Cinryze: Indications, Dosage, Precautions, Adverse Effects
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Cinryze - Product Information

Manufacture: Shire, Inc.
Country: Canada
Condition: Hereditary Angioedema
Class: Miscellaneous coagulation modifiers
Form: Intravenous (IV), Powder
Ingredients: c1 esterase inhibitor, human, L-alanine, L-threonine, L-valine, sodium chloride, sodium citrate, sucrose, sterile water for injections

(C1 inhibitor [human])

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Nonmedicinal
Ingredients
Intravenous injectionLyophilized powder, 500 IU/vialNone.

For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING.

Description

CINRYZE (C1 inhibitor [human]) is a sterile, stable, lyophilized preparation of C1 inhibitor derived from human plasma. CINRYZE is manufactured from large pools of human plasma purified by a combination of filtration and chromatographic procedures.

Following reconstitution with 5 mL of Sterile Water for Injections, each vial contains approximately 500 IU of functionally active C1 inhibitor. One IU of CINRYZE corresponds to the mean quantity of C1 inhibitor present in 1 mL of normal fresh plasma.

Indications and Clinical Use

CINRYZE is indicated for:

  • Routine prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE).

Geriatrics

No special investigations have been performed.

Pediatrics

The safety and effectiveness of CINRYZE have not been established in children. A total of 46 subjects who have received CINRYZE in the clinical trials were under 18 years of age (3 were less than 6 years of age, 17 were between 6 to 11 years of age, and 26 were between 12 to 17 years of age).

Contraindications

CINRYZE is contraindicated in patients who have manifested life-threatening immediate hypersensivity reactions, including anaphylaxis, to the product, or who are hypersensitive to any ingredient in the formulation or component of the container. For a complete listing, see Dosage Forms, Composition and Packaging.

Warnings and Precautions

Transmissible Agents

CINRYZE is made from human blood and it may carry a risk of transmitting infectious agents, e.g. viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. This also applies to unknown or emerging viruses and other pathogens.

Cardiovascular

Thrombotic events

Thrombotic events have been reported in patients receiving CINRYZE. Patients with known risk factors for thrombotic events should be monitored closely.

An animal study identified that there is a potential thrombogenic threshold at doses greater than 200 Units/kg.

In an open-label trial where 146 subjects received CINRYZE for prevention of HAE attacks, 5 serious thrombotic events (including myocardial infarction, deep vein thrombosis, pulmonary embolism and 2 events of cerebrovascular accident) occurred. None of these events were considered by the investigator to be related to CINRYZE.

Hypersensitivity

Severe hypersensitivity reactions may occur. Hypersensitivity reactions may have symptoms similar to angioedema attacks. Patients should be informed of the early signs of hypersensitivity reactions including hives, urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis, which may occur during or after injection of CINRYZE. In case of hypersensitivity, discontinue CINRYZE infusion and initiate appropriate treatment.

Home-treatment and Self-administration

Potential risks associated with home-treatment are related to the administration itself as well as the handling of adverse drug reactions, particularly hypersensitivity. The decision on the use of home-treatment for an individual patient should be made by the treating physician, who should ensure that appropriate training is provided and the use reviewed at intervals.

Special Populations

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 pregnant women only if clearly indicated.

Nursing Women

It is unknown whether C1 inhibitor 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.

Pediatrics

The safety and effectiveness of CINRYZE have not been established in children (see Pediatric population and Action and Clinical Pharmacology, Special Populations and Conditions).

Thrombotic events have been reported in neonatal and infant subjects undergoing cardiac bypass procedures while receiving off-label high doses of another C1 inhibitor product to prevent capillary leak syndrome.

Geriatrics

No special investigations have been performed.

Monitoring and Laboratory Tests

Monitor patients with known risk factors for thrombotic events.

Adverse Reactions

Adverse Drug Reaction Overview

In clinical studies, there were a total of 262 subject exposures involving over 14,500 infusions of CINRYZE.

The most common adverse reaction observed following CINRYZE infusion in clinical studies was rash. Descriptions of rash characteristics were nonspecific, but were typically described as involving the upper extremities, chest, abdomen, or injection site. None of the rashes were serious, and none led to discontinuation of medicinal product.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions, the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adverse reaction frequency was estimated primarily based on summation of unique adverse events related to CINRYZE reported across 8 completed clinical studies in HAE subjects (Table 1). This includes data from two placebo-controlled studies, three open-label studies, and three compassionate-use single -subject studies. There were a total of 262 subject exposures involving over 14,500 infusions of CINRYZE in these studies.

The most common adverse reaction observed following CINRYZE infusion in clinical studies was rash.

Table 1. Adverse reactions with suspected relationship to CINRYZE reported in clinical studies by investigators
System Organ ClassFrequency*: Adverse reaction
Metabolism and nutrition disordersUncommon: Hyperglycemia
Nervous system disordersUncommon: Dizziness, headache
Vascular disordersUncommon: Hot flush, phlebitis, venous burning, venous
 thrombosis
Respiratory, thoracic and mediastinal disordersUncommon: Cough
Gastrointestinal disordersUncommon: Abdominal pain, diarrhea, nausea, vomiting
Skin and subcutaneous tissue disordersCommon: Rash
Uncommon: Contact dermatitis, erythema, pruritus
Musculoskeletal and connective tissue disordersUncommon: Arthralgia, joint swelling, myalgia
General disorders and administration site conditionsUncommon: Chest discomfort, infusion site pain, injection site rash/erythema, pyrexia

* Frequencies are defined as very common (≥10%), common (≥1% to <10%), uncommon (≥0.1% to <1%), rare (≥0.01% to <0.1%), and very rare (<0.01%).

Post-Market Adverse Drug Reactions

Because post-marketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.

Post-marketing thrombotic events have been reported, including catheter-related and deep venous thromboses, transient ischemic attack, and stroke. Patients with known risk factors for thrombotic events should be monitored closely (see Warnings and Precautions, Thrombotic events).

Other post-marketing adverse reactions reported include abdominal pain, anxiety, chest pain, diarrhea, dizziness, fatigue, headache, hypersensitivity, local infusion site reactions (including pain, rash, erythema, inflammation or hematoma at the infusion site), malaise, migraine, nausea, pain (of any type), rash, sinusitis, swelling (of any type), urticaria, and vomiting.

Drug Interactions

No formal drug interaction studies have been conducted with CINRYZE, and to date no relevant interactions are known.

Dosage and Administration

A healthcare practitioner, caregiver or patient can administer CINRYZE. The decision on the use of home-treatment for an individual patient should be made by a healthcare practitioner. Appropriate training must be provided by the healthcare practitioner prior to a caregiver or patient administering CINRYZE.

A patient should not attempt to self-administer unless trained by a healthcare provider.

Recommended Dose

Routine prevention of angioedema attacks

  • 1000 IU of CINRYZE every 3 or 4 days for routine prevention against angioedema attacks.

The dosing interval may need to be adjusted according to individual response. The continued need for regular prophylaxis with CINRYZE should be reviewed on a regular basis.

Administration

Reconstitution and administration of CINRYZE

For intravenous use only.

The reconstituted product should be administered by intravenous injection at a rate of 1 mL per minute.

Preparation and handling

CINRYZE is intended for intravenous administration after reconstitution with Sterile Water for Injections.

Each pack contains:
Two powder vials and two diluent vials.

Reconstitution, product administration and handling of the needles must be done with caution. A silicone-free syringe is recommended for reconstitution and administration of CINRYZE.

Use either a filter transfer device or any commercially available double-ended needle (see Dosage Forms, Composition and Packaging).

Reconstitution

Parenteral Products

Vial SizeVolume of
Diluent to be
Added to Vial
Approximate Available
Volume
Nominal
Concentration per mL
8 mL5 mL of Sterile Water for InjectionsAfter reconstitution, one vial contains 500 IU of C1 inhibitor (human) in 5 mL5 mL of C1 inhibitor corresponding to a concentration of 100 IU/mL

Each product vial should be reconstituted with 5 mL Sterile Water for Injections. Two vials of reconstituted CINRYZE are combined for ONE dose (1000 IU).

  1. Bring the powder vial and the diluent vial to room temperature (15ºC – 25ºC) prior to reconstitution.
  2. Wash your hands before performing the following procedures.
  3. Aseptic technique should be used during the reconstitution procedure.
  4. Remove plastic caps from the powder and diluent vials.
  5. Cleanse stoppers with an alcohol wipe and allow them to dry prior to use.
  6. Remove protective covering from the top of the transfer device package. To maintain sterility, do not remove the device from the package.
  7. Note: the transfer device must be attached to the diluent vial before being attached to the powder vial, so that the vacuum in the powder vial is not lost. Place the diluent vial on a flat surface and insert the blue end of the transfer device into the diluent vial, pushing down until the spike penetrates through the centre of the diluent vial stopper and the device snaps in place. The transfer device must be vertical prior to penetrating the stopper closure.
  8. Remove the plastic package from the transfer device and discard it. Take care not to inadvertently remove the transfer device or touch the exposed end of the transfer device.
  9. Place the powder vial on a flat surface. Invert the transfer device and the diluent vial containing Sterile Water for Injections and insert the clear end of the transfer device into the powder vial, pushing down until the spike penetrates the rubber stopper and the transfer device snaps into place. The transfer device must be vertical prior to penetrating the stopper closure of the powder vial. The vacuum in the powder vial will draw in the diluent. If there is no vacuum in the vial, do not use the product.
  10. Gently swirl the powder vial until all powder is completely dissolved. Do not shake the powder vial.
  11. Disconnect the diluent vial by turning it counter-clockwise. Do not remove the clear end of the transfer device from the powder vial.

ONE vial of reconstituted CINRYZE contains 500 IU of C1 inhibitor in 5 mL, resulting in a concentration of 100 IU/mL.

TWO vials of CINRYZE powder must be reconstituted to make one dose (1000 IU/10 mL). Therefore, repeat instructions 1 to 11 above using an additional transfer device to reconstitute the second of two powder vials. Do not reuse the transfer device. CINRYZE must be administered at room temperature within 3 hours after reconstitution.

Administration process
  1. Aseptic technique should be used during the administration procedure.
  2. After reconstitution, the CINRYZE solutions are colorless to slightly blue and clear. Do not use the product if the solutions are turbid or discolored.
  3. Using a sterile, disposable 10 mL syringe, draw back the plunger to allow approximately 5 mL of air into the syringe. Use of a silicone-free syringe is recommended.
  4. Attach the syringe onto the top of the clear end of the transfer device by turning it clockwise.
  5. Invert the vial and inject air into the solution and then slowly withdraw the reconstituted CINRYZE solution into the syringe.
  6. Detach the syringe from the vial by turning it counter-clockwise and releasing it from the clear end of the transfer device.
  7. Using the same syringe, repeat steps 3 to 6 with a second vial of reconstituted CINRYZE to make one complete 10 mL dose. CINRYZE should be administered promptly after preparation in the syringe and should not be used if particles are observed or if the solution is turbid.
  8. Attach a needle to the syringe containing CINRYZE solution and inject intravenously into the patient. Administer 1000 IU (reconstituted in 10 mL of Sterile Water for Injections) of CINRYZE by intravenous injection at a rate of 1 mL per minute over 10 minutes.

Any unused product or waste material should be disposed of in accordance with local requirements.

Overdosage

There has been no overdosage of CINRYZE reported during clinical studies. The maximum dose administered to HAE patients in clinical trials was 4000 Units given over approximately 4 hours (an average dose of 57 Units/kg) and 10,000 Units given over a 7 day period.

Thrombotic events have been reported in association with another C1 inhibitor product when used off label at high doses.

For management of a suspected drug overdose, contact your regional Poison Control Center.

Action and Clinical Pharmacology

Mechanism of Action

C1 inhibitor is a normal constituent of human blood and is a member of the serine protease inhibitor, or serpin, superfamily of proteins. The main function of serpins is to regulate the activity of serine proteases. C1 inhibitor is a single chain glycoprotein found in human plasma which, in its mature state, consists of 478 amino acids with a molecular mass of 105 kilodaltons.

C1 inhibitor inhibits the complement system by binding C1r and C1s, two of the active enzyme subunits of the first component of the complement system (C1) in the classical pathway, as well as binding to mannose-binding lectin-associated serine proteases in the lectin pathway. The primary substrate of the activated C1 enzyme is C4; uninhibited C1 results in diminished C4 levels. C1 inhibitor is the most important inhibitor of contact activation and regulates the contact system and the intrinsic coagulation pathway by binding to and inactivating kallikrein and factor XIIa. Because these pathways are part of enzyme amplification cascades, without C1 inhibitor, spontaneous or trigger-induced activation of these pathways can lead to unopposed activation and swelling.

Pharmacodynamics

In a study of acute treatment of HAE, intravenous administration of CINRYZE resulted in a significant increase in systemic levels of antigenic and functional C1 inhibitor within 1 hour after administration. Administration of C1 inhibitor increases serum levels and temporarily restores the natural regulation of the contact, complement, and fibrinolytic systems, thereby controlling swelling or the propensity to swell.

Low C4 levels may be seen in patients with HAE attacks. Treatment with CINRYZE in 35 subjects showed the subsequent increase in plasma C4 levels, from an average of C4 8.1 mg/dL at baseline to C4 8.6 mg/dL, 12 hours after infusion of CINRYZE.

Pharmacokinetics

A randomised, parallel group, open-label pharmacokinetic study of CINRYZE was performed in subjects with non-symptomatic HAE. The subjects received either a single intravenous dose of 1000 Units or a 1000 Unit dose followed by a second dose of 1000 Units 60 minutes later.

After intravenous administration of a single dose of CINRYZE to HAE subjects, the serum concentration of functional C1 inhibitor doubled within 1 to 2 hours. The maximum serum concentration (Cmax) and area under the serum concentration-time curve (AUC) appeared to increase from the single to double dose, although the increase was not dose-proportional.

Metabolism

Because C1 inhibitor is an endogenous human plasma protein, it is not subject to metabolism by cytochrome P450 iso-enzymes, excretion, or pharmacokinetic drug-drug interactions exhibited by many low molecular weight compounds.

The mean elimination half-life of functional C1 inhibitor after administration of CINRYZE was 56 hours for a single dose and 62 hours for the double dose.

Special Populations and Conditions

Pediatrics

Functional C1 inhibitor activity was measured in children in the open-label study. Mean increases from baseline in functional C1 inhibitor activity measured 1 hour post-dose in children 3 to <18 years of age ranged from 22% to 46% in study LEVP 2006-4 compared with 25% to 32% in adults.

Geriatrics

No special investigations have been performed.

Hepatic or Renal Insufficiency

No specific studies have been conducted to evaluate the pharmacokinetics of CINRYZE in patients with hepatic or renal impairment.

Storage and Stability

Temperature

When stored between 2ºC–25ºC this product is stable in its original container. Do not freeze. Store in the original package in order to protect from light.

Keep in a safe place out of the reach of children.

The reconstituted solution must be used within 3 hours of reconstitution. After reconstitution, the product should be used immediately. However, chemical and physical in-use stability has been demonstrated for 24 hours at room temperature (15ºC–25ºC).

Do not use beyond the kit expiration date.

Special Handling Instructions

Any unused product or waste material should be disposed of in accordance with local requirements.

Dosage Forms, Composition and Packaging

CINRYZE is supplied in a package containing 2 single-use vials with 500 IU of lyophilized human C1 inhibitor for reconstitution and 2 vials with 5 mL of Sterile Water for Injections (diluent).

Each vial of CINRYZE is for single use only and is supplied as 500 IU of C1 inhibitor in a colorless glass vial (Type I), sealed with a rubber stopper (Type I) and an aluminum seal with a plastic flip-off cap. Non-medicinal ingredients include L-alanine, L-threonine, L-valine, sodium chloride, sodium citrate and sucrose.

Sterile Water for Injections (5 mL) is needed for reconstitution. This is supplied in a colourless glass vial (Type I), closed with a rubber stopper (Type I) and an aluminum seal with a plastic flip-off cap.