Pronativ

PACKAGE LEAFLET: INFORMATION FOR THE USER

Pronativ, 500 IU, powder and solvent for solution for infusion

Human prothrombin complex
Pronativ, 1000 IU, powder and solvent for solution for infusion
Human prothrombin complex
Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it could be harmful.
• If you experience any adverse reactions, including those not listed in this leaflet, contact your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet:

1. What Pronativ is and what it is used for
2. What you need to know before using Pronativ
3. How to use Pronativ
4. Possible side effects
5. How to store Pronativ
6. Contents of the pack and other information

1. WHAT PRONATIV IS AND WHAT IT IS USED FOR

Pronativ belongs to the group of medicines known as coagulation factors and
contains human vitamin K-dependent coagulation factors II, VII, IX, and X.
Pronativ is used for the treatment and prevention of bleeding:

• caused by medicines known as vitamin K antagonists (such as warfarin). These medicines counteract the effect of vitamin K and cause a deficiency in vitamin K-dependent coagulation factors in the human body. Pronativ is used when rapid correction of the deficiency is required
• in individuals with congenital deficiency of coagulation factors II and X dependent on vitamin K. It is used when the purified specific coagulation factor is not available.

2. WHAT YOU SHOULD KNOW BEFORE USING PRONATIV

Do not use Pronativ:

• if you are allergic to any of the components of this product (listed in section 6).
• if you are allergic to heparin or if heparin has previously caused a reduction in platelet levels in your blood.
• if you have IgA deficiency with known antibodies against IgA.

Warnings and precautions

• Follow the advice of a specialist physician experienced in treating coagulation disorders when taking Pronativ.
• If you have an acquired deficiency of vitamin K-dependent coagulation factors (e.g., induced by treatment with vitamin K antagonist medications), Pronativ should only be used when rapid correction of this deficiency is required, such as in major bleeding or surgical emergencies.

In other cases, reducing the dose of vitamin K antagonists and/or administering vitamin K is usually sufficient.

• If you are taking a vitamin K antagonist (such as warfarin), you may have an increased risk of blood clot formation. In such cases, treatment with Pronativ may further increase this risk.
• If you have a congenital deficiency of one of the vitamin K-dependent coagulation factors, you should use, when available, the specific coagulation factor.
• In case of allergic or anaphylactic reactions, your doctor will immediately stop the infusion and administer appropriate treatment.
• When you are administered Pronativ (especially if administered regularly), you are at risk of thrombosis or disseminated intravascular coagulation (a serious condition involving widespread clotting throughout the body). Be vigilant for early signs or symptoms of intravascular coagulation or thrombosis. This is particularly important if you have coronary artery disease or liver disease, if you are about to undergo surgery, or if Pronativ is administered to very young children.
• There are no data available on the use of Pronativ for perinatal bleeding due to vitamin K deficiency in the newborn.

Viral safety

• When medicines are prepared from human blood or plasma, certain measures are taken to prevent transmission of infections to patients. These include careful selection of blood and plasma donors to ensure that those at risk of carrying infections are excluded, screening of individual donations and plasma pools for viruses/infections. In addition, manufacturers of blood- or plasma-derived medicinal products include virus inactivation/removal steps in the production process. Nevertheless, when administering medicinal products prepared from human blood or plasma, the possibility of transmitting infectious agents cannot be completely ruled out. This also applies to unknown or new viruses and other types of infections. The measures taken are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). The measures taken may have limited effectiveness against non-enveloped viruses such as hepatitis A virus (HAV) and parvovirus B19. Parvovirus B19 infection may be severe in pregnant women (fetal infection) and in patients with weakened immune systems or suffering from certain types of anemia (such as sickle cell anemia or hemolytic anemia). It is strongly recommended that the name and batch number of the product be recorded each time you receive a dose of Pronativ, in order to maintain traceability of the batches used.
• Appropriate vaccination (against hepatitis A and B) is also recommended if you are regularly or repeatedly treated with human prothrombin complex concentrates derived from plasma.

Children and adolescents
There are no data available on the use of Pronativ in children and adolescents.
Other medicines and Pronativ
Pronativ must not be mixed with other medicines.
Pronativ counteracts the effect of treatment with vitamin K antagonists (such as warfarin), but
no interactions with other medicines are known.
Pronativ may alter the results of coagulation tests that are sensitive to heparin.
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicine.
Pregnancy and breastfeeding
Pronativ should only be used during pregnancy and breastfeeding if clearly needed and unambiguously justified. Consult your doctor or pharmacist before using any medicine.
Driving and using machines
No effects of Pronativ on the ability to drive or use machines are known.
Important information about some excipients in Pronativ

• Heparin may cause allergic reactions and reduce blood cell counts, possibly affecting the coagulation system. Patients with a history of heparin-induced allergic reactions should avoid medicines containing heparin.
• This medicine contains 75 - 125 mg (500 IU vial) or 150 - 250 mg (1,000 IU vial) of sodium (main component of table salt) per vial. This corresponds to 3.8 - 6.3% or 7.5 - 12.5% of the maximum daily recommended dietary intake for an adult.

3. HOW TO USE PRONATIV

Treatment with Pronativ must be initiated under the supervision of a specialist physician experienced in the
treatment of coagulation disorders.

• First, the powder must be dissolved in water for preparations for injection
• Then the solution must be injected intravenously (intravenous route of administration)

The dose of Pronativ to be administered and the duration of treatment depend on:

• the severity of your condition,
• the location and extent of bleeding,
• your general health status.

If you take more Pronativ than you should
In case of overdose, there is an increased risk of developing:

• coagulation complications (such as myocardial infarction and blood clots in veins or lungs)
• disseminated intravascular coagulation (a serious disorder in which blood clots form throughout the body).

4. POSSIBLE ADVERSE REACTIONS

Like all medicines, this medicine can cause adverse reactions, although not everyone experiences them.
Common (may affect up to 1 in 10 people)
Blood clots in blood vessels.

Uncommon (may affect up to 1 in 100 people)
Anxiety, increased blood pressure, asthma-like symptoms, coughing up blood, nosebleed, burning at injection site, clots in the device.

Rare (may affect up to 1 in 1,000 people)
Allergic-type reactions may occur.
A transient increase in liver function test results (transaminases) has been observed.
Patients treated with Pronativ for replacement therapy may develop neutralizing antibodies (inhibitors) that inhibit one or more of the coagulation factors contained in the medicine. If these inhibitors form, replacement therapy will not be fully effective.

Very rare (may affect up to 1 in 10,000 people)
Increase in body temperature (fever) has been observed.
There is a risk of blood clot formation following administration of this medicine.

Not known (frequency cannot be estimated from the available data)
Severe allergic reaction and shock, hypersensitivity, tremor, heart failure, increased heart rate, circulatory failure, drop in blood pressure, respiratory failure, breathing difficulties, nausea, hives, skin rash, chills.
The presence of heparin in the product may cause a sudden drop in the number of platelets in the blood. This is an allergic reaction known as "heparin-induced type II thrombocytopenia".
In rare cases, in patients who had never previously shown hypersensitivity reactions to heparin, this drop in platelet count may occur 6–14 days after starting treatment. In patients who had previously shown hypersensitivity reactions to heparin, this condition may appear just a few hours after starting treatment.
Pronativ treatment must be immediately discontinued in patients who experience these allergic reactions.
These patients must never again be treated with medicines containing heparin.

For information on viral safety, see section 2.

Reporting of adverse reactions
If you experience any adverse reaction, including those not listed in this leaflet, talk to your doctor, pharmacist, or nurse. You can also report adverse reactions directly via the national reporting system at:
http://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting adverse reactions, you can help provide more information on the safety of this medicine.

5. HOW TO STORE PRONATIV

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label. The expiry date refers to the
last day of that month.
Do not store above 25°C. Do not freeze. Store in the original packaging to protect from light.
The powder must be dissolved immediately before injection. Solution stability has been demonstrated
for up to 8 hours at +25°C. However, to prevent contamination, the solution should be used
immediately and for a single use only.

6. PACKAGING CONTENTS AND OTHER INFORMATION

What Pronativ contains, per vial and after reconstitution with 20 mL (500 IU) or 40 mL (1,000 IU) of solvent

• The active substances are:

The specific activity of the product is ≥ 0.6 IU/mg, expressed as Factor IX activity.
The other components are:
heparin, trisodium citrate dihydrate, water for injections.
Description of the appearance of Pronativ and pack contents
Pronativ is supplied as a powder and solvent for solution for infusion; it is a white or slightly coloured, hygroscopic, friable solid, contained in a glass vial. The solvent is water for injections, supplied in a glass vial. The reconstituted solution is clear or slightly opalescent and may be coloured.
Pronativ is supplied in a pack containing:

• 1 vial of powder for solution for infusion.
• 1 vial of solvent (water for injections)
• 1 Nextaro transfer set

Marketing Authorization Holder and Manufacturer
Octapharma Italy SpA
Via Cisanello 145
56124 Pisa - Italy
For any further information on this medicinal product, please contact the local representative of the Marketing Authorization Holder.
Responsible lot release manufacturer
Octapharma Pharmazeutika Produktionsges.m.b.H.
Oberlaaer Str. 235
1100 Vienna
Austria
Octapharma Lingolsheim S.A.S.
72 Rue du Maréchal Foch
67380 Lingolsheim
France
This medicinal product is authorized in the European Economic Area countries under the following names:
Octaplex:
Austria, Belgium, Bulgaria, Croatia, Cyprus, Denmark, Estonia, Finland, France, Germany, Hungary, Iceland, Ireland, Latvia, Lithuania, Luxembourg, Malta, Netherlands, Norway, Poland, Portugal, Republic of Slovenia, Slovak Republic, Spain, United Kingdom.
Ocplex:
Czech Republic, Sweden.
Pronativ
Italy and Romania.

THE FOLLOWING INFORMATION IS INTENDED EXCLUSIVELY FOR PHYSICIANS

OR HEALTHCARE PROFESSIONALS
General information on how to use Pronativ is contained in paragraph 3.
The following information is intended exclusively for physicians or healthcare professionals.
Instructions for Treatment
Please read all instructions and follow them carefully!
Sterile conditions must be maintained throughout the procedure described below!
The product reconstitutes rapidly at room temperature.
The reconstituted solution should be clear or slightly opalescent.
Do not use cloudy solutions or those containing precipitates.
Before administration, reconstituted products must be visually inspected for particulate matter and discoloration.
After reconstitution, the solution must be used immediately.
Any unused product or waste material must be disposed of in accordance with current regulations.
Dosage
Bleeding and bleeding prophylaxis during treatment with vitamin K antagonists:
The dose depends on the International Normalized Ratio (INR) value prior to treatment and on body weight. Approximate treatment doses (units/kg body weight of reconstituted product) are provided in the following table.

The units refer to International Units.
The dose is based on a maximum body weight not exceeding 100 kg. For patients weighing
more than 100 kg, the maximum single dose (IU of factor IX) should therefore not exceed
2500 IU for INR values of 2 – < 4; 3500 IU for INR values of 4 – 6; and 5000 IU for INR values > 6.
Since these recommendations are based on empirical observations and recovery and duration of effect may vary, INR monitoring during treatment is essential.

Bleeding episodes and perioperative prophylaxis of hemorrhage in cases of congenital deficiency of vitamin K-dependent coagulation factors II and X, when a specific coagulation factor product is not available:

The calculation of the required therapeutic dose is based on the empirical observation that approximately 1 IU of factor II or factor X per kg of body weight increases plasma factor II or plasma factor X activity by approximately 0.02 and 0.017 IU/mL, respectively.

• Units required = body weight (kg) × desired increase in factor X (IU/mL) × 60
• where 60 (mL/kg) is the reciprocal of the estimated recovery.
• Required dosage for factor II:
• Units required = body weight (kg) × desired increase in factor II (IU/mL) × 50

If individual recovery is known, this value should be used for calculation.

Reconstitution instructions:

1. If necessary, bring the solvent (water for injections) and the powder vials to room temperature while still closed. This temperature must be maintained during reconstitution. If using a water bath for warming, ensure that water does not come into contact with the rubber stoppers or vial caps. The water bath temperature must not exceed 37°C.
2. Remove the pull-off caps from the powder and solvent vials and appropriately disinfect the rubber stoppers.
3. Remove the cap from the outer casing of the Nextaro. Place the solvent vial on a flat surface and hold it firmly. Without removing the outer casing, position the blue part of the Nextaro onto the top of the solvent vial and press firmly downward until it locks into place (Fig. 1). Do not rotate the components during this procedure! While holding the solvent vial, gently remove the outer casing from the Nextaro, taking care to leave the Nextaro securely attached to the solvent vial (Fig. 2).

Fig. 2
Fig. 1

4. Place the powder vial on a flat surface and hold it firmly.
   Grasp the solvent vial with the attached Nextaro and invert it.
   Place the white part of the Nextaro connector onto the top of the
   powder vial and press firmly downward until it locks into place
   (Fig. 3). Do not rotate the components during this procedure!
   The solvent will automatically transfer into the powder vial.
   Fig. 3

5. With both vials still connected,

gently swirl the powder vial until the product is completely dissolved. At room temperature, Pronativ dissolves rapidly into a solution ranging from colorless to slightly bluish-clear. Unscrew the Nextaro into two parts (Fig. 4).
Discard the empty solvent vial together with the blue part of the Nextaro.
Fig. 4
Do not use the preparation if the concentrate does not dissolve completely or if aggregates form.

Infusion instructions:
As a precautionary measure, monitor the patient's pulse rate before and during infusion. If a marked increase in pulse rate occurs, reduce the infusion rate or interrupt administration.

1. Attach a 20 mL syringe (for 500 IU) or 40 mL syringe (for 1000 IU) to the Luer lock port of the white part of the Nextaro. Invert the vial and draw the solution into the syringe. Once the solution has been transferred, firmly hold the syringe plunger (with the syringe pointing downward) and remove the syringe from the Nextaro. Discard the Nextaro and the empty vial.

2. Appropriately disinfect the injection site.

3. Administer the solution intravenously at a rate of 0.12 mL/kg/min (~3 units/kg/min), up to a maximum rate of 8 mL/min (~210 units/min), under aseptic conditions.

Blood must not enter the syringe due to the risk of fibrin clot formation. The Nextaro is for single use only.