ALTUVIIIO Dailymed

8use In Specific Populations

Pediatric Use: No dosing adjustment is needed in this population. (8.4)

8.1 Pregnancy

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.

8.2Lactation

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.

8.4Pediatric Use

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)].

8.5 Geriatric Use

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.

11description

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.

12clinical Pharmacology

12.1Mechanism of Action

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.

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.

12.2Pharmacodynamics

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.

12.3Pharmacokinetics

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.

Table 4: Pharmacokinetic Parameters Following a Single Dose of ALTUVIIIO by age (one-stage clotting assay)

PK Parameters(mean SD)	Pediatric Study	Pediatric Study	Adult and Adolescent Study	Adult and Adolescent Study
	1 to <6 YearsN = 14	6 to <12 YearsN = 18	12 to <18 yearsN = 25	AdultsN = 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).

Table 5: Pharmacokinetic Parameters at Steady State of ALTUVIIIO by age (one-stage clotting assay)

PK ParametersMean (SD)	Pediatric StudySteady 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 yearsN = 20	6 to <12 yearsN = 35	12 to <18 yearsN = 24	AdultsN = 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)

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.

12.6Immunogenicity

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.

13 Nonclinical Toxicology

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or mutagenicity studies have been conducted with of ALTUVIIIO. No studies have been conducted to evaluate the effects of ALTUVIIIO on fertility.

14clinical Studies

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.

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).

Table 6: Summary of Annualized Bleeding Rate (ABR) with ALTUVIIIO Prophylaxis, ALTUVIIIO On-demand Treatment, and After Switch to ALTUVIIIO Prophylaxis in Patients ≥12 Years of Age

EndpointReflects all bleeds reported by patients including those where no ALTUVIIIO was administered.	Arm AProphylaxisSubjects assigned to receive ALTUVIIIO prophylaxis for 52 weeks.	Arm BOn-demandSubjects assigned to receive ALTUVIIIO for 26 weeks.	Arm BProphylaxis
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%).

16how Supplied/storage And Handling

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.

STORAGE AND HANDLING SECTION

Storage and Handling

Prior to reconstitution:

• Store ALTUVIIIO in the original package to protect the ALTUVIIIO vials from light.
• Store ALTUVIIIO in powder form at 2°C to 8°C (36°F to 46°F). Do not freeze to avoid damage to the prefilled diluent syringe.
• ALTUVIIIO may be stored at room temperature, not to exceed 30°C (86°F), for a single period of up to 6 months, within the expiration date printed on the label.
• If stored at room temperature, record the date that ALTUVIIIO is removed from refrigeration on the carton in the area provided. After storage at room temperature, do not return the product to the refrigerator.
• Do not use beyond the expiration date printed on the vial or 6 months after the date that was written on the carton, whichever is earlier.

After Reconstitution:

• The reconstituted product may be stored at room temperature, not to exceed 30°C (86°F), for up to 3 hours. Protect from direct sunlight. After reconstitution, if the product is not used within 3 hours, it must be discarded.
• Do not use ALTUVIIIO if the reconstituted solution is cloudy or has particulate matter.
• Discard any unused ALTUVIIIO.

17patient Counseling Information

Advise the patients to:

• Read the FDA-approved patient labeling (Patient Information and Instructions for Use).
• Call their healthcare provider or go to the emergency department right away if a hypersensitivity reaction occurs. Early signs of hypersensitivity reactions may include rash, hives, itching, facial swelling, tightness of the chest, and wheezing.
• Contact their healthcare provider or treatment facility for further treatment and/or assessment if they experience a lack of a clinical response to Factor VIII therapy because this may be a sign of inhibitor development.

Manufactured by:Bioverativ Therapeutics Inc.Waltham, MA 02451A SANOFI COMPANYUS License Number 2078

©2023 Bioverativ Therapeutics Inc. All rights reserved.

For patent information: https://www.sanofi.us/en/products-and-resources/patents

ALTUVIIIOâ„¢ is a trademark of Bioverativ Therapeutics Inc.

Patient Information

ALTUVIIIOâ„¢ (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:

• Any medical problems that you have or had.
• All prescription and non-prescription medicines that you take, including over-the-counter medicines, supplements or herbal medicines.
• Pregnancy or if you are planning to become pregnant. It is not known if ALTUVIIIO may harm your unborn baby.
• Breastfeeding. It is not known if ALTUVIIIO passes into the milk and if it can harm your baby.

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?

• Keep ALTUVIIIO in its original package.
• Protect it from light.
• Do not freeze.
• Store refrigerated 2°C to 8°C (36°F to 46°F) up to 48 months or at room temperature [not to exceed 30°C (86°F)], for a single period up to 6 months. Do not use ALTUVIIIO after the expiration date printed on the label and carton of each vial.
• When storing at room temperature:
  • – Note on the carton the date on which the product is removed from refrigeration.
  • – Use the product before the end of this 6-month period or discard it.
  • – Do not return the product to the refrigerator.

After mixing with the diluent:

• Do not use ALTUVIIIO if the mixed solution is not clear and colorless to slightly yellowish.
• Use mixed product as soon as possible.
• You may store mixed ALTUVIIIO at room temperature, not to exceed 30°C (86°F), for up to 3 hours. Protect the mixed ALTUVIIIO from direct sunlight. Discard any mixed ALTUVIIIO not used within 3 hours.

What else should I know about ALTUVIIIO?

Medicines are sometimes prescribed for purposes other than those uled 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.

This Patient Information has been approved by the US Food and Drug Administration.

Manufactured by:Bioverativ Therapeutics Inc.Waltham, MA 02451A SANOFI COMPANYUS License Number 2078

©2023 Bioverativ Therapeutics Inc. All rights reserved.

ALTUVIIIOâ„¢ is a trademark of Bioverativ Therapeutics Inc.

Revised: March 2023

Instructions For Use Section

made of a heavy-duty plastic,

can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,

upright and stable during use,

leak-resistant, and

properly labeled to warn of hazardous waste inside the container. 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.
Do not dispose of your used FDA-cleared sharps disposal container in your household trash unless your community guidelines permit this.

Do not recycle your used FDA-cleared sharps disposal container.
Keep your FDA-cleared sharps disposal container out of the reach of children.

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INSTRUCTIONS FOR USEALTUVIIIOâ„¢ (al too'vee oh)[antihemophilic factor (recombinant), Fc-VWF-XTEN fusion protein-ehtl]for intravenous use after reconstitution onlySingle-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 ALTUVIIIOIt is important that you do not try to inject ALTUVIIIO unless you have received training from a healthcare provider. Read all of the instructions carefully before using the ALTUVIIIO. ALTUVIIIO is supplied as a single-dose vial of powder for mixing (reconstitution). Before you inject ALTUVIIIO, you must mix (reconstitute) ALTUVIIIO powder with liquid (diluent) that comes in a prefilled diluent syringe. After the powder and diluent are mixed the medicine is given in the vein (intravenous injection). The vial and the diluent syringe are not made with natural rubber latex. Do not use ALTUVIIIO if it has been dropped on a hard surface or damaged. Do not use if the syringe cap has been removed or is not securely attached. Do not use the mixed ALTUVIIIO if it contains visible particles or is cloudy. Do not give mixed ALTUVIIIO in the same tubing or container with other medicines.
Storing ALTUVIIIO Keep unused ALTUVIIIO kit in the original carton and store in the refrigerator between 2ºC and 8ºC (36ºF and 46ºF). The product may be stored at room temperature up to 30ºC (86ºF). If stored at room temperature, the product (prior to mixing) expires after 6 months or after the expiration date on the product vial, whichever is earlier. Remove the product kit from the refrigerator and allow the ALTUVIIIO vial and the prefilled diluent syringe to come to room temperature prior to injection. Do not use external heat sources such as putting the vial or prefilled diluent syringe in hot water. Do not return room temperature ALTUVIIIO to refrigerator. Keep away from direct sunlight. Do not freeze. Storing of Mixed (Reconstituted) ALTUVIIIO ALTUVIIIO should be given within 3 hours after mixing. Keep away from direct sunlight. Do not refrigerate after mixing. Keep ALTUVIIIO and all medicines out of the reach of children.
Preparing to Inject ALTUVIIIOMixing (Reconstitution)
Step 1:
	Look at the ALTUVIIIO kit: Check that you have the correct medicine and dose. Check the expiration date. Do not use ALTUVIIIO if the expiration date has passed.
Step 2:
	Wash your hands with soap and water.Find a clean, flat work surface. Remove the supplies from the carton: Vial adapter in its package Vial with powdered medicine Plunger rod Prefilled diluent syringe Also ensure you have the following supplies (not included in the carton): Infusion set Tourniquet 2 alcohol wipes 1 cotton ball or gauze pad 1 adhesive bandage, if required (See Step 22) 1 tape, if required (See Step 20) 1 larger luer lock syringe, if required (See Step 13) FDA-cleared sharps disposal container (See Step 23) Do not use ALTUVIIIO (vial or prefilled diluent syringe) if it has been dropped on a hard surface or damaged.
Step 3:
	Allow the ALTUVIIIO vial and the prefilled diluent syringe to come to room temperature before use. Do not use external heat sources such as putting the vial or prefilled diluent syringe in hot water. Do not put ALTUVIIIO in direct sunlight. Do not return room temperature ALTUVIIIO to the refrigerator.
Step 4:
	Remove the plastic cap from the ALTUVIIIO vial.Wipe the rubber stopper of the vial with an alcohol wipe and allow it to dry. After cleaning, do not touch the rubber stopper with your hand or allow it to touch any surface.
Step 5:
	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 vial adapter.
Step 6:
	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. Push the vial adapter straight down until the spike on the vial adapter punctures the center of the vial stopper and is fully inserted.
Step 7:
	Lift the package cover away from the vial adapter and throw away the cover.
Step 8:
	Note: Only use the prefilled diluent syringe provided to mix (reconstitute) the powdered medicine. Hold the plunger rod by the circular disk. Place the tip of the plunger rod into the end of the prefilled diluent syringe. Turn the plunger rod to the right until it is firmly attached.
Step 9:
	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. Do not use if the cap has been removed or is not securely attached.
Step 10:
	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. Do not touch the glass tip of the prefilled diluent syringe or the inside of the cap.
Step 11:
	Note: Be sure the vial is sitting on a flat surface. Insert the tip of the prefilled diluent syringe into the vial adapter opening. Turn the prefilled diluent syringe to the right until it is securely attached to the vial adapter.
Step 12:
	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:
	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. Do not shake. Do not use the mixed (reconstituted) ALTUVIIIO if it contains visible particles or is cloudy.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 larger luer lock syringe to the next vial. Keep the vial adapter attached to the vial as you will need it for attaching a larger 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:
	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:
	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. Do not touch the syringe tip or the inside of the cap. 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. Do not give mixed (reconstituted) ALTUVIIIO if it contains particles, is discolored, or is cloudy.
Step 16:
	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. Do not give mixed (reconstituted) ALTUVIIIO in the same tubing or container with other medicines. Note: Ask your healthcare provider which infusion set can be used with ALTUVIIIO.
Step 17:
	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:
	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. Do not push ALTUVIIIO through the needle.
Step 19:
	Remove the protective needle cover from the infusion set needle and throw away (discard it). Do not touch the needle and do not put the needle cover back onto needle after use. Insert the needle on the infusion set tubing into the vein as instructed by your healthcare provider.
Step 20:
	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:
	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:
	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:
	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. Do not throw away (dispose of) the infusion set or syringe in your household trash.
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:

This Instructions for Use has been approved by the US Food and Drug Administration.

Manufactured by:Bioverativ Therapeutics Inc.Waltham, MA 02451A SANOFI COMPANYUS License Number 2078

©2023 Bioverativ Therapeutics Inc. All rights reserved.

For more information go to www.ALTUVIIIO.com or call 1-800-633-1610

Revised: March 2023

Principal Display Panel - 250 Iu Kit Carton

250 IU Nominal

NDC 71104-978-01

ALTUVIIIOâ„¢[Antihemophilic Factor (Recombinant),Fc-VWF-XTEN Fusion Protein-ehtl]

For Intravenous Use

This package contains:

• (1) Single-dose vial containing lyophilized powder for reconstitution forintravenous injection
• (1) Prefilled diluent syringe containing 3 mL sterile water for injection (sWFI) withplunger rod
• (1) Sterile vial adapter reconstitution device
• (1) Package Insert

Rx Only

Manufactured by:Bioverativ Therapeutics Inc.Waltham, MA 02451

A SANOFI COMPANYUS License Number 2078

www.ALTUVIIIO.com1-800-633-1610

Diluent origin GermanyPlunger Rod origin FranceVial Adapter origin Israel

sanofi

Principal Display Panel - 500 Iu Kit Carton

500 IU Nominal

NDC 71104-979-01

ALTUVIIIOâ„¢[Antihemophilic Factor (Recombinant),Fc-VWF-XTEN Fusion Protein-ehtl]

For Intravenous Use

This package contains:

• (1) Single-dose vial containing lyophilized powder for reconstitution forintravenous injection
• (1) Prefilled diluent syringe containing 3 mL sterile water for injection (sWFI) withplunger rod
• (1) Sterile vial adapter reconstitution device
• (1) Package Insert

Rx Only

Manufactured by:Bioverativ Therapeutics Inc.Waltham, MA 02451

A SANOFI COMPANYUS License Number 2078

www.ALTUVIIIO.com1-800-633-1610

Diluent origin GermanyPlunger Rod origin FranceVial Adapter origin Israel

sanofi

Principal Display Panel - 1000 Iu Kit Carton

1000 IU Nominal

NDC 71104-981-01

ALTUVIIIOâ„¢[Antihemophilic Factor (Recombinant),Fc-VWF-XTEN Fusion Protein-ehtl]

For Intravenous Use

This package contains:

• (1) Single-dose vial containing lyophilized powder for reconstitution forintravenous injection
• (1) Prefilled diluent syringe containing 3 mL sterile water for injection (sWFI) withplunger rod
• (1) Sterile vial adapter reconstitution device
• (1) Package Insert

Rx Only

Manufactured by:Bioverativ Therapeutics Inc.Waltham, MA 02451

A SANOFI COMPANYUS License Number 2078

www.ALTUVIIIO.com1-800-633-1610

Diluent origin GermanyPlunger Rod origin FranceVial Adapter origin Israel

sanofi

Principal Display Panel - 2000 Iu Kit Carton

2000 IU Nominal

NDC 71104-982-01

ALTUVIIIOâ„¢[Antihemophilic Factor (Recombinant),Fc-VWF-XTEN Fusion Protein-ehtl]

For Intravenous Use

This package contains:

• (1) Single-dose vial containing lyophilized powder for reconstitution forintravenous injection
• (1) Prefilled diluent syringe containing 3 mL sterile water for injection (sWFI) withplunger rod
• (1) Sterile vial adapter reconstitution device
• (1) Package Insert

Rx Only

Manufactured by:Bioverativ Therapeutics Inc.Waltham, MA 02451

A SANOFI COMPANYUS License Number 2078

www.ALTUVIIIO.com1-800-633-1610

Diluent origin GermanyPlunger Rod origin FranceVial Adapter origin Israel

sanofi

Principal Display Panel - 3000 Iu Kit Carton

3000 IU Nominal

NDC 71104-983-01

ALTUVIIIOâ„¢[Antihemophilic Factor (Recombinant),Fc-VWF-XTEN Fusion Protein-ehtl]

For Intravenous Use

This package contains:

• (1) Single-dose vial containing lyophilized powder for reconstitution forintravenous injection
• (1) Prefilled diluent syringe containing 3 mL sterile water for injection (sWFI) withplunger rod
• (1) Sterile vial adapter reconstitution device
• (1) Package Insert

Rx Only

Manufactured by:Bioverativ Therapeutics Inc.Waltham, MA 02451

A SANOFI COMPANYUS License Number 2078

www.ALTUVIIIO.com1-800-633-1610

Diluent origin GermanyPlunger Rod origin FranceVial Adapter origin Israel

sanofi

Principal Display Panel - 4000 Iu Kit Carton

4000 IU Nominal

NDC 71104-984-01

ALTUVIIIOâ„¢[Antihemophilic Factor (Recombinant),Fc-VWF-XTEN Fusion Protein-ehtl]

For Intravenous Use

This package contains:

• (1) Single-dose vial containing lyophilized powder for reconstitution forintravenous injection
• (1) Prefilled diluent syringe containing 3 mL sterile water for injection (sWFI) withplunger rod
• (1) Sterile vial adapter reconstitution device
• (1) Package Insert

Rx Only

Manufactured by:Bioverativ Therapeutics Inc.Waltham, MA 02451

A SANOFI COMPANYUS License Number 2078

www.ALTUVIIIO.com1-800-633-1610

Diluent origin GermanyPlunger Rod origin FranceVial Adapter origin Israel

sanofi