Immune Globulin Subcutaneous

Immune globulin subcutaneous is injected under the skin using an infusion pump. The medicine enters the body through a catheter placed under your skin. You may be shown how to use injections at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, tubing, and other items used to inject the medicine.

Immune globulin is usually given once every week. Follow your doctor's dosing instructions. If you use this medication at home, keep a diary of the days and times you gave the injection and where you injected it on your body.

Immune globulin must be given slowly, and the infusion can take about 1 hour to complete. You may need to use up to 4 catheters to inject this medicine into different body areas at the same time. Your care provider will show you the best places on your body to inject the medication. Follow your doctor's instructions.

Do not shake the medication bottle or you may ruin the medicine. Prepare your dose only when you are ready to give an injection. Do not mix immune globulin with other medications in the same infusion. Do not use if the medicine has changed colors or has particles in it. Call your pharmacist for new medicine.

Immune globulin subcutaneous should not be injected into a vein.

Before injecting the medicine, test to make sure the infusion pump needle is not in a vein. To do this, gently pull back on the plunger of the syringe connected to the infusion tube. If blood flows back into the syringe, remove the catheter and tubing and throw them away. Start over with a new catheter and syringe, insert the needle in a new place on your body, and test for blood flow-back again.

Each single-use vial (bottle) of this medicine is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.

Use disposable injection items (needle, catheter, tubing) only once. Throw away the used items in a puncture-proof container (ask your pharmacist where you can get one and how to dispose of it). Keep this container out of the reach of children and pets.

While using this medicine, you may need frequent blood tests.

This medication can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using immune globulin.

Store Hizentra in the original carton at room temperature, away from moisture, heat, and light. Do not freeze.

Store Vivaglobin in its original carton in the refrigerator. Do not freeze. Take the medicine out and allow it to reach room temperature before preparing your dose.

Throw away any immune globulin that has become frozen. Throw away any unused medication after the expiration date on the label has passed.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Call your doctor for instructions if you miss a dose of this medicine.

The most common adverse reactions (ARs), observed in ≥ 5% of study subjects receiving Hizentra, were local reactions (e.g., swelling, redness, heat, pain, and itching at the injection site), headache, diarrhea, fatigue, back pain, nausea, pain in extremity, cough, rash, pruritus, vomiting, abdominal pain (upper), migraine, and pain.

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, AR rates observed in clinical studies of a product cannot be directly compared to rates in the clinical studies of another product and may not reflect the rates observed in clinical practice.

The safety of Hizentra was evaluated in a clinical study in the US for 15 months (3-month wash-in/wash-out period followed by a 12-month efficacy period) in subjects with PI who had been treated previously with IGIV every 3 or 4 weeks. The safety analyses included 49 subjects in the intention-to-treat (ITT) population. The ITT population consisted of all subjects who received at least one dose of Hizentra [see Clinical Studies].

Subjects were treated with Hizentra at weekly median doses ranging from 66 to 331 mg/kg body weight (mean: 181.4 mg/kg) during the wash-in/wash-out period and from 72 to 379 mg/kg (mean: 213.2 mg/kg) during the efficacy period. The 49 subjects received a total of 2264 weekly infusions of Hizentra.

Table 2 summarizes the most frequent adverse reactions (ARs) (experienced by at least 2 subjects) occurring during or within 72 hours after the end of an infusion. Local reactions were assessed by the investigators 15 to 45 minutes post-infusion and by the subjects 24 hours post-infusion. The investigators then evaluated the ARs arising from the subject assessments. Local reactions were the most frequent ARs observed, with injection-site reactions (e.g., swelling, redness, heat, pain, and itching at the site of injection) comprising 98% of local reactions.

Table 2: Incidence of Subjects with Adverse Reactions (ARs)* (Experienced by 2 or More Subjects) and Rate per Infusion (ITT Population), US Study

The ratio of infusions with ARs, including local reactions, to all infusions was 1303 to 2264 (57.6%). Excluding local reactions, the corresponding ratio was 56 to 2264 (2.5%).

Table 3 summarizes injection-site reactions based on investigator assessments 15 to 45 minutes after the end of the 683 infusions administered during regularly scheduled visits (every 4 weeks).

Table 3: Investigator Assessments* of Injection-Site Reactions by Infusion, US Study

Most local reactions were either mild (93.4%) or moderate (6.3%) in intensity.

No deaths or serious ARs occurred during the study. Two subjects withdrew from the study due to ARs. One subject experienced a severe injection-site reaction one day after the third weekly infusion, and the other subject experienced moderate myositis. Both reactions were judged to be “at least possibly related” to the administration of Hizentra.

In a clinical study conducted in Europe, the safety of Hizentra was evaluated for 10 months (3-month wash-in/wash-out period followed by a 7-month efficacy period) in 51 subjects with PI who had been treated previously with IGIV every 3 or 4 weeks or with IGSC weekly. Subjects were treated with Hizentra at weekly median doses ranging from 59 to 267 mg/kg body weight (mean: 118.8 mg/kg) during the wash-in/wash-out period and from 59 to 243 mg/kg (mean: 120.1 mg/kg) during the efficacy period. The 51 subjects received a total of 1831 weekly infusions of Hizentra.

Table 4 summarizes the most frequent ARs (experienced by at least 2 subjects) occurringduring or within 72 hours after the end of an infusion. Local reactions were assessed by the subjects between 24 and 72 hours post-infusion. The investigators then evaluated the ARs arising from the subject assessments.

Table 4: Incidence of Subjects with Adverse Reactions (ARs)* (Experienced by 2 or More Subjects) and Rate per Infusion, European Study

The proportion of subjects reporting local reactions decreased over time from approximately 20% following the first infusion to < 5% by the end of the study.

Three subjects withdrew from the study due to ARs of mild to moderate intensity. One subject experienced injection-site pain and injection-site pruritus; the second subject experienced injection-site reaction, fatigue, and feeling cold; and the third subject experienced injection-site reaction and hypersensitivity. All reactions were judged by the investigator to be “at least possibly related” to the administration of Hizentra.

No data regarding ARs are available for these alternative Hizentra dosing regimens because no clinical trials using these regimens were conducted; however, it is unlikely that the safety profile is qualitatively different from that of weekly dosing.

Postmarketing Experience

Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

The following adverse reactions have been identified during postmarketing use of Hizentra.This list does not include reactions already reported in clinical studies with Hizentra [see Clinical Trials Experience above].

• Infusion reactions: Allergic-anaphylactic reactions such as swollen face or tongue and pharyngeal edema, pyrexia, chills, dizziness, hypertension/changes in blood pressure, malaise.
• Cardiovascular: Chest discomfort (including chest pain)
• Respiratory: Dyspnea
• Neurological: Tremor, burning sensation

The following adverse reactions have been reported during postmarketing use of immune globulin products5:

• Infusion reactions: Tachycardia, flushing, wheezing, rigors, myalgia
• Renal: Osmotic nephropathy
• Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), cyanosis, hypoxemia, pulmonary edema, bronchospasm
• Cardiovascular: Cardiac arrest, vascular collapse, hypotension
• Neurological: Coma, loss of consciousness, seizures, aseptic meningitis syndrome
• Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g., bullous dermatitis)
• Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs') test
• Gastrointestinal: Hepatic dysfunction

To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring Pharmacovigilance at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

REFERENCES

5. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev 2003;17:241-251.

Vivaglobin® Immune Globulin Subcutaneous (Human), is a pasteurized, polyvalent human normal immunoglobulin for subcutaneous infusion. Vivaglobin® is manufactured from large pools of human plasma by cold alcohol fractionation and is not chemically altered or enzymatically degraded.

Vivaglobin® (immune globulin subcutaneous human) is supplied as a sterile liquid to be administered by the subcutaneous route. Vivaglobin® (immune globulin subcutaneous human) is a 16% (160 mg/mL) protein solution, with a content of at least 96% immunoglobulin G (IgG). The distribution of IgG subclasses is similar to that present in normal human plasma. Vivaglobin® (immune globulin subcutaneous human) contains 2.25% glycine, 0.3% sodium chloride, and water for injection, U.S.P. The pH of Vivaglobin® (immune globulin subcutaneous human) is 6.4 to 7.2. Vivaglobin® (immune globulin subcutaneous human) contains no preservative.

All plasma used in the manufacture of Vivaglobin® (immune globulin subcutaneous human) is tested using FDA-licensed serological assays for hepatitis B surface antigen and antibodies to hepatitis C virus (HCV) and human immunodeficiency virus types 1 and 2 (HIV-1/2) as well as FDA-licensed Nucleic Acid Testing (NAT) for HCV and HIV-1 and found to be nonreactive (negative). For hepatitis B virus (HBV), an investigational NAT procedure is used and the plasma found to be negative. However, the significance of a negative result has not been established. In addition, the plasma has been tested by NAT for hepatitis A virus (HAV) and parvovirus B19 (B19). Only plasma that passed virus-screening is used for production and the limit for B19 in the fractionation pool is set not to exceed 104 IU of B19 DNA per mL.

The manufacturing procedure for Vivaglobin® (immune globulin subcutaneous human) includes multiple processing steps that reduce the risk of virus transmission. The virus reduction capacity of two steps was evaluated in a series of in vitro spiking experiments; the steps were ethanol - fatty alcohol / pH precipitation and pasteurization in aqueous solution at 60°C for 10 hours. Total mean cumulative virus reductions ranged from 9.0 to ≥ 14.1 log10 as shown in Table 1.

Table 1: Mean Virus Reduction Factors CSL Behring

You should not use this medication if you have ever had an allergic reaction to an immune globulin, if you have immune globulin A (IgA) deficiency with antibody to IgA, or if you have a condition called hyperprolinemia (high level of a certain amino acid in the blood).

You may need a dose adjustment if you are exposed to measles, or if you travel to an area where this disease is common.

If you have any of these other conditions, you may need a dose adjustment or special tests:

• blood circulation problems or a blood vessel disorder;
• a history of stroke or blood clot; or
• if you have been bed-ridden due to severe illness.

You may need a dose adjustment if you are exposed to measles, or if you travel to an area where this disease is common.

FDA pregnancy category C. It is not known whether immune globulin will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medication.

It is not known whether immune globulin passes into breast milk or if it could harm a nursing baby. Do not use this medication without telling your doctor if you are breast-feeding a baby.

Immune globulin is made from human plasma (part of the blood) which may contain viruses and other infectious agents. Donated plasma is tested and treated to reduce the risk of it containing infectious agents, but there is still a small possibility it could transmit disease. Talk with your doctor about the risks and benefits of using this medication.

Immune globulin is a sterilized solution made from human plasma. It contains the antibodies to help your body protect itself against infection from various diseases.

Immune globulin subcutaneous (for injection under the skin) is used to treat primary immunodeficiency (PI).

Immune globulin may also be used for purposes not listed in this medication guide.

You should not use immune globulin subcutaneous if you have a condition called hyperprolinemia (high level of a certain amino acid in the blood).

This medicine can cause blood clots. A blood clot may be more likely if you have risk factors such as heart disease, blood circulation problems, estrogen use, a history of blood clots, if you are 65 years or older, if you have been bed-ridden, or if you are using a catheter.

Stop using immune globulin and call your doctor at once if you have:

• signs of a blood clot in the brain--sudden numbness or weakness (especially on one side of the body), slurred speech, problems with vision or balance;

• signs of a blood clot in the heart or lung--chest pain, rapid heart rate, sudden cough, wheezing, rapid breathing, coughing up blood; or

• signs of a blood clot in your leg--pain, swelling, warmth, or redness in one or both legs.

Immune globulin subcutaneous can also harm your kidneys, especially if you already have kidney disease or if you also use certain other medicines. Many other drugs (including some over-the-counter medicines) can be harmful to the kidneys.

Call your doctor at once if you have signs of a kidney problem, such as swelling, rapid weight gain, and little or no urinating.

Drink plenty of liquids while you are using this medicine to help improve your blood flow and keep your kidneys working properly.

Call your doctor for instructions if you miss a dose of this medicine.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; wheezing, difficulty breathing; dizziness, feeling like you might pass out; swelling of your face, lips, tongue, or throat.

Stop using this medicine and call your doctor at once if you have:

• signs of a blood clot in the brain--sudden numbness or weakness (especially on one side of the body), slurred speech, problems with vision or balance;

• signs of a blood clot in the heart or lung--chest pain, rapid heart rate, sudden cough, wheezing, rapid breathing, coughing up blood;

• signs of a blood clot in your leg--pain, swelling, warmth, or redness in one or both legs;

• signs of a kidney problem--swelling, rapid weight gain, and little or no urinating;

• liver problems--fast heart rate, tired feeling, dark urine, jaundice (yellowing of the skin or eyes);

• lung problems--chest pain, trouble breathing, blue lips, pale or blue colored appearance in your fingers or toes; or

• signs of new infection--high fever, flu symptoms, mouth sores, severe headache, neck stiffness, increased sensitivity to light, nausea and vomiting.

Common side effects may include:

• redness, bruising, itching, and swelling where the medicine was injected;

• nausea, vomiting, diarrhea, bloating, stomach pain;

• tired feeling, headache, migraine;

• mild itching or rash;

• back pain; or

• pain anywhere in your body.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
• Fever or chills.
• Change in color of skin to a bluish color like on the lips, nail beds, fingers, or toes.
• Feeling very tired or weak.
• Seizures.
• Bloating.
• Feeling confused.
• Swelling.
• Very bad dizziness or passing out.
• A heartbeat that does not feel normal.
• Any unexplained bruising or bleeding.
• Mood changes.
• Muscle or joint pain.
• Change in speech.
• Change in eyesight.
• Blurred eyesight.
• Shakiness.
• Sweating a lot.
• Very bad belly pain.
• Dark urine or yellow skin or eyes.
• Very bad irritation where the shot was given.
• Lung problems have happened with this drug. Call your doctor right away if you have lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse.
• This drug may raise the chance of a very bad brain problem called aseptic meningitis. Call your doctor right away if you have a headache, fever, chills, very upset stomach or throwing up, stiff neck, rash, bright lights bother your eyes, feeling sleepy, or feeling confused.

Applies to immune globulin subcutaneous: subcutaneous solution

Local

Local side effects have been reported the most frequently. Up to 92% of patients reported adverse events at the injection site.[Ref]

Gastrointestinal

Gastrointestinal side effects have been reported often (37%), including nausea (18%) and diarrhea (10%).[Ref]

Dermatologic

Dermatologic side effects have included rash (17%).[Ref]

Hypersensitivity

Hypersensitivity side effects have rarely included immediate anaphylactoid and hypersensitivity reactions. Allergic reactions (11%) have also been reported.[Ref]

General

General side effects have included headache (48%), fever (25%), sore throat (17%), and pain (10%).[Ref]

Respiratory

Respiratory side effects have included an increase in cough (10%).[Ref]

Some side effects of immune globulin subcutaneous may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.