This information is intended for use by health professionals

1. Name of the medicinal product

Ruconest 2100 Units powder and solvent for solution for injection.

2. Qualitative and quantitative composition

Powder vial:

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 a recombinant analogue of the human C1 esterase inhibitor (rhC1-INH) 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.

Excipient with known effect:

Each powder vial contains approximately 19.5 mg sodium.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Powder and solvent for solution for injection.

White to off-white powder.

The solvent is a clear, colourless liquid.

4. Clinical particulars
4.1 Therapeutic indications

Ruconest is indicated for treatment of acute angioedema attacks in adults, adolescents, and children (aged 2 years and above) 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.

Posology in adults, adolescents and children aged 2 years and above

Body weight up to 84 kg

- One intravenous injection of 50 U/kg body weight.

Body weight of 84 kg or greater

- One intravenous injection of 4200 U (2 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).

- In adults and adolescents an additional dose may be administered if the patient has not responded adequately after 120 minutes.

- In children an additional dose may be administered if the patient has not responded adequately after 60 minutes.

Not more than two doses should be administered within 24 hours.

Dose calculation

Determine the patient's body weight.

Body weight up to 84 kg

- For patients up to 84 kg calculate the volume required to be administered according to the formula below:

Body weight of 84 kg 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

Ruconest may be used in paediatric patients (2 years and older) at the same dose as in adults (50 U/kg body weight).

The safety and efficacy of Ruconest in children less than 2 years old have not been established. No clinical data are available.

Elderly (≥65 years old)

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.

Ruconest must be administered by a healthcare professional until the patient (or caregiver) is competent to administer after having been properly trained and in agreement with the healthcare professional.

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 listed in section 6.1

4.4 Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered products should be clearly recorded.

Conestat alfa is derived from milk of transgenic rabbits and contains traces of rabbit protein. Before initiating treatment with Ruconest, patients should be queried about prior exposure to rabbits and signs and symptoms suggestive of an allergic reaction.

Hypersensitivity reactions cannot be excluded.

All patients must be closely monitored and carefully observed for any symptoms of hypersensitivity during and after 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 and the patient should be observed for signs and symptoms of hypersensitivity following Ruconest administration.

Sodium

Each vial of Ruconest contains 19.5 mg of sodium. 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- 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.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Scientific literature indicates an interaction of tissue-type plasminogen activator (tPA) and C1-INH containing medicinal products. Ruconest should not be administered simultaneously with tPA.

4.6 Fertility, 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, vertigo and dizziness 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, vertigo or dizziness.

4.8 Undesirable effects

Summary of the safety profile

One case of hypersensitivity was observed in clinical trials with Ruconest. The most common adverse reaction observed after administration of Ruconest is nausea.

Tabulated lists of adverse reactions

Adverse reactions obtained from clinical trials in patients with HAE following acute attack treatment with Ruconest are tabulated below. 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 adverse reactions listed below is defined using the following convention:

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),

Not known (cannot be estimated from the available data).

System Organ Class

Adverse reaction

Frequency

Nervous system disorders

Headache

Uncommon

Vertigo

Uncommon

Hypoaesthesia

Uncommon

Dizziness

Uncommon

Ear and labyrinth disorders

Auricular swelling

Uncommon

Respiratory, thoracic and mediastinal disorders

Throat irritation

Uncommon

Gastrointestinal disorders

Nausea

Common

Diarrhoea

Uncommon

Abdominal discomfort

Uncommon

Oral paraesthesia

Uncommon

Skin and subcutaneous tissue disorders

Urticaria

Uncommon

Paediatric population

In the clinical development program, 37 children and adolescents (aged 5 to 17 years) with HAE were treated for 124 acute angioedema attacks. Frequency, type and severity of adverse reactions in children and adolescents were similar to those in adults.

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

4.9 Overdose

No clinical information on overdose is available.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other haematological agents, drugs used in hereditary angioedema, ATC code: B06AC04.

The plasma protein C1-INH is the main regulator of activation of the contact and complement systems in vivo. HAE patients have a heterozygous deficiency of the plasma protein C1-INH. 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, a recombinant human complement component 1 (C1) esterase inhibitor (rhC1-INH), is an analogue of human C1-INH and is obtained from the milk of rabbits expressing the gene coding for human C1-INH. The amino acid sequence of conestat alfa is identical to that of endogenous C1-INH.

C1-INH 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 C1-INH.

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 C1-INH, the pharmacodynamic effects of conestat alfa on C4 show dose-dependent restoration of complement homeostasis in HAE patients at a plasma C1-INH 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 C1-INH 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 adult and adolescent 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:

Study

Treatment

Time (minutes) to beginning of relief median (95% CI)

Time (minutes) to minimal symptoms median (95% CI)

C1 1205 RCT

100 U/kg

n =13

68 (62, 132)

p = 0.001

245 (125, 270)

p = 0.04

50 U/kg

n =12

122 (72, 136)

p < 0.001

247 (243, 484)

Saline

n = 13

258 (240, 495)

1101 (970, 1494)

C1 1304 RCT

100 U/kg

n =16

62 (40, 75)

p = 0.003

480 (243, 723)

p = 0.005

Saline

n = 16

508 (70, 720)

1440 (720, 2885)

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 146/151 (97%) 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 17/168 (10%) attacks.

Paediatric population

Children

In an open label study with 20 children with HAE (aged 5 to 14 years), 64/67 (96%) 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 3/73 (4%) attacks.

Adolescents

Ten adolescent HAE patients (aged 13 to 17 years) were treated with 50 U/kg for 27 acute angioedema attacks, and 7 (aged 16 to 17 years) with 2100 U for 24 acute angioedema attacks.

The efficacy and safety results in children and adolescents were consistent with those in adults.

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.

Paediatric population

Children

After receiving a conestat alfa dose of 50 U/kg, a total of 18/20 children had concentrations of functional C1-INH that were >70% of normal (the lower limit of the normal range) at the 5-minute and/or 2-4 hour post-dose time points. The arithmetic mean functional C1-INH Cmax for the first attack was 123% of normal (range 62% to 168%) and the AUC0-3 was 171% of normal (range 95% to 244%).

A population PK model shows that a dose of 50 U/kg will achieve concentrations of functional C1-INH that are >70% of normal in 96.0% of children aged 2 to ≤13 years and in 90.5% of children aged 2 to <5 years.

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.

Embryofoetal studies in rat and rabbit; Daily single doses of vehicle or 625 U/kg/administration of conestat alfa were administered intravenously to mated rats and rabbits. In the study in rats there were no malformed foetuses in either the conestat alfa or the control group. In a rabbit embryotoxicity study an increase in the incidence of foetal 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

Powder vial:

Sucrose

Sodium citrate (E331)

Citric acid

Solvent vial:

Water for injections

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 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Powder vial:

Do not store above 25°C.

Store in the original package in order to protect from light.

Solvent vial:

Do no store above 25°C.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Powder vial: 2100 units of conestat alfa powder in a vial (type 1 glass) with a stopper (siliconized chlorobutyl rubber) and a flip-off seal (aluminium and coloured plastic).

Solvent vial: 20 ml of water for injections in a vial (type 1 glass) with a stopper (siliconized chlorobutyl rubber) and a flip-off seal (aluminium and coloured plastic).

Administration kit:

- 1 powder vial

- 1 solvent vial

- 2 vial adapters

- 1 syringe

- 1 infusion set with 35 cm tubing and 25G needle

- 2 alcohol pads

- 1 sterile non-woven pad

- 1 self-adhesive plaster

6.6 Special precautions for disposal and other handling

Preparation and handling

Each vial of Ruconest is for single use only.

Ruconest is intended for intravenous administration after reconstitution with water for injections. An aseptic technique should be used for reconstitution, combining and mixing the solutions.

Reconstitution

1. Each vial of Ruconest (2100 U) should be reconstituted with 14 ml of solvent.

2. Disinfect the rubber stoppers of the powder and solvent vials and put a vial adapter onto each solvent and powder vial until it snaps onto the vial neck.

3. Attach the syringe to the adapter on the solvent vial and turn clockwise until it locks. Draw in 14 ml of solvent. Unlock the syringe from the adapter by turning counter clockwise and discard the vial with adapter.

4. Attach the syringe with solvent to the adapter on the powder vial and turn clockwise until it locks. The solvent should be added slowly to avoid forceful impact on the powder and mixed gently to minimise foaming of the solution. Leave the syringe on the adapter. Repeat steps 3 and 4 if you need to prepare a second solution (this requires a second kit).

5. 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. Small amounts of foam are acceptable. The medicinal product should be used immediately (see section 6.3).

Administration

1. Draw in the required volume of prepared solution. Never exceed 14 ml per syringe. Unlock the syringe(s) by turning counter clockwise and discard the vial with adapter.

2. Attach the infusion set to the syringe and turn clockwise until it locks. Hold the syringe with the tip pointing upwards and gently press the plunger to fill the infusion set with the solution.

3. Disinfect the injection site with an alcohol pad. Remove the needle cap from the needle of the infusion set and carefully insert the needle into the vein.

4. Ensure that the tourniquet is released. Gently inject the solution into the vein – inject over about 5 minutes.

5. If two syringes were prepared: fold over the tubing to prevent backflow, unscrew the empty syringe from the infusion set (counter clockwise) and immediately replace it with the second syringe. Gently inject the solution of the second syringe.

Disposal

Please safely dispose of the used infusion set with needle, any unused solution, the syringe and the empty vial in an appropriate medical waste container as these materials may hurt others if not disposed of properly. Do not reuse equipment.

7. Marketing authorisation holder

Pharming Group N.V.

Darwinweg 24

2333 CR Leiden

The Netherlands

8. Marketing authorisation number(s)

EU/1/10/641/002

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 28 October 2010

Date of latest renewal: 18 September 2015

10. Date of revision of the text

04/2020

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.