C1 Esterase Inhibitor [Human] Freeze Dried Powder

CINRYZE (C1 esterase inhibitor [human]) (Freeze-Dried powder for Reconstitution) 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 LValine, 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 log reductions are shown in Table 4.

Table 4 Log10 Virus Reduction Factor for Selected Viruses

Mechanism Of Action

C1 inhibitor is a normal constituent of human blood and is one of the serine proteinase inhibitors (serpins). The primary function of C1 inhibitor is to regulate the activation of the complement and intrinsic coagulation (contact system) pathway. C1 inhibitor also regulates the fibrinolytic system. Regulation of these systems is performed through the formation of complexes between the proteinases and the inhibitor, resulting in inactivation of both and consumption of the C1 inhibitor.

HAE patients have low levels of endogenous or functional C1 inhibitor. Although the events that induce attacks of angioedema in HAE patients are not well defined, it is thought by some that increased vascular permeability and the clinical manifestation of HAE attacks are primarily mediated through contact system activation. Suppression of contact system activation by C1 inhibitor through the inactivation of plasma kallikrein and factor XIIa is thought to modulate this vascular permeability by preventing the generation of bradykinin1. Administration of CINRYZE increases plasma levels of C1 inhibitor activity.

Pharmacodynamics

In clinical studies, the intravenous administration of CINRYZE demonstrated an increase in plasma levels of C1 inhibitor within approximately one hour or less of administration.

Biological activity of CINRYZE was shown in 35 subjects by the subsequent increase in plasma C4 levels from an average of C4 8.1 mg/mL at baseline to C4 8.6 mg/mL 12 hours after infusion of CINRYZE.

Pharmacokinetics

A randomized, parallel group, open-label pharmacokinetics (PK) study of CINRYZE was performed in patients with non-symptomatic hereditary angioedema (HAE). The patients received either a single dose of 1,000 Units or 1,000 Units followed by a second 1,000 Units 60 minutes later. The PK results for functional C1 inhibitor are presented the following table:

Table 5 Mean pharmacokinetic parameters of Functional C1 Inhibitor

The maximum plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) increased from the single to double dose, although the increase was not dose proportional. The mean half-lives of CINRYZE were 56 hours (range 11 to 108 hours) for a single dose and 62 hours (range 16 to 152 hours) for the double dose.

Studies have not been conducted to evaluate the PK of CINRYZE in special patient populations identified by gender, race, age (pediatric or geriatric), or the presence of renal or hepatic impairment.

Animal Toxicology And/Or Pharmacology

Acute toxicity of CINRYZE was studied in a combined acute toxicity and 7-day repeat dose/ dose range finding (DRF) study in Sprague Dawley rats followed by a pivotal 14-day repeat dose study. The acute and 14-day repeat dose toxicity studies were performed with intravenous administration of CINRYZE at dose levels of 1, 7 and 28 times normal dose. No signs of toxicity were observed in the single dose or repeat dose studies. Repeat dosing in the rat resulted in an antibody response between days 1 and 14 that was not characterized for neutralizing activity. However, there was no change in the functional activity of CINRYZE over the dosing period.

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 with another C1 esterase inhibitor product 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 Thromboembolic Events in WARNINGS AND PRECAUTIONS).

Clinical Studies

The safety and efficacy of CINRYZE prophylaxis therapy to reduce the incidence, severity, and duration of HAE attacks was demonstrated in a single randomized, double blind, placebo controlled multi-center cross-over study of 24 patients. Patients were screened to confirm a diagnosis of HAE and a history of at least two HAE attacks per month. 24 patients (mean age 38.1 years with a range of 9 to 73 years) were randomized to one of two treatment groups: either CINRYZE prophylaxis for 12 weeks followed by 12 weeks of placebo prophylaxis; or randomized to placebo prophylaxis for 12 weeks followed by 12 weeks of CINRYZE prophylaxis. Two subjects dropped out (one in each arm); 22 patients crossed over into period 2 and were included in the efficacy analysis. Patients were given blinded injections (CINRYZE or placebo) every 3 to 4 days, approximately 2 times per week. Patients recorded all angioedema symptoms daily. An attack was defined as the subject-reported indication of swelling at any location following a report of no swelling on the previous day.

The efficacy determination was based on the number of attacks during the 12 week period while receiving CINRYZE as compared to the number of attacks during the placebo treatment period. The effectiveness of C1 esterase inhibitor prophylaxis in reducing the number of HAE attacks was variable among the subjects as shown in table 6:

Table 6 The Randomized, Placebo-Controlled, Cross over, Routine Prophylaxis Trial Prevention of HAE Attacks Clinical Trial Results by Subject

Table 7 Summary Statistics on Number of HAE Attacks in the Randomized, Placebo-Controlled, Cross over, Routine Prophylaxis Trial

Patients treated with CINRYZE had a 66% reduction in days of swelling (p<0.0001), and decreases in the average severity of attacks (p=0.0006) and the average duration of attacks (p=0.0023), as shown in table 8.

Table 8 The Randomized, Placebo-Controlled, Cross over, Routine Prophylaxis Trial Secondary Efficacy Outcomes

REFERENCES

1. Davis AE, The pathophysiology of hereditary angioedema. Clin Immunol. 2005; 114:3-9.

2. Arzneimittelkommission der Deutschen Aertzteschaft. Schwerwiegende Thrombenbildung nach Berinert HS. Dtsch Aerztebl. 2000; 97:B-864

3. Horstick, G et al, 2001. Circulation 104:3125-3131

You should not use this medication if have ever had a life-threatening allergic reaction to complement C1 esterase inhibitor.

Before you receive complement C1 esterase inhibitor, tell your doctor if you have a history of stroke or blood clot.

Do not give this medication to a child without medical advice.

You may be shown how to use Cinryze in an IV at home. This medication comes with patient instructions for safe and effective use. Follow all directions carefully. Ask your doctor or pharmacist if you have any questions.

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. Be sure you understand how to properly mix and store the medication.

Stop your IV infusion and get emergency medical help if you have any of these signs of an allergic reaction: hives; wheezing or difficult breathing; feeling like you might pass out; or swelling of your face, lips, tongue, or throat.

Other serious side effects may include sudden numbness or weakness, chest pain, confusion, pain or swelling, and problems with vision, speech, or balance.

Complement C1 esterase inhibitor is made from human plasma (part of the blood) which may contain viruses and other infectious agents. Donated plasma is tested and treated to reduce the risk of it containing infectious agents, but there is still a small possibility it could transmit disease. Talk with your doctor about the risks and benefits of using this medication.

Use the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not use extra medicine to make up the missed dose.