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2015年3月28日，美国FDA批准Alprolix（重组凝血因子IX Fc融合蛋白）用于患有B型血友病的成人及儿童患者。在预防或减少出血频次方面，Alprolix是首款旨在减少注射频次的B型血友病治疗药物。
Routine prophylaxis: 50 IU/kg once weekly or 100 IU/kg once every 10 days. Adjust dosing regimen based on individual response. (2.1) DOSAGE FORMS AND STRENGTHS ALPROLIX™ is available as a lyophilized powder in single use vials containing nominally 500, 1000, 2000, or 3000 international units (IU). (3) CONTRAINDICATIONS Do not use in individuals who have a known history of hypersensitivity reactions, including anaphylaxis, to the product or its excipients. (4) WARNINGS AND PRECAUTIONS Hypersensitivity reactions, including anaphylaxis, may occur. Should symptoms occur, discontinue ALPROLIX™ and administer appropriate treatment. (5.1) Development of neutralizing antibodies (inhibitors) to ALPROLIX™ may occur. Perform an assay that measures Factor IX inhibitor concentration if plasma Factor IX level fails to increase as expected or if bleeding is not controlled with an appropriate dose. (5.2, 5.4) The use of Factor IX products has been associated with the development of thromboembolic complications. (5.3) ADVERSE REACTIONS Common adverse reactions (incidence ≥1%) from clinical trials were headache and oral paresthesia. (6) To report SUSPECTED ADVERSE REACTIONS, contact Biogen Idec, Inc. at 1-800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch USE IN SPECIFIC POPULATIONS Pregnancy: No human or animal data. Use only if clearly needed. (8.1) Pediatric: In pediatric patients under 12 years of age, recovery may be lower and body weight adjusted clearance may be higher. Dose adjustment may be needed. (8.4) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 3/2014 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE ALPROLIX™, Coagulation Factor IX (Recombinant), Fc Fusion Protein, is a recombinant DNA derived, coagulation Factor IX concentrate indicated in adults and children with hemophilia B (congenital Factor IX deficiency) for: Control and prevention of bleeding episodes, Perioperative management, Routine prophylaxis to prevent or reduce the frequency of bleeding episodes. ALPROLIX™ is not indicated for induction of immune tolerance in patients with hemophilia B [see Warnings and Precautions (5.3)]. 2 DOSAGE AND ADMINISTRATION For intravenous use after reconstitution only 2.1 Dosing Guidelines Initiate treatment with ALPROLIX™ under the supervision of a qualified healthcare professional experienced in the treatment of hemophilia B. Dose and duration of treatment depend on the severity of the Factor IX deficiency, the location and extent of bleeding, and the patient's clinical condition. Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses. Base the dose and frequency of ALPROLIX™ on the individual clinical response. Each vial label for ALPROLIX™ states the Factor IX potency in international units (IU). ALPROLIX™ potency is assigned using an in vitro, activated partial thromboplastin time (aPTT)-based, one-stage clotting assay calibrated against the World Health Organization (WHO) international standard for Factor IX concentrates. Factor IX activity measurements in the clinical laboratory may be affected by the type of aPTT reagent or laboratory standard used.[see Warnings and Precautions (5.4)] One IU of ALPROLIX™ per kg body weight increases the circulating level of Factor IX by 1% [IU/dL]. Estimate the required dose or the expected in vivo peak increase in Factor IX level expressed as IU/dL (or % of normal) using the following formulas: IU/dL (or % of normal) = [Total Dose (IU)/Body Weight (kg)] x Recovery (IU/dL per IU/kg) OR Dose (IU) = Body Weight (kg) x Desired Factor IX Rise (IU/dL or, % of normal) x Reciprocal of Recovery (IU/kg per IU/dL) Dose adjustment may be necessary in pediatric patients under 12 years of age [see Use in Specific Populations (8.4)]. For patients 12 years of age or older, dose adjustment is not usually required. Control and Prevention of Bleeding Episodes ALPROLIX™ dosing for the control and prevention of bleeding episodes is provided in Table 1. Table 1: Dosing for Control and Prevention of Bleeding Episodes
ALPROLIX™ dosing for perioperative management is provided in Table 2 . Table 2: Dosing for Perioperative Management
The recommended starting regimens are either 50 IU/kg once weekly, or 100 IU/kg once every 10 days. Adjust dosing regimen based on individual response. 2.2 Reconstitution Use aseptic technique (clean and germ-free) and a flat work surface during the reconstitution procedure. Allow the vial of ALPROLIX™ and the pre-filled diluent syringe to reach room temperature before use. Remove the plastic cap from the vial and wipe the rubber stopper of the vial with an alcohol wipe. Allow the rubber stopper to dry. Completely remove the backing from the vial adapter package by peeling back the lid. Do not remove the vial adapter from the package or touch the inside of the package of the adapter.
Lift the package cover away from the vial adapter and discard the cover.
Obstructive uropathy was reported in one subject with hematuria who developed an obstructing clot in the urinary collecting system. The event resolved with hydration and the subject continued prophylactic treatment with ALPROLIX™. A causal relationship of clot formation to ALPROLIX™ was not established. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Animal reproductive studies have not been conducted with ALPROLIX™. It is also not known whether ALPROLIX™ can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. ALPROLIX™ should be given to a pregnant woman only if clearly needed. 8.2 Labor and Delivery There is no information available on the effect of Factor IX replacement therapy on labor and delivery. Use only if the potential benefit justifies the potential risk. 8.3 Nursing Mothers It is not known if ALPROLIX™ is excreted into human milk. Because many drugs are excreted in human milk, caution should be exercised if ALPROLIX™ is administered to nursing women. 8.4 Pediatric Use Safety, efficacy, and pharmacokinetics of ALPROLIX™ have been evaluated in previously treated pediatric patients 12 years of age and older. No dose adjustment is required for adolescents. Children under 12 years of age may have higher Factor IX body weight-adjusted clearance, shorter half-life, and lower recovery. Higher dose per kilogram body weight or more frequent dosing may be needed in these patients [see Clinical Pharmacology (12.3)]. The use of ALPROLIX™ in children younger than 12 years of age is supported by the clinical study of ALPROLIX™ in subjects 12 years of age and older and interim pharmacokinetic and safety data from a study of pediatric subjects including 8 subjects 2 to 5 years of age and 15 subjects 6 to 11 years of age who were exposed for a median of 21.3 weeks (1.1 to 45.7 weeks). The safety profile in subjects under 12 years of age is acceptable. Efficacy can be extrapolated from pharmacokinetic data to subjects < 2 years of age. [see Clinical Pharmacology (12.3)] 8.5 Geriatric Use Clinical studies of ALPROLIX™ did not include a sufficient number of subjects age 65 and over to determine whether or not they respond differently than younger subjects. 11 DESCRIPTION Coagulation Factor IX (Recombinant), Fc Fusion Protein [rFIXFc], the active ingredient in ALPROLIX™, is a recombinant coagulation Factor IX protein consisting of the human coagulation Factor IX sequence covalently linked to the Fc domain of human immunoglobulin G1 (IgG1). The Factor IX portion of rFIXFc has a primary amino acid sequence that is identical to the Thr148 allelic form of plasma derived Factor IX and has structural and functional properties similar to endogenous Factor IX. The Fc domain of rFIXFc contains the hinge, CH2, and CH3 regions of IgG1. rFIXFc contains 867 amino acids with a molecular weight of approximately 98 kilodaltons. ALPROLIX™ is not derived from human blood and contains no preservatives. The recombinant Factor IX Fc fusion protein is expressed in a human embryonic kidney (HEK) cell line, which produces rFIXFc into a defined cell culture medium that does not contain proteins derived from animal or human sources. The purification process for rFIXFc does not include use of a monoclonal antibody reagent. To enhance viral safety, the purification process incorporates a nanofiltration step and a column chromatography purification step that have been validated for viral clearance. The content of activated Factor IX Fc fusion protein (FIXaFc) is limited to ≤0.035 mole percent FIXaFc/FIXFc. ALPROLIX™ is a sterile, non-pyrogenic, preservative-free, white to off-white, lyophilized powder to cake for reconstitution with the provided diluent, for intravenous injection. After reconstitution, the solution has a clear to slightly opalescent appearance and contains the excipients: sucrose, mannitol, sodium chloride, L-histidine and polysorbate 20. ALPROLIX™ is available in single-use vials containing the labeled amount of Factor IX activity, expressed in international units. Each vial contains nominally 500 IU, 1000 IU, 2000 IU or 3000 IU. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action ALPROLIX™ is a recombinant, fusion protein that temporarily replaces the missing coagulation Factor IX needed for effective hemostasis. ALPROLIX™ contains the Fc region of human IgG1, which binds to the neonatal Fc receptor (FcRn). FcRn is part of a naturally occurring pathway that delays lysosomal degradation of immunoglobulins by cycling them back into circulation, and prolonging their plasma half-life. 12.2 Pharmacodynamics Hemophilia B is a bleeding disorder characterized by a deficiency of functional coagulation Factor IX (FIX), which leads to a prolonged clotting time in the activated partial thromboplastin time (aPTT) assay, an established in vitro test for the biological activity of Factor IX. Treatment with ALPROLIX™ shortens the aPTT over the effective dosing period. 12.3 Pharmacokinetics The pharmacokinetics (PK) of ALPROLIX™ (rFIXFc) were evaluated in 22 subjects following a 10 minute intravenous infusion of a single dose of 50 IU/kg. The PK parameters (Table 4) were based on plasma FIX activity measured by the one-stage clotting assay. Blood samples for PK analysis were collected prior to dosing and at 11 time points up to 240 hours (10 days) after dosing. The PK data demonstrate that ALPROLIX™ has a prolonged circulating half-life. Table 4: Pharmacokinetic Parameters (Arithmetic Mean, CV)
The ALPROLIX™ PK profile was stable over repeated dosing as shown by comparable PK parameters at Week 26. The PK parameters following a 100 IU/kg dose of ALPROLIX™ were evaluated in a subset of 27 subjects. For this subset, the mean drug clearance (CL) was 2.65 (21.7%) mL/kg/h, the maximum activity (Cmax) was 99.89 IU/dL (20.1%) and the time to 1% FIX activity was 15.8 days (21.3%). Pediatric and Adolescent Pharmacokinetics Pharmacokinetic (PK) parameters of ALPROLIX™ (rFIXFc) were determined for adolescents (12 to 17 years of age) and children (2 to 11 years of age) in open-label, multi-center studies of previously treated patients [see Use in Specific Populations (8.4)]. Pharmacokinetic parameters were evaluated following a 10 minute intravenous infusion in 11 evaluable adolescents who received a single dose of ALPROLIX™. PK samples were collected prior to dosing and at multiple time points up to 336 hours (14 days) after dosing. In a separate study, PK parameters were evaluated following a 10 minute intravenous infusion in 18 evaluable children (2 to 11 years of age) who received a single dose of ALPROLIX™. PK samples were collected prior to dosing and at multiple time points up to 168 hours (7 days) after dosing. PK parameters for ALPROLIX™ were estimated based on the plasma FIX activity over time profile. Table 5 presents the PK parameters calculated from the pediatric data of 29 subjects 2 to 17 years of age. Compared to adults, incremental recovery appeared to be lower and body weight- adjusted clearance appeared to be higher in children under 12 years of age. This may result in a need for per kg body weight dose and interval adjustments in children under 12 years of age. [see Use in Specific Populations (8.4)] Table 5: Comparison of Pharmacokinetic Parameters of rFIXFc by Age Category
Abbreviations: IR = incremental recovery; AUC = area under the FIX activity time curve; T ½= elimination half-life; MRT = mean residence time; CL = body weight adjusted clearance; Vss = body weight adjusted volume of distribution at steady-state 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term studies in animals to evaluate the carcinogenic potential of ALPROLIX™, or studies to determine the effects of ALPROLIX™ on genotoxicity or fertility have not been performed. An assessment of the carcinogenic potential of ALPROLIX™ was completed and no carcinogenic risk from product use has been identified. 14 CLINICAL STUDIES The safety and efficacy of ALPROLIX™ was evaluated in a multi-center, prospective, open-label clinical trial that compared each of two prophylactic treatment regimens (fixed weekly and individualized interval) to episodic (on-demand) treatment; determined hemostatic efficacy in the treatment of bleeding episodes; and determined hemostatic efficacy during perioperative management of subjects undergoing major surgical procedures. A total of 123 previously treated patients (PTPs) with severe hemophilia B (≤ 2% endogenous FIX activity), ages 12-71, were followed for up to 77 weeks. Sixty three subjects in the fixed weekly interval arm received ALPROLIX™ for routine prophylaxis starting at an initial dose of 50 IU/kg. The dose was adjusted to maintain FIX trough level between 1% and 3% above baseline or higher, as clinically indicated to prevent bleeding. Fifty subjects required at least one dose adjustment and the median number of dose adjustments was one. The overall median dose on study was 45.2 IU/kg (interquartile range: 38.1, 53.7). The median weekly dose during the last 6 months on study in 58 subjects who were on study for at least 9 months was 40.7 IU/kg (interquartile range: 32.3, 54.1). Twenty nine subjects in the individualized interval arm received ALPROLIX™ for routine prophylaxis at a dose of 100 IU/kg every 10 days, with the interval adjusted to maintain FIX trough level between 1% and 3% above baseline or higher, as clinically indicated to prevent bleeding. The overall median interval on study was 12.5 days (interquartile range: 10.4, 13.4). The median interval during the last 6 months in 26 subjects who were on study for at least 9 months was 13.8 days (interquartile range: 10.5, 14.0). Twenty seven subjects received ALPROLIX™ as needed for the treatment of bleeding episodes in the episodic (on-demand) treatment arm. Twelve subjects received ALPROLIX™ for perioperative management in 14 major surgical procedures. Major surgery was defined as any surgical procedure with or without general anesthesia in which a major body cavity was penetrated and exposed, or a substantial impairment of physical or physiological functions was produced. Four subjects in this arm did not participate in the other arms. Control and Prevention of Bleeding Episodes A total of 636 bleeding events were observed by 114 subjects in the fixed weekly interval prophylaxis, individualized interval prophylaxis, and the episodic (on-demand) arms. The median total dose to treat a bleeding episode was 46.99 IU/kg (interquartile range: 33.33, 62.50). Assessment of response to each injection was recorded by subjects at 8-12 hours after treatment. Efficacy in control of bleeding episodes is summarized in Table 6. Table 6: Efficacy in Control of Bleeding
Routine Prophylaxis Using a negative binomial model, a reduction in annualized bleeding rate (ABR) of 83% (76-89%) for subjects in the fixed weekly interval arm and a reduction of 87% (80-92%) for subjects in the individualized interval arm compared to the episodic (on-demand) treatment arm was observed. The median duration of treatment on study was 51.4 weeks (range <1-77). A comparison of the ABRs in subjects evaluable for efficacy is summarized in Table 7. Table 7: Median Annualized Bleeding Rate (ABR) by Treatment Arm
Five subjects (2 in prophylaxis fixed weekly interval arm, 3 in prophylaxis individualized interval arm) did not have sufficient data to be included in the efficacy analysis. Perioperative Management Fourteen major surgical procedures were performed in 12 subjects, including 5 knee replacements, abdominal surgery and a complex dental procedure. Perioperative Factor IX replacement with ALPROLIX™ was by bolus infusion only. The safety of continuous infusion was not evaluated. Hemostasis was assessed by the investigator at 24 hours after surgery using a 4-point scale of excellent, good, fair, and none. The hemostatic response was rated as excellent (n=13) or good (n=1) in 100% of major surgeries. There were an additional 15 minor surgical procedures in 13 subjects. There was no clinical evidence of thrombotic complications in any of the subjects. 15 REFERENCES 1.Chitlur M, Warrier I, Rajpurkar M, et al. Inhibitors in factor IX deficiency a report of the ISTH-SSC international FIX inhibitor registry (1997-2006). Haemophilia. 2009;15(5):1027-31. 16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied ALPROLIX™ is supplied as a kit comprising: one single-use rFIXFc vial, one pre-filled syringe containing 5 mL diluent and sealed with a plunger stopper and tip-cap, and one sterile vial adapter (reconstitution device). ALPROLIX™ vials are available in 500, 1000, 2000, or 3000 IU nominal dosage strengths. The actual Factor IX potency, expressed in IU is stated on every rFIXFc vial and kit carton label.
Store ALPROLIX™ in the original package in order to protect it from light. Store ALPROLIX™ at 2°C to 8°C (36°F to 46°F). If stored at room temperature, do not to exceed 30°C (86°F) for a single 6 month period. On the carton, record the date when the product was removed from refrigeration. Use the product before the end of this 6 month period or discard it. Do not place the product back into refrigeration after warming to room temperature. Do not freeze. Freezing will damage the pre-filled diluent syringe. Do not use product or diluent after the expiration date printed on the carton, vial or syringe. Reconstituted product may be stored at room temperature, not to exceed 30°C (86°F) for no longer than 3 hours. Protect from direct sunlight. Discard any product not used within 3 hours after reconstitution. 17 PATIENT COUNSELING INFORMATION Advise patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Advise patients to report any adverse reactions or problems following ALPROLIX™ administration to their physician or healthcare provider. Advise patients to contact their healthcare provider or treatment facility for further treatment and/or assessment if they experience a lack of a clinical response to Factor IX therapy, as this may indicate the development of an inhibitor. Inform patients of the early signs of hypersensitivity reactions (including hives, chest tightness, wheezing, difficulty breathing and swelling of the face) and anaphylaxis. Instruct patients to discontinue use of the product and contact their healthcare provider if these symptoms occur. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1ae6e28d-7133-4c36-c949-4fdc82f210e9 |
