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Recombinate
Overview
What is Recombinate?
RECOMBINATE [Antihemophilic Factor (Recombinant)] is a glycoprotein synthesized by a genetically engineered Chinese Hamster Ovary (CHO) cell line. In culture, the CHO cell line secretes recombinant Factor VIII (rFVIII) into the cell culture medium. The rFVIII is purified from the culture medium utilizing a series of chromatography columns. A key step in the purification process is an immunoaffinity chromatography methodology in which a purification matrix, prepared by immobilization of a monoclonal antibody directed to Factor VIII, is utilized to selectively isolate the rFVIII in the medium. The synthesized rFVIII produced by the CHO cells has the same biological effects as human Factor VIII. Structurally the protein has a similar combination of heterogenous heavy and light chains as found in human Factor VIII.
RECOMBINATE is formulated as a sterile, nonpyrogenic, off-white to faint yellow, lyophilized powder preparation of concentrated recombinant Factor VIII for intravenous injection. RECOMBINATE is available in single-dose vials, which contain nominally 250, 500 and 1000 International Units per vial. When reconstituted with the appropriate volume of diluent, the product contains the following stabilizers in maximum amounts: For 10 mL reconstitution volume: 12.5 mg/mL Albumin (Human), 0.20 mg/mL calcium, 1.5 mg/mL polyethylene glycol (3350), 180 mEq/L sodium, 55 mM histidine, 1.5 µg/Factor VIII International Unit (IU) polysorbate-80. Recombinant Von Willebrand Factor (rVWF) is coexpressed with the rFVIII and helps to stabilize it. The final product contains not more than 2 ng rVWF/IU rFVIII, which will not have any clinically relevant effect in patients with von Willebrand’s disease. The product contains no preservative.
Manufacturing of RECOMBINATE is shared by Baxter Healthcare Corporation and Wyeth BioPharma. The recombinant Antihemophilic Factor Concentrate (For Further Manufacturing Use), is produced by Baxter Healthcare Corporation and Wyeth BioPharma (For Further Manufacturing Use) and subsequently formulated and packaged at Baxter Healthcare Corporation.
Each vial of RECOMBINATE is labeled with the Factor VIII activity expressed in IU per vial. Biological potency is determined by an assay which is referenced to the World Health Organization (WHO) International Standard for Factor VIII:C Concentrate.
What does Recombinate look like?
What are the available doses of Recombinate?
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What should I talk to my health care provider before I take Recombinate?
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How should I use Recombinate?
The use of RECOMBINATE [Antihemophilic Factor (Recombinant)] is indicated in hemophilia A (classical hemophilia) for the prevention and control of hemorrhagic episodes. RECOMBINATE is also indicated in the perioperative management of patients with hemophilia A (classical hemophilia).
RECOMBINATE can be of therapeutic value in patients with acquired Factor VIII inhibitors not exceeding 10 Bethesda Units per mL. In clinical studies with RECOMBINATE, patients with inhibitors who were entered into the previously treated patient trial and those previously untreated children who have developed inhibitor activity on study, showed clinical hemostatic response when the titer of inhibitor was less than 10 Bethesda Units per mL. However, in such uses, the dosage of RECOMBINATE should be controlled by frequent laboratory determinations of circulating Factor VIII levels as well as the clinical status of the patient.
RECOMBINATE is not indicated in von Willebrand’s disease.
Each vial of RECOMBINATE is labeled with the Factor VIII activity expressed in IU per vial. This potency assignment is referenced to the World Health Organization International Standard for Factor VIII:C Concentrate and is evaluated by appropriate methodology to ensure accuracy of the results.
The expected peak increase in Factor VIII level expressed as IU/dL of plasma or % (percent) of normal can be estimated by multiplying the dose administered per kg body weight (IU/kg) by two. This calculation is based on the clinical findings of Abildgaard
and is supported by the data generated by 419 clinical pharmacokinetic studies with RECOMBINATE in 67 patients over time. This pharmacokinetic data demonstrated a peak recovery point above the pre-infusion baseline of approximately 2.0 IU/dL per IU/kg body weight.
Examples (Assuming patient’s baseline Factor VIII level is at <1%):
(1) A dose of 1750 IU RECOMBINATE administered to a 70 kg patient, 25 IU/kg (1750 IU/70 kg), should be expected to cause a peak post-infusion Factor VIII increase of 25 IU/kg x 2 (IU/dL)/(IU/kg) = 50 IU/dL (50% of normal).
(2) A peak level of 70% is required in a 40 kg child. In this situation, the dose would be 70 IU/dL/[2(IU/dL)/(IU/kg)] x 40 kg = 1400 IU.
What interacts with Recombinate?
RECOMBINATE is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including bovine, mouse or hamster proteins.
What are the warnings of Recombinate?
General
The clinical response to RECOMBINATE may vary. If bleeding is not controlled with the recommended dose, the plasma level of factor VIII should be determined and a sufficient dose of RECOMBINATE should be administered to achieve a satisfactory clinical response. If the patient’s plasma factor VIII level fails to increase as expected or if bleeding is not controlled after the expected dose, the presence of an inhibitor (neutralizing antibodies) should be suspected and appropriate testing performed. (see
).
Anaphylaxis and Severe Hypersensitivity Reactions
Allergic type hypersensitivity reactions, including anaphylaxis, have been reported with RECOMBINATE and have been manifested as dizziness pruritus, rash, urticaria, flushing, angioedema/face swelling, laryngeal edema, dyspnea, pallor, pyrexia, nausea, paresthesia, hypotension, and loss of consciousness. Discontinue RECOMBINATE if symptoms occur and seek immediate emergency treatment. RECOMBINATE contains trace amounts of bovine proteins, mouse immunoglobulin G (MuIgG), and hamster (CHO) proteins. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.
Neutralizing Antibodies
Patients treated with antihemophilic factor (AHF) products should be carefully monitored for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests. Inhibitors have been reported following administration of RECOMBINATE predominantly in previously untreated and minimally treated patients. The risk of developing inhibitors is highest during the first 20 exposure days. If expected plasma factor VIII activity levels are not attained, or if bleeding is not controlled with an expected dose, an assay that measures factor VIII inhibitor concentration should be performed ().
What are the precautions of Recombinate?
General
Certain components used in the packaging of this product contain natural rubber latex.
Identification of the clotting defect as a Factor VIII deficiency is essential before the administration of RECOMBINATE [Antihemophilic Factor (Recombinant)] is initiated.
Formation of Antibodies to Mouse, Hamster or Bovine Protein
As RECOMBINATE contains trace amounts of mouse protein (maximum of 0.1 ng/IU RECOMBINATE), hamster protein (maximum of 1.5 ng CHO protein/IU RECOMBINATE), and bovine protein (maximum of 1 ng BSA/IU RECOMBINATE), the remote possibility exists that patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.
Information for Patients
The patient and physician should discuss the risks and benefits of this product.
Allergic type hypersensitivity reactions have been observed with RECOMBINATE. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, symptoms of laryngeal edema, and anaphylaxis. Patients should be advised to discontinue use of the product and contact their physician if these symptoms occur.
Monitoring Laboratory Tests
Carcinogenesis, Mutagenesis, Impairment of Fertility
RECOMBINATE was tested for mutagenicity at doses considerably exceeding plasma concentrations of Factor VIII and at doses up to ten times the expected maximum clinical dose , and did not cause reverse mutations, chromosomal aberrations, or an increase in micronuclei in bone marrow polychromatic erythrocytes. Long-term studies in animals have not been performed to evaluate carcinogenic potential.
Pediatric Use
RECOMBINATE is appropriate for use in children of all ages, including the newborn. Safety and efficacy studies have been performed in both previously treated (n=23) and previously untreated (n=75) children. (See and ).
Pregnancy
Pregnancy Category C. Animal reproduction studies have not been conducted with RECOMBINATE. The safety of RECOMBINATE for use in pregnant women has not been established. It is not known whether RECOMBINATE can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Physicians should carefully consider the potential risks and benefits for each specific patient before prescribing RECOMBINATE. RECOMBINATE should be given to a pregnant woman only if clearly needed.
Nursing Mother
It is not known whether this drug is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised if RECOMBINATE is administered to nursing mothers. RECOMBINATE should be given to nursing mothers only if clinically needed.
What are the side effects of Recombinate?
Adverse Reactions from Clinical Trials
During controlled clinical studies with RECOMBINATE enrolling 210 subjects, the most commonly reported adverse drug reactions were chills, flushing, rash and epistaxis.
During the Previously Treated Patients (PTP) study, none of the 71 subjects developed evidence of Factor VIII inhibitor. However, during the phase II/III portion of the study, 1 subject with a history of inhibitors exhibited inhibitor activity at 6 months (0.8 Bethesda Units [BU]), which resolved by 9 months. One other subject in this study had detectable Factor VIII inhibitor at baseline (1.26 BU) and exhibited an anamnestic response at 6 months (10.3 BU). During a prospective pharmaco-surveillance study of subjects who received batches of RECOMBINATE containing modestly increased Chinese Hamster Ovary (CHO) cell protein levels, none of the 34 treated subjects developed a Factor VIII inhibitor.
During the Previously Untreated Patients (PUP) study, 22 of the 73 evaluable subjects developed inhibitors to Factor VIII. Of these, 13 subjects displayed no detectable Factor VIII inhibitors at study exit.
| System Organ Class (SOC) | Preferred MedDRA Term | Number of Subjects | Percent of Evaluable Subjects |
| GASTROINTESTINAL DISORDERS | Nausea | 1 | 0.48 |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS | |||
| INFECTIONS AND INFESTATIONS | Ear infections | 1 | 0.48 |
| INVESTIGATIONS | Acoustic stimulation tests abnormal | 1 | 0.48 |
| MUSCULOSKELETAL AND CONNECTIVE TISSUES DISORDERS | Pain in extremity | 1 | 0.48 |
| NERVOUS SYSTEM DISORDERS | Dizziness | 1 | 0.48 |
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS | Pharyngolaryngeal pain | 1 | 0.48 |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS | |||
| VASCULAR DISORDERS |
Post-Marketing Adverse Reactions
In addition to the adverse reactions noted in clinical trials, the following adverse reactions have been reported in the post-marketing experience. These adverse reactions are listed by MedDRA (version 12.1) System Organ Class (SOC), then by MedDRA coding system Preferred Term in order of severity.
BLOOD AND LYMPHATIC SYSTEM DISORDERS:
CARDIAC DISORDERS:
GASTROINTESTINAL DISORDERS
:
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS:
IMMUNE SYSTEM DISORDERS:
NERVOUS SYSTEM DISORDERS:
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS:
SKIN AND SUBCUTANEOUS TISSUE DISORDERS:
What should I look out for while using Recombinate?
RECOMBINATE is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including bovine, mouse or hamster proteins.
What might happen if I take too much Recombinate?
Sorry No Records found
How should I store and handle Recombinate?
Store at 20° to 25ºC (68° to 77°F).[See USP Controlled Room Temperature]Dispense in a tight container as defined in the USP.Store at 20° to 25ºC (68° to 77°F).[See USP Controlled Room Temperature]Dispense in a tight container as defined in the USP.Store at 20° to 25ºC (68° to 77°F).[See USP Controlled Room Temperature]Dispense in a tight container as defined in the USP.RECOMBINATE is available in three different strengths in single-dose vials. The strength is designated on the outer box and on the vial label using the following color codes:RECOMBINATE is packaged with 10 mL of Sterile Water for Injection, USP, a double-ended needle, a filter needle, one physician insert and one patient insert.RECOMBINATE is available in three different strengths in single-dose vials. The strength is designated on the outer box and on the vial label using the following color codes:RECOMBINATE is packaged with 10 mL of Sterile Water for Injection, USP, a double-ended needle, a filter needle, one physician insert and one patient insert.
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Factor VIII is the specific clotting factor deficient in patients with hemophilia A (classical hemophilia). Hemophilia A is a genetic bleeding disorder characterized by hemorrhages, which may occur spontaneously or after minor trauma. The administration of RECOMBINATE provides an increase in plasma levels of Factor VIII and can temporarily correct the coagulation defect in these patients. Pharmacokinetic studies on sixty-nine (69) patients revealed the circulating mean half-life for RECOMBINATE to be 14.6 ± 4.9 hours (n=67), which was not statistically significantly different from plasma-derived HEMOFIL M, [Antihemophilic Factor (Human), Method M, Monoclonal Purified]. The mean half-life of HEMOFIL M was 14.7 ± 5.1 hours (n=61). The actual baseline recovery observed with RECOMBINATE was 123.9 ± 47.7 IU/dL (n=23), which is significantly higher than the actual HEMOFIL M baseline recovery of 101.7 ± 31.6 IU/dL (n=61). However, the calculated ratio of actual to expected recovery with RECOMBINATE (121.2 ± 48.9%) is not different on average from HEMOFIL M (123.4 ± 16.4%).
The clinical study of RECOMBINATE in previously treated patients (individuals with hemophilia A who had been treated with plasma derived Factor VIII) was based on observations made on a study group of 69 patients. These individuals received cumulative amounts of Factor VIII ranging from 20,914 to 1,383,063 IU over the 48 month study. Patients were given a total of 17,700 infusions totaling 28,090,769 IU RECOMBINATE.
These patients were successfully treated for bleeding episodes on a demand basis and also for the prevention of bleeds (prophylaxis). Spontaneous bleeding episodes successfully managed include hemarthroses, soft tissue and muscle bleeds. Management of hemostasis was also evaluated in surgeries. A total of 24 procedures on 13 patients were performed during this study. These included minor (e.g. tooth extraction) and major (e.g. bilateral osteotomies, thoracotomy and liver transplant) procedures. Hemostasis was maintained perioperatively and postoperatively with individualized Factor VIII replacement.
A study of RECOMBINATE in previously untreated patients was also performed as part of an ongoing study. The study group was comprised of seventy-nine (79) patients , of whom seventy-six (76) had received at least one infusion of RECOMBINATE. To date, this cohort has been given 12,209 infusions totaling over 11,277,043 IU of RECOMBINATE. Hemostasis was appropriately managed in spontaneous bleeding episodes, intracranial hemorrhage and surgical procedures.
Non-Clinical Toxicology
RECOMBINATE is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis, to the product or its components, including bovine, mouse or hamster proteins.Anticoagulants (Oral): The activity of anticoagulants may be potentiated by anti-vitamin-K activity attributed to propylthiouracil.
β-Adrenergic Blocking Agents: Hyperthyroidism may cause an increased clearance of beta blockers with a high extraction ratio. A dose reduction of beta-adrenergic blockers may be needed when a hyperthyroid patient becomes euthyroid.
Digitalis Glycosides: Serum digitalis levels may be increased when hyperthyroid patients on a stable digitalis glycoside regimen become euthyroid; a reduced dosage of digitalis glycosides may be required.
Theophylline: Theophylline clearance may decrease when hyperthyroid patients on a stable theophylline regimen become euthyroid; a reduced dose of theophylline may be needed.
Certain components used in the packaging of this product contain natural rubber latex.
Identification of the clotting defect as a Factor VIII deficiency is essential before the administration of RECOMBINATE [Antihemophilic Factor (Recombinant)] is initiated.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
While we update our database periodically, we cannot guarantee it is always updated to the latest version.
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