RUCONEST 2100U powder for injection medication leaflet

Ruconest 2100 Units powder for solution for injection.

One vial contains 2100 units of conestat alfa, corresponding to 2100 units per 14 ml after reconstitution, or aconcentration of 150 units/ml.

Conestat alfa is a recombinant analogue of the human C1 esterase inhibitor (rhC1-INH) produced byrecombinant 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 ofpooled normal plasma.

Each vial contains approximately 19.5 mg sodium.

For the full list of excipients, see section 6.1.

Powder for solution for injection.

White to off-white powder.

Ruconest is indicated for treatment of acute angioedema attacks in adults, adolescents, and children (aged2 years and above) with hereditary angioedema (HAE) due to C1 esterase inhibitor deficiency.

Ruconest should be initiated under the guidance and supervision of a physician experienced in the diagnosisand 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 beadministered at the discretion of the physician (see section 5.1).

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

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

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:

Volume to be body weight (kg) times 50 (U/kg) body weight (kg)= =administered (ml) 150 (U/ml) 3

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).

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

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

Data in patients older than 65 years are limited.

There is no rationale for patients older than 65 years to respond differently to Ruconest.

No dose adjustment is necessary in patients with renal impairment since conestat alfa does not undergo renalclearance.

There is no clinical experience with Ruconest in patients with hepatic impairment. Hepatic impairment mayprolong the plasma half-life of conestat alfa, but this is not thought to be a clinical concern. Norecommendation on a dose adjustment can be made.

For intravenous use.

Ruconest should be administered by a 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 injectionover approximately 5 minutes.

* 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

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

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

Hypersensitivity reactions cannot be excluded and may have symptoms similar to angioedema attacks.

All patients must be closely monitored and carefully observed for any symptoms of hypersensitivity duringand after the administration period. Patients should be informed of the early signs of hypersensitivityreactions e.g., hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. Ifthese 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 across-reactivity in a patient who has evidence of clinical allergy to cow milk cannot be excluded and thepatient should be observed for signs and symptoms of hypersensitivity following Ruconest administration.

Serious arterial and venous thromboembolic (TE) events have been reported at the recommended dose ofplasma derived C1 esterase inhibitor products in patients with known risk factors (e.g., indwelling catheters,prior history of thrombosis, underlying atherosclerosis, use of oral contraceptives or certain androgens,morbid obesity, immobility). Patients with known risk factors should be monitored closely.

Each vial of Ruconest contains 19.5 mg of sodium. To be taken into consideration by patients on a controlledsodium diet.

No interaction studies have been performed.

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

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 foruse during pregnancy or breast-feeding, unless the treating physician judges the benefits to outweigh thepossible risks.

There are no data on the effects of Ruconest on male or female fertility.

Based on the known pharmacology and adverse reaction profile of Ruconest, effects on the ability to driveand use machines are not expected. However, headache, vertigo and dizziness have been reported followingthe use of Ruconest, but may also occur as a result of an attack of HAE. Patients should be advised not todrive and use machines if they experience headache, vertigo or dizziness.

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

Tabulated lists of adverse reactions

Adverse reactions reported with Ruconest in the treatment of acute HAE attacks obtained from clinical trialsand post-marketing surveillance are tabulated below. In clinical trials, the incidence of adverse reactions wassimilar for all dose groups and did not increase upon repeated administration.

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

Headache Uncommon

Vertigo Uncommon

Hypoaesthesia Uncommon

Dizziness Uncommon

Ear and labyrinth disorders Auricular swelling Uncommon

Respiratory, thoracic and Throat irritation Uncommonmediastinal disorders

Nausea Common

Diarrhoea Uncommon

Abdominal discomfort Uncommon

Oral paraesthesia Uncommon

Skin and subcutaneous tissue Urticaria Uncommondisorders

Anaphylaxis* Uncommon

Hypersensitivity reactions* Not known

*Further information is found in section 4.4

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

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 professionalsare asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

No clinical information on overdose is available.

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 invivo. HAE patients have a heterozygous deficiency of the plasma protein C1-INH. As a result they maysuffer from uncontrolled activation of contact and complement systems, with formation of inflammatorymediators, 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 ananalogue 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 complementsystems. 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 observedfor plasma-derived human C1-INH.

The complement component (protein) C4, is a substrate for activated C1s. Patients with HAE have lowlevels of C4 in the circulation. As for plasma-derived C1-INH, the pharmacodynamic effects of conestat alfaon C4 show dose-dependent restoration of complement homeostasis in HAE patients at a plasma C1-INHactivity level greater than 0.7 U/ml, which is the lower limit of the normal range. In HAE patients, Ruconestat a dose of 50 U/kg increases plasma C1-INH activity level to greater than 0.7 U/ml for approximately2 hours (see section 5.2).

The efficacy and safety of Ruconest as a treatment of acute angioedema attacks in adult and adolescentpatients with HAE has been evaluated in two double blind randomized placebo controlled and four openlabel 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 acuteangioedema attacks was demonstrated by significantly shorter time to beginning of relief of symptoms andtime to minimal symptoms and few therapeutic failures. The table below shows the results (primary andsecondary endpoints) of the two randomized controlled trials:

Time (minutes) to Time (minutes) to

Study Treatment beginning of relief minimal symptomsmedian (95% CI) median (95% CI)

C1 1205 RCT 100 U/kg 68 (62, 132) 245 (125, 270)n =13 p = 0.001 p = 0.0450 U/kg 122 (72, 136) 247 (243, 484)n =12 p < 0.001

Saline 258 (240, 495) 1101 (970, 1494)n = 13

C1 1304 RCT 100 U/kg 62 (40, 75) 480 (243, 723)n =16 p = 0.003 p = 0.005

Saline 508 (70, 720) 1440 (720, 2885)n = 16

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 beginningof relief within 4 hours. In an open label study 146/151 (97%) attacks treated with a single dose of 50 U/kgreached time to beginning of relief within 4 hours. An additional dose of 50 U/kg was administered for17/168 (10%) attacks.

In an open label study with 20 children with HAE (aged 5 to 14 years), 64/67 (96%) attacks treated with asingle dose of 50 U/kg reached time to beginning of relief within 4 hours. An additional dose of 50 U/kg wasadministered for 3/73 (4%) attacks.

Ten adolescent HAE patients (aged 13 to 17 years) were treated with 50 U/kg for 27 acute angioedemaattacks, 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.

No formal distribution studies have been performed. The distribution volume of conestat alfa wasapproximately 3 L, comparable to plasma volume.

Based on animal data, conestat alfa is cleared from the circulation by the liver via receptor-mediatedendocytosis followed by complete hydrolysis/degradation.

After administration of Ruconest (50 U/kg) to asymptomatic HAE patients, a Cmax of 1.36 U/ml wasobserved. 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 endocytosisfollowed by complete hydrolysis/degradation in the liver.

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 thatare >70% of normal in 96.0% of children aged 2 to ≤13 years and in 90.5% of children aged 2 to <5 years.

Preclinical data do not indicate any safety concern for the use of conestat alfa in humans based on studies ofsafety pharmacology, single-dose toxicity, two-week sub-chronic toxicity and local tolerance in variousanimal species including rats, dogs, rabbits and cynomolgus monkeys. Genotoxic and carcinogenic potentialis not expected.

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

Sucrose

Sodium citrate (E331)

Citric acid

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

4 years.

Chemical and physical in-use stability has been demonstrated for 48 hours between 5˚C and 25˚C. From amicrobiological 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 belonger than 24 hours at 2 to 8ºC, unless reconstitution has taken place in controlled and validated asepticconditions.

Do not store above 25°C.

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

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

2100 units of conestat alfa powder in a 25 ml vial (type 1 glass) with a stopper (siliconized chlorobutylrubber) and a flip-off seal (aluminium and coloured plastic).

Pack size of 1.

Each vial of Ruconest is for single use only.

An aseptic technique should be used for reconstitution, combining and mixing the solutions.

Each vial of Ruconest (2100 U) should be reconstituted with 14 ml water for injections. Water for injectionsshould be added slowly to avoid forceful impact on the powder and mixed gently to minimise foaming of thesolution. The reconstituted solution contains 150 U/ml conestat alfa and appears as a clear colourlesssolution.

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 usedimmediately (see section 6.3).

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Pharming Group N.V.

Darwinweg 242333 CR Leiden

The Netherlands

EU/1/10/641/001

Date of first authorisation: 28 October 2010

Date of latest renewal: 18 September 2015

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.