What You Need to Know About Subcutaneous Immunoglobulin for the Treatment of CIDP and PI

Subcutaneous immunoglobulin (Hizentra, CSL Behring) was initially approved to treat primary immunodeficiency (PI) in 2010. PI is a genetic defect of the immune system, leading to frequent and severe infections. The prevalence of PI is rare, between 40 to 50 cases per 100,000 people.¹

In March 2018, subcutaneous immunoglobulin received a new indication for use as maintenance therapy in adults with chronic inflammatory demyelinating polyneuropathy (CIDP).² CIDP is a rare neurological disorder that causes weakness, paralysis, and sensory disturbance, believed to an autoimmune disorder. The prevalence of CIDP is approximately 5 to 7 cases per 100,000 people.³

Dosage and Administration (CIDP)

Subcutaneous immunoglobulin is dosed at 0.2 g/kg (1 mL/kg) subcutaneously every week. Doses of 0.4 g/kg (2 mL/kg) are also safe and effective. Initiation of subcutaneous immunoglobulin is done 1 week after the last immune globulin intravenous infusion (IGIV).⁴

If CIDP symptoms worsen, consider reinitiating IGIV while discontinuing subcutaneous immunoglobulin. If symptoms improve and stabilize, IGIV can be discontinued, and subcutaneous immunoglobulin can be reinitiated at 0.4 g/kg per week. If CIDP symptoms worsen on 0.4 g/kg, revert to IGIV and discontinue subcutaneous immunoglobulin.

Table 1. Administration Information for subcutaneous immunoglobulin in CIDP

Infusion Parameters

First Infusion

Subsequent Infusions

Volume (mL/site)

≤ 20

≤ 50

Rate (mL/hr/site)

≤ 20

≤ 50

*Up to 8 infusion sites are allowed at 1 time, with at least 2 inches separating sites of injection. CIDP indicates chronic inflammatory demyelinating polyneuropathy.

Dosage and Administration (PI)

subcutaneous immunoglobulin is started 1 week after the last IGIV infusion and obtaining the patient’s IgG trough level.⁴ Weekly dosing frequency of subcutaneous immunoglobulin is calculated through the following formula:

Initial weekly dose = Previous IGIV dose (in grams) x 1.37 / Number of weeks between IGIV doses

Biweekly doses of subcutaneous immunoglobulin are started 1 or 2 weeks after the last IGIV infusion with a dose of twice the calculated weekly dose from the formula above (2 x initial weekly dose).

More frequent dosing schedules of subcutaneous immunoglobulin are started 1 week after the last IGIV infusion and is calculated by dividing the calculated weekly dose by the desired number of infusions per week (eg, daily administrations would be calculated as initial weekly dose/ 7).

Table 2. Administration Information for subcutaneous immunoglobulin in PI

Infusion Parameters

First Infusion

Subsequent Infusions

Volume (mL/site)

≤ 15

≤ 25

Rate (mL/hr/site)

≤ 15

≤ 25

*Up to 8 infusion sites are allowed at 1 time, with at least 2 inches separating sites of injection. PI indicates primary immunodeficiency.

Pharmacology

Subcutaneous immunoglobulin provides IgG antibodies against many bacterial and viral agents. The full mechanism of action is not clear, but it involves immunomodulatory effects.⁴

Table 3. Method of Supply

Subcutaneous immunoglobulin is supplied in a single-use vial containing 0.2g of protein per mL.⁴

Drug Packaging

NDC Information

5mL (Vial containing 1 gram of protein)

Carton NDC: 44206-0451-01

Vial NDC: 44206-0451-90

10mL (Vial containing 2 grams of protein)

Carton NDC: 44206-0452-02

Vial NDC: 44206-0452-91

20mL (Vial containing 4 grams of protein)

Carton NDC: 44206-0454-04

Vial NDC: 44206-0454-92

50mL (Vial containing 10 grams of protein)

Carton NDC: 44206-0455-10

Vial NDC: 44206-0455-93

NDC indicates National Drug Code.

Storage

Subcutaneous immunoglobulin should be stored at room temperature up to 25°C [77°F]. Subcutaneous immunoglobulin is stable for up to 30 months and should be kept in its original container, away from light.⁴

Drug Interactions/Contraindications

The administration of live vaccines such as measles, mumps, rubella, and varicella, may be affected by subcutaneous immunoglobulin. The immunizing clinician should be aware of any recent administration of subcutaneous immunoglobulin. Subcutaneous immunoglobulin can also cause inaccurate serologic tests due to the interfering antibodies.⁴

Subcutaneous immunoglobulin is contraindicated in patients with a history of a severe allergic reaction to human immune globulin or any inactive ingredients in subcutaneous immunoglobulin such as polysorbate 80. Subcutaneous immunoglobulin is also contraindicated in patients with hyperprolinemia type 1 or 2, and patients with IgA deficiency with antibodies against IgA.

Warnings and Precautions

Subcutaneous immunoglobulin and polysorbate 80 can cause severe hypersensitivity reactions to occur. If a severe hypersensitivity reaction occurs, subcutaneous immunoglobulin should be discontinued immediately. Patients with IgA deficiency can develop anti-IgA antibodies and suffer anaphylactic reactions. Patients with IgA deficiency or known antibodies to IgA should not receive subcutaneous immunoglobulin to avoid the risk of a severe hypersensitivity reaction.⁴

There is a black-box warning for thrombosis in patients treated with immune globulin products, including subcutaneous immunoglobulin. Thrombosis can occur in any patient, but the risk of thrombosis may be increased in patients with the following risk factors: advanced age, hypercoagulable conditions, history of venous or arterial thrombosis, indwelling central vascular catheters, hyperviscosity, cardiovascular risk factors, and use of estrogen, and the use of other drugs that increase clotting. Baseline assessments of blood viscosity is recommended in patients at risk of hyperviscosity: cryoglobulins, fasting chylomicronemia, and high triglyceride or monoclonal gammopathies. Patients at risk of thrombosis should receive the lowest dose and infusion rate of subcutaneous immunoglobulin and receive adequate hydration prior to treatment.

Aseptic meningitis syndrome has been seen within several hours to 2 days following treatment. Signs and symptoms include severe headache, nuchal rigidity, fever, photophobia, nausea, and vomiting. Abnormalities include cerebrospinal fluid showing pleocytosis and elevated protein levels.

Acute renal dysfunction/failure, and other kidney diseases can occur while on subcutaneous immunoglobulin. Patients should have their renal function monitored, including blood urea nitrogen and serum creatinine at the first dose, and periodically afterward. Lower and more frequent doses are suggested for patients at risk for developing renal dysfunction. Ensure proper hydration prior to administering subcutaneous immunoglobulin. Subcutaneous immunoglobulin should be discontinued if renal function worsens after use.

Subcutaneous immunoglobulin can also cause hemolysis, noncardiogenic pulmonary edema, and potentially transmissible infectious agents. Patients who report pulmonary adverse events (AE) should receive oxygen therapy, and clinicians who suspect anemia should perform the appropriate laboratory tests to confirm so. Any viral or infectious diseases transmitted by subcutaneous immunoglobulin must be reported to CSL Behring Pharmacovigilance at 1-866-915-6958.

Adverse Reactions

AEs reported in ≥5% of subjects in clinical trials were local reactions, headache, diarrhea, fatigue, back pain, nausea, upper respiratory tract infections, rash, vomiting, pruritis, migraine, abdominal pain, arthralgia, falls, and nasopharyngitis.⁴

Table 4. Adverse Reactions Reported in US Clinical Study of 49 Patients

Adverse Reactions

Percentage of Patients

Local reactions^a

100%

Headache

24.5%

Diarrhea

10.2%

Fatigue

8.2%

Back pain

8.2%

Nausea

8.2%

Cough

8.2%

Vomiting

6.1%

Abdominal pain

6.1%

Migraine

6.1%

Contusion

4.1%

Rash

4.1%

Urticaria

4.1%

^aLocal reactions include infusion-site reactions, bruising, scabbing, eczema, nodules, pain and irritation at the site of injection.

Table 5. Infusion Site Reactions From US Clinical Study in 49 Patients

Infusion-Site Reactions

Rate of Reactions

Edema/induration

68%

Erythema

51%

Local heat

16%

Local pain

13%

Itching

9%

Pregnancy and Lactation

There is no data in humans or animals for subcutaneous immunoglobulin on teratogenicity or whether it will affect reproduction capacities. There is also no data on lactation. Subcutaneous immunoglobulin should only be given to pregnant women if needed and should only be given to breastfeeding mothers after weighing the risk and benefits.⁴

Pediatric Population

subcutaneous immunoglobulin has been shown to be safe and effective for pediatric use in patients aged 2 and older for the treatment of PI. There are no specific pediatric doses that are necessary for this population. The safety and efficacy of patients below the age of 2 has not been established.⁴

Clinical Studies

Two studies listed on the package insert mention the use of subcutaneous immunoglobulin for PI. In the clinical study conducted in the US, 49 adult and pediatric patients with PI were treated, and 38 of them were analyzed for efficacy. Patients in this study were initially treated with monthly treatments of IGIV and then switched to weekly doses of subcutaneous immunoglobulin. There were no serious bacterial infections in this study (bacteremia, osteomyelitis, meningitis, visceral abscess), and the annual rate of any infection was 2.76 infections/year. The total number of subjects requiring antibiotic use was 27, and the number of days out of work or school due to infections was 71. The total number of days hospitalized was 7. The average trough levels increased by 24.2% during the efficacy period when comparing subcutaneous immunoglobulin to IGIV, accounting for the 49% increased dose of subcutaneous immunoglobulin from the previous IGIV dose.⁴

Similar tests were done in Europe in 51 adult and pediatric patients with PI switching from monthly IGIV to subcutaneous immunoglobulin. None of the patients in this study developed a serious bacterial infection, and the annualized rate of infections was 5.18 infections per patient.

A phase 3 study evaluated the use of subcutaneous immunoglobulin for CIDP. In this study, subcutaneous immunoglobulin 0.4 g/kg and 0.2 g/kg versus placebo was tested in 172 adult patients with CIDP previously treated with IGIV. The efficacy end point was CIDP relapse or withdrawal from the study. CIDP relapse was determined by ≥1-point increase in adjusted inflammatory neuropathy cause and treatment score compared with baseline. When considering both withdrawal and CIDP relapse, both doses of subcutaneous immunoglobulin (0.4 g/kg and 0.2 g/kg) were superior to placebo (P < .001 and P = .007, respectively). When only considering relapse, both subcutaneous immunoglobulin doses were significantly superior to placebo, with CIDP relapse rates of 19.0% for 0.4 g/kg subcutaneous immunoglobulin , 33.3% for 0.2 g/kg subcutaneous immunoglobulin , and 56.1% for placebo (P < .001 and P = .012, respectively). Eighty-one percent (81%), 67%, and 44% of patients receiving subcutaneous immunoglobulin 0.4 g/kg, subcutaneous immunoglobulin 0.2 g/kg, and placebo, respectively, remained relapse-free for up to 24 weeks.

Costs and Availability

The costs of the different packaging sizes are listed below. There is a copay assistance program that patients or clinicians can ask about by calling 1-877-355-4447.⁵

Table 6.Costs of subcutaneous immunoglobulin from Red Book Online

Drug

NDC

Quantity

Wholesale Acquisition Cost

Average Wholesale Price

subcutaneous immunoglobulin

44206-0454-04

20 mL

$ 686.00

$ 823.20

subcutaneous immunoglobulin

44206-0455-10

50 mL

$ 1715.00

$ 2058.00

subcutaneous immunoglobulin

44206-0452-02

10 mL

$ 343.00

$ 411.60

subcutaneous immunoglobulin

44206-0451-01

5 mL

$ 171.50

$ 205.80

NDC indicates National Drug Code.

Patient Counseling

subcutaneous immunoglobulin is a prescription drug used for PI and CIDP. Subcutaneous immunoglobulin is administered as an infusion in up to 8 different areas of the body each time. Subcutaneous immunoglobulin is administered weekly for CIDP and infused as often as every day up to every 2 weeks for PI.⁴

Patients should be advised to inform their clinicians before taking a serological test or receiving vaccines. Serological tests may not be accurate and live vaccines may not work as well after taking subcutaneous immunoglobulin.

Some common AEs that a patient may experience are infusion site reactions, migraines, nausea, vomiting, diarrhea, pain, fatigue, cough, rash, fever, and dizziness. Patients should be made aware to identify any potential allergic reactions, to immediately call their doctor or go to the emergency department. Other AEs include acute kidney injury, thrombosis, and serious infections.

Patients that should not take subcutaneous immunoglobulin include patients with hyperprolinemia, patients with reactions to subcutaneous immunoglobulin or polysorbate 80, patients with a deficiency to IgA. Patients with heart conditions such as a history of blood clots, have prolonged immobility, or are on drugs that may increase the risk of thrombosis should inform their clinician prior to starting subcutaneous immunoglobulin.

The use of subcutaneous immunoglobulin is not advised in pregnant or breastfeeding patients unless the need for subcutaneous immunoglobulin outweighs the risk.

Directions for Use

1. Gather all the supplies together: alcohol wipes, syringes, gauze and tape, gloves, needle or catheter sets, infusion administration tubing, antiseptic skin preps, Y-site connectors (if needed), and transfer device.
2. Clean the surface of the table you are using with alcohol wipes.
3. Wash and dry hands and put on gloves if instructed to.
4. Check subcutaneous immunoglobulin vials to make sure that they are pale yellow to light brown in color. Do not use the vial if the liquid is cloudy, contains particles, or has changed colors. Additionally, do not use if the protective cap is missing, or if the medication is expired.
5. Take the protective cap off the vial. Clean the vial stopper with an alcohol wipe and let it dry.
6. Attach the sterile transfer to a sterile syringe.
7. Pull out the plunger of the syringe to the amount of subcutaneous immunoglobulin that will be transferred from the vial. Do this step on a flat surface, with the vial upright.
8. With the needle not in the liquid, push the plunger of the syringe down, and then flip the vial upside down.
9. Draw the amount of subcutaneous immunoglobulin needed by pulling the plunger of the syringe back.
10. Take the filled syringe out of the stopper, take off the needle and throw it away in the sharps container.
11. Prepare the infusion pump and connect the syringe filled with subcutaneous immunoglobulin to the infusion tubing. Push on the syringe plunger to fill the tubing with subcutaneous immunoglobulin.
12. Pick an infusion site (abdomen, thigh, upper arm, side of upper leg/hip) that is a different site from the last infusion time, and at least 1 inch from previous site. Do not pick an area of skin that is tender, bruised, red, or hard.
13. There can be up to 8 injection sites at the same time but must be at least 2 inches apart.
14. Clean the site of infusion and let the skin dry.
15. Pinch the skin around the infusion site with two fingers and insert the needle under the skin.
16. Put the sterile gauze and tape or a transparent dressing over the infusion site to prevent the needle from coming out.
17. Turn on the infusion pump.
18. Record the treatment in the log book by removing the label of the subcutaneous immunoglobulin vial.
19. Turn off the pump after subcutaneous immunoglobulin has been infused.
20. Take off the dressing and take the needle out. Disconnect the tubing from the pump.
21. Discard any leftover subcutaneous immunoglobulin in a single-use vial, along with all disposable supplies in the sharps or other containers.
22. Clean and store the infusion pump.

REFERENCES

1. Kobrynski L, Powell RW, Bowen S. Prevalence and morbidity of primary immunodeficiency diseases, United States 2001-2007. J Clin Immunol. 2014;34(8):954-961. doi: 10.1007/s10875-014-0102-8.

2. FDA approves subcutaneous immunoglobulin (immune globulin subcutaneous [human] 20% liquid) for the treatment of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) [news release]. CSL Behring. Updated March 16, 2018. Accessed September 13, 2018.

3. Chronic inflammatory demyelinating polyneuropathy. National Organization for Rare Disorders. rarediseases.org/rare-diseases/chronic-inflammatory-demyelinating-polyneuropathy. Published 2015. Accessed September 13, 2018.

4. Subcutaneous immunoglobulin [prescribing information]. Bern, Switzerland: CSL Behring; 2010. www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM203150.pdf. Accessed September 13, 2018.

5. Subcutaneous immunoglobulin. Red Book Online. Micromedex Healthcare Series [online database]. Greenwood Village, CO: Truven Health Analytics; 2010. Accessed September 13, 2018.