What is CINRYZE?

CINRYZE Safety Profile¹

Contraindications

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

Hypersensitivity Reactions

Severe hypersensitivity reactions may occur during or after administration of CINRYZE. Consider treatment methods carefully, because hypersensitivity reactions may have symptoms similar to HAE attacks. In case of hypersensitivity, discontinue CINRYZE infusion and institute appropriate treatment. Have epinephrine immediately available for treatment of an acute severe hypersensitivity reaction.

Thromboembolic Events

Serious arterial and venous thromboembolic (TE) events have been reported at the recommended dose of C1 Esterase Inhibitor (Human) products, including CINRYZE, following administration in patients with HAE. Risk factors may include presence of an indwelling venous catheter/access device, prior history of thrombosis, underlying atherosclerosis, use of oral contraceptives, certain androgens, morbid obesity, and immobility. Benefits of CINRYZE for routine prophylaxis of HAE attacks should be weighed against the risks of TE events in patients with underlying risk factors. Monitor patients with known risk factors for TE events during and after CINRYZE administration.

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 disease (CJD) agent. ALL infections thought by a physician possibly to have been transmitted by CINRYZE should be reported to Takeda Medical Information at 1-800-828-2088.

Adverse Reactions

The only serious adverse reaction observed in clinical studies of CINRYZE was cerebrovascular accident. The most common adverse reactions (≥5%) observed were headache, nausea, rash, vomiting, and fever. Post marketing adverse reactions include local infusion site reactions and hypersensitivity. Post marketing thromboembolic events have been reported, including catheter-related and deep venous thromboses, transient ischemic attack, and stroke.

Pharmacokinetics

In comparison to adults receiving 1000 U of CINRYZE, PK modelling exposure was lower for pediatric patients receiving 500 U and higher for those receiving 1000 U.

Clinical trials experience

Because clinical studies 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.

Routine prophylaxis

Twenty-four subjects age 9 to 73 years old were evaluated in the randomized, placebo-controlled, crossover, routine prophylaxis trial. There were no serious adverse reactions in the randomized, placebo-controlled, crossover, routine prophylaxis trial.

Adverse reactions in the randomized, placebo-controlled, crossover, routine prophylaxis trial (n=24) that occurred in at least two subjects (≥8%) receiving CINRYZE are given in the following table:

Adverse reactions in the randomized, placebo-controlled, crossover, routine prophylaxis trial

Adverse Reaction	Number of Adverse Reactions	Number of Subjects (n=24)
Rash	8	5
Headache	4	4
Pruritus	2	2
Vomiting	2	2

In an open-label follow-on trial, 146 subjects age 3 to 82 years old received a median of 243.5 days of CINRYZE (maximum = 959 days). The most common adverse reaction observed was headache. No subjects were discontinued due to an adverse reaction.

Adverse reactions in the open-label follow-on trial (n=146) that occurred in at least three subjects (≥2%) receiving CINRYZE, are given in the following table:

Adverse reactions in the open-label follow-on trial

Adverse Reaction	Number (%) of Subjects (n=146) With Adverse Reactions	Number (%) of Infusion Days (n=11,435) With Adverse Reaction
Headache	28 (19)	62 (0.5)
Nausea	26 (18)	29 (0.3)
Rash	15 (10)	30 (0.3)
Vomiting	15 (10)	17 (0.1)
Pyrexia	7 (5)	7 (<0.1)
Catheter Site Pain	4 (3)	5 (<0.1)
Dizziness	3 (2)	4 (<0.1)
Erythema	3 (2)	3 (<0.1)
Pruritus	3 (2)	4 (<0.1)

Adverse Reactions in Pediatric Patients

Twelve pediatric subjects aged 7 to 11 years old were evaluated in a randomized, dose-ranging, crossover routine prophylaxis trial (500 U and 1000 U). No new adverse reactions (compared to the placebo-controlled routine prophylaxis trial or the open label follow-on trial) were identified. The adverse reactions among the pediatric subjects were headache, nausea, pyrexia (fever), and infusion site erythema. None of the adverse reactions were severe, and none led to discontinuation of CINRYZE. The safety profile with 500 U or 1000 U of CINRYZE treatment was comparable. Overall, the safety and tolerability of CINRYZE are similar in pediatric, adolescent and adult subjects.

Use in specific populations

Pregnancy

There are no data with CINRYZE use in pregnant women to inform a drug-associated risk. Animal reproduction studies have not been conducted with CINRYZE. It is unknown 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.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Lactation

There are no data regarding the presence of CINRYZE in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CINRYZE and any potential adverse effects on the breastfed child from CINRYZE or from the underlying maternal condition.

Pediatric use

The safety and effectiveness of CINRYZE have been evaluated in 12 pediatric subjects with HAE (age range 7 to 11 years old) in a pediatric randomized, dose-ranging, crossover routine prophylaxis trial. Additionally, four of the 24 subjects in the pediatric/adult randomized, placebo-controlled, crossover, routine prophylaxis trial, were under the age of 18 years (9, 14, 16, and 17 years of age). Overall the safety and tolerability of CINRYZE are similar in pediatric, adolescent and adult subjects. The pharmacokinetics of CINRYZE was evaluated in pediatric subjects (7 to 11 years old).

Geriatric use

Clinical studies of CINRYZE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.