Emicizumab-Kxwh Injection, for Subcutaneous Use

Emicizumab-kxwh is a humanized monoclonal modified immunoglobulin G4 (IgG4) antibody with a bispecific antibody structure binding factor IXa and factor X. Emicizumab-kxwh has an approximate molecular weight of 145.6 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells. Emicizumab-kxwh has no structural relationship or sequence homology to FVIII and, as such, does not induce or enhance the development of direct inhibitors to FVIII.

HEMLIBRA (emicizumab-kxwh) injection is a sterile, preservative-free, colorless to slightly yellow solution for subcutaneous injection supplied in single-dose vials containing emicizumab239 kxwh at 30 mg/mL, 60 mg/0.4 mL, 105 mg/0.7 mL, or 150 mg/mL.

Each single-dose 30 mg vial contains a 1 mL solution of emicizumab-kxwh (30 mg), L-arginine (26.1 mg), L-histidine (3.1 mg), and poloxamer 188 (0.5 mg), adjusted to pH 6.0 with L-aspartic acid.

Each single-dose 60 mg vial contains a 0.4 mL solution of emicizumab-kxwh (60 mg), L-arginine (10.5 mg), L-histidine (1.2 mg), and poloxamer 188 (0.2 mg), adjusted to pH 6.0 with L-aspartic acid.

Each single-dose 105 mg vial contains a 0.7 mL solution of emicizumab-kxwh (105 mg), L-arginine (18.3 mg), L-histidine (2.2 mg), and poloxamer 188 (0.4 mg), adjusted to pH 6.0 with L-aspartic acid.

Each single-dose 150 mg vial contains a 1 mL solution of emicizumab-kxwh (150 mg), L-arginine (26.1 mg), L-histidine (3.1 mg), and poloxamer 188 (0.5 mg), adjusted to pH 6.0 with L-aspartic acid.

The following serious adverse reactions are described elsewhere in the labeling:

• Thrombotic Microangiopathy Associated with HEMLIBRA and aPCC [see WARNINGS AND PRECAUTIONS]
• Thromboembolism Associated with HEMLIBRA and aPCC [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The following adverse reactions are based on pooled data from a randomized trial (HAVEN 1), single-arm trial (HAVEN 2), and a dose-finding trial, in which a total of 189 male patients with hemophilia A received at least one dose of HEMLIBRA as routine prophylaxis. Ninety-four patients (50%) were adults (18 years and older), 38 (20%) were adolescents (12 years up to less than 18 years), 55 (29%) were children (2 years up to less than 12 years), and two (1%) were infants (1 month up to less than 2 years). Seven of the 189 patients (4%) included in the safety population were patients without FVIII inhibitors from the dose-finding trial. The median duration of exposure across the studies was 38 weeks (0.8 to 177.2 weeks).

The most frequently reported adverse reactions observed in ≥10% of patients treated with at least one dose of HEMLIBRA were injection site reactions, headache, and arthralgia.

Four patients (2.1%) in the clinical trials receiving HEMLIBRA prophylaxis withdrew from treatment due to adverse reactions, which were thrombotic microangiopathy, skin necrosis and superficial thrombophlebitis, and injection site reaction.

Adverse reactions observed in patients who received HEMLIBRA are shown in Table 2.

Table 2 Adverse Reactions Reported in ≥ 5% of Patients from Pooled Clinical Trials with HEMLIBRA

There were 125 instances of aPCC treatment in 36 patients, of which 13 instances (10.4%) consisted of on average a cumulative amount of >100 U/kg/24 hours of aPCC for 24 hours or more; two of the 13 were associated with thrombotic events and three of the 13 were associated with TMA (Table 3). No TMA or thrombotic events were associated with the remaining instances of aPCC treatment.

Table 3 Characterization of aPCC Treatment* in Pooled Clinical Trials Duration of aPCC treatment

In total, 35 patients (19%) reported injection site reactions (ISRs). All ISRs observed in HEMLIBRA clinical trials were reported as mild to moderate intensity and 88% resolved without treatment. The commonly reported ISR symptoms were injection site erythema (7.4%), injection site pruritus (5.3%), and injection site pain (5.3%).

Immunogenicity

As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to emicizumab-kxwh in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

The immunogenicity of HEMLIBRA was evaluated using an enzyme-linked immunosorbent assay (ELISA) or an electrochemiluminescence (ECL) assay. No patients tested positive for anti emicizumab antibodies in HAVEN 1 and HAVEN 2 (n = 171). Four patients tested positive for anti-emicizumab antibodies in the dose-finding trial (n = 18). The anti-emicizumab antibody positive rate may be under-reported due to the limitation of the assay.

HEMLIBRA®
(hem-lee-bruh)
(emicizumab-kxwh) Injection, for Subcutaneous Use

What is the most important information I should know about HEMLIBRA?

HEMLIBRA increases the potential for your blood to clot. Discontinue prophylactic use of bypassing agents the day before starting HEMLIBRA prophylaxis. Carefully follow your healthcare provider’s instructions regarding when to use an on-demand bypassing agent, and the dose and schedule you should use.

HEMLIBRA may cause the following serious side effects when used with aPCC (FEIBA®), including:

• Thrombotic microangiopathy (TMA). This is a condition involving blood clots and injury to small blood vessels that may cause harm to your kidneys, brain, and other organs. Get medical help right away if you have any of the following signs or symptoms during or after treatment with HEMLIBRA:
  • confusion
  • stomach (abdomen) or back pain
  • weakness
  • nausea or vomiting
  • swelling of arms and legs
  • feeling sick
  • yellowing of skin and eyes
  • decreased urination
• Blood clots (thrombotic events). Blood clots may form in blood vessels in your arm, leg, lung, or head. Get medical help right away if you have any of these signs or symptoms of blood clots during or after treatment with HEMLIBRA:
  • swelling in arms or legs
  • feel faint
  • pain or redness in your arms or legs
  • headache
  • shortness of breath
  • numbness in your face
  • chest pain or tightness
  • eye pain or swelling
  • fast heart rate
  • trouble seeing
  • cough up blood

If aPCC (FEIBA®) is needed, talk to your healthcare provider in case you feel you need more than 100 U/kg of aPCC (FEIBA®) total.

See “What are the possible side effects of HEMLIBRA?” for more information about side effects.

What is HEMLIBRA?

HEMLIBRA is a prescription medicine used for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia A with factor VIII inhibitors.

• Hemophilia A is a bleeding condition people can be born with where a missing or faulty blood clotting factor (factor VIII) prevents blood from clotting normally.
• HEMLIBRA is a therapeutic antibody that bridges clotting factors to help your blood clot.

Before using HEMLIBRA, tell your healthcare provider about all of your medical conditions, including if you:

• are pregnant or plan to become pregnant. It is not known if HEMLIBRA may harm your unborn baby. Females who are able to become pregnant should use birth control (contraception) during treatment with HEMLIBRA.
• are breastfeeding or plan to breastfeed. It is not known if HEMLIBRA passes into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, or herbal supplements. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I use HEMLIBRA?

See the detailed “Instructions for Use” that comes with your HEMLIBRA for information on how to prepare and inject a dose of HEMLIBRA, and how to properly throw away (dispose of) used needles and syringes.

• Use HEMLIBRA exactly as prescribed by your healthcare provider.
• HEMLIBRA is given as an injection under your skin (subcutaneous injection) by you or a caregiver.
• Your healthcare provider should show you or your caregiver how to prepare, measure, and inject your dose of HEMLIBRA before you inject yourself for the first time.
• Do not attempt to inject yourself or another person unless you have been taught how to do so by a healthcare provider.
• Your healthcare provider will prescribe your dose based on your weight. If your weight changes, tell your healthcare provider.
• If you miss a dose of HEMLIBRA on your scheduled day, you should give the dose as soon as you remember. You must give the missed dose before the next scheduled dosing day and then continue with your normal weekly dosing schedule. Do not double your dose to make up for a missed dose.
• HEMLIBRA may interfere with laboratory tests that measure how well your blood is clotting and may cause a false reading. Talk to your healthcare provider about how this may affect your care.

What are the possible side effects of HEMLIBRA?

• See “What is the most important information I should know about HEMLIBRA?”

The most common side effects of HEMLIBRA include:

• redness, tenderness, warmth, or itching at the site of injection
• headache
• joint pain

These are not all of the possible side effects of HEMLIBRA.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store HEMLIBRA?

• Store HEMLIBRA in the refrigerator at 36°F to 46°F (2°C to 8°C). Do not freeze.
• Store HEMLIBRA in the original carton to protect the vials from light.
• Do not shake HEMLIBRA.
• If needed, unopened vials of HEMLIBRA can be stored out of the refrigerator and then returned to the refrigerator.
  HEMLIBRA should not be stored out of the refrigerator for more than 7 days at 86°F (30°C) or below.
• After HEMLIBRA is transferred from the vial to the syringe, HEMLIBRA should be used right away.
• Throw away (dispose of) any unused HEMLIBRA left in the vial.

Keep HEMLIBRA and all medicines out of the reach of children.

General information about the safe and effective use of HEMLIBRA.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use HEMLIBRA for a condition for which it was not prescribed. Do not give HEMLIBRA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about HEMLIBRA that is written for health professionals.

What are the ingredients in HEMLIBRA?

Active ingredient: emicizumab

Inactive ingredients: L-arginine, L-histidine, poloxamer 188, and L-aspartic acid.

Instructions for Use

HEMLIBRA®
(hem-lee-bruh)
(emicizumab-kxwh) injection, for subcutaneous use

Be sure that you read, understand, and follow the Instructions for Use before injecting HEMLIBRA. Your healthcare provider should show you how to prepare, measure, and inject HEMLIBRA properly before you use it for the first time. Ask your healthcare provider if you have any questions.

Important Information:

• Do not inject yourself or someone else unless you have been shown how to by your healthcare provider.
• Make sure the name HEMLIBRA appears on the box and vial label.
• Before opening the vial, read the vial label to make sure you have the medicine strength(s) needed to give the dose prescribed by your healthcare provider.
• HEMLIBRA comes in four strengths. Depending on your dose, you may need to use more than one vial to give your total prescribed dose. Your healthcare provider will determine your dose in milliliters (mL) that you will need to give based on your body weight. Do not use different HEMLIBRA vials of different concentrations when combining vials to achieve the prescribed dose.
• Check the expiration date on the box and vial label. Do not use if the expiration date has passed.
• Only use the vial one time. After you inject your dose, dispose of (throw away) any unused HEMLIBRA left in the vial. Do not save unused HEMLIBRA in the vial for later use.
• Only use the syringes, transfer needles, and injection needles that your healthcare provider prescribes.
• Only use the syringes, transfer needles and injection needles one time. Dispose of (throw away) any used syringes and needles.
• If your prescribed dose is more than 2 mL, you will need to give more than one injection of HEMLIBRA.

Storing HEMLIBRA:

• Store HEMLIBRA in the refrigerator at 36°F to 46°F (2°C to 8°C). Do not freeze.
• Store HEMLIBRA in the original carton to protect the vials from light.
• Do not shake HEMLIBRA.
• Take the vial out of the refrigerator 15 minutes before use and allow it to reach room temperature before preparing an injection.
• Before giving the injection, unopened vials of HEMLIBRA may be stored out of the refrigerator and then returned to the refrigerator. HEMLIBRA should not be stored out of the refrigerator:
  • for more than 7 days or
  • at a temperature greater than 86°F (30°C)

Keep HEMLIBRA and all medicines out of the reach of children.

Inspecting the HEMLIBRA vial and your supplies:

• Collect all supplies listed below to prepare and give your injection.
• Check the expiration date on the box, on the vial label, and on the supplies listed below. Do not use if the expiration date has passed.
• Inspect the supplies for damage. Do not use if they appear damaged or if they have been dropped.
• Place the supplies on a clean, well-lit flat work surface.

HEMLIBRA is colorless to slightly yellow in color. Do not use the vial if:

• the medicine is cloudy, hazy, or colored.
• the medicine contains particles.
• the cap covering the stopper is missing.

Included in the box:

• Vial containing HEMLIBRA
• HEMLIBRA Instructions for Use

Not included in the box:

• Alcohol wipes

Note: If you need to use more than one vial to inject your prescribed dose, you must use a new alcohol wipe for each vial.

• Gauze
• Cotton Ball
• Syringe

Note: For injection amount up to 1 mL, use a 1 mL syringe. For injection amount between 1 mL and 2 mL, use a 2 mL or 3 mL syringe.

• 18G Transfer Needle

Note: If you need to use more than one vial to inject your prescribed dose, you must use a new transfer needle for each vial. Do not use the transfer needle to inject HEMLIBRA.

• 26G Injection Needle with safety shield Do not use the injection needle to withdraw HEMLIBRA from vial.
• Sharps disposal container

Get ready:

• Before use, allow the vial(s) to warm up to room temperature for about 15 minutes on a clean flat surface away from direct sunlight.
• Do not try to warm the vial by any other way.
• Wash your hands well with soap and water.

Selecting and preparing an injection site:

• Clean the chosen injection site area using an alcohol wipe.
• Let the skin dry for about 10 seconds. Do not touch, fan, or blow on the cleaned area before your injection.
• You can use your:
  • Thigh (front and middle).
  • Stomach area (abdomen), except for 2 inches around the navel (belly button).
  • Outer area of the upper arm (only if a caregiver is giving the injection).
• You should use a different injection site each time you give an injection, at least 1 inch away from the area you used for your previous injection.
• Do not inject into areas that could be irritated by a belt or waistband. Do not inject into moles, scars, bruises, or areas where the skin is tender, red, hard, or the skin is broken.

Preparing the syringe for injection:

• HEMLIBRA must not be stored in the syringe.
• HEMLIBRA in the syringe must be injected under the skin (subcutaneous injection) immediately.
• Dispose of (throw away) any used vial(s), needles, vial and injection needle caps, and used syringes in a sharps or puncture-proof container.

Important information after the injection:

• Do not rub the injection site after an injection.
• If you see drops of blood at the injection site, you can press a sterile cotton ball or gauze over the injection site for at least 10 seconds, until bleeding has stopped.
• If you have bruising (small area of bleeding under the skin), an ice pack can also be applied with gentle pressure to the site. If bleeding does not stop, please contact your healthcare provider.

Disposing of used HEMLIBRA vial(s), needles, and syringes:

• Put your used needles and syringes in a FDA-cleared sharps disposal container right away after use. Do not dispose of (throw away) any loose needles and syringes in your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
  • made of heavy-duty plastic.
  • can be closed with a tight-fitting, puncture resistant lid, without sharps being able to come out.
  • upright and stable during use.
  • leak-resistant.
  • properly labeled to warn of hazardous waste inside the container.
• When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.
• Do not dispose of (throw away) any used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

Important: Always keep the sharps disposal container out of reach of children.

Step 1. Remove vial cap and clean top

• Take the cap off the vial(s).
• Clean the top of the vial(s) stopper with an alcohol wipe.
• Dispose of (throw away) the vial cap(s) into the sharps disposal container.

Step 2. Attach transfer needle to syringe

• Push and twist the transfer needle clockwise on to the syringe until it is fully attached.
• Slowly pull back on the plunger and draw air into the syringe that is the same amount for your prescribed dose.

Step 3. Uncap transfer needle

• Hold the syringe by the barrel with the transfer needle pointing up.
• Carefully pull the transfer needle cap straight off and away from your body. Do not throw the cap away. Place the transfer needle cap down on a clean flat surface. You will need to recap the transfer needle after transferring the medicine.
• Do not touch the needle tip or place it on a surface after the needle cap has been removed.

Step 4. Inject air into vial

• Keep the vial on the flat working surface and insert the transfer needle and syringe straight down into the center of the vial stopper.
• Keep the needle in the vial and turn the vial upside down.
• With the needle pointing upwards, push on the plunger to inject the air from the syringe above the medicine.
• Keep your finger pressed down on the syringe plunger.
• Do not inject air into the medicine.

Step 5. Transfer HEMLIBRA to syringe

• Slide the tip of the needle down so that it is within the medicine.
• Slowly pull back the plunger to fill the syringe with more than the amount of HEMLIBRA needed for your prescribed dose.
• Be careful not to pull the plunger out of the syringe.

Important: If your prescribed dose is more than the amount of HEMLIBRA in the vial, withdraw all HEMLIBRA and go to the “Combining Vials” section now.

Step 6. Remove air bubbles

• Keep the needle in the vial and check the syringe for larger air bubbles. Too large an air bubble can reduce the dose you receive.
• Remove the larger air bubbles by gently tapping the syringe barrel with your fingers until the air bubbles rise to the top of the syringe. Move the tip of the needle above the medicine and slowly push the plunger up to push the air bubbles out of the syringe.
• If the amount of HEMLIBRA in the syringe is now at or below your prescribed dose, move the tip of the needle to within the medicine and slowly pull back the plunger until you have more than the amount of HEMLIBRA needed for your prescribed dose.
• Be careful not to pull the plunger out of the syringe.
• Repeat the steps above until you have removed the larger air bubbles.

Note: Ensure you have enough HEMLIBRA in the syringe to complete your dose before moving on to the next step. If you cannot remove all of HEMLIBRA, turn the vial upright to reach the remaining amount.

Do not use the transfer needle to inject HEMLIBRA as this may cause harm such as pain and bleeding.

Step 7. Recap transfer needle

• Remove the syringe and transfer needle from the vial.
• Using one hand, slide the transfer needle into the cap and scoop upwards to cover the needle.
• Once the needle is covered, push the transfer needle cap towards the syringe to fully attach it with one hand to prevent accidentally sticking yourself with the needle.

Step 8. Clean injection site

• Select and clean your injection site with an alcohol wipe.
• Let the skin dry for about 10 seconds. Do not touch, fan, or blow on the cleaned area before your injection.

Step 9. Remove transfer needle

• Remove the transfer needle from the syringe by twisting counter-clockwise and gently pulling.
• Dispose of (throw away) the used transfer needle into a sharps disposal container.

Step 10. Attach injection needle to syringe

• Push and twist the injection needle clockwise on to the syringe until it is fully attached.

Step 11. Move safety shield

• Move the safety shield away from the needle and towards the syringe barrel.

Step 12. Uncap injection needle

• Carefully pull the injection needle cap away from the syringe.
• Dispose of (throw away) the cap into a sharps disposal container.
• Do not touch the needle tip or allow it to touch any surface.
• After the injection needle cap has been removed, HEMLIBRA in the syringe must be injected immediately.

Step 13. Adjust plunger to prescribed dose

• Slowly push the plunger to your prescribed dose.
• Ensure the top rim of the plunger is in line with the mark on the syringe for your prescribed dose.

Step 14. Subcutaneous (under the skin) injection

• Pinch the selected injection site and fully insert the needle at a 45° to 90° angle with a quick, firm action. Do not hold or push on the plunger while inserting the needle.
• Hold the position of the syringe and let go of the pinched injection site.

Step 15. Inject HEMLIBRA

• Slowly inject all of HEMLIBRA by gently pushing the plunger all the way down.
• Remove the needle and syringe from the injection site at the same angle as inserted.

Step 16. Cover needle with safety shield

• Move the safety shield forward 90°, away from the syringe barrel.
• Holding the syringe with one hand, press the safety shield down against a flat surface with a firm, quick motion until you hear a “click”.
• If you do not hear a click, look to see that the needle is fully covered by the safety shield.
• Keep your fingers behind the safety shield and away from the needle at all times.
• Do not remove the injection needle from the syringe.

Step 17. Dispose of (throw away) the used HEMLIBRA vial(s), needle, and syringe

• Put your used needles and syringes in a FDA-cleared sharps disposal container right away after use. For further information, refer to the section “Disposing of used HEMLIBRA vial(s), needles, and syringes”.
• Do not try to remove the used injection needle from the used syringe.
• Do not recap the injection needle with the cap.
• Important: Always keep the sharps disposal container out of reach of children.
• Dispose of (throw away) any used vial(s), needles, vial and injection needle caps, and used syringes in a sharps or puncture-proof container.

Combining Vials

If you need to use more than one vial to get to your total prescribed dose, follow these steps after you have drawn up HEMLIBRA from the first vial:

Step A. Recap transfer needle

• Remove the syringe and transfer needle from the first vial.
• Using one hand, slide the transfer needle into the cap and scoop upwards to cover the needle.
• Once the needle is covered, push the transfer needle cap toward the syringe to fully attach it with one hand to prevent accidentally sticking yourself with the needle.

Step B. Remove transfer needle

• Remove the transfer needle from the syringe by twisting counter- clockwise and gently pulling.
• Dispose of (throw away) the used transfer needle into a sharps disposal container.

Step C. Attach a new transfer needle to syringe

Note: You must use a new transfer needle each time you withdraw HEMLIBRA from a new vial.

• Push and twist a new transfer needle clockwise on to the syringe until it is fully attached.
• Slowly pull back the plunger and draw some air into the syringe.

Step D. Uncap transfer needle

• Hold the syringe by the barrel with the transfer needle cap pointing up.
• Carefully pull the transfer needle cap straight off and away from your body. Do not throw the cap away. You will need to recap the transfer needle after drawing up the medicine.
• Do not touch the needle tip.

Step E. Inject air into vial

• With the new vial on the flat working surface, insert the new transfer needle and syringe, straight down into the center of the vial stopper.
• Keep the transfer needle in the vial and turn the vial upside down.
• With the needle pointing upwards, inject the air from the syringe above the medicine.
• Keep your finger pressed down on the syringe plunger.
• Do not inject air into the medicine.

Step F. Transfer HEMLIBRA to syringe

• Slide the tip of the needle down so that it is within the medicine.
• Slowly pull back the plunger to fill the syringe barrel more than the amount of HEMLIBRA needed for your prescribed dose.
• Be careful not to pull the plunger out of the syringe.

Note: Ensure you have enough HEMLIBRA in the syringe to complete your dose before moving onto the next steps. If you cannot remove all of HEMLIBRA, turn the vial upright to reach the remaining amount.

Do not use the transfer needle to inject HEMLIBRA as this may cause harm such as pain and bleeding.

Repeat steps A to F with each additional vial until you have more than the amount of HEMLIBRA needed for your prescribed dose. Once completed, keep the transfer needle inserted in the vial and return to Step 6. Continue with the remaining steps.

This Medication Guide has been approved by the U.S. Food and Drug Administration