Provertinum

Package leaflet: Information for the patient

Provertinum

600 IU powder and solvent for solution for infusion
Human coagulation Factor VII
Please read all of this leaflet carefully before you start 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 other people, even if their symptoms are the same as yours, as it may 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 Provertinum is and what it is used for
2. What you need to know before using Provertinum
3. How to use Provertinum
4. Possible side effects
5. How to store Provertinum
6. Contents of the pack and other information

1. What Provertinum is and what it is used for

Provertinum contains coagulation factor VII, a substance necessary for forming blood clots and thereby stopping bleeding (haemorrhage).
Factor VII, obtained by extraction from human plasma, is involved in blood coagulation mechanisms. A deficiency of this factor in the blood leads to a risk that the blood will not clot within normal (physiological) timeframes, resulting in an increased tendency to bleed. By administering Provertinum, circulating levels of this factor are increased, thereby temporarily correcting blood coagulation mechanisms (haemostasis).
Provertinum is used for the treatment and prevention of bleeding in patients of all ages who suffer from congenital or acquired coagulation disorders caused by factor VII deficiency.
If you have a coagulation disorder present from birth (congenital) and have factor VII deficiency requiring replacement therapy, your doctor will administer Provertinum for:

• spontaneous bleeding or bleeding caused by trauma
• surgical procedures

In these cases, administration of Provertinum is sufficient to normalize coagulation.
If you have an acquired coagulation disorder with factor VII deficiency related to acute or chronic liver diseases, or arising following accidental or suicidal ingestion of oral anticoagulants, your doctor will administer Provertinum:

• prior to biopsies or surgical procedures
• for the treatment of spontaneous bleeding or bleeding caused by trauma
• if you have developed hepatic coma

2. What you need to know before using Provertinum

Do not use Provertinum

• if you are allergic to coagulation factor VII or to any of the other ingredients of this medicine (listed in section 6);
• if you are allergic to heparin or have previously experienced a reduction in blood platelet count (thrombocytopenia) following heparin administration;
• if you are at high risk of developing a blood clot in a blood vessel or have a blood coagulation disorder (disseminated intravascular coagulation, DIC).

Warnings and precautions
Talk to your doctor before using Provertinum.
In particular, inform your doctor:

• if you suffer from blood coagulation disorders (e.g., disseminated intravascular coagulation (DIC) or thrombosis);
• if you have previously suffered from coronary artery disease (the arteries supplying blood to the heart);
• if you have liver disease;
• if you are about to undergo surgery or have recently undergone surgery;
• if the recipient of the medicine is a newborn.

Viral safety
Provertinum is a medicine derived from human plasma (the liquid fraction of blood). When medicines are manufactured from human blood or plasma, several safety measures are applied to prevent transmission of infections to patients. These include careful selection of blood and plasma donors to ensure that potential carriers of infection are excluded, and testing of each donation and plasma pool to detect the presence of viruses and infections. In addition, manufacturers of these medicines include in the manufacturing process certain steps capable of inactivating or removing pathogenic viruses. Despite these measures, whenever medicines prepared from human blood or plasma are administered, the possibility of transmitting an infection cannot be completely ruled out. This also applies to emerging or unknown viruses or other types of infections.

The measures taken during the production of Provertinum are considered effective against lipid-enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), and against the non-lipid-enveloped hepatitis A virus (HAV).
The measures taken may have limited effectiveness against non-lipid-enveloped viruses such as parvovirus B19.
Parvovirus B19 infection may be severe in pregnant women (fetal infection) and in individuals with immunodeficiency or certain types of anemia (e.g., sickle cell anemia or hemolytic anemia).
Appropriate vaccination (hepatitis A and B) should be considered for patients undergoing regular/repeated treatment with human Factor VII products derived from human plasma.
It is strongly recommended that each time Provertinum is administered to you, the name and batch number of the product be recorded, in order to maintain a traceable link between the patient and the product batch.

Other medicines and Provertinum
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.
No pharmacological interactions of human coagulation factor VII with other medicines are known.
In particular, inform your doctor:

• if you need to undergo blood tests, as Provertinum may alter the results of coagulation tests.

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, planning to become pregnant, or are breastfeeding, consult your doctor before using this medicine.
During pregnancy and breastfeeding, your doctor will administer Provertinum only if strictly necessary.

Driving and using machines
Provertinum has no effect on the ability to drive vehicles or operate machinery.

Provertinum contains sodium and heparin

Sodium
This medicine contains approximately 40 mg of sodium (a main component of table salt) per vial. This corresponds to 2% of the maximum recommended daily dietary intake for an adult.

Heparin
Heparin may cause allergic reactions and a reduction in red blood cell count, which may impair blood coagulation. If you have previously experienced allergic reactions caused by heparin, do not take medicines containing heparin.

3. How to use Provertinum

Use this medicine exactly as instructed by your doctor. If you have any doubts, consult your doctor.
Provertinum must be administered only intravenously (into a vein).
The dose and duration of treatment depend on the severity of factor VII deficiency, the site and extent of bleeding, as well as the patient's clinical condition and characteristics (body weight).
Treatment must be initiated under the supervision of a physician specialized in replacement therapy with coagulation factors.

Use in children and adolescents
The dose will be determined by the doctor based on the child's body weight and clinical condition.

If you use more Provertinum than you should
It is highly unlikely that you could receive a higher dose than intended, since your doctor or nurse will monitor you during treatment.
If high doses of Provertinum are administered, the doctor will discontinue administration and monitor you closely to prevent adverse events such as disseminated intravascular coagulation (DIC), heart attack (myocardial infarction), venous occlusion (thrombosis), and/or pulmonary artery occlusion (embolism). In case of overdose, there is an increased risk of clot formation leading to circulatory blockage.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
Provertinum contains other human proteins, as it is a plasma-derived factor VII concentrate.
Hypersensitivity reactions, including anaphylactic reactions, have been reported with the use of factor VII products.
If you experience any of the following side effects during treatment with Provertinum, inform your doctor or nurse immediately, who will IMMEDIATELY STOP administration at the first sign of an alert, and will provide appropriate therapy to treat these symptoms, which may be life-threatening:
o Hypersensitivity and allergic reactions, which in some cases may progress to severe allergic reactions (anaphylactic shock). Allergic reactions may also cause reduced blood flow to the body (hypovolemic shock).

The additional side effects are summarized below by frequency:
Common (may affect up to 1 in 10 people)

• Flushing
• Skin rash
• Fever
• Chest pain
• Feeling of blurred head

Not known (frequency cannot be estimated from the available data)

• Formation of circulating antibodies that negatively affect your response to the medicine
• Confusional state
• Insomnia
• Restlessness
• Blockage of a blood vessel in the brain (cerebral venous thrombosis)
• Dizziness
• Sensory disturbance causing abnormal and mostly painful reactions to stimuli (dysesthesia)
• Headache (cephalalgia)
• Heart rhythm disorders (arrhythmia)
• Low blood pressure (hypotension)
• Blockage of a blood vessel (deep venous thrombosis)
• Inflammation and blockage of a superficial blood vessel (superficial thrombophlebitis)
• Hot flushes
• Breathing difficulties (bronchospasm, dyspnea)
• Diarrhea
• Nausea
• Itching (pruritus)
• Chest discomfort

The following side effects have been reported with medicines belonging to the same class:

• Allergic or anaphylactic-type reactions,
• Fever,
• Vomiting,
• Urticaria,
• Obstruction of normal blood flow in a blood vessel caused by a blood clot or an air bubble (thromboembolic events – see section 2 Warnings and precautions). Cases of interrupted blood supply to the brain (stroke), heart attack (myocardial infarction), blood clot in an artery (arterial thrombosis), blockage of a blood vessel in the lungs (pulmonary embolism), and widespread blood clotting (disseminated intravascular coagulation) have been reported.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, please contact your doctor. You can also report side effects directly via the national reporting system:

https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Provertinum

Keep this medicine out of the sight and reach of children.
Store in a refrigerator (2 °C – 8 °C). Do not freeze.
Keep the container in the outer packaging to protect the medicine from light.
After reconstitution, Provertinum must be used immediately, as the product does not contain preservatives.
Do not use this medicine after the expiry date stated on the carton after "Exp.:". The expiry date refers to the last day of that month.
Do not use this medicine if the reconstituted solution appears cloudy or contains particles or has an abnormal colour.
Do not dispose of medicines via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package Contents and Other Information

What Provertinum Contains

• The active substance is human coagulation factor VII 600 IU (International Units)
• The other components are Sodium heparin (≤ 0.5 IU/IU FVII), Sodium citrate dihydrate, Sodium chloride (see section 2, "Provertinum contains heparin and sodium"), water for injections.

Description of the Appearance of Provertinum and Contents of the Package
Provertinum is a lyophilized powder or friable solid, white or slightly colored.
After reconstitution, the solution may vary in color from colorless to pale yellow or light brown.
Do not use cloudy solutions or those containing particles or precipitates.
Provertinum is available in a pack containing 1 vial of 600 IU powder + 1 vial of 10 ml solvent + reconstitution and infusion set.

Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
Baxalta Innovations GmbH, Industriestrasse 67, 1221 Vienna
Representative in Italy:
Takeda Italia S.p.A.
Tel. +39 06 502601

Manufacturer
Baxter AG
Industriestrasse 67
A - 1221 Vienna, Austria
Takeda Manufacturing Austria AG
Industriestrasse 67
A-1221 Vienna, Austria

The following information is intended exclusively for physicians or healthcare professionals:
DOSAGE, METHOD AND TIME OF ADMINISTRATION
Due to the rarity of the disease, clinical data on the use of factor VII-containing products are limited. Therefore, only general dosage guidelines can be provided, while the required individual dosages must be determined based on regular monitoring of plasma factor VII levels and continuous assessment of the patient's clinical condition.
The dosage and duration of replacement therapy depend on the severity of the factor VII deficiency, the location and extent of bleeding, and the patient's clinical status. The relationship between individual residual factor VII levels and clinical bleeding tendency is less predictable than in classical hemophilia.

The administered amount of factor VII is expressed in International Units (IU), which are standardized according to the current WHO standard for factor VII-containing medicinal products. Plasma factor VII activity is expressed either as a percentage (relative to normal human plasma) or in International Units (relative to an international standard for factor VII concentrates).

One International Unit (IU) of factor VII activity corresponds to the amount of factor VII present in 1 ml of normal human plasma.

The required dose of factor VII is calculated based on the empirical observation that 1 International Unit (IU) of factor VII per kg of body weight increases plasma factor VII activity by approximately 1.9% (0.019 IU/ml) above baseline.

The required dose is calculated using the following formula:
Required Units = Body weight (kg) × Desired increase in factor VII (IU/ml) ×
53*{reciprocal of observed recovery (ml/kg)}
* (since 1/0.019 = 52.6)

Maintenance replacement therapy should be continued consistently until complete absorption of tissue hemorrhage or full wound healing. Therapy should be monitored by repeated coagulation tests.

In acquired factor VII deficiencies, normalization of the hemorrhagic profile can be reliably achieved only by combined administration of Provertinum and Protromplex Tim 3; however, it should be noted that the dose of Provertinum must be twice that of Protromplex Tim 3 due to the differing half-lives. The efficacy of replacement therapy with Provertinum alone or in combination with Protromplex Tim 3 should be monitored using the prothrombin time (Quick's test), or more accurately, the Thrombotest and Normotest. Quantitative assessment is performed by measuring factor VII activity. A decrease in factor V, which occurs only in severe parenchymal liver disease, is not corrected by combined treatment with Protromplex Tim 3 and Provertinum.

In patients undergoing biopsy or surgical intervention, factor VII levels should be raised to 50% for several days. This can be monitored using prothrombin time (Quick's test) or Normotest.

The amount administered and the frequency of administration should always be guided by clinical efficacy in individual cases. This is particularly important in the treatment of factor VII deficiency, as individual bleeding tendency is not strictly correlated with plasma factor VII activity as measured in laboratory tests. The dosing intervals should reflect the short circulating half-life of factor VII, approximately 3–5 hours. When Provertinum is administered by intermittent injection/infusion, an interval of 6–8 hours between doses is often adequate.

In general, in the treatment of factor VII deficiency, lower levels of the deficient factor are required (relative to activity in normal plasma) compared to classical hemophilia (hemophilia A and B). The following table may be used as a guide for intermittent injection/infusion administration based on limited clinical experience. There is no clinical trial evidence supporting efficacy.

| Bleeding Severity / Surgical Procedure | Required Factor VII Level (IU/ml)* | Dosing Frequency (hours) / Duration of Therapy (days) | |----------------------------------------|--------------------------------------|--------------------------------------------------------| | Minor bleeding | 0.10–0.20 | Single dose | | Severe bleeding | 0.25–0.40 (minimum peak) | For 8–10 days or until complete healing** | | Minor surgical procedures | 0.20–0.30 | Single dose before surgery or, if bleeding risk is higher, until wound healing | | Major surgical procedures | Pre-surgery >0.50
Post-surgery 0.25–0.45 (minimum peak) | For 8–10 days or until complete healing** |

* 1 IU/mL = 100 IU/dL = 100% of normal plasma. Plasma factor VII activity is expressed as a percentage (relative to normal plasma) or in International Units (relative to an international standard for plasma factor VII).
** Based on clinical judgment in individual cases, lower doses may be sufficient toward the end of treatment, provided adequate hemostasis has been achieved.

Available data are insufficient to recommend administration of Provertinum in children under 6 years of age.

Method of Administration
The reconstituted product must be administered intravenously.
Administer the solution slowly (not exceeding 2 ml per minute).
Provertinum must be reconstituted only immediately before administration.
Use exclusively the infusion set provided in the package for administration.
Any unused residue must not be reused.

Reconstitution of the Powder

1. Warm the closed vial containing the solvent (10 ml) to room temperature (not exceeding 37°C).
2. Remove the protective caps from the lyophilized powder and solvent vials (Fig. 1) and disinfect the rubber stoppers of both vials.
3. The transfer needle has protective plastic caps on both ends, connected by a welded seal. Rotate one cap to break the seal (Fig. 2), free the needle, and insert it into the rubber stopper of the solvent vial (Fig. 3).
4. Remove the other cap from the transfer needle, taking care not to touch the needle.
5. Invert the solvent vial and insert the free end of the transfer needle halfway into the rubber stopper of the lyophilized powder vial (Fig. 4). Since the lyophilized powder vial is under vacuum, the solvent will be drawn in automatically.
6. Separate the solvent vial (with the needle attached) from the lyophilized powder vial (Fig. 5), and gently swirl the latter to aid dissolution.
7. After complete dissolution of the lyophilized powder, insert the vent needle (Fig. 6); any foam formed will dissipate rapidly. Remove the vent needle.

Administration

1. Rotate the protective cap of the filter needle to break the seal and remove it. Attach the filter needle to the single-use syringe and draw the solution into the syringe (Fig. 7).
2. Remove the filter needle and attach the injection needle (or butterfly needle) to the syringe. Administer the solution slowly (not exceeding 2 ml/min) intravenously.
3. For home treatment, ensure that used needles and syringes are returned to the reconstitution set box and returned to the hemophilia center.

If the solution is administered using an infusion set, the set must include a filter.
Unused medicine and waste material derived from this medicine must be disposed of in accordance with local regulations.
The solution may vary in color from colorless to pale yellow or light brown. Do not use cloudy solutions or those with particles or deposits. The reconstituted product should be inspected visually for particulate matter and discoloration before administration.
The product must be used immediately after reconstitution.

COMPOSITION, PHARMACEUTICAL FORM AND CONTENT
One vial of Provertinum powder contains nominally 600 IU of human coagulation factor VII.
Once reconstituted with 10 ml of water for injections, the product contains approximately 60 IU/ml (600 IU / 10 ml) of human coagulation factor VII.

Powder:

• The active substance is human coagulation factor VII.
• Other components: Sodium heparin (≤ 0.5 IU/IU FVII), Sodium citrate dihydrate, Sodium chloride

Solvent:

• Water for injections

The reconstituted product contains no more than 20 IU FII / 100 IU FVII, no more than 15 IU FIX / 100 IU FVII, and no more than 35 IU FX / 100 IU FVII.

Powder and solvent for solution for infusion.
Lyophilized powder or friable solid, white or slightly colored. After reconstitution, the solution has a pH between 6.5 and 7.5 and an osmolality of not less than 240 mosmol/kg.
Pack: 1 vial of 600 IU powder + 1 vial of 10 ml solvent + reconstitution and infusion set.