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

General

Identification of the clotting defect as Factor VIII deficiency is essential before the administration of ZONOVATE. No benefit may be expected from this product in treating other coagulation factor deficiencies.

Carcinogenesis and Mutagenesis

Long-term studies in animals to evaluate the carcinogenic potential of ZONOVATE, or studies to determine the effects of ZONOVATE on genotoxicity or fertility have not been performed. An assessment of the carcinogenic potential of ZONOVATE was completed, and no carcinogenic risk from product use has been identified.

Driving and Operating Machinery

ZONOVATE has no influence on the ability to drive and use machines.

Immune

Hypersensitivity

As with any intravenous protein product, allergic type hypersensitivity reactions are possible with ZONOVATE. The product contains traces of hamster proteins, which in some patients may cause allergic reactions. If symptoms of hypersensitivity occur, patients should be advised to discontinue use of ZONOVATE immediately and contact their physician and/or seek emergency medical treatment. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis.

In case of anaphylactic shock, standard medical treatment should be implemented.

Inhibitors

The formation of neutralizing antibodies (inhibitors) to Factor VIII is a known complication in the management of individuals with hemophilia A. These inhibitors are usually IgG immunoglobulins directed against the Factor VIII procoagulant activity, which are quantified in Bethesda Units (BU) per mL of plasma using the modified assay.

The risk of developing inhibitors is correlated to the exposure to Factor VIII, the risk being highest within the first 50 exposure days but continues throughout life although the risk is uncommon. The clinical relevance of inhibitor development will depend on the titre of the inhibitor, with low titre inhibitors which are transiently present or remain consistently low titre, posing less of a risk of insufficient clinical response than high titre inhibitors.

All patients treated with ZONOVATE should be carefully monitored for the development of inhibitors by appropriate clinical observation and laboratory testing (see Monitoring and Laboratory Tests Section).

Monitoring and Laboratory Tests

Patients should be monitored for the development of Factor VIII inhibitors. If the expected plasma levels of Factor VIII activity are not attained, or if bleeding is not controlled with an appropriate dose, an assay should be performed to determine if a Factor VIII inhibitor is present. In patients with high levels of inhibitors, Factor VIII therapy may not be effective and other therapeutic options should be considered. Management of such patients should be directed by physicians with experience in the care of patients with hemophilia and Factor VIII inhibitors.

When using an in vitro thromboplastin time (aPTT)-based one stage clotting assay for determining Factor VIII activity in blood samples, plasma Factor VIII activity results can be significantly affected by both the type of aPTT reagent and the reference standard used in the assay. Also, there can be significant discrepancies between assay results obtained by aPTTbased one stage clotting assay and the chromogenic assay. This is of importance particularly when changing the laboratory and/or reagents used in the assay.

Peri-Operative Considerations

ZONOVATE is indicated in the perioperative management of patients with hemophilia A. Careful control of replacement therapy is important, especially in cases of major surgery or life threatening hemorrhages. There is limited experience of surgery in pediatric patients.

Reproductive Health: Female and Male Potential

Fertility

It is not known if ZONOVATE can affect fertility.

7.1 Special Populations

7.1.1 Pregnant Women

Animal reproduction studies have not been conducted with ZONOVATE. Based on the rare occurrence of hemophilia A in women, experience regarding the use of Factor VIII during pregnancy is not available. Therefore, ZONOVATE should only be used during pregnancy if clearly indicated.

7.1.2 Breast-feeding

It is not known whether ZONOVATE is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ZONOVATE is administered to a nursing woman.

7.1.3 Pediatrics

Pediatrics (<18 years of age)

Children have a shorter half-life and lower recovery of Factor VIII than adults. Because clearance (based on per kg body weight) has been demonstrated to be higher in the pediatric population, higher or more frequent dosing based on body weight may be needed [see ACTION AND CLINICAL PHARMACOLOGY/ Pharmacokinetics (10.3)].

7.1.4 Geriatrics

Geriatrics (>65 years of age)

Clinical studies of ZONOVATE did not include patients above 65 to determine whether they respond differently from younger patients.

8.1 Adverse Reaction Overview

In previously treated patients (PTPs) during all clinical studies (3 clinical and 4 pharmacokinetic trials) with ZONOVATE, a total of 35 adverse reactions were reported in 23 of 242 patients exposed to ZONOVATE. Of the 35 adverse reactions, 2 were reported in 1 out of 31 patients below 6 years of age, none in 32 patients from 6 to 12 years of age, 1 in 1 of 24 patients from 12 to <18 years of age, and 32 in 21 of 155 adults (≥18 years). The most frequently reported adverse reactions were injection site reactions (1.2%).

In previously untreated patients (PUPs) aged 0-6 years, a total of 46 adverse reactions were reported in 33 of 60 patients exposed to ZONOVATE during 1 clinical trial. The most frequently reported adverse reaction was Factor VIII inhibition (44.8%) and pyrexia (3.3%).

Immunogenicity

Patients were monitored for neutralizing antibodies (inhibitors) against Factor VIII, as well as for antibodies against Chinese Hamster Ovaries (CHO) and murine proteins.

FVIII inhibitors:

In PTPs without a history of inhibitors, FVIII inhibitor development was not observed during an accumulated exposure of more than 130,000 EDs (854.9 patient years) in the 3 clinical trials and 4 pharmacokinetic trials. A twenty-two month old child had one positive FVIII inhibitor test (1.3 BU) in the Bethesda assay after fifteen exposure days. However, the result was not confirmed by a second sample taken after an additional five days of exposure. In vivo recovery of Factor VIII was normal and no clinical adverse findings were observed in the patient.

In the PUP trial (accumulated exposure of more than 10,000 EDs or 115.4 patient years), FVIII inhibitor development was observed in 26 of 58 (44.8%) patients. High titre inhibitors defined as a peak titre ≥5 BU accounted for 16 of the 26 inhibitor cases (61.5%) [or for 16 of 58 patients (27.6%)]. Mean time to inhibitor development was 17.5 EDs. High risk genetic mutations (e.g., nonsense, deletions, insertions, inversions) were identified in 92.3% of the 26 cases.

Anti-CHO antibodies:

No clinical adverse findings were observed in relation to anti-CHO antibodies (Ab). Anti-CHO Ab were detected in 19 patients. In two patients, anti-CHO Ab were detected only after treatment, whereas in 6 patients anti-CHO Ab were only detected prior to treatment. In the remaining 11 subjects, Ab were either detected throughout the trial (in 6 subjects), detected only transiently (in 2 subjects), or detected at baseline and end-of trial but undetectable during treatment (in 3 subjects). No data is available in PUPs.

Anti-murine antibodies:

No patients developed de novo anti-murine antibodies.

8.2 Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information fr om clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 1-6 summarises the Adverse Drug Reactions from all clinical studies (3 clinical and 4 pharmacokinetic trials) in previously treated patients (PTPs); Table 1-7 summarises the Adverse Drug Reactions from a clinical trial in previously untreated patients (PTPs).

Table 1-6. Summary of Adverse Drug Reactions with a Frequency of ≥ 1% in Clinical Studies in Previously Treated Patients*:

^* Calculated based on total number of unique patients in all clinical studies (242).
^** Injection site reactions include: injection site erythema, injection site extravasation and injection site pruritus.

Table 1-7. Summary of Adverse Drug Reactions with a Frequency of ≥1% in a Clinical Study in Previously Untreated Patients:

8.3 Less Common Clinical Trial Adverse Reactions (<1%)

Cardiac disorders: Acute myocardial infarction (0.4%), sinus tachycardia (0.4%)

General disorders and administration site conditions: Pyrexia (0.8%), fatigue (0.4%), feeling hot (0.4%), peripheral swelling (0.4%)

Injury, poisoning and procedural complications: Contusion (0.4%)

Investigations: Hepatic enzymes increased (0.8%), alanine aminotransferase increased (0.4%), aspartate aminotransferase increased (0.4%), heart rate increased (0.4%)

Musculoskeletal and connective tissue disorders: Arthropathy (0.8%), musculoskeletal pain (0.4%), musculoskeletal stiffness (0.4%), pain in extremity (0.4%)

Nervous System Disorders: Burning sensation (0.4%), dizziness (0.4%), headache (0.4%)

Psychiatric disorders: Insomnia (0.4%)

Skin and subcutaneous tissue disorders: Lichenoid keratosis (0.4%), rash (0.4%), skin burning sensation (0.4%)

Vascular disorders: Hyperemia (0.4%), hypertension (0.4%), lymphedema (0.4%)

8.4 Post-Market Adverse Reactions

Overall, the distribution, pattern and type of adverse drug reactions received from postmarketing sources are comparable to the adverse drug reactions from clinical trials. Postmarketing cases of inhibitor development have been reported in both previously untreated patients (PUPs) and previously treated patients (PTPs).

9.1 Overview

No interactions of human coagulation Factor VIII (rDNA) products with other medicinal products have been reported.