Carimune

Carimune® NF, Nanofiltered, Immune Globulin Intravenous (Human), is a sterile, highly purified polyvalent antibody product containing in concentrated form all the IgG antibodies which regularly occur in the donor population.15 This immunoglobulin preparation is produced by cold alcohol fractionation from the plasma of US donors. Part of the fractionation may be performed by another US-licensed manufacturer. Carimune® NF is made suitable for intravenous use by treatment at acid pH in the presence of trace amounts of pepsin.16,17 The manufacturing process by which Carimune® NF is prepared from plasma consists of fractionation and purification steps that comprise filtrations in the presence of filter aids. Four of these steps were validated for virus elimination of both enveloped and non-enveloped viruses. Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents.18 To complement the existing virus elimination / inactivation mechanism in the Carimune® NF manufacturing process, nanofiltration (removing viruses via size-exclusion) was introduced as an additional virus removal step into the manufacturing process.19,20 Nanofiltration is performed prior to the viral inactivation step (pH 4 in presence of pepsin) in order to reduce the potential viral load before inactivation is performed. Treatment with pepsin at pH 4 rapidly inactivates enveloped viruses.21

The Carimune® NF manufacturing process provides a significant virus reduction capacity as shown in in vitro studies. The results, summarized in Table 1, demonstrate virus clearance during Carimune® NF manufacturing using model viruses for lipid enveloped and nonenveloped viruses.

Table 1: Virus Elimination and Inactivation

PRV and the two model viruses for HCV, BVDV and SFV, were inactivated within 1/10, and HIV within ½ of the incubation time (pH 4/pepsin treatment) used during production of Carimune® NF.

Several of the individual production steps in the Carimune® NF manufacturing process have been shown to decrease TSE infectivity of an experimental model agent. TSE reduction steps include precipitation (3.5 logs), depth filtrations (7.3 logs), and nanofiltration (4.4 logs).  These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed.

The preparation contains at least 96% of IgG and after reconstitution with a neutral unbuffered diluent has a pH of 6.6 ± 0.2. Most of the immunoglobulins are monomeric (7 S) IgG; the remainder consists of dimeric IgG and a small amount of polymeric IgG, traces of IgA and IgM and immunoglobulin fragments.22 The distribution of the IgG subclasses corresponds to that of normal serum.23–26 Final container lyophilized units are prepared so as to contain 3, 6, or 12 g protein with 1.67 g sucrose and less than 20 mg NaCl per gram of protein. The lyophilized preparation contains no preservative and may be reconstituted with sterile water, 5% dextrose or 0.9% saline to a solution with protein concentrations ranging from 3% to 12% (see Table 4). See Table 2 for calculated Carimune® NF osmolality (mOsm/kg) at each protein concentration. The patient's fluid, electrolyte, caloric requirements and renal function should be considered in selecting an appropriate diluent and concentration.

Table 2: Calculated Carimune® NF Osmolality (mOsm/kg)

REFERENCES

1. Dalakas MC: High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994; 44:223–226.

2. Caress JB, Cartwright MS, Donofrio PD, Peacock JE: The clinical features of 16 cases of stroke associated with administration of IVIg. Neurology 2003; 60:1822–1824.

3. Woodruff RK, Grigg AP, Firkin FC, Smith IL: Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 1986; 2:217–218.

4. Jordan S, Cunningham-Rundles C, McEwan R: Utility of intravenous immune globulin in kidney transplantation: efficacy, safety, and cost implications. Am J Transplant 2003; 3:653–664.

5. Wolberg AS, Kon RH, Monroe DM, Hoffman M: Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000; 65:30–34.

6. Zaidan R, Al Moallem M, Wani BA, Shameena AR, Al Tahan AR, Daif AK, Al Rajeh S: Thrombosis complicating high dose intravenous immunoglobulin: report of three cases and review of the literature. Eur J Neurology 2003; 10:367–372.

7. Okuda D, Flaster M, Frey J, Sivakumar, K: Arterial thrombosis induced by IVIg and its treatment with tPA. Neurology 2003; 60:1825–1826.

8. Dalakas MC, Clark WM: Strokes, thromboembolic events, and IVIg. Rare incidents blemish an excellent safety record. Neurology 2003; 60:1736–1737.

9. Winward DB, Brophy MT: Acute renal failure after administration of intravenous immunoglobulin: Review of the literature and case report. Pharmacotherapy 1995; 15:765–772.

10. Cantú TG, Hoehn-Saric EW, Burgess KM, Racusen L, Scheel P: Acute renal failure associated with immunoglobulin therapy. Am J Kidney Dis 1995; 25:228–234.

11. Cayco AV, Perazella MA, Hayslett JP: Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature. J Amer Soc Nephrology 1997; 8:1788–1793.

12. Rault R, Piraino B, Johnston JR, Oral A: Pulmonary and renal toxicity of intravenous immunoglobulin. Clin Nephrol 1991, 36:83–86.

13. Michail S, Nakopoulou L, Stravrianopoulos I, Stamatiadis D, Avdikou K, Vaiopoulos G, Stathakis C: Acute renal failure associated with immunoglobulin administration. Nephrol Dial Transplant 1997; 12:1497–99.

14. Ashan N, Wiegand LA, Abendroth CS, Manning EC: Acute renal failure following immunoglobulin therapy. Am J Nephrol 1996; 16:532–6.

15. Gardi A: Quality control in the production of an immunoglobulin for intravenous use. Blut 1984; 48:337–344.

16. Römer J, Morgenthaler JJ, Scherz R, et al: Characterization of various immunoglobulinpreparations for intravenous application. I. Protein composition and antibody content. Vox Sang 1982; 42:62–73.

17. Römer J, Späth PJ, Skvaril F, et al: Characterization of various immunoglobulin preparations for intravenous application. II. Complement activation and binding to Staphylococcus protein A. Vox Sang 1982; 42:74–80.

18. Gregori L, Maring JA, MacAuley C et al: Partitioning of TSE infectivity during ethanol fractionation of human plasma. Biologicals 2004; 32:1–10.

19. Omar A, and Kempf C: Removal of neutralized model Parvoviruses and Enteroviruses in human IgG solutions by nanofiltration. Transfusion 2002; 42:1005–1010.

20. Späth P, Kempf C, and Gold R: Herstellung, Verträglichkeit und Virussicherheit von intravenösem Immunglobulin. In “Immunglobuline in der Neurobiologie” (P. Berlit, ed.), Steinkopff Verlag, Darmstadt, BRD 2001, pp 1–42.

21. Kempf C, Morgenthaler JJ, Rentsch M, and Omar A: Viral safety and manufacturing of an intravenous immunoglobulin. In “Intravenous Immunoglobulin Research and Therapy” Kazatchkine and Morell, eds. Parthenon Publishing Group. 1996, pp 11–18.

22. Römer J, Späth PJ: Molecular composition of immunoglobulin preparations and its relation to complement activation, in Nydegger UE (ed): Immunohemotherapy: A Guide to Immunoglobulin Prophylaxis and Therapy. London, Academic Press 1981, pp 123–130.

23. Skvaril F, Roth-Wicky B, and Barandun S: IgG subclasses in human-g-globulin preparations for intravenous use and their reactivity with Staphylococcus protein A. Vox Sang 1980; 38:147.

24. Skvaril F: Qualitative and quantitative aspects of IgG subclasses in i.v. immunoglobulin preparations, in Nydegger UE (ed): Immunohemotherapy: A Guide to Immunoglobulin Prophylaxis and Therapy. London, Academic Press, 1981, pp 113–122.

25. Skvaril F, and Barandun S: In vitro characterization of immunoglobulins for intravenous use, in Alving BM, Finlayson JS (eds): Immunoglobulins: Characteristics and Uses of Intravenous Preparations, DHHS Publication No. (FDA)-80-9005. US Government Printing Office, 1980, pp 201–206.

26. Burckhardt JJ, Gardi A, Oxelius V, et al: Immunoglobulin G subclass distribution in three human intravenous immunoglobulin preparations. Vox Sang 1989; 57:10–14.

Immune globulin injection is used to prevent or treat diseases that occur when your body has a weak immune system. Immune globulin contains antibodies that make your immune system stronger. It is used for patients who have primary humoral immunodeficiency (PI), idiopathic thrombocytopenic purpura (ITP), chronic immune thrombocytopenic purpura, or chronic inflammatory demyelinating polyneuropathy (CIDP). It is also used to improve muscle strength and disability in patients with multifocal motor neuropathy (MMN). Immune globulin injection belongs to a group of medicines known as immunizing agents.

This medicine is to be given only by or under the supervision of your doctor.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of immune globulin injection in children. Some of the products are only used in children who are 2 or 3 years of age and older, and other products are not approved for use in children. Immune globulin injection is used to treat primary humoral immunodeficiency (PI), idiopathic thrombocytopenic purpura (ITP), and chronic immune thrombocytopenic purpura in children. Safety and efficacy have not been established for use in chronic inflammatory demyelinating polyneuropathy (CIDP) or multifocal motor neuropathy (MMN).

Geriatric

Appropriate studies performed to date have not demonstrated geriatric-specific problems that would limit the usefulness of immune globulin injection in the elderly. However, elderly patients are more likely to have age-related blood clotting problems, kidney disease, or heart disease, which may require caution for patients receiving immune globulin injection.

Pregnancy

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Allergy to corn—Use with caution. May cause an allergic reaction to occur again.

• Anemia, history of or
• Bleeding problems, history of or
• Hyponatremia (low sodium in the blood) or
• Kidney problems—Use with caution. May make these conditions worse.

• Atherosclerosis (hardening of the arteries), history of or
• Blood clotting problems, history of or
• Diabetes or
• Heart attack or stroke, recent or
• Heart or blood vessel disease or
• Hyperproteinemia (high protein in the blood) or
• Hyperviscosity (thick blood), known or suspected or
• Hypovolemia (low blood volume or major loss of body fluids) or
• IgA (immunoglobulin A) deficiency with antibodies against IgA or
• Paraproteinemia (paraproteins in the blood) or
• Sepsis (serious infection in the body)—Use with caution. May cause side effects to become worse.

• Hereditary intolerance to fructose or sucrose or
• IgA (immunoglobulin A) deficiency with antibodies against IgA—Gammaplex® should not be used in patients with these conditions.

• Hyperprolinemia (too much proline in the blood) or
• IgA (immunoglobulin A) deficiency with antibodies against IgA—Hizentra® should not be used in patients with these conditions.

• IgA (immunoglobulin A) deficiency with antibodies against IgA—Octagam® should not be used in patients with this condition.

This section provides information on the proper use of a number of products that contain immune globulin. It may not be specific to Carimune. Please read with care.

A doctor or other trained health professional will give you this medicine. This medicine is given through a needle placed in one of your veins, as a shot into one of your muscles, or as a shot under your skin.

This medicine comes with a patient information insert. Read and follow the instructions carefully. Ask your doctor if you have any questions.

While you are being treated with immune globulin injection, do not have any immunizations (vaccines) without your doctor's approval. Live virus vaccines should not be given for 3 months after receiving immune globulin.

The Gammagard Liquid, Gammaked™, Gamunex®-C, and Hizentra® products may be given at home to patients who do not need to be in the hospital or clinic. They are given as an infusion under your skin once every week. The Hizentra® product may also be given once every 2 weeks. If you are using this medicine at home, your doctor will teach you how to prepare and infuse the medicine. You will be shown the body areas where the medicine can be given. Use a different body area for each infusion. Keep track of where you give an infusion to make sure you rotate sites. This will help prevent skin problems.

Do not change the brand or type of your immune globulin unless your doctor tells you to. If you must change the brand of medicine, talk to your doctor before giving yourself an infusion. Make sure you understand the instructions on how to use the new brand.

Allow the Gammagard Liquid, Gammaked™, or Gamunex®-C brand to reach room temperature before using it.

To use Gammagard Liquid, Gammaked™, Gamunex®-C, or Hizentra®:

• First, gather the items you will need on a clean, flat surface using a cloth or towel in a well-lighted area.
• Wash your hands with soap and water before and after using this medicine.
• If you have been told to wear gloves when preparing your infusion, put the gloves on.
• Check the liquid in the vial (glass container). It should be clear and slightly yellow to light brown in color. If it is cloudy, discolored, or contains large flecks (particles), do not use the vial. Select another vial.
• If the liquid is clear, place it on the clean, flat surface. Do not heat up or shake the medicine.
• Follow your doctor's instructions on how to prepare the correct amount of medicine.
• Choose an injection site on your body (eg, abdomen or stomach area, thigh, upper arm, upper leg, hip). Clean the injection site with a fresh alcohol wipe, and let it dry.
• With two fingers, pinch together the skin at the injection site. Insert the needle with the tube under the skin.
• Put sterile gauze and tape over the injection site to keep the needle from coming out.
• Before starting the infusion, make sure no blood is flowing into the infusion tube. If blood is present, remove and throw away the used needle and tube.
• Follow your doctor's instructions on how to use the infusion pump.
• Remove the peel-off portion of the label from the used vial. Place this label in your treatment diary or log book. Write down the amount of medicine you used, the date, and the time of your treatment.
• It usually takes about 60 minutes for each infusion.
• When all of the medicine has been infused, turn off the pump.
• Take the gauze off and remove the needle and tube from your skin.
• Clean and store the infusion pump.
• Throw away used needles and tubes in a hard, closed container that the needles cannot poke through. Keep this container away from children and pets.

Missed Dose

This medicine needs to be given on a fixed schedule. If you miss a dose or forget to use your medicine, call your doctor or pharmacist for instructions.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the Hizentra® product at room temperature, away from heat and moisture, for up to 30 months. Keep from freezing. Protect the product from direct light. Keep the medicine in the original package until you are ready to use it.

Store the Gamunex®-C product in the original container and in the refrigerator, but do not freeze it.

You may store the Gammagard Liquid or Gammaked™ product in the refrigerator or at room temperature. Check the box or label of the vials for expiration dates. Store it in the original container. Do not freeze. Talk with your pharmacist if you have questions about storage of this product.

Increases in creatinine and blood urea nitrogen (BUN) have been observed as soon as one to two days following infusion. Progression to oliguria or anuria, requiring dialysis has been observed. Types of severe renal adverse events that have been seen following IGIV therapy include: acute renal failure, acute tubular necrosis, proximal tubular nephropathy and osmotic nephrosis.31–36,64,71–73

Inflammatory adverse reactions have been described in agammaglobulinemic and hypogammaglobulinemic patients who have never received immunoglobulin substitution therapy before or in patients whose time from last treatment is greater than 8 weeks and whose initial infusion rate exceeds 2 mg/kg/min.

This occurs in approximately 10% of such cases. Such reactions may also be observed in some patients during chronic substitution therapy.

Reactions, which may become apparent only 30 minutes to 1 hour after the beginning of the infusion, are as follows: flushing of the face, feelings of tightness in the chest, chills, fever, dizziness, nausea, diaphoresis, and hypotension or hypertension. In such cases, the infusion should be slowed or temporarily stopped until the symptoms subside. The infusion may then be resumed at a lower rate that is comfortable for the patient. If anaphylaxis or other severe reactions occur, the infusion should be stopped immediately.

Arthralgia, myalgia, and transient skin reactions (such as rash, erythema, pruritus, urticaria, eczema or dermatitis) have also been reported.

Immediate anaphylactoid and hypersensitivity reactions due to previous sensitization of the recipient to certain antigens, most commonly IgA, may be observed in exceptional cases, described under CONTRAINDICATIONS.16,17,65 In patients with ITP, who receive higher doses (0.4 g/kg/day or greater), 2.9% of infusions may result in adverse reactions.21 Headache, generally mild, is the most common symptom noted, occurring during or following 2% of infusions. A few cases of usually mild hemolysis have been reported after infusion of intravenous immunoglobulin products.51–53 These were attributed to transferal of blood group (e.g., anti-D) antibodies.

Postmarketing

The following adverse reactions have been identified and reported during the post-approval use of IGIV products:

Respiratory
Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion-Related Acute Lung Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm
Cardiovascular
Cardiac arrest, thromboembolism, vascular collapse, hypotension
Neurological
Coma, loss of consciousness, seizures, tremor
Integumentary
Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis
Hematologic
Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs) test
General/Body as a Whole
Pyrexia, rigors
Musculoskeletal
Back pain
Gastrointestinal
Hepatic dysfunction, abdominal pain

Because postmarketing reporting of these reactions is voluntary and the at-risk populations are of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to exposure to the product. Such is also the case with literature reports authored independently.66

It is generally advisable not to dilute plasma derivatives with other infusable drugs. Carimune® NF should be given by a separate infusion line. No other medications or fluids should be mixed with Carimune® NF preparation.

Carimune® NF should be used with caution in patients with pre-existing renal insufficiency and in patients judged to be at increased risk of developing renal insufficiency (including, but not limited to those with diabetes mellitus, age greater than 65, volume depletion, paraproteinemia, sepsis, and patients receiving known nephrotoxic drugs). In these cases especially it is important to assure that patients are not volume depleted prior to Carimune® NF infusion. No prospective data are presently available to identify a maximum safe dose, concentration, and rate of infusion in patients determined to be at increased risk of acute renal failure. In the absence of prospective data, recommended doses should not be exceeded and the concentration and infusion rate selected should be the minimum practicable. For patients judged to be at risk for developing renal dysfunction, Carimune® NF should be infused at a rate less than 2 mg/kg/min.

For patients judged to be at an increased risk for thromboembolic events, a maximum infusion rate of less than 2 mg/kg/min for patients is recommended (see PRECAUTIONS: Thrombotic Events).

If side effects occur, the infusion should be stopped or slowed until the symptoms subside.

Adult and Child Substitution Therapy

The recommended dose of Carimune® NF in primary immunodeficiency is 0.4 to 0.8 g/kg of body weight administered once every three to four weeks by intravenous infusion.

The first infusion of Carimune® NF in previously untreated agammaglobulinemic or hypogammaglobulinemic patients must be given as a 3% immunoglobulin solution (see Reconstitution). Subsequent infusions may be administered at a higher concentration if the patient shows good tolerance.

An initial infusion rate of 0.5 mg/kg/min is recommended. If tolerated, after 30 minutes, the rate may be increased to 1 mg/kg/min for the next 30 minutes. Thereafter, the rate may be gradually increased in a stepwise manner up to a maximum of 3 mg/kg/min as tolerated. Refer to Table 3 for the corresponding infusion rates in mg/kg/min or mL/kg/min for all product concentrations.

The first infusion of Carimune® NF in previously untreated agammaglobulinemic and hypogammaglobulinemic patients may lead to systemic side effects. The nature of these effects has not been fully elucidated. Some of them may be due to the release of proinflammatory cytokines by activated macrophages in immunodeficient recipients.67,68 Subsequent administration of Carimune® NF to immunodeficient patients as well as to normal individuals usually does not cause further untoward side effects.

Therapy of Idiopathic Thrombocytopenic Purpura (ITP)

The recommended dose of Carimune® NF for the treatment of ITP is 0.4 g/kg of body weight on 2–5 consecutive days. An immunoglobulin solution of 6% (see Reconstitution) is recommended for use in ITP.

The recommended initial infusion rate for the treatment of ITP is 0.5 mg/kg/min. If tolerated, after 30 minutes, the rate may be increased to 1 mg/kg/min for the next 30 minutes. Thereafter, the rate may be gradually increased in a stepwise manner up to a maximum of 3 mg/kg/min as tolerated. Refer to Table 3 for the corresponding infusion rates in mg/kg/min or mL/kg/min for all product concentrations.

In acute ITP of childhood, if an initial platelet count response to the first two doses is adequate (30–50,000/µL), therapy may be discontinued after the second day of the 5 day course.21

In adults and children, if after induction therapy the platelet count falls to less than 30,000/µL and/or the patient manifests clinically significant bleeding, 0.4 g/kg of body weight may be given as a single infusion. If an adequate response does not result, the dose can be increased to 0.8–1 g/kg of body weight given as a single infusion.22,69,70

Reconstitution

(see also pictures next page)

To reconstitute Carimune® NF from the individual vial package, or when using other diluents or higher concentrations, Table 4 indicates the volume of sterile diluent required. Observing aseptic technique, this volume should be drawn into a sterile hypodermic syringe and needle. The diluent is then injected into the corresponding Carimune® NF vial size.

If large doses of Carimune® NF are to be administered, several reconstituted vials of identical concentration and diluent may be pooled in an empty sterile glass or plastic i.v. infusion container using aseptic technique.

Carimune® NF normally dissolves within a few minutes, though in exceptional cases it may take up to 20 minutes.

DO NOT SHAKE! Excessive shaking will cause foaming.

Any undissolved particles should respond to careful rotation of the bottle. Avoid foaming. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Filtering of Carimune® NF is acceptable but not required. Pore sizes of 15 microns or larger will be less likely to slow infusion, especially with higher Carimune® NF concentrations. Antibacterial filters (0.2 microns) may be used. When reconstitution of Carimune® NF occurs outside of sterile laminar air flow conditions, administration must begin promptly with partially used vials discarded. When reconstitution is carried out in a sterile laminar flow hood using aseptic technique, administration may begin within 24 hours provided the solution has been refrigerated during that time. Do not freeze Carimune® NF solution.

PROCEED WITH INFUSION ONLY IF SOLUTION IS CLEAR AND AT APPROXIMATELY ROOM TEMPERATURE.

Carimune® NF is available as a white lyophilized powder in 3, 6 and 12 g size vials. The only diluents which may be used to reconstitute the product are sterile (0.9%) Sodium Chloride Injection USP, 5% Dextrose, or Sterile Water.

Carimune® NF is available in individual vial packages as follows:

Store and Dispense

Carimune® NF should be stored at room temperature not exceeding 30°C (86°F). The preparation should not be used after the expiration date printed on the label.

NDC 44206-416-03

3 g

Immune Globulin
Intravenous (Human)

Carimune® NF
Nanofiltered

3 Grams lyophilized
(single use vial)

For intravenous administration
Rx only

CSL Behring

NDC 44206-418-12

12 g

Immune Globulin
Intravenous (Human)

Carimune® NF
Nanofiltered

12 Grams lyophilized
(single use vial)

For intravenous administration
Rx only

CSL Behring