Carimune Nanofiltered
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Questions & Answers
Side Effects & Adverse Reactions
Immune Globulin Intravenous (Human) (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death.9-14
Patients predisposed to acute renal failure include patients with:
- any degree of pre-existing renal insufficiency
- diabetes mellitus
- age greater than 65
- volume depletion
- sepsis
- paraproteinemia
- patients receiving known nephrotoxic drugs
In such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. Carimune® NF contains sucrose. See PRECAUTIONS and DOSAGE AND ADMINISTRATION sections for important information intended to reduce the risk of acute renal failure.
IgA deficient patients, especially those with known antibodies against IgA, are at greater risk of developing severe hypersensitivity and anaphylactic reactions.
Carimune® NF is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and through the application of viral elimination/reduction steps such as alcohol fractionation in the presence of filter aids, nanofiltration and pH 4/pepsin treatment19-21 (see Table 1). Despite these measures, such products may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. There is also the possibility that unknown infectious agents may be present in such products. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to CSL Behring Pharmacovigilance at 1-866-915-6958. The physician should discuss the risks and benefits of this product with the patient.
Patients with agamma- or extreme hypogammaglobulinemia who have never before received immunoglobulin substitution treatment or whose time from last treatment is greater than 8 weeks, may be at risk of developing inflammatory reactions on rapid infusion (greater than 2 mg/kg/min) of Carimune® NF. These reactions are manifested by a rise in temperature, chills, nausea, and vomiting. The patient's vital signs should be monitored continuously. The patient should be carefully observed throughout the infusion, since these reactions on rare occasions may lead to shock. Epinephrine and other appropriate resuscitative drugs and equipment should be available for treatment of an acute anaphylactic reaction.
Legal Issues
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FDA Safety Alerts
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Manufacturer Warnings
There is currently no manufacturer warning information available for this drug.
FDA Labeling Changes
There are currently no FDA labeling changes available for this drug.
Uses
Carimune® NF is indicated for the maintenance treatment of patients with primary immunodeficiencies (PID), e.g., common variable immunodeficiency, X-linked agammaglobulinemia, severe combined immunodeficiency.30,32-34 Carimune® NF is preferable to intramuscular Immune Globulin (Human) preparations in treating patients who require an immediate and large increase in the intravascular immunoglobulin level28, in patients with limited muscle mass, and in patients with bleeding tendencies for whom intramuscular injections are contraindicated. The infusions must be repeated at regular intervals.
Please see DOSAGE AND ADMINISTRATION section.
A controlled study was performed in children in which Carimune® was compared with steroids for the treatment of acute (defined as less than 6 months duration) ITP. In this study sequential platelet levels of 30,000, 100,000, and 150,000/µL were all achieved faster with Carimune® than with steroids and without any of the side effects associated with steroids.29,35 However, it should be noted that many cases of acute ITP in childhood resolve spontaneously within weeks to months. Carimune® has been used with good results in the treatment of acute ITP in adult patients.36-38 In a study involving 10 adults with ITP of less than 16 weeks duration, Carimune® therapy raised the platelet count to the normal range after a 5 day course. This effect lasted a mean of over 173 days, ranging from 30 to 372 days.39
Children and adults with chronic (defined as greater than 6 months duration) ITP have also shown an increase (sometimes temporary) in platelet counts upon administration of Carimune®.35,39-43 Therefore, in situations that require a rapid rise in platelet count, for example prior to surgery or to control excessive bleeding, use of Carimune® should be considered. In children with chronic ITP, Carimune® therapy resulted in a mean rise in platelet count of 312,000/µL with a duration of increase ranging from 2 to 6 months.40,43 Carimune® therapy may be considered as a means to defer or avoid splenectomy.42-44 In adults, Carimune® therapy has been shown to be effective in maintaining the platelet count in an acceptable range with or without periodic booster therapy. The mean rise in platelet count was 93,000/µL and the average duration of the increase was 20–24 days.39,40 However, it should be noted that not all patients will respond. Even in those patients who do respond, this treatment should not be considered to be curative.
History
There is currently no drug history available for this drug.
Other Information
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 non-enveloped viruses.
| Virus | HIV | BVDV | PRV | SFV | SV | BEV | |
|---|---|---|---|---|---|---|---|
| HIV: | Human immunodeficiency virus, model for HIV 1 and HIV 2 | ||||||
| BVDV: | Bovine viral diarrhea virus, model for HCV (Hepatitis C virus) | ||||||
| PRV: | Pseudorabies virus, model for large, enveloped DNA viruses (e.g., herpes virus) | ||||||
| SFV: | Semliki Forest virus, model for HCV | ||||||
| SV: | Sindbis virus, model for HCV | ||||||
| BEV: | Bovine enterovirus, model for HAV (Hepatitis A virus) | ||||||
| nt: | not tested | ||||||
| Genome | RNA | RNA | DNA | RNA | RNA | RNA | |
| Envelope | Yes | Yes | Yes | Yes | Yes | No | |
| Size (nm) |
80–100 | 40–60 | 120–200 | 50–70 | 50–70 | 28–30 | |
| Fractionation & Depth filtration | 15.5 | nt | 16.0 | 9.3 | 12.4 | 14.1 | |
| pH 4 / pepsin | ≥ 6.1 | ≥ 4.4 | ≥ 5.3 | ≥ 6.8 | nt | nt | |
| Nanofiltration | ≥ 4.9 | ≥ 4.5 | ≥ 4.4 | nt | ≥ 7.5 | ≥ 5.1 | |
| Overall reduction | ≥ 26 | ≥ 9 | ≥ 25 | ≥ 16 | ≥ 19 | ≥ 19 | |
PRV and the two model viruses for HCV, BVDV and SFV, were inactivated within 1/10, and HIV within 1/2 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.
| Concentration | ||||
|---|---|---|---|---|
| Diluent | 3% | 6% | 9% | 12% |
| 0.9% NaCl | 498 | 690 | 882 | 1074 |
| 5% Dextrose | 444 | 636 | 828 | 1020 |
| Sterile Water | 192 | 384 | 576 | 768 |
Sources
Carimune Nanofiltered Manufacturers
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Csl Behring Ag
![Carimune Nanofiltered (Human Immunoglobulin G) Injection, Powder, Lyophilized, For Solution [Csl Behring Ag]](/wp-content/themes/bootstrap/assets/img/loading2.gif)
Carimune Nanofiltered | Csl Behring Ag
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 thrombosis, a maximum infusion rate of less than 2 mg/kg/min for patients is recommended (see PRECAUTIONS: Thrombosis).
If side effects occur, the infusion should be stopped or slowed until the symptoms subside.
Adult and Child Substitution TherapyThe 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) InductionThe 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.
Acute ITP – ChildhoodIn 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.35
Maintenance – Chronic ITPIn 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.36,69,70
Table 3: Infusion Rates for Carimune® NF Concentrations Concentration
(%) Initial Infusion Rate:
0.5 mg/kg/min 1 mg/kg/min 2 mg/kg/min* Maximum Infusion Rate†:
3 mg/kg/min * Maximum infusion rate for patients at risk of renal dysfunction or thromboembolic events. † For patients not at risk of renal dysfunction of thromboembolic events. 3% 0.0167 mL/kg/min 0.033 mL/kg/min 0.067 mL/kg/min 0.10 mL/kg/min 6% 0.008 mL/kg/min 0.0167 mL/kg/min 0.033 mL/kg/min 0.050 mL/kg/min 9% 0.006 mL/kg/min 0.011 mL/kg/min 0.022 mL/kg/min 0.033 mL/kg/min 12% 0.004 mL/kg/min 0.008 mL/kg/min 0.016 mL/kg/min 0.025 mL/kg/min Reconstitution(see also pictures next page)
1. Remove the protective plastic caps from the lyophilisate (LYO) and diluent bottles and disinfect both rubber stoppers with alcohol. Remove the protective cover from one end of the transfer set and insert the exposed needle through the rubber stopper into the bottle containing the diluent (picture 1). 2a. and 2b. Remove the second protective cover from the other end of the transfer set. Grasp both bottles as shown in picture 2a, quickly plunge the diluent bottle onto the lyophilisate bottle and bring the bottles into an upright position. Only if this is done quickly and the bottles are immediately brought into an upright position can the vacuum in the lyophilisate bottle be maintained, thus speeding up reconstitution and facilitating the transfer. Allow the diluent to flow into the lyophilisate bottle (picture 2b). 3. Once the appropriate amount of diluent is transferred (see Table 4), lift the diluent bottle off the spike to release the vacuum (picture 3). This will reduce foaming and facilitate dissolution. Remove the spike. 4. Swirl vigorously but do not shake, otherwise a foam will form which is very slow to subside (picture 4). The lyophilisate dissolves within a few minutes.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.
Table 4: Required Diluent Volume* Target Concentration 3 g Vial 6 g Vial 12 g Vial * In patients judged to be at increased risk of developing renal insufficiency and thromboembolic events, the concentration and infusion rate of Carimune ® NF should be the minimum practicable. † Container not large enough to permit this concentration. 3% 100 mL 200 mL † 6% 50 mL 100 mL 200 mL 9% 33 mL 66 mL 132 mL 12% 25 mL 50 mL 100 mLIf 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.
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