Cinryze

Cinryze (C1 esterase inhibitor [human]) is a prescription medicine used for routine prevention (prophylaxis) of angioedema attacks in adults, adolescents, and children 6 years and older with hereditary angioedema (HAE). It is given as an intravenous (IV) injection every 3 or 4 days, and you can be taught by your healthcare provider to give it yourself at home.

HAE is caused by low levels or poor function of a protein in the blood called C1 esterase inhibitor, which helps control swelling. Cinryze is made from purified human plasma and replaces the missing protein, raising C1 inhibitor levels in the blood within about an hour.

Cinryze is used to prevent HAE attacks, not to treat an attack once it starts. Other products, such as Berinert (C1 esterase inhibitor [human]), are used to treat acute attacks.

Cinryze was approved by the FDA on October 10, 2008, for adults and adolescents, and its use was later expanded to children 6 years and older.

C1 inhibitor is a natural protein in the blood that controls the complement and contact (kallikrein) systems. People with HAE do not have enough working C1 inhibitor. Cinryze increases C1 inhibitor activity, which is thought to block plasma kallikrein and factor XIIa and prevent the production of bradykinin, a substance that makes blood vessels leak fluid and causes swelling.

In a 12-week, randomized, double-blind, placebo-controlled crossover study in 22 people with HAE aged 9 to 73 years, each person received Cinryze 1,000 units and placebo every 3 to 4 days for 12 weeks each.

Cinryze reduced days of swelling by 66%. Response varied between individuals: 4 of 22 people had no attacks while on Cinryze, while 2 people had more attacks on Cinryze than on placebo.

In a study of 12 children aged 7 to 11 years, monthly HAE attacks fell by an average of 71% with 500 units and 85% with 1,000 units compared with before treatment. Both doses also reduced attack severity and the need for acute treatment.

Cinryze is a freeze-dried powder that is dissolved in Sterile Water for Injection and injected slowly into a vein at about 1 mL per minute. Do not try to give Cinryze yourself unless your healthcare provider has taught you how.

• Each 500 IU vial is mixed with one 5 mL vial of Sterile Water for Injection using a Mix2Vial transfer device. Two vials are needed for a 1,000 IU dose.
• Let both vials reach room temperature first. Always pierce the diluent vial before the Cinryze vial to keep the vacuum.
• Gently swirl (do not shake) until the powder is fully dissolved. The solution should be clear and colorless to slightly blue. Do not use it if it is cloudy or discolored, and call Takeda at 1-877-825-3327.
• A silicone-free syringe is recommended.
• Use the mixed solution at room temperature within 3 hours. Cinryze contains no preservative, so throw away any unused solution.
• Inject a 500 IU dose over 5 minutes, or a 1,000 IU dose over 10 minutes.
• Do not reuse the Mix2Vial device. Dispose of vials, needles, and syringes in a sharps container.
• Record the lot number from the vial label each time you use Cinryze.

Read the Instructions for Use that come with Cinryze for step-by-step directions.

Do not use Cinryze if you have had a life-threatening allergic reaction, including anaphylaxis, to Cinryze.

Allergic reactions

Severe allergic reactions can happen during or after a Cinryze injection. Stop the injection and get emergency help right away if you have wheezing, difficulty breathing, chest tightness, turning blue (look at lips and gums), fast heartbeat, swelling of the face, faintness, rash, or hives. Allergic reactions can look similar to an HAE attack, so your healthcare provider may advise you to keep epinephrine available.

Blood clots

Serious blood clots in the veins and arteries have been reported with C1 esterase inhibitor (human) products, including Cinryze, at recommended doses. Clots have also been reported when these products were used off-label at higher than approved doses. Your risk may be higher if you have:

• An indwelling venous catheter or access device
• A history of blood clots
• Atherosclerosis (hardening of the arteries)
• Severe obesity or reduced mobility
• Use of birth control pills or certain androgens (male hormones).

Call your healthcare provider or get emergency help right away if you have pain or swelling of an arm or leg with warmth over the area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid heart rate, or numbness or weakness on one side of the body.

Infection risk from human plasma

Because Cinryze is made from human blood, it may carry a risk of transmitting infectious agents, such as viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk has been reduced, but not eliminated, by screening donors, testing plasma, and two virus-removal steps during manufacturing (heat treatment and nanofiltration). In clinical studies, no one tested positive for parvovirus B19, hepatitis B, hepatitis C, or HIV after receiving Cinryze.

Call your healthcare provider right away if your swelling is not controlled after using Cinryze.

Tell your healthcare provider about all your medical conditions, including if you:

• Have an indwelling catheter or access device in one of your veins
• Have a history of blood clots, heart disease, or stroke
• Take birth control pills or androgens
• Are pregnant or plan to become pregnant. It is not known if Cinryze can harm an unborn baby.
• Are breastfeeding or plan to breastfeed. It is not known if Cinryze passes into breast milk.

Cinryze has not been studied in people with kidney or liver problems. Clinical studies did not include enough people aged 65 and older to know if they respond differently.

The most common side effects of Cinryze are headache, nausea, rash, vomiting, and fever. In a long-term study of 146 people (aged 3 to 82 years) who received Cinryze for a median of about 8 months, side effects included:

No one stopped treatment because of a side effect in this study. Side effects in children were similar to those in adults. Since approval, infusion site reactions (such as inflammation or bruising at the injection site) and allergic reactions have also been reported.

Tell your healthcare provider about any side effect that bothers you or does not go away. You can report side effects to Takeda Pharmaceuticals U.S.A., Inc. at 1-877-TAKEDA-7 (1-877-825-3327) or to the FDA at 1-800-FDA-1088.

Adults and adolescents 12 years and older

• 1,000 IU intravenously every 3 or 4 days, given at 1 mL per minute (over 10 minutes).
• If the response is not adequate, doses up to 2,000 IU (not exceeding 80 IU/kg) every 3 or 4 days may be considered.

Children 6 to 11 years

• 500 IU intravenously every 3 or 4 days, given at 1 mL per minute (over 5 minutes).
• The dose may be adjusted based on response, up to 1,000 IU every 3 or 4 days.

Cinryze is supplied as a carton containing one 500 IU single-dose vial and one 5 mL vial of Sterile Water for Injection.

Call your healthcare provider for instructions if you miss a dose. When traveling, plan to bring enough Cinryze for your treatment.

Call your healthcare provider if you use too much Cinryze. No overdoses were reported in clinical studies, where the highest doses given were 4,000 units over about 4 hours and 10,000 units over 7 days. In an emergency, call the Poison Help line at 1-800-222-1222.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, supplements, and herbal remedies. In particular, tell them if you take:

• Birth control pills (oral contraceptives)
• Androgens (male hormones), such as testosterone.

These medicines may increase your risk of blood clots while using Cinryze. Cinryze should not be mixed with other materials.

• Store Cinryze in the refrigerator or at room temperature between 36°F and 77°F (2°C and 25°C).
• Do not freeze, and do not use Cinryze if it has been frozen.
• Keep the vial in the original carton to protect it from light.
• Do not use after the expiration date on the vial.

Active ingredient: C1 esterase inhibitor (human), 500 IU per vial.

Inactive ingredients (after mixing with 5 mL Sterile Water for Injection): sodium chloride, sucrose, trisodium citrate, L-valine, L-alanine, and L-threonine.

Cinryze is manufactured by Takeda Pharmaceuticals U.S.A., Inc., Cambridge, MA 02142. U.S. License Number 1898.