ZONOVATE Powder for solution, lyophilized Ref.[49705] Active ingredients: Octocog alfa

3.1 Dosing Considerations

• For intravenous use after reconstitution only.
• ZONOVATE treatment should be initiated under the supervision of a physician experienced in the treatment of hemophilia A.
• The number of units of Factor VIII administered is expressed in International Units (IU), which is related to the current WHO standard for Factor VIII products. The activity of Factor VIII in plasma is expressed either as a percentage (relative to normal human plasma) or in IU (relative to an International Standard for Factor VIII in plasma).
• One IU of Factor VIII activity is equivalent to that quantity of Factor VIII in one mL normal human plasma. The calculation of the required dose of Factor VIII is based on the empirical finding that 1 IU Factor VIII per kg body weight raises the plasma Factor VIII activity by 2 IU/dL. The required dose is determined using the following formula:

Dosage Required (IU) = Body Weight (kg) × Desired Factor VIII Increase (IU/dL or % normal) × 0.5 (IU/kg per IU/dL)

• The dosage and duration of the substitution therapy depend on the severity of the Factor VIII deficiency, on the location and extent of the bleeding and the patient’s clinical condition.
• The amount of ZONOVATE to be administered and frequency of administration should always be oriented to the clinical effectiveness in the individual case.
• When an inhibitor is present, the dosage requirement for ZONOVATE is extremely variable and the dosage can be determined only by the clinical response.

3.2 Recommended Dose and Dosage Adjustment

Treatment and Control of Bleeding Episodes

A guide for dosing ZONOVATE for the treatment and control of bleeding episodes is provided in Table 1-1. Dosing should aim at maintaining a plasma Factor VIII activity level at or above the plasma levels (in % of normal or IU/dL) outlined in Table 1-1.

Table 1-1. Dosing for Treatment and Control of Bleeding Episodes:

Perioperative Management

A guide for dosing ZONOVATE during surgery (perioperative management) is provided in Table 1-2. Consideration should be given to maintaining a plasma Factor VIII activity level at or above the plasma levels (in % of normal or in IU/dL) outlined in Table 1-2.

Table 1-2. Dosing for Perioperative Management:

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

Routine Prophylaxis

A guide for dosing ZONOVATE for routine prophylaxis is included below in Table 1-3.

Table 133. Dosing for Routine Prophylaxis:

Immune Tolerance

Factor VIII products have been administered to patients on a high dose schedule in order to induce immune tolerance to Factor VIII, which resulted in disappearance of the inhibitor activity. There is currently no consensus among treaters to the optimal treatment schedule.

3.3 Administration

• The recommended infusion rate for ZONOVATE is 1-2 mL/min. The rate should be determined by the patient’s comfort level.
• Do not mix ZONOVATE with any other intravenous infusions or medications.

Injecting ZONOVATE via needleless connectors for intravenous (IV) catheters

The prefilled solvent syringe with sterile vial adapter, together serve as a needleless reconstitution system named the MixPro.

Caution: The MixPro prefilled solvent syringe is made of glass and is designed to be compatible with standard luer-lock connections. Some needleless connectors with an internal spike are incompatible with the prefilled syringe. This incompatibility may prevent administration of the drug and/or result in damage to the needleless connector.

Follow the instructions for use that come with the needleless connector. Administration through a needleless connector may require withdrawal of the reconstituted solution into a standard 10 mL sterile luer-lock plastic syringe.

If you have encountered any problems with attaching the prefilled solvent syringe to any luerlock compatible device, or have any questions please contact Novo Nordisk at 1-800-465-4334.

For detailed instructions on how to administer ZONOVATE refer to the PATIENT MEDICATION INFORMATION section of the Product Monograph.

3.4 Reconstitution

Table 1-4. Reconstitution:

• ZONOVATE is recommended to be used immediately after it has been reconstituted.
• If you cannot use the reconstituted ZONOVATE solution immediately, it must be used within 24 hours when stored in the refrigerator at 2°C-8°C, within 4 hours when stored at room temperature ≤30°C, or within 2 hours when stored between 30°C and 40°C. Store the reconstituted product in the vial, with the vial adapter and the syringe still attached.
• Do not freeze reconstituted ZONOVATE solution or store it in syringes. Keep reconstituted ZONOVATE solution out of direct light.
• After reconstitution, the solution appears as a clear or slightly opalescent (slightly unclear) solution. Do not use solutions that are cloudy or have deposits.

3.5 Missed Dose

Double doses are generally not required to compensate for forgotten individual doses. Patients should be advised to proceed immediately with a regular administration of ZONOVATE and to continue treatment at regular intervals as required.

No symptoms associated with overdose were reported.

For management of a suspected drug overdose, contact your hemophilia treatment centre or your regional poison control centre.

Prior to Reconstitution

Store in refrigerator (2°C-8°C). Do not freeze.

Keep the vial in the outer carton in order to protect from light.

ZONOVATE vials can be stored in the refrigerator (2°C-8°C) up to the expiration date stated on the label.

During the shelf-life, ZONOVATE may also be stored at room temperature:

• up to 30°C for a single period not exceeding 12 months or
• up to 40°C for a single period not exceeding 3 months

Once the product has been taken out of the refrigerator the product must not be returned to the refrigerator. Record the date when the product was removed from the refrigerator in the space provided on the product carton.

Do not use ZONOVATE after the end of the specified room temperature storage period at up to 30°C or 40°C, or after the expiration date stated on the carton, whichever occurs earlier.

After Reconstitution

Chemical and physical in-use stability have been demonstrated for 24 hours when stored in a refrigerator at 2°C-8°C, 4 hours when stored at room temperature up to 30°C, and 2 hours when stored between 30°C and 40°C.

From a microbiological point of view, ZONOVATE should be used immediately after reconstitution. If the reconstituted product is not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than as stated above, unless reconstitution has taken place in controlled and validated aseptic conditions.

The reconstituted solution should be stored in the vial, with the vial adapter and the syringe still attached.

Discard any unused reconstituted product.