CINRYZE Powder and solvent for solution for injection Ref.[6464] Active ingredients: C1-inhibitor

Source: Medicines & Healthcare Products Regulatory Agency (GB)  Revision Year: 2019  Publisher: Shire Services BVBA, Rue Montoyer 47, B-1000, Brussels, Belgium

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Special warnings and precautions for use

Thrombotic events

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 (up to 500 Units()/kg) to prevent capillary leak syndrome. Based upon an animal study there is a potential thrombogenic threshold at doses greater than 200 Units()/kg. Patients with known risk factors for thrombotic events (including indwelling catheters) should be monitored closely.

(*) [Historically assigned potency values were relative to an in-house reference standard whereby 1 Unit (U) is equal to the mean quantity of C1 inhibitor present in 1 ml of normal human plasma.] An international reference standard (IU) has now been implemented where IU is also defined as the amount of C1 inhibitor present in 1 ml of normal human plasma.

Transmissible agents

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped viruses HAV and parvovirus B19.

Appropriate vaccination (hepatitis A and B) should be considered for patients in regular/repeated receipt of human plasma-derived C1 inhibitor product.

It is strongly recommended that every time Cinryze is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Hypersensitivity

As with any biological product 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, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. If these symptoms occur after administration, they should alert their physician. In case of anaphylactic reactions or shock, emergency medical treatment should be administered.

Home-treatment and self-administration

There are limited data on the use of this medicinal product in home- or self administration. Potential risks associated with home-treatment are related to the administration itself as well as the handling of adverse 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.

Paediatric population

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 (up to 500 Units(*)/kg) to prevent capillary leak syndrome.

Sodium

Each vial of Cinryze contains approximately 11.5 mg of sodium. To be taken into consideration by patients on a controlled sodium diet.

Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Fertility, pregnancy and lactation

Pregnancy

Data on a limited number of exposed pregnancies indicate no adverse effects of C1 inhibitor on pregnancy or on the health of the foetus/newborn child. To date, no other relevant epidemiological data are available. No maternal or embryofoetal effects of treatment were observed in reproductive studies in rats at dose levels up to 28-times the recommended human dose (1000 IU) based on an average adult body weight of 70 kg. The potential risk for humans is unknown.

Therefore, Cinryze should be given to pregnant women only if clearly indicated.

Breast-feeding

It is unknown whether C1 inhibitor is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Cinryze therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

No specific studies on fertility, early embryonic and postnatal development, or carcinogenicity studies were conducted (see section 5.3).

Effects on ability to drive and use machines

Based upon the clinical data currently available, Cinryze has minor influence on the ability to drive and use machines.

Undesirable effects

Summary of the safety profile

The very common adverse reactions observed following Cinryze infusion in clinical studies were headache and nausea.

Tabulated list of adverse reactions

Adverse reaction frequencies were estimated from 2 pivotal placebo-controlled and 2 open-label studies in 251 unique subjects. Only frequencies based on reporting rates from clinical trials are used to assign frequency category.

Adverse reactions to treatment with Cinryze are classified by MedDRA System Organ Class and absolute frequency in Table 1. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from the available data).

Table 1. Adverse reactions reported in clinical studies and in postmarketing reports:

Immune system disorders

Common: Hypersensitivity

Metabolism and nutrition disorders

Uncommon: Hyperglycaemia

Nervous system disorders

Very common: headache

Common: Dizziness

Vascular disorders

Uncommon: Venous thrombosis, phlebitis, venous burning, hot flush

Respiratory, thoracic and mediastinal disorders

Uncommon: Cough

Gastrointestinal disorders

Very common: Nausea

Common: vomiting

Uncommon: Diarrhoea, abdominal pain

Skin and subcutaneous tissue disorders

Common: Rash, erythema, pruritus

Uncommon: Contact dermatitis

Musculoskeletal and connective tissue disorders

Uncommon: Joint swelling, arthralgia, myalgia

General disorders and administration site conditions

Common: Injection site rash/erythema, infusion site pain, pyrexia

Uncommon: Chest discomfort

Description of selected adverse reactions

Among reports of venous thrombosis, the most common underlying risk factor was presence of an indwelling catheter.

Local reactions at the injection site were uncommon. In clinical studies local reactions (described as pain, bruising, or rash at the injection/catheter site, venous burning or phlebitis) occurred in association with approximately 0.2% of infusions.

Paediatric population

Across clinical studies, there were 61 unique paediatric subjects enrolled and exposed to over 2,500 infusions of Cinryze (2-5 years, n=3; 6-11 years, n=32; 12-17 years, n=26). Among these children, the only adverse reactions with Cinryze included headache, nausea, pyrexia, and infusion site erythema. None of these adverse reactions were severe, and none led to discontinuation of medicinal product.

Overall, the safety and tolerability of Cinryze are similar in children, adolescents and adults.

For safety with respect to transmissible agents, see section 4.4.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

United Kingdom, Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Ireland: HPRA Pharmacovigilance, Website: www.hpra.ie.

Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

Only use a silicone-free syringe (provided in the pack) for administration of the product.

© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.