Replenin-VF (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Bio Products Laboratory (United Kingdom)

Contact Information

Bio Products Laboratory (United Kingdom)

ATC Code

B02BD04 (Blood coagulation factor IX)

Active Substance

Human coagulation factor IX

Human coagulation factor IX (Ph.Eur. European Pharmacopoeia)

Dosage Form

Replenin-VF

Lyophilizate for the preparation of solution for intravenous administration 500 IU: vial 1 pc. in a set with a filter needle

Dosage Form, Packaging, and Composition

Lyophilizate for the preparation of solution for intravenous administration in the form of a porous mass or powder, white or almost white in color; the prepared solution is clear or slightly opalescent, from colorless to light yellow in color.

Excipients: L-lysine monohydrochloride, glycine, trisodium citrate, citric acid, sodium hydrogen phosphate dihydrate, sodium chloride.

Colorless glass vials (1) in a set with a sterile filter needle – cardboard packs.

Clinical-Pharmacological Group

Blood coagulation factor IX preparation

Pharmacotherapeutic Group

Hemostatic agent

Pharmacological Action

Hemostatic preparation. It is a highly purified concentrate of human blood coagulation factor IX, isolated from the blood of carefully selected donors, tested for the absence of HIV, hepatitis B and C viruses, and also subjected to special processing to remove the aforementioned and other possible viruses. It is a glycoprotein chain with a molecular weight of about 68,000 Da.

It replenishes the deficiency of coagulation factor IX and thus eliminates hypocoagulation in patients with its deficiency. The drug introduced into the blood increases the level of K-dependent coagulation factors (II, VII, IX, X) in the plasma.

In the process of blood coagulation, it is converted into activated factor IX (factor IXa), which in combination with factor VIII converts factor X into the active form Xa. Under the influence of the latter, prothrombin is converted into thrombin, which converts fibrinogen into fibrin, resulting in the formation of a fibrin clot.

Pharmacokinetics

T_1/2 after intravenous administration of the drug in patients with hemophilia B is about 1 day.

Indications

• Treatment and prevention of bleeding in patients with hemophilia B, acquired deficiency of coagulation factor IX.

ICD codes

Dosage Regimen

Treatment should be carried out under the supervision of a physician with the necessary experience in the treatment of patients with hemophilia B. The dose and duration of treatment depend on many factors and are assessed by the attending physician.

Factor IX preparations rarely require administration more than once a day.

The amount of factor IX administered is expressed in IU, which corresponds to the generally accepted WHO standard for preparations containing factor IX.

The activity of factor IX in blood plasma is expressed either as a percentage (corresponding to normal human blood plasma) or in International Units (corresponding to the International Standard for factor IX in blood plasma).

1 IU of factor IX activity is equivalent to the same amount of factor IX in 1 ml of normal human plasma.

The calculation of the required dose of factor IX is based on the results of empirical studies that have shown that the administration of 1 IU of Replenin-VF per kg of body weight increases the level of factor IX in blood plasma by 1.3% of normal activity.

The drug dose is calculated using the following formula:

Required number of units of the drug = body weight (kg) × required level of increase in factor IX activity (%) × 0.8

The table below provides an approximate estimate of the required dose for various situations.

Under certain circumstances, especially when determining the initial dose, it may be necessary to administer a larger dose of the drug than calculated above. In particular, during major surgical interventions, replacement therapy should be monitored by blood coagulation analysis (factor IX activity in the patient’s blood plasma).

During the first few days after surgery, the concentration of plasma factor IX should be monitored and, if necessary, Replenin-VF should be re-administered every 12-24 hours. After a few days, the dose and frequency of administration can be reduced. Treatment is usually continued for 10 days or more.

If the factor IX concentration does not reach the desired level or decreases faster than expected (within 12 hours), the presence of factor IX inhibitors should be suspected and necessary studies should be conducted to determine these inhibitors.

In children, a dose equal to 1 IU/kg may lead to a smaller increase in factor IX activity. Currently, there is insufficient data on the use of Replenin-VF in children under 6 years of age.

The prepared solution of the drug should be administered intravenously slowly (at a rate of approximately 3 ml/min).

To administer the drug, a suitable needle (for example, a butterfly-type needle) should be attached to the syringe. Despite the low likelihood of side effects, the drug dose (especially the first one) should be administered slowly (at a rate of approximately 3 ml/min). If it is necessary to administer the contents of more than 1 vial of the drug, the contents of the required number of vials should be collected into 1 syringe of a suitable volume, transferring the solution from each vial through a separate sterile filter needle.

Preparation of the injection solution

Water for injections should be used to prepare the injection solution. The drug and the vial of water for injections are warmed to a temperature from 20°C (68°F) to 30°C (86°F). The flip-off caps are removed from the vials and the stoppers are wiped with an alcohol swab.

Then, one of the following methods is used to prepare the injection solution:

1. Using a sterile needle and syringe (which are disposed of after use), draw water for injections into the syringe and transfer it to the vial with the drug. After piercing the stopper of the drug vial, the water flows into the vial by itself because a vacuum has been created in it. Special attention should be paid to the fact that the supplied filter needle cannot be used to transfer water for injections.
2. Remove the protective tip from one end of the double-ended needle and insert it through the stopper into the vial with water for injections. Remove the tip from the other end of the needle, place the vial with water over the vial with the drug, and insert the free end of the needle through the stopper into the vial with the drug. After piercing the stopper of the drug vial, the water flows into the vial by itself. A small amount of water will remain in the vial with water for injections. Special attention should be paid to the fact that if the water does not flow into the drug vial, the packaging integrity has been compromised and the drug must not be used.

Then proceed as follows: remove the syringe from the needle, remove the needle from the drug vial. Or disconnect the 2 vials by first removing the needle from the water vial, then from the drug vial.

Gently rotate the drug vial between the palms to dissolve the drug. Within no more than 5 minutes, a clear or slightly opalescent liquid should form. If the required dose requires more drug than is contained in 1 vial, the contents of the required number of vials should be pooled together.

After preparing the drug solution, wipe the vial stopper with an alcohol swab. The dissolved drug should be transferred from the vial into a plastic “transfer filter” through the supplied sterile filter needle to free the solution from any possible minute undissolved particles.

The solution should be used within no more than 1 hour after preparation. If the diluted drug forms a gel or clots, if there are flakes in the solution or a precipitate has formed, the drug must not be used. Such instances, as well as instances of compromised packaging integrity, should be reported to the manufacturer.

Adverse Reactions

From the digestive system: rarely – nausea, jaundice, loss of appetite, abdominal distension.

From the CNS: rarely – headache, confusion.

From the cardiovascular system: rarely – tachycardia, postoperative thrombosis.

Allergic reactions: rarely – fever, chills, pyrexia, urticaria, anaphylactic reactions.

Other: rarely – weight loss, tingling sensation in the body, back pain, malaise, increased body temperature, decreased resistance to infectious diseases, appearance of antibodies to factor IX in the blood.

Contraindications

• Severe liver dysfunction;
• DIC syndrome;
• Hypersensitivity to factor IX or other components of the drug.

Not recommended for use in patients with inhibitors of blood coagulation factor VIII, as well as for the correction of coagulation factor disorders in patients with liver diseases, upon withdrawal of oral anticoagulants.
Use with caution in children.

Use in Pregnancy and Lactation

No complications have been noted with the use of Replenin-VF during pregnancy and breastfeeding. However, the use of the drug during pregnancy is only possible if the intended benefit to the mother outweighs the potential risk to the fetus and newborn.

Use in Hepatic Impairment

Contraindicated in severe liver dysfunction.

Use with caution for the correction of coagulation factor disorders in patients with liver diseases.

Pediatric Use

Use with caution in children.

Special Precautions

Sterile water for injections should be used to dilute the drug.

When administering drugs prepared from human plasma to patients, the risk of infection with known or yet unknown viruses cannot be completely excluded. To reduce the risk of infection, strict control is exercised during the selection of blood donors.

Furthermore, during the production process, Replenin-VF undergoes 2 special stages for virus removal:

1. Solvent/detergent treatment, which destroys HIV, hepatitis B virus, hepatitis C virus.
2. Special viral filtration to remove viruses such as hepatitis A virus and parvoviruses.

Nevertheless, human blood products cannot be completely guaranteed to be free of the mentioned viruses, so the manufacturer recommends that the patient be vaccinated against hepatitis A and hepatitis B before starting treatment.

When using low-purity factor IX preparations (prothrombin complex concentrate), there have been cases of thromboembolism. To date, clinical experience shows that when using high-purity factor IX preparations, such as Replenin-VF, this risk is significantly reduced. However, this potential risk should be taken into account when prescribing Replenin-VF to patients with heart disease, liver disease, after recent surgeries, if there is a history of thrombosis or thromboembolism, or if there are reasons to fear thrombus formation or extensive hematomas.

In case of allergic reactions or anaphylactic reactions, the administration of the drug should be immediately interrupted and anti-shock therapy should be carried out if necessary.

In some patients with congenital factor IX deficiency, antibodies to it may form after a course of treatment. This may lead to the ineffectiveness of the drug. If the presence of antibodies to factor IX is suspected, tests should be conducted to detect them, especially before a planned surgery.

The level of factor IX in the blood should be checked before and after the course of treatment, especially during the first course.

Use in pediatrics

The drug should be prescribed to children with particular caution.

Effect on the ability to drive vehicles and operate machinery

No information is available on the effect of the drug on the ability to drive a vehicle or operate any other machinery.

Overdose

No reports of drug overdose have been received.

Drug Interactions

No interactions of the drug with other medicinal products have been noted to date.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature from 2°C (35.6°F) to 8°C (46.4°F); do not freeze.

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.