Altuviiio Drug Information
Generic name: ANTIHEMOPHILIC FACTOR (RECOMBINANT), FC-VWF-XTEN FUSION PROTEIN-EHTL
Uses of Altuviiio
ALTUVIIIO is indicated for use in adults and pediatric patients with hemophilia A (congenital factor VIII deficiency) for: Routine prophylaxis to reduce the frequency of bleeding episodes On-demand treatment and control of bleeding episodes Perioperative management of bleeding ALTUVIIIO is a recombinant DNA-derived, Factor VIII concentrate indicated for use in adults and children with hemophilia A (congenital factor VIII deficiency) for: Routine prophylaxis to reduce the frequency of bleeding episodes On-demand treatment & control of bleeding episodes Perioperative management of bleeding Limitation of Use: ALTUVIIIO is not indicated for the treatment of von Willebrand disease.
Dosage & Administration of Altuviiio
Dose Each
ALTUVIIIO vial label states the Factor VIII potency in international units (IU). One IU corresponds to the Factor VIII activity contained in one milliliter of normal human plasma, as defined by the current World Health Organization (WHO) international standard for Factor VIII concentrate. Potency assignment for ALTUVIIIO is determined using an activated partial thromboplastin time (aPTT)-based one-stage clotting assay.
It is recommended to use a validated one-stage clotting assay to measure ALTUVIIIO Factor VIII activity in plasma. 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. 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).
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. Table 1: Dosing for On-demand Treatment and Control of Bleeding Episodes 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. Table 2: Dosing for Perioperative Management
Preparation and Reconstitution
Use aseptic technique and a flat work surface during the reconstitution procedure. Allow the ALTUVIIIO vial, containing the white to off-white lyophilized powder, and the prefilled diluent syringe to reach room temperature before use. Remove the plastic cap from the ALTUVIIIO 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.
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. 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. Lift the package cover away from the vial adapter and throw away the cover. Only use the prefilled diluent syringe provided to 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.
With one hand, hold the prefilled diluent syringe directly under the cap with the cap pointing up. 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.
With your other hand, grasp the cap and bend it at a 90 degree angle until it snaps off. 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.
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.
Slowly push down on the plunger rod to inject all of the liquid (diluent) from the prefilled diluent syringe into the vial. The plunger rod may rise slightly afterward. This is normal.
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. The solution should look clear and colorless to opalescent.
Do not shake. Do not use the 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 3–12) 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 Steps 13–14. Repeat this pooling procedure with each vial you will be using. Once you have pooled the required dose, proceed with the administration steps using the larger luer lock syringe.
Make sure the plunger rod is pressed all the way down and the diluent 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 diluent syringe.
Be careful not to pull the plunger rod completely out of the diluent syringe. Gently unscrew the diluent syringe from the vial adapter by turning it to the right. Dispose of the vial with the adapter still attached.
If you are not ready to inject, put the syringe cap carefully back onto the syringe tip. Use the reconstituted ALTUVIIIO as soon as possible, but no later than 3 hours after reconstitution. Do not touch the glass tip of the syringe if not used immediately after reconstitution.
Protect from direct sunlight. Do not refrigerate after reconstitution. Image Image Image Image
Administration
For intravenous use only. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use ALTUVIIIO solution if particulate matter or discoloration is observed.
Do not administer reconstituted ALTUVIIIO in the same tubing or container with other medications. Administration Steps: Attach the syringe to the connector end of the infusion set tubing by turning it to the right until it is securely attached. Push the plunger rod until all air is removed from the syringe and ALTUVIIIO has filled the infusion set needle.
Do not push ALTUVIIIO solution through the needle. Remove the protective needle cover from the infusion set needle. Perform intravenous injection slowly over 1 to 10 minutes, based on the patient's comfort level.
After infusing ALTUVIIIO, remove and properly discard the infusion set.
| 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. |
| 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. |
Side Effects of Altuviiio
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described in this section reflects exposure to ALTUVIIIO in two clinical studies, Study 1 and Study 2 and are pooled for analysis. In Study 1, a total of 159 previously treated patients (PTPs) (134 adults and 25 adolescents) with severe Hemophilia A received at least one dose of ALTUVIIIO for either routine prophylaxis, on-demand treatment of bleeding episodes or perioperative management.
Overall exposure was monitored for a total of 151.5 patient-years. In Study 2, the safety of ALTUVIIIO was evaluated in 74 male PTPs <12 years of age with severe hemophilia A who received at least one dose of ALTUVIIIO. Adverse events were monitored for a total of 210.7 patient-years in 2 completed clinical studies in PTPs.
The most common ADRs (>10%) in adults and adolescents were headache (20.1%) and arthralgia (16.4%). In children below 12 years, pyrexia (12.2%) was the most common ADR (>10%). In the studies, no inhibitors to FVIII were detected and no ADRs of anaphylaxis were reported.
The most common adverse reactions (>10% of patients) reported in clinical trials were headache and arthralgia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: Factor VIII inhibitor development.
Immune system disorders: Hypersensitivity reactions, including anaphylaxis.
| MedDRA System Organ Class | Adverse Drug Reactions | Number of Patients n (%) (N = 233) |
|---|---|---|
| Nervous system disorders | Headache | 35 (15) |
| Musculoskeletal and connective tissue disorders | Arthralgia | 31 (13) |
| Pain in extremity | 10 (4) | |
| Back pain | 9 (4) | |
| General disorders and administration | Pyrexia | 10 (4) |
| Gastrointestinal disorders | Vomiting | 7 (3) |
Warnings & Cautions for Altuviiio
Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis, have occurred with ALTUVIIIO. Signs and symptoms include, but not limited to, hives, shortness of breath, chest tightness, wheezing, hypotension, nausea, vomiting, and itching. Discontinue ALTUVIIIO if hypersensitivity reaction occurs and manage symptoms as appropriate.
Neutralizing Antibodies Formation of neutralizing antibodies (inhibitors) to Factor VIII has been reported following administration of ALTUVIIIO. 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.
Monitoring Laboratory Tests
If assessment of plasma Factor VIII activity is needed, it is recommended to use a validated one-stage clotting assay. 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. 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).
Pregnancy Safety for Altuviiio
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.
Pediatric Use of Altuviiio
Pediatric Use The safety and effectiveness of ALTUVIIIO for routine prophylaxis, on-demand treatment, and perioperative management of bleeding episodes have been established in pediatric patients <18 years old. The use of ALTUVIIIO for these indications is supported by evidence from two clinical studies which enrolled 99 previously treated 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. Data from the pediatric study (74 patients) <12 years of age showed that no dosing adjustment was required.
Contraindications for Altuviiio
ALTUVIIIO is contraindicated in patients who have had severe hypersensitivity reactions, including anaphylaxis, to the product or its excipients. Do not use in patients who have had severe hypersensitivity reactions, including anaphylaxis, to ALTUVIIIO or excipients of ALTUVIIIO.
Clinical Studies of Altuviiio
The safety, efficacy, and pharmacokinetics of ALTUVIIIO were evaluated in two multicenter, prospective, open-label clinical studies, Study 1 (NCT04161495) and Study 2 (NCT04759193), as described below. 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 patients undergoing major or minor surgical procedures. All 159 enrolled patients received at least one dose of ALTUVIIIO and were evaluable for efficacy.
A total of 149 patients (93.7%) completed the 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 patients, 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). The ABR in patients evaluable for efficacy with at least 26 weeks of exposure are summarized in Table 6. 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 Study An intra - patient 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 patients 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). Of the 74 enrolled patients, all received at least 1 dose of ALTUVIIIO. Seventy-two patients were evaluable for efficacy.
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). Table 7: Summary of Annualized Bleeding Rate (ABR) with ALTUVIIIO Prophylaxis in Patients <12 Years of Age Study 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 patients 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. The efficacy of ALTUVIIIO in control of bleeding in children <12 years of age was assessed in the pediatric study.
Bleeding was resolved with a single 50 IU/kg injection of ALTUVIIIO in 95.3% of bleeding episodes. The median (Q1; Q3) total dose to treat a bleeding episode was 52.6 IU/kg (50.0; 55.8). Of the 14 major surgeries, 13 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 pre-operative dose per surgery was 50 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 14 of 14 surgeries (100%).
Types of major surgeries assessed include major orthopedic procedures such as arthroplasties (joint replacements of knee, hip, and elbow), joint revisions and ankle fusion. Other major surgeries included molar tooth extractions, dental restoration and tooth extraction, circumcision, and rhinoplasty/mentoplasty. The hemostatic response was evaluated by the investigator/surgeon in 21 of these minor surgeries; an excellent response was reported in all (100%).
| Endpoint Reflects all bleeds reported by patients including those where no ALTUVIIIO was administered. | Arm A Prophylaxis Patients assigned to receive ALTUVIIIO prophylaxis for 52 weeks. | Arm B On-demand Patients 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) |
| % patients 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) |
| % patients 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) |
| % patients 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) |
| % patients with zero bleeds, n (%) | 71 (55.5) | 0 | 19 (73.1) |
| Endpoint Reflects all bleeds reported by patients including those where no ALTUVIIIO was administered. | <6 years | 6 to <12 years | Overall |
|---|---|---|---|
| N = 37 A patient in the <6 years old age group who had a positive inhibitor result at baseline (pre-exposure to study drug) and was withdrawn after 3 EDs was excluded. | N = 35 A patient in the 6 to <12 years old age group who received an intense consolidation treatment (2 to 3 injections per week) for 15 weeks, after 2 traumatic hip joint bleeds was excluded from the efficacy analysis as the patient did not receive the weekly prophylaxis treatment as specified in the protocol for an extended period. | N = 72 | |
| ABR = annualized bleed rate; CI = confidence interval; Q1 = 25th percentile, Q3 = 75th percentile. | |||
| Treated bleeds | |||
| Mean ABR (95% CI) Based on negative binomial model. | 0.5 (0.3, 0.8) | 0.8 (0.4, 1.4) | 0.6 (0.4, 0.9) |
| Median ABR (Q1, Q3) | 0 (0, 1.0) | 0 (0, 1.1) | 0 (0, 1.0) |
| % patients with zero bleeds, n (%) | 23 (62.2) | 23 (65.7) | 46 (63.9) |
| Treated spontaneous bleeds | |||
| Mean ABR (95% CI) | 0.2 (0.1, 0.4) | 0.2 (0, 0.6) | 0.2 (0.1, 0.3) |
| Median ABR (Q1, Q3) | 0 (0, 0) | 0 (0, 0) | 0 (0, 0) |
| % patients with zero bleeds, n (%) | 31 (83.8) | 32 (91.4) | 63 (87.5) |
| Treated joint bleeds | |||
| Mean ABR (95% CI) | 0.2 (0.1, 0.6) | 0.4 (0.2, 0.9) | 0.3 (0.2, 0.6) |
| Median ABR (Q1, Q3) | 0 (0, 0) | 0 (0, 0) | 0 (0, 0) |
| % patients with zero bleeds, n (%) | 33 (89.2) | 27 (77.1) | 60 (83.3) |
| All Bleeds (treated and untreated) | |||
| Mean ABR (95% CI) | 2.8 (1.4, 5.6) | 2.3 (1.3, 4.1) | 2.6 (1.6, 4.0) |
| Median ABR (Q1, Q3) | 0 (0, 2.0) | 1.0 (0, 2.9) | 0.5 (0, 2.1) |
| % patients with zero bleeds, n (%) | 20 (54.1) | 16 (45.7) | 36 (50.0) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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