Nuwiq (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Octapharma AB (Sweden)

Manufactured By

Octapharma AB (Sweden)

Primary Packaging

OCTAPHARMA AB (Sweden)

Secondary Packaging

OCTAPHARMA DESSAU GmbH (Germany)

Or

SCOPINPHARM, LLC (Russia)

Quality Control Release

OCTAPHARMA AB (Sweden)

Contact Information

OCTAPHARMA NORDIC AB (Sweden)

ATC Code

B02BD02 (Blood coagulation factor VIII)

Active Substance

Simoctocog alfa (Rec.INN registered by WHO)

Dosage Forms

	Nuwiq	Lyophilisate for preparation of solution for intravenous administration 250 IU: vial 1 pc. in a kit with solvent, adapter, administration system, and wipes
		Lyophilisate for preparation of solution for intravenous administration 500 IU: vial 1 pc. in a kit with solvent, adapter, administration system, and wipes
		Lyophilisate for preparation of solution for intravenous administration 1000 IU: vial 1 pc. in a kit with solvent, adapter, administration system, and wipes
		Lyophilisate for preparation of solution for intravenous administration 2000 IU: vial 1 pc. in a kit with solvent, adapter, administration system, and wipes

Dosage Form, Packaging, and Composition

Lyophilisate for preparation of solution for intravenous administration as a white mass, possibly with a small amount of white powder; reconstituted solution – a clear or slightly opalescent colorless solution.

Excipients: sodium chloride – 45 mg, sucrose – 13.5 mg, arginine hydrochloride – 13.5 mg, calcium chloride dihydrate – 0.75 mg, poloxamer 188 – 3 mg, sodium citrate dihydrate – 3 mg.

Solvent: water for injections 2.5 ml in a syringe.

250 IU – vials of transparent colorless glass (1) in a kit with solvent (1 syringe in blister packaging), 1 vial adapter in blister packaging, 1 administration system (“butterfly needle”) in blister packaging, 2 disinfectant wipes in individual sealed packages – cardboard packs with an insert.

Lyophilisate for preparation of solution for intravenous administration as a white mass, possibly with a small amount of white powder; reconstituted solution – a clear or slightly opalescent colorless solution.

Excipients: sodium chloride – 45 mg, sucrose – 13.5 mg, arginine hydrochloride – 13.5 mg, calcium chloride dihydrate – 0.75 mg, poloxamer 188 – 3 mg, sodium citrate dihydrate – 3 mg.

Solvent: water for injections 2.5 ml in a syringe.

500 IU – vials of transparent colorless glass (1) in a kit with solvent (1 syringe in blister packaging), 1 vial adapter in blister packaging, 1 administration system (“butterfly needle”) in blister packaging, 2 disinfectant wipes in individual sealed packages – cardboard packs with an insert.

Lyophilisate for preparation of solution for intravenous administration as a white mass, possibly with a small amount of white powder; reconstituted solution – a clear or slightly opalescent colorless solution.

Excipients: sodium chloride – 45 mg, sucrose – 13.5 mg, arginine hydrochloride – 13.5 mg, calcium chloride dihydrate – 0.75 mg, poloxamer 188 – 3 mg, sodium citrate dihydrate – 3 mg.

Solvent: water for injections 2.5 ml in a syringe.

1000 IU – vials of transparent colorless glass (1) in a kit with solvent (1 syringe in blister packaging), 1 vial adapter in blister packaging, 1 administration system (“butterfly needle”) in blister packaging, 2 disinfectant wipes in individual sealed packages – cardboard packs with an insert.

Lyophilisate for preparation of solution for intravenous administration as a white mass, possibly with a small amount of white powder; reconstituted solution – a clear or slightly opalescent colorless solution.

Excipients: sodium chloride – 45 mg, sucrose – 13.5 mg, arginine hydrochloride – 13.5 mg, calcium chloride dihydrate – 0.75 mg, poloxamer 188 – 3 mg, sodium citrate dihydrate – 3 mg.

Solvent: water for injections 2.5 ml in a syringe.

2000 IU – vials of transparent colorless glass (1) in a kit with solvent (1 syringe in blister packaging), 1 vial adapter in blister packaging, 1 administration system (“butterfly needle”) in blister packaging, 2 disinfectant wipes in individual sealed packages – cardboard packs with an insert.

Clinical-Pharmacological Group

Human recombinant blood coagulation factor VIII

Pharmacotherapeutic Group

Hemostatic agent

Pharmacological Action

Simoctocog alfa, human blood coagulation factor VIII (rDNA), is a highly purified protein consisting of 1440 amino acids. The amino acid sequence is comparable to that of coagulation factor VIII (factor VIII) from human plasma, consisting of two chains with a molecular weight of 90 kDa and 80 kDa and lacking the B-domain. The drug is produced using recombinant DNA technology from human embryonic kidney cell lines (HEK 293F cells). No human or animal-derived substances are added during the production process or to the finished product.

The post-translational modifications of Nuwiq are similar to those of endogenous factor VIII in healthy individuals, and unlike factor VIII preparations from hamster cell lines, the recombinant factor VIII preparation from human cell lines does not have carbohydrate epitopes with antigenic properties.

The factor VIII/von Willebrand factor complex consists of two molecules (factor VIII and von Willebrand factor) with different physiological functions. When administered to patients with hemophilia, factor VIII binds to von Willebrand factor in the bloodstream. Activated factor VIII acts as a co-factor for activated factor IX, accelerating the conversion of factor X to activated factor X. Activated factor X converts prothrombin to thrombin. Thrombin then converts fibrinogen to fibrin, allowing a clot to form. Hemophilia A is a sex-linked hereditary coagulation disorder associated with reduced levels of factor VIII, leading to profuse bleeding into joints, muscles, or internal organs, either spontaneously or as a result of accidental trauma or surgery. Replacement therapy achieves temporary correction of the factor VIII deficiency in plasma and correction of bleeding.

The immunogenicity of Nuwiq was studied in clinical trials involving 135 patients with severe hemophilia A, previously treated (74 adults and 61 children). None of the patients developed inhibitors.

In a clinical study involving 32 adult patients with severe hemophilia A, the average consumption of Nuwiq for prophylaxis was 468.7 IU/kg per month. The average dose for treating acute bleeding episodes was 33.0 IU/kg for patients receiving Nuwiq prophylactically. In another clinical study, 22 adult patients received on-demand treatment. A total of 986 bleeding episodes required treatment with an average dose of 30.9 IU/kg. In general, minor bleeding requires slightly lower doses of the drug, while more severe bleeding requires doses up to three times the average dose.

Pharmacodynamics in children

Data were obtained from 29 previously treated children aged 2 to 5 years, 31 aged 6 to 12 years, and one over 14 years old. The average dose of prophylactic infusions was 37.8 IU/kg. Twenty patients received an average dose of more than 45 IU/kg. The average consumption of Nuwiq for prophylaxis was 521.9 IU/kg per month. Studies have shown that for treating bleeding episodes in children, the average dose of Nuwiq (43.9 IU/kg) is higher than in adults (33.0 IU/kg), and also that the average dose required to stop moderate to severe bleeding is higher than for mild bleeding (78.2 IU/kg vs. 41.7 IU/kg). Younger children generally require a higher average dose (6-12 years: 43.9 IU/kg, 2-5 years: 52.6 IU/kg).

Pharmacokinetics

Table 1. Pharmacokinetics of Nuwiq (50 IU/kg) in adults aged 18 to 65 years with severe hemophilia A, previously treated (n=20)

AUC = area under the curve (FVIII:C), T_1/2 = half-life, IVR = in vivo recovery, CL = clearance, SD = standard deviation.

Pharmacokinetics in children

According to the literature, the recovery time and T_1/2 are somewhat shorter in children than in adults, while the clearance of the drug is higher in children, which may be related to the known fact that plasma volume per kilogram of body weight is higher in children than in adults.

Subgroup analysis by body weight

Table 4. Pharmacokinetics of Nuwiq (50 IU/kg) depending on body weight in adults aged 18 to 65 years with severe hemophilia A, previously treated (n=20)

Normal body weight: BMI 18.5-25 kg/m²
Pre-obesity: BMI 25-30 kg/m²
Obesity: BMI >30 kg/m²

Indications

• Treatment and prophylaxis of bleeding in patients with hemophilia A (congenital deficiency of blood coagulation factor VIII).

Nuwiq can be used in all age groups of patients.

ICD codes

Dosage Regimen

Treatment should be carried out by a physician experienced in the treatment of patients with hemophilia. The drug is administered intravenously after reconstitution with the supplied solvent (water for injections). Only the supplied devices for reconstitution and administration should be used, as adsorption of factor VIII onto the inner surface of any other containers and devices for injection may render the treatment ineffective.

The infusion rate should not exceed 4 ml/min.

The dose and duration of replacement therapy depend on the degree of factor VIII deficiency, the location and severity of the bleeding, and the patient’s clinical condition.

The number of factor VIII units in the preparation is expressed in International Units (IU), established by the current WHO standard for factor VIII preparations. Factor VIII activity in plasma is expressed as a percentage (relative to the factor VIII content in normal human plasma) or in IU (relative to the International Standard for factor VIII).

1 IU of factor VIII activity is equivalent to the factor VIII content in 1 ml of normal human plasma.

On-demand therapy regimen

The calculation of the required dose is based on empirically obtained results, according to which 1 IU of factor VIII/kg body weight increases the plasma factor VIII activity level by approximately 2% of normal activity (or 2 IU/dl). The required dose is calculated using the formula

• Required dose = body weight (kg) × desired increase in factor VIII level (%) (IU/dl) × 0.5 (IU/kg per IU/dl)
• Expected increase in factor VIII level (% of normal): 2 × administered factor VIII (IU) / body weight (kg)

Doses and frequency of administration should always be tailored to achieve the clinical effect in each individual case.

In the case of subsequent bleeding episodes, the factor VIII activity level should not fall below the target plasma activity level (% of normal) at the appropriate time. The table below can be used as a guide for selecting doses for various bleeding episodes and surgical interventions.

Table 5. Recommended doses of Nuwiq for various types of bleeding and surgical interventions

Prophylaxis therapy regimen

For long-term prophylaxis of bleeding in patients with severe hemophilia A, the average dose of factor VIII is 20-40 IU/kg body weight at intervals of 2-3 days.

In some cases, especially in younger patients, it may be necessary to shorten the interval between administrations or to increase the dose.

During the course of treatment, it is recommended to determine the factor VIII level to adjust the dose and frequency of repeated administrations. In the case of major surgical interventions, careful monitoring of replacement therapy by monitoring blood coagulation (plasma factor VIII activity) is necessary. The response to treatment may vary among individual patients, indicating differences in half-life and recovery.

Previously untreated patients

Information on the safety and efficacy of Nuwiq in previously untreated patients is currently unavailable.

Use in children

The use of the drug in children corresponds to that in adults; however, shorter administration intervals or higher doses may be required for children.

Preparation of the drug for administration

The lyophilisate is reconstituted using the supplied solvent (2.5 ml water for injections) and the devices for reconstitution and administration. The reconstituted solution should be colorless, clear or slightly opalescent, with a pH from 6.5 to 7.5.

The reconstituted drug should be used immediately.

Instructions for preparation and administration

1. Bring the syringe with solvent (water for injections) and the closed vial with lyophilisate to room temperature. They can be warmed in the hand. Do not use any other heating methods. Maintain room temperature of the preparation during reconstitution.
2. Remove the plastic flip-off cap from the vial with lyophilisate. Do not remove the aluminum cap and do not remove the rubber stopper.

1. Wipe the top of the vial with a disinfectant alcohol wipe. Allow the alcohol to dry.
2. Remove the paper cover from the vial adapter packaging. Do not remove the adapter from the packaging.

1. Place the vial with lyophilisate on a flat surface and hold it. Place the packaging with the adapter tip down in the center of the rubber stopper. Press firmly on the adapter so that the needle pierces the stopper. When the adapter is correctly positioned, a click will be heard.

1. Remove the paper cover from the syringe packaging. Hold the plunger rod by the end and do not touch the pin. Insert the threaded end of the plunger rod into the plunger of the syringe with solvent. Turn the plunger rod clockwise until slight resistance is felt.

1. Break off the plastic cap with the tamper evidence from the solvent syringe along the cap’s perforation. Do not touch the inside of the cap or the exposed end of the syringe. If the solution is not to be used immediately, the syringe must be closed with the plastic cap for storage.

1. Remove the packaging from the vial adapter and place it in the waste container.
2. Firmly connect the solvent syringe to the vial adapter by turning clockwise until resistance is felt.

1. By pressing the plunger rod, gently introduce the solvent into the vial with the lyophilisate.

1. Without removing the syringe, gently rotate the vial or swirl it until the lyophilisate is completely dissolved. Do not shake the vial.
2. Before administration, be sure to inspect the solution for particles and discoloration. The solution should be clear and colorless. Do not use a cloudy solution or a solution containing particles.
3. Turn the vial with the attached syringe upside down and slowly draw the solution back into the syringe. Ensure that all the contents of the vial are transferred into the syringe.

1. Disconnect the filled syringe from the vial adapter by turning it counterclockwise, and place the empty vial in the waste container.
2. The solution in the syringe is ready for administration. Do not refrigerate after reconstitution. The prepared solution after reconstitution should be used immediately.
3. Clean the injection site with one of the provided disinfectant wipes.
4. Attach the provided administration system (butterfly needle) to the syringe. Insert the butterfly needle into the selected vein. If a tourniquet is used to facilitate vein puncture, the tourniquet must be removed before administering the solution. Care should be taken to prevent blood from entering the syringe to avoid the risk of fibrin clot formation.
5. Slowly inject the solution into the vein (at a rate not exceeding 4 ml/min).

If multiple vials of the drug are planned for a single administration procedure, the same needle can be used to administer the reconstituted drug from other vials.

The vial adapter and syringe are for single use only.

Unused drug or waste materials should be disposed of in accordance with local regulations.

Adverse Reactions

Overall safety profile

Hypersensitivity or allergic reactions (which may include angioedema, burning and itching at the injection site, chills, facial flushing, generalized urticaria, headache, localized urticaria, hypotension, lethargy, nausea, restlessness, tachycardia, chest tightness, tinnitus, vomiting, wheezing) have been observed rarely with Factor VIII products, but in some cases have progressed to severe anaphylaxis (including shock).

In clinical studies of Nuwiq in previously treated children (2 to 11 years, n=58), adolescents (12 to 17 years, n=3), and adult patients (n=74) with severe hemophilia A, a total of 8 adverse reactions (6 in adults and 2 in children) were reported in 5 patients (3 adults and 2 children). No adverse reactions were observed in adolescents. The total number of patients in the studies was 135.

Table 6. Summary of adverse reaction frequencies in clinical studies in previously treated patients with severe hemophilia A

* All listed adverse reactions occurred once.

Description of selected adverse reactions

Non-neutralizing antibodies to Factor VIII were detected in one adult patient. The test was performed in a central laboratory at eight dilutions. The result was positive only at a dilution factor of 1, with a very low antibody titer. Inhibitory activity was not detected by the modified Bethesda assay. Clinical efficacy and in vivo recovery of Nuwiq activity were unchanged in this patient.

Use in children

The frequency, type, and severity of adverse reactions in children are expected to be similar to those in adults.

Contraindications

• Hypersensitivity to the active substance or to any of the components of the drug.

Use in Pregnancy and Lactation

Since hemophilia A is rarely observed in women, there is no experience with the use of Factor VIII during pregnancy and breastfeeding. Therefore, Nuwiq should be used during pregnancy and lactation only if absolutely indicated.

Pediatric Use

Nuwiq can be used in all age groups of patients.

Geriatric Use

Nuwiq can be used in all age groups of patients.

Special Precautions

Hypersensitivity

As with any protein product for intravenous administration, allergic hypersensitivity reactions may occur. Nuwiq contains traces of human host proteins other than Factor VIII. If symptoms of a hypersensitivity reaction occur, the patient should discontinue use of the drug immediately and consult a doctor. Patients should be informed of the early signs of hypersensitivity reactions, including allergic rash, generalized urticaria, chest tightness, wheezing, hypotension, and anaphylaxis.

In case of shock, standard treatment should be administered.

Inhibitors

The formation of neutralizing antibodies (inhibitors) to Factor VIII is a known complication in the treatment of patients with hemophilia A. These inhibitors are typically immunoglobulins IgG directed against the procoagulant activity of Factor VIII, measured in modified Bethesda units (BU) per ml of plasma using a modified method.

The risk of inhibitor development correlates with the number of exposure days to Factor VIII and is highest during the first 20 exposure days. In rare cases, inhibitors may appear after the first 100 exposure days.

Cases of recurrent inhibitor development (with low titer) have been observed after switching from treatment with one Factor VIII product to another in previously treated patients (more than 100 exposure days) with a history of inhibitor development. Therefore, careful monitoring of patients for inhibitor development is recommended after switching from one Factor VIII product to another.

In general, patients receiving treatment with Factor VIII products should be carefully monitored for the development of inhibitors through appropriate clinical observation and laboratory tests (periodic determination of Factor VIII activity levels should be performed). If the expected plasma level of Factor VIII activity is not achieved, or if bleeding is not controlled with an adequate dose, an appropriate analysis for Factor VIII inhibitors should be performed. In patients with high levels of inhibitors, treatment with Factor VIII may be ineffective, and the use of alternative treatments (e.g., immune tolerance induction) should be considered. Treatment of such patients should be managed by a physician experienced in the treatment of hemophilia with Factor VIII inhibitors.

Catheter-related complications

When using a central venous access device, the risk of complications associated with its use should be considered, including local infections, bacteremia, and catheter site thrombosis.

With each administration of Nuwiq, the patient is strongly advised to record the name of the drug and the batch number so that a connection between the patient’s condition and the administration of a specific batch can be traced.

Use in children

The above instructions apply equally to adults and children.

Limitations related to excipients

One vial of the drug contains < 1 mmol (23 mg) of sodium. However, depending on body weight and indications, a patient may use more than one vial of the drug. This should be considered for patients on a sodium-restricted diet.

Effect on ability to drive and use machines

Nuwiq does not affect the ability to drive vehicles and operate machinery or engage in other potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Overdose

No cases of overdose have been reported.

Drug Interactions

Studies of interactions of Nuwiq with other medicinal products have not been conducted.

Due to the lack of compatibility studies, this drug should not be mixed with other drugs.

Storage Conditions

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

Shelf Life

Shelf life is 2 years. Do not use after the expiration date.

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.