Eloctate

Mechanism Of Action

ELOCTATE is a recombinant fusion protein that temporarily replaces the missing Coagulation Factor VIII needed for effective hemostasis. ELOCTATE contains the Fc 12 region of human immunoglobulin G1 (IgG1), which binds to the neonatal Fc receptor (FcRn). FcRn is part of a naturally occurring pathway that delays lysosomal degradation of immunoglobulins by cycling them back into circulation and prolonging their plasma half-life.

Pharmacodynamics

Hemophilia A is a bleeding disorder characterized by a deficiency of functional coagulation Factor VIII, resulting in a prolonged, patient plasma clotting time as measured by the activated partial thromboplastin time (aPTT) assay. Treatment with ELOCTATE™ normalizes the aPTT over the effective dosing period.

Pharmacokinetics

The pharmacokinetics (PK) of ELOCTATE™ (rFVIIIFc) were evaluated in 28 subjects following a 10 minute intravenous infusion of a single dose of 50 IU/kg. The PK parameters (Table 4) were based on plasma FVIII activity measured by the one-stage clotting assay. The PK profile obtained at week 14, after repeated dosing, was comparable with the PK profile obtained after the first dose. The PK data demonstrate that ELOCTATE™ has a prolonged circulating half-life.

Table 4: Pharmacokinetic Parameters (Arithmetic Mean, 95% CI)

Pharmacokinetic (PK) parameters of ELOCTATE were determined for adolescents (ages 12 to 17 years) in the phase 3 study and for children (ages 2 to 5 years and 6 to 11 years) in an open-label, multi-center study of pediatric, previously treated patients. [see Pediatric Use]

Table 5 presents the PK parameters calculated from the pediatric data of 48 subjects, less than 18 years of age, after receiving a single 50 IU/kg dose. Compared to adults and adolescents, body weight adjusted clearance was higher in children 2 to 5 years of age. These results indicate a need for dose adjustments in children 2 to 5 years of age. [see Pediatric Use]

The PK evaluation of pediatric subjects, ages 6 to 17 years, showed that their PK profiles and arithmetic means of PK parameters are similar to those of adults. Therefore, for subjects 6 years and older, an age-based dose adjustment is not required.

Table 5: Comparison of PK Parameters of ELOCTATE by Age

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long term animal studies investigating the carcinogenic effects of ELOCTATE have not been conducted. Iin vitro and in vivo testing of ELOCTATE for mutagenicity or effects on fertility was not performed.

Clinical Studies

The safety and efficacy of ELOCTATE was evaluated in a multi-center, prospective, open-label, clinical trial that compared the efficacy of each of two prophylactic treatment regimens (individualized interval and fixed weekly) to episodic (on-demand) treatment; determined hemostatic efficacy in the treatment of bleeding episodes; and determined hemostatic efficacy during perioperative management in subjects undergoing major surgical procedures. The study enrolled a total of 165 previously treated male patients (PTPs) with severe Hemophilia A ( < 1% endogenous Factor VIII activity or a genetic mutation consistent with severe Hemophilia A). Subjects were aged 12 to 65 years, including 13 pediatric subjects aged 12 to 17 years. Of the 165 enrolled subjects, 164 received at least one dose of ELOCTATE and 163 (98%) were evaluable for efficacy. A total of 153 subjects (93%) completed the study.

A total of 757 bleeding episodes in 106 subjects were treated with ELOCTATE. The majority of the bleeding episodes were spontaneous and localized in joints. The median dose per injection used to treat a bleeding episode was 27.35 (IQR 22.73, 32.71) IU/kg. Assessment of response to each injection was recorded by subjects at 8-12 hours after treatment. Efficacy in control of bleeding episodes is summarized in Table 6.

Table 6: Summary of ELOCTATE Efficacy in Control of Bleeding

Nine major surgical procedures (two laparoscopic, inguinal hernia repairs, five knee surgeries, one appendectomy and one arthroscopy) were performed in nine subjects. The median, pre-operative dose was 51 IU/kg (range 50 – 77). The total dose on the day of surgery ranged from 66 to 115 IU/kg. The hemostatic response for all but one surgery was rated as excellent (blood loss/transfusions less than or similar to a nonhemophilic patient; no extra dose of ELOCTATE needed) and the remaining surgery was rated as good (blood loss no more than 250 mL greater than expected, no extra dose of ELOCTATE needed). An additional 14 minor surgical procedures were performed in 12 subjects. Hemostatic response was available for 12 minor surgeries; it was rated as excellent for 11 and good for 1.

The efficacy of routine prophylaxis (individualized and fixed-weekly regimens) was evaluated against on-demand treatment. A total of 117 subjects received an individualized, twice weekly regimen, which started with 25 IU/kg on the first day followed by 50 IU/kg on the fourth day. The dose and interval were adjusted within the range of 25 – 65 IU/kg every 3-5 days to maintain trough levels between 1% and 3% above baseline, or higher, as clinically indicated to prevent bleeding. The median dosing interval was 3.5 days. Among the 112 subjects treated for at least 6 months, 111 (99%) achieved a dosing interval of three days or longer, 39 (35%) achieved a dosing interval of 4 days or longer, and 33 (29%) achieved a dosing interval of 5 days or longer during the last 3 months on study. Twenty-three subjects received 65 IU/kg of ELOCTATE once weekly for a median period of 28 weeks. An additional 23 subjects received episodic (on-demand) doses of ELOCTATE for the treatment of bleeding episodes and were on study for a median period of 29 weeks. Using a negative binomial model to analyze the annualized bleeding rate (ABR), there was a statistically significant reduction in ABR of 92% (p < 0.001) for subjects in the individualized prophylaxis arm and a statistically significant reduction of 76% (p < 0.001) for subjects in the weekly prophylaxis arm compared to the episodic (on-demand) arm. Fifty-three (53) of 117 (45%) subjects experienced no bleeding episodes while on individualized prophylaxis and 4 of 23 (17%) subjects experienced no bleeding episodes while on weekly prophylaxis.

Median ABRs in subjects evaluable for efficacy is summarized in Table 7.

Table 7: Median (IQR)1 Annualized Bleed Rate by ELOCTATE Treatment Arm

REFERENCES

1. Sommer JM, Moore N, McGuffie-Valentine B, et al. Comparative field study evaluating the activity of recombinant factor VIII Fc fusion protein in plasma samples at clinical haemostasis laboratories. Haemophilia. 2014;20 : 294 – 300.

ELOCTATE™ /el' ok' tate /
[Antihemophilic Factor (Recombinant), Fc Fusion Protein] for Intravenous Injection

Please read this Patient Information carefully before using ELOCTATE and each time you get a refill, as there may be new information. This Patient Information does not take the place of talking with your healthcare provider about your medical condition or your treatment.

What is ELOCTATE?

ELOCTATE is an injectable medicine that is used to help control and prevent bleeding in people with Hemophilia A (congenital Factor VIII deficiency).

Your healthcare provider may give you ELOCTATE when you have surgery.

Who should not use ELOCTATE?

You should not use ELOCTATE if you had an allergic reaction to it in the past.

What should I tell my healthcare provider before using ELOCTATE?

Talk to your healthcare provider about:

• Any medical problems that you have or had.
• All prescription and non-prescription medicines that you take, including over-the-counter medicines, supplements or herbal medicines.
• Pregnancy or if you are planning to become pregnant. It is not known if ELOCTATE may harm your unborn baby.
• Breastfeeding. It is not known if ELOCTATE passes into the milk and if it can harm your baby.

How should I use ELOCTATE?

You get ELOCTATE as an infusion into your vein. Your healthcare provider will instruct you on how to do infusions on your own, and may watch you give yourself the first dose of ELOCTATE.

Contact your healthcare provider right away if bleeding is not controlled after using ELOCTATE.

What are the possible side effects of ELOCTATE?

Common side effects of ELOCTATE are joint pain and general discomfort.

Allergic reactions may occur. Call your healthcare provider or emergency department right away if you have any of the following symptoms: difficulty breathing, chest tightness, swelling of the face, rash or hives. 20

Your body can also make antibodies called, “inhibitors,” against ELOCTATE, which may stop ELOCTATE from working properly. Your healthcare provider may give you blood tests to check for inhibitors.

How should I store ELOCTATE?

• Keep ELOCTATE in its original package.
• Protect it from light.
• Do not freeze.
• Store refrigerated (2°C to 8°C or 36°F to 46°F) or at room temperature [not to exceed 30°C (86°F)], for up to six months.
• When storing at room temperature:
  • Note on the carton the date on which the product is removed from refrigeration.
  • Use the product before the end of this 6 month period or discard it.
  • Do not return the product to the refrigerator.

Do not use ELOCTATE after the expiration date printed on the vial or, if you removed it from the refrigerator, after the date that was noted on the carton, whichever is earlier.

After reconstitution (mixing with the diluent):

• Do not use ELOCTATE if the reconstituted solution is not clear to slightly opalescent and colorless.
• Use reconstituted product as soon as possible
• You may store reconstituted solution at room temperature, not to exceed 30°C (86°F), for up to three hours. Protect the reconstituted product from direct sunlight. Discard any product not used within three hours.

What else should I know about ELOCTATE?

Medicines are sometimes prescribed for purposes other than those listed here. Do not use ELOCTATE for a condition for which it was not prescribed. Do not share ELOCTATE with other people, even if they have the same symptoms that you have.

• Biogen Idec Inc.

• Importance of advising patients to read the manufacturer-provided patient information and instructions for use.1 2

  Importance of patients reporting to their clinician any adverse reactions or other issues following administration of the drug.1

• Importance of advising patients to immediately contact a clinician or proceed to an emergency room if a hypersensitivity reaction occurs; early signs of such hypersensitivity include rash, urticaria, pruritus, chest tightness, wheezing, or swelling of the face.1

• Possible development of neutralizing antibodies (inhibitors); advise patients to inform clinician if they experience a lack of response to therapy.1

• Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Appropriate studies performed to date have not demonstrated pediatric-specific problems that would limit the usefulness of antihemophilic factor injection in children.

No information is available on the relationship of age to the effects of Hemofil® M in the pediatric population. Safety and efficacy have not been established.

Geriatric

Although appropriate studies on the relationship of age to the effects of Advate®, Adynovate®, Eloctate™, Kogenate® FS, Kovaltry®, Novoeight®, and Xyntha® have not been performed in the geriatric population, no geriatric-specific problems have been documented to date. However, elderly patients are more likely to have age-related medical problems, which may require caution and an adjustment in the dose for patients receiving Advate®, Adynovate®, Eloctate™, Kogenate® FS, Kovaltry®, Novoeight®, and Xyntha®.

No information is available on the relationship of age to the effects of antihemophilic factor injection in geriatric patients.

Pregnancy

Breast Feeding

Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. Tell your healthcare professional if you are taking any other prescription or nonprescription (over-the-counter [OTC]) medicine.

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. Discuss with your healthcare professional the use of your medicine with food, alcohol, or tobacco.

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

• Allergy to hamster or mouse proteins, history of or
• von Willebrand disease (blood clotting disorder)—Should not be used in patients with these conditions.

• Heart or blood vessel disease—Use with caution. May make these conditions worse.

This section provides information on the proper use of a number of products that contain antihemophilic factor. It may not be specific to Eloctate. Please read with care.

A doctor or other trained health professional will give you or your child this medicine in a hospital or clinic setting. This medicine is given through a needle placed in one of your veins.

This medicine may also be given at home to patients who do not need to be in a hospital or clinic. If you or your child is using this medicine at home, your doctor will teach you how to prepare and inject the medicine. Make sure you understand all of the instructions before giving yourself an injection. Your dose may change based on where you are bleeding. Do not use more medicine or use it more often than your doctor tells you to.

Use only the brand of this medicine that your doctor prescribed. Not all brands are prepared in the same way and the dose may be different.

Every package of medicine comes with a patient information leaflet. Read and follow the instructions carefully. Ask your doctor if you have any questions.

To prepare the medicine using 2 bottles (vials) or containers:

• Take the bottles of powder medicine and liquid (diluent) out of the refrigerator and warm them to room temperature.
• Wipe the rubber surface of the bottles with an alcohol swab and allow them to dry.
• Follow the specific directions for your brand of medicine when you prepare the injection.
• Add the liquid to the powder using the special transfer needle or transfer device that comes with the package.
• When injecting the liquid into the dry medicine, aim the stream of liquid against the wall of the container of dry medicine to prevent foaming.
• Swirl the bottle gently to dissolve the medicine. Do not shake the bottle. Shaking will create foam in the mixture.
• Check the mixture to make sure it is clear. Do not use the medicine if you can see anything solid in the mixture or if the mixture is cloudy.
• Use a plastic disposable syringe to remove the mixture from the bottle. Use a special filter needle if your brand of medicine provides one.
• Give the injection as directed by your doctor.
• If you are using more than one bottle of medicine for your dose, prepare the second bottle the same way. Add the mixture from the second bottle to the same syringe.

To prepare the medicine using a prefilled dual-chamber syringe (Xyntha®):

• Take the prefilled dual-chamber syringe out of the refrigerator and warm it to room temperature.
• The dual-chamber syringe has the powder medicine in one part and the liquid (diluent) in the second part of the syringe.
• Attach the plunger rod to the syringe according to the directions. Keep the syringe pointed up to prevent leaking of the liquid.
• Remove the white seal and the grey rubber tip cap. Put the blue vented cap on the syringe. Do not touch the open ends of the syringe and the blue cap.
• Slowly push the plunger until the 2 stoppers inside the syringe are together. This will push all of the liquid into the chamber with the powder medicine.
• Keep the syringe pointed up and gently swirl the syringe to mix the liquid and powder.
• Check the mixture to make sure it is clear. Do not use the medicine if you can see anything solid in the mixture or if the mixture is cloudy.
• Keep the syringe pointed up and push the plunger until most of the air is removed.
• A special infusion set comes with the package. Remove the blue cap and attach the infusion set to the syringe.
• Give the injection as directed by your doctor.
• If you are using more than one syringe of medicine for your dose, prepare the second dual-chamber syringe the same way. The mixture from each syringe will be combined together in a separate syringe before your injection. Your doctor will show you how to do this.

Use the mixture within 3 or 4 hours after it is prepared. It must not be stored and used later. Do not put the mixture in the refrigerator.

Do not reuse syringes and needles. Put used syringes and needles in a puncture-resistant disposable container, or dispose of them as directed by your doctor.

Talk to your doctor before traveling. You should plan to bring enough medicine for your treatment when traveling.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For injection dosage form (injection):
  • For bleeding episodes in patients with hemophilia A:
    • Adults and teenagers—Dose is based on body weight and the type of bleeding episode. The dose must be determined by your doctor.
    • Children—Dose is based on body weight and the type of bleeding episode. The dose must be determined by your child's doctor.

Missed Dose

Call your doctor or pharmacist for instructions.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

The AHF products should be stored in the original container in the refrigerator. Do not let the packages freeze. They can also be kept at room temperature for short periods of time, such as 3 to 12 months. Store the medicine as directed by your doctor or by the manufacturer of the brand you are using. Protect the container from heat and direct light.

If you move the medicine from the refrigerator to room temperature, write the date you take it from the refrigerator on the container. The length of time the medicine can remain at room temperature will depend on the brand you use. If you have already stored the medicine at room temperature, do not return it to the refrigerator. If you do not use the medicine within the time recommended by the manufacturer, you must destroy the medicine.

Use Eloctate as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• It is given as a shot into a vein.
• This medicine may be given at home.
• If you will be giving yourself the shot, your doctor or nurse will teach you how to give the shot.
• Follow how to use as you have been told by the doctor or read the package insert.
• Wash your hands before and after use.
• If stored in a refrigerator, let this medicine come to room temperature before mixing. Do not heat Eloctate.
• This medicine needs to be mixed before use. Follow how to mix as you were told by the doctor.
• Do not shake.
• Use within 3 hours of making.
• Do not use if the solution is cloudy, leaking, or has particles.
• Do not use if solution changes color.
• After mixing, do not refrigerate.
• Throw away any part of opened vial not used after use.
• Throw away needles in a needle/sharp disposal box. Do not reuse needles or other items. When the box is full, follow all local rules for getting rid of it. Talk with a doctor or pharmacist if you have any questions.

What do I do if I miss a dose?

• Call your doctor to find out what to do.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Irritation where the shot is given.
• Headache.
• Muscle or joint pain.
• Feeling tired or weak.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

Applies to antihemophilic factor: intravenous kit, intravenous powder for injection

Nervous system

Nervous system side effects have included headache, dizziness, somnolence, and asthenia.[Ref]

Respiratory

Respiratory side effects have included dyspnea and rhinitis.[Ref]

Musculoskeletal

Musculoskeletal side effects have included arthralgia.[Ref]

Local

Local side effects have included injection site pain.[Ref]

General

General side effects have included pyrexia and chills.[Ref]

Gastrointestinal

Gastrointestinal side effects have included nausea, diarrhea, and vomiting.[Ref]

Dermatologic

Dermatologic side effects have include pruritus, rash, and urticaria.[Ref]

Cardiovascular

Cardiovascular side effects have included hemorrhage, hypotension, and vasodilatation.[Ref]

Some side effects of Eloctate may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.