Normal human Immunoglobulin: price, reviews, instructions for use in pregnancy

Normal human Immunoglobulin: price, reviews, instructions for use in pregnancy

Composition

Immunoglobusline human normal has an active ingredient — an immunoglobulin fraction. It is initially released from human plasma, after which it is purified and concentrated. As a part of the preparation there is no antibodies to human immunodeficiency viruses and hepatitis C, it does not contain antibiotics .The protein concentration is 4.5% -5.5%.Low anticomplementary activity of the drug is noted.

Immunoglobulin preparations are available in two forms. It is a solution for intramuscular injection and a dry powder for infusion( Immunoglobulin IV).A solution is a clear or slightly opalescent liquid without color.

Pharmacological action of

This drug provides immunostimulating and with the immunomodulating action of .It contains many opsonizing and neutralizing antibodies. Their presence provides effective resistance to bacteria, viruses and a number of other pathogens.

Under the influence of this remedy, the amount of missing IgG antibodies is replenished. As a result, the risk of developing infection in people diagnosed with primary and secondary immunodeficiency is reduced. Immunoglobulin replaces and replaces natural antibodies in human blood serum.

To understand the essence of the effect on the body of this drug, one should understand how immunoglobulin functions in the human body, what it is. Wikipedia testifies that immunoglobulins are unique immune molecules that can neutralize a number of toxins and many pathogens in the human body.

To neutralize a specific type of virus or bacteria, the body produces unique types of immunoglobulins. There is a classification according to which classes of immunoglobulins are determined depending on antigenic features, properties, and structure.

If necessary, a blood test for immunoglobulin, general and specific. This examination allows you to determine the presence of allergic diseases and to prescribe the right treatment. The expert can determine the results of the analysis in detail, determining whether the immunoglobulin is elevated( the norm of its content depends on the person’s age).If a certain class is upgraded, what this means is explained in detail by the specialist.

Pharmacokinetics and pharmacodynamics

When carrying out intravenous infusion of , the bioavailability level is 100%.The highest concentration of antibodies in human blood is observed for 14 days. The half-life of antibodies is 4-5 weeks. It penetrates the placenta and enters the breast milk.

Indications for use

A normal human immunoglobulin is indicated as a substitute treatment if the patient needs to undergo substitution treatment to replace and replenish natural antibodies.

In order to prevent infections, it is prescribed in the following cases:

  • during bone marrow transplantation;
  • with agammaglobulinemia;
  • in case of primary and secondary immunodeficiency, with variable immunodeficiency;
  • with lymphatic leukemia, which is chronic;
  • with AIDS in children;
  • with thrombocytopenic purpura, which is of an immune origin;
  • for severe bacterial and viral infections;
  • with Kawasaki Syndrome;
  • with Guillain-Barre Syndrome;
  • with erythrocyte aplasia;
  • with neutropenia, which is of autoimmune origin;
  • with demyelinating polyneuropathy of chronic type;
  • for hemolytic anemia and thrombocytopenia, having an autoimmune origin;
  • with hemophilia, provoked and induced by the synthesis of antibodies to factor P;
  • during the treatment of myastenia gravis;
  • in order to prevent the habitual miscarriage;
  • for the prevention of infectious diseases in preterm infants.

Contraindications

The following contraindications for the use of this drug are determined:

  • high sensitivity of to human immunoglobulins;
  • IgA deficiency due to the presence of antibodies to it;
  • allergic processes of in acute form;
  • renal failure;
  • diabetes mellitus;
  • anaphylactic shock for blood products.

When prescribing a remedy, not only contraindications should be considered, but also those conditions and diseases in which treatment should be performed with caution.

Very cautiously prescribed remedy for people suffering from migraine , decompensated heart failure of a chronic nature, and also to pregnant women , mothers during the natural feeding period .With care and only after the appointment of a doctor, people suffering from diseases whose origin is associated with immunopathological mechanisms( collagenosis , nephritis , immune diseases of the blood ) are treated with caution.

Side effects of

If the patient is prescribed Immunoglobulin is normal, and the correct treatment regimen, dosage and administration are observed, then the side effects are rare. However, it should be noted that side effects can occur within hours or even days after the drug has been injected. In most cases, negative manifestations completely disappear after the drug has been discontinued.

In general, side effects are observed due to too high a rate of infusion of the drug. If you temporarily suspend the introduction or reduce its speed, then most of the negative effects will disappear. If the negative symptoms persist, it is necessary to practice symptomatic treatment.

The most common side effects occur when Immunoglobulin is administered to a person for the first time, moreover, it develops within the first hour. These can be the following symptoms:

  • flu-like syndrome( body temperature rise, chills, headaches, weakness);
  • dry cough, shortness of breath;
  • vomiting , diarrhea, severe salivation, stomach pain;
  • tachycardia, cyanosis, flushes to the face, pain in the chest;
  • weakness, drowsiness, sensitivity to light, impaired consciousness, in rare cases — signs of aseptic of meningitis;
  • in rare cases shows acute tubular necrosis, the condition may worsen in people with kidney failure;
  • allergic manifestations of;
  • local reactions.

In addition to the above symptoms, there may be a feeling of aches in the joints, myalgia , sweating , hiccough , back pain. Very rarely there is loss of consciousness, collapse , hypertension in severe form. If the response to therapy is very serious, you must cancel the treatment. If necessary, you can enter epinephrine , antihistamines, solutions that replace the plasma.

Instruction for use Immunoglobulin( Method and dosage)

The Instruction for Immunoglobulin provides the possibility of drip intravenous and intramuscular administration of the drug. As a rule, the dose of the drug is prescribed individually, taking into account the severity of the disease, the state of immunity , etc.

Instruction for the use of drugs for children involves the introduction of 3-4 ml of funds per 1 kg of the child’s weight, with the dose not exceeding 25 ml. Before the introduction of Immunoglobulin, dilute with 0.9% sodium chloride solution( sterile) or 5% glucose solution, respectively 1 part of the drug and 4 parts of the solvent. Drip intravenously is introduced, while the speed should be 8-10 drops per minute. Infusions are carried out within 3-5 days.

Adult patients receive a single dose of 25-50 ml. Dilute additionally the drug is not required, injected intravenously, while the rate of administration is 30-40 drops per minute. The course of treatment is assigned 3-10 transfusions, which are conducted after 24-72 hours.

If the question arises where to put a dropper, it should be noted that the drug can be administered intravenously only in the hospital, while it is important to strictly comply with aseptic requirements. Where it is possible to make an injection of Immunoglobulin, you can find out in the nearest medical institution. It is also possible to obtain information on the conditions under which Immunoglobulin is administered to children free of charge.

Before entering the product, the bottle should be kept at a temperature of 18 to 22 ° C for at least 2 hours. If the solution is cloudy or there is a sediment in it, it can not be injected.

Overdose of

Possibility of overdosing of the drug when administered intravenously. Such symptoms are hypervolemia and high blood viscosity .It is more likely that overdose symptoms occur in the elderly and in patients with kidney disease.

Interaction

The pharmaceutical incompatibility of the drug with other medicines is noted. It should not be confused with other drugs, you should always use a separate dropper for Immunoglobulin.

The effectiveness of the drug may decrease if it is administered at the same time as the immunization medication with rubella , with chickenpox , with measles .

If it is necessary to apply parenterally live viral vaccines with chickenpox, etc., they may be used 1 month after treatment with Immunoglobulin, but it is advisable to withstand a break of 3 months.

Do not use the drug concomitantly with calcium gluconate when treating infants.

Terms of sale

In pharmacy chains sold by prescription.

Storage conditions

The preparation must be transported and stored, respectively, with SP 3.3.2.038-95, temperature conditions — 2-8 ° C.You can not freeze.

Shelf life

Shelf life 1 year. Can not be applied after the expiration of this period.

Specific instructions for

Patients diagnosed with a disease whose origin is related to immunological mechanisms can be treated with Immunoglobulin only after consulting a physician involved in the treatment of such diseases.

Administration of the drug must be recorded in the appropriate registration form, in which it is necessary to indicate the series, number, date of manufacture, shelf life, date of administration, dosage and response to receipt of the drug.

Do not use the drug if the container has been damaged. After opening the container, the medicine is used in the same section, it can not be stored open.

The protective effect of the drug is noted after 24 hours and lasts for 30 days.

After the application of Immunoglobulin, a passive increase in the number of antibodies in the blood is noted. Therefore, when the blood is given for analysis, the transcription of the blood test for immunoglobulin can later be incorrect.

Patients who are diagnosed with allergic diseases or are noted to be addicted to allergic manifestations of should receive antihistamines on the day of solution administration and for eight days after its administration.

After the drug was administered to the patient, it is necessary to observe it for another half an hour. The specialist should have access to funds for anti-shock therapy.

Analogs

  • Pentaglobin
  • Octagam

In medicine, a number of analogues of this agent are used. This medication Gamunex , Immunovenin , Intraglobin , Pentaglobin , Intratekt , Gabriglobin , Endobulin and others.

To find an adequate analogue should be understood that such an Immunoglobulin and be sure to consult with your doctor. To determine which particular drug will be the most optimal for the treatment or prevention of diseases, for example, Immunoglobulin or Yodantipyrine for the prevention of tick-borne encephalitis should be consulted with a specialist.

For children

It is possible to prescribe the drug to children in the presence of indications, it is important to follow the dosage described in the instructions clearly.

With alcohol

Immunoglobulin and alcohol are incompatible, since alcohol is an immunosuppressant, it worsens the functioning of the human immune system. When you drink alcohol on the background of treatment with this drug, the probability of side effects increases sharply. In addition, diseases and conditions requiring the appointment of Immunoglobulin, imply a categorical ban on the use of alcohol.

Immunoglobulin in pregnancy and lactation

No information is available on the use of for pregnant women .However, intravenous injection or injection of Immunoglobulin during pregnancy are performed only if there are clear indications.

When discussing the effectiveness of Immunoglobulin, women leave the reviews in pregnancy different, noting that the drug can alleviate the condition in many diseases, in particular with cytomegalovirus , herpes , etc. With lactation , the drug is used cautiously,enters the breast milk and ensures the transmission of antibodies to the infant. Women after the birth of the drug is administered if there is evidence.

Reviews about Immunoglobulin

Reviews for Immunoglobulin human normal intramuscular and intravenous evidence both of the effectiveness of the drug in many diseases, and the manifestation of negative effects in its use. It is noted that after the administration of the remedy, weakness, malaise, and chills are often felt.

Reviews during pregnancy are also sometimes contradictory: some women are sure that taking risks even if there are indications should not be. Nevertheless, experts assure that under the supervision of a doctor such treatment benefits.

medsides.com

Immunoglobulin Replacement Therapy in Primary Immunodeficiencies

Immunoglobulin (antibody) replacement therapy (IRT) is one of the most effective and commonly used therapies for some primary immunodeficiency diseases (PIDs). Many people with PIDs have insufficient antibodies to adequately fight infections, and this therapy can be life saving.

Why is IRT used?

In people with PIDs, IRT can:

  • Treat existing infections
  • Prevent new infections from occurring
  • Prevent long term damage from chronic infections (such as bronchiectasis in the lung)

How is IRT made?

Immunoglobulin products are purified from pooled plasma of many healthy blood donors. Plasma is the liquid part of blood that remains when all red blood cells have been removed. When donors give blood, the red cells and plasma are separated. The plasma is pooled together and processed in highly specialised and regulated facilities to produce immunoglobulin, which contains a wide variety of antibodies.

How is IRT given?

There are two ways that IRT can be given:

  • Intravenous immunoglobulin (IVIG) infusions are delivered directly into the person’s vein, usually in a hospital day clinic. The infusion can take approximately 2 to 4 hours. The dose and frequency vary, and depend on the person’s weight and immunoglobulin levels. Most people receive IVIg doses once every month.
  • Subcutaneous immunoglobulin (SCIg) — This involves slowly infusing the antibody preparation directly under the skin, which can be done at home, often by using a pump. This is usually done once or more each week, as only 10-15mL can be infused into any one site. A 10mL infusion can be delivered in half an hour. It may be necessary in some cases for infusions to be more frequent, particularly during introduction to therapy. When beginning SCIg therapy, red lumps may form under the skin. These usually disappear quite quickly and after a few weeks of therapy usually stop appearing.

Are there any side effects of IRT?

IRT is normally very well tolerated and serious side effects are very rare. However, there are some side effects that people receiving IRT should be aware of:

  • Risk of blood-borne infections
    Current preventative measures have been greatly enhanced so that the risk of infection from antibody therapy is now close to zero. Nevertheless, you may wish to discuss this risk with your medical team.
  • Other side effects
    Some people get minor side effects such as low grade fevers or headaches, which can usually be reduced by a slower infusion rate or treated with paracetamol. Occasionally people experience hives or wheezing or rarely severe headaches. Severe allergic reactions and abnormal kidney function due to IRT are rare.
  • IgA reactions
    In rare cases, when a person lacks Immunoglobulin A (IgA) antibodies, reactions similar to severe allergic reactions may occur when receiving blood products containing IgA. However, most IgA deficient people receive blood products without difficulty. These reactions are less likely with current IgA depleted Immunoglobulin products.

You should notify your doctor of any side effects you might experience.

Limitations of IRT

IRT does not cure the antibody deficiency, and does not usually reverse long term organ injury from chronic infections. IRT contains only one of the important components of the immune system’s response to infection. For these reasons it is best to start IRT before organ damage has occurred.

Availability of IRT

IRT is derived from blood (plasma), are in limited supply, and access is restricted. Doctors must follow specific guidelines to ensure that the product goes to people most in need.

See also:  Instruction for use: Povidone - DR

IRT should only be used in these cases where scientific and clinical evidence supports its use, and where other therapies are considered less favorable.

IRT is reserved for those people with confirmed abnormalities in antibody production, and who experience recurrent infections.

IRT is also of great benefit for patients with certain autoimmune diseases (such as immune thrombocytopenia and Guillain Barre syndrome), where it is used to alter the course of the disease (immunomodulation) rather than to replace antibodies that are deficient.

© ASCIA 2019

ASCIA is the peak professional body of clinical immunology/allergy specialists in Australia and New Zealand.

ASCIA resources are based on published literature and expert review, however, they are not intended to replace medical advice. The content of ASCIA resources is not influenced by any commercial organisations.

allergy.org.au

Cuvitru

CUVITRU
Immune Globulin Subcutaneous (Human) Solution

  • 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.

DESCRIPTION

CUVITRU is a ready-for-use, sterile, liquid preparation of highly purified and concentrated immunoglobulin G (IgG) antibodies. The distribution of the IgG subclasses is similar to that of normal plasma. The Fc and Fab functions are maintained in CUVITRU.

CUVITRU has a purity ≥98% IgG and a pH of 4.6 to 5.1. The osmolality is 280-292 milli-osmoles per kilogram. CUVITRU contains 200 milligram/mL protein. The average immunoglobulin A (IgA) concentration is 80 mcg/mL. CUVITRU contains a broad spectrum of IgG antibodies against bacterial and viral agents. Glycine (0.25M) serves as a stabilizing and buffering agent, and there are no added sugars, sodium or preservatives.

CUVITRU is manufactured from large pools of human plasma. IgG preparations are purified from plasma pools using a modified Cohn-Oncley cold ethanol fractionation process, as well as cation and anion exchange chromatography.

Screening against potentially infectious agents begins with the donor selection process and continues throughout plasma collection and plasma preparation. Each individual plasma donation used in the manufacture of CUVITRU is collected only at FDA approved blood establishments and is tested by FDA licensed serological tests for Hepatitis B Surface Antigen (HBsAg), and for antibodies to Human Immunodeficiency Virus (HIV-1/HIV-2) and Hepatitis C Virus (HCV) in accordance with U.S. regulatory requirements. As an additional safety measure, mini-pools of the plasma are tested for the presence of HIV-1 and HCV by FDA licensed Nucleic Acid Testing (NAT) and found to be negative.

To further improve the margin of safety, validated virus inactivation/removal steps have been integrated into the manufacturing and formulation processes, namely solvent/detergent (S/D) treatment 13 , 35 nm nanofiltration, and a low pH incubation at elevated temperature (30°C to 32°C). The S/D process includes treatment with an organic mixture of tri-n-butyl phosphate, octoxynol 9 and polysorbate 80 at 18°C to 25°C for a minimum of 60 minutes. S/D treatment inactivates the lipid-enveloped viruses investigated to below detection limits within minutes 13 . The ethanol fractionation process provides an additional virus clearance capacity.

In vitro virus spiking studies have been used to validate the capability of the manufacturing process to inactivate and remove viruses. To establish the minimum applicable virus clearance capacity of the manufacturing process, these virus clearance studies were performed under extreme conditions (e.g., at minimum S/D concentrations, incubation time and temperature for the S/D treatment).

Virus clearance studies for CUVITRU performed in accordance with good laboratory practices are summarized in Table 7.

Table 7 Three Dedicated Independent Virus Inactivation/Removal Steps Mean Log10 Reduction Factors a (RFs) For Each Virus and Manufacturing Step

Enveloped Enveloped Non-enveloped Non-enveloped
Virus type RNA DNA RNA DNA
Family Retroviridae Flaviviridae Herpesviridae Picornaviridae Parvoviridae
Virus HIV-1 BVDV WNV PRV HAV EMCV MMV
Fractionation >5.1 1.3 >6.1 >4.9 3.9 4.2 4.9
SD treatment >4.5 >6.2 n.a. >4.8 n.d. n.d. n.d.
35 nm nanofiltration >4.5 >5.1 >6.2 >5.6 5.7 1.4 2.0
Low pH treatment >5.8 >5.5 >6.0 >6.5 n.d. b >6.3 3.1
Overall log reduction factor (ORF) >19.9 >18.1 >18.3 >21.8 9.6 b >11.9 10.1
Abbreviations: HIV-1, Human Immunodeficiency Virus Type 1; BVDV, Bovine Viral Diarrhea Virus (model for Hepatitis C Virus and other lipid enveloped RNA viruses); WNV, West Nile Virus; PRV, Pseudorabies Virus (model for lipid enveloped DNA viruses, including Hepatitis B Virus); EMCV, Encephalomyocarditis Virus (model for non-lipid enveloped RNA viruses, including Hepatitis A virus [HAV]); MMV, Mice Minute Virus (model for non-lipid enveloped DNA viruses, including B19 virus [B19V]); n.d. (not done), n.a. (not applicable).
a For the calculation of these RF data from virus clearance study reports, applicable manufacturing conditions were used. Log10 RFs on the order of 4 or more are considered effective for virus clearance in accordance with the Committee for Medicinal Products for Human Use (CHMP, formerly CPMP) guidelines.
b No RF obtained due to immediate neutralization of HAV by the anti-HAV antibodies present in the product.

1. Kreil TR, Berting A, Kistner O, Kindermann J. West Nile virus and the safety of plasma derivatives: verification of high safety margins, and the validity of predictions based on model virus data. Transfusion 2003;43:1023-1028.

INDICATIONS

CUVITRU is an Immune Globulin Subcutaneous (Human) (IGSC), 20% Solution indicated as replacement therapy for primary humoral immunodeficiency (PI) in adult and pediatric patients two years of age and older. This includes, but is not limited to, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies 1,2 .

DOSAGE AND ADMINISTRATION

For subcutaneous administration only. Do not administer intravenously or intramuscularly.

Preparation And Handling

  • Inspect the drug product visually for particulate matter and discoloration prior to administration. CUVITRU is a clear and colorless or pale yellow or light brown solution and clear of particulate matter. Do not use if the solution is cloudy, turbid, or if it contains particulates.
  • Do not mix CUVITRU with other products.
  • Do not shake.
  • Do not dilute.
  • CUVITRU vial is for single use only. Any vial that has been entered should be used promptly. Partially used vials should be discarded. CUVITRU contains no preservative.
  • Record the name and lot number of the product in the recipient’s records.
  • CUVITRU can be administered at regular intervals from daily up to every two weeks (biweekly).
  • Individualize the dose based on the patient’s pharmacokinetic and clinical response.
  • Monitor serum IgG trough levels regularly to guide subsequent dose adjustments and dosing intervals as needed (see Dose Adjustment).
For Patients Switching From Immune Globulin Intravenous (Human) Treatment (IGIV) Or Adult Patients Switching From HYQVIA [Immune Globulin Infusion 10% (Human) With Recombinant Human Hyaluronidase]:
  • Begin treatment with CUVITRU one week after the patient’s last IGIV or HYQVIA infusion.
  • Establish the initial weekly dose by converting the monthly IGIV or HYQVIA dose into an equivalent weekly dose and increasing it using a dose adjustment factor.
  • To calculate the initial weekly dose, divide the previous IGIV or HYQVIA dose in grams by the number of weeks between intravenous doses; then multiply this dose by the dose adjustment factor of 1.30.
Initial Weekly dose = Previous IGIV or HYQVIA dose (in grams) x 1.30
Number of weeks between IGIV or HYQVIA doses
  • To convert the dose (in grams) to milliliters (mL), multiply the calculated dose (in grams) by 5.
  • Doses divided over the course of a week, or once weekly, or biweekly, achieve similar exposure when administered regularly at steady-state.
  • To determine the dose for alternative regular dosing intervals:
    • Frequent dosing (2-7 times per week): Divide the calculated weekly dose by the desired number of times per week.
    • Biweekly dosing: Multiply the calculated weekly dose by 2.
  • To guide dose adjustments, see section Dose Adjustments (Table 1).

    For Patients Switching From Immune Globulin Subcutaneous (Human) Treatment (IGSC):
    • The weekly dose of CUVITRU (in grams) is recommended to be the same as the weekly dose of prior IGSC treatment (in grams).
    • Doses divided over the course of a week, once weekly, or biweekly, achieve similar exposure when administered regularly at steady-state.
    • To determine the dose for alternative regular dosing intervals:
      • Biweekly dosing: Multiply the calculated weekly dose by 2.
      • To convert the dose (in grams) to milliliters (mL), multiply the calculated dose (in grams) by 5.

    To guide dose adjustments, see section Dose Adjustments (Table 1).

    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 Table 1 and the corresponding amount (in mL) by which to increase (or decrease) the weekly/biweekly dose based on the patient’s body weight. If the difference between measured and target trough levels is less than 100 milligram/dL, then no adjustment is necessary. However, the patient’s clinical response should be the primary consideration in dose adjustment.

    Table 1 Change in Volume to Be Administered Weekly/Biweekly for Intended IgG Trough Level Change a

    Body Weight
    Difference from Target Serum IgG Trough Levels Dosing Frequency 30 kg 50 kg 70 kg 90 kg 110 kg
    100 mg/dL Weekly 3 mL 5 mL 7 mL 9 mL 11 mL
    Biweekly 6 mL 10 mL 13 mL 17 mL 21 mL
    200 mg/dL Weekly 6 mL 10 mL 13 mL 17 mL 21 mL
    Biweekly 12 mL 19 mL 27 mL 35 mL 42 mL
    300 mg/dL Weekly 9 mL 14 mL 20 mL 26 mL 32 mL
    Biweekly 17 mL 29 mL 40 mL 52 mL 63 mL
    a Derived using a linear approximation of trough levels and weekly dose per kg body mass with a slope of 52.1 kg/dL.

    Example 1: A patient with a body weight of 70 kg who is on a weekly treatment has a measured IgG trough level of 600 milligrams/dL, and the target trough level is 800 milligrams/dL. The desired target trough level difference is 200 milligrams/dL (800 milligrams/dL minus 600 milligrams/dL). The weekly dose of CUVITRU should be increased by 13 mL.

    Example 2: A patient with a body weight of 50 kg who is on a biweekly treatment has a measured IgG trough of 900 milligrams/dL, and the target trough level is 700 milligrams/dL. The desired target trough level difference is 200 milligrams/dL (900 milligrams/dL minus 700 milligrams/dL). The biweekly dose of CUVITRU should be decreased by 19 mL.

    Administration

    Table 2 Infusion Volume and Rate*

    Infusion Parameters First 2 Infusions Subsequent Infusions
    Patients

    Selection Of Infusion Site

    Suggested areas for subcutaneous infusion of CUVITRU are abdomen, thighs, upper arms, or lateral hip. CUVITRU may be infused into multiple infusion sites. Use up to 4 sites simultaneously. Infusion sites should be at least four inches apart, avoiding bony prominences. Rotate sites with each administration.

    Volume Per Site

    To calculate the number of sites to be used, divide the total volume to be infused by the maximum volume/site (up to 60 mL/site) to be infused. Simultaneous subcutaneous infusion at multiple sites can be facilitated by use of a multi-needle administration set.

    Infusion Rate

    For the first two infusions of CUVITRU, the recommended infusion rate is 10-20 mL/hr/site. For subsequent infusions, the infusion rate may be increased to 60 mL/hr/site as tolerated (e.g., 60 mL/hr/site x 2 sites = 120 mL/hr). For patients utilizing 4 infusion sites, the maximum infusion rate for all sites combined is 240 mL/hr.

    Instructions for Administration

    Use aseptic technique when preparing and administering CUVITRU for infusion.

    1. Inspect the vials: Inspect for clarity, color, and expiration date(s). [See Preparation and Handling]
    2. Prepare for infusion:
      • Gather supplies: CUVITRU vial(s), ancillary supplies, sharps container and infusion pump.
      • Prepare a clean work area.
      • Wash hands.
    3. Prepare the CUVITRU:
      • Wipe each stopper with a sterile alcohol wipe and allow to dry.
      • Transfer into syringe(s), preferably using a vented spike.
      • Start the infusion promptly after drawing CUVITRU into the syringe. It is suggested to complete the administration within 2 hours due to the potential formation of particles caused by siliconized syringes.
  • Prepare the infusion pump and tubing:
    • Follow manufacturer directions for priming the tubing and pump usage.
    • Attach the syringe filled with CUVITRU to the needle set.
    • Prime the needle set up to the needle hub.
  • Prepare the infusion site(s):
    • Potential sites for infusion include the abdomen, thighs, upper arms, or lateral hip.
    • Avoid: bony areas, visible blood vessels, scars and any areas of inflammation (irritation) or infection.
    • The number and location of infusion sites depends on the volume of the total dose.
    • Infusion sites should be at least 4 inches apart.
    • Rotate sites of the body between successive infusions.
    • Cleanse the infusion site(s) with a sterile alcohol wipe beginning at the center of each infusion site and moving outward in a circular motion. Allow the infusion site(s) to dry.
  • Insert and secure the subcutaneous needle set:
    • Pinch at least one inch of skin between two fingers. Insert the needle at a 90-degree angle into the subcutaneous tissue and secure the needle with sterile tape.
    • If more than one site is used, repeat steps.
    • Check placement: gently pull back on the plunger of attached syringe and monitor for any blood return in the tubing.
      • If blood is seen in the tubing, remove and discard the needle and repeat steps 4, 5 and 6 with a new subcutaneous needle and infusion site.
    • Secure the needle in place with a sterile protective dressing.

    • Start the infusion of CUVITRU based on prescriber’s order:
      Follow the manufacturer’s instructions to turn on the infusion pump.
    • Remove subcutaneous needle(s) from the infusion site(s):
      After the infusion is complete, remove the needle set and cover with a protective dressing. Discard any partially used vial(s) and disposable supplies in accordance with local requirements.
    • Document the infusion:
      Remove the peel-off label from each vial of CUVITRU used and affix to the patient’s treatment record or infusion log. In addition, record the time, date, dose, infusion site location and any reactions after each infusion.
    • For self-administration, provide the patient with instructions and training for infusion in the home or other appropriate setting.

      HOW SUPPLIED

      Dosage Forms And Strengths

      CUVITRU is a 200 mg/mL (20%) protein solution for subcutaneous infusion.

      Storage And Handling

      CUVITRU is supplied in single use vials containing the labeled amount of functionally active IgG. The components used in the packaging for CUVITRU are not made with natural rubber latex.

      The following presentations of CUVITRU are available:

      NDC Number Volume Grams Protein
      0944-2850-01 5 mL 1.0
      0944-2850-03 10 mL 2.0
      0944-2850-05 20 mL 4.0
      0944-2850-07 40 mL 8.0
      Storage And Handling
      • Store at refrigeration temperature: 2°C to 8°C [36°F to 46°F] for up to 36 months or
      • Room temperature: not to exceed 25°C [77°F]) for up to 12 months.
      • Do not return CUVITRU to the refrigerator if you take it out to room temperature.
      • Do not freeze.
      • Do not shake.
      • Keep the vials in the carton in order to protect from light.
      • Discard any unused product.
      • Do not use past the expiration date.

      1. Orange JS, Hossny EM, Weiler CR, Ballow M, Berger M, Bonilla FA, Buckley R, Chinen J, El-Gamal Y, Mazer BD, Nelson Jr. RP, Patel DD, Secord E, Sorenson RU, Wasserman RL, Cunningham-Rundles C, Use of Intravenous Immunoglobulin in Human Disease: A Review of Evidence by Members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma, and Immunology. J Allergy Clin Immunol 2006; 117:S525-53.

      2. Bonilla FA, Bernstein IL, Khan DA, Ballas ZK, Chinen J, Frank MM, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005; 94(suppl 1):S1-63.

      Manufactured by: Baxalta US Inc. Westlake Village, CA 91362 USA. Revised: Sep 2016

      QUESTION

      SIDE EFFECTS

      The most common adverse reactions observed in ≥5% of subjects were: local adverse reactions, systemic adverse reactions including headache, nausea, fatigue, diarrhea, and vomiting.

      Clinical Trials Experience

      Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

      CUVITRU was administered subcutaneously in two prospective, open-label, non-controlled, multi-center studies to evaluate efficacy, safety, tolerability, and pharmacokinetics in subjects with primary immunodeficiency (PI). One study was performed in North America and the other was performed in Europe.

      North American Study

      In a clinical study conducted in North America, 67 out of 74 subjects treated with CUVITRU completed the study including 20/21 subjects aged 2 to a in =5% of Subjects Associated with Infusions of CUVITRU

      Adverse Reactions By Subject
      N (%) b
      (N=74 Subjects)
      By Infusion
      N (Rate) c
      (N=4327 infusions)
      Local Adverse Reactions 23 (31.1%) 96 (0.022)
      Systemic Adverse Reactions 41 (55.4%) 182 (0.042)
      Headache 10 (13.5%) 50 (0.012)
      Nausea 9 (12.2%) 16 (0.004)
      Fatigue 6 (8.1%) 9 (0.002)
      Diarrhea 5 (6.8%) 5 (0.001)
      Vomiting 4 (5.4%) 5 (0.001)
      a Excluding infections
      b Number and percentages of affected subjects
      c Rate = Total number of adverse reactions divided by the total number of infusions under treatment

      Systemic adverse reactions to immune globulin intravenous in part 1 of the study occurred at a rate of 0.302 relative to a rate of 0.042 during treatment with CUVITRU. The CUVITRU systemic adverse reaction rate was approximately 7-fold lower than the immune globulin intravenous rate.

      Local Adverse Reactions

      The most frequent local adverse reactions are listed by frequency in Table 4. Of the total 96 local adverse reactions, 100% were either mild (92.5%) or moderate (7.5%) in severity. No severe local adverse reactions were reported. During the clinical study, no local adverse reactions were observed in 68.9% (51/74) of subjects and in 98.2% (4247/4327) of infusions. The overall rate of local adverse reactions (excluding infections) during the clinical study was 0.022 (0.021 mild and 0.002 moderate). The rate of local adverse reactions was not associated with increased rate of infusion or volume per site.

      Table 4 Most Frequent Local Adverse Reactions Reported in =5% of Subjects

      Events Total Number of Adverse Reactions By Subject
      N (%) a
      (N =74 Subjects)
      By Infusion
      N (Rate) b
      (N=4327 infusions)
      Mild Moderate
      Pain 33 3 15 (20.3%) 36 (0.008)
      Erythema 22 1 8 (10.8%) 23 (0.005)
      Pruritus 7 1 4 (5.4%) 8 (0.002)
      a Number and percentages of affected subjects
      b Rate= Total number of adverse reactions divided by the total number of infusions under treatment

      Efficacy and safety during treatment with CUVITRU were evaluated in 48 subjects in a clinical trial in Europe. CUVITRU was administered for a median treatment duration of 358 days (range: 127.0-399 days) and a mean (± SD) of 347.4 ± 47.9 days. CUVITRU treatment: 45/48 subjects treated with CUVITRU completed the study, including 23/25 subjects aged 2 to a in =5% of Subjects Associated with Infusions of CUVITRU

      Adverse Reactions By Subject
      N (%) b
      (N=48 Subjects)
      By Infusion
      N (Rate) c
      (N=2349 infusions)
      Local Adverse Reactions 18 (37.5%) 176 (0.075)
      Systemic Adverse Reactions 33 (68.8%) 205 (0.087)
      Headache 14 (29.2%) 59 (0.025)
      Diarrhea 9 (18.8%) 58 (0.025)
      Cough 5 (10.4%) 7 (0.003)
      Fatigue 6 (12.5) 8 (0.003)
      Arthralgia 3 (6.3%) 5 (0.002)
      Oropharyngeal pain 3 (6.3%) 3 (0.001)
      a Causally Related and/or Temporally Associated (Within 72 Hour) AEs (Excluding Infections)
      b Total number of affected subjects divided by the total number of subjects under treatment
      c Total number of AEs divided by the total number of infusions under treatment
      Local Adverse Reactions

      Among the 176 local adverse reactions in total (adverse reaction defined as adverse events occurring during or within 72 hours of infusion or any causally related event occurring within the study period), none was severe. In total, 175 adverse reactions (99.4%) were mild, and 1 adverse reaction (0.6%) was moderate. The overall rate of local adverse reactions was 0.075 per infusion. The most common reactions (by subject) were infusion site pain, infusion site erythema and infusion site pruritus.

      Table 6 EU Study: Most Frequent Local Adverse Reactions Reported in =5% of Subjects

      Events Total Number of Adverse Reactions By Subject
      N (%) a
      (N =48 Subjects)
      By Infusion
      N (Rate) b
      (N=2349 infusions)
      Mild Moderate
      Pain 34 10 (20.8%) 34 (0.014)
      Erythema 54 10 (20.8%) 54 (0.023)
      Pruritus 30 7 (14.6%) 30 (0.013)
      Swelling 46 4 (8.3%) 46 (0.020)
      a Number and percentages of affected subjects
      b Rate= Total number of adverse reactions divided by the total number of infusions under treatment

      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.

      Postmarketing Experience Of Immune Globulin Products

      The following adverse reactions have been identified and reported during the postmarketing use of immune globulin products administered subcutaneously:

      Immune system disorders Anaphylactic reaction
      Cardiac disorders Tachycardia
      Nervous system disorders Tremor and paresthesia
      Respiratory, Thoracic and Mediastinal disorders Dyspnea and laryngospasm
      General disorders and administration site conditions Injection site reaction (such as induration and warmth) and chest discomfort

      DRUG INTERACTIONS

      Passive transfer of antibodies may transiently impair the immune responses to live attenuated virus vaccines such as mumps, rubella and varicella for up to 6 months and for a year or more to measles (rubeola). Inform the immunizing physician of recent therapy with CUVITRU so that appropriate precautions can be taken. [See PATIENT INFORMATION]

      WARNINGS

      Included as part of the «PRECAUTIONS» Section

      PRECAUTIONS

      Hypersensitivity

      Severe hypersensitivity reactions may occur, even in patients who had tolerated previous treatment with human immune globulin. If a hypersensitivity reaction occurs, discontinue CUVITRU infusion immediately and institute appropriate treatment.

      CUVITRU contains trace amounts of IgA (average concentration of 80 mcg/mL). Patients with known antibodies to IgA have a greater risk of developing potentially severe hypersensitivity reactions, including anaphylaxis, with administration of CUVITRU.

      Renal Dysfunction/Failure

      Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis, and death may occur upon use of immune globulin treatment, especially those containing sucrose 3,4 . CUVITRU does not contain sucrose. Ensure that patients are not volume depleted prior to the initiation of infusion of CUVITRU. In patients who are at risk of developing renal dysfunction because of pre-existing renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs), monitor renal function and consider lower, more frequent dosing. [See DOSAGE AND ADMINISTRATION]

      Periodic monitoring of renal function and urine output is particularly important in patients predisposed to be at increased risk for developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of CUVITRU and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of CUVITRU. [See DOSAGE AND ADMINISTRATION]

      Thrombosis

      Thrombosis may occur following treatment with immune globulin products. 5,6 Risk factors may include advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors.

      Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. 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 for hyperviscosity. [See BOX WARNING, DOSAGE AND ADMINISTRATION, PATIENT INFORMATION]

      Aseptic Meningitis Syndrome (AMS)

      AMS has been reported with the use of immune globulin. The syndrome usually begins within several hours to two days following immune globulin treatment. AMS may occur more frequently in female patients.

      AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea and vomiting. [See PATIENT INFORMATION] Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis up to several thousand cells per mm 3 , predominantly from the granulocytic series, and elevated protein levels up to several hundred milligram/dL, but negative culture results. Conduct a thorough neurological examination, including CSF studies, on patients exhibiting such signs and symptoms, to rule out other causes of meningitis. Discontinuation of treatment has resulted in remission of AMS within several days without sequelae.

      Hemolysis

      CUVITRU can contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBC) with immune globulin. This may cause a positive direct antiglobulin test [DAT (Coomb’s test)] 7,8 . Delayed hemolytic anemia can develop subsequent to CUVITRU therapy due to enhanced RBC sequestration; acute hemolysis, consistent with intravascular hemolysis, can occur 7-11 .

      The following risk factors may be related to the development of hemolysis: high doses (e.g., ≥2 grams/kg, single administration or divided over several days) and non-O blood group 7, 11 . Underlying inflammatory state in an individual patient may increase the risk of hemolysis7 but its role is uncertain 10,12 .

      Monitor patients for clinical signs and symptoms of hemolysis, particularly patients with risk factors noted above. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit prior to infusion and within approximately 36 to 96 hours post infusion.

      Transfusion-Related Acute Lung Injury (TRALI)

      Non-cardiogenic pulmonary edema (TRALI) has been reported in patients following treatment with immune globulin products. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically occur within 1 to 6 hours after treatment.

      Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil and anti-HLA antibodies in both the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support.

      Transmittable Infectious Agents

      Because CUVITRU is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the Creutzfeldt-Jakob disease agent. This also applies to unknown or emerging viruses and other pathogens. No confirmed cases of viral transmission or vCJD have been associated with CUVITRU.

      All infections thought by a physician to possibly have been transmitted by this product should be reported by the physician or other healthcare provider to Baxalta US Inc., at 1-800-423-2090.

      Monitoring: Laboratory Tests

      • Periodic monitoring of renal function and urine output is particularly important in patients predisposed to be at increased risk of developing acute renal failure. Assess renal function, including measurement of BUN and serum creatinine, before the initial infusion of CUVITRU and at appropriate intervals thereafter.
      • Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies, because of the potentially increased risk of thrombosis 3,5 .
      • If signs and/or symptoms of hemolysis are present after an infusion of CUVITRU, perform appropriate laboratory testing for confirmation.
      • If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-HLA antibodies in both the product and patient’s serum.

      Interference With Laboratory Tests

      • After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield false positive serological test results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test.
      • Administration of CUVITRU can lead to false positive readings in assays that depend on detection of beta-D-glucans for diagnosis of fungal infections; this may persist during the weeks following infusion of the product.

      Patient Counseling Information

      • Advise patients to read the FDA-approved patient labeling (Information for Patients and Instructions for Use).
      • Prior to starting CUVITRU ask about a history of IgA deficiency, allergic reactions to immune globulin or other blood products. Patients with a history of allergic reactions should not be treated subcutaneously at home until several treatments have been administered and tolerated under medical supervision. [See WARNINGS AND PRECAUTIONS]
      • Inform patients to immediately report the following signs and symptoms to their healthcare provider:
        • Decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath. [See WARNINGS AND PRECAUTIONS]
        • Instruct patients to immediately report symptoms of thrombosis. These symptoms may include pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body. [See WARNINGS AND PRECAUTIONS]
        • Severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea, and vomiting. [See WARNINGS AND PRECAUTIONS]
        • Increased heart rate, fatigue, yellowing of the skin or eyes, and dark-colored urine. [See WARNINGS AND PRECAUTIONS]
        • Trouble breathing, chest pain, blue lips or extremities, or fever that can occur 1 to 6 hours after an infusion of CUVITRU. [See WARNINGS AND PRECAUTIONS]
      • Inform patients that CUVITRU is made from human plasma and may contain infectious agents that can cause disease (e.g., viruses and, theoretically, the vCJD agent). The risk of CUVITRU transmitting an infectious agent has been reduced by screening plasma donors for prior exposure, testing donated plasma, and inactivating or removing certain viruses during manufacturing. Patients should report any symptoms that concern them which might be caused by virus infections. [See WARNINGS AND PRECAUTIONS]
      • Inform patients that CUVITRU can interfere with their immune response to live viral vaccines such as measles, mumps, rubella and varicella, and instruct patients to notify their healthcare professional of this potential interaction when they are receiving vaccinations. [See DRUG INTERACTIONS]
      Self-Administration

      If self-administration is deemed to be appropriate by the physician, clear instructions and training on subcutaneous infusion should be given to the patient/caregiver, and the demonstration of their ability to independently administer subcutaneous infusions should be documented.

      • Ensure the patient understands the importance of consistent subcutaneous infusions to maintain appropriate steady IgG levels.
      • Inform the patient to start the infusion promptly after drawing CUVITRU into the syringe. Ensure the patient understands that it is suggested to complete the administration within 2 hours due to the potential formation of particles caused by siliconized syringes.
      • Instruct the patient to keep a treatment diary/log book. This diary/log book should include information about each infusion such as, the time, date, dose, lot number(s), infusion sites, and any reactions.
      • Inform the patient that mild to moderate local infusion-site reactions (e.g., pain, redness and itching) are a common side effect of subcutaneous treatment, but to contact their healthcare professional if a local reaction increases in severity or persists for more than a few days.

      Nonclinical Toxocology

      Carcinogenesis, Mutagenesis, Impairment Of Fertility

      No animal studies were conducted to evaluate the carcinogenic or mutagenic effects of CUVITRU or its effects on fertility.

      Use In Specific Populations

      Pregnancy

      Risk Summary

      No human data are available to indicate the presence or absence of drug-associated risk. Animal reproduction studies have not been conducted with CUVITRU. It is also not known whether CUVITRUcan cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Immune globulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation. CUVITRU should be given to a pregnant woman only if clearly indicated. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

      Lactation

      Risk Summary

      No human data are available to indicate the presence or absence of drug-associated risk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CUVITRU and any potential adverse effects on the breastfed infant from CUVITRU or from the underlying maternal condition.

      Pediatric Use

      CUVITRU was evaluated in 21 pediatric subjects with PI (2 to 16 years of age) in a multicenter clinical study. The safety and efficacy profiles were similar to adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels.

      Safety and effectiveness of CUVITRU has not been evaluated in neonates or infants

      OVERDOSE

      No Information Provided

      CONTRAINDICATIONS

      • CUVITRU is contraindicated in patients who have had an anaphylactic or severe systemic hypersensitivity reaction to the subcutaneous administration of human immune globulin.
      • CUVITRU is contraindicated in IgA-deficient patients with antibodies against IgA and a history of hypersensitivity to human immune globulin treatment.

      CLINICAL PHARMACOLOGY

      Mechanism Of Action

      CUVITRU supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents. CUVITRU also contains a spectrum of antibodies capable of interacting with and altering the activity of cells of the immune system as well as antibodies capable of reacting with cells such as erythrocytes. The role of these antibodies and the mechanisms of action of IgG in CUVITRU have not been fully elucidated.

      Pharmacodynamics

      Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of antibodies against infectious agents. Human normal immunoglobulin contains the IgG antibodies present in the normal population. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma.

      Adequate doses of CUVITRU may restore abnormally low immunoglobulin G levels to the normal range.

      Pharmacokinetics

      Pharmacokinetic (PK) parameters of subcutaneously administered CUVITRU were evaluated in 60 subjects with primary immunodeficiency (PI) during a clinical study in North America. [See Clinical Studies] Subjects were treated intravenously for 13 weeks with a comparator product [GAMMAGARD LIQUID, Immune Globulin (Human), 10%] and then switched to weekly subcutaneous CUVITRU infusions. Initially, subjects were treated for up to 12 to 16 weeks at a subcutaneous dose that was 145% of the intravenous dose. A comparison of the area under the curve (AUC) for subcutaneous versus intravenous infusions was performed on 15 subjects aged 12 years and older. Subsequently, all subjects were treated with this dose for 12 weeks after which the dose was individualized for all subjects using the trough IgG levels, as described below. After approximately 4 months treatment at this subcutaneous dose, a PK evaluation was conducted on all subjects.

      At this dose adjustment, the geometric mean ratio of the AUC for subcutaneous CUVITRU versus intravenous administration immune globulin 10% was 109%. The peak IgG level occurred at a geometric mean of 79 hours after subcutaneous CUVITRU administration.

      In part 4 of the study, pharmacokinetic parameters for CUVITRU were assessed for 60 subjects aged 2 years and older. The pharmacokinetic parameters of CUVITRU administered subcutaneously are shown in Table 8. The median peak IgG levels were lower (1809 mg/dL) during subcutaneous treatment with CUVITRU compared to IGIV 10% administration (2602 mg/dL for 3 week intervals and 2521 mg/dL for 4 week intervals), consistent with the lower weekly dose compared with the dose administered every 3 or 4 weeks intravenously. In contrast, the geometric mean trough levels were higher with CUVITRU (1474 mg/dL), compared with those when given intravenously (1158 mg/dL for 3 week intervals and 1019 mg/dL for 4 week intervals), a result of both higher monthly dose and more frequent dosing. Weekly subcutaneous administration resulted in relatively stable steady-state serum IgG levels compared with IGIV administered at 3 to 4 week intervals. Pharmacokinetic parameters for CUVITRU did not significantly differ between age groups. The pharmacokinetic parameters of CUVITRU for the different age groups are shown in Table 9.

      Table 8: Pharmacokinetic Parameters

      Parameter Median (95% Cl)
      N=60
      AUC [g*days/L] 115 (110 to 121)
      Apparent clearance [mL/kg/day] 1.86 (1.80 to 2.17)
      Cmax [mg/dL] 1809 (1745 to 2068)
      Cmin [mg/dL] 1477 (1323 to 1535)
      Tmax [hours] 105 (71 to 119)

      Table 9 Pharmacokinetic Parameters by Age Group

      Parameter Age Groups
      2 to 65
      (n=7)
      Median
      (95% CI)
      AUC [g*days/L] 106
      (N/A)
      110
      (87 to 121)
      116
      (N/A)
      114
      (103 to 127)
      139
      (90 to 158)
      Apparent clearance [mL/kg/day] 1.86
      (N/A)
      1.85
      (1.31 to 2.37)
      1.80
      (N/A)
      1.98
      (1.81 to 2.23)
      1.72
      (0.90 to 2.36)
      Cmax [mg/dL] 1619
      (N/A)
      1725
      (1518 to 1892)
      1732
      (N/A)
      1940
      (1778 to 2220)
      2419
      (1480 to 3201)
      Cmin [mg/dL] 1527
      (N/A)
      1351
      (1130 to 1635)
      1554
      (N/A)
      1423
      (1231 to 1524)
      1585
      (976 to 2000)
      Tmax [hours] 70
      (N/A)
      164
      (70 to 168)
      68
      (N/A)
      74
      (68 to 119)
      119
      (24 to 164)

      Animal Toxicology And/Or Pharmacology

      Animal studies were conducted to evaluate possible toxicity of CUVITRU. In a local tolerance study in mini-pigs, 50 mL of CUVITRU were administered subcutaneously to anesthetized mini-pigs. Subcutaneous administration of CUVITRU was well tolerated in this study.

      In local tolerance studies in rabbits, mild to moderate inflammatory reactions were observed locally after subcutaneous administration of 2.5 mL/kg of CUVITRU. These reactions are considered to be a consequence of the animals’ immune response to the human IgG preparation and thus model specific and of minor relevance for the assessment of clinical local tolerability.

      Clinical Studies

      North America Study

      A prospective, open-label, non-controlled, multi-center clinical study was conducted in North America to determine the efficacy, tolerability and PK of CUVITRU in 77 adult and pediatric subjects with PI. Efficacy was determined in 53 adults aged 16 years or older, 6 adolescents aged 12 to

      Parameters Results
      Number of subjects 74
      Total number of subject-years on treatment 83.70
      Annual rate of any infections (per subject-year) 2.41 (95% CI: 1.89 to 3.03)
      Days on antibiotics (rate per subject-year) 57.59 (95% CI: 40.71 to 78.59)
      Days off work/school/unable to perform normal daily activities due to illness or infection (rate per subject-year) 1.16 (95% CI: 0.70 to 1.79)
      Number of hospitalizations due to infections (rate per subject-year) 0.012 (95% CI: 0.006 to 0.022)
      Number of days in hospital due to infections (rate per subject-year) 0.06 (95% CI: 0.03 to 0.11)

      In the clinical study, across all age groups, the median maximum infusion rate was 60 mL/hr/site. This infusion rate was achieved in 57.3% (2480/4327) of completed CUVITRU infusions. CUVITRU infusion rate of 60 mL/h/site was achieved in 28.6% (6/21) of pediatric subjects (2 years to 14 (pediatric subjects) or the self-administered SF-36 survey 15 (adult subjects). Quality of life was analyzed separately for the age groups 2 to 4 and 5 to 7 years (PEDS-QL, observer: parent), 8 to 12 and 13 years (PEDS-QL, observer: subject) and 14 years and older (SF-36, observer: subject). Treatment satisfaction was measured using the Life Quality Index questionnaire (LQI) 16,17 and the Treatment Satisfaction Questionnaire for Medication (TSQM-9) 18 . The LQI was assessed for the age group 2 years to 12 years (observer: parent) and the age group 13 years and older (observer: subject) in three domains: Treatment Interference, Therapy-related Problems and Therapy Settings. The TSQM-9 was assessed in subjects aged 2 to 12 years (observer: parent) and 13 years and older (observer: subject) in 3 domains: Effectiveness, Convenience and Global Satisfaction. Differences between scores during the intravenous study part and subcutaneous 20% study part were calculated for selected domains of the instruments, see Table 11.

      Table 11 Selected Patient Reported Outcomes: Differences Between the Intravenous and Subcutaneous Treatment

      European Study

      A prospective, open-label, non-controlled, multi-center study conducted in 16 sites in Europe to evaluate the efficacy, safety, tolerability, and PK parameters of CUVITRU in subjects with PI aged 2 years and older at time of screening. The study consisted of 2 parts. In study part 1, subjects were treated with IGSC 16% for 12 weeks or with IGIV 10% for 13 weeks. Administration, dosage frequency, and dose were dependent on the pre-study treatment. However, the dose range had to be within 0.3-1.0 g/kg BW/4 weeks.

      During study part 2, subjects received weekly CUVITRU infusions for 51 weeks at the dose used during study part 1, adjusted to a weekly equivalent dose if necessary. PK assessments were performed before the end of study part 1 and after approximately 5 months in study part 2 in subjects aged ≥12 years. For younger subjects (aged 2 to

      Scale Difference p-value
      SF-36 Physical Component Score 0.89 0.067
      SF-36 Mental Component Score 1.31 0.976
      Total Score (PedsQL) 1.09 0.449
      Treatment Interference (LQI) 1.50 0.008
      Convenience (TSQM-9) 11.11
      Parameters Results
      Number of subjects 48
      Annual rate a of any infections (rate per subject-year) 4.38 (95% CI: 3.38 to 5.56)
      Days on antibiotics (rate per subject-year) 18.11 (95% CI: 13.01 to 24.41)
      Days off work/school/unable to perform normal daily activities due to illness or infection (rate per subject-year) 15.55 (95% CI: 10.06 to 22.75)
      Number of hospitalizations due to infections (rate per subject-year) 0.04 (95% CI: 0.02 to 0.08)
      Number of days in hospital due to infections (rate per subject-year) 0.11 (95% CI: 0.05 to 0.21)
      a Rate = number of infections divided by the total number of subject-years under treatment

      1. Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life inventory. Med.Care 1999;37:126-139.

      2. Ware JE, Jr., Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med.Care 1992;30:473-483.

      3. Daly PB, Evans JH, Kobayashi RH et al. Home-based immunoglobulin infusion therapy: quality of life and patient health perceptions. Ann.Allergy 1991;67:504-510.

      4. Nicolay U, Haag S, Eichmann F et al. Measuring treatment satisfaction in patients with primary immunodeficiency diseases receiving lifelong immunoglobulin replacement therapy. Qual.Life Res. 2005;14:1683-1691.

      5. Bharmal M, Payne K, Atkinson MJ et al. Validation of an abbreviated treatment satisfaction questionnaire for medication (TSQM-9) among patients on antihypertensive medications. Health Qual.Life Outcomes 2009;7:36.

      PATIENT INFORMATION

      CUVITRU
      (CUE-vih-troo)
      Immune Globulin Subcutaneous (Human), 20% Solution
      Subcutaneous Administration

      Information for Patients

      The following summarizes important information about CUVITRU. Please read it carefully before using this medicine. This information does not take the place of talking with your healthcare provider, and it does not include all of the important information about CUVITRU. If you have any questions after reading this, ask your healthcare provider.

      What is the most important information I need to know about CUVITRU?

      CUVITRU can cause the following serious reactions:

      • Severe allergic reactions causing difficulty in breathing or skin rashes
      • Decreased kidney function or kidney failure
      • Blood clots in the heart, brain, lungs, or elsewhere in the body
      • Severe headache, drowsiness, fever, painful eye movements, or nausea and vomiting
      • Dark colored urine, swelling, fatigue, or difficulty breathing

      What is CUVITRU?

      CUVITRU is a ready-to-use, liquid medicine that contains immunoglobulin G (IgG) antibodies, which protect the body against infection. CUVITRU is used to treat patients with primary immunodeficiency diseases (PI).

      There are many forms of PI. The most common types of PI result in an inability to make a very important type of protein called antibodies, which help the body fight off infections from bacteria or viruses. CUVITRU is made from human plasma that is donated by healthy people. CUVITRU contains antibodies collected from these healthy people that replace the missing antibodies in PI patients.

      Who should not use CUVITRU?

      Do not use CUVITRU if you have a known history of a severe allergic reaction to immune globulin or other blood products. If you have such a history, discuss this with your healthcare provider to determine if CUVITRU can be given to you. Tell your healthcare provider if you have a condition called selective (or severe) immunoglobulin A (IgA) deficiency.

      How should I use CUVITRU?

      CUVITRU is given under the skin (subcutaneously). Most of the time infusions under the skin are given at home by self infusion or by caregivers. Instructions for giving CUVITRU under the skin (subcutaneously) are provided in the Instructions for Use brochure. Only use CUVITRU by yourself after you have been instructed by your healthcare provider.

      What should I avoid while taking CUVITRU?

      CUVITRU can make vaccines (like measles/mumps/rubella or chickenpox vaccines) not work as well for you. Before you get any vaccines, tell your healthcare provider that you take CUVITRU.

      Tell your healthcare provider if you are pregnant, or plan to become pregnant, or if you are nursing.

      What are the possible or reasonably likely side effects of CUVITRU?

      The following one or more possible reactions may occur at the site of infusion. These generally go away within a few hours, and are less likely after the first few infusions.

      • Mild or moderate pain
      • Redness
      • Itching

      The most common side effects with CUVITRU are:

      If any of the following problems occur after starting treatment with CUVITRU, stop the infusion immediately and contact your healthcare provider or call emergency services. These could be signs of a serious problem.

      • Hives, swelling in the mouth or throat, itching, trouble breathing, wheezing, fainting or dizziness. These could be signs of a serious allergic reaction.
      • Bad headache with nausea, vomiting, stiff neck, fever, and sensitivity to light. These could be signs of irritation of the lining around your brain.
      • Reduced urination, sudden weight gain, or swelling in your legs. These could be signs of a kidney problem.
      • Pain, swelling, warmth, redness, or a lump in your legs or arms. These could be signs of a blood clot.
      • Brown or red urine, fast heart rate, yellow skin or eyes. These could be signs of a liver problem or a blood problem.
      • Chest pain or trouble breathing, or blue lips or extremities. These could be signs of a serious heart or lung problem.
      • Fever over 100°F. This could be a sign of an infection.

      These are not all of the possible side effects with CUVITRU. You can ask your healthcare provider for physician’s information leaflet. Tell your healthcare provider about any side effect that bothers you or that does not go away.

      Whenever giving yourself treatments at home, you should have another responsible person present to help treat side effects or get help if you have a serious adverse reaction occur. Ask your healthcare provider whether you should have rescue medications, such as antihistamines or epinephrine.

      How do I store CUVITRU?

      Store CUVITRU refrigerated or at room temperature.

      • You can store CUVITRU in the refrigerator (36°F to 46°F [2°C to 8°C]) for up to 36 months or
      • You can store CUVITRU at room temperature (up to 77°F [25°C]) for up to 12 months.
      • Do not return CUVITRU to the refrigerator if you take it out to room temperature.
      • Do not freeze.
      • Do not shake.
      • Check the expiration date on the carton and vial label. Do not use CUVITRU after the expiration date.
      • Protect from light. You can use the original CUVITRUcontainers to protect it from light.

      Resources at Baxalta Available to the Patients:

      For more information on patient resources, education, or insurance assistance please visit www.immunedisease.com.

      Detailed Instructions for Administration for Patients

      Do not use CUVITRU at home until you get instructions and training from your healthcare professional.

      Prepare CUVITRU vial(s):

      • Remove CUVITRU from the box. Allow vials to reach room temperature. This may take up to 90 minutes.
      • Do not apply heat or place in microwave.
      • Do not shake the vial(s).
      1. Check the vial(s):

      • Do not use beyond expiration date.
      • Do not use if the protective cap is missing or broken.
      • Look at the color: it should be clear and colorless to pale yellow or light brown.
      • Do not use if the solution is cloudy or has particles.
      2. Gather all supplies

      • Gather all supplies: Items include: vial(s) of CUVITRU, infusion supplies: subcutaneous needle set, transfer device(s), syringe(s), sterile tip caps, sterile clear bandage, tape, gauze, sharps container, infusion pump, infusion log.
      • Clean work area.
      • Program the infusion pump according to prescribed infusion rates and manufacturer’s instructions. S
      • Wash hands thoroughly and allow to dry.
      • Open supplies as shown by your healthcare professional.
      3. Prepare the syringe(s):

      • Remove the cap from the vial.
      • Wipe each stopper with a sterile alcohol wipe and allow to dry.
      • Attach a sterile syringe to a vented spike.
      • Insert the vented spike into the center of the IG vial.
      • Turn the vial upside down and pull back on the plunger to pull the IG into the syringe(s).
      • Repeat these steps, if using multiple vials to achieve the desired dose.
      • Start the infusion promptly after drawing CUVITRU into the syringe(s). It is suggested to complete the administration within 2 hours.

      If using a sterile needle: Attach a sterile syringe to the sterile needle and pull back the plunger of syringe to fill with air which should equal the amount of the solution you will be taking from the vial. Insert the needle into the center of the stopper, and inject air in. Pull back on the plunger to withdraw the desired volume.

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