Alprolix
(coagulation factor IX recombinant immunoglobulin G1 fusion protein)Dosage & Administration
For intravenous use after reconstitution only.
On-demand treatment and control of bleeding episodes:
| Initial Dose: Type of Bleeding | Target Circulating FIX (IU/dL) | Dosing Interval (hours) |
|---|---|---|
| Minor and Moderate | 30–60 | Repeat every 48 hours as needed if there is further evidence of bleeding. |
| Major | 80–100 | Consider repeat dose after 6–10 hours, then every 24 hours for 3 days, then every 48 hours until healing achieved. |
Perioperative management:
Routine prophylaxis:
For adults and adolescents ≥12 years of age, start at 50 IU/kg once weekly or 100 IU/kg once every 10 days. For children <12 years of age, start at 60 IU/kg once weekly. Adjust dosing regimen based on individual response. More frequent or higher doses may be needed in children <12 years of age.
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Alprolix Prescribing Information
ALPROLIX, Coagulation Factor IX (Recombinant), Fc Fusion Protein, is a recombinant DNA derived coagulation Factor IX concentrate indicated in adults and children with hemophilia B (congenital Factor IX deficiency) for:
- On-demand treatment and control of bleeding episodes,
- Perioperative management of bleeding,
- Routine prophylaxis to reduce the frequency of bleeding episodes.
Limitation of Use:
ALPROLIX is not indicated for induction of immune tolerance in patients with hemophilia B.
For intravenous use after reconstitution only
Dose
- Dose and duration of treatment depend on the severity of the Factor IX deficiency, the location and extent of bleeding, the individual patient's pharmacokinetic profile, and/or the patient's clinical condition.
- Patients may vary in their pharmacokinetic (e.g., half-life, in vivo recovery) and clinical responses. Base the dose and frequency of ALPROLIX on the individual clinical response.
- More frequent or higher doses may be needed in children <12 years of age, especially in children <6 years of age [see Use in Specific Populations (8.4)]. For patients 12 years of age or older, age-based dose adjustment is not usually required.
- In addition to the nominal (target) potency, the actual Factor IX potency in international units (IU), determined by the quality control laboratory at product release, is stated on each ALPROLIX vial label. ALPROLIX potency is assigned using a validated in vitro, activated partial thromboplastin time (aPTT)–based, one-stage clotting assay calibrated against the World Health Organization (WHO) international standard for Factor IX concentrates.
- Factor IX activity measurements in the clinical laboratory may be affected by the type of aPTT reagent or laboratory standard used [see Warnings and Precautions (5.4)].
On average, one IU of ALPROLIX per kg body weight increases the circulating level of Factor IX by approximately 1% (IU/dL) in adults and children ≥6 years of age and by 0.6% (IU/dL) in children under 6 years of age. Estimate the required dose or the expected in vivo peak increase in Factor IX level expressed as IU/dL (or % of normal) using the following formulas:
| IU/dL (or % of normal) = (Total Dose [IU]/Body Weight [kg]) × Recovery (IU/dL per IU/kg) OR Dose (IU) = Body Weight (kg) × Desired Factor IX Rise (IU/dL or, % of normal) × Reciprocal of Recovery (IU/kg per IU/dL) |
- Consider determining the patient's in vivo recovery (in IU/dL per IU/kg) prior to elective major surgery and verify that the target Factor IX level has been achieved prior to major surgery and for major bleeds.
On-demand Treatment and Control of Bleeding Episodes
ALPROLIX dosing for on-demand treatment and control of bleeding episodes is provided in Table 1.
| Type of Bleeding | Circulating Factor IX Level Required (IU/dL or % of normal) | Dosing Interval (hours) |
|---|---|---|
| Minor and Moderate For example: Uncomplicated hemarthroses, superficial muscle (except iliopsoas) without neurovascular compromise, superficial soft tissue, mucous membranes | 30–60 | Repeat every 48 hours if there is further evidence of bleeding. |
| Major For example: Iliopsoas and deep muscle with neurovascular injury, or substantial blood loss; Pharyngeal, retropharyngeal, retroperitoneal, CNS | 80–100 | Consider a repeat dose after 6–10 hours and then every 24 hours for the first 3 days. Due to the long half-life of ALPROLIX, the dose may be reduced and frequency of dosing may be extended after day 3 to every 48 hours or longer until bleeding stops and healing is achieved. |
Perioperative Management of Bleeding
ALPROLIX dosing for perioperative management is provided in Table 2.
| Type of Surgery | Circulating Factor IX Level Required (IU/dL or % of normal) | Dosing Interval (hours) |
|---|---|---|
| Minor (including uncomplicated dental extraction) | 50–80 | A single infusion may be sufficient. Repeat as needed after 24–48 hours until bleeding stops and healing is achieved. |
| Major | 60–100 (initial level) | Consider a repeat dose after 6–10 hours and then every 24 hours for the first 3 days. Due to the long half-life of ALPROLIX, the dose may be reduced and frequency of dosing in the post-surgical setting may be extended after day 3 to every 48 hours or longer until bleeding stops and healing is achieved. |
Routine Prophylaxis
- The recommended starting regimens for adults and adolescents ≥12 years of age are either 50 IU/kg once weekly, or 100 IU/kg once every 10 days.
- For children <12 years of age, start with 60 IU/kg once weekly.
- Adjust dosing regimen based on individual response. More frequent or higher doses may be needed in children <12 years of age, especially in children <6 years of age.
Reconstitution
- Use aseptic technique (clean and germ-free) and a flat work surface during the reconstitution procedure.
- Allow the vial of ALPROLIX, 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 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.
Place the vial on a flat surface and use one hand to hold the vial steady. Use the other hand to place the vial adapter over the vial. Place the adapter spike directly above the center of the rubber stopper and push the adapter straight down until the spike punctures the center of the vial stopper and is fully inserted.
Lift the package cover away from the vial adapter and discard the cover.
Hold the plunger rod at the circular disk. Place the tip of the plunger rod into the end of the syringe. Turn clockwise until it is securely attached. Only use the diluent syringe provided in the ALPROLIX package.
- With one hand, hold the diluent syringe by the ridged part directly under the cap, with the cap pointing up. 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° angle until it snaps off. After the cap snaps off, you will see the glass tip of the syringe. Do not touch the glass tip of the syringe or the inside of the cap.
- With the vial sitting on a flat surface, insert the tip of the syringe into the adapter opening. Turn the syringe clockwise until it is securely attached to the adapter.
- Slowly depress the plunger rod to inject all of the diluent into the vial. The plunger rod may rise slightly after this process. This is normal.
- With the syringe still connected to the adapter, gently swirl the vial until the product is completely dissolved. The final solution should be clear to slightly opalescent and colorless. Do not shake. Do not use the reconstituted ALPROLIX if it contains visible particles or is cloudy.
- Make sure the plunger rod is completely depressed. Turn the vial upside-down. Slowly pull on the plunger rod to draw the solution into the syringe. Be careful not to pull the plunger rod completely out of the syringe.
- Gently unscrew the syringe from the vial adapter and dispose of the vial with the adapter still attached. Do not touch the syringe tip or the inside of the cap.
- Use the reconstituted ALPROLIX as soon as possible, but no later than 3 hours after reconstitution. Protect from direct sunlight. Do not refrigerate after reconstitution.
To combine two or more vials of ALPROLIX, after step 12 above, follow these pooling steps:
- Remove the diluent syringe from the vial adapter by turning it counterclockwise until it is completely detached. Do not detach the diluent syringe or the large luer lock syringe until ready to attach the large luer lock syringe to the next vial (with vial adapter attached).
- Leave the vial adapter attached to the vial, as it is needed for attaching a large luer lock syringe.
- Attach a separate, large luer lock syringe by turning clockwise until it is securely in place.
- Slowly pull on the plunger rod to draw the solution into the syringe.
- Repeat this pooling procedure with each vial necessary to obtain the required dose. Once you have pooled the required dose, proceed to administration using the large luer lock syringe.
Administration
For intravenous injection only
- Inspect the reconstituted ALPROLIX solution visually for particulate matter and discoloration prior to administration. Do not use if particulate matter or discoloration is observed.
- Do not administer reconstituted ALPROLIX 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 clockwise until it is securely in place.
- Depress the plunger until all air is removed from the syringe and ALPROLIX has reached the end of the infusion set tubing. Do not push ALPROLIX through the needle.
- Remove the protective needle cover from the infusion set tubing.
- Perform intravenous bolus infusion. The rate of administration should be determined by the patient's comfort level, and no faster than 10 mL per minute.
After infusing ALPROLIX, remove and properly discard the infusion set.
ALPROLIX is available as a white to off-white lyophilized powder in single-dose vials containing nominally (approximately) 250, 500, 1000, 2000, 3000, or 4000 international units (IU) of Factor IX potency per vial. The actual Factor IX potency is stated on each ALPROLIX vial.
Pregnancy
Risk Summary
There are no studies of ALPROLIX use in pregnant women to inform a drug-associated risk.
The background risk of major birth defects and miscarriage for the indicated population is unknown; however, the background risk in the U.S. general population of major birth defects is 2%–4% and of miscarriage is 15%–20% of clinically recognized pregnancies.
Animal reproductive and developmental toxicity studies have not been conducted with ALPROLIX. In a placental transfer study, ALPROLIX was detected in murine fetal blood samples at approximately 2.6% of the maternal blood levels (range, 1.7% to 3.3%), 3 to 4 hours following dosing of pregnant mice with 3.3 to 6.6 times the clinical dose of 50 to 100 IU/kg ALPROLIX [see Data].
It is not known whether ALPROLIX can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. If ALPROLIX is clearly needed to treat a pregnant woman, advise the patient that the risks to the mother and to the fetus are unknown.
Data
Animal data
Pregnant, genetically-modified, FIX-deficient mice (HemB mice) were injected intravenously with a single dose of 330 IU/kg ALPROLIX at the end of pregnancy on Gestation Day 18, or with repeat doses of 330 IU/kg ALPROLIX on Gestation Days 18 and 20. Blood samples were collected from the maternal mice and the fetuses after dosing, and FIX activity was measured in both maternal and fetal plasma using a FIX chromogenic assay. After dosing pregnant HemB mice with ALPROLIX, FIX activity in fetal blood was approximately 2.6% of the maternal blood levels, suggesting that placental transfer of ALPROLIX may occur in pregnant female patients. The relevance of these data to humans is unknown.
Lactation
Risk Summary
It is not known whether ALPROLIX is excreted into human milk. There are no data available to assess the effects of ALPROLIX on milk production or the breastfed child.
The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ALPROLIX and any potential adverse effects on the breastfed child from ALPROLIX or from the underlying maternal condition.
Pediatric Use
Safety, efficacy, and pharmacokinetics of ALPROLIX have been evaluated in previously treated patients (PTPs) from the adult and adolescent study (12 to <17 years of age) and from the pediatric study (1 to 11 years of age) [see Adverse Reactions (6), Clinical Trials Experience (6.1), Clinical Pharmacology (12.3) and Clinical Studies (14)]. Safety of ALPROLIX has been evaluated in previously untreated patients (PUPs) less than 18 years of age (median: 0.6 year; range: 0.08–2 years) in the PUPs study [see Adverse Reactions (6), Clinical Trials Experience (6.1), and Clinical Pharmacology (12.3)].
No dose adjustment is required for adolescents. Children under 12 years of age may have higher Factor IX body weight-adjusted clearance and lower recovery. More frequent or higher doses may be needed in children <12 years of age. When calculating target peak doses for treatment of bleeding or surgery, use the average in vivo recovery value of 0.6 IU/dL per IU/kg, or individually determined in vivo recovery, for children under 6 years of age [see Clinical Pharmacology (12.3)].
Geriatric Use
Clinical studies of ALPROLIX did not include a sufficient number of subjects age 65 and over to determine whether or not they respond differently than younger subjects.
ALPROLIX is contraindicated in individuals who have a known history of hypersensitivity reactions, including anaphylaxis, to the product or its excipients (sucrose, mannitol, sodium chloride, L-histidine and polysorbate 20).
Hypersensitivity Reactions
Allergic-type hypersensitivity reactions, including anaphylaxis, have been reported with ALPROLIX.
The presence of inhibitors has been associated with allergic reactions with Factor IX replacement therapies, including with ALPROLIX. Evaluate patients experiencing allergic reactions for the presence of an inhibitor. Early signs of allergic reactions, which can progress to anaphylaxis, may include angioedema, chest tightness, hypotension, rash, nausea, vomiting, paresthesia, restlessness, wheezing and dyspnea. Discontinue use of ALPROLIX if hypersensitivity symptoms occur, and initiate appropriate treatment.
Neutralizing Antibodies
Formation of neutralizing antibodies (inhibitors) to Factor IX has been reported following administration of ALPROLIX. Monitor all patients regularly for the development of inhibitors by appropriate clinical observations and laboratory tests [see Warnings and Precautions (5.4)].
Evaluate patients experiencing allergic reactions for the presence of an inhibitor. Closely observe patients for signs and symptoms of acute hypersensitivity reactions, particularly during the early phases of exposure to the product.
Individuals with Factor IX inhibitors may be at an increased risk of anaphylaxis upon subsequent challenge with ALPROLIX.
Thromboembolic Complications
The use of Factor IX products has been associated with the development of thromboembolic complications, especially in individuals receiving continuous infusion through a central venous catheter. ALPROLIX should be administered as bolus infusion over several minutes [see Dosage and Administration (2.3)]. The safety of ALPROLIX administration by continuous infusion has not been studied.
Monitoring Laboratory Tests
- To confirm adequate Factor IX levels have been achieved and maintained, monitor patient plasma Factor IX levels by performing a validated one-stage clotting assay [see Dosage and Administration (2.1)]. Factor IX results can be affected by the type of aPTT reagent used. Measurement with a one-stage clotting assay using a kaolin-based aPTT reagent has been shown to result in an underestimation of Factor IX levels.
- Monitor for the development of Factor IX inhibitors if the expected Factor IX levels in patient plasma are not attained, or if bleeding is not controlled with the recommended dose of ALPROLIX. Perform a Bethesda assay to determine if Factor IX inhibitors are present.
Nephrotic Syndrome
Nephrotic syndrome has been reported following attempted immune tolerance induction in hemophilia B patients with Factor IX inhibitors and a history of allergic reactions to Factor IX. The safety and efficacy of using ALPROLIX for immune tolerance induction have not been established.