthma and Immunology. 2010 Annual Conference. 2010 Feb 26 – Mar 2; New Orleans, LO.

19. MICROMEDEX® 1.0 (Healthcare Series). DRUGDEX® Evaluations. Immune Globulin. Available at: http://www.thomsonhc.com. Accessed January 17, 2012

20. CSL Behring. Important Information about Vivaglobin®. Accessed 3/25/11: http://www.cslbehring-us.com/ecampaigns/CSLBUS/Alert/web/vivaglobinUpdate201102e.htm

21. Baxter Healthcare Corporation. Gammagard Liquid package insert. Westlake Village, CA. June 2016.

22. Grifols Therapeutics Inc. Gamunex-C package insert. Research Triangle Park, NC. June 2018.

23. Wasserman RL, Irani AM, Tracy J, et al. Pharmacokinetics and safety of subcutaneous immune globulin (human), 10% caprylate/chromatography purified in patients with primary immunodeficiency disease. Clin Exp Immunol. 2010;161(3):518-26.

24. Re: United States Only – Important Information About Vivaglobin. http://www.vivaglobinaccess.com/. Updated 2013. Accessed February 26, 2013.

25. Gifols Therapeutics Inc. Gammaked package insert. Research Triangle Park, NC June 2018.

26. Baxter Healthcare Corporation. HyQvia package insert. Westlake Village, CA. January 2019.

27. Chapel, H M. Spickett, G P. Ericson, D. Engl, W. Eibl, M M. Bjorkander, J. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. J Clin Immunol. 2000;20:94-100.

28. Gardulf A. Nicolay U, Asensio O, et al. Rapid subcutaneous IgG replacement therapy is effective and safe in children and adults with primary immunodeficiencies – a prospective, multi-national study. J Clin Immunol. 2006;26:177–185.

29. Koterba AP, Stein MR. Initiation of immunoglobulin therapy by subcutaneous administration in immunodeficiency patients naive to replacement therapy. Allergy Asthma Clin Immunol. 2014 Dec 6;11(1):63. doi: 10.1186/s13223-014-0063-8. eCollection 2015.

30. Borte M, Quinti I, Soresina A, et al. Efficacy and safety of subcutaneous vivaglobin® replacement therapy in previously untreated patients with primary immunodeficiency: a prospective, multicenter study. J Clin Immunol. 2011 Dec;31(6):952-61. doi: 10.1007/s10875-011-9588-5. Epub 2011 Sep 20.

31. Jolles S, Stein MR, Longhurst HJ, et al. New Frontiers in Subcutaneous Immunoglobulin Treatment. Biol Ther. 2011 Dec 14;1:3. eCollection 2011.

32. Jeffrey Modell Foundation Medical Advisory Board, 2013. 10 Warning Signs of Primary Immunodeficiency. Jeffrey Modell Foundation, New York, NY.

33. Wimperis J, et al. National Health Service. Clinical Guidelines for Immunoglobulin Use: second edition update. Available from: https://www.gov.uk/​government/​uploads/​system/​uploads/​attachment_data/​file/​153238/​dh_131107.pdf

34. Koleba T, Ensom MH. Pharmacokinetics of intravenous immunoglobulin: a systematic review. Pharmacotherapy. 2006;26(6);813-827

35. Hodkinson J, et al. Therapeutic immunoglobulin should be dosed by clinical outcome rather than by body weight in obese patients. Clinical & Experimental Immunology, 2015; 181: 179–187.

36. Anderson C, Olson J, et al. Correlation of weight-based I.V. immune globulin doses with changes in serum immunoglobulin G levels. Am J Health-System Pharm. 2015. DOI 10.2146/ajhp140171. 1079-2082.

37. Shapiro R. Subcutaneous immunoglobulin therapy in obese patients with primary immunodeficiency: a retrospective analysis of administration by infusion pump or subcutaneous rapid push. 2013. Clinical and Experimental Immunology, 173: 365–371.

38. Leonard M, White D. Acute stroke with high-dose intravenous immune globulin. Am J Health-Syst Pharm. 2007; 64:1611-4.

39. Leonard M, Lehman M, Travis D, et al. Intravenous Immune Globulin (IVIG) A Review of Formulary Restrictions. Cleveland Clinic Pharmacotherapy Update From the Department of Pharmacy. Vol XI, No I January 2008.

40. Baxalta US, Inc. Cuvitru package insert. Westlake Village, CA. May 2019.

41. Borte M, Krivan G, Derfalvi B, et al. Efficacy, safety, tolerability and pharmacokinetics of a novel human immune globulin subcutaneous, 20%: a phase 2/3 study in Europe in patients with primary immunodeficiencies. Clin Exp Immunol. 2016 Sep 10. doi: 10.1111/cei.12866. [Epub ahead of print]

42. Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of multifocal motor neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society--first revision. J Peripher Nerv Syst. 2010 Dec;15(4):295-301. doi: 10.1111/j.1529-8027.2010.00290.x.

43. Octapharma USA, Inc. Cutaquig package insert. Hoboken, NJ. August 2019.

44. "IDF Diagnostic & Clinical Care Guidelines For Primary Immunodeficiency Diseases 2Nd Edition | Immune Deficiency Foundation". Primaryimmune.Org, 2019, https://primaryimmune.org/resource/idf-diagnostic-clinical-care-guidelines-primary-immunodeficiency-diseases-2nd-edition-1. Accessed 7 Jan 2019.

45. Gifols Therapeutics Inc. Xembify package insert. Research Triangle Park, NC July 2019.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

90284

J1559
J1575
J1561
J1562
J1569
J3590
J1555
J7799
J1558