RECOMBINATE Dailymed

 Lyophilized Powder for Reconstitution for injection

Reconstitute with 5 mL of Sterile Water for Injection using BAXJECT II

Description

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, 1000, 1500, and 2000 International Units per vial. When reconstituted with the appropriate volume of diluent, the product contains the following stabilizers in maximum amounts: For 5 mL reconstitution volume: 25 mg/mL Albumin (Human), 0.40 mg/mL calcium, 3 mg/mL polyethylene glycol (3350), 360 mEq/L sodium, 110 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.

Each vial of RECOMBINATE is labeled with the Factor VIII activity expressed in IU per vial. Biological potency is determined by an in vitro assay which is referenced to the World Health Organization (WHO) International Standard for Factor VIII:C Concentrate.

Clinical 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)¹ 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.

Indications And Usage

The use of RECOMBINATE [Antihemophilic Factor (Recombinant)] is indicated in hemophilia A (classical hemophilia) for the prevention and control of hemorrhagic episodes.² 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.³Â  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.

Contraindications

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.

Warnings

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 PRECAUTIONS - Monitoring Laboratory Tests ).

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 (see PRECAUTIONS - Monitoring Laboratory Tests ).

Precautions

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. No benefit may be expected from this product in treating other deficiencies.

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. Additionally, patients should be informed that local tissue irritation may occur when infusing RECOMBINATE reconstituted with 5 mL sWFI.

Monitoring Laboratory Tests

• Monitor plasma factor VIII activity levels by the one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained, when clinically indicated. (see DOSAGE AND ADMINISTRATION ).
• Monitor for development of factor VIII inhibitors. Perform assay to determine if factor VIII inhibitor is present if expected factor VIII activity plasma levels are not attained, or if bleeding is not controlled with the expected dose of RECOMBINATE. Use Bethesda Units (BU) to titer inhibitors.
  • If the inhibitor is less than 10 BU per mL, the administration of additional RECOMBINATE concentrate may neutralize the inhibitor, and may permit an appropriate hemostatic response.
  • Adequate hemostasis may not be achieved if inhibitor titers are above 10 BU per mL. The inhibitor titer may rise following RECOMBINATE infusion as a result of an anamnestic response to factor VIII. The treatment or prevention of bleeding in such patients requires the use of alternative therapeutic approaches and agents.

Carcinogenesis, Mutagenesis, Impairment of Fertility

RECOMBINATE was tested for mutagenicity at doses considerably exceeding plasma concentrations of Factor VIII in vitro and at doses up to ten times the expected maximum clinical dose in vivo, 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 CLINICAL PHARMACOLOGY and PRECAUTIONS ).

Pregnancy

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 Mothers

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.

Adverse Reactions

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.

System Organ Class(SOC)	Preferred MedDRATerm	Number of Subjects	Percent of Evaluable SubjectsNumber of evaluable subjects experiencing the event/total number of evaluable subjects [% relative to 210, the total number of unique subjects who received at least 1 infusion of RECOMBINATE].
GASTROINTESTINAL DISORDERS	Nausea	1	0.48
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS	Chills Fatigue Pyrexia	3 1 1	1.43 0.48 0.48
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 Tremors	1 1	0.48 0.48
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS	Pharyngolaryngeal pain	1	0.48
SKIN AND SUBCUTANEOUS TISSUE DISORDERS	Hyperhidrosis Pruritus Rash Rash maculopapular	1 1 2 1	0.48 0.48 0.95 0.48
VASCULAR DISORDERS	Epistaxis Flushing Hematoma Hypotension Pallor Peripheral coldness	1One subject experienced 11 events of epistaxis. 2 1 1 1 1	0.48 0.95 0.48 0.48 0.48 0.48

During the Previously Treated Patients (PTP) study, none of the 71 subjects developed de novo 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.

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 uled 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: Factor VIII inhibition

 CARDIAC DISORDERS: Tachycardia, Cyanosis

GASTROINTESTINAL DISORDERS: Vomiting, Abdominal pain

GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS: Malaise, Injection site reactions, Chest pain, Chest discomfort

IMMUNE SYSTEM DISORDERS: Anaphylactic reaction, Hypersensitivity

NERVOUS SYSTEM DISORDERS: Loss of consciousness, Headache, Paresthesia

RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS: Dyspnea, Cough, Laryngeal edema

SKIN AND SUBCUTANEOUS TISSUE DISORDERS: Angioedema, Urticaria, Erythema