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`Berinert 500 IU
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`Summary of Product Characteristics Updated 02-Sep-2015 | CSL Behring UK Limited
`
`1. Name of the medicinal product
`
`Berinert 500 IU
`
`Powder and solvent for solution for injection / infusion
`
`2. Qualitative and quantitative composition
`
`Active substance: human C1-esterase inhibitor
`
`Berinert 500 contains 500 IU per injection vial.
`
`The potency of C1-esterase inhibitor is expressed in International Units (IU), which are related to the current WHO
`Standard for C1-esterase inhibitor products.
`
`Berinert 500 contains 50 IU/ml C1-esterase inhibitor after reconstitution with 10 ml water for injections.
`
`The total protein content of the reconstituted 500 IU solution is 6.5 mg/ml.
`
`Excipients with known effect:
`
`Sodium up to 486 mg (approximately 21 mmol) per 100 ml solution.
`
`For the full list of excipients, see section 6.1.
`
`3. Pharmaceutical form
`
`Powder and solvent for solution for injection / infusion.
`
`White Powder.
`
`4. Clinical particulars
`
`4.1 Therapeutic indications
`
`Hereditary angioedema type I and II (HAE)
`
`Treatment and pre-procedure prevention of acute episodes.
`
`4.2 Posology and method of administration
`
`Treatment should be initiated under the supervision of a physician experienced in the treatment of C1-esterase
`inhibitor deficiency.
`
`Posology
`
`Adults
`
`Treatment of acute angioedema attacks:
`
`20 IU per kilogram body weight (20 IU/kg b.w.)
`
`Pre-procedure prevention of angioedema attacks:
`
`1000 IU, less than 6 hours prior to a medical, dental, or surgical procedure.
`
`Paediatric population
`
`Treatment of acute angioedema attacks:
`
`20 IU per kilogram body weight (20 IU/kg b.w.).
`
`Pre-procedure prevention of angioedema attacks:
`
`15 to 30 IU per kilogram body weight (15-30 IU/kg b.w.), less than 6 hours prior to a medical, dental, or surgical
`procedure.
`
`Dose should be selected taking into account clinical circumstances (e.g. type of procedure and disease severity).
`
`Method of administration
`
`Berinert is to be reconstituted according to section 6.6. The reconstituted solution should be colourless and clear.
`
`The solution is to be administered by slow i.v. injection or infusion (4 ml/minute).
`
`4.3 Contraindications
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`CSL EXHIBIT 1073
`CSL v. Shire
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`Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
`
`4.4 Special warnings and precautions for use
`
`In patients with known tendency towards allergies, antihistamines and corticosteroids should be administered
`prophylactically.
`
`If allergic or anaphylactic-type reactions occur, the administration of Berinert has to be stopped immediately (e.g.
`discontinue injection/infusion) and an appropriate treatment has to be initiated. Therapeutic measures depend on the
`kind and severity of the undesirable effect. The current medical standards for shock treatment are to be observed.
`
`Patients with laryngeal oedema require particularly careful monitoring with emergency treatment in stand-by.
`
`Unlicensed use or treatment of Capillary Leak Syndrome (CLS) with Berinert (see also section "4.8 Undesirable
`effects") is not advised.
`
`Berinert contains up to 486 mg sodium (approximately 21 mmol) per 100 ml solution. To be taken into consideration
`by patients on a controlled sodium diet.
`
`Home treatment and self-administration
`
`There are limited data on the use of this medicinal product in home treatment or 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.
`
`Virus safety
`
`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, HCV and for the non-
`enveloped viruses HAV and parvovirus B19.
`
`Appropriate vaccination (hepatitis A and B) should be generally considered for patients in regular/repeated receipt of
`human plasma-derived products.
`
`It is strongly recommended that every time Berinert 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.
`
`4.5 Interaction with other medicinal products and other forms of interaction
`
`No interaction studies have been performed.
`
`4.6 Fertility, pregnancy and lactation
`
`Pregnancy
`
`There are limited amount of data that indicate no increased risk from the use of Berinert in pregnant women. Berinert
`is a physiological component of human plasma. Therefore, no studies on reproduction and developmental toxicity
`have been performed in animals and no adverse effects on fertility, pre- and postnatal development are expected in
`humans.
`
`Therefore, Berinert should be given to a pregnant woman only if clearly needed.
`
`Breastfeeding
`
`It is unknown whether Berinert is excreted in human milk, but due to its high molecular weight, the transfer of Berinert
`into breast milk seems unlikely. However, breastfeeding is questionable in women suffering from hereditary
`angioedema. A decision must be made whether to discontinue breastfeeding or to discontinue the Berinert therapy
`taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.
`
`Fertility
`
`Berinert is a physiological component of human plasma. Therefore, no studies on reproduction and developmental
`toxicity have been performed in animals and no adverse effects on fertility, pre- and postnatal development are
`expected in humans.
`
`4.7 Effects on ability to drive and use machines
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`Berinert has no or negligible influence on the ability to drive and use machines.
`
`4.8 Undesirable effects
`
`The following adverse reactions are based on post marketing experience as well as scientific literature. The following
`standard categories of frequency are used:
`
`Very common:
`Common:
`
`a 1/10
`2 1/100 to < 1/10
`
`Uncommon:
`
`a 1/1,000 to < 1/100
`
`Rare:
`
`2 1/10.000 to < 1/1,000
`
`< 1/10.000 (including reported single cases)
`Very rare:
`Undesired reactions with Berinert are rare.
`
`Organ class
`
`Vascular disorders
`
`General disorders
`and administration
`site conditions
`
`Immune system
`
`Development of
`thrombosis“
`
`temperature,
`reactions at the
`
`injection side
`
`anaphylactic—type
`reactions (e.g.
`tachycardia.
`hyper- or
`hypotension,
`flushing. hives.
`dyspnoea.
`headache.
`diziness.
`nausea)
`
`22 .05 .201 7
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`" In treatment attempts with high doses of Berinert for prophylaxis or therapy of Capillary Leak Syndrome (CLS)
`before. during or after cardiac surgery under extra-corporal circulation (unlicensed indication and dose), in single
`ses with fatal outcome.
`
`For safety with respect to transmissible agents, see section 4.4.
`
`Rearing 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 the UK Yellow Card Scheme.
`
`Website: www.mhra.gov.uflyellowcard
`
`4.9 Overdose
`
`No case of overdose has been reported.
`
`5. Pharmacological properties
`
`5.1 Pharmacodynamic properties
`
`Pharmacotherapeutic group: C1-inhibitor, plasma derived
`ATC code: BOGACO1
`
`C1-esterase inhibitor is a plasma giycoprotein with a molecular weight of 105 kD and a carbohydrate moiety of40 %.
`Its concentration in human plasma ranges around 240 mg/I. Besides its occurrence in human plasma. also the
`placenta. the liver cells. monocytes and platelets contain C1-esterase inhibitor.
`
`Ct-esterase inhibitor belongs to the serine-protease—inhibitor-(serpin)-system of human plasma as do also other
`proteins like antithrombin III, alpha-2-antiplasmin, alpha-1-antitrypsin and others.
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`Under physiological conditions C1-esterase inhibitor blocks the classical pathway of the complement system by
`inactivating the enzymatic active components C1s and C1r. The active enzyme forms a complex with the inhibitor in a
`stoichiometry of 1:1.
`
`Furthermore, C1-esterase inhibitor represents the most important inhibitor of the contact activation of coagulation by
`inhibiting factor XIIa and its fragments. In addition, it serves, besides alpha-2-macroglobulin, as the main inhibitor of
`plasma kallikrein.
`
`The therapeutic effect of Berinert in hereditary angioedema is induced by the substitution of the deficient C1-esterase
`inhibitor activity.
`
`5.2 Pharmacokinetic properties
`
`The product is to be administered intravenously and is immediately available in the plasma with a plasma
`concentration corresponding to the administered dose.
`
`The pharmacokinetic properties of Berinert have been investigated in two studies.
`
`A phase I study conducted in 15 healthy, adult subjects provided PK data that was used to assess the relative
`bioavailability of Berinert 1500 and Berinert 500.
`
`Comparable bioavailability of the two presentations of Berinert was demonstrated.
`
`For C1-INH antigen concentrations the Cmax and AUC0-last geometric mean ratios (90% CIs) were 1.02 (0.99, 1.04)
`and 1.02 (0.99, 1.05) respectively. Half-life was estimated in a subset of subjects using non-compartmental PK
`analyses. The mean half-life of Berinert 1500 and Berinert 500 was 87.7 hours and 91.4 hours, respectively.
`
`Pharmacokinetic properties have been investigated in patients with hereditary angioedema (34 patients > 18 years, 6
`patients < 18 years). These included 15 patients under prophylactic treatment (with frequent/severe attacks), as well
`as 25 patients with less frequent/mild attacks and "on demand" treatment. The data were generated in an attack-free
`interval.
`
`The median in-vivo recovery (IVR) was 86.7 % (range: 54.0 – 254.1 %). The IVR for children was slightly higher (98.2
`%, range: 69.2 – 106.8 %)) than for adults (82.5 %, range: 54.0 – 254.1 %). Patients with severe attacks had a higher
`IVR (101.4 %) compared to patients with mild attacks (75.8 %, range: 57.2 – 195.9 %).
`
`The median increase in activity was 2.3%/IU/kg b.w. (range: 1.4 – 6.9 %/IU/kg b.w.). No significant differences were
`seen between adults and children. Patients with severe attacks showed a slightly higher increase in activity than
`patients with mild attacks (2.9, range: 1.4 – 6.9 vs. 2.1, range: 1.5 – 5.1 %/IU/kg b.w.).
`
`The maximum concentration of C1-esterase inhibitor activity in plasma was reached within 0.8 hours after
`administration of Berinert without significant differences between the patient groups.
`
`The median half-life was 36.1 hours. It was slightly shorter in children than in adults (32.9 vs. 36.1 hours) and in
`patients with severe attacks than in patients with mild attacks (30.9 vs. 37.0).
`
`5.3 Preclinical safety data
`
`Berinert contains as active ingredient C1-esterase inhibitor. It is derived from human plasma and acts like an
`endogenous constituent of plasma. Single-dose application of Berinert in rats and mice and repeated-dose
`applications in rats did not show any evidence of toxicity.
`
`Preclinical studies with repeated-dose application to investigate carcinogenicity and reproductive toxicity have not
`been conducted because they cannot be reasonably performed in conventional animal models due to the
`development of antibodies following the application of heterologous human proteins.
`
`The in-vitro Ouchterlony test and the in-vivo PCA model in guinea pigs did not show any evidence of newly arising
`antigenic determinants in Berinert following pasteurisation.
`
`In-vivo thrombogenicity tests in rabbits were performed with doses up to 800 IU/kg of Berinert. There was no pro-
`thrombotic risk associated with the i.v. administration of Berinert up to 800 IU/kg.
`
`Local tolerance studies in rabbits demonstrated that Berinert was clinically, locally and histologically well-tolerated
`after intravenous, subcutaneous, intra-arterial and intramuscular application.
`
`6. Pharmaceutical particulars
`
`6.1 List of excipients
`
`Powder:
`
`Glycine
`
`Sodium chloride
`
`Sodium citrate
`
`Solvent:
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`Water for injections
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`6.2 Incompatibilities
`
`In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products and
`diluents in the syringe/infusion set.
`
`6.3 Shelf life
`
`30 months
`
`After reconstitution, the physico-chemical stability has been demonstrated for 48 hours at room temperature (max.
`25°C).
`
`From a microbiological point of view and as Berinert contains no preservative, the reconstituted product should be
`used immediately.
`
`If it is not administered immediately, storage shall not exceed 8 hours at room temperature. The reconstituted product
`should only be stored in the vial.
`
`6.4 Special precautions for storage
`
`Do not store above 25 °C.
`
`Do not freeze.
`
`Keep the vial in the outer carton in order to protect from light.
`
`For storage conditions after reconstitution of the medicinal product, see section 6.3.
`
`6.5 Nature and contents of container
`
`Powder (500 IU) in a vial (Type II glass) with a stopper (bromobutyl rubber), seal (aluminium) and flip-off cap (plastic).
`
`10 ml of solvent in a vial (Type I glass) with a stopper (chlorobutyl rubber), seal (aluminium) and flip-off cap (plastic).
`
`Administration set: 1 filter transfer device 20/20, 1 disposable 10 ml syringe, 1 venipuncture set, 2 alcohol swabs, 1
`plaster.
`
`Pack size of 1.
`
`6.6 Special precautions for disposal and other handling
`
`Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
`
`Method of administration
`
`General instructions
`
`- The solution should be colourless and clear.
`
`- After filtering/withdrawal (see below) reconstituted product should be inspected visually for particulate matter and
`discoloration prior to administration.
`
`- Do not use solutions that are cloudy or have deposits.
`
`- Reconstitution and withdrawal must be carried out under aseptic conditions. Use the syringe provided with the
`product.
`
`Reconstitution
`
`Bring the solvent to room temperature. Ensure product and solvent vial flip caps are removed and the stoppers are
`treated with an antiseptic solution and allowed to dry prior to opening the Mix2Vial package.
`
`1. Open the Mix2Vial package by peeling off the lid. Do not
`remove the Mix2Vial from the blister package!
`
`2. Place the solvent vial on an even, clean surface and hold the
`vial tight. Take the Mix2Vial together with the blister package
`and push the spike of the blue adapter end straight down
`through the solvent vial stopper.
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`3. Carefully remove the blister package from the Mix2Vial set
`by holding at the rim, and pulling vertically upwards. Make
`sure that you only pull away the blister package and not the
`Mix2Vial set.
`
`4. Place the product vial on an even and firm surface. Invert
`the solvent vial with the Mix2Vial set attached and push the
`spike of the transparent adapter end straight down through
`the product vial stopper. The solvent will automatically flow into
`the product vial.
`
`5. With one hand grasp the product-side of the Mix2Vial set,
`and with the other hand grasp the solvent-side and unscrew
`the set carefully into two pieces.
`
`Discard the solvent vial with the blue Mix2Vial adapter
`attached.
`
`6. Gently swirl the product vial with the transparent adapter
`attached until the substance is fully dissolved. Do not shake.
`
`7. Draw air into an empty, sterile syringe. Use the syringe
`provided with the product. While the product vial is upright,
`connect the syringe to the Mix2Vial's Luer Lock fitting. Inject air
`into the product vial.
`
`Withdrawal and application
`
`8. While keeping the syringe plunger pressed, invert the
`system upside down and draw the solution into the syringe by
`pulling the plunger back slowly.
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`9. Now that the solution has been transferred into the syringe,
`firmly hold on to the barrel of the syringe (keeping the syringe
`plunger facing down) and disconnect the transparent Mix2Vial
`adapter from the syringe.
`
`7. Marketing authorisation holder
`
`CSL Behring GmbH
`
`Emil-von-Behring-Strasse 76
`
`35041 Marburg
`
`Germany
`
`8. Marketing authorisation number(s)
`
`PL 15036/0030
`
`9. Date of first authorisation/renewal of the authorisation
`
`29 January 2009 / 12 December 2013
`
`10. Date of revision of the text
`
`13 August 2015
`
`Company Contact Details
`
`CSL Behring UK Limited
`
`http://www.cslbehring.co.uk
`
`Address
`
`Hayworth House, Market Place, Haywards Heath,
`West Sussex, RH16 1DB, UK
`
`Fax
`
`+44 (0)1444 447 403
`
`Medical Information e-mail
`
`medinfo@cslbehring.com
`
`Out of Hours contact
`
`+44 (0)1444 447 405
`
`Telephone
`
`+44 (0)1444 447 400
`
`Medical Information Direct Line
`
`+44 (0)1444 447 405
`
`Customer Care direct line
`
`+44 (0)1444 447 402
`
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