Afstyla

Lonoctocog alfa.

One vial contains nominally 250/500/1000/2000/3000 IU recombinant, single chain coagulation factor VIII (rVIII-SingleChain, INN = lonoctocog alfa).
After reconstitution with 2.5 ml water for injections (250/500/1000 IU) the solution contains 100/200/400 IU/ml of rVIII-SingleChain. When reconstituted with 5 ml water for injections (2000/3000 IU) the solution contains 400/600 IU/ml of rVIII-SingleChain.
The potency (IU) is determined using the European Pharmacopoeia chromogenic assay. The specific activity of AFSTYLA is 7400 - 16000 IU/mg protein.
AFSTYLA is a single chain recombinant factor VIII produced in Chinese hamster ovary (CHO) cells. It is a construct where most of the B-domain occurring in wild-type, full-length factor VIII and 4 amino acids of the adjacent acidic a3 domain were removed (amino acids 765 to 1652 of full-length factor VIII).
The newly formed linkage of the heavy and light chain of factor VIII introduces a new N-glycosylation site. As the furin cleavage site present in wild type factor VIII between the B-domain and the a3 domain was removed, AFSTYLA is expressed as a single chain factor VIII molecule.
Excipient with known effect: Sodium approximately 0.23-0.30 mmol/ml (5.4-7.0 mg/ml).
Excipients/Inactive Ingredients: L-Histidine, Polysorbate 80, Calcium chloride di-hydrate, Sodium chloride, Sucrose.

Pharmacotherapeutic group: Antihemorrhagics: Blood coagulation factor VIII. ATC code: B02BD02.
Pharmacology: Pharmacodynamics: Mechanism of Action: AFSTYLA (INN: lonoctocog alfa) is a recombinant protein that replaces the missing coagulation factor VIII needed for effective hemostasis. AFSTYLA is a single chain recombinant factor VIII construct where most of the B-domain occurring in wild-type, full-length factor VIII is removed. After activation the AFSTYLA molecule formed has an amino acid sequence identical to factor VIIIa formed from endogenous, full length factor VIII. Additionally the single-chain design results in high binding affinity of AFSTYLA to von Willebrand Factor.
Pharmacodynamic effects: Hemophilia A is an x-linked hereditary disorder of blood coagulation due to decreased levels of factor VIII and results in profuse bleeding into joints, muscles or internal organs, either spontaneously or as result of accidental or surgical trauma. By replacement therapy the plasma levels of factor VIII are increased, thereby enabling a temporary correction of the factor deficiency and correction of the bleeding tendencies.
Clinical efficacy and safety: Adult and adolescent population 12 - 65 years of age: Study 1001 determined the efficacy and safety in the prevention of bleeding events in prophylaxis, hemostatic efficacy in the control of bleeding events and during perioperative management. The study enrolled 175 previously treated patients (12 to 65 years of age) with severe haemophilia A (1 subject >60 years of age was enrolled) who accumulated a total of 14,306 EDs with rVIII-SingleChain. No patient developed an inhibitor or experienced an anaphylactic reaction.
Prophylaxis: 146 subjects were assigned to a prophylaxis regimen (median ABR, 1.14 (interquartile range: 0.0, 4.2)), 79 (54%) were assigned a 3-times per week regimen and 47 (32%) a 2-times per week regimen. Patients on prophylaxis 2- and 3-times per week were assigned median doses of 35 and 30 IU/kg per injection respectively with a median annual consumption across all prophylaxis regimens of 4,283 IU/kg year.
Treatment of bleeding: Of the 848 bleeding events observed during Study 1001, 93.5% were controlled with 2 or fewer injections. The median dose to treat a bleeding episode was 34.7 IU/kg.
Perioperative management (surgical prophylaxis): A total of 16 major surgical procedures were performed and assessed in 13 subjects in Study 1001. Hemostatic efficacy of rVIII-SingleChain in surgical prophylaxis was rated as excellent or good in all surgeries. No paediatric subjects <18 years of age were included in the surgery population.
Paediatric population <12 years of age: Study 3002 enrolled a total of 84 previously treated patients <12 years of age (35 <6 years of age and 49 6 to <12 years of age). The study participants accumulated a total of 5,239 EDs with rVIII-SingleChain.
No patient developed an inhibitor or experienced an anaphylactic reaction.
Individualised prophylaxis: Of the 81 patients on prophylaxis (median ABR 3.69 (interquartile range: 0.00, 7.20)), 43 (53%) were assigned to a 2-times weekly regimen and 25 (31%) to a 3-times per week regimen. Patients on prophylaxis 2- and 3-times per week were assigned median doses of 35 and 32 IU/kg per injection respectively with a median annual consumption across all prophylaxis regimens of 4,109 IU/kg year.
Treatment of bleeding: Of the 347 bleeding events observed during Study 3002, 95.7% were controlled with 2 or fewer injections. The median dose used to treat a bleeding event was 27.6 IU/kg.
Of note, annualized bleeding rate (ABR) is not comparable between different factor concentrates and between different clinical studies.
Pharmacokinetics: Adult population: The pharmacokinetics (PK) of AFSTYLA were evaluated in 81 adult subjects following an intravenous injection of a single dose of 50 IU/kg.
The PK parameters were based on plasma factor VIII activity measured by the chromogenic substrate assay. The PK profile obtained 3 to 6 months after the initial PK assessment was comparable with the PK profile obtained after the first dose.
Pharmacokinetic Parameters (Arithmetic Mean, CV%) Following a Single Injection of 50 IU/kg of AFSTYLA - Chromogenic Substrate Assay: (See Table 1).

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Pediatric population: The pharmacokinetics (PK) of AFSTYLA were evaluated in 10 adolescents (12 to <18 years of age) and 39 children (0 to <12 years of age) following an intravenous injection of a single dose of 50 IU/kg.
The PK parameters were based on plasma factor VIII activity measured by the chromogenic substrate assay.
Comparison of Pharmacokinetic Parameters by Age Category (Arithmetic Mean, CV%) Following a Single Injection of 50 IU/kg of AFSTYLA - Chromogenic Assay: (See Table 2).

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Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity studies, local tolerability and thrombogenicity assessments.

AFSTYLA is indicated in adults and pediatrics with hemophilia A (congenital factor VIII deficiency) for: Control and prevention of bleeding episodes.
Routine prophylaxis to prevent or reduce the frequency of bleeding episodes.
Perioperative prophylaxis (surgical prophylaxis).

Initiate treatment of AFSTYLA under the supervision of a physician experienced in the treatment of hemophilia.
The decision for an individual patient on the use of home treatment of bleeding and prophylaxis of bleeding in patients with hemophilia A should be made by the treating physician who should ensure that appropriate training is provided and the use is reviewed at intervals.
Posology: The dose and duration of the treatment depend on the severity of the factor VIII deficiency, the location and extent of the bleeding, and the patient's clinical condition.
The number of units of factor VIII administered is expressed in International Units (IU), which are related to the current WHO standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an International Standard for factor VIII in plasma).
Each vial label of AFSTYLA states the factor VIII potency in International Units (IU). One IU corresponds to the activity of factor VIII contained in one milliliter of normal human plasma.
Potency assignment is determined using a chromogenic substrate assay.
Plasma factor VIII levels can be monitored using either a chromogenic substrate assay or a one-stage clotting assay (see Precautions).
On demand treatment: Calculation of the required dose of factor VIII is based on the empirical finding that 1 IU factor VIII per kg body weight raises the plasma factor VIII activity by 2 IU/dL. The expected in vivo peak increase in factor VIII level expressed as IU/dL (or % of normal) is estimated using the following formula: (See Equation 1).

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The dose to achieve a desired in vivo peak increase in factor VIII level may be calculated using the following formula: (See Equation 2).

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The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case.
A guide for dosing AFSTYLA for the control and prevention of bleeding episodes is provided in the following table. Consideration should be given to maintaining a factor VIII activity at or above the target range: (See Table 3).

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Prophylaxis: The recommended starting regimen is 20 to 50 IU/kg of AFSTYLA administered 2 to 3 times weekly.
The regimen may be adjusted based on patient response.
Previously untreated patients: The safety and efficacy of AFSTYLA in previously untreated patients have not yet been established.
Pediatric population: The recommended starting regimen in children (0 to <12 years of age) is 30 to 50 IU per kg of AFSTYLA administered 2 to 3 times weekly. More frequent or higher doses may be required in children <12 years of age to account for the higher clearance in this age group.
For adolescents of 12 years of age and above, the dose recommendations are the same as for adults (see Pharmacology: Pharmacokinetics under Actions).
Geriatric population: Clinical studies of AFSTYL did not include subjects aged over 65 years.
Monitoring for inhibitors: Patients should be monitored for the development of factor VIII inhibitors. See also Precautions.
Method of administration: Intravenous use.
For instructions on reconstitution of the medicinal product before administration, see Precautions for disposal and other handling under Cautions for Usage. The reconstituted preparation should be injected slowly at a rate comfortable for the patient.
The patient should be observed for any immediate reaction. If any reaction takes place that might be related to the administration of AFSTYLA, the rate of injection should be decreased or the application should be stopped, as required by the clinical condition of the patient (see also Precautions).

No symptoms of overdose with AFSTYLA have been reported. One patient was reported to have received more than double the prescribed dose. No related adverse events were reported with this overdose.

AFSTYLA is contraindicated in patients who have had life-threatening hypersensitivity reactions, including anaphylaxis to AFSTYLA or any of its components, or hamster proteins.

Hypersensitivity: Allergic type hypersensitivity reactions, including anaphylaxis, are possible with AFSTYLA. Patients should be informed of the early signs of hypersensitivity reactions that may progress to anaphylaxis including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and pruritus. Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur.
Advise patients to discontinue use of AFSTYLA and to contact their physician.
For patients with previous hypersensitivity reactions pre-medication with antihistamines may be considered.
Neutralizing antibodies: Formation of neutralizing antibodies (inhibitors) to factor VIII has been reported following administration of factor VIII products, including AFSTYLA. Previously untreated patients (PUPs) are at greatest risk for inhibitor development with all Factor VIII products, including AFSTYLA.
Patients should be monitored for the development of neutralizing antibodies (inhibitors) by appropriate clinical observations and laboratory tests. If expected factor VIII plasma activity level is not attained or if bleeding is not controlled after AFSTYLA administration, the presence of an inhibitor (neutralizing antibody) should be suspected.
A specialized hemophilia treatment center should be contacted if a patient develops an inhibitor.
Perform a Bethesda inhibitor assay if expected factor VIII plasma levels are not attained or if bleeding is not controlled with the expected dose of AFSTYLA. Use Bethesda Units (BU) to report inhibitor levels.
Monitoring Laboratory Tests: Factor VIII plasma activity in patients receiving AFSTYLA can be monitored using either a chromogenic substrate assay or a one-stage clotting assay due to the consistent and predictable discrepancy in factor VIII activity measurements between the two assay formats.
Efficacy results of a large pivotal clinical study confirmed that the chromogenic substrate assay results most accurately reflect the clinical hemostatic potential. Therefore the chromogenic substrate assay should be used to determine factor VIII activity in patient samples if available. If the one-stage method is used to determine factor VIII activity in patient samples, results should be interpreted taking into account that one-stage assay results are approximately 45% lower than those of the chromogenic substrate assay (i.e. the one-stage assay results can be aligned to chromogenic substrate acquired results by multiplying the one-stage result with 2).
It is strongly recommended that every time that AFSTYLA is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the medicinal product.
Catheter-related complications: If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteraemia and catheter site thrombosis should be considered.
Effects on ability to drive and use machines: No effects on ability to drive and use machines have been observed.
Use in Children: The listed warnings and precautions apply both to adults and children.

Animal reproduction studies have not been conducted with AFSTYLA. It is not known whether or not AFSTYLA can cause fetal harm when administered to a pregnant woman or can affect reproduction. Therefore, AFSTYLA should be used during pregnancy and lactation only if clearly indicated.
It is not known whether or not is excreted into human milk. Because many drugs are excreted into human milk, caution should be exercised when AFSTYLA is administered to a nursing mother.

Summary of the safety profile: Hypersensitivity or allergic reactions (which may include angioedema, burning and stinging at the injection site, chills, flushing, generalized urticaria, headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of the chest, tingling, vomiting, wheezing) have been observed rarely with the use of factor VIII products and may in some cases progress to severe anaphylaxis (including shock) (see also Precautions). Hypersensitivity reactions were observed in clinical trial of AFSTYLA (see ADR table as follows), no anaphylactic reactions were reported.
Patients with hemophilia A may develop neutralizing antibodies (inhibitors) to factor VIII, including AFSTYLA. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialized hemophilia center be contacted. No such reactions have been observed in completed clinical trials in previously treated patients with AFSTYLA.
Tabulated list of adverse reactions: The table presented as follows is according to the MedDRA system organ classification (SOC and Preferred Term level).
Frequencies have been evaluated on a per patient basis based on data from completed clinical trials according to the following convention: very common: ≥ 1/10; common ≥ 1/100 and <1/10; uncommon: ≥ 1/1,000 and <1/100; rare: ≥ 1/10,000 and <1/1,000; very rare < 1/10,000; not known (cannot be estimated from the available data). (See Table 4).

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Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions.

No interactions of AFSTYLA with other medicinal products have been reported.

Incompatibilities: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products, diluents or solvents except those mentioned in Description and Presentation.
Precautions for disposal and other handling: General instructions: The solution should be almost colourless, clear or slightly opalescent. After filtering/withdrawal (see as follows) the reconstituted product should be inspected visually for particulate matter and discoloration prior to administration.
Do not use visibly cloudy solutions or solutions still containing flakes or particles.
Reconstitution and withdrawal must be carried out under aseptic conditions.
Reconstitution: Bring the solvent to room temperature. Ensure product and solvent vial flip caps are removed and the stoppers are treated with an antiseptic solution and allowed to dry prior to opening the Mix2Vial package.
1. Open the Mix2Vial package by peeling off the lid. Do not remove the Mix2Vial from the blister package.
2. Place the solvent vial on an even, clean surface and hold the vial tight. Take the Mix2Vial together with the blister package and push the spike of the blue adapter end straight down through the solvent vial stopper.
3. Carefully remove the blister package from the Mix2Vial set by holding at the rim, and pulling vertically upwards. Make sure to only pull away the blister package and not the Mix2Vial set.
4. Place the product vial on an even and firm surface. Invert the solvent vial with the Mix2Vial set attached and push the spike of the transparent adapter end straight down through the product vial stopper. The solvent will automatically flow into the product vial.
5. With one hand grasp the product-side of the Mix2Vial set and with the other hand grasp the solvent-side and unscrew the set carefully counterclockwise into two pieces.
Discard the solvent vial with the blue Mix2Vial adapter attached.
6. Gently swirl the product vial with the transparent adapter attached until the substance is fully dissolved. Do not shake.
7. Draw air into an empty, sterile syringe. While the product vial is upright, connect the syringe to the Mix2Vial's Luer Lock fitting by screwing clockwise. Inject air into the product vial.
Withdrawal and application: 8. While keeping the syringe plunger pressed, turn the system upside down and draw the solution into the syringe by pulling the plunger back slowly.
9. Now that the solution has been transferred into the syringe, firmly hold on to the barrel of the syringe (keeping the syringe plunger facing down) and disconnect the transparent Mix2Vial adapter from the syringe by unscrewing counterclockwise.
For injection of AFSTYLA the provided administration sets are recommended to be used because treatment failure can occur as a consequence of factor VIII adsorption to the internal surface of some injection equipment.
Care should be taken that no blood enters the syringe filled with product, as there is a risk that the blood could coagulate in the syringe and fibrin clots could therefore be administered to the patient.
The AFSTYLA solution must not be diluted.
The reconstituted solution should be administered by a separate injection/infusion line by slow intravenous injection, at a rate comfortable to the patient, up to a maximum of 10 ml/min.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store at 2-8°C.
Do not freeze. Keep vials in the outer carton in order to protect from light.
AFSTYLA may be stored at room temperature, not to exceed 25°C (77°F), for a single period of up to 3 months, within the expiration date printed on the carton and vial labels.
For storage conditions after reconstitution of the medicinal product, see Shelf life as follows.
Shelf life: 36 months.
After reconstitution the chemical and physical in-use stability has been demonstrated for 48 hours at room temperature (below 25°C). From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use should not be longer than 4 hours up to 25°C.

Haemostatics

B02BD02 - coagulation factor VIII ; Belongs to the class of blood coagulation factors. Used in the treatment of hemorrhage.

B