Cinryze

Serious side effects have been reported with Cinryze including the following:

• Serious allergic reactions. The signs and symptoms of serious allergic reactions may include the appearance of hives, skin redness, itching, tightness of the chest, and/or wheezing experienced during or after injection of Cinryze. If you experience any of these symptoms, discontinue use immediately and seek emergency medical attention.
• Blood clots. Serious blood clots have been reported in patients taking the recommended doses of Cinryze. Risk factors may include presence of a permanent catheter, prior history of blood clots, heart disease, use of oral contraceptives, morbid obesity, and immobility. Benefits of Cinryze should be weighed against the risks of blood clots in people with underlying risk factors. Consult with your physician about the risks for developing serious blood clots before beginning treatment with Cinryze.
• Transmission of infectious agents. Because Cinryze is made from human blood products, it may carry a risk of transmitting infectious agents including viruses like HIV. Consult with your physician about this risk before beginning treatment with Cinryze.

Cinryze can also cause dizziness. Do not drive or operate heavy machinery until you know how Cinryze affects you.

Do not take Cinryze if you are allergic to Cinryze or to any of its ingredients.

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Complement C1 esterase inhibitor is injected into a vein through an IV. A healthcare provider will give you a Berinert in a clinic or hospital setting. You may be shown how to use Cinryze in an IV at home. Do not self-inject this medicine if you do not fully understand how to give the injection and properly dispose of used needles, IV tubing, and other items used to inject the medicine.

Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions.

Complement C1 esterase inhibitor is a powder medicine that must be mixed with a liquid (diluent) before using it. If you are using Cinryze home, you will need to use two vials of Cinryze to make up a single dose. Follow all directions carefully. Be sure you understand how to properly mix and store the medicine.

Gently swirl but do not shake the mixed medicine or you may ruin it. Prepare your dose only when you are ready to give yourself an injection.

Mixed Berinert should be clear and colorless. Mixed Cinryze should be clear or slightly blue in color. Do not use the mixed medicine if it has changed colors, is cloudy, or has any particles in it. Call your doctor for a new prescription.

Cinryze is usually given every 3 or 4 days to prevent angioedema attacks. An IV infusion takes about 10 minutes to complete.

Complement C1 esterase inhibitor contains no preservative. Once you have pierced the rubber top of a vial with a needle, you must use that vial right away or throw it away.

Each single use vial (bottle) of this medicine is for one use only. Throw away after one use, even if there is still some medicine left in it after injecting your dose.

Use a disposable needle and syringe only once. Follow any state or local laws about throwing away used needles and syringes. Use a puncture-proof "sharps" disposal container (ask your pharmacist where to get one and how to throw it away). Keep this container out of the reach of children and pets.

Store the unmixed dry powder in a refrigerator or in a dark cool place. Keep the medicine protected from light and do not allow it to freeze. Throw away any unused vial after the expiration date on the label has passed.

After mixing Berinert with the diluent, use it right away or store the mixture at room temperature and use it within 8 hours.

After mixing Cinryze with the diluent, use it right away or store the mixture at room temperature and use it within 3 hours.

Contraindications

• Known life-threatening hypersensitivity (e.g., anaphylaxis) to C1-esterase inhibitor (human) or any ingredient in the formulation.1 21

Warnings/Precautions

Warnings

Risk of thromboembolic events (e.g., MI, cerebrovascular accident, DVT, PE); reported in association with recommended as well as with higher than recommended (e.g., ≥100 units/kg) doses.1 17 21 28

Closely monitor patients with known risk factors for thrombosis.1 21

Potential vehicle for transmission of human viruses (e.g., HIV, hepatitis A virus [HAV], HBV, HCV, parvovirus B19) or other infectious agents (e.g., Creutzfeldt-Jakob disease [CJD]).1 9 12 13 21 Risk substantially reduced with current donor screening practices and viral inactivating procedures; however, possibility of disease transmission still exists.1 12 15 19 21

Although cases of suspected viral transmission (including HCV) have been reported with use of Berinert outside the US, manufacturer states no causal relationship to the drug has been established since introduction of a pasteurization step in 1985.21

Weigh risks of viral infection against benefits of therapy.1 12 21 Some experts recommend that patients who receive long-term treatment with blood products be vaccinated against hepatitis A and hepatitis B.12 13 Report any suspected infections thought to be associated with C1-esterase inhibitor (human) to the manufacturer.1 21

Because of potential for airway obstruction, patients who self-administer C1-esterase inhibitor (human) for treatment of a laryngeal attack should seek immediate medical attention in an appropriate healthcare facility after the drug is administered.21

Potential for immunogenicity with use of all therapeutic proteins, including C1-esterase inhibitor (human).1 Development of noninhibitory antibodies to C1-esterase inhibitor (human) reported in clinical trials; however, clinically important effects not observed.1 38 39

Sensitivity Reactions

Risk of severe hypersensitivity reactions (e.g., hives, urticaria, chest tightness, wheezing, hypotension, anaphylaxis).1 21 If hypersensitivity occurs, discontinue drug immediately and initiate appropriate treatment.1 21 Because symptoms of hypersensitivity can resemble acute attacks of hereditary angioedema, carefully consider treatment method.1 21 Epinephrine should be available for immediate use.1 21

Specific Populations

Category C.1 21

Not known whether C1-esterase inhibitor (human) is distributed into milk.1 21 Use with caution and only if clearly needed.1 21

Safety and efficacy of Cinryze not established in neonates, infants, and children <13 years of age; use in adolescents 13–18 years of age supported by data from approval study.1 20

Safety and efficacy of Berinert not established in pediatric patients ≤12 years of age, although used successfully for the treatment of acute HAE attacks in a limited number of children as young as 6 years of age.21 25 37

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.1 21

Pharmacokinetics not evaluated in patients with hepatic impairment.1 21

Pharmacokinetics not evaluated in patients with renal impairment.1 21

Common Adverse Effects

Headache,1 21 22 33 nausea,1 21 22 rash,1 vomiting,1 22 dysgeusia,21 abdominal pain.21 22 33

No formal drug interaction studies to date.1 21

In the U.S.

• Berinert
• Cinryze
• Haegarda

Available Dosage Forms:

• Powder for Solution

Therapeutic Class: Immune Modulator

• If you have an allergy to C1 inhibitor or any other part of Cinryze (C1 inhibitor (human) (cinryze)).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.

This medicine may interact with other drugs or health problems.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

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

• It is given as a shot into a vein.
• 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.
• This medicine needs to be mixed before use. Follow how to mix as you were told by the doctor.
• If stored in a refrigerator, let this medicine come to room temperature before mixing. Do not heat Cinryze.
• Do not use if the solution is cloudy, leaking, or has particles.
• This medicine is colorless to slightly blue after mixing. Do not use if the solution changes color.
• Use within 3 hours of making.
• 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?

• Take a missed dose as soon as you think about it.
• If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.

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

Pregnancy

Pregnancy Category C. No animal data are available. No adequate and well-controlled studies were conducted in pregnant women. It is not known whether Cinryze can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Cinryze should be given to a pregnant woman only if clearly needed.

Labor and Delivery

The safety and effectiveness of Cinryze administration prior to or during labor and delivery have not been established. Use only if clearly needed.

Nursing Mothers

It is not known whether Cinryze is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Cinryze is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of Cinryze have not been established in neonates, infants, or children. Three of the 24 subjects in Study LEVP2005-1/B were under the age of 18 years (9, 14, and 16 years of age).

Geriatric Use

The clinical study LEVP2005-1/B did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger subjects.

The maximum dose administered in clinical studies was 4000 Units given over approximately 5 hours (an average dose of 57 Units/kg) and 9000 Units given over a 7 day period. There have been no overdosages of Cinryze reported during clinical studies.

In vitro and in vivo animal thrombogenicity studies with Cinryze showed a potential for clot formation when Cinryze was administered at doses 14 times the recommended clinical dose (greater than 200U/kg). 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 Section 13.2 Animal Toxicology and/or Pharmacology and Section 5.2 Thrombotic events in WARNINGS AND PRECAUTIONS).

Cinryze (C1 esterase inhibitor [human]) is a sterile, stable, lyophilized preparation of C1 esterase inhibitor derived from human plasma. Cinryze is manufactured from human plasma purified by a combination of filtration and chromatographic procedures. The specific activity of Cinryze is 4.0 – 9.0 units/mg protein. The purity is ≥ 90% human C1 esterase inhibitor. Following reconstitution with 5 mL of Sterile Water for Injection, USP, each vial contains approximately 500 units of functionally active C1 esterase inhibitor, pH 6.6 - 7.4, and an osmolality between 200 – 400 mosmol/kg. One Unit (U) of Cinryze corresponds to the mean quantity of C1 esterase inhibitor present in 1 mL of normal fresh plasma.

Cinryze, when reconstituted with 5 mL of Sterile Water for Injection, USP contains the following excipients: 4.1 mg/mL sodium chloride, 21 mg/mL sucrose, 2.6 mg/mL trisodium citrate, 2.0 mg/mL L-Valine, 1.2 mg/mL L-Alanine, and 4.5 mg/mL L-Threonine.

The following manufacturing steps are designed to reduce the risk of viral transmission:

• Screening donors at U.S. licensed blood collection centers to rule out infection with Human Immunodeficiency Virus (HIV-1/HIV-2), Hepatitis B Virus, or Hepatitis C Virus.
• Testing plasma pools by in-process NAT for parvovirus B19 via minipool testing and the limit of B19 in the manufacturing pool is set not to exceed 104 IU of B19 DNA per mL.
• Use of two independent viral reduction steps in the manufacture of Cinryze: pasteurization (heat treatment at 60°C for 10 hours in solution with stabilizers) and nanofiltration through two sequential 15 nm filters.

These viral reduction steps, along with a step in the manufacturing process, PEG precipitation, have been validated in a series of in vitro experiments for their capacity to inactivate/remove a wide range of viruses of diverse physicochemical characteristics including: Human Immunodeficiency Virus (HIV), Hepatitis A Virus (HAV), and the following model viruses: Bovine Viral Diarrhea Virus (BVDV) as a model virus for HCV, Canine Parvovirus (CPV) as a model virus for Parvovirus B19, Pseudorabies Virus (PRV) as a model virus for large enveloped DNA viruses (e.g. herpes virus). Total mean log10 reductions are shown in Table 3.

• Cinryze is available in single-use vials that contain 500 Units per vial.
• Cinryze is supplied as a single glass vial of Cinryze powder to be reconstituted with 5 mL Sterile Water for Injection, USP (Not supplied).
• Cinryze, packaged for sale, is stable for 18 months when stored at 2°C–25°C (36°F-77°F).
• Do not freeze.
• Store the vial in the original carton to protect it from light.
• The reconstituted solution must be used within 3 hours of reconstitution.
• Do not use beyond the expiration date on the Cinryze vial.

Cinryze (complement C1 esterase inhibitor) is a man-made form of a protein that occurs naturally in the blood stream and helps control inflammation in the body. In people with hereditary angioedema, complement C1 esterase inhibitor does not function properly or occurs in low levels.

Complement C1 esterase inhibitor is used in people with hereditary angioedema. Hereditary angioedema can cause attacks of swelling and symptoms such as stomach problems or trouble breathing. The Cinryze brand is used to prevent attacks of angioedema. The Berinert brand of this medicine is used to treat attacks of angioedema.

Common side effects of Cinryze include: headache. Other side effects include: abdominal pain, nausea, vomiting, and muscle spasm. See below for a comprehensive list of adverse effects.