ELOCTATE Powder for solution, lyophilized Ref.[49696] Active ingredients: Coagulation factor VIII

General

The clinical response to Eloctatemay vary. If bleeding is not controlled with the recommended dose, the plasma level of factor VIII should be determined, and a sufficient dose of Eloctate should be administered to achieve a satisfactory clinical response. If the patient’s plasma factor VIII level fails to increase as expected or if bleeding is not controlled after Eloctate administration, the presence of an inhibitor (neutralizing antibodies) should be suspected, and appropriate testing performed (see Monitoring and Laboratory Tests).

Catheter-Related Complications

If a central venous access device (CVAD) is required, risk of CVAD-related complications including local infections, bacteremia and catheter site thrombosis should be considered (see ADVERSE REACTIONS).

Carcinogenesis and Mutagenesis

No animal studies investigating carcinogenic effects of Eloctate have been conducted.

Eloctate has not been evaluated in mutagenicity or chromosomal aberration assays.

Cardiovascular

In patients with existing cardiovascular risk factors, substitution therapy with Factor VIII may increase the cardiovascular risk.

Hepatic / Biliary / Pancreatic

Specific studies of Eloctate in patients with hepatic impairment have not been performed.

Immune

Neutralizing Antibodies (Inhibitors)

Inhibitors have been reported with factor replacement therapy in the treatment of hemophilia A. Patients using Eloctate should be monitored for the development of Factor VIII inhibitors by appropriate clinical observations and laboratory tests. Inhibitors have been reported with Eloctate in the treatment of hemophilia A, including in previously untreated patients. If the patient’s plasma Factor VIII level fails to increase as expected or if bleeding is not controlled after Eloctate administration, the presence of an inhibitor (neutralizing antibodies) should be suspected, and appropriate testing performed (see Monitoring and Laboratory Tests).

Anaphylaxis and Hypersensitivity Reactions

Allergic type hypersensitivity reactions, including anaphylaxis, are possible with factor replacement therapies. Hypersensitivity reactions have been reported with ELOCTATE. Advise patients to discontinue use of ELOCTATE if hypersensitivity symptoms occur and contact a physician and/or seek immediate emergency care.

Monitoring and Laboratory Tests

Monitor plasma factor VIII activity levels by performing a suitable test (one-stage clotting assay or chromogenic substrate assay) to confirm adequate factor VIII levels have been achieved and maintained, when clinically indicated (see DOSAGE AND ADMINISTRATION). The potency assignment of Eloctate is determined using a chromogenic substrate assay.

Monitor for the development of factor VIII inhibitors. If bleeding is not controlled with Eloctate and the expected factor VIII activity plasma levels are not attained, perform an assay to determine if factor VIII inhibitors are present (use Bethesda Units to titer inhibitors).

Renal

Eloctate has not been studied in patients with renal impairment.

Reproductive Health: Female and Male Potential

Eloctate has not been evaluated in animal fertility studies. It is not known whether Eloctate can affect fertility or sperm development in hemophilia A patients.

7.1 Special Populations

7.1.1 Pregnant Women

Eloctate should be used during pregnancy only if the potential benefit justifies the potential risk. Animal reproductive studies have not been conducted with Eloctate; however, Eloctate has been shown to cross the placenta in mice. Experience regarding the use of factor VIII during pregnancy is not available. It is not known whether Eloctate can affect reproductive capacity or cause fetal harm when given to pregnant women.

7.1.2 Breast-feeding

Experience regarding the use of factor VIII during breast-feeding is not available. Eloctate should only be administered to nursing mothers if clinically indicated. Lactation studies have not been conducted with Eloctate. It is not known whether Eloctate is excreted into human milk. Caution should be exercised if Eloctate is administered to nursing mothers.

7.1.3 Pediatrics

Pediatrics (<18 years of age): Safety and efficacy of Eloctate have been evaluated in 13 previously treated adolescents aged between 12 to 17 years old in one clinical trial (Study 1). Eleven (11) of them received Eloctate as routine prophylaxis and 2 of them received Eloctate for control of bleeding episodes. No dose adjustment is required. Safety and efficacy of Eloctate have been evaluated in previously untreated pediatric patients (PUPs) <6 years of age (median 0.58 year; range: 0.02-4.00 years) in Study 4 (see ADVERSE REACTIONS and CLINICAL TRIALS).

Study 2 evaluated the safety and efficacy of Eloctate in 71 previously treated patients <12 years of age. All patients received Eloctate as routine prophylaxis. In comparison with adolescents and adults, patients <12 years of age may have a higher clearance and a shorter half-life of Eloctate. These differences should be taken into account when dosing. More frequent or higher dosing may be needed in patients <12 years of age (see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY, Pharmacokinetics).

7.1.4 Geriatrics

Geriatrics (≥ 65 years of age): Clinical studies of Eloctate did not include sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. Dose selection for an elderly patient should be individualized (see DOSAGE AND ADMINISTRATION).

8.1 Adverse Reaction Overview

Hypersensitivity or allergic reactions have been reported with Eloctate and may in some cases progress to anaphylaxis (including shock).

Development of neutralising antibodies (inhibitors) may occur in patients with haemophilia A treated with factor VIII, including with Eloctate. If such inhibitors occur, the condition will manifest itself as an insufficient clinical response. In such cases, it is recommended that a specialised haemophilia centre be contacted.

8.2 Clinical Trial Adverse Reactions

Previously treated patients (PTPs)

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, 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 from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

Eloctate has been evaluated in 276 subjects in five completed studies (Study 1, 2, 3 and two pharmacokinetic studies) in previously treated patients (PTPs) with severe hemophilia A (<1% endogenous FVIII activity or a genetic mutation consistent with severe hemophilia A). Sixty-nine (25%) were pediatric subjects <12 years of age, 25 (9.1%) were adolescents (12 to <18 years of age) and 182 (65.9%) were adults (≥18 years of age). There were 200 subjects treated for at least 104 weeks (2 years), 151 subjects treated for at least 156 weeks (3 years) and 107 subjects treated for at least 208 weeks (4 years). The total number of exposure days (EDs) was 80,848 with a median of 294 (range 1-735) EDs per subject. Adverse events (AEs) were monitored for a total of 893.72 subject-years. A total of 255 subjects had ≥50 EDs; 66 of these were <12 years of age. The subjects received a total of 82,024 injections with a median of 303.5 injections of Eloctate (range 1-755) per subject.

Adverse drug reactions (ADRs) are considered adverse events assessed as related to treatment with Eloctate.

ADRs were reported in 11 of 276 (4.0%) subjects treated with routine prophylaxis or episodic (ondemand) therapy. The ADRs with an incidence ≥0.5% for Eloctate were arthralgia, malaise, myalgia, headache, and rash. No serious ADRs were reported in subjects who received Eloctate. Adverse drug reactions are considered adverse events assessed as related to treatment with Eloctate. No agespecific differences in adverse drug reactions were observed between pediatric and adult subjects. All adverse drug reactions were uncommon (≥1/1,000 to 1/100) and most were mild or moderate in severity. ADRs in PTPs are summarized in Table 4.

One subject was withdrawn from a study due to an adverse drug reaction of rash. In the studies, no inhibitors were detected and no events of anaphylaxis were reported.

Table 4. Adverse Drug Reactions reported for Eloctate in PTPs:

^* The Eloctate clinical program included 276 previously treated patient (PTPs) on routine prophylaxis or episodic (on-demand) therapy from 5 completed studies
¹ Investigator term: vascular pain after injection of study drug
² MedDRA Version 15.0

Previously untreated patients (PUPs)

Eloctate safety was evaluated in 1 completed study (Study 4) in 103 subjects with severe hemophilia A (<1% endogenous FVIII activity). At enrollment, the median age was 0.58 years of age (range: 0.02-4 years). Overall, the median number of weeks on treatment was 64.24 weeks (range: 0.0-206.8 weeks). The number of subjects with at least 10 exposure days (EDs) was 87 (84.5%), at least 20 EDs was 85 (82.5%), and at least 50 EDs was 81 (78.6%).

Adverse drug reactions (ADRs) were reported in 29 of 103 (28.2%) subjects treated with Eloctate. ADRs in PUPs are summarized in Table 5.

Table 5. Adverse Drug Reactions Reportedfor Eloctate in PUPs:

¹ MedDRA version 22.0
² The Eloctate clinical program included 103 previously untreated patients (PUPs) on routine prophyla xis or episodic (ondemand) therapy from 1 study
³ Includes device related thrombosis and deep vein thrombosis, each event occurred in 1 subject with an indwelling central venous catheter

Immunogenicity

No PTPs developed neutralizing antibodies (inhibitors) to Factor VIII in clinical studies (Study 1, 2, 3 and two pharmacokinetic studies).

In Study 4 in PUPs, development of neutralizing antibodies (inhibitors) was observed in 28 subjects, 14 of them had a high-titer inhibitor. Based on subjects with an inhibitor test following an exposure day (ED) milestone or who developed an inhibitor at any time during the study, the incidence of Factor VIII inhibitor development was:

• 28/90 subjects (31.11%) with at least 10 EDs
• 28/86 subjects (32.56%) with at least 50 EDs

The median time to inhibitor development for the 28 subjects was 9 EDs (interquartile range: 6.5-12).

The detection of antibodies that are reactive to Factor VIII is highly dependent on many factors, including the sensitivity and specificity of the assay, sample handling, timing of sample collection, concomitant medications and underlying disease. Therefore, it may be misleading to compare of the incidence of antibodies to Eloctate with the incidence of antibodies to other products.

8.5 Post-Market Adverse Reactions

During post-approval use, the following adverse reactions have been reported: FVIII inhibitor development and hypersensitivity reactions.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

9.4 Drug-Drug Interactions

There are no known drug interactions reported with Eloctate. No drug interaction studies have been performed.

9.5 Drug-Food Interactions

There is no known effect of food on exposure of Eloctate. Therefore, Eloctate may be taken with or without food.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.