The following Structured Product Label (SPL) was submitted to the FDA by Bioverativ Therapeutics Inc. for the product Altuviiio (NDC 71104-979). This document serves as the official prescribing information, containing essential scientific data and clinical materials required for healthcare providers and patients.
This specific version of the label includes detailed information regarding 1 indications and usage, other, 2 dosage and administration, 2.1 dose, 2.2 preparation and reconstitution, 2.3 administration, 3 dosage forms and strengths, 4 contraindications, and other regulatory disclosures. Use the navigation below to review specific sections of the FDA submission.
ALTUVIIIO [antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl] is a von Willebrand Factor (VWF) independent recombinant DNA-derived, Factor VIII concentrate indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency) for:
Limitation of Use
ALTUVIIIO is not indicated for the treatment of von Willebrand disease.
Routine Prophylaxis
The recommended dosing for routine prophylaxis for adults and children is 50 IU/kg of ALTUVIIIO administered once weekly.
On-demand Treatment and Control of Bleeding Episodes
ALTUVIIIO dosing for the on-demand treatment and control of bleeding episodes is provided in Table 1.
| Type of Bleeding | Recommended Dose | Additional Information |
|---|---|---|
| Minor and Moderate For example: uncomplicated joint bleeds, minor muscular bleeds, mucosal or subcutaneous bleeds | Single dose of 50 IU/kg | For minor and moderate bleeding episodes occurring within 2 to 3 days after a prophylactic dose, a lower dose of 30 IU/kg dose may be used. Additional doses of 30 or 50 IU/kg every 2 to 3 days may be considered. |
| Major For example: Intracranial, retroperitoneal, iliopsoas and neck bleeds, muscle bleeds with compartment syndrome and bleeds associated with a significant decrease in the hemoglobin level | Single dose of 50 IU/kg | Additional doses of 30 or 50 IU/kg every 2 to 3 days can be considered. |
For resumption of prophylaxis (if applicable) after treatment of a bleed, it is recommended to allow an interval of at least 72 hours between the last 50 IU/kg dose for treatment of a bleed and resuming prophylaxis dosing. Thereafter, prophylaxis can be continued as usual on the patient's regular schedule.
Perioperative Management
ALTUVIIIO dosing for perioperative management is provided in Table 2.
| Type of Surgery | Pre-operative Dose | Post-operative Dose |
|---|---|---|
| Minor For example: Tooth extraction | Single dose of 50 IU/kg | An additional dose of 30 or 50 IU/kg after 2 to 3 days may be considered. |
| Major For example: Intracranial, intra-abdominal, joint replacement surgery, or complicated dental procedures. | Single dose of 50 IU/kg | Additional doses of 30 or 50 IU/kg every 2 to 3 days may be administered as clinically needed for perioperative management. |
Administration Steps:
Immunogenicity
All subjects were monitored for neutralizing antibodies (inhibitors) to Factor VIII in the clinical program. No subjects developed neutralizing antibodies to Factor VIII [see Immunogenicity (12.6)].
Risk Summary
There are no data with ALTUVIIIO use in pregnant women to inform a drug-associated risk. Animal developmental and reproductive studies have not been conducted with ALTUVIIIO. Therefore, it is not known whether ALTUVIIIO can affect reproductive capacity or cause fetal harm when given to pregnant women.
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.
Risk Summary
There is no information regarding the presence of ALTUVIIIO in human milk, its effects on the breastfed infant, or its effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ALTUVIIIO and any potential adverse effects on the breastfed infant from ALTUVIIIO or from the underlying maternal condition.
Mechanism of Half-life Extension
ALTUVIIIO is a recombinant FVIII analogue fusion protein that is independent of endogenous VWF in order to overcome the half-life limit imposed by FVIII-VWF interactions. The D'D3 domain of VWF is the region that interacts with FVIII. Appending the D'D3 domain of VWF to a recombinant FVIII-Fc fusion protein provides protection and stability to FVIII, and prevents FVIII interaction with endogenous VWF, thus overcoming the limitation on FVIII half-life imposed by VWF clearance.
The Fc region of human immunoglobulin G1 (IgG1) binds to the neonatal Fc receptor (FcRn). FcRn is part of a naturally occurring pathway that delays lysosomal degradation of immunoglobulins by recycling them back into circulation, thus prolonging the plasma half-life of the fusion protein.
ALTUVIIIO contains 2 XTEN polypeptides, which alter the hydrodynamic radius of the fusion protein, thus reducing rates of clearance and degradation, and improving pharmacokinetic properties. In ALTUVIIIO, the natural FVIII B domain (except 5 amino acids) is replaced with the first XTEN, inserted in between FVIII N745 and E1649 amino acid residues; and the second XTEN is inserted in between the D'D3 domain and Fc.
Specific Populations
The following factors have no clinically meaningful effect on the pharmacokinetics of ALTUVIIIO: age (1.4 to 72 years), sex, race (White, Asian), VWF antigen activity (40 to 339 IU/dL), hematocrit level (28% to 57%), blood type, HCV status, or HIV status. Body weight (12.5 to 133 kg) is expected to alter weight normalized clearance (dL/h/kg) by 79% to -18% compared to a typical patient.
Routine Prophylaxis to Reduce Bleeding Episodes
Adult and Adolescent Study
The efficacy of weekly 50 IU/kg ALTUVIIIO as routine prophylaxis was evaluated as estimated by the mean annualized bleed rate (ABR) and by comparing the ABR during on-study prophylaxis vs. the ABR during pre-study FVIII prophylaxis. A total of 133 adults and adolescents, who were on pre-study FVIII prophylaxis, were assigned to receive ALTUVIIIO for routine prophylaxis at a dose of 50 IU/kg IV once weekly for 52 weeks (Arm A). An additional 26 subjects, who were on pre-study episodic (on-demand) treatment with FVIII, received episodic (on-demand) treatment with ALTUVIIIO at doses of 50 IU/kg IV for 26 weeks, followed by routine prophylaxis at a dose of 50 IU/kg IV once weekly for 26 weeks (Arm B). Overall, 115 subjects received at least a total number of 50 exposure days (EDs) in Arm A and 17 subjects completed at least 25 EDs of routine prophylaxis in Arm B.
The ABR in subjects evaluable for efficacy with at least 26 weeks of exposure are summarized in Table 6. Routine prophylaxis resulted in a mean ABR (95% CI) of 0.7 (0.5, 1.0), a median (Q1, Q3) ABR of 0 (0, 1.0), and a median (Q1, Q3) annualized joint bleeding rate of 0 (0, 1.0).
| Endpoint Reflects all bleeds reported by patients including those where no ALTUVIIIO was administered. | Arm A Prophylaxis Subjects assigned to receive ALTUVIIIO prophylaxis for 52 weeks. | Arm B On-demand Subjects assigned to receive ALTUVIIIO for 26 weeks. | Arm B Prophylaxis |
|---|---|---|---|
| ABR = annualized bleed rate; CI = confidence interval; Q1= 25th percentile, Q3=75th percentile. | |||
| N = 128 | N = 26 | N = 26 | |
| Treated bleeds | |||
| Mean ABR (95% CI) Based on negative binomial model. | 0.7 (0.5, 1.0) | 21.4 (18.8, 24.4) | 0.7 (0.3, 1.5) |
| Median ABR (Q1, Q3) | 0 (0, 1.0) | 21.1 (15.1, 27.1) | 0 (0, 0) |
| subjects with zero bleeds, n (%) | 82 (64.1) | 0 | 20 (76.9) |
| Treated spontaneous bleeds | |||
| Mean ABR (95% CI) | 0.3 (0.2, 0.4) | 15.8 (12.3, 20.4) | 0.4 (0.2, 1.2) |
| Median ABR (Q1, Q3) | 0 (0, 0) | 16.7 (8.6, 23.8) | 0 (0, 0) |
| % subjects with zero bleeds, n (%) | 103 (80.5) | 1 (3.8) | 22 (84.6) |
| Treated joint bleeds | |||
| Mean ABR (95% CI) | 0.5 (0.4, 0.7) | 17.5 (14.9, 20.5) | 0.6 (0.3, 1.5) |
| Median ABR (Q1, Q3) | 0 (0, 1.0) | 18.4 (10.8, 23.9) | 0 (0, 0) |
| % subjects with zero bleeds, n (%) | 92 (71.9) | 0 | 21 (80.8) |
| All Bleeds (treated and untreated) | |||
| Mean ABR (95% CI) | 1.1 (0.8, 1.5) | 22.2 (19.4, 25.4) | 0.9 (0.4, 1.8) |
| Median ABR (Q1, Q3) | 0 (0, 1.2) | 21.1 (16.8, 27.1) | 0 (0. 1.9) |
| % subjects with zero bleeds, n (%) | 71 (55.5) | 0 | 19 (73.1) |
An intra-subject comparison (N = 78) between mean ABR during on-study prophylaxis with ALTUVIIIO and that during pre-study FVIII prophylaxis yielded a 77% reduction in treated bleeds (95% CI: 58%, 87%).
All subjects with target joints at baseline (defined as ≥3 spontaneous bleeding episodes in a major joint which occurred in a consecutive 6-month period) achieved resolution of all target joints (45/45, 100%) with 12 months of prophylactic treatment with ALTUVIIIO (defined as ≤2 bleeding episodes in the target joint in 12 months).
Pediatric Study
The efficacy of weekly 50 IU/kg ALTUVIIIO as routine prophylaxis in children <12 years was evaluated as estimated by the mean annualized bleed rate (ABR). At the time of the interim analysis, a total of 67 children (31 children <6 years of age and 36 children 6 to <12 years of age) were enrolled to receive ALTUVIIIO for routine prophylaxis at a dose of 50 IU/kg IV once weekly for 52 weeks. In subjects with at least 26 weeks of exposure (N=23), routine prophylaxis resulted in a mean ABR (95% CI) of 0.5 (0.2, 1.3) and a median (Q1, Q3) ABR of 0 (0, 1.3) for treated bleeds. For all bleeds (treated and non treated), the mean ABR (95% CI) was 3.6 (1.6, 8.4) and the median (Q1, Q3) ABR was 0 (0, 4.5).
Efficacy in Control of Bleeding
In the adult and adolescent study, a total of 362 bleeding episodes were treated with ALTUVIIIO, most occurring during on-demand treatment in Arm B. Majority of bleeding episodes were localized in joints. Response to the first injection was assessed by subjects at least 8 hours after treatment. A 4-point rating scale of excellent, good, moderate, and no response was used to assess response. Bleeding was resolved with a single 50 IU/kg injection of ALTUVIIIO in 96.7% of bleeding episodes. The median (Q1; Q3) total dose to treat a bleeding episode was 50.9 IU/kg (50.0; 51.9). Control of bleeding episodes was similar across the treatment arms.
Perioperative Management of Bleeding
Perioperative hemostasis was assessed in 13 major surgeries in 12 subjects (11 adults and 1 child). Of the 13 major surgeries, 12 surgeries required a single pre-operative dose to maintain hemostasis during surgery; for 1 major surgery during routine prophylaxis no pre-operative loading dose was administered on the day of/or before surgery. The median dose per pre-operative injection was 49.96 IU/kg (range 12.7 – 61.9).
The clinical evaluation of hemostatic response during major surgery was assessed using a 4-point scale of excellent, good, moderate, or poor/none. The hemostatic effect of ALTUVIIIO was rated as "excellent" in 13 of 13 surgeries (100%). No surgery had an outcome rated as "poor/none" or "missing."
Types of major surgeries assessed include major orthopedic procedures such as joint arthroplasties (joint replacements of knee, hip, and elbow), joint revisions and ankle fusion. Other major surgeries included molar extractions and rhinoplasty/mentoplasty.
Perioperative hemostasis was assessed in 22 minor surgeries in 19 subjects (12 adults and 7 children). The hemostatic response was evaluated by the investigator/surgeon in 15 of these minor surgeries; an excellent response was reported in all (100%).
How Supplied
ALTUVIIIO is supplied in kits comprising a single-dose vial containing nominally, 250, 500, 750, 1000, 2000, 3000, or 4000 international units (IU) of Factor VIII potency, a prefilled syringe with 3 mL sterile water for injection, and a sterile vial adapter (reconstitution device). The actual amount of ALTUVIIIO in IU is stated on the label and carton of each vial.
Not made with natural rubber latex.
| Strength | Potency Color Code | Kit NDC Number |
|---|---|---|
| 250 IU | Yellow | 71104-978-01 |
| 500 IU | Red | 71104-979-01 |
| 750 IU | Garnet | 71104-980-01 |
| 1000 IU | Green | 71104-981-01 |
| 2000 IU | Royal Blue | 71104-982-01 |
| 3000 IU | Mist Grey | 71104-983-01 |
| 4000 IU | Orange | 71104-984-01 |
Not all pack sizes may be marketed.
Manufactured by:
Bioverativ Therapeutics Inc.
Waltham, MA 02451
A SANOFI COMPANY
US License Number 2078
©2023 Bioverativ Therapeutics Inc. All rights reserved.
For patent information: https://www.sanofi.us/en/products-and-resources/patents
ALTUVIIIO™ is a trademark of Bioverativ Therapeutics Inc.
For intravenous use after reconstitution only.
For the dose of 50 IU/kg, the expected in vivo peak increase in Factor VIII level expressed as IU/dL (or % of normal) is estimated using the following formula:
Estimated Increment of Factor VIII (IU/dL or % of normal) = 50 IU/kg × 2 (IU/dL per IU/kg)
To achieve a specific target Factor VIII activity level, use the following formula: Dosage (IU) = Body Weight (kg) × Desired Factor VIII Increase (IU/dL or % normal) × 0.5 (IU/kg per IU/dL).
Image (Altuviiio 01)
Image (Altuviiio 02)
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For intravenous use only.
ALTUVIIIO is available as a white to off-white lyophilized powder for reconstitution in single-dose vials containing nominally 250, 500, 750, 1000, 2000, 3000, or 4000 international units (IU) per vial.
ALTUVIIIO is contraindicated in patients who have had severe hypersensitivity reactions, including anaphylaxis, to the product or its excipients [see Description (11)].
Allergic-type hypersensitivity reactions, including anaphylaxis, may occur with ALTUVIIIO. Allergic-type hypersensitivity reactions were not reported in the clinical trials. Inform patients of signs of hypersensitivity reactions that may progress to anaphylaxis (including hives, shortness of breath, chest tightness, wheezing, hypotension and itching). Advise patients to discontinue use of ALTUVIIIO if hypersensitivity symptoms occur and contact a physician and/or seek immediate emergency care.
Formation of neutralizing antibodies (inhibitors) to Factor VIII are possible following administration of ALTUVIIIO. Neutralizing antibodies were not reported in the clinical trials. Monitor all patients for the development of Factor VIII inhibitors by appropriate clinical observations and laboratory tests. If the patient's plasma Factor VIII level fails to increase as expected or if bleeding is not controlled after ALTUVIIIO administration, the presence of an inhibitor (neutralizing antibodies) should be suspected, and appropriate testing performed [see Warnings and Precautions (5.3)].
If assessment of plasma Factor VIII activity is needed, it is recommended to use a validated one-stage clotting assay [see Dosage and Administration (2)]. The ALTUVIIIO Factor VIII activity level is overestimated by the chromogenic assay and a specific ellagic acid based aPTT reagent in one-stage clotting assay by approximately 2.5-fold. If these assays are used, divide the result by 2.5 to approximate the patient's ALTUVIIIO Factor VIII activity level. Use of a reference laboratory is recommended when a qualified one-stage clotting assay or chromogenic assay is not available locally.
Monitor for the development of Factor VIII inhibitors. If bleeding is not controlled with ALTUVIIIO and the expected factor VIII activity plasma levels are not attained, perform an assay to determine if Factor VIII inhibitors are present (use Bethesda Units to titer inhibitors).
The most common adverse reactions (>10% of subjects) reported in clinical trials were headache and arthralgia.
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 the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of ALTUVIIIO has been evaluated in 159 previously treated patients (PTPs) (134 adults and 25 adolescents) with severe Hemophilia A (<1% endogenous FVIII activity or a genetic mutation consistent with severe Hemophilia A) who received at least one dose of ALTUVIIIO for either routine prophylaxis, on-demand treatment of bleeding episodes or perioperative management. A total of 152 (96%) subjects achieved at least 25 exposure days and 115 (72%) subjects achieved at least 50 exposure days with a median of 53.0 (range 2–63) for both exposure days and injections per subject. Overall exposure was monitored for a total of 151.5 subject-years. Adverse drug reactions (ADRs) (summarized in Table 3) were reported in 57 (36%) of the 159 subjects treated with routine prophylaxis or on-demand therapy. There were no age-specific differences in ADRs observed between adolescent and adult subjects. In the study, no inhibitors were detected and no ADRs of anaphylaxis were reported.
| MedDRA System Organ Class | Adverse Drug Reactions | Number of Subjects n (%) (N = 159) |
|---|---|---|
| Nervous system disorders | Headache Includes preferred terms of headache (32 subjects) and migraine (1 subject). | 33 (21) |
| Musculoskeletal and connective tissue disorders | ||
| Arthralgia | 26 (16) | |
| Back pain | 9 (6) | |
In the ongoing pediatric study, the safety of ALTUVIIIO was evaluated in 67 male PTPs <12 years of age with severe hemophilia A who received at least one dose of ALTUVIIIO. At the time of the interim analysis, a total of 23 (34%) subjects achieved at least 25 exposure days with a median of 14.0 (range 1–46) for both exposure days and injections per subject.
Adverse drug reactions, headache, were reported in 1 (1%) of subjects. In the study, no inhibitors were detected and no ADRs of anaphylaxis were reported.
Thromboembolic events occurred in 1% (3/206) of subjects in the long term safety extension study; these three subjects had pre-existing risk factors.
Safety, efficacy, and pharmacokinetics (PK) have been evaluated in 92 previously treated, pediatric patients <18 years of age who received at least one dose of ALTUVIIIO as part of routine prophylaxis, treatment of bleeding episodes, or perioperative management. Adolescent subjects were enrolled in the adult and adolescent study and pediatric subjects <12 years of age were enrolled in an ongoing pediatric trial. Thirty-one subjects (33.7%) were <6 years of age, 36 (39.1%) subjects were 6 to <12 years of age, and 25 subjects (27.2%) were adolescents (12 to <18 years of age). Interim data from a pediatric study of the 67 subjects <12 years of age showed that no dosing adjustment was required [see Clinical Pharmacology (12)].
Clinical studies of ALTUVIIIO did not include sufficient numbers of subjects 65 years of age and older to determine whether or not they respond differently from younger subjects. However, clinical experience with other Factor VIII products has not identified differences between the elderly and younger patients.
ALTUVIIIO [antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl] is a sterile, non-pyrogenic, white to off-white lyophilized powder for reconstitution for intravenous injection. The product is supplied in single-dose vials containing nominal potencies of 250, 500, 750, 1000, 2000, 3000, or 4000 international units (IU). Each vial of ALTUVIIIO is labeled with the actual Factor VIII activity content in IU. The powder for injection is reconstituted with 3 mL sterile water for injection (sWFI) supplied in a sterile prefilled syringe. The reconstituted solution should be essentially free of particles. The final product contains the excipients: arginine hydrochloride (250 mM), calcium chloride dihydrate (5 mM), histidine (10 mM), polysorbate 80 (0.05% w/v), and sucrose (5% w/v).
The active ingredient in ALTUVIIIO is a fully recombinant fusion protein comprising a single chain B-domain deleted (BDD) analogue of human FVIII covalently fused to the Fc domain of human immunoglobulin G1 (IgG1), the FVIII-binding D'D3 domain of human von Willebrand factor (VWF), and 2 XTEN polypeptides. ALTUVIIIO contains 2829 amino acids with an apparent molecular weight of 312 kDa. ALTUVIIIO is synthesized as 2 polypeptide chains which are covalently linked by 2 Fc hinge disulfide bonds. The first FVIII-XTEN-Fc polypeptide chain contains the A1A2 domain of FVIII along with 5 amino acids from B-domain (1–745 amino acids) fused to the 288-XTEN polypeptide (in place of the natural FVIII B-domain), the A3C1C2 domain of FVIII (1649–2332), and the Fc domain of human IgG1. The second VWF-XTEN-a2-Fc polypeptide chain contains the D'D3 domain of VWF (1–477 amino acids) fused to the 144-XTEN polypeptide, a thrombin cleavable acidic region 2 sequence from FVIII and the Fc domain of human IgG1. The Fc domain includes the hinge, CH2, and CH3 domains of IgG1. The Fc, VWF, and XTEN portions of the molecule extend the half-life of ALTUVIIIO in plasma.
ALTUVIIIO is produced by recombinant DNA technology in a human embryonic kidney (HEK) cell line, which has been extensively characterized. ALTUVIIIO is manufactured without addition of human- or animal-derived components and purified by a combination of multiple chromatography steps, a detergent viral inactivation step, a nano filtration step for viral clearance, and ultrafiltration steps.
ALTUVIIIO [antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl] temporarily replaces the missing coagulation factor VIII needed for effective hemostasis. ALTUVIIIO has demonstrated 3- to 4-fold prolonged half-life relative to other standard and extended half-life FVIII products.
Hemophilia A is a bleeding disorder characterized by a deficiency of functional coagulation factor VIII (FVIII), which leads to a prolonged clotting time in the activated partial thromboplastin time (aPTT)-based one-stage clotting assay. Administration of ALTUVIIIO increases plasma levels of FVIII, temporarily correcting the coagulation defect in hemophilia A patients.
Based on FVIII pharmacokinetic/pharmacodynamic analyses, the risk of bleeding is negatively correlated with FVIII activity. Once weekly 50 IU/kg ALTUVIIIO provided factor VIII activity levels that were associated with a low bleed risk.
The PK of ALTUVIIIO were evaluated in prospective, open-label clinical studies, enrolling 159 adults and adolescents, and 67 children <12 years old, respectively, receiving weekly IV injection of 50 IU/kg. Among children <12 years old, 32 subjects had ALTUVIIIO single dose PK profiles available.
PK parameters following a single dose of ALTUVIIIO are presented in Table 4. The PK parameters were based on plasma FVIII activity measured by the aPTT-based one-stage clotting assay. After a single dose of 50 IU/kg, ALTUVIIIO exhibited high sustained FVIII activity with prolonged half-life across age cohorts. There was a trend of increasing area under the curve (AUC), and decreasing clearance, with increasing age in the pediatric cohorts. The PK profile at steady state (Week 26) was comparable with the PK profile obtained after the first dose.
| PK Parameters (mean SD) | Pediatric Study | Pediatric Study | Adult and Adolescent Study | Adult and Adolescent Study |
|---|---|---|---|---|
| 1 to <6 Years N = 14 | 6 to <12 Years N = 18 | 12 to <18 years N = 25 | Adults N = 134 | |
| AUC0–tau = area under the activity-time curve over the dosing interval, CL = clearance, MRT = mean residence time, SD = standard deviation, t1/2z = terminal half-life, Vss = volume of distribution at steady state. | ||||
| AUC (IU×h/dL) | 6710 (1190) | 7190 (1450) | 8350 (1550) | 9850 (2010) Calculation based on 128 profiles. |
| t1/2 (h) | 39.9 (5.71) | 42.4 (3.70) | 44.6 (4.99) | 48.2 (9.31) |
| CL (mL/h/kg) | 0.740 (0.128) | 0.681 (0.139) | 0.582 (0.115) | 0.493 (0.121) |
| Vss (mL/kg) | 38.0 (7.19) | 38.1 (6.80) | 34.9 (7.38) | 31.0 (7.32) |
| MRT (hr) | 51.9 (9.06) | 56.3 (5.10) | 60.0 (5.54) | 63.9 (10.2) |
ALTUVIIIO at steady state maintained normal to near normal (>40 IU/dL) FVIII activity for a mean (SD) of 4.1 (0.7) days with once weekly prophylaxis in adults. The FVIII activity over 10 IU/dL was maintained in 83.5% of adults and adolescent subjects throughout the study. In children <12 years ALTUVIIIO maintained normal to near normal (>40 IU/dL) FVIII activity for 2 to 3 days and >10 IU/dL FVIII activity for approximately 6 to 7 days. The majority of children <12 years maintained FVIII activity in mild hemophilia range (>5 IU/dL) 7 days after the dosing (see Table 5).
| PK Parameters Mean (SD) | Pediatric Study Steady state peak, trough and IR were computed using available measurements at week 4 and week 52/End of study PK sampling visit for pediatric and adult and adolescent studies, respectively. | Pediatric Study | Adult and Adolescent Study | Adult and Adolescent Study |
|---|---|---|---|---|
| 1 to <6 years N = 20 | 6 to <12 years N = 35 | 12 to <18 years N = 24 | Adults N = 124 | |
| Peak = 15 min post dose at steady state, IR = incremental recovery, Trough – predose FVIII activity value at steady state, SD = standard deviation. | ||||
| Peak (IU/dL) | 113 (26.2) | 121 (25.31) | 124 (31.2) | 150 (35.0) |
| IR (kg×IU/dL/IU) | 2.10 (0.53) | 2.17 (0.46) | 2.25 (0.61) | 2.64 (0.61) |
| Time to 40 IU/dL (h) Time to FVIII activity was predicted using population PK model. | 59.2 (7.68) | 72.2 (11.2) | 81.7 (13.1) | 97.0 (20.2) |
| Time to 20 IU/dL (h) | 99.3 (9.15) | 117 (13.9) | 130 (15.7) | 150 (27.7) |
| Time to 10 IU/dL (h) | 139 (11.7) | 163 (17.1) | 179 (21.4) | 200 (35.4) |
| Trough (IU/dL) | 6.75 (2.29) | 9.77 (3.64) | 9.23 (4.77) | 18.0 (16.6) |
The observed incidence of anti-drug antibodies (ADAs) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, or of other Factor VIII products.
All subjects were monitored for neutralizing antibodies (inhibitors) to Factor VIII in the clinical program. No subjects developed neutralizing antibodies to Factor VIII.
During treatment (up to 49.64 weeks) in the clinical studies, 4/277 (2.2%) of ALTUVIIIO patients developed anti-drug antibodies.
No impact of ADAs on the FVIII activity-time profiles and PK exposure parameters was observed.
No impact of ADAs with respect to bleeding episodes and in the pharmacodynamic response was noted.
No carcinogenicity or mutagenicity studies have been conducted with of ALTUVIIIO. No studies have been conducted to evaluate the effects of ALTUVIIIO on fertility.
The safety, efficacy, and pharmacokinetics of ALTUVIIIO were evaluated in two multicenter, prospective, open-label clinical studies (one study in adults and adolescents ≥12 years of age and one pediatric study in children <12 years of age) in previously treated patients (PTPs) with severe hemophilia A (<1% endogenous Factor VIII activity or a documented genetic mutation consistent with severe hemophilia A).
All studies evaluated the efficacy of routine prophylaxis with a weekly dose of 50 IU/kg and determined hemostatic efficacy in the treatment of bleeding episodes and during perioperative management in subjects undergoing major or minor surgical procedures.
The completed adult and adolescent study enrolled a total of 159 PTPs (158 male and 1 female subjects) with severe hemophilia A. Subjects were aged 12 to 72 years and included 25 adolescent subjects aged 12 to 17 years. All 159 enrolled subjects received at least one dose of ALTUVIIIO and were evaluable for efficacy. A total of 149 subjects (93.7%) completed the study.
The ongoing pediatric study enrolled 67 male PTPs <12 years of age with severe hemophilia A (31 subjects were 1 to 5 years of age and 36 were 6 to 11 years of age) at data cut-off. Of the 67 enrolled subjects, all received at least 1 dose of ALTUVIIIO.
Storage and Handling
Prior to reconstitution:
After Reconstitution:
Advise the patients to:
ALTUVIIIO™ (al too'vee oh)
[antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl]
for intravenous use after reconstitution only
Single-dose vial
Please read this Patient Information carefully before using ALTUVIIIO and each time you get a refill, as there may be new information. This Patient Information does not take the place of talking with your healthcare provider about your medical condition or your treatment.
What is the most important information I need to know about ALTUVIIIO?
Do not attempt to give yourself an injection unless you have been taught how by your healthcare provider or hemophilia center.
You must carefully follow your healthcare provider's instructions regarding the dose and schedule for injecting ALTUVIIIO so that your treatment will work best for you.
What is ALTUVIIIO?
ALTUVIIIO is an injectable medicine that is used to control and reduce the number of bleeding episodes in people with Hemophilia A (congenital Factor VIII deficiency).
Your healthcare provider may give you ALTUVIIIO when you have surgery.
Who should not use ALTUVIIIO?
You should not use ALTUVIIIO if you had an allergic reaction to it in the past.
What should I tell my healthcare provider before using ALTUVIIIO?
Talk to your healthcare provider about:
How should I use ALTUVIIIO?
You get ALTUVIIIO as an injection into your vein. Your healthcare provider will instruct you on how to do injections on your own, and may watch you give yourself the first dose of ALTUVIIIO.
Contact your healthcare provider right away if bleeding is not controlled after using ALTUVIIIO.
What are the possible side effects of ALTUVIIIO?
You can have an allergic reaction to ALTUVIIIO. Call your healthcare provider or emergency department right away if you have any of the following symptoms: difficulty breathing, chest tightness, swelling of the face, rash or hives.
Your body can also make antibodies called "inhibitors" against ALTUVIIIO. This can stop ALTUVIIIO from working properly. Your healthcare provider may give you blood tests to check for inhibitors.
The common side effects of ALTUVIIIO are headache, joint pain, and back pain.
These are not the only possible side effects of ALTUVIIIO. Tell your healthcare provider about any side effect that bothers you or does not go away.
What are the ALTUVIIIO dosage strengths?
ALTUVIIIO comes in seven different dosage strengths with 3 mL sterile water for injection (sWFI). The actual number of international units (IU) of Factor VIII activity in the vial will be imprinted on the label and on the box. The seven different strengths are as follows:
| Strength | Cap Color |
|---|---|
| 250 IU | Yellow |
| 500 IU | Red |
| 750 IU | Garnet |
| 1000 IU | Green |
| 2000 IU | Royal Blue |
| 3000 IU | Mist Grey |
| 4000 IU | Orange |
Always check the actual dosage strength printed on the label to make sure you are using the strength prescribed by your healthcare provider.
How should I store ALTUVIIIO?
After mixing with the diluent:
What else should I know about ALTUVIIIO?
Medicines are sometimes prescribed for purposes other than those listed here. Do not use ALTUVIIIO for a condition for which it was not prescribed. Do not share ALTUVIIIO with other people, even if they have the same symptoms that you have.
Manufactured by:
Bioverativ Therapeutics Inc.
Waltham, MA 02451
A SANOFI COMPANY
US License Number 2078
©2023 Bioverativ Therapeutics Inc. All rights reserved.
ALTUVIIIO™ is a trademark of Bioverativ Therapeutics Inc.
| INSTRUCTIONS FOR USE ALTUVIIIO™ (al too'vee oh) [antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl] for intravenous use after reconstitution only Single-dose vial | |
| Read the Instructions for Use before you start using ALTUVIIIO and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. Your healthcare provider should show you or your caregiver how to mix (reconstitute) and give ALTUVIIIO the first time ALTUVIIIO is used. Any further questions? Ask your healthcare provider or call 1-800-633-1610. | |
| Important Information You Need to Know Before Injecting ALTUVIIIO It is important that you do not try to inject ALTUVIIIO unless you have received training from a healthcare provider.
| |
Storing ALTUVIIIO
Storing of Mixed (Reconstituted ALTUVIIIO) | |
| Preparing to Inject ALTUVIIIO Mixing (Reconstitution) | |
| Step 1: | |
 Image (Altuviiio 05) | Look at the ALTUVIIIO kit:
 Image (Altuviiio 06) |
| Step 2: | |
 Image (Altuviiio 07)  Image (Altuviiio 08) | Wash your hands with soap and water. Find a clean, flat work surface. Remove the supplies from the carton:
Also ensure you have the following supplies (not included in the carton):  Image (Altuviiio 09) |
| Step 3: | |
 Image (Altuviiio 10) | Allow the ALTUVIIIO vial and the prefilled diluent syringe to come to room temperature before use.  Image (Altuviiio 11)  Image (Altuviiio 12)  Image (Altuviiio 13) |
| Step 4: | |
 Image (Altuviiio 14) | Remove the plastic cap from the ALTUVIIIO vial. Wipe the rubber stopper of the vial with an alcohol wipe and allow it to dry.  Image (Altuviiio 15) |
| Step 5: | |
 Image (Altuviiio 16) | Completely remove the backing from the vial adapter package by peeling back the lid.  Image (Altuviiio 17) |
| Step 6: | |
 Image (Altuviiio 18) | Keep the vial on a flat surface. Hold the vial with one hand and using the other hand, place the vial adapter in its package over the vial. Note: The spike should be placed directly above the center of the rubber stopper.
|
| Step 7: | |
 Image (Altuviiio 19) | Lift the package cover away from the vial adapter and throw away the cover. |
| Step 8: | |
 Image (Altuviiio 20) | Note: Only use the prefilled diluent syringe provided to mix (reconstitute) the powdered medicine.
|
| Step 9: | |
 Image (Altuviiio 21) | With one hand, hold the prefilled diluent syringe directly under the cap with the cap pointing up. Note: Make sure you are holding the prefilled diluent syringe by the ridged part directly under the cap.  Image (Altuviiio 22) |
| Step 10: | |
 Image (Altuviiio 23) | With your other hand, grasp the cap and bend it at a 90-degree angle until it snaps off. Note: After the cap snaps off, you will see the glass tip of the prefilled diluent syringe.  Image (Altuviiio 24) |
| Step 11: | |
 Image (Altuviiio 25) | Note: Be sure the vial is sitting on a flat surface.
|
| Step 12: | |
 Image (Altuviiio 26) | Slowly push down on the plunger rod to inject all of the liquid (diluent) from the prefilled diluent syringe into the vial. Note: The plunger rod may rise slightly afterward. This is normal. |
Step 13: | |
 Image (Altuviiio 27) | With the prefilled diluent syringe still connected to the adapter, gently swirl the vial until the powder is completely dissolved. Check the solution through the vial to make sure the powder is fully dissolved. Note: The solution should look clear and colorless to slightly yellowish.  Image (Altuviiio 28)  Image (Altuviiio 29) POOLING: pooling is the process of combining two or more reconstituted vials into a larger luer lock syringe (not provided in the carton). If the dose requires more than one vial, reconstitute each vial as described above (See Steps 4–13) with the prefilled diluent syringe provided. Do not detach the prefilled diluent syringe until you are ready to attach the large luer lock syringe to the next vial. Keep the vial adapter attached to the vial as you will need it for attaching a large luer lock syringe. Use a larger luer lock plastic syringe to combine the contents of the reconstituted vials into the syringe, similar as described in the Steps 14–15. Repeat this pooling procedure with each vial you will be using. Once you have pooled the required dose, proceed with Step 16 (Injecting ALTUVIIIO) using the larger luer lock syringe. |
| Step 14: | |
 Image (Altuviiio 30) | Make sure the plunger rod is pressed all the way down and the syringe is firmly attached to the vial adapter. Turn the vial upside-down. Slowly pull down on the plunger rod to draw all the solution from the vial into the syringe. Note: Be careful not to pull the plunger rod completely out of the syringe. |
| Step 15: | |
 Image (Altuviiio 31) | Gently unscrew the syringe from the vial adapter by turning it to the right. Throw away (dispose of) the vial with the adapter still attached (See Step 23). If you are not ready to inject, put the syringe cap carefully back onto the syringe tip.  Image (Altuviiio 32) Note: Mixed (reconstituted) ALTUVIIIO should be given within 3 hours after mixing. Protect from direct sunlight. Do not refrigerate after reconstitution |
| Injecting ALTUVIIIO | |
| ALTUVIIIO is given in the vein (intravenous injection) after mixing (reconstitution) of the powdered medicine with the diluent. These are very generic instructions so your healthcare provider should teach you how to inject ALTUVIIIO. After you have been taught to self-inject, you can follow these instructions.  Image (Altuviiio 33) | |
| Step 16: | |
 Image (Altuviiio 34) | Using aseptic technique (clean and germ free), attach the syringe to the connector end of the infusion set tubing by turning it to the right until securely attached. Image (Altuviiio 35) Note: Ask your healthcare provider which infusion set can be used with ALTUVIIIO. |
| Step 17: | |
 Image (Altuviiio 36) | Apply a tourniquet to the upper arm. Then, using a new alcohol wipe, clean the skin where you will insert the needle and wait for it to dry. |
| Step 18: | |
 Image (Altuviiio 37) | Prime the syringe and the tubing. Push the plunger rod until all air is removed from the syringe and ALTUVIIIO has filled the infusion set needle. Image (Altuviiio 38) |
| Step 19: | |
 Image (Altuviiio 39) | Remove the protective needle cover from the infusion set needle and throw away (discard it). Image (Altuviiio 40)
|
Step 20: | |
 Image (Altuviiio 41) | Use tape to secure the plastic wings of the needle in place at the injection site if needed. Remove the tourniquet. Note: Always make sure you have correctly inserted the needle into a vein when you perform an intravenous injection. |
| Step 21: | |
 Image (Altuviiio 42) | Slowly push the plunger rod on the syringe all the way down to give ALTUVIIIO. Your healthcare provider will provide your rate of administration based on your comfort level and the minimum injection time recommendation per vial. Note: A small amount of medicine will be left in the infusion set after injection. This is normal. |
Step 22: | |
 Image (Altuviiio 43) | After delivering ALTUVIIIO, remove the tape and the needle from the vein. Use a cotton ball or gauze pad to put pressure on the injection site for several minutes to stop any bleeding. Note: You may apply an adhesive bandage if needed. |
Step 23: | |
 Image (Altuviiio 44) | Put the infusion set and the syringe in FDA-cleared sharps disposal container right away after use. Dispose of all unused solution according to your local regulations. Dispose of all empty vial(s), and other used medical supplies in your household trash.  Image (Altuviiio 45) |
| Disposing of ALTUVIIIO Throw away (dispose of) the infusion set and the syringe in FDA-cleared sharps disposal container right away after use. If you do not have FDA-cleared sharps disposal container you may use a household container that is:
When your FDA-cleared sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of FDA-cleared sharps disposal container. There may be state or local laws about how you should throw away used ALTUVIIIO supplies.  Image (Altuviiio 46)  Image (Altuviiio 47) Keep your FDA-cleared sharps disposal container out of the reach of children. | |
Manufactured by:
Bioverativ Therapeutics Inc.
Waltham, MA 02451
A SANOFI COMPANY
US License Number 2078
©2023 Bioverativ Therapeutics Inc. All rights reserved.
For more information go to www.ALTUVIIIO.com or call 1-800-633-1610
Initial approval: February 2023
250 IU Nominal
NDC 71104-978-01
ALTUVIIIO™
[Antihemophilic Factor (Recombinant),
Fc-VWF-XTEN Fusion Protein-ehtl]
For Intravenous Use
This package contains:
Rx Only
Manufactured by:
Bioverativ Therapeutics Inc.
Waltham, MA 02451
A SANOFI COMPANY
US License Number 2078
www.ALTUVIIIO.com
1-800-633-1610
Diluent origin Germany
Plunger Rod origin France
Vial Adapter origin Israel
sanofi
Principal Display Panel (250 IU Kit Carton)
500 IU Nominal
NDC 71104-979-01
ALTUVIIIO™
[Antihemophilic Factor (Recombinant),
Fc-VWF-XTEN Fusion Protein-ehtl]
For Intravenous Use
This package contains:
Rx Only
Manufactured by:
Bioverativ Therapeutics Inc.
Waltham, MA 02451
A SANOFI COMPANY
US License Number 2078
www.ALTUVIIIO.com
1-800-633-1610
Diluent origin Germany
Plunger Rod origin France
Vial Adapter origin Israel
sanofi
Principal Display Panel (500 IU Kit Carton)
1000 IU Nominal
NDC 71104-981-01
ALTUVIIIO™
[Antihemophilic Factor (Recombinant),
Fc-VWF-XTEN Fusion Protein-ehtl]
For Intravenous Use
This package contains:
Rx Only
Manufactured by:
Bioverativ Therapeutics Inc.
Waltham, MA 02451
A SANOFI COMPANY
US License Number 2078
www.ALTUVIIIO.com
1-800-633-1610
Diluent origin Germany
Plunger Rod origin France
Vial Adapter origin Israel
sanofi
Principal Display Panel (1000 IU Kit Carton)
2000 IU Nominal
NDC 71104-982-01
ALTUVIIIO™
[Antihemophilic Factor (Recombinant),
Fc-VWF-XTEN Fusion Protein-ehtl]
For Intravenous Use
This package contains:
Rx Only
Manufactured by:
Bioverativ Therapeutics Inc.
Waltham, MA 02451
A SANOFI COMPANY
US License Number 2078
www.ALTUVIIIO.com
1-800-633-1610
Diluent origin Germany
Plunger Rod origin France
Vial Adapter origin Israel
sanofi
Principal Display Panel (2000 IU Kit Carton)
3000 IU Nominal
NDC 71104-983-01
ALTUVIIIO™
[Antihemophilic Factor (Recombinant),
Fc-VWF-XTEN Fusion Protein-ehtl]
For Intravenous Use
This package contains:
Rx Only
Manufactured by:
Bioverativ Therapeutics Inc.
Waltham, MA 02451
A SANOFI COMPANY
US License Number 2078
www.ALTUVIIIO.com
1-800-633-1610
Diluent origin Germany
Plunger Rod origin France
Vial Adapter origin Israel
sanofi
Principal Display Panel (3000 IU Kit Carton)
4000 IU Nominal
NDC 71104-984-01
ALTUVIIIO™
[Antihemophilic Factor (Recombinant),
Fc-VWF-XTEN Fusion Protein-ehtl]
For Intravenous Use
This package contains:
Rx Only
Manufactured by:
Bioverativ Therapeutics Inc.
Waltham, MA 02451
A SANOFI COMPANY
US License Number 2078
www.ALTUVIIIO.com
1-800-633-1610
Diluent origin Germany
Plunger Rod origin France
Vial Adapter origin Israel
sanofi
Principal Display Panel (4000 IU Kit Carton)
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