1. Name Of The Medicinal Product
Ruconest 2100 U powder for solution for injection.
2. Qualitative And Quantitative Composition
One vial contains 2100 units of conestat alfa, corresponding to 2100 units per 14 ml after reconstitution, or a concentration of 150 units/ml.
Conestat alfa is the recombinant analogue of the human C1 esterase inhibitor (rhC1INH) produced by recombinant DNA technology in the milk of transgenic rabbits.
1 Unit of conestat alfa activity is defined as the equivalent of C1 esterase inhibiting activity present in 1 ml of pooled normal plasma.
For a full list of excipients, see section 6.1
3. Pharmaceutical Form
Powder for solution for injection.
White to off-white powder.
4. Clinical Particulars
4.1 Therapeutic Indications
Ruconest is indicated for treatment of acute angioedema attacks in adults with hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency.
4.2 Posology And Method Of Administration
Ruconest should be initiated under the guidance and supervision of a physician experienced in the diagnosis and treatment of hereditary angioedema.
Ruconest should be administered by a healthcare professional.
Patients who have not previously received Ruconest should be tested for the presence of IgE antibodies against rabbit epithelium (dander) prior to initiation of Ruconest (see section 4.4).
Posology
- Adults up to 84 kg body weight
One intravenous injection of 50 U/kg body weight.
- Adults of 84 kg body weight or greater
One intravenous injection of 4200 U (two vials).
In the majority of cases a single dose of Ruconest is sufficient to treat an acute angioedema attack.
In case of an insufficient clinical response, an additional dose (50 U/kg body weight up to 4200 U) can be administered (see section 5.1).
Not more than two doses should be administered within 24 hours.
Dose calculation
Determine the patient's body weight.
- Adults up to 84 kg body weight
For patients up to 84 kg calculate the volume required to be administered according to the formula below:
- Adults of 84 kg body weight or greater
For patients of 84 kg or above the volume required to be administered is 28 ml, corresponding to 4200 U (2 vials).
Paediatric population
The safety and efficacy of Ruconest in children (age 0 to 12 years) has not yet been established. Currently available data on adolescents (age 13 to 17 years) are described in section 5.1, but no recommendation on a posology can be made.
Elderly (
Data in patients older than 65 years are limited.
There is no rationale for patients older than 65 years to respond differently to Ruconest.
Renal impairment
No dose adjustment is necessary in patients with renal impairment since conestat alfa does not undergo renal clearance.
Hepatic impairment
There is no clinical experience with Ruconest in patients with hepatic impairment. Hepatic impairment may prolong the plasma half-life of conestat alfa, but this is not thought to be a clinical concern. No recommendation on a dose adjustment can be made.
Method of Administration
For intravenous use.
For instructions on reconstitution of Ruconest before administration, see section 6.6.
The required volume of the reconstituted solution should be administered as a slow intravenous injection over approximately 5 minutes.
4.3 Contraindications
• Known or suspected allergy to rabbits (see section 4.4)
• Hypersensitivity to the active substance or to any of the excipients
4.4 Special Warnings And Precautions For Use
Conestat alfa is derived from milk of transgenic rabbits and contains traces of rabbit protein. Before initiating treatment with Ruconest, patients should be tested for the presence of IgE antibodies against rabbit allergens using a validated test for IgE antibodies against rabbit epithelium (dander) e.g. ImmunoCap system, Phadia, Sweden. Only patients who have been shown to have negative results for such a test, should be treated with Ruconest. IgE antibody testing should be repeated once a year or after 10 treatments, whichever occurs first.
As with any intravenously administered protein product, hypersensitivity reactions cannot be excluded.
Patients must be closely monitored and carefully observed for any symptoms of hypersensitivity throughout the administration period. 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.
Although cross-reactivity between cow milk and rabbit milk is considered unlikely, the possibility of such a cross-reactivity in a patient who has evidence of clinical allergy to cow milk cannot be excluded.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No drug-drug interaction studies have been performed.
Scientific literature indicates an interaction of tissue-type plasminogen activator (tPA) and C1INH containing medicinal products. Ruconest should not be administered simultaneously with tPA.
4.6 Pregnancy And Lactation
Pregnancy and breast-feeding
There is no experience with the use of Ruconest in pregnant and breast-feeding women.
In one animal study reproductive toxicity was observed (see section 5.3). Ruconest is not recommended for use during pregnancy or breast-feeding, unless the treating physician judges the benefits to outweigh the possible risks.
Fertility
There are no data on the effects of Ruconest on male or female fertility.
4.7 Effects On Ability To Drive And Use Machines
Based on the known pharmacology and adverse reaction profile of Ruconest, effects on the ability to drive and use machines are not expected. However headache or vertigo have been reported following the use of Ruconest, but may also occur as a result of an attack of HAE. Patients should be advised not to drive and use machines if they experience headache or vertigo.
4.8 Undesirable Effects
The clinical experience supporting safety of Ruconest consists of 300 administrations (83 administrations to healthy subjects or asymptomatic HAE patients and 217 administrations to 119 HAE patients). The table below lists all adverse reactions occurring within 7 days after treatment with Ruconest, as reported in the six treatment studies.
Adverse reactions were usually mild to moderate in severity. The incidence of adverse reactions was similar for all dose groups and did not increase upon repeated administrations.
The frequency of possible adverse reactions listed below is defined using the following convention:
Very common (
Common (
Uncommon (
Rare (
Very rare (<1/10,000),
Not known, frequency could not be estimated from the available data.
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4.9 Overdose
No clinical information on overdose is available.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group and ATC code: not yet assigned
The plasma protein C1INH is the main regulator of activation of the contact and complement systems in vivo. HAE patients have a heterozygous deficiency of the plasma protein C1INH. As a result they may suffer from uncontrolled activation of contact and complement systems, with formation of inflammatory mediators, which clinically becomes manifest as the occurrence of acute angioedema attacks.
Conestat alfa, recombinant human complement component 1 (C1) esterase inhibitor (rhC1INH), is an analogue of human C1INH and is obtained from the milk of rabbits expressing the gene encoding for human C1INH. The amino acid sequence of conestat alfa is identical to that of endogenous C1INH.
C1INH exerts an inhibitory effect on several proteases (target proteases) of the contact and complement systems. The effect of conestat alfa on the following target proteases was assessed in vitro: activated C1s, kallikrein, factor XIIa and factor XIa. Inhibition kinetics were found to be comparable with those observed for plasma-derived human C1INH.
The complement component (protein) C4, is a substrate for activated C1s. Patients with HAE have low levels of C4 in the circulation. As for plasma-derived C1INH, the pharmacodynamic effects of conestat alfa on C4 show dose-dependent restoration of complement homeostasis in HAE patients at a plasma C1INH activity level greater than 0.7 U/ml, which is the lower limit of the normal range. In HAE patients, Ruconest at a dose of 50 U/kg increases plasma C1INH activity level to greater than 0.7 U/ml for approximately 2 hours (see section 5.2).
The efficacy and safety of Ruconest as a treatment of acute angioedema attacks in patients with HAE has been evaluated in two double blind randomized placebo controlled and four open label clinical studies. The doses evaluated in the clinical studies ranged from a single vial of 2100 U (corresponding to 18-40 U/kg), to 50 and 100 U/kg. Efficacy of Ruconest as a treatment for acute angioedema attacks was demonstrated by significantly shorter time to beginning of relief of symptoms and time to minimal symptoms and few therapeutic failures. The table below shows the results (primary and secondary endpoints) of the two randomized controlled trials:
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The results of the open label studies were consistent with the above findings and support the repeated use of Ruconest in the treatment of subsequent attacks of angioedema.
In the randomized controlled trials 39/41 (95%) of patients treated with Ruconest reached time to beginning of relief within 4 hours. In an open label study 114/119 (95%) attacks treated with a single dose of 50 U/kg reached time to beginning of relief within 4 hours. An additional dose of 50 U/kg was administered for 13/133 (10%) attacks.
Paediatric population
Nine adolescent HAE patients (aged 13 to 17 years) were treated with 50 U/kg for 26 acute angioedema attacks, and 7 (aged 16 to 17 years) with 2100 U for 24 acute angioedema attacks.
The European Medicines Agency has deferred the obligation to submit the results of studies with Ruconest in one or more subsets of the paediatric population in treatment of acute angioedema attacks (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic Properties
Distribution
No formal distribution studies have been performed. The distribution volume of conestat alfa was approximately 3 L, comparable to plasma volume.
Biotransformation and elimination
Based on animal data, conestat alfa is cleared from the circulation by the liver via receptor-mediated endocytosis followed by complete hydrolysis/degradation.
After administration of Ruconest (50 U/kg) to asymptomatic HAE patients, a Cmax of 1.36 U/ml was observed. The elimination half-life of conestat alfa was approximately 2 hours.
Excretion
There is no excretion, as conestat alfa is cleared from the circulation via receptor-mediated endocytosis followed by complete hydrolysis/degradation in the liver.
5.3 Preclinical Safety Data
Preclinical data do not indicate any safety concern for the use of conestat alfa in humans based on studies of safety pharmacology, single-dose toxicity, two-week sub-chronic toxicity and local tolerance in various animal species including rats, dogs, rabbits and cynomolgus monkeys. Genotoxic and carcinogenic potential is not expected.
Embryofetal studies in rat and rabbit; Daily single doses of vehicle or 625 U/kg/administration of rhC1INH were administered intravenously to mated rats and rabbits. In the study in rats there were no malformed fetuses in either the conestat alfa or the control group. In a rabbit embryotoxicity study an increase in the incidence of fetal cardiac vessel defects (1.12% in the treatment group versus 0.03% in historical controls) was observed for animals that were administered conestat alfa.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sucrose
Sodium citrate (E331)
Citric acid (E330)
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf Life
4 years.
Reconstituted solution
Chemical and physical in-use stability has been demonstrated for 48 hours between 5˚C and 25˚C. From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8ºC, unless reconstitution has taken place in controlled and validated aseptic conditions.
6.4 Special Precautions For Storage
Do not store above 25°C.
Store in the original package in order to protect from light.
For storage conditions of the reconstituted medicinal product, see section 6.3.
6.5 Nature And Contents Of Container
2100 U of conestat alfa in a powder in a 25 ml vial (type 1 glass) with a stopper (siliconized chlorobutyl rubber) and a flip-off seal (aluminium and coloured plastic).
Pack size of 1.
6.6 Special Precautions For Disposal And Other Handling
Each vial of Ruconest is for single use only.
An aseptic technique should be used for reconstitution, combining and mixing the solutions.
Reconstitution
Each vial of Ruconest (2100 U) should be reconstitued with 14 ml water for injections. Water for injections should be added slowly to avoid forceful impact on the powder and mixed gently to avoid foaming of the solution. The reconstituted solution contains 150 U/ml conestat alfa and appears as a clear colourless solution.
The reconstituted solution in each vial should be visually inspected for particulate matter and discoloration. A solution exhibiting particulates or discoloration should not be used. The medicinal product should be used immediately (see section 6.3).
There are no special requirements for disposal.
7. Marketing Authorisation Holder
Pharming Group N.V.,
Darwinweg 24,
NL-2333 CR LEIDEN,
The Netherlands
8. Marketing Authorisation Number(S)
EU/1/10/641/001
9. Date Of First Authorisation/Renewal Of The Authorisation
Date of first authorisation: 28/10/2010
10. Date Of Revision Of The Text
08/2011
Detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu
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