Haegarda for subcutaneous injection is indicated for prevention of recurrent Hereditary Angioedema (HAE) attacks in adolescent and adult patients with C1-esterase inhibitor deficiency.

Haegarda is intended for self-administration by subcutaneous injection. The patient or care giver should be trained on how to administer Haegarda as needed.

Posology

The recommended dose of Haegarda is 60 IU/kg body weight twice weekly (every 3-4 days)

Paediatric population

Posology in adolescents is the same as in adults.

Method of administration

Subcutaneous injection only

For instructions on reconstitution of the medicinal product before administration see section 6.6.

The suggested site for the subcutaneous injection of Haegarda is the abdominal area. In the clinical trials, Haegarda was injected into a single site.

The reconstituted preparation should be administered by subcutaneous injection at a rate tolerated by the patient.

Traceability

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

Hypersensitivity reactions

If severe allergic reactions occur, the administration of Haegarda must be stopped immediately (e.g. discontinue injection) and appropriate medical care must be initiated.

In case of an acute HAE attack, individualized treatment should be initiated.

Thromboembolic events (TEE)

Thrombosis has occurred in treatment attempts with high doses of C1-INH i.v. for prophylaxis or therapy of capillary leak syndrome before, during or after cardiac surgery under extracorporeal circulation (unlicensed indication and dose). At the recommended s.c. doses, a causal relationship between TEEs and the use of C1-INH concentrate has not been established.

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 human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (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.

Haegarda 2000 IU contains less than 1 mmol sodium (23mg) per vial, that is to say essentially “sodium-free”.

Haegarda 3000 IU contains up to 29 mg sodium (main component of cooking/table salt) in each vial. This is equivalent to 1.5 % of the recommended maximum daily dietary intake of sodium for an adult.

No interaction studies have been performed.

Pregnancy

There are limited data that suggest no increased risk from the use of human C1-esterase inhibitor products in pregnant women. Human C1-esterase inhibitor is a physiological component of human plasma. No studies on reproduction and developmental toxicity have been performed with Haegarda in animals. No adverse effects on fertility, pre- and postnatal development are expected in humans.

In three studies, which included 344 patients, data from 36 women (50 pregnancies) were collected and no adverse events were associated with C1-INH treatment before, during, or after pregnancy and women delivered healthy babies.

Breastfeeding

There is no information regarding the excretion of Haegarda in human milk, the effect on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Haegarda and any potential adverse effects on the breastfed infant from Haegarda or from the underlying maternal condition.

Fertility

Human C1-esterase inhibitor is a physiological component of human plasma. No studies on reproduction and developmental toxicity have been performed with Haegarda in animals.

Haegarda has no or negligible influence on the ability to drive and use machines.

Adverse reactions were collected from Study 3001, the pivotal phase 3 study in patients (n= 86) with HAE who received Haegarda subcutaneously. Eligible patients were also able to participate in an open-label extension study (Study 3002) for up to 140 weeks (n= 126). The frequency of adverse reactions is based on events related to Haegarda. It is estimated on a per-patient basis and categorised 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)

Paediatric population

The safety profile of Haegarda was evaluated in a subgroup of eleven patients, 8 to < 17 years of age, in both studies (Study 3001, Study 3002) and was consistent with overall safety results.

Other special populations

Elderly population

The safety profile of Haegarda was evaluated in a subgroup of ten patients, 65 to 72 years of age, in both studies (Study 3001, Study 3002) and was consistent with overall safety results.

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.

To reports any side effect(s):

Saudi Arabia:

The National Pharmacovigilance Centre (NPC):

SFDA Call Center: 19999

E-mail: npc.drug@sfda.gov.sa

Website: https://ade.sfda.gov.sa

·       United Arab Emirates:

Pharmacovigilance & Medical Device section

P.O.Box: 1853

Tel: 80011111

Email: pv@mohap.gov.ae

Drug Department

Ministry of Health & Prevention

Dubai, UAE

Other GCC States:

Please contact the relevant competent authority.

No case of overdose has been reported. Doses corresponding to up to 117 IU/kg s.c. have been administered twice weekly in a fixed-dose clinical study and were well tolerated.

Pharmacotherapeutic group: Other haematological agents, Drugs used in hereditary angioedema: C1-inhibitor, plasma derived

ATC code: B06AC01

C1-esterase inhibitor is a plasma glycoprotein with a molecular weight of 105 kD and a carbohydrate moiety of 40 %. Its concentration in human plasma ranges around 240 mg/l. Besides its occurrence in human plasma, also the placenta, the liver cells, monocytes and platelets contain C1-esterase inhibitor.

C1-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.

Mechanism of action

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 Haegarda in hereditary angioedema is induced by the substitution of the deficient C1-esterase inhibitor activity.

Clinical efficacy and safety

The efficacy and safety of Haegarda for routine prophylaxis to prevent HAE attacks were demonstrated in a multicentre, randomized, double‑blind, placebo‑controlled, crossover study (Study 3001). The study assessed 90 adult and adolescent subjects with symptomatic HAE type I or II. The median (range) age of subjects was 40 (12 to 72) years; 60 subjects were female and 30 subjects were male. Subjects were randomized to receive either 60 IU/kg or 40 IU/kg Haegarda in one 16‑week treatment period and placebo in the other 16‑week treatment period. Patients self‑administered Haegarda or placebo subcutaneously 2 times per week. Efficacy was evaluated for the last 14 weeks of each treatment period.  Eligible patients were also able to participate in an open-label extension study for up to 140 weeks (Study 3002). Approximately half of the subjects enrolled in the extension study participated in Study 3001 (64/126, 50.8%), which contributed to the similarities between study populations. 

Study 3001:

Twice per week S.C. doses of 60 IU/kg or 40 IU/kg Haegarda resulted in a significant difference in the time‑normalized number of HAE attacks (the rate of attacks) relative to placebo (Table 1). The time normalized number of HAE attacks in subjects dosed with 60 IU/kg was 0.52 attacks per month compared to 4.03 attacks per month while receiving placebo (p <0.001). The time normalized number of HAE attacks in subjects dosed with 40 IU/kg was 1.19 attacks per month compared to 3.61 attacks per month while receiving placebo (p <0.001).

Table 1. Time‑normalized Number of HAE Attacks (Number/Month)

CI = confidence interval; HAE = hereditary angioedema; N = number of randomized subjects; n = number of subjects with data; LS = Least squares.

^* From a mixed model.

The median (25th, 75th percentile) percentage reduction in the time‑normalized number of HAE attacks relative to placebo was 95% (79, 100) on 60 IU/kg and 89% (70, 100) on 40 IU/kg Haegarda among subjects with evaluable data in both treatment periods.

The percentage of responders (95% CI) with a ≥50% reduction in the time‑normalized number of HAE attacks on Haegarda relative to placebo was 83% (73%, 90%). Ninety percent (90%) of subjects on 60 IU/kg responded to treatment and 76% of subjects on 40 IU/kg responded to treatment.

Seventy-one percent (71%) of subjects on 60 IU/kg and 53% of subjects on 40 IU/kg had ≥1 HAE attack per 4 week period on placebo and <1 HAE attack per 4 week period on Haegarda.

A total of 40% of subjects on 60 IU/kg and 38% of subjects on 40 IU/kg were attack-free, and the median rate of HAE attacks per month was 0.3 on both doses.

Haegarda resulted in a significant difference in the time‑normalized number of uses of rescue medication (the rate of rescue medication use) relative to placebo. A dose of 60 IU/kg resulted in a mean rate of rescue medication of 0.3 uses per month, compared to 3.9 uses per month with placebo. A dose of 40 IU/kg resulted in a mean rate of rescue medication use of 1.1 uses per month, compared to 5.6 uses per month with placebo.

Study 3002:

The long-term safety and efficacy of Haegarda for routine prophylaxis to prevent HAE attacks were demonstrated in an open-label, randomized, parallel-arm study. The study assessed 126 adult and paediatric subjects with symptomatic HAE type I or II, consisting of 64 roll-over patients from study 3001 and 62 non-rollover patients. The median (range) age of subjects was 41.0 (8-72) years. Patients with a monthly attack rate of 4.3 in 3 months before entry in the study were enrolled and treated for a mean of 1.5 years; 44 patients (34.9%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 52.0% with 40 IU/kg and 66.6% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11.3 and 8.5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively).

The mean (SD) time-normalized number of HAE attacks was 0.45 (0.737) attacks per month for 40 IU and 0.45 (0.858) attacks per month for 60 IU.

The percentage of responders (95 % CI) with a ≥ 50 % reduction in the time-normalized number of HAE attacks on Haegarda relative to the time-normalized number of HAE attacks used to qualify for participation in Study 3002 was 93.5 % (84.6 %, 97.5 %) in the 40 IU/kg treatment arm and 91.7 % (81.9 %, 96.4 %) in the 60 IU/kg treatment arm.

The percentage of subjects with a time-normalized HAE attack frequency of < 1 HAE attack per 4-week period was 79.4 % for 40 IU/kg and 85.7 % for 60 IU/kg.

The percentage of HAE attack-free subjects was 34.9 % for 40 IU/kg and 44.4 % for 60 IU/kg (throughout the study duration with the maximum duration of exposure of > 2.5 years). Of 23 patients receiving 60 IU/kg for more than 2 years, 19 (83 %) were attack-free during months 25 to 30 of treatment.

The mean time-normalized number of uses of rescue medication was 0.26 (0.572) use per month for 40 IU/kg and 0.31 (0.804) uses per month for 60 IU/kg.

Paediatric population

The safety and effectiveness of Haegarda were evaluated in a subgroup of 11 patients 8 to <17 years of age, in the randomized, double-blind, placebo-controlled, crossover, routine prophylaxis trial (Study 3001) and the randomized, open-label, active treatment-controlled study (Study 3002). Results of subgroup analysis by age were consistent with overall study results.

The pharmacokinetic (PK) characteristics of Haegarda subcutaneous were primarily described using population PK methods on pooled data from 3 clinical trials in healthy subjects and HAE patients. 

Absorption

Following twice weekly subcutaneous dosing, Haegarda is slowly absorbed, with a median (95% CI) time to peak concentration (t_max) of approximately 59 hours (23, 134 hours). Based on a median (95% CI) apparent plasma half-life of 69 hours (24, 250 hours), steady state for C1-INH is expected within 3 weeks of dosing. A mean (95% CI) steady state trough functional C1-INH of 48% (25.1 102%) is expected after twice weekly s.c. administration of 60 IU/kg Haegarda. The mean (95% CI) relative bioavailability (F) of Haegarda after s.c. administration was estimated to be approximately 43% (35.2, 50.2%).

Distribution and Elimination

The population mean (95% CI) clearance and apparent volume of distribution of Haegarda were estimated to be approximately 83 mL/hr (72.7, 94.2 mL/hr) and 4.33 L (3.51, 5.15 L). C1-INH clearance was found to be positively correlated with total body weight. The steady state PK of s.c. Haegarda was found to be independent of dose between 20-80 IU/kg in HAE subjects.

Studies have not been conducted to evaluate the PK of C1 INH in specific patient populations stratified by gender, race, age, or the presence of renal or hepatic impairment. The population analysis, evaluating age (8 to 72 years), was found not to influence the PK of C1-INH.

Non-clinical data following intravenous and or subcutaneous administration reveal no special hazard for humans based on conventional studies of safety pharmacology, single and repeat dose toxicity, local tolerability and thrombogenicity.

No investigations on carcinogenicity and reproductive toxicology have been conducted.

Powder:

Glycine

Sodium chloride

Sodium citrate

Solvent:

Water for injections

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

Do not store above 30 °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.

Immediate containers

Haegarda 2000 IU:     Powder (2000 IU) in a vial (Type II glass) with a stopper (bromobutyl rubber), blue seal (aluminium) and grey flip-off cap (plastic).

4 ml of solvent in a vial (Type I glass) with a stopper (chlorobutyl or bromobutyl rubber), blue seal (aluminium) and grey flip-off cap (plastic).

Haegarda 3000 IU:     Powder (3000 IU) in a vial (Type II glass) with a stopper (bromobutyl rubber), blue seal (aluminium) and lemon flip-off cap (plastic).

5.6 ml of solvent in a vial (Type I glass) with a stopper (chlorobutyl or bromobutyl rubber), blue seal (aluminium) and lime flip-off cap (plastic).

Presentations:

Box containing:

1 vial with powder

1 solvent vial (Haegarda 2000 IU: 4 ml, Haegarda 3000 IU: 5.6 ml)

1 filter trasfer device 20/20

Administration set (inner box):

1 disposable syring (Haegarda 2000 IU: 5 ml, Haegarda 3000 IU: 10 ml)

1 hypodermic needle

1 subcutaneous injection set

2 alcohol swabs,

1 plaster

Not all pack sizes may be marketed.

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

Method of administration

General instructions

-       The reconstituted solution for Haegarda should be colourless and clear to slightly opalescent.

-       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.

Withdrawal and application

Application

The product can be administered using a hypodermic needle or a subcutaneous infusion kit.