Human C1 esterase inhibitor

Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Berinert (CSL)
vials containing 500 units as freeze-dried powder for reconstitution
Approved indication: hereditary angioedema
Australian Medicines Handbook Appendix A

C1 esterase inhibitor is a protein derived from human plasma. It is indicated for the treatment of acute attacks of hereditary angioedema. This condition is characterised by episodes of swelling in the skin or mucosa and can occur anywhere in the body (face, larynx, gut, limbs). It can be painful, particularly with gastrointestinal attacks, and if the larynx is affected asphyxiation and death can occur.

Type I and type II hereditary angioedema are caused by mutations in the gene encoding the C1 esterase inhibitor. Although not well defined, the absence or dysfunction of this protein is thought to lead to increased vascular permeability due to unregulated bradykinin activation. Replacing C1 esterase inhibitor intravenously during an acute attack reduces ongoing inflammatory processes. Treatments for histamine-induced angioedema, such as corticosteroids, antihistamines or adrenaline, have no effect in patients with hereditary angioedema.

The efficacy of C1 esterase inhibitor has been investigated in a randomised controlled trial in 125 adults and children with confirmed acute moderate to severe hereditary angioedema. Overall, 79% of patients presented with a gastrointestinal attack and 20.2% with a facial attack. Patients were randomised to receive C1 esterase inhibitor 10 U/kg or 20 U/kg (39 and 43 patients) or placebo (42 patients). Within four hours of treatment, 70% of patients had responded in the C1 esterase inhibitor 20 U/kg group compared to 43% in the placebo group. The median time to onset of symptom relief was significantly shorter for C1 esterase inhibitor 20 U/kg (0.5 hours) than for placebo (1.5 hours). The median response time for the lower-dose C1 esterase inhibitor (10 U/kg) was only slightly shorter than for placebo (1.2 vs 1.5 hours). Median time to complete resolution of symptoms was much shorter for C1 esterase inhibitor 20 U/kg than for placebo (4.9 vs 7.8 hours) but not for C1 esterase inhibitor 10 U/kg (20 hours).¹ The 20 U/kg dose is currently recommended for hereditary angiodema.

In the trial, the most frequent adverse events were nausea, diarrhoea, abdominal pain and muscle spasms. Most of the adverse events were more common with placebo than with C1 esterase inhibitor 20 U/kg (43.9% vs 19.6%) and may have been related to the patients' angioedema attacks.¹ Taste disturbance was reported with C1 esterase inhibitor 20 U/kg (2/46 patients) but not with placebo (0/41 patients). An increase in severity of pain associated with hereditary angioedema was the most severe adverse effect reported by patients who received the active treatment. Antibodies to C1 esterase inhibitor and their effect on efficacy or adverse reactions were not measured in the trial.

In an observational study of three women, the commencement of frequent treatments with C1 esterase inhibitor was associated with an increase in angioedema attacks (4-fold, 5-fold and 12-fold). A control group of 24 age-matched men and women did not show the same increase in attacks over a nine-year period. It was not clear what caused this increase, but investigators speculated that frequent treatments may have lowered the threshold for activation of an attack.²

This C1 esterase inhibitor is made from human plasma sourced from overseas. Like all plasma products, it has the potential to transmit infections caused by viruses and prions (e.g. variant Creutzfeldt-Jakob disease). During the randomised controlled trial, none of the patients seroconverted to produce antibodies to HIV, hepatitis or human parvovirus 19 virus.¹ The infectious disease risk of C1 esterase inhibitor has been reduced by screening blood donors and their plasma for evidence of viral infections such as HIV and hepatitis C. Also during fractionation, plasma undergoes processes to inactivate or remove certain viruses. Nevertheless, patients should be warned that there is still an infectious disease risk with this product. Vaccination against viruses that could potentially be present in plasma, such as hepatitis B, should be considered.

Severe hypersensitivity reactions can occur with C1 esterase inhibitor and adrenaline should be available when injections are given. For patients who are known to have a tendency to allergies, antihistamines and corticosteroids should be given prophylactically. Prescribers should be aware that thrombosis has been reported with C1 esterase inhibitor when used at doses higher than 20 U/kg and for unapproved indications.

C1 esterase inhibitor seems to be an effective treatment for hereditary angioedema and has been used overseas for more than 30 years. However, there have been reports in a minority of patients that it may increase the frequency of angioedema attacks.

manufacturer declined to supply data

The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.

Notes on references

At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).

At the time the comment was prepared, information about this drug was available on the website of the Therapeutic Goods Administration (www.tga.gov.au/industry/pm-auspar.htm).