Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Baxalta Innovations GmbH, Industriestrasse 67, A-1221, Vienna, Austria
Treatment and prophylaxis of bleeding in patients 12 years and above with haemophilia A (congenital factor VIII deficiency).
Treatment should be under the supervision of a physician experienced in the treatment of haemophilia.
The safety and efficacy of ADYNOVI in previously untreated patients have not yet been established.
No data are available.
During the course of treatment, appropriate determination of factor VIII levels is advised to guide the dose to be administered and the frequency of repeated infusions. Individual patients may vary in their response to factor VIII, demonstrating different half-lives and recoveries. Dose based on bodyweight may require adjustment in underweight or overweight patients. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor VIII activity) is indispensable.
A field study has indicated that plasma factor VIII levels can be monitored using either a chromogenic substrate assay or a one stage clotting assay routinely used in clinical laboratories.
The dose and duration of the substitution therapy depend on the severity of the factor VIII deficiency, on the location and extent of the bleeding and on 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 concentrate standard for factor VIII products. Factor VIII activity in plasma is expressed either as a percentage (relative to normal human plasma) or preferably in International Units (relative to an International Standard for factor VIII in plasma).
One International Unit (IU) of factor VIII activity is equivalent to that quantity of factor VIII in one ml of normal human plasma.
The 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 required dose is determined using the following formula:
Required international units (IU) = body weight (kg) x desired factor VIII rise (%) x 0.5
The amount to be administered and the frequency of administration should always be oriented to the clinical effectiveness in the individual case.
In the case of the following haemorrhagic events, factor VIII activity should not fall below the given plasma activity level (in % of normal or IU/dl) in the corresponding period.
The following Table 1 can be used to guide dosing in bleeding episodes and surgery.
Table 1. Guide for dosing in bleeding episodes and surgery:
| Degree of haemorrhage/type of surgical procedure | Factor VIII level required (% or IU/dl) | Frequency of doses (hours)/duration of therapy (days) |
|---|---|---|
| Haemorrhage | ||
| Early haemarthrosis, muscle bleeding or oral bleeding. | 20–40 | Repeat injections every 12 to 24 hours. At least 1 day, until the bleeding episode, as indicated by pain, is resolved or healing is achieved. |
| More extensive haemarthrosis, muscle bleeding or haematoma | 30–60 | Repeat injections every 12 to 24 hours for 3–4 days or more until pain and acute disability are resolved. |
| Life threatening haemorrhages. | 60–100 | Repeat injections every 8 to 24 hours until threat is resolved. |
| Surgery | ||
| Minor Including tooth extraction. | 30–60 | Every 24 hours at least 1 day, until healing is achieved. |
| Major | 80–100 (pre- and postoperative) | Repeat injections every 8 to 24 hours until adequate wound healing, then continue therapy for at least another 7 days to maintain a factor VIII activity of 30% to 60% (IU/dl). |
For long term prophylaxis, the recommended dose is 40 to 50 IU of ADYNOVI per kg bodyweight twice weekly in 3 to 4 day intervals. Adjustments of doses and administration intervals may be considered based on achieved FVIII levels and individual bleeding tendency (see section 5.2).
On demand treatment dosing in paediatric patients (12 to 18 years of age) is the same as for adult patients. Prophylactic treatment for patients from 12 to <18 years is the same as for adult patients. The long-term safety of ADYNOVI in children below 12 years has not yet been established. Adjustments of doses and administration intervals may be considered based on achieved FVIII levels and individual bleeding tendency (see section 5.2).
ADYNOVI is for intravenous use. The rate of administration should be determined to ensure the comfort of the patient up to a maximum of 10 ml/min.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
No symptoms of overdose with recombinant coagulation factor VIII have been reported.
Unopened vial: 2 years.
Before opening the product may be stored at room temperature (up to 30°C) for a period of up to 3 months. The end of the 3-month storage at room temperature should be recorded on the product carton. This date should never exceed the one initially mentioned on the outer carton. At the end of this period the product shall not be put back in the refrigerator, but shall be used or discarded.
After reconstitution: Chemical and physical in-use stability has been demonstrated for 3 hours at a temperature not above 30°C. From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user. Do not refrigerate.
Store refrigerated (2° to 8°C).
Do not freeze.
ADYNOVI with BAXJECT II Hi-Flow device: Keep the vial in the outer carton in order to protect from light.
ADYNOVI in BAXJECT III system: Keep the sealed blister in the outer carton in order to protect from light. For storage conditions after reconstitution of the medicinal product, see section 6.3.
Type I glass vial, closed with a chlorobutyl rubber stopper, containing 250 IU, 500 IU, 1000 IU or 2000 IU of powder.
Type I glass vial, closed with a chlorobutyl rubber stopper, containing 5 ml of sterilised water for injections.
The medicinal product is provided in one of the following configurations:
The reconstituted medicinal product should be inspected visually for particulate matter and discoloration prior to administration. The solution should be clear or slightly opalescent. Solutions that are cloudy or have deposits should not be used.
After reconstitution, the solution has a pH of 6.7 to 7.3. The osmolality is ≥380 mOsmol/kg.
For reconstitution use only the solvent vial and the reconstitution device provided in the pack.
Administration Steps:
It is strongly recommended that every time ADYNOVI is administered, the name and batch number of the product are recorded. Peel-off labels are provided on the powder vial.
Do not use if the lid is not completely sealed on the blister
Administration Steps:
It is strongly recommended that every time ADYNOVI is administered, the name and batch number of the product are recorded. Peel-off labels are provided on the blister.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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