Generic name: antihemophilic factor (recombinant) pegylated-aucl
Dosage form: injection
Drug class: Miscellaneous coagulation modifiers
Indications and Usage for Jivi
Jivi, antihemophilic factor (recombinant), PEGylated-aucl, is a recombinant DNA-derived, Factor VIII concentrate indicated for use in previously treated adults and adolescents (12 years of age and older) with hemophilia A (congenital Factor VIII deficiency) for:•On-demand treatment and control of bleeding episodes•Perioperative management of bleeding•Routine prophylaxis to reduce the frequency of bleeding episodes
Limitations of Use
Jivi is not indicated for use in children < 12 years of age due to greater risk for hypersensitivity reactions [see Use in Specific Populations ( 8.4 )]. Jivi is not indicated for use in previously untreated patients (PUPs).
Jivi is not indicated for the treatment of von Willebrand disease.
Jivi Dosage and Administration
For intravenous use after reconstitution only.
•Each vial label of Jivi states the Factor VIII potency in international units (IU). One IU is defined by the current WHO (World Health Organization) international standard for Factor VIII concentrate.•Dosage and duration of treatment depend on the severity of the Factor VIII deficiency, the location and extent of bleeding, and the patient’s clinical condition. Careful control of replacement therapy is especially important in cases of major surgery or life-threatening bleeding episodes.•Potency assignment for Jivi is determined using a chromogenic substrate assay.•Monitor the Factor VIII activity of Jivi in plasma using either a validated chromogenic substrate assay or a validated one-stage clotting assay [see Warnings and Precautions ( 5.4 )].•Calculation of the required dose of Factor VIII is based on the empirical finding that 1 IU of Factor VIII per kilogram body weight increases the plasma Factor VIII level by 2 IU/dL.•Estimate the required dose for on-demand treatment and control of bleeding and perioperative management using the following formula:
Required dose (IU) = body weight (kg) x desired Factor VIII rise (% of normal or IU/dL)
x reciprocal of expected recovery (or observed recovery, if available) (e.g., 0.5 for a recovery of 2 IU/dL per IU/kg)Estimate the expected in vivo peak increase using the following formula:Estimated increment of Factor VIII (IU/dL or % of normal) = [Total dose (IU)/body weight (kg)]
x 2 (IU/dL per IU/kg)1.Adjust dose and frequency to the patient’s clinical response. Patients may vary in their pharmacokinetic [e.g., half-life, incremental recovery and AUC (area under the curve)] and clinical responses to Jivi.2.The total recommended maximum dose per infusion is approximately 6000 IU (rounded to vial size) [see Clinical Studies ( 14 )]. On-demand Treatment and Control of Bleeding Episodes
A guide for dosing Jivi for the on-demand treatment and control of bleeding episodes is provided in Table 1. The goal of treatment is to maintain a plasma Factor VIII activity level at or above the plasma levels (in % of normal or in IU/dL) outlined in Table 1.
|Degree of BleedingHemorrhage/Hemorrhagic Event||Factor VIII Level Required|
(IU/dL or % of normal)
|Dose(IU/kg)||Frequency of Doses (hours)||Duration of Treatment|
|Minor (e.g., early hemarthrosis, minor muscle bleeding, oral bleeds)||20–40||10–20||Repeat every|
|Until bleeding is resolved|
|Moderate (e.g., more extensive hemarthrosis, muscle bleeding, or hematoma)||30–60||15–30||Repeat every|
|Until bleeding is resolved|
|Major (e.g., intracranial, intra-abdominal or intrathoracic hemorrhages, gastrointestinal bleeding, central nervous system bleeding, bleeding in the retropharyngeal or retroperitoneal spaces, or iliopsoas sheath, life- or limb- threatening hemorrhage)||60–100||30–50||Repeat every|
|Until bleeding is resolved|
Perioperative Management of Bleeding
A guide for dosing Jivi during surgery (perioperative management) is provided in Table 2. The goal of treatment is to maintain a plasma Factor VIII activity level at or above the plasma level (in % of normal or in IU/dL) outlined in Table 2. During major surgery, monitoring with appropriate laboratory tests, including serial Factor VIII activity assays, is highly recommended [see Warnings and Precautions ( 5.4 )].
|Type of Surgery||Factor VIII Level Required|
(IU/dL or % of normal)
|Dose(IU/kg)||Frequency of Doses (hours)||Duration of Treatment (days)|
|Minor (e.g., tooth extraction)||30–60|
(pre- and post-operative)
|15-30||Repeat every 24 hours||At least 1 day until healing is achieved|
|Major (e.g., intracranial, intra-abdominal, intrathoracic, or joint replacement surgery)||80–100|
(pre- and post-operative)
|Until adequate wound healing is complete, then continue therapy for at least another 7 days to maintain Factor VIII activity of|
Routine Prophylaxis•The recommended initial regimen is 30–40 IU/kg twice weekly.•Based on the bleeding episodes:•The regimen may be adjusted to 45–60 IU/kg every 5 days.•A regimen may be further individually adjusted to less or more frequent dosing.
Preparation and Reconstitution
Reconstitute and administer Jivi with the components provided with each package. If any component of the package is opened or damaged, do not use this component. Reconstitution
Work on a clean surface and wash hands thoroughly using soap and warm water before performing the procedures.
|1.Warm both unopened Jivi vial and prefilled diluent syringe in your hands to a comfortable temperature (do not exceed 37°C or 99°F).|
|1.Remove the protective cap from the vial (A). Aseptically cleanse the rubber stopper with a sterile alcohol swab, being careful not to handle the rubber stopper.|
|1.Place the product vial on a firm, non-skid surface. Peel off the paper cover on the vial adapter plastic housing. Do not remove the adapter from the plastic housing. Holding the adapter housing, place over the product vial and firmly press down (B). The adapter will snap over the vial cap. Do not remove the adapter housing at this step.|
|1.Holding the syringe by the barrel, snap the syringe cap off the tip (C). Do not touch the syringe tip with your hand or any surface. Set the syringe aside for further use.|
|1.Now remove and discard the adapter plastic housing (D).|
|1.Attach the prefilled syringe to the vial adapter thread by turning clockwise (E).|
|1.Remove the clear plastic plunger rod from the carton. Grasp the plunger rod by the top plate. Avoid touching the sides and threads of the plunger rod. Attach the plunger rod by turning it clockwise into the threaded rubber stopper of the prefilled syringe (F).|
|1.Inject the diluent slowly by pushing down on the plunger rod (G).|
|1.Swirl vial gently until all powder on all sides of the vial is dissolved (H). Do not shake vial. Be sure that all powder is completely dissolved. Do not use if solution contains visible particles or is cloudy.|
|1.Push down on the plunger to push all air back into the vial. Then while holding the plunger down, turn the vial with syringe upside-down (invert) so the vial is now above the syringe (I).|
Pooling: If the dose requires more than one vial, reconstitute each vial as described above with the diluent syringe provided. Use a larger plastic syringe (not provided) to combine the contents of the vials into the syringe.
|1.Filter the reconstituted product to remove potential particulate matter in the solution. Filtering is achieved by using the vial adapter. Withdraw all the solution through the vial adapter into the syringe by pulling the plunger rod back slowly and smoothly (J). Tilt the vial to the side and back to make sure all the solution has been drawn toward the large opening in the rubber stopper and into the syringe. Remove as much air as possible before removing the syringe from the vial by slowly and carefully pushing the air back into the vial.|
|1.Detach the syringe with plunger rod from the vial adapter by turning counter-clockwise. Attach the syringe to the infusion set provided and inject the reconstituted product intravenously (K).Note: follow instructions for infusion set provided.|
For intravenous use only.•Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.•Do not use if you notice any particulate matter or discoloration and immediately contact Bayer Medical Communications at 1-888-84-BAYER (1-888-842-2937).•Administer reconstituted Jivi as soon as possible. If not, store at room temperature for no longer than 3 hours.•Infuse Jivi intravenously over a period of 1 to 15 minutes. Adapt the rate of administration to the response of each individual patient (maximum infusion rate 2.5 mL/min).
Dosage Forms and Strengths
Jivi is available as a white to slightly yellow lyophilized powder in single-use glass vials containing nominally 500, 1000, 2000, or 3000 IU of Factor VIII potency per vial.
Each vial of Jivi is labeled with actual Factor VIII potency expressed in IU determined using a chromogenic substrate assay. This potency assignment employs a Factor VIII concentrate standard that is referenced to the current WHO International Standard for Factor VIII concentrate, and is evaluated by appropriate methodology to ensure accuracy of the results.
Jivi is contraindicated in patients who have a history of hypersensitivity reactions to the active substance, polyethylene glycol (PEG), mouse or hamster proteins, or other constituents of the product [see Description ( 11 )].
Warnings and Precautions
Hypersensitivity reactions, including severe allergic reactions, have occurred with Jivi. Monitor patients for hypersensitivity symptoms. Early signs of hypersensitivity reactions, which can progress to anaphylaxis, may include chest or throat tightness, dizziness, mild hypotension and nausea. If hypersensitivity reactions occur, immediately discontinue administration and initiate appropriate treatment.
Jivi may contain trace amounts of mouse and hamster proteins [see Description ( 11 )]. Patients treated with this product may develop hypersensitivity to these non-human mammalian proteins.
Hypersensitivity reactions may also be related to antibodies against polyethylene glycol (PEG) [see Warnings and Precautions ( 5.3 )].
Neutralizing antibody (inhibitor) formation can occur following administration of Jivi. Carefully monitor patients for the development of Factor VIII inhibitors, using appropriate clinical observations and laboratory tests. If expected plasma Factor VIII activity levels are not attained or if bleeding is not controlled as expected with administered dose, suspect the presence of an inhibitor (neutralizing antibody) [see Warnings and Precautions ( 5.4 )].
Immune Response to PEG
A clinical immune response associated with IgM anti-PEG antibodies, manifested as symptoms of acute hypersensitivity and/or loss of drug effect, has been observed primarily in patients < 6 years of age [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations ( 8.4 )]. The symptoms of the clinical immune response were transient. Anti-PEG IgM titers decreased over time to undetectable levels. No immunoglobulin class switching was observed.
In case of clinical suspicion of loss of drug effect, conduct testing for Factor VIII inhibitors [see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.1 )] and Factor VIII recovery.
A low post-infusion Factor VIII level in the absence of detectable Factor VIII inhibitors indicates that loss of drug effect is likely due to anti‑PEG antibodies. Discontinue Jivi and switch patients to a previously effective Factor VIII product.
Monitoring Laboratory Tests
•If monitoring of Factor VIII activity is performed, use a validated chromogenic assay or a selected validated one-stage clotting assay [see Dosage and Administration ( 2.1 )].•Laboratories intending to measure the Factor VIII activity of Jivi should check their procedures for accuracy. For Jivi, select silica-based one-stage assays may underestimate the Factor VIII activity of Jivi in plasma samples; some reagents, e.g., with kaolin-based activators, have the potential for overestimation1. Therefore, the suitability of the assay must be ascertained. If a validated one-stage clotting or chromogenic assay is not available locally, then use of a reference laboratory is recommended.•Monitor for development of Factor VIII inhibitors. Perform a Bethesda inhibitor assay if expected Factor VIII plasma levels are not attained or if bleeding is not controlled with the expected dose of Jivi. Use Bethesda Units (BU) to report inhibitor titers.
The most frequently (≥ 5%) reported adverse reactions in clinical trials in previously treated patients (PTPs) ≥ 12 years of age were headache, cough, nausea and fever (see Table 3) .
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 clinical trials of another drug and may not reflect the rates observed in clinical practice.
A total of 221 subjects constituted the safety population from three studies. Subjects who received Jivi for perioperative management (n=17) with treatment period of 2 to 3 weeks were excluded from pooled safety analysis but included in analysis for inhibitor development. The median EDs for adults and adolescents (≥ 12 years of age) was 131 EDs (range: 1–309) per subject; and the median EDs for subjects < 12 years of age was 53 EDs (range: 1–68) per subject.
|MedDRA StandardSystem Organ ClassPreferred term||All Subjectsn (%)n=221||Subjects ≥12 years of agen (%)n=148|
|Abdominal pain||9 (4%)||5 (3%)|
|Nausea||9 (4%)||8 (5%)|
|Vomiting||10 (5%)||5 (3%)|
|General Disorders and Administration Site Conditions|
|Injection site reactions1||4 (2%)||2 (1%)|
|Pyrexia (fever)||20 (9%)||8 (5%)|
|Immune System Disorders|
|Hypersensitivity||8 (4%)||3 (2%)|
|Nervous System Disorders|
|Dizziness||3 (1%)||3 (2%)|
|Dysgeusia (distorted sense of taste)||1 (1%)||0|
|Headache||29 (13%)||21 (14%)|
|Insomnia||5 (2%)||4 (3%)|
|Respiratory, Thoracic and Mediastinal Disorders|
|Cough||18 (8%)||10 (7%)|
|Skin and Subcutaneous Tissue Disorders|
|Erythema2 (redness)||3 (1%)||2 (1%)|
|Pruritus (itching)||2 (1%)||1 (1%)|
|Rash3||9 (4%)||3 (2%)|
|Flushing||1 (1%)||1 (1%)|
1 Includes Injection site pruritus and Injection site rash
2 Includes Erythema and Erythema multiforme
3 Includes Rash and Rash papular Immunogenicity
Immunogenicity was evaluated during clinical trials with Jivi in 158 (including surgery subjects) previously treated adult and adolescent (≥ 12 years of age) severe hemophilia A (Factor VIII activity < 1%) subjects with previous exposure to Factor VIII concentrates ≥ 150 EDs. There were 73 previously treated pediatric subjects < 12 years of age [see Use in Specific Populations ( 8.4 )].
Factor VIII Inhibitors
A Factor VIII inhibitor (1.7 BU/mL) was reported in one previously treated adult subject. Repeat testing did not confirm the presence of a Factor VIII inhibitor.
Immunogenicity against PEG was evaluated by anti-PEG screening and specific IgM anti-PEG ELISA assays. One subject (19 years of age) with asthma, presented at 4 exposure days (EDs) with a clinical hypersensitivity reaction after infusion of Jivi. The subject reported headache, abdominal pain, shortness of breath, and flushing, all of which resolved following his standard asthma treatment. No further medical intervention was required. The event was associated with a transient increase of IgM anti-PEG antibody titer, which was negative upon retest during follow-up within 30 days.
The detection of antibody formation depends on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, it may be misleading to compare the incidence of antibodies to Jivi with the incidence of antibodies to other products.
USE IN SPECIFIC POPULATIONS
There are no data with Jivi use in pregnant women to inform on drug-associated risk. Animal developmental and reproductive toxicity studies have not been conducted with Jivi. It is not known whether Jivi can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity.
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.
There is no information regarding the presence of Jivi in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Jivi and any potential adverse effects on the breastfed infant from Jivi or from the underlying maternal condition.
The safety and effectiveness in patients below the age of 12 have not been established.
Jivi is not indicated for use in previously untreated patients.
Jivi is not indicated for use in children below 12 years of age [see Clinical Studies ( 14 )].
In completed clinical studies with 73 pediatric previously treated patients (PTPs) < 12 years of age (44 PTPs < 6 years, 29 PTPs 6 to < 12 years), adverse reactions due to immune response to PEG were observed in children less than 6 years of age. In 23% of subjects in the age group < 6 years of age, loss of drug effect due to neutralizing anti-PEG IgM antibodies during the first 4 exposure days (EDs) was observed. In 7% of the subjects < 6 years of age, loss of drug effect was combined with hypersensitivity reactions [see Warnings and Precautions ( 5.3 )].
Clinical studies of Jivi did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease and other drug therapy.
Jivi [antihemophilic factor (recombinant), PEGylated-aucl] is a sterile, nonpyrogenic, preservative-free, white to slightly yellow lyophilized powder for reconstitution with sterile Water for Injection (sWFI) as diluent for intravenous (IV) administration. The product is supplied in single-use vials containing dosage strengths of 500, 1000, 2000 and 3000 IU in 2.5 mL fill size. For each dosage strength, the actual assayed potency is directly printed on each vial label. The container closure system consists of a 10 mL, Type I glass vial sealed with a bromobutyl grey stopper and an aluminum crimp seal with plastic flip-off cap plus vial adapter. The vial adapter was designed to connect with the sWFI, prefilled diluent syringe. Jivi is formulated with the following excipients: 59 mg glycine, 27 mg sucrose, 8.4 mg histidine, 4.7 mg sodium chloride, 0.7 mg calcium chloride, and 0.216 mg polysorbate 80. The pH of the reconstituted product is 6.6 to 7.0.
The specific activity of Jivi is approximately 10,000 IU/mg protein.
The active protein (or starting molecule), prior to conjugation is a recombinant B-domain deleted human coagulation Factor VIII (BDD-rFVIII) produced by recombinant DNA technology in Baby Hamster Kidney (BHK) cells.
Jivi is produced by site-specific conjugation of the BDD-rFVIII variant K1804C at the cysteine amino acid position 1804 (within the A3 domain) with a single maleimide-derivatized, 60 kilodalton (kDa) branched PEG (two 30 kDa PEG) moiety. The A3 domain was selected for conjugation to provide both a consistent coagulation activity and high PEGylation efficiency.
The molecular weight of Jivi is approximately 234 kDa based on the calculated average molecular weight of the BDD-rFVIII variant of 165 kDa, plus glycosylation (~4 kDa), and the average molecular weight of the PEG-maleimide of approximately 60 kDa. Functional characterization of Jivi shows comparable mechanism of action to that of rFVIII product with an extended plasma half-life [see Clinical Pharmacology ( 12.1 )].
The manufacturing process of Jivi involves propagation of the recombinant production cell line with the harvest isolation process consisting of continuous filtration of tissue culture fluid and anion exchange chromatography on a membrane adsorber capsule. The process intermediate is purified from process- and product-related impurities using a series of chromatography and filtration steps, including 20 nm viral filtration, prior to conjugation to the 60 kDa maleimide PEG moiety. The mono-PEGylated Jivi active molecule is separated from product-related species by chromatography and then formulated by ultrafiltration. The cell culture, PEGylation, purification process and formulation used in the manufacture of Jivi do not use any additives of human or animal origins.
Jivi – Clinical Pharmacology
Mechanism of Action
Jivi, a site-specifically PEGylated recombinant antihemophilic factor [see Description ( 11 )], temporarily replaces the missing coagulation Factor VIII. The site-specific PEGylation in the A3 domain reduces binding to the physiological Factor VIII clearance receptors resulting in an extended half-life and increased AUC [see Clinical Pharmacology ( 12.3 )].
The aPTT is prolonged in people with hemophilia A.
Determination of aPTT is a conventional in vitro assay for biological activity of Factor VIII. Treatment with Jivi normalizes the aPTT similar to that achieved with plasma-derived Factor VIII. The administration of Jivi increases plasma levels of Factor VIII and can temporarily correct the coagulation defect in hemophilia A patients.
The PK of Jivi was evaluated in two cohorts after single doses of 25 IU/kg and 60 IU/kg and after 25 IU/kg given twice weekly and 60 IU/kg given once weekly for 8 weeks.
The PK profile obtained at Week 8, after repeated dosing, was comparable with the PK profile obtained after the first dose.
In Study 1, the PK of Jivi was investigated in 22 previously treated severe Hemophilia A patients (≥ 12 years of age) following administration of a single dose, 60 IU/kg, of Jivi prior to initiation of prophylactic treatment and in 16 subjects after 6 months of prophylaxis treatment with Jivi. Table 4 summarizes the PK parameters after a single dose, based on plasma Factor VIII activity measured by the chromogenic and one-stage assay.
|Chromogenic assay||One-stage assay|
|PK Parameters (unit)||25 IU/kg||60 IU/kg *||25 IU/kg||60 IU/kg *|
|AUC (IU*h/dL)||1640 ± 550||4060 ± 1420||1640 ± 660||4150 ± 1060|
|Cmax (IU/dL)||64.2 ± 9.2||167 ± 30||69.4 ± 11.3||213 ± 71|
|t½ (h)||18.6 ± 4.6||17.9 ± 4.0||21.4 ± 13.1||17.4 ± 3.8|
|MRTIV (h)||26.7 ± 6.6||25.8 ± 5.9||29.0 ± 14.0||24.5 ± 5.4|
|Vss (mL/kg)||42.8 ± 5.0||39.4 ± 6.3||44.7 ± 5.4||36.0 ± 6.5|
|CL (mL/h)||142 ± 33||121 ± 53||146 ± 44||114 ± 41|
|CL (mL/h/kg)||1.68 ± 0.39||1.63 ± 0.52||1.74 ± 0.54||1.52 ± 0.38|
|Recovery [(IU/dL)/(IU/kg)]||2.13 ± 0.47||2.53 ± 0.43 †||2.21 ± 0.55||3.25 ± 0.84 †|
|* Combined data from Phase 1 and Phase 2/3 study † Recovery value could not be calculated for one subject|
Carcinogenesis, Mutagenesis, Impairment of Fertility
Studies in animals to evaluate the carcinogenic or genotoxic potential of Jivi, or studies to determine the effects of Jivi on fertility, have not been performed. No effect on male and female reproductive organs was seen in repeated-administration toxicity studies. Genotoxicity studies conducted with the PEG component of Jivi showed no indication of genotoxicity.
Animal Toxicology and/or Pharmacology
No adverse effects were observed in immune-deficient rats intravenously injected with Jivi (40-1200 IU/kg/injection), twice weekly for 26 weeks. No evidence of accumulation of the PEG component of Jivi was detected by immunohistochemical staining in the brain (including the choroid plexus), spleen, or kidneys in animals sacrificed at 13 and 26 weeks.
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