Version May 2024
Hemophilia A: Individualize dosage based on clinical response and factor VIII activity evaluated at baseline and at regular intervals during treatment. Patients with inhibitory antibodies to factor VIII may require higher doses, more frequent administration, and/or selection of alternative therapy.
General dosing for control and prevention of bleeding episodes or perioperative management: Note: Dosage is expressed in units of factor VIII activity and must be individualized based on formulation, severity of factor VIII deficiency, extent and location of bleed, individualized incremental recovery using factor VIII activity assays, and clinical situation of patient.
Children and Adolescents: IV: Utilize steps 1 through 3 to determine intermittent bolus dosing strategy. Individualize dosage based on coagulation studies performed prior to treatment and at regular intervals during treatment. In general, administration of factor VIII 1 unit/kg will increase circulating factor VIII levels by ~2 units/dL (Ref). Note: If bleeding occurs 2 to 3 days after a prophylactic dose, a smaller dose may be indicated; determine dose based on factor VIII levels.
Step 1: Determine desired factor VIII peak level and anticipated duration of therapy based on the World Federation of Hemophilia (WFH) treatment recommendations; see table. These recommendations reflect WFH guidelines for higher-dose practice patterns; this dosing is typically used in areas where no significant resource constraints exist; recommendations may vary from those found within prescribing information or practitioner preference. Frequency is based on type of bleed or surgery and varies by product; see specific product labeling for details. Dosing frequency most commonly corresponds to the half-life of factor VIII but should be determined based on an assessment of factor VIII levels (if available) before the next dose (Ref).
|
Site of Hemorrhage/Clinical Situation |
Desired Factor VIII Peak Level |
Durationb |
|---|---|---|
|
a WFH = World Federation of Hemophilia; (WFH [Srivastava 2020]). | ||
|
b Depending on procedure; the number of doses would depend on the half-life of the clotting factor concentrate (CFC) used. | ||
|
c May be longer if response is inadequate. | ||
|
d A single dose may be sufficient for some joint bleeds; determine need for additional doses based on clinical response. | ||
|
e Sometimes longer as secondary prophylaxis during physical therapy. | ||
|
Joint |
40 to 60 units/dL |
1 to 2 daysc,d |
|
Superficial muscle/no neurovascular compromise |
40 to 60 units/dL |
2 to 3 daysc |
|
Iliopsoas or deep muscle with neurovascular injury, or substantial blood loss |
Initial: 80 to 100 units/dL |
1 to 2 days |
|
Maintenance: 30 to 60 units/dL |
3 to 5 dayse | |
|
CNS/Head |
Initial: 80 to 100 units/dL |
1 to 7 days |
|
Maintenance: 50 units/dL |
8 to 21 days | |
|
Throat and neck |
Initial: 80 to 100 units/dL |
1 to 7 days |
|
Maintenance: 50 units/dL |
8 to 14 days | |
|
Gastrointestinal |
Initial: 80 to 100 units/dL |
7 to 14 days |
|
Maintenance: 50 units/dL |
Not specified | |
|
Renal |
50 units/dL |
3 to 5 days |
|
Deep laceration |
50 units/dL |
5 to 7 days |
|
Surgery (major) |
Preop: 80 to 100 units/dL |
Single dose |
|
Postop: 60 to 80 units/dL |
1 to 3 days | |
|
Postop: 40 to 60 units/dL |
4 to 6 days | |
|
Postop: 30 to 50 units/dL |
7 to 14 days | |
|
Surgery (minor) |
Preop: 50 to 80 units/dL |
Single dose |
|
Postop: 30 to 80 units/dL |
1 to 5 days | |
Step 2: Calculate dose using desired peak factor VIII level from step 1 and the following equation:
Formula for units required to raise blood level:
Factor VIII units required = ([desired peak factor VIII level − patient's baseline factor VIII level] × body weight [kg])/2
Example for 25 kg patient with a desired peak factor VIII level of 35 units/dL and baseline factor VIII level of 5 units/dL:
Factor VIII units required = (35 units/dL − 5 units/dL) × 25 kg/2 = 375 units of factor VIII
Step 3: Determine the frequency of repeat dosing based on half-life of product used (see product-specific labeling for details), type of bleed or surgery, and patient response. A single dose may be adequate. If subsequent factor VIII levels are available for individual patients these should be taken into consideration when determining the frequency of repeat dose.
Routine prophylaxis to reduce the frequency of bleeding episodes: Note: Maintain trough factor VIII levels >3% to 5% or higher as clinically indicated based on individual level of activity, lifestyle, and pharmacokinetics. Dose escalation should be considered for patients adherent to prescribed prophylaxis but still experiencing breakthrough bleeding events (Ref).
Children and Adolescents: IV: 50 units/kg once weekly. Note: After treatment of a bleed, it is recommended to allow an interval of at least 72 hours between the last dose for treatment of a bleed and resuming prophylaxis dosing.
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
(For additional information see "Factor VIII, recombinant human with VWF fusion: Drug information")
H emophilia A, without inhibitors:
Treatment and control of bleeding episodes or perioperative management:
Approach to dosing when factor VIII levels are available:
Intermittent IV bolus dosing: IV: Utilize steps 1 to 3 to determine intermittent bolus dosing strategy. Individualize dosage based on coagulation studies performed prior to treatment and at regular intervals during treatment. In general, administration of factor VIII 1 unit/kg will increase circulating factor VIII levels by ~2.6 units/dL (Ref).
Step 1: Determine desired factor VIII peak level and anticipated duration of therapy based on the World Federation of Hemophilia (WFH) treatment recommendations; see table. Selection of the lower-dose practice pattern requires closer observation with the potential for requiring escalation to higher doses based on clinical response.
Note: For patients without inhibitors and receiving emicizumab who experience breakthrough bleeding, antihemophilic factor should be dosed to target the desired peak factor VIII levels outlined in the table as emicizumab is not indicated for treatment of bleeding episodes.
|
Type of hemorrhage or surgery |
Lower-dose practice pattern |
Higher-dose practice pattern | ||
|---|---|---|---|---|
|
Desired peak factor VIII level |
Treatment duration |
Desired peak factor VIII level |
Treatment duration | |
|
a May be longer if response is inadequate. b Sometimes longer as secondary prophylaxis during physical therapy. c A single dose may be sufficient for some joint bleeds; determine need for additional doses based on clinical response. d WFH [Srivastava 2020]. | ||||
|
Joint |
10 to 20 units/dL |
1 to 2 daysa,c |
40 to 60 units/dL |
1 to 2 daysa,c |
|
Superficial muscle/no neurovascular compromise (except iliopsoas) |
10 to 20 units/dL |
2 to 3 daysa |
40 to 60 units/dL |
2 to 3 daysa |
|
Iliopsoas or deep muscle with neurovascular injury or substantial blood loss | ||||
|
Initial |
20 to 40 units/dL |
1 to 2 days |
80 to 100 units/dL |
1 to 2 days |
|
Maintenance |
10 to 20 units/dL |
3 to 5 daysb |
30 to 60 units/dL |
3 to 5 daysb |
|
Intracranial | ||||
|
Initial |
50 to 80 units/dL |
1 to 3 days |
80 to 100 units/dL |
1 to 7 days |
|
Maintenance |
30 to 50 units/dL |
4 to 7 days |
50 units/dL |
8 to 21 days |
|
20 to 40 units/dL |
8 to 14 days |
- |
- | |
|
Throat and neck | ||||
|
Initial |
30 to 50 units/dL |
1 to 3 days |
80 to 100 units/dL |
1 to 7 days |
|
Maintenance |
10 to 20 units/dL |
4 to 7 days |
50 units/dL |
8 to 14 days |
|
GI | ||||
|
Initial |
30 to 50 units/dL |
1 to 3 days |
80 to 100 units/dL |
7 to 14 days |
|
Maintenance |
10 to 20 units/dL |
4 to 7 days |
50 units/dL |
- |
|
Renal |
20 to 40 units/dL |
3 to 5 days |
50 units/dL |
3 to 5 days |
|
Deep laceration |
20 to 40 units/dL |
5 to 7 days |
50 units/dL |
5 to 7 days |
|
Surgery (major) | ||||
|
Preop |
60 to 80 units/dL |
- |
80 to 100 units/dL |
- |
|
Postop |
30 to 40 units/dL |
1 to 3 days |
60 to 80 units/dL |
1 to 3 days |
|
20 to 30 units/dL |
4 to 6 days |
40 to 60 units/dL |
4 to 6 days | |
|
10 to 20 units/dL |
7 to 14 days |
30 to 50 units/dL |
7 to 14 days | |
|
Surgery (minor) | ||||
|
Preop |
40 to 80 units/dL |
- |
50 to 80 units/dL |
- |
|
Postop |
20 to 50 units/dL |
1 to 5 days |
30 to 80 units/dL |
1 to 5 days |
Step 2: Calculate dose using desired peak factor VIII level from step 1 and the following equation:
Factor VIII units required = [(desired peak factor VIII level − patient's baseline factor VIII level) × body weight (kg)]/2.6
Note: Factor VIII level units are units/dL.
Example for 50 kg patient with desired peak factor VIII level of 35 units/dL and baseline factor VIII level of 5 units/dL:
Factor VIII units required = [(35 units/dL − 5 units/dL) × 50 kg]/2.6 = 577 units of factor VIII
Step 3: Repeat dosing can be considered every 2 to 3 days as needed; frequency of administration must also take into consideration subsequent factor VIII activity measurements and the clinical response (Ref).
Approach to dosing when factor VIII levels are NOT available:
|
Product |
Bleeding event |
Surgery | ||
|---|---|---|---|---|
|
Minor and moderate severity |
Major severity |
Minor bleeding risk |
Major bleeding risk | |
|
Altuviiio |
IV: Initial: Single dose 50 units/kg (Note: If a prophylactic dose was given within the previous 2 to 3 days, may consider an initial dose of 30 units/kg); may consider repeat doses of 30 or 50 units/kg every 2 to 3 days as needed. |
IV: Initial: 50 units/kg; repeat 30 or 50 units/kg every 2 to 3 days as needed. |
IV: Initial: Single dose of 50 units/kg; may consider repeat doses of 30 or 50 units/kg every 2 to 3 days as needed. |
IV: Initial: 50 units/kg, repeat 30 or 50 units/kg every 2 to 3 days as needed. |
Routine prophylaxis to prevent or reduce the frequency of bleeding episodes in patients with moderate/severe hemophilia A, without inhibitors: IV: 50 units/kg once weekly (Ref). Preferably, dosing should be tailored to ensure trough factor VIII levels of at least 1% and ideally ≥3% to 5% are achieved, but prophylaxis targets should be tailored to individual level of activity, lifestyle, and pharmacokinetics. Dose escalation should be considered for patients adherent to prescribed prophylaxis but still experiencing breakthrough bleeding events (Ref). Note: After treatment of a bleed, it is recommended to allow an interval of at least 72 hours between the last dose for treatment of a bleed and resuming prophylaxis dosing (Ref).
There are no dosage adjustments provided in the manufacturer's labeling.
There are no dosage adjustments provided in the manufacturer's labeling.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adolescents and adults unless otherwise indicated.
>10%:
Nervous system: Headache (children: 1%; adolescents and adults: 21%)
Neuromuscular & skeletal: Arthralgia (16%)
1% to 10%:
Neuromuscular & skeletal: Back pain (6%)
Severe hypersensitivity reactions (eg, anaphylaxis) to antihemophilic factor (recombinant [Fc-VWF-XTEN fusion protein]) or any component of the formulation.
Concerns related to adverse effects:
• Antibody formation: Neutralizing antibodies (inhibitors) may develop to factor VIII. Monitor for signs of formation of antibodies to factor VIII. Suspect factor VIII antibodies if the plasma factor VIII level does not increase as expected or if bleeding is not controlled after administration.
• Hypersensitivity reactions: Hypersensitivity reactions (including anaphylaxis) may occur; discontinue immediately if hypersensitivity symptoms occur and administer appropriate treatment.
Dosage form specific issues:
• Polysorbate 80: May contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's labeling.
• Sucrose: May contain sucrose.
Other warnings/precautions:
• Dose requirements: The dosage requirement will vary in patients with factor VIII inhibitors; optimal treatment should be determined by clinical response.
Allergic-type hypersensitivity reactions including anaphylaxis may occur; discontinue therapy immediately if urticaria, hives, hypotension, tightness of the chest, wheezing, or anaphylaxis develop; emergency treatment and resuscitative measures (eg, epinephrine, oxygen) may be needed. Clinical response to antihemophilic factor administration may vary; dosage must be individualized based on coagulation studies (performed prior to treatment and at regular intervals during treatment) and clinical response. If bleeding is not controlled with the recommended dose, determine plasma level of factor VIII and follow with a sufficient dose to achieve satisfactory clinical response. If plasma levels of factor VIII fail to increase as expected or bleeding continues, suspect the presence of an inhibitor; test as appropriate. Formation of factor VIII inhibitors (neutralizing antibodies to AHF) may occur at any time; in general, formation of inhibitors are more common in young children with severe hemophilia during the first years of therapy, or in patients at any age who received little prior therapy with factor VIII; monitor patients appropriately (WFH [Srivastava 2020]).
Strengths expressed with approximate values. Consult individual vial labels for exact potency within each vial.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution Reconstituted, Intravenous [preservative free]:
Altuviiio: Antihemophilic factor (Recombinant [Fc-VWF-XTEN)-ehtl 250 units (1 ea); Antihemophilic factor (Recombinant [Fc-VWF-XTEN)-ehtl 500 units (1 ea); Antihemophilic factor (Recombinant [Fc-VWF-XTEN)-ehtl 1000 units (1 ea); Antihemophilic factor (Recombinant [Fc-VWF-XTEN)-ehtl 2000 units (1 ea); Antihemophilic factor (Recombinant [Fc-VWF-XTEN)-ehtl 3000 units (1 ea); Antihemophilic factor (Recombinant [Fc-VWF-XTEN)-ehtl 4000 units (1 ea) [latex free]
No
Solution (reconstituted) (Altuviiio Intravenous)
250 unit (Price provided is per AHF Unit): $6.31
500 unit (Price provided is per AHF Unit): $6.31
1000 unit (Price provided is per AHF Unit): $6.31
2000 unit (Price provided is per AHF Unit): $6.31
3000 unit (Price provided is per AHF Unit): $6.31
4000 unit (Price provided is per AHF Unit): $6.31
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Parenteral: IV: For IV administration only. Administer via infusion set; do not administer in the same tubing or container as other medications.
Children:
<20 kg: Infuse no faster than 6 minutes per vial.
≥20 kg: Infuse no faster than 2 to 3 minutes per vial.
Adolescents: Infuse no faster than 1 to 2 minutes per vial.
IV: For IV use only. Administer no faster than 1 to 2 minutes per vial. Do not administer in the same tubing or container with other medications.
Store kits at 2°C to 8°C (36°F to 46°F); do not freeze. Alternatively, may store kits at room temperature (not to exceed 30°C [86°F]) for up to 6 months or until the vial expiration date, whichever occurs first; do not return to the refrigerator after storing at room temperature. Vials should be kept in original package to protect from light. Reconstituted vials may be stored at room temperature (not to exceed 30°C [86°F]) for up to 3 hours; protect from direct sunlight.
Treatment of hemophilia A (congenital factor VIII deficiency) in any of the following: On-demand treatment and control of bleeding episodes; perioperative management; routine prophylaxis to reduce the frequency of bleeding episodes (All indications: FDA approved in ages ≥1 year and adults).
Note: Antihemophilic factor (recombinant [Fc-VWF-XTEN fusion protein]) is not indicated for the treatment of von Willebrand disease.
Factor VIII may be confused with Factor XIII
Confusion may occur due to the omitting of “Factor VIII” from some product labeling. Review product contents carefully prior to dispensing any antihemophilic factor.
None known.
There are no known significant interactions.
Animal reproduction studies have not been conducted with antihemophilic factor (recombinant [Fc-VWF-XTEN fusion protein]).
Factor VIII levels prior to and during treatment; typically during treatment of an acute bleeding event or in the perioperative setting, factor VIII levels should be measured as peaks 15 to 30 minutes after infusion to assess target level achievement (WFH [Srivastava 2020]). Note: It is recommended to use a validated one-stage clotting assay if assessment of plasma factor VIII activity is needed. Factor VIII activity is overestimated by the chromogenic assay and a specific ellagic acid based aPTT reagent in one-stage clotting assay by ~2.5-fold. If these assays are used, divide the result by 2.5 to approximate the patient's factor VIII activity. Use of a reference laboratory is recommended when a qualified one-stage clotting assay or chromogenic assay is not available locally.
Heart rate and blood pressure before and during IV administration; signs and symptoms of bleeding, hemoglobin, hematocrit, and signs and symptoms of hypersensitivity reactions; monitor for the development of inhibitor antibodies by clinical observations (eg, inadequate control of bleeding with adequate doses) and laboratory tests (eg, inhibitor level, Bethesda assay).
Classification of hemophilia (WFH [Srivastava 2020]):
Severe: Factor level <1% of normal.
Moderate: Factor level 1% to 5% of normal.
Mild: Factor level 5% to <40% of normal.
Factor VIII replacement, necessary for clot formation and maintenance of hemostasis, activates factor X in conjunction with activated factor IX. Activated factor X converts prothrombin to thrombin, which converts fibrinogen to fibrin, and with factor XIII forms a stable clot. This product has demonstrated a 3- to 4-fold prolonged half-life relative to other standard and extended half-life factor VIII products. This is achieved by covalent fusion of factor VIII to the Fc domain of human immunoglobulin G1, the inclusion of 2 XTEN polypeptides, and covalently linking the factor VIII-binding D’D3 domain of von Willebrand factor.
Onset: ~15 minutes.
Distribution:
Children and Adolescents <18 years of age:
1 to <6 years of age: 38 mL/kg.
6 to <12 years of age: 38.1 mL/kg.
12 to <18 years: 34.9 mL/kg.
Adolescents >18 years of age and Adults: 31 mL/kg.
Half-life elimination:
Children and Adolescents <18 years of age:
1 to <6 years of age: 39.9 hours.
6 to <12 years of age: 42.4 hours.
12 to <18 years of age: 44.6 hours.
Adolescents >18 years of age and Adults: 48.2 hours.
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