Posology : מינונים

4.2   Posology and method of administration

Treatment should be initiated under the supervision of a physician experienced in the treatment of haemophilia.

Posology
The dosage and duration of the substitution therapy depend on the severity of the factor IX deficiency, on the location and extent of the bleeding and on the patient’s clinical condition.

The number of units of factor IX administered is expressed in International Units (IU), which are related to the current WHO standard for factor IX products. Factor IX 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 IX in plasma).

One International Unit (IU) of factor IX activity is equivalent to that quantity of factor IX in one ml of normal human plasma.

On demand treatment
The calculation of the required dose of factor IX is based on the empirical finding that 1 IU factor IX per kg body weight raises the plasma factor IX activity by 1.0 % of normal activity. The required dosage is determined using the following formula: 
Required units = body weight [kg] × desired factor IX rise [% or IU/dl] × 1.0 
The amount to be administered, the method as well as the frequency of administration should always be oriented to the clinical effectiveness in the individual case.

In the case of the following haemorrhagic events, the factor IX activity should not fall below the given plasma activity level (in % of normal or IU/dl) in the corresponding period.
The following tables can be used to guide dosing in bleeding episodes and surgery: 

Table 1: Single Intravenous Injection
Degree of haemorrhage/ Type of      Factor IX level required     Frequency of doses surgical procedure                  (% or IU/dl)                 (hours)/Duration of therapy (days)

Haemorrhage
Early haemarthrosis, muscle                     20-40            Repeat every 24 hours. At bleeding or oral bleeding                                        least 1 day, until the bleeding episode as indicated by pain is resolved or healing is achieved.
More extensive haemarthrosis,                  30 – 60           Repeat infusion every 24 muscle bleeding or haematoma                                     hours for 3 - 4 days or more until pain and acute disability are resolved.
Life-threatening haemorrhages                 60 – 100           Repeat infusion every 8 to 24 hours until threat is resolved.

Surgery
Minor                                          30 – 60           Every 24 hours, at least 1 including tooth extraction                                       day, until healing is achieved
Major                                         80 – 100         Repeat infusion every 8 -24 (pre- and postoperative) hours until adequate wound healing, then therapy for at least another 7 days to maintain a factor IX activity of 30 % to 60 %
(IU/dl).

Table 2: Continuous Infusion in Surgery
Desired levels of factor IX for     40 – 100 % (or IU/dl) haemostasis
Initial loading dose to achieve     Single bolus dose 90 IU per kg (range 75-100 IU/kg) desired level                       body weight or pK-guided dosing
Frequency of dosing                 Continuous i.v. infusion, depending on clearance and measured factor IX levels
Duration of treatment               Up to 5 days,
further treatment may be necessary depending upon nature of surgery

Prophylaxis
For long-term prophylaxis against bleeding in patients with severe haemophilia B, the usual doses are 20 to 40 IU of factor IX per kg body weight at intervals of 3 to 4 days. In some cases, especially in younger patients, shorter dosage intervals or higher doses may be necessary.

During the course of treatment, appropriate determination of factor IX levels is advised to guide the dose to be administered and the frequency of repeated infusions. In the case of major surgical interventions in particular, precise monitoring of the substitution therapy by means of coagulation analysis (plasma factor IX activity) is indispensable. Individual patients may vary in their response to factor IX, achieving different levels of in vivo recovery and demonstrating different half-lives.

Patients should be monitored for the development of factor IX inhibitors.
See also section 4.4.

Previously untreated patients
The safety and efficacy of Mononine in previously untreated patients have not yet been established.

Paediatric population
Dosing in children is based on body weight and is therefore generally based on the same guidelines as for adults. The frequency of administration should always be oriented to the clinical effectiveness in the individual case.

Method of administration
For intravenous use.
Reconstitute the product as described in section 6.6. The preparation should be warmed to room or body temperature before administration. Mononine should be administered via the intravenous route at a slow rate, so as to observe the patient for any immediate reaction. If any reaction takes place that is thought to be related to the administration of Mononine the rate of infusion should be decreased or the infusion stopped, as required by the clinical condition of the patient (see also section 4.4).

Single intravenous injection
Perform venipuncture using the accompanying venipuncture set. Attach the syringe to the luer end of the device.

Inject slowly intravenously at a rate comfortable to the patient (max. 2 ml/min).

Continuous infusion
Mononine should be reconstituted with water for injections as described in section 6.6. After reconstitution, Mononine can be given by continuous infusion undiluted using a syringe pump.

The potency of undiluted, reconstituted Mononine is approximately 100 IU/ml.

A diluted solution is obtained as follows:
• Dilute the reconstituted, filtered solution by transferring the appropriate quantity of Mononine to the desired volume of normal saline using aseptic technique.
• In dilutions of up to 1:10 (concentration of 10 IU factor IX/ml) activity of factor IX remains stable for up to 24 hours.
• A reduction in factor IX activity may result at higher dilutions. Factor IX activity should be monitored to maintain the desired blood level.

Example for diluting 1,000 IU of reconstituted Mononine:

Targeted Dilution Potency        10 IU/ml         20 IU/ml
Volume of reconstituted          10.0 ml          10.0 ml
Mononine
Volume of normal saline          90.0 ml          40.0 ml needed
Achieved dilution                1:10             1:5
•   The use of polyvinylchloride (PVC) IV bags and tubing is recommended.
•   Mix thoroughly and check bag for leaks.
•   It is recommended to replace the bags with freshly diluted Mononine every 12-24 hours.

The recommended rate for continuous infusion with Mononine to maintain a steady state factor IX level of approximately 80 % is 4 IU/kg b.w./hour, but will depend on the pharmacokinetic profile of the patient and the desired factor IX target level. In patients where the clearance of factor IX is known, the infusion rate can be calculated for the individual patient.

Rate (IU/kg b.w./hr) = Clearance (ml/hr/kg b.w.) × desired factor IX increase (IU/ml) 
The safety and efficacy in children have not been studied under continuous infusion (see section 4.4). Therefore, in children and adolescents, continuous infusion of Mononine should only be considered if pre-surgical pharmacokinetic data (i.e. incremental recovery and clearance) are obtained for the calculation of the dosage and levels are carefully monitored perioperatively.