CINRYZE™ (C1 Esterase Inhibitor [Human])

Freeze dried powder

1 INDICATIONS AND USAGE

CINRYZE is a C1 esterase inhibitor indicated for routine prophylaxis against angioedema attacks in adolescent and adult patients with Hereditary Angioedema (HAE).

2 DOSAGE AND ADMINISTRATION

For Intravenous Use, Freeze-Dried powder for Reconstitution.

2.1 Routine prophylaxis against HAE Attacks

• A dose of 1,000 Units CINRYZE can be administered every 3 or 4 days for routine prophylaxis against angioedema attacks in HAE patients.
• CINRYZE is administered at an injection rate of 1 mL per minute.

2.2 Instructions for Use

The procedures below are provided as general guidelines for the reconstitution and administration of CINRYZE. Use either the Mix2Vial® transfer device or a commercially available double-ended needle.

CINRYZE IS A LYOPHILIZED POWDER THAT IS SUPPLIED IN A VACUUM-SEALED VIAL.

Always work on a clean surface and wash your hands before performing the following procedures.

Reconstitution, product administration, and handling of the administration set and needles must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious viruses including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in a sharps container after single use. Discard all equipment, including any reconstituted CINRYZE in an appropriate container.

2.3 Preparation and Handling

• Prior to reconstitution, CINRYZE should be protected from light.
• CINRYZE should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution should be colorless to slightly blue, and free from visible particles. Do not use if turbid or discolored.
• The CINRYZE vial is for single use only. CINRYZE contains no preservative. Any vial that has been entered should be used promptly. Partially used vials should be discarded in accordance with biohazard procedures.
• Do not mix CINRYZE with other materials.
• Do not use if frozen.
• Do not use after expiration date.

Reconstitution:

Two vials of reconstituted CINRYZE are combined for a single dose. Sterile Water for Injection, USP, is required and not supplied with CINRYZE.

1. Aseptic technique should be used during the reconstitution procedure.
2. Bring the CINRYZE (powder) and Sterile Water for Injection, USP (diluent) (not supplied) to room temperature if refrigerated.
3. Remove caps from the CINRYZE and diluent vials.
4. Cleanse stoppers with an alcohol wipe or swab, and allow them to dry prior to use.
5. Remove protective covering from the top of the Mix2Vial transfer device package. Do not remove the device from the package.
6. Note: Diluent vial must be accessed prior to CINRYZE vial to prevent loss of vacuum. Place diluent on a flat surface and insert the blue end of the device into the diluent vial, pushing down until the spike penetrates through the center of the diluent vial stopper and the device snaps in place (Figure 1). The Mix2Vial transfer device must be positioned completely vertical prior to penetrating the stopper closure.
7. Remove the plastic package and discard it (Figure 2). Take care not to touch the exposed end of the device.
8. Place vial of CINRYZE on a flat surface. Invert diluent vial containing 5 mL Sterile Water for Injection, USP, and insert the clear end into the CINRYZE vial, pushing down until the spike penetrates the rubber stopper and the device snaps into place. The Mix2Vial transfer device must be positioned completely vertical prior to penetrating the stopper closure. The Sterile Water for Injection, USP will automatically flow into the vial of CINRYZE (Figure 3), because the vacuum in the vial will draw in the diluent. If there is no vacuum in the vial, do not use the product.
9. Gently swirl (do not shake) the CINRYZE vial until all powder is dissolved. Be sure that CINRYZE is completely dissolved (Figure 4). Disconnect the Sterile Water for Injection, USP vial by turning it counterclockwise (Figure 5). Do not remove the clear end of the Mix2Vial transfer device from the vial of CINRYZE.

One vial of reconstituted CINRYZE contains 5 mL of C1 esterase inhibitor at a concentration of 100 Units/mL. Reconstitute two vials of CINRYZE for one dose. Repeat steps 1 to 9 above using an additional package containing a Mix2Vial transfer device to reconstitute the second of two vials of CINRYZE. Do not reuse the Mix2Vial transfer device.

2.4 Administration

Two vials of reconstituted CINRYZE are combined for a single dose.

1. Use Aseptic Technique.
2. After reconstitution, the solutions are colorless to slightly blue and clear. Do not use the product if the solutions are turbid or discolored.
3. CINRYZE must be administered at room temperature within 3 hours after reconstitution.
4. Please refer to the illustrations in steps 7 to 9 included within the Patient Information Leaflet. Utilizing a sterile, disposable 10 mL syringe, draw back the plunger to admit 5 mL air into the syringe.
5. Attach the syringe onto the top of the clear end of the Mix2Vial transfer device by turning it clockwise.
6. Invert the vial and inject air into the solution and then slowly withdraw the reconstituted CINRYZE into the syringe.
7. Detach the syringe from the vial by turning it counterclockwise and releasing it from the clear end of the Mix2Vial transfer device.
8. Using the same syringe, repeat steps 4 to 7 with a second vial of CINRYZE to make the complete dose.
9. Attach a suitable needle or infusion set with winged adapter, and inject intravenously. As a guideline, administer 1,000 Units (reconstituted in 10 mL) of CINRYZE by intravenous injection at a rate of 1 mL per minute over 10 minutes. (see Clinical Studies, [14]) Please refer to the illustration in step 3 of the self administration section within the Patient Information Leaflet.
10. Dispose of all unused solution, the empty vial(s), and the used needles and syringes in an appropriate container for throwing away waste that might hurt others if not handled properly.

3. DOSAGE FORMS AND STRENGTHS

• CINRYZE is a lyophilized preparation available in a single-use vial that contains 500 Units (U) human C1 esterase inhibitor.
• Each vial must be reconstituted with 5 mL Sterile Water for Injection, USP (diluent) (not supplied).
• Two reconstituted vials must be used to make a single, 1,000 Units, dose.

4 CONTRAINDICATIONS

CINRYZE is contraindicated in patients who have manifested life-threatening immediate hypersensitivity reactions, including anaphylaxis to the product.

5 WARNINGS AND PRECAUTIONS

5.1 Sensitivity

Severe hypersensitivity reactions may occur. The signs and symptoms of hypersensitivity reactions may include the appearance of hives, urticaria, tightness of the chest, wheezing, hypotension and/or anaphylaxis experienced during or after injection of CINRYZE.

Because hypersensitivity reactions may have symptoms similar to HAE attacks, treatment methods should be carefully considered.

In case of hypersensitivity, CINRYZE infusion should be discontinued and appropriate treatment instituted. Epinephrine should be immediately available for treatment of acute severe hypersensitivity reaction. (See Patient Counseling Information [17])

5.2 Thrombotic Events

Thrombotic events have been reported in association with C1 esterase inhibitor products when used off-label at high doses.2 Animal studies have supported a concern about the risk of thrombosis from intravenous administration of C1 esterase inhibitor products. 3 (see Sections 10 OVERDOSAGE and 13.2 Animal Toxicology and/or Pharmacology)

In an open label trial further investigating the use of CINRYZE for prevention (n=146) of HAE attacks, 5 serious thrombotic events (including myocardial infarction, deep vein thrombosis, pulmonary embolism and 2 events of cerebrovascular accident) occurred. Subjects had underlying risk factors for thrombotic events. Patients with known risk factors for thrombotic events should be monitored closely while taking CINRYZE.

5.3 Transmissible Infectious Agents

Because CINRYZE is made from human blood, it may carry a risk of transmitting infectious agents, e.g. viruses, and, theoretically, the Creutzfeldt-Jakob (CJD)