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Description for Andembry

Garadacimab-gxii, an activated Factor XII (FXIIa) inhibitor, is a recombinant, fully human, monoclonal antibody (IgG4/λ-light chain) produced in Chinese Hamster Ovary (CHO) cells. Based on the amino acid sequence, the molecular weight of garadacimab-gxii is approximately 148 kDa.

ANDEMBRY (garadacimab-gxii) injection is a sterile, preservative-free, slightly opalescent to clear, brownish-yellow to yellow solution for subcutaneous use.

Each 1.2 mL prefilled autoinjector or prefilled syringe with needle safety device of ANDEMBRY contains 200 mg of garadacimab-gxii, arginine monohydrochloride (37.9 mg), histidine (3.7 mg), polysorbate 80 (0.24 mg), proline (19.3 mg), and water for injection, USP. The pH is 6.1.

Uses for Andembry

ANDEMBRY is indicated for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients aged 12 years and older.

Dosage for Andembry

Recommended Dosage

The recommended dosage of ANDEMBRY is an initial loading dose of 400 mg (two injections of 200 mg) administered subcutaneously on the first day of treatment followed by a maintenance dosage of 200 mg administered subcutaneously every month.

Missed Dose(s)
If a dose of ANDEMBRY is missed, administer the dose as soon as possible.

Preparation and Administration Instructions for ANDEMBRY Prefilled Autoinjector and Prefilled Syringe with Needle Safety Device

• For subcutaneous use only.
• ANDEMBRY is intended for self-administration or administration by a caregiver. Prior to treatment initiation, train patients/caregivers on proper preparation and subcutaneous (SC) administration technique of ANDEMBRY [see Instructions for Use].
• Prior to administration, remove ANDEMBRY from the refrigerator and allow to sit for 30 minutes at room temperature before use.
• Inspect ANDEMBRY visually for particulate matter and discoloration prior to administration, whenever solution and container permit. ANDEMBRY is a slightly opalescent to clear, brownish-yellow to yellow solution.
• Administer ANDEMBRY subcutaneously into the thigh or abdomen ensuring to stay 1 inch (2 cm) away from the navel. The upper arm can also be used if a caregiver administers the subcutaneous injection.
• Discard the used ANDEMBRY into a sharps disposal container (closed puncture-resistant container).
• For detailed instructions on the preparation and administration of ANDEMBRY [see Instructions for Use].

HOW SUPPLIED

DOSAGE FORMS AND STRENGTHS

Injection: a sterile, preservative-free, slightly opalescent to clear, brownish-yellow to yellow solution available in the following:

• 200 mg/1.2 mL of garadacimab solution in a single-dose prefilled autoinjector
• 200 mg/1.2 mL (167 mg/mL) of garadacimab solution in a single-dose prefilled syringe with needle safety device

How Supplied

ANDEMBRY (garadacimab-gxii) injection is a ready-to-use, slightly opalescent to clear, brownishyellow to yellow solution in the following presentations, supplied in single-dose prefilled autoinjector or prefilled syringe with needle safety device.

Table 5 provides the available presentations and strengths of ANDEMBRY.

Table 5 Presentations and Strengths for ANDEMBRY

Presentation	Strength	Unit Count	NDC (Device)	NDC (Carton)
Prefilled autoinjector	200 mg/1.2 mL	1	63833-925-20	63833-925-01
Prefilled syringe with needle safety device	200 mg/1.2 mL (167 mg/mL)	1	63833-920-20	63833-920-01

Each single-dose prefilled autoinjector or prefilled syringe with needle safety device is supplied in a carton.

Storage and Handling

• Do not freeze. Do not shake.
• Keep the prefilled autoinjector and prefilled syringe with needle safety device in the original carton to protect from light.
• Store the prefilled autoinjector and prefilled syringe with needle safety device refrigerated at 36°F to 46°F (2°C - 8°C).

Warnings for Andembry

Included as part of the PRECAUTIONS section.

Precautions for Andembry

Ocular Symptoms, Developmental Delay and Hyperkeratotic Plaques Due to Elevated Plasma Tyrosine Levels

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Animal studies have not been conducted to evaluate the carcinogenic or mutagenic potential of garadacimab-gxii.

Fertility and reproductive performance were unaffected in sexually mature male and female rabbits that received garadacimab-gxii at intravenous doses up to 100 mg/kg once every three days (resulting in exposures in male and female rabbits up to approximately 100 and 80 times the MRHD on an AUC basis).

Clinical Pharmacology for Andembry

Mechanism Of Action

Garadacimab-gxii is an inhibitor of activated FXII that binds to the catalytic domain of activated Factor XII (FXIIa and βFXIIa) and inhibits its catalytic activity. FXII is the first factor activated in the contact activation pathway and initiates the inflammatory bradykinin-producing kallikrein-kinin system. The inhibition of FXIIa decreases the activation of prekallikrein to kallikrein and the generation of bradykinin, which is associated with inflammation and swelling in HAE attacks, thus reducing the cascade of events leading to an HAE attack.

Pharmacodynamics

Garadacimab-gxii concentration-dependent inhibition of FXIIa-mediated kallikrein activity was observed in patients with HAE. Inhibition of FXIIa-mediated kallikrein activity was observed after the first dose.

Pharmacokinetics

The pharmacokinetics of garadacimab-gxii are provided in Table 2 following subcutaneous administration of a single 200 mg dose to healthy volunteers and are presented as mean (SD), unless otherwise specified.

Table 2 Garadacimab-gxii Pharmacokinetics Following Subcutaneous Administration*

Parameter	Garadacimab-gxii
Exposure
Cmax	18.4 (7.23) mcg/mL
AUC0-inf	11470 (4103) mcg∙h/mL
Ctrough,Steady Statea,b	8.09 (4.28) to 8.69 (3.93) mcg /mL
Absorption
Absolute Bioavailability	39 (34, 43)%
Tmax	6 (2, 15) days
Distribution
Apparent Volume of Distribution	11.8 (5.17) Liters (L)
Elimination
Half-Lifeb	17.4 (3.14) days
Apparent Clearance	0.02 (0.008) L/h
Metabolism
Primary Pathway	Expected to be metabolized into small peptides by catabolic pathways

Abbreviations: AUC = area under the plasma concentration-time curve; CI = confidence interval; Cmax = maximum plasma concentration; Ctrough,steady state = trough plasma concentration at steady state; Tmax = time to peak concentration
Tmax is reported as median (range) and absolute bioavailability is reported as estimate (95% CI)
* The PK of garadacimab-gxii is similar between healthy volunteers and subjects with HAE
a HAE patients enrolled in the VANGUARD trial
b Garadacimab-gxii exposure (based on AUCtau and Cmax) following the initial subcutaneous administration of loading dose of
400 mg (2 doses of 200 mg) is 133% of steady-state exposures following 200 mg subcutaneous once monthly.

Specific Populations

No clinically significant differences in the pharmacokinetics of garadacimab-gxii were observed based on age (age range: 12 to 73 years), gender, race, body weight (range: 43 to 153 kg), and mild to moderate renal impairment (eGFR 30 to <90 mL/min/1.73 m2). The effect of severe renal impairment (eGFR <30 mL/min/1.73 m2) on garadacimab-gxii pharmacokinetics is unknown.

Pediatric Patients

No clinically significant difference in garadacimab-gxii Cmax and AUCtau was observed between pediatric patients (age range: 12 to 17 years) and adults who received the recommended dosage of garadacimab-gxii (200 mg of garadacimab-gxii once monthly).

Drug Interactions

No dedicated drug interaction studies have been conducted in humans.

Immunogenicity

The observed incidence of anti-drug antibodies (ADA) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of garadacimab-gxii or other garadacimab products.

In VANGUARD, 2.6% (1/39) of patients who received garadacimab-gxii tested positive for antigaradacimab- antibodies during the 6-month treatment period.

The development of ADA against garadacimab-gxii did not affect pharmacokinetics (PK), safety, or clinical response.

Patient Information for Andembry

INSTRUCTIONS FOR USE
ANDEMBRY (an-DEM-bree)
(garadacimab-gxii)
injection, for subcutaneous use
Prefilled Syringe Important:
This prefilled syringe works differently than other injection devices. Read the Instructions for Use carefully before using it, and each time you get a new prefilled syringe. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Children should inject ANDEMBRY under the supervision of an adult.
Make sure you have been trained by your healthcare provider before you use this prefilled syringe for the first time.

Parts of the Prefilled Syringe (see Figure A):

Read the Following Safety Information:

• Keep the prefilled syringe in its original carton box until use, to protect it from light.
• Do not remove the needle cap until you are ready to inject the medicine.
• Do not recap the prefilled syringe.
• Do not reuse the same prefilled syringe. The prefilled syringe contains 1 dose and is for one time use only.
• The prefilled syringe is for subcutaneous (under the skin) injection only.
• Do not use the prefilled syringe if it looks damaged, has cracks, or is leaking medicine, or has been dropped. Throw away the prefilled syringe and use a new one.
• Do not inject the prefilled syringe through clothing.
• Keep ANDEMBRY and all medicines out of reach of children.

How Should I Store ANDEMBRY?

• Store in a refrigerator, between 36ËšF to 46ËšF (2ËšC to 8ËšC), in its original carton box until use, to protect it from light.
• Do not shake
• Do not freeze. If the prefilled syringe has been frozen, do not use the prefilled syringe even if it is thawed.
• The refrigerated prefilled syringe may be used until the expiration date (EXP) printed on the label.
• Take the prefilled syringe out of the refrigerator 30 minutes before use, allowing it to reach room temperature.
• Do not put the prefilled syringe back in the refrigerator after it has reached room temperature.

Supplies needed for the Prefilled Syringe Injection (see Figure B):

Included in the carton box:

• 1 prefilled syringe

Required but not included:

• Alcohol pad
• Cotton ball or gauze pad
• FDA-cleared sharps container or puncture-resistant container for disposal (see Step 12. Disposing of the Syringe)

Preparing for an Injection

Step 1. Let the Prefilled Syringe Reach Room Temperature

• Remove the prefilled syringe from the carton box and place it on a clean flat surface.
• Do not remove the prefilled syringe from the carton box by holding onto the needle cap or plunger.
• Do not move or pull on the plunger.
• Wait 30 minutes for the medicine to reach room temperature if after taking it out of the refrigerator (see Figure C).
• Injecting the medicine cold could cause you some discomfort.
• Do not try to speed up the warming process in any way. Do not microwave the prefilled syringe, run hot water over it, or leave it in direct sunlight.

Step 2. Check the Expiration Date

• Check the expiration date on the prefilled syringe (see Figure D).
• Do not use the prefilled syringe if the expiration date has passed. If the expiration date (EXP) has passed, then safely dispose of the prefilled syringe and get a new one (see Step 12. Disposing of the Syringe).

Step 3. Inspect the Prefilled Syringe

• Inspect the medicine through the clear window of the prefilled syringe (see Figure E and Figure F).
• Peel back the label to inspect the medicine if you cannot see enough of the medicine through the clear window of the prefilled syringe (see Figure F).
• It is normal to see air bubbles. Do not try to remove the air bubbles.
• The medicine should be brownish-yellow to yellow and may appear slightly opalescent to clear.
• If the medicine is discolored or contains particles (see Figure E), then do not use. Safely dispose of the prefilled syringe and get a new one (see Step 12. Disposing of the Syringe).
• Check the prefilled syringe. If it looks damaged, has cracks or is leaking medicine, or has been dropped, then safely dispose of the prefilled syringe and get a new one.

Choose and Prepare an Injection Site

Step 4. Clean Your Hands

• Wash your hands well with soap and water or use hand sanitizer (see Figure G).

Step 5. Select the Injection Site

• Inject into the thigh or belly (abdomen) area, but stay 1 inch (2 cm) away from the belly button (navel) (see Figure H).
• If somebody else (like a caregiver) gives you the injection, you can also use the upper arm.
• Rotate your injection sites. Do not inject in the same injection site multiple times if you see that the skin is damaged.
• Do not inject into the belly button, moles, scars or bruises, or into areas where the skin is tender, red, hard, or injured.

Step 6. Prepare the Injection Site

• Clean the injection site with an alcohol pad in a circular motion (see Figure I).
• Allow the injection site to air dry.
• Do not touch the cleaned injection site before giving the injection.
• Do not fan or blow on the skin area that you cleaned.

Injecting the Medicine with the Prefilled Syringe

Complete the Injection without stopping. Read all steps first before beginning.

Step 7. Remove Needle Cap and Dispose of the Cap

• Do not remove the needle cap until you are ready to inject.
• Hold the prefilled syringe by the body, with the needle facing away from you.
• Pull the needle cap straight off with one hand while holding the prefilled syringe with the other hand (see Figure J). If you cannot remove the cap, you should ask a caregiver for help or contact your healthcare provider.
• Do not touch or hold the plunger during needle cap removal.
• Do not re-cap the prefilled syringe.
• Dispose of the needle cap in an FDA-cleared sharps container.
• You may see a drop of liquid at the end of the needle. This is normal.
• The needle should be kept sterile after removing the needle cap. Do not touch the needle or let it touch any surfaces after removing the needle cap.

Step 8. Pinch the skin and Insert the Needle

Immediately after removing the needle cap, complete the following steps without stopping:

• Gently pinch the area of cleaned skin around the injection site and hold that area firmly until the injection is complete (see Figure K).
• Fully insert the needle at an angle between 45Ëš and 90Ëš. Do not change the angle during the injection. (see Figure K: images show an example of injection at 90Ëš angle).
• Do not hold or push on the plunger while inserting the needle into the skin.

Step 9. Inject Medicine

• Hold the prefilled syringe in place and inject all of the medicine by firmly pushing the plunger all the way down (see Figure L).
• Press the plunger all the way down until it stops to get the full dose. Push firmly on the plunger until the end of the injection (see Figure M).

Step 10. Release plunger

• After the plunger has been fully pushed down and the full dose injected, slowly remove the thumb from the plunger before removing the syringe from the skin (see Figure N). This will make the needle retract inside the syringe.

Caution: Do not remove the syringe from the skin before removing the thumb, as this could result in a needle stick injury.

Step 11. Release the Pinch and Remove the Prefilled Syringe

• Release the pinch and remove the prefilled syringe from the injection site (see Figure O).

• If there is a little bleeding at the injection site, you can press a cotton ball or gauze over the injection site.
• Do not rub the injection site.
• If needed, you may cover the injection site with a small adhesive bandage.

Disposal

Step 12. Disposing of the Syringe

• Do not reuse the prefilled syringe.
• After injecting the dose, put the syringe into an FDA-cleared sharps disposal container or closed punctureresistant container (see Figure P).

• If you do not have an 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 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 local 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, go to the FDA’s website at: https://www.fda.gov/safesharpsdisposal.
• Do not dispose of your used sharps disposal container in your household trash unless your local guidelines permit this.
• Do not recycle your used sharps disposal container.

Step 13. Keep Track of Treatment

• If required by your healthcare provider, record your injection in a diary to help keep track of your medicine.

Manufactured by:
CSL Behring LLC
King of Prussia, PA 19406
US License No. 1767

This Instructions for Use has been approved by the U.S. Food and Drug Administration.